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WO2018121678A1 - Promédicament d'analogues nucléosidiques antiviraux, composition et utilisation associées - Google Patents

Promédicament d'analogues nucléosidiques antiviraux, composition et utilisation associées Download PDF

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Publication number
WO2018121678A1
WO2018121678A1 PCT/CN2017/119448 CN2017119448W WO2018121678A1 WO 2018121678 A1 WO2018121678 A1 WO 2018121678A1 CN 2017119448 W CN2017119448 W CN 2017119448W WO 2018121678 A1 WO2018121678 A1 WO 2018121678A1
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Prior art keywords
alkyl
group
heteroaryl
aryl
butyl
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PCT/CN2017/119448
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English (en)
Chinese (zh)
Inventor
张英俊
谢洪明
方清洪
罗明
蒋海港
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广东东阳光药业有限公司
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Publication of WO2018121678A1 publication Critical patent/WO2018121678A1/fr

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Classifications

    • 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
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicines, and relates to an antiviral nucleoside analog prodrug, a composition thereof, and a use thereof, and particularly relates to a nucleoside analog prodrug of anti-hepatitis C virus.
  • These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication, and for the treatment of hepatitis C infection in mammals.
  • Hepatitis C virus (HCV) infection is a major health problem leading to chronic liver disease such as cirrhosis and hepatocellular carcinoma, with infected individuals estimated to account for 2-15% of the world's population.
  • WHO World Health Organization
  • the viral disease is transmitted parenterally through contaminated blood and blood products, contaminated needles or sexual acts, and from the mother of the infected mother or carrier to the offspring.
  • the present invention provides a compound having a structure represented by formula (I'), or a stereoisomer, tautomer, oxynitride, solvate of the structure represented by formula (I').
  • a metabolite a pharmaceutically acceptable salt or a prodrug,
  • G is an alkyl group, an aryl-substituted alkyl group, an alkoxycarbonyl-substituted alkyl group, an aryl group or an alkylcarbonyl group;
  • Y is an aryl group, a heteroaryl group or an alkyl group; wherein the aryl or heteroaryl group may be optionally substituted by halogen or alkyl;
  • X is F, Cl or Br
  • R 1 is H, hydrazine or alkyl
  • R 4 and R 5 are each independently an alkyl group
  • R 6 and R 7 are each independently H, hydrazine, alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylane Or heterocyclylalkyl;
  • R 8 is H or an alkyl group
  • R 8 and R 9 together with the N atom to which they are attached form a nitrogen-containing heterocyclic group or a nitrogen-containing heteroaryl group;
  • R 10 is alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, heteroaryl or heterocyclic;
  • W is a 3-8 membered nitrogen-containing heterocycle, a nitrogen-containing C 5-12 fused heterobicyclic ring or a nitrogen-containing C 5-12 spirobicyclo ring;
  • R 11 is H, alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;
  • R 14 and R 15 are each independently alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • n is independently 1, 2, 3, 4 or 5;
  • n 0, 1, 2, 3 or 4;
  • G is C 1-10 alkyl, C 6-12 aryl substituted C 1-10 alkyl, C 1-10 alkoxycarbonyl substituted C 1-10 alkyl, C 6- 12 aryl or C 1-10 alkylcarbonyl;
  • Y is a C 6-12 aryl group, a C 1-9 heteroaryl group or a C 1-10 alkyl group; wherein the C 6-12 aryl group or the C 1-9 heteroaryl group may be optionally halogenated, C 1-6 alkane Base substitution
  • R 1 is H, hydrazine or C 1-10 alkyl
  • R 4 and R 5 are each independently C 1-10 alkyl
  • R 6 and R 7 are each independently H, oxime, C 1-10 alkyl, C 1-10 heteroalkyl, C 6-10 aryl, C 3-10 cycloalkyl, C 1-9 heteroaryl , C 2-9 heterocyclic group, C 6-10 aryl C 1-6 alkyl group, C 2-9 heteroaryl C 1-6 alkyl group, C 3-6 cycloalkyl C 1-6 alkyl group or C 2-9 heterocyclyl C 1-6 alkyl;
  • R 8 is H or C 1-10 alkyl
  • R 8 and R 9 together with the N atom to which they are attached form a nitrogen-containing C 2-8 heterocyclic group or a nitrogen-containing C 1-9 heteroaryl group;
  • R 10 is C 1-10 alkyl, C 1-10 heteroalkyl, C 6-12 aryl, C 3-10 cycloalkyl, C 6-12 aryl C 1-10 alkyl, C 1-9 Heteroaryl C 1-10 alkyl, C 3-10 cycloalkyl C 1-10 alkyl, C 2-8 heterocyclyl C 1-10 alkyl, C 1-9 heteroaryl or C 2-8 Heterocyclic group;
  • R 11 is H, C 1-10 alkyl, C 3-8 cycloalkyl, C 2-8 heterocyclic, C 1-9 heteroaryl or C 6-12 aryl;
  • R 14 and R 15 are each independently C 1-10 alkyl, C 3-10 cycloalkyl, C 2-8 heterocyclic, C 6-12 aryl or C 1-9 heteroaryl;
  • the 10 alkylamino group, C 1-9 heteroaryl group or C 2-8 heterocyclic group is optionally 1, 2, 3 or 4 independently selected from the group consisting of hydroxyl, amino, halogen, cyano, carboxyl, nitro, C 1 -6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy C 1-6 alkyl
  • the invention provides a compound having formula (II'), (III'), (IV'), (V'), (VI'), (VII'), (VIII' , (IX'), (IIa'), (IIIa'), (IVa'), (Va'), (VIa'), (VIIa'), (VIIIa') or (IXa') Or formula (II'), (III'), (IV'), (V'), (VI'), (VII'), (VIII'), (IX'), (IIa'), (IIIa Stereoisomers, tautomers, oxynitrides of structures represented by '), (IVa'), (Va'), (VIa'), (VIIa'), (VIIIa') or (IXa') a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the present invention provides a compound having a structure represented by formula (I), or a stereoisomer, tautomer, oxynitride, solvent of the structure represented by formula (I). a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • R 1 is H, hydrazine or alkyl
  • R 4 and R 5 are each independently an alkyl group
  • R 6 and R 7 are each independently H, hydrazine, alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylane Or heterocyclylalkyl;
  • R 8 is H or an alkyl group
  • R 8 and R 9 together with the N atom to which they are attached form a nitrogen-containing heterocyclic group or a nitrogen-containing heteroaryl group;
  • R 10 is alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, heteroaryl or heterocyclic;
  • W is a 3-8 membered nitrogen-containing heterocycle, a nitrogen-containing C 5-12 fused heterobicyclic ring or a nitrogen-containing C 5-12 spirobicyclo ring;
  • R 11 is H, alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;
  • R 14 and R 15 are each independently alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • n is independently 1, 2, 3, 4 or 5;
  • n 0, 1, 2, 3 or 4;
  • the present invention provides a compound having a structure represented by formula (Ia), or a stereoisomer, tautomer, oxynitride, solvent of the structure represented by formula (Ia) a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • R 1 is H, hydrazine or C 1-6 alkyl
  • R 4 and R 5 are each independently C 1-6 alkyl
  • R 6 and R 7 are each independently H, oxime, C 1-4 alkyl, C 1-4 heteroalkyl, C 6-10 aryl, C 3-6 cycloalkyl, C 1-9 heteroaryl , C 2-9 heterocyclic group, C 6-10 aryl C 1-6 alkyl group, C 2-9 heteroaryl C 1-6 alkyl group, C 3-6 cycloalkyl C 1-6 alkyl group or C 2-9 heterocyclyl C 1-6 alkyl;
  • R 8 is H or C 1-6 alkyl
  • R 8 and R 9 together with the N atom to which they are attached form a nitrogen-containing C 2-6 heterocyclic group or a nitrogen-containing C 1-9 heteroaryl group;
  • R 10 is C 1-6 alkyl, C 1-4 heteroalkyl, C 6-10 aryl, C 3-6 cycloalkyl, C 6-12 aryl C 1-6 alkyl, C 1-9 Heteroaryl C 1-6 alkyl, C 3-10 cycloalkyl C 1-6 alkyl, C 2-8 heterocyclyl C 1-6 alkyl, C 1-9 heteroaryl or C 2-9 Heterocyclic group;
  • R 14 and R 15 are each independently C 1-6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocyclic, C 6-10 aryl or C 1-9 heteroaryl;
  • R 1 is H, hydrazine, methyl, ethyl, n-propyl or isopropyl;
  • R 4 and R 5 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl , n-hexyl, isohexyl or sec- hexyl;
  • R 6 and R 7 are each independently H, hydrazine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, methylthiomethyl, methylthioethyl , methylthiopropyl, methylthiobutyl, phenyl, naphthyl, phenylmethyl, phenylethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, ring Pentyl, cyclohexyl, thiazolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, tetrahydropyrrolyl or tetrahydrofuranyl;
  • R 8 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, n-hexyl, Isohexyl or sec-hexyl;
  • R 8 and R 9 together with the N atom to which they are attached form azetidinyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, Polinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, 1,2,3,4-tetrahydroisoquinolinyl, imidazolyl, pyrrolyl, tetrazolyl, triazolyl, pyrazolyl , pyrimidinyl, benzimidazolyl, benzopyrazolyl, decyl, porphyrin, pyridoimidazolyl, pyridopyrazolyl, pyridopyrrolyl, pyridazinazolyl, fluorenyl or pyrimidine And pyrazolyl;
  • R 10 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, n-hexyl, isohexyl , sec-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl, tetrahydrofuranyl, phenyl, naphthyl, benzyl, naphthylmethyl, thiazolylmethyl, imidazolylmethyl, Cyclopentylmethyl, cyclohexylmethyl, tetrahydropyrrolylmethyl, tetrahydrofuranylmethyl,
  • R 14 and R 15 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, benzyl, methylthioethyl, phenyl, naphthyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • t 1 is 1, 2, 3 or 4;
  • t 2 , t 3 and t 4 are each independently 1, 2 or 3;
  • t 5 and t 6 are each independently 1, 2, 3, 4 or 5;
  • t 7 is 1 or 2;
  • k 1 , k 2 , k 3 and k 4 are each independently 0, 1 or 2; wherein k 1 and k 2 are not 0 at the same time; k 3 and k 4 are not 0 at the same time;
  • Each R 13 is independently H, oxime, carboxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
  • each R 13 is independently H, oxime, carboxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-6 heterocyclic , C 6-10 aryl or C 1-9 heteroaryl.
  • R 11 is H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 heterocyclyl, C 1-9 heteroaryl or C 6-10 aryl;
  • R 11 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, Orolinyl, piperazinyl or phenyl;
  • the invention provides a structure of a compound having the formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) Or a stereoisomer, tautomer, nitrogen of the structure of formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX)
  • the invention provides a compound having the formula of formula (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa) or (IXa) Or a stereoisomer, tautomer, nitrogen of the structure of formula (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa) or (IXa) An oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
  • Each R 1 is independently H, hydrazine or C 1-6 alkyl
  • Each R 6 is independently H, oxime, C 1-6 alkyl, C 1-6 heteroalkyl, C 6-10 aryl, C 3-8 cycloalkyl, C 1-9 heteroaryl, C 2 -9 heterocyclyl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkyl or C 2- 9 heterocyclic C 1-6 alkyl;
  • Each R 8 is independently H or C 1-6 alkyl
  • R 8 and R 9 together with the N atom to which they are attached form a nitrogen-containing C 2-9 heterocyclic group or a nitrogen-containing C 1-9 heteroaryl group
  • Each R 10 is independently C 1-6 alkyl, C 1-6 heteroalkyl, C 6-10 aryl, C 3-8 cycloalkyl, C 6-10 aryl C 1-6 alkyl, C 1-9heteroaryl C 1-6 alkyl, C 3-10 cycloalkyl C 1-6 alkyl, C 2-9 heterocyclyl C 1-6 alkyl, C 1-9 heteroaryl or C 2-9 heterocyclic group;
  • Each R 11 is independently H, C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 1-9 heteroaryl or C 6-10 aryl;
  • each of R 1 , R 6 , R 8 , R 9 , R 10 , R 11 or R 12 is C 1-6 alkyl, C 1-6 heteroalkyl, C 6-10 aryl, C 3-8 Cycloalkyl, C 1-9 heteroaryl, C 2-9 heterocyclic, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylamino
  • the ground is replaced by 1, 2, 3 or 4 hydroxyl, amino, F, Cl, Br, cyano, carboxyl, nitro groups.
  • Each R 1 is independently H, hydrazine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl;
  • Each R 6 is independently H, hydrazine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, methylthiomethyl, 1-methylthioethyl, 2-Methylthioethyl, 1-methylthiopropyl, 2-methylthiopropyl, 3-methylthiopropyl, 1-methylthiobutyl, 2-methylthiobutyl, 3- Methylthiobutyl, 4-methylthiobutyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-methoxypropyl, 2-methoxypropene , 3-methoxypropyl, 1-methoxybutyl, 2-methoxybutyl, 3-methoxybutyl, 4-methoxybutyl, phenyl, naphthyl, cyclopropane Base, cyclobutyl, cyclopentyl,
  • Each R 8 is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, Orthohexyl, isohexyl or sec-hexyl;
  • R 8 and R 9 together with the N atom to which they are attached form azetidinyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, Polinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, 1,2,3,4-tetrahydroisoquinolinyl, imidazolyl, pyrrolyl, tetrazolyl, triazolyl, pyrazolyl , pyrimidinyl, benzimidazolyl, benzopyrazolyl, decyl, porphyrin, pyridoimidazolyl, pyridopyrazolyl, pyridopyrrolyl, pyridazinazolyl, fluorenyl or pyrimidine And pyrazolyl;
  • Each R 10 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, n-hexyl , isohexyl, sec-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl, tetrahydrofuranyl, phenyl, naphthyl, benzyl, naphthylmethyl, thiazolylmethyl, imidazolyl Methyl, cyclopentylmethyl, cyclohexylmethyl, tetrahydropyrrolylmethyl, tetrahydrofuranylmethyl,
  • Each R 11 is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrole Base, morpholinyl, piperazinyl or phenyl;
  • the invention provides a compound having one of the following structures, or a stereoisomer, tautomer, oxynitride, solvate, metabolite, pharmaceutically acceptable salt or pre- medicine,
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.
  • the pharmaceutical composition of the present invention further comprises other anti-HCV drugs, wherein the anti-HCV drug is interferon ribavirin, interleukin 2, interleukin 6, interleukin 12, promotes production of type 1 Helper T cell response compounds, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, baviximab, hepatitis C Immunoglobulin, civacir, boceprevir, telaprevir, erlotinib, dacaviride, simipiride, anapyvir, cilostry, danopepte, radipavir , nitazoxanide, nevirapine, alisporivir, imivirvir, vaniprevir, faldaprevir, paritaprevir, sovaprevir, grazoprevir, elbasvir, vedropre
  • the invention provides the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for the prevention, treatment, treatment or alleviation of a HCV infection or a hepatitis C disease in a patient.
  • the invention provides the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for inhibiting HCV replication and/or inhibiting the function of an HCV viral protein; said HCV replication process Includes HCV entry, HCV uncoating, HCV translation, HCV replication, HCV assembly, or HCV release; the HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, or NS5B, as well as for HCV viral replication. Internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH).
  • IRS Internal ribosome entry point
  • IMPDH inosine monophosphate dehydrogenase
  • the invention provides the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament for inhibiting the function of an HCV viral protein; the HCV viral protein is NS5B.
  • the invention provides the use of a compound or pharmaceutical composition of the invention for preventing, treating, treating or ameliorating a HCV infection or a hepatitis C disease in a patient.
  • the invention provides a compound or pharmaceutical composition of the invention for use in inhibiting HCV replication and/or inhibiting HCV viral protein; said HCV replication process comprising HCV entry, HCV uncoating, HCV translation , HCV replication, HCV assembly, or HCV release; the HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, or NS5B, as well as internal ribosome entry points (IRES) and muscles required for HCV viral replication. Glycoside monophosphate dehydrogenase (IMPDH).
  • IMPDH Glycoside monophosphate dehydrogenase
  • the invention provides a compound or pharmaceutical composition of the invention for use in inhibiting the function of an HCV viral protein; the HCV viral protein is NS5B.
  • the invention provides a method of preventing, treating, treating or ameliorating a HCV infection or a hepatitis C disease in a patient comprising administering to the patient a therapeutically effective amount of a compound or pharmaceutical composition of the invention.
  • the invention provides a method of inhibiting HCV replication and/or inhibiting the function of an HCV viral protein comprising administering to a patient a therapeutically effective amount of a compound or pharmaceutical composition of the invention; said HCV replication process comprising HCV Entry, HCV uncoating, HCV translation, HCV replication, HCV assembly or HCV release; the HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A or NS5B, as well as internal ribose required for HCV viral replication. Body entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH).
  • IRS body entry point
  • IMPDH inosine monophosphate dehydrogenase
  • the invention provides a method of inhibiting the function of an HCV viral protein comprising administering to a patient a therapeutically effective amount of a compound or pharmaceutical composition of the invention; said HCV viral protein is NS5B.
  • Another aspect of the invention relates to formulas (I'), (II'), (III'), (IV'), (V'), (VI'), (VII'), (VIII'), (IX' ), (Ia'), (IIa'), (IIIa'), (IVa'), (Va'), (VIa'), (VIIa'), (VIIIa'), (IXa'), (I) , (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (Ia), (IIa), (IIIa), (IVa), Process for the preparation, isolation and purification of compounds comprised by Va), (VIa), (VIIa), (VIIIa), or (IXa).
  • the articles used herein are used to refer to the articles of one or more than one (ie, at least one).
  • a component refers to one or more components, that is, there may be more than one component contemplated for use or use in embodiments of the embodiments.
  • subject refers to an animal. Typically the animal is a mammal. Subjects, for example, also refer to primates (eg, humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
  • primates eg, humans, males or females
  • the subject is a primate. In other embodiments, the subject is a human.
  • patient refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to a human.
  • Stereoisomer refers to a compound that has the same chemical structure but differs in the way the atoms or groups are spatially aligned. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotomers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • “Chirality” is a molecule that has properties that cannot overlap with its mirror image; “non-chiral” refers to a molecule that can overlap with its mirror image.
  • Diastereomer refers to a stereoisomer that has two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. The mixture of diastereomers can be separated by high resolution analytical procedures such as electrophoresis and chromatography, such as HPLC.
  • optically active compounds Many organic compounds exist in optically active forms, i.e., they have the ability to rotate a plane of plane polarized light.
  • the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to one or more of its chiral centers.
  • the prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light caused by the compound, wherein (-) or l indicates that the compound is left-handed.
  • Compounds prefixed with (+) or d are dextrorotatory.
  • a particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as a mixture of enantiomers.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
  • any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched form, such as the (R)-, (S)- or (R, S)-configuration presence.
  • each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the invention may be one of the possible isomers or mixtures thereof, such as racemates and mixtures of diastereomers (depending on the number of asymmetric carbon atoms) The form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituent of the cycloalkyl group may have a cis or trans configuration.
  • the resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography, depending on the difference in physicochemical properties of the components. Method and / or step crystallization.
  • the structural formulae described herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational)): for example, R containing an asymmetric center , the S configuration, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E).
  • R containing an asymmetric center for example, R containing an asymmetric center , the S configuration, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E).
  • the single stereochemical isomer of the compound of the invention or its enantiomer Isomers, diastereomers, or mixtures of geometric isomers (or conformational isomers) are within the scope of the invention.
  • prodrug denotes a compound which is converted in vivo to a compound of formula (I). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue.
  • the prodrug-like compound of the present invention may be an ester.
  • the ester may be used as a prodrug such as a phenyl ester, an aliphatic (C 1-24 ) ester, an acyloxymethyl ester, or a carbonate. , carbamates and amino acid esters.
  • a compound of the invention comprises a hydroxyl group, i.e., it can be acylated to give a compound in the form of a prodrug.
  • Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxy group on the parent.
  • racemate of any of the resulting end products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art by known methods, for example, by obtaining the diastereomeric salts thereof. Separation. Racemic products can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert) E.
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion of a pentane-2,4-dione and a 4-hydroxypent-3-en-2-one tautomer.
  • Another example of tautomerization is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridine-4(1H)-one tautomers. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
  • salts referred to in the present invention are pharmaceutically acceptable salts, of which "pharmaceutically acceptable salts" are well known in the art, as in the literature: Berge et al., describe pharmaceutically acceptable salts in detail in J Pharmacol Sci, 1997, 66, 1-19.
  • pharmaceutically acceptable non-limiting salts include inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, metaphosphates, sulfates, sulfites, nitrates.
  • organic acid salts such as carboxylates, sulfonates, sulfinates, sulfur carboxylates, etc., such as, but not limited to, methanesulfonate, ethanesulfonate, A Acid salts, acetates, succinates, benzoates, succinates, pamoate, salicylates, galactosides, glucohesates, mandelates, 1,2 - ethane disulfonate, 2-naphthalene sulfonate, carbonate, trifluoroacetate, hydroxyacetate, isethionate, oxalate, maleate, tartrate, Citrate, succinate, malonate, besylate, p-toluenesulfonate, malate, fumarate, lactate, lactate or oxalic acid, or as described in the literature Other methods such as ion exchange to obtain these salts.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, disulfate, borate, butyrate, camphorate, camphorsulfonic acid Salt, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, glucoheptonate, glycerol phosphate, gluconate, hemisulfate, heptanoate, Acid salt, hydroiodide salt, 2-hydroxy-ethanesulfonate, lactobionate, laurate, lauryl sulfate, nicotinate, nitrate, oleate, palmitate, pamoate, Pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate, etc.
  • the pharmaceutically acceptable salt also includes salts obtained by a suitable base such as an alkali metal, an alkaline earth metal, ammonium and a salt of N + (C 1-4 alkyl) 4 .
  • a suitable base such as an alkali metal, an alkaline earth metal, ammonium and a salt of N + (C 1-4 alkyl) 4 .
  • the present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • the pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed by anti-equilibrium ions, such as halides, carboxylates, sulfates, phosphates, nitrates, C 1-8 sulfonation And aromatic sulfonates.
  • Pharmaceutically acceptable salts can be formed with inorganic and organic acids such as acetates, aspartates, benzoates, besylate, bromide/hydrobromide, bicarbonate/carbonate , hydrogen sulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorophylline, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate , glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, Malonate, mandelate, methanesulfonate, methyl sulfate, naphthoate, naphthalene sulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palm Acid salt, pamoate,
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid. , ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.
  • hydrate means that the solvent molecule is an association formed by water.
  • protecting group refers to a substituent that is typically used to block or protect a particular functionality when reacted with other functional groups.
  • protecting group of an amino group refers to a substituent attached to an amino group to block or protect the functionality of an amino group in a compound.
  • Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl. (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxycarbonyl (Fmoc).
  • a “hydroxy protecting group” refers to a substituent used to block or protect a hydroxyl group, and suitable protecting groups include acetyl and silyl groups.
  • Carboxy protecting group means a substituent of a carboxy group used to block or protect the functionality of a carboxy group.
  • Typical carboxy protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfonyl)ethyl, 2-(diphenyl Phosphine) ethyl, nitroethyl, and the like.
  • a general description of protecting groups can be found in TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
  • “Pharmaceutical composition” means a salt of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or mixture of a prodrug thereof with other chemical components, such as physiologically/pharmaceutically Accepted carrier or excipient.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
  • any disease or condition as used in the present invention refers to ameliorating a disease or condition (ie, slowing or preventing or alleviating the progression of a disease or at least one of its clinical symptoms).
  • “treating” refers to alleviating or ameliorating at least one physical parameter, including physical parameters that may not be perceived by the patient.
  • “treating” refers to modulating a disease or condition from the body (eg, stabilizing a detectable symptom) or physiologically (eg, stabilizing the body's parameters) or both.
  • “treating” refers to preventing or delaying the onset, onset, or exacerbation of a disease or condition.
  • any structural formula given by the present invention is also intended to indicate that these compounds are not isotopically enriched and isotopically enriched.
  • Isotopically enriched compounds have the structure depicted by the general formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • Exemplary isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the compounds of the invention include isotopically enriched compounds of the invention, for example, those in which a radioisotope such as 3 H, 14 C and 18 F is present, or in which a non-radioactive isotope is present, such as 2 H and 13 C.
  • a radioisotope such as 3 H, 14 C and 18 F
  • a non-radioactive isotope such as 2 H and 13 C.
  • isotopically enriched compounds can be used for metabolic studies (using 14 C), reaction kinetic studies (using, for example, 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single photon emission computed tomography (SPECT) of substrate tissue distribution assays, or may be used in patient radiation therapy.
  • 18 F enriched compounds are particularly desirable for PET or SPECT studies.
  • substitution of heavier isotopes may provide certain therapeutic advantages resulting from higher metabolic stability. For example, increased in vivo half-life or reduced dose requirements or improved therapeutic index.
  • the hydrazine in the present invention is regarded as a substituent of the compound of the formula (I).
  • Isotopic enrichment factors can be used to define the concentration of such heavier isotopes, particularly ruthenium.
  • isotopic enrichment factor refers to the ratio between the isotope abundance and the natural abundance of a given isotope.
  • a substituent of a compound of the invention is designated as hydrazine
  • the compound has at least 3500 for each of the specified hydrazine atoms (52.5% of ruthenium incorporation at each of the specified ruthenium atoms), at least 4,000 (60% of ruthenium incorporation), At least 4,500 (67.5% of cerium incorporation), at least 5,000 (75% of cerium incorporation), at least 5,500 (82.5% of cerium incorporation), at least 6,000 (90% of cerium incorporation), at least 6333.3 (95%) Iridium enrichment factor with at least 6466.7 (97% cerium incorporation), at least 6600 (99% cerium incorporation) or at least 6633.3 (99.5% cerium incorporation).
  • the present invention can include pharmaceutically acceptable solvates wherein the solvent of crystallization may be isotopically substituted, for example D 2 O, acetone -d 6, DMSO-d 6 solvate of those.
  • the compounds of the invention may be optionally substituted with one or more substituents, such as the compounds of the above formula, or as specific examples, subclasses, and inclusions of the invention.
  • substituents such as the compounds of the above formula, or as specific examples, subclasses, and inclusions of the invention.
  • a class of compounds may be understood that the term “optionally substituted” is used interchangeably with the term “substituted or unsubstituted.” In general, the term “optionally” whether preceded by the term “substituted” means that one or more hydrogen atoms in a given structure are replaced by a particular substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substitutable position of the group.
  • substituents When more than one position in the given formula can be substituted by one or more substituents selected from a particular group, the substituents may be substituted at the various positions, either identically or differently.
  • the substituents described therein may be, but are not limited to, anthracene, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkyne.
  • alkyl as used herein, means 1-20 carbon atoms, or 1-10 carbon atoms, or 1-8 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or A saturated linear or branched monovalent hydrocarbon group of from 1 to 3 carbon atoms, wherein the alkyl group may be independently and optionally substituted by one or more substituents described herein.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), Isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH) 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH) 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2 -butyl (-C(
  • alkyl and its prefix “alk” are used herein to encompass both straight-chain and branched saturated carbon chains.
  • alkylene is used herein to mean a saturated divalent hydrocarbon radical derived by the elimination of two hydrogen atoms from a linear or branched saturated hydrocarbon, examples of which include, but are not limited to, methylene, hypoethyl , isopropyl and so on.
  • heteroalkyl denotes the insertion of one or more heteroatoms in the middle of the alkyl chain, wherein the alkyl group and heteroatom have the meaning as described herein.
  • a heteroalkyl group contains from 1 to 10 carbon atoms, and in other embodiments, a heteroalkyl group contains from 1 to 8 carbon atoms.
  • a heteroalkyl group contains 1 -6 carbon atoms, in other embodiments, the heteroalkyl group contains 1-4 carbon atoms, and in other embodiments, the heteroalkyl group contains 1-3 carbon atoms.
  • Such examples include, but are not limited to, CH 3 OCH 2 -, CH 3 CH 2 OCH 2 -, CH 3 SCH 2 -, CH 3 SCH 2 CH 2 -, (CH 3 ) 2 NCH 2 -, (CH 3 2 CH 2 OCH 2 -, CH 3 OCH 2 CH 2 -, CH 3 CH 2 OCH 2 CH 2 -, and the like.
  • alkoxy as used in the present invention relates to an alkyl group, as defined in the present invention, attached to the main carbon chain through an oxygen atom, examples of which include, but are not limited to, methoxy, ethoxy Base, propoxy, butoxy, and the like.
  • the alkoxy group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, a hydroxyl group, an amino group, a halogen group, a cyano group, an alkoxy group, an alkyl group, an alkenyl group, an alkynyl group, a decyl group, a nitrate Base and so on.
  • alkynyl means a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, at least one of which The position is an unsaturated state, that is, one CC is a sp triple bond, wherein the alkynyl group can be independently and optionally substituted by one or more substituents described in the present invention, wherein specific examples of alkynyl groups include, but Not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), and the like.
  • cycloalkyl refers to a monovalent or multivalent, non-aromatic, saturated or partially unsaturated ring and does not contain a heteroatom, including a single ring of 3 to 12 carbon atoms or 7 to 12 carbon atoms.
  • the second ring A bicyclic carbocyclic ring having 7 to 12 atoms may be a bicyclo[4,5], [5,5], [5,6] or [6,6] system, and a bicyclic carbocyclic ring having 9 or 10 atoms. It may be a bicyclo[5,6] or [6,6] system.
  • Suitable cyclic aliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl.
  • Examples of the cyclic aliphatic group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1- Cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptane Base, cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl, cyclododecyl and the like.
  • heterocycle refers to a monocyclic, bicyclic, or tricyclic system wherein one or more rings are present.
  • the carbon atoms are independently and optionally substituted by a hetero atom having the meaning as described herein, and the ring may be fully saturated or contain one or more unsaturations, but are by no means aromatic. Only one connection point is connected to other molecules.
  • the hydrogen atoms on one or more of the rings are independently and optionally substituted by one or more substituents described herein.
  • a “heterocycle”, “heterocyclyl”, “heteroalicyclic” or “heterocyclic” group is a 3-7 membered ring of a monocyclic ring (1-6 carbon atoms and selected from 1-3 heteroatoms of N, O, P, S, wherein S or P is optionally substituted with one or more oxygen atoms to give a group such as SO, SO 2 , PO, PO 2 when said When the ring is a three-membered ring, there is only one hetero atom), or a 7-10 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, in this S Or P is optionally substituted with one or more oxygen atoms to give a group such as SO, SO 2 , PO, PO 2 ).
  • heterocyclic group may be a carbon group or a hetero atom group.
  • Heterocyclyl also includes groups formed by the union of a heterocyclic group with a saturated or partially unsaturated ring or heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, Morpholinyl, thiomorpholinyl, thiamethane, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thioheterobutyl , piperidinyl, homopiperidinyl, epoxypropyl, azepanyl, oxet
  • heterocyclic group further include a 1,1-dioxothiomorpholinyl group, and wherein two carbon atoms in the ring are substituted with an oxygen atom such as a pyrimidinedione group.
  • heterocyclic group may also be the following structure:
  • aryl may be used alone or as a large part of "aralkyl”, “aralkyloxy” or “aryloxyalkyl”, meaning a monocyclic ring, a bicyclic ring, and a 6-14 membered ring.
  • a tricyclic carbocyclic ring system in which at least one ring system is aromatic, wherein each ring system comprises a 3-7 membered ring and only one attachment point is attached to the remainder of the molecule.
  • aryl may be used interchangeably with the term “aromatic ring”, and the aromatic ring may include phenyl, naphthyl and anthracenyl.
  • the substituent may be, but not limited to, a hydroxyl group, an amino group, a halogen, a cyano group, an
  • heteroaryl denotes a monocyclic, bicyclic, and tricyclic ring system containing a 5-14 membered ring, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein Atoms have the meanings described herein, wherein each ring system contains a 3-7 membered ring and only one attachment point is attached to the remainder of the molecule.
  • heteroaryl can be used interchangeably with the terms “aromatic heterocycle” or "heteroaromatic”.
  • heteroaryl group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, a hydroxyl group, an amino group, a halogen, a cyano group, an aryl group, a heteroaryl group, an alkoxy group, an alkylamino group, an alkyl group.
  • the heteroaryl group includes the following monocyclic rings, but is not limited to these monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazole- 5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, Pyridazinyl (eg 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (eg 5-tetrazolyl), triazolyl (eg 2-triazolyl and
  • heteroatom denotes one or more of the O, S, N, P and Si atoms, including the form of any of the oxidation states of N, S and P; the form of primary, secondary, tertiary and quaternary ammonium salts; a form in which a hydrogen atom on a nitrogen atom is substituted, for example, N (for example, N in a 3,4-dihydro-2H-pyrrolyl group), NH (for example, NH in a pyrrolidinyl group) or NR (for example, an N-substituted pyrrole). NR in an alkyl group.
  • halogen means F, Cl, Br or I.
  • Halo as used in the present invention means a group substituted with a halogen followed by one or more.
  • hydroxy substituted as used in the present invention means a group substituted with a hydroxy group, and the number of substitutions may be one or more.
  • arylalkyl means an aryl-substituted alkyl group
  • alkoxyalkoxy group means an alkoxy group. Substituted alkoxy.
  • unsaturated as used in the present invention means that the moiety contains one or more degrees of unsaturation.
  • the present invention provides a compound having a structure represented by formula (I'), or a stereoisomer, tautomer, oxynitride, solvate of the structure represented by formula (I').
  • a metabolite a pharmaceutically acceptable salt or a prodrug,
  • G is an alkyl group, an aryl-substituted alkyl group, an alkoxycarbonyl-substituted alkyl group, an aryl group or an alkylcarbonyl group;
  • Y is an aryl group, a heteroaryl group or an alkyl group; wherein the aryl or heteroaryl group may be optionally substituted by halogen or alkyl;
  • X is F, Cl or Br
  • R 1 is H, hydrazine or alkyl
  • R 4 and R 5 are each independently an alkyl group
  • R 6 and R 7 are each independently H, hydrazine, alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylane Or heterocyclylalkyl;
  • R 8 is H or an alkyl group
  • R 8 and R 9 together with the N atom to which they are attached form a nitrogen-containing heterocyclic group or a nitrogen-containing heteroaryl group;
  • R 10 is alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, heteroaryl or heterocyclic;
  • W is a 3-8 membered nitrogen-containing heterocycle, a nitrogen-containing C 5-12 fused heterobicyclic ring or a nitrogen-containing C 5-12 spirobicyclo ring;
  • R 11 is H, alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;
  • R 14 and R 15 are each independently alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • n is independently 1, 2, 3, 4 or 5;
  • n 0, 1, 2, 3 or 4;
  • a cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, alkenyl, alkynyl, alkoxy, alkylamino, heteroaryl or heterocyclic group is optionally 1, 2, 3 or 4 are selected from the group consisting of hydroxyl, amino, halogen, cyano, carboxyl, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkoxy Substituents in the group, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino
  • G is C 1-10 alkyl, C 6-12 aryl substituted C 1-10 alkyl, C 1-10 alkoxycarbonyl substituted C 1-10 alkyl, C 6- 12 aryl or C 1-10 alkylcarbonyl.
  • G is C 1-6 alkyl, C 6-10 aryl substituted C 1-6 alkyl, C 1-6 alkoxycarbonyl substituted C 1-6 alkyl, C 6- 10 aryl or C 1-6 alkylcarbonyl.
  • G is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenylmethyl, phenylethyl, phenyl Propyl, 1-ethoxycarbonylethyl, 1-propoxycarbonylethyl, 1-isopropoxycarbonylethyl, phenyl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl or isopropyl Carbonyl.
  • Y is C 6-12 aryl, C 1-9 heteroaryl or C 1-10 alkyl; wherein C 6-12 aryl or C 1-9 heteroaryl can be optionally halogenated , C 1-6 alkyl substituted.
  • Y is C 6-10 aryl, C 2-9 heteroaryl or C 1-6 alkyl; wherein C 6-10 aryl or C 2-9 heteroaryl can be optionally halogenated , C 1-4 alkyl substituted.
  • Y is phenyl, naphthyl, m-chlorophenyl, p-chlorophenyl, m-fluorophenyl, fluorenyl phenyl, p-methylphenyl.
  • X is F, Cl or Br.
  • R 1 is H, hydrazine or C 1-10 alkyl.
  • R 1 is H, hydrazine or C 1-6 alkyl.
  • R 1 is H, hydrazine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • R 4 and R 5 are each independently C 1-10 alkyl.
  • R 4 and R 5 are each independently C 1-6 alkyl.
  • R 4 and R 5 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • R 6 and R 7 are each independently H, hydrazine, C 1-10 alkyl, C 1-10 heteroalkyl, C 6-10 aryl, C 3-10 cycloalkyl, C 1-9heteroaryl , C 2-9 heterocyclyl, C 6-10 aryl C 1-6 alkyl, C 2-9 heteroaryl C 1-6 alkyl, C 3-6 cycloalkyl C 1-6 alkyl or C 2-9 heterocyclyl C 1-6 alkyl.
  • R 6 and R 7 are each independently H, ⁇ , C 1-6 alkyl, C 1-6 heteroalkyl, C 6-10 aryl, C 3-10 cycloalkyl, C 1-9heteroaryl , C 2-9 heterocyclyl, C 6-10 aryl C 1-4 alkyl, C 2-9 heteroaryl C 1-4 alkyl, C 3-6 cycloalkyl C 1-4 alkyl or C 2-9 heterocyclyl C 1-4 alkyl.
  • R 6 and R 7 are each independently H, hydrazine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, benzyl, A Thiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl, phenyl, naphthyl, phenylmethyl, phenylethyl, methoxy, 2-methoxyethyl , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, thiazolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, tetrahydropyrrolyl or tetrahydrofuranyl.
  • R 8 is H or C 1-10 alkyl
  • R 8 and R 9 together with the N atom to which they are attached form a nitrogen-containing C 2-8 heterocyclic group or a nitrogen-containing C 1-9 heteroaryl group.
  • R 8 is H or C 1-6 alkyl
  • R 8 and R 9 together with the N atom to which they are attached form a nitrogen-containing C 2-8 heterocyclic group or a nitrogen-containing C 1-9 heteroaryl group.
  • R 8 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, n-hexyl, Isohexyl or sec-hexyl;
  • R 8 and R 9 together with the N atom to which they are attached form azetidinyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, Polinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, 1,2,3,4-tetrahydroisoquinolinyl, imidazolyl, pyrrolyl, tetrazolyl, triazolyl, pyrazolyl , pyrimidinyl, benzimidazolyl, benzopyrazolyl, decyl, porphyrin, pyridoimidazolyl, pyridopyrazolyl, pyridopyrrolyl, pyridazinazolyl, fluorenyl or pyrimidine And pyrazolyl.
  • R 10 is C 1-10 alkyl, C 1-10 heteroalkyl, C 6-12 aryl, C 3-10 cycloalkyl, C 6-12 aryl C 1-10 alkane , C 1-9 heteroaryl C 1-10 alkyl, C 3-10 cycloalkyl C 1-10 alkyl, C 2-8 heterocyclic C 1-10 alkyl, C 1-9 heteroaryl Or a C 2-8 heterocyclic group.
  • R 10 is C 1-6 alkyl, C 1-6 heteroalkyl, C 6-12 aryl, C 3-6 cycloalkyl, C 6-12 aryl C 1-6 alkane , C 1-9 heteroaryl C 1-6 alkyl, C 3-6 cycloalkyl C 1-6 alkyl, C 2-8 heterocyclic C 1-6 alkyl, C 1-9 heteroaryl Or a C 2-8 heterocyclic group.
  • R 10 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl , n-hexyl, isohexyl, sec-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl, tetrahydrofuranyl, phenyl, naphthyl, benzyl, naphthylmethyl, thiazolylmethyl , imidazolylmethyl, cyclopentylmethyl, cyclohexylmethyl, tetrahydropyrrolylmethyl, tetrahydrofuranylmethyl,
  • R 11 is H, C 1-10 alkyl, C 3-8 cycloalkyl, C 2-8 heterocyclyl, C 1-9 heteroaryl or C 6-12 aryl.
  • R 11 is H, C 1-6 alkyl, C 3-8 cycloalkyl, C 2-8 heterocyclyl, C 1-9 heteroaryl or C 6-12 aryl.
  • R 11 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, pyrrolyl, morpholinyl, piperazinyl or phenyl.
  • R 14 and R 15 are each independently C 1-10 alkyl, C 3-10 cycloalkyl, C 2-8 heterocyclyl, C 6-12 aryl or C 1-9 hetero Aryl.
  • R 14 and R 15 are each independently C 1-6 alkyl, C 3-6 cycloalkyl, C 2-8 heterocyclyl, C 6-10 aryl or C 1-9 hetero Aryl.
  • R 14 and R 15 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, benzyl, methylthioethyl Phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • the invention provides a compound having formula (II'), (III'), (IV'), (V'), (VI'), (VII'), (VIII' Or the structure of (IX'), or formula (II'), (III'), (IV'), (V'), (VI'), (VII'), (VIII') or (IX) a stereoisomer, tautomer, oxynitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown,
  • the invention provides a compound having the structure of formula (II'), (V'), (VIII') or (IX'), or formula (II'), (V) Stereoisomers, tautomers, oxynitrides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the structures shown in '), (VIII') or (IX'),
  • the invention provides a compound having the formula (IIa'), (IIIa'), (IVa'), (Va'), (VIa'), (VIIa'), (VIIIa' Or a structure of the formula (IIa'), or (IIa'), (IIIa'), (IVa'), (Va'), (VIa'), (VIIa'), (VIIIa') or (IXa) a stereoisomer, tautomer, oxynitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure shown,
  • the invention provides a compound having the structure of formula (IIa'), (Va'), (VIIIa') or (IXa'), or formula (IIa'), (Va) Stereoisomers, tautomers, oxynitrides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of the structures shown in '), (VIIIa') or (IXa'),
  • the invention provides a compound having a structure as shown in formula (I) or (Ia), or a stereoisomer, tautomerism of the structure of formula (I) or (Ia) a construct, an oxynitride, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • R 1 is H, hydrazine or alkyl
  • R 4 and R 5 are each independently an alkyl group
  • R 6 and R 7 are each independently H, hydrazine, alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylane Or heterocyclylalkyl;
  • R 8 is H or an alkyl group
  • R 8 and R 9 together with the N atom to which they are attached form a nitrogen-containing heterocyclic group or a nitrogen-containing heteroaryl group;
  • R 10 is alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, heteroaryl or heterocyclic;
  • W is a 3-8 membered nitrogen-containing heterocycle, a nitrogen-containing C 5-12 fused heterobicyclic ring or a nitrogen-containing C 5-12 spirobicyclo ring;
  • R 11 is H, alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;
  • R 14 and R 15 are each independently alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • n is independently 1, 2, 3, 4 or 5;
  • n 0, 1, 2, 3 or 4;
  • a cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, alkenyl, alkynyl, alkoxy, alkylamino, heteroaryl or heterocyclic group is optionally 1, 2, 3 or 4 independently selected from the group consisting of hydroxy, amino, halogen, cyano, carboxy, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, alkane Substituents such as oxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino,
  • W is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • t 1 is 1, 2, 3 or 4;
  • t 2 , t 3 and t 4 are each independently 1, 2 or 3;
  • t 5 and t 6 are each independently 1, 2, 3, 4 or 5;
  • t 7 is 1 or 2;
  • k 1 , k 2 , k 3 and k 4 are each independently 0, 1 or 2; wherein k 1 and k 2 are not 0 at the same time; k 3 and k 4 are not 0 at the same time;
  • Each R 13 is independently H, oxime, carboxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
  • R 1 is H, hydrazine or C 1-6 alkyl.
  • R 4 and R 5 are each independently C 1-6 alkyl.
  • R 6 and R 7 are each independently H, ⁇ , C 1-4 alkyl, C 1-4 heteroalkyl, C 6-10 aryl, C 3-6 cycloalkyl, C 1-9heteroaryl , C 2-9 heterocyclyl, C 6-10 aryl C 1-6 alkyl, C 2-9 heteroaryl C 1-6 alkyl, C 3-6 cycloalkyl C 1-6 alkyl or C 2-9 heterocyclyl C 1-6 alkyl.
  • R 8 is H or C 1-6 alkyl.
  • R 10 is C 1-6 alkyl, C 1-4 heteroalkyl, C 6-10 aryl, C 3-6 cycloalkyl, C 6-12 aryl C 1-6 alkane Base, C 1-9 heteroaryl C 1-6 alkyl, C 3-10 cycloalkyl C 1-6 alkyl, C 2-8 heterocyclic C 1-6 alkyl, C 1-9 heteroaryl Or a C 2-9 heterocyclic group.
  • R 11 is H, C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 heterocyclyl, C 1-9 heteroaryl or C 6-10 aryl.
  • R 14 and R 15 are each independently C 1-6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl or C 1-9 Aryl.
  • the 9 heterocyclic group is optionally 1, 2, 3 or 4 selected from the group consisting of hydroxyl, amino, F, Cl, Br, I, cyano, carboxyl, nitro, C 1-4 alkyl, C 1-4 haloalkyl , C 1-4 alkoxy C 1-4 alkyl, C 1-4 haloalkoxy C 1-4 alkyl, C 1-4
  • R 1 is H, hydrazine, methyl, ethyl, n-propyl or isopropyl.
  • R 4 and R 5 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, Isoamyl, sec-pentyl, n-hexyl, isohexyl or sec-hexyl.
  • R 6 and R 7 are each independently H, hydrazine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, benzyl, Methylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl, phenyl, naphthyl, phenylmethyl, phenylethyl, methoxy, 2-methoxy Base, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, thiazolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, tetrahydropyrrolyl or tetrahydrofuranyl.
  • R 8 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, A sec-pentyl group, a n-hexyl group, an isohexyl group or a sec-hexyl group.
  • R 8 and R 9 together with the N atom to which they are attached form azetidinyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, Polinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, 1,2,3,4-tetrahydroisoquinolinyl, imidazolyl, pyrrolyl, tetrazolyl, triazolyl, pyrazolyl , pyrimidinyl, benzimidazolyl, benzopyrazolyl, decyl, porphyrin, pyridoimidazolyl, pyridopyrazolyl, pyridopyrrolyl, pyridazinazolyl, fluorenyl or pyrimidine And pyrazolyl.
  • R 10 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl Base, n-hexyl, isohexyl, sec-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl, tetrahydrofuranyl, phenyl, naphthyl, benzyl, naphthylmethyl, thiazolyl Base, imidazolylmethyl, cyclopentylmethyl, cyclohexylmethyl, tetrahydropyrrolylmethyl, tetrahydrofuranylmethyl,
  • R 11 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, pyrrolyl, morpholinyl, piperazinyl or phenyl.
  • R 14 and R 15 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, benzyl, methylthio Base, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • methyl, ethyl, n-propyl as described in R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 14 or R 15 Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, n-hexyl, isohexyl, benzyl, methylthiomethyl, methyl sulfide Ethyl ethyl, methylthiopropyl, methylthiobutyl, phenyl, naphthyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, thiazolyl, thienyl, furyl, Pyrrolyl, pyridyl, pyrimidinyl,
  • W is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • each R 13 is independently H, hydrazine, carboxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 -6 heterocyclyl, C 6-10 aryl or C 1-9 heteroaryl.
  • each R 13 is independently H, hydrazine, carboxyl, methyl, ethyl, propyl, vinyl, ethynyl, cyclopropyl, cyclopentyl, cyclohexyl, morpholinyl, benzene Base or pyridyl.
  • the present invention provides a compound having the structure of formula (II), or a stereoisomer, tautomer, oxynitride, solvate, or the structure of formula (II), a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the present invention provides a compound having the structure of formula (IIa), or a stereoisomer, tautomer, oxynitride, solvate, or the structure of formula (IIa), a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the present invention provides a stereoisomer, tautomer, oxynitride, solvate, or a compound having the structure represented by formula (III) or the structure represented by formula (III), a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the present invention provides a stereoisomer, tautomer, oxynitride, solvate, or a compound having the structure represented by formula (IIIa) or the structure represented by formula (IIIa), a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the present invention provides a stereoisomer, tautomer, oxynitride, solvate, or a compound having the structure represented by formula (IV) or the structure represented by formula (IV), a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the present invention provides a stereoisomer, tautomer, oxynitride, solvate, or a compound having the structure represented by formula (IVa) or the structure represented by formula (IVa), a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the present invention provides a stereoisomer, tautomer, oxynitride, solvate, or a compound having the structure represented by formula (V) or the structure represented by formula (V), a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the present invention provides a stereoisomer, tautomer, oxynitride, solvate, or a compound having the structure represented by formula (Va) or the structure represented by formula (Va), a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the present invention provides a stereoisomer, tautomer, oxynitride, solvate, or a compound having the structure represented by formula (VI) or the structure represented by formula (VI), a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the present invention provides a stereoisomer, tautomer, oxynitride, solvate, or a compound having the structure represented by formula (VIa) or the structure represented by formula (VIa), a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the present invention provides a stereoisomer, tautomer, oxynitride, solvate, or a compound having the structure represented by formula (VII) or the structure represented by formula (VII), a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the present invention provides a stereoisomer, tautomer, oxynitride, solvate, or a compound having the structure represented by formula (VIIa) or the structure represented by formula (VIIa), a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the present invention provides a stereoisomer, tautomer, oxynitride, solvate, or a compound having the structure represented by formula (VIII) or the structure represented by formula (VIII), a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the present invention provides a stereoisomer, tautomer, oxynitride, solvate, or a compound having the structure represented by formula (VIIIa) or the structure represented by formula (VIIIa), a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the present invention provides a stereoisomer, tautomer, oxynitride, solvate, or a compound having the structure represented by formula (IX) or the structure represented by formula (IX), a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the present invention provides a stereoisomer, tautomer, oxynitride, solvate, or a compound having the structure represented by formula (IXa) or the structure represented by formula (IXa), a metabolite, a pharmaceutically acceptable salt or a prodrug,
  • the invention provides a compound having formula (II), (IIa), (III), (IIIa), (IV), (IVa), (V), (Va), (VI) , (VIa), (VII), (VIIa), (VIII), (VIIIa), (IX) or (IXa), or the formula (II), (IIa), (III), (IIIa) , (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIII), (VIIIa), (IX) or (IXa) Structural stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • each R 1 is independently H, oxime or C 1-6 alkyl.
  • each R 6 is independently H, hydrazine, C 1-6 alkyl, C 1-6 heteroalkyl, C 6-10 aryl, C 3-8 cycloalkyl, C 1-9 Heteroaryl, C 2-9 heterocyclyl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 Alkyl or C 2-9 heterocyclyl C 1-6 alkyl.
  • Each R 8 is independently H or C 1-6 alkyl
  • R 8 and R 9 together with the N atom to which they are attached form a nitrogen-containing C 2-9 heterocyclic group or a nitrogen-containing C 1-9 heteroaryl group.
  • each R 10 is independently C 1-6 alkyl, C 1-6 heteroalkyl, C 6-10 aryl, C 3-8 cycloalkyl, C 6-10 aryl C 1 -6 alkyl, C 1-9 heteroaryl C 1-6 alkyl, C 3-10 cycloalkyl C 1-6 alkyl, C 2-9 heterocyclyl C 1-6 alkyl, C 1- 9 heteroaryl or C 2-9 heterocyclic.
  • each R 11 is independently H, C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 1-9 heteroaryl, or C 6-10 aryl base.
  • each of R 1 , R 6 , R 8 , R 9 , R 10 , R 11 or R 12 is C 1-6 alkyl, C 1-6 heteroalkyl, C 6-10 aryl , C 3-8 cycloalkyl, C 1-9 heteroaryl, C 2-9 heterocyclyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 1
  • the -6 alkylamino group is independently optionally substituted by 1, 2, 3 or 4 hydroxyl groups, amino groups, F, Cl, Br, cyano groups, carboxyl groups, nitro groups.
  • each R 1 is independently H, hydrazine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl;
  • each R 6 is independently H, hydrazine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, methylthiomethyl, 1- Methylthioethyl, 2-methylthioethyl, 1-methylthiopropyl, 2-methylthiopropyl, 3-methylthiopropyl, 1-methylthiobutyl, 2-methylthio Butyl, 3-methylthiobutyl, 4-methylthiobutyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-methoxypropyl, 2-methoxypropyl, 3-methoxypropyl, 1-methoxybutyl, 2-methoxybutyl, 3-methoxybutyl, 4-methoxybutyl, phenyl , naphthyl, cyclopropyl, cyclobutyl, cyclopentyl,
  • Each R 8 is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, Orthohexyl, isohexyl or sec-hexyl;
  • R 8 and R 9 together with the N atom to which they are attached form azetidinyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, Polinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, 1,2,3,4-tetrahydroisoquinolinyl, imidazolyl, pyrrolyl, tetrazolyl, triazolyl, pyrazolyl , pyrimidinyl, benzimidazolyl, benzopyrazolyl, decyl, porphyrin, pyridoimidazolyl, pyridopyrazolyl, pyridopyrrolyl, pyridazinazolyl, fluorenyl or pyrimidine And pyrazolyl.
  • each R 10 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, Sec-pentyl, n-hexyl, isohexyl, sec-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl, tetrahydrofuranyl, phenyl, naphthyl, benzyl, naphthylmethyl, thiazole Methyl, imidazolylmethyl, cyclopentylmethyl, cyclohexylmethyl, tetrahydropyrrolylmethyl, tetrahydrofuranylmethyl,
  • each R 11 is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentane Base, cyclohexyl, pyrrolyl, morpholinyl, piperazinyl or phenyl.
  • methyl, ethyl, n-propyl, isopropyl, n-butyl, iso is as defined in R 1 , R 6 , R 8 , R 9 , R 10 , R 11 or R 12 Butyl, sec-butyl, methylthiomethyl, 1-methylthioethyl, 2-methylthioethyl, 1-methylthiopropyl, 2-methylthiopropyl, 3-methylthio Propyl, 1-methylthiobutyl, 2-methylthiobutyl, 3-methylthiobutyl, 4-methylthiobutyl, methoxymethyl, 1-methoxyethyl, 2 -methoxyethyl, 1-methoxypropyl, 2-methoxypropyl, 3-methoxypropyl, 1-methoxybutyl, 2-methoxybutyl, 3-methyl Oxybutyl, 4-methoxybutyl, phenyl, naphthyl, cyclopropyl
  • compositions, formulation and administration of a compound of the invention are provided.
  • the pharmaceutical composition comprises any one of the compounds of the invention.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.
  • the pharmaceutical composition can be used for the treatment of hepatitis C virus (HCV) infection or hepatitis C disease, in particular, it has a good inhibitory effect on the HCV NS5B protein.
  • HCV hepatitis C virus
  • Substances which may be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, sorbus Potassium acid, a partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking polymer, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Cellulose sodium, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talcum powder; excipients such as cocoa
  • the pharmaceutical composition further comprises a drug that is resistant to HCV.
  • the anti-HCV drug may be any other known anti-HCV drug different from the compound of the present invention.
  • it may be interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, a compound that promotes a type 1 helper T cell response, interfering RNA, antisense RNA, imiquimod, inosine 5'- monophosphate dehydrogenase inhibitor, amantadine, rimantadine, Bavi infliximab (Bavituximab), hepatitis C immune globulin (Civacir TM), boceprevir (of boceprevir), telaprevir (of telaprevir ), erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, paritaprevir (ABT-450), rememberoprevir ( Danoprevir), sova
  • interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha-2a, complex alpha interferon, interferon gamma or combination.
  • the pharmaceutical composition further comprises at least one HCV inhibitor for inhibiting HCV replication and/or inhibiting HCV viral protein function, wherein the HCV replication process is selected from the group consisting of HCV entry, husking, translation , replication, assembly, and release of the complete viral cycle of HCV; the HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B; and the internal ribosome entry point required for HCV viral replication (IRES) And inosine monophosphate dehydrogenase (IMPDH).
  • HCV replication process is selected from the group consisting of HCV entry, husking, translation , replication, assembly, and release of the complete viral cycle of HCV
  • the HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B
  • IVS internal ribosome entry point required for HCV viral
  • a therapeutically effective amount of a compound of the invention can be administered as a raw chemical and as an active ingredient in a pharmaceutical composition.
  • the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • therapeutically effective amount refers to the total amount of each active ingredient sufficient to exhibit a meaningful patient benefit, such as a reduction in viral load.
  • the term refers only to that ingredient.
  • the term refers to the combined amount of the active ingredient which results in a therapeutic effect, whether administered sequentially or simultaneously.
  • the carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • a process for the preparation of a pharmaceutical formulation which comprises mixing a compound of the invention with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • pharmaceutically acceptable means a compound, a raw material, a composition and/or a dosage form of the present invention which, within the scope of sound medical judgment, is suitable for contact with a patient's tissue without excessive toxicity or irritation. , allergies or other problems and complications commensurate with a reasonable benefit/risk ratio and effective for the intended use.
  • a composition of the present invention comprises a combination of a compound of the present invention and one or more other therapeutic or prophylactic agents
  • the dosage levels of the compound and the additional drug are typically in a monotherapy regimen that occupies a normal dosage. It is about 10-150%, more preferably about 10-80% of the normal administered dose.
  • the pharmaceutical preparations are suitable for administration by any suitable route, for example by oral administration (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal) , intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion).
  • Such formulations may be prepared by any of the methods known in the art of pharmacy, for example by mixing the active ingredient with carriers or excipients. Oral administration or injection administration is preferred.
  • compositions suitable for oral administration are provided in separate units, such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or nonaqueous liquids; edible foam preparations or foaming preparations (whip ); or an oil-in-water emulsion or a water-in-oil emulsion.
  • the active drug component can be mixed with a pharmaceutically acceptable oral non-toxic inert carrier such as ethanol, glycerol, water, and the like.
  • a pharmaceutically acceptable oral non-toxic inert carrier such as ethanol, glycerol, water, and the like.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible sugar such as starch or mannitol. Flavoring agents, preservatives, dispersing agents, and coloring agents may also be present.
  • a capsule is prepared by preparing a powdery mixture as described above and filling it into a shaped gelatin shell.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture prior to the filling operation. It is also possible to add a disintegrating or solubilizing agent (for example, agar, calcium carbonate or sodium carbonate) which will improve the availability of the drug when the capsule is taken.
  • suitable binders include starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic gums (such as acacia, tragacanth or sodium alginate), carboxymethylcellulose. , polyethylene glycol, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like.
  • Disintegrators include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • a tablet is prepared by preparing a powdery mixture, granulating or pre-compacting, adding a lubricant and a disintegrating agent, and compressing into a tablet.
  • a powdery mixture for example carboxymethylcellulose, alginate, gelatin or polyvinylpyrrolidone
  • a dissolution inhibitor for example paraffin
  • a powder mixture is prepared by mixing an absorption accelerator (quaternary salt) and/or an absorbent (for example, bentonite, kaolin or dicalcium phosphate).
  • the powdered mixture can be granulated by wetting with a binder such as syrup, starch syrup, acadiamucilage or cellulosic material or a solution of polymeric material.
  • a binder such as syrup, starch syrup, acadiamucilage or cellulosic material or a solution of polymeric material.
  • An alternative to granulation is that the powdered mixture can be passed through a tablet press, with the result that poorly formed agglomerates are broken down into granules.
  • the granules can be lubricated by the addition of stearic acid, stearate, talc or mineral oil to prevent sticking to the die of the tablet press.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with a free flowing inert carrier which can be compressed into tablets without the need for granulation or pre-tabletting steps.
  • a protective or coating material consisting of a shellac seal coat, a sugar
  • Oral liquid preparations such as solutions, syrups and elixirs may be prepared in dosage unit form such that a predetermined amount of the compound is contained in a given amount.
  • a syrup can be prepared by dissolving the compound in a suitably flavored aqueous solution, and the elixirs can be prepared by using a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether
  • preservatives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners
  • flavoring additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners
  • Dosage unit formulations for oral administration can be microencapsulated, if appropriate.
  • the formulations may also be formulated for extended or sustained release, for example by coating or embedding in particulate materials such as polymers, waxes and the like.
  • the compounds of the invention may also be administered in liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be composed of a variety of phospholipids, such as cholesterol, octadecylamine or phosphatidylcholine.
  • the compounds of the invention may also be delivered by the use of monoclonal antibodies as separate carriers to which the compound molecules are coupled.
  • the compound can also be coupled to a soluble polymer as a targetable drug carrier.
  • soluble polymer may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenol, polyhydroxyethylaspartamide phenol or polyoxyethylene polylysine substituted with palmitoyl residues.
  • the compounds are coupled to a class of biodegradable polymers for controlled release of such polymers, such as polylactic acid, poly ⁇ -caprolactone, polyhydroxybutyrate, polyorthoesters, polycondensation A crosslinked copolymer or an amphiphilic block copolymer of an aldehyde, a polydihydropyran, a polycyanoacrylate, and a hydrogel.
  • a class of biodegradable polymers for controlled release of such polymers, such as polylactic acid, poly ⁇ -caprolactone, polyhydroxybutyrate, polyorthoesters, polycondensation A crosslinked copolymer or an amphiphilic block copolymer of an aldehyde, a polydihydropyran, a polycyanoacrylate, and a hydrogel.
  • compositions suitable for transdermal administration can be used as a discrete patch to maintain intimate contact with the recipient's epidermis over a prolonged period of time.
  • the active ingredient can be delivered by an iontophoretic patch, generally see Pharmaceutical Research 1986, 3(6), 318.
  • compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils or transdermal patches. .
  • compositions suitable for rectal administration can be presented as a suppository or as an enemas.
  • a pharmaceutical preparation suitable for nasal administration wherein the carrier is a solid comprises a coarse powder having a particle size of, for example, 20 to 500 micrometers, which is administered by nasal inhalation, i.e., through a nasal passage from a coarse powder container close to the nose. Inhalation.
  • suitable formulations wherein the carrier is a liquid, suitable for administration as a nasal spray or nasal drops include aqueous or oily solutions of the active ingredient.
  • Fine particle dust or mist which can be delivered by various types of metered dose compressed aerosols, nebulizers, insufflators or the like. Prepared in the device.
  • compositions suitable for vaginal administration may be presented as pessaries, pessaries, creams, creams, gels, pastes, foams or sprays.
  • compositions suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions and aqueous and non-aqueous sterile suspensions, aqueous and non-aqueous sterile injectable solutions containing antioxidants, buffers, bacteriostatic And solute which renders the formulation isotonic with the blood of the recipient, aqueous and nonaqueous sterile suspensions may include suspending and thickening agents.
  • the formulations may be presented in unit or multi-dose containers, such as sealed Ankai and vials, and may be stored under lyophilized (lyophilized) conditions by the addition of a sterile liquid carrier, such as water for injection, just prior to use.
  • Injectable solutions and suspensions for constitutional use may be prepared from sterile powders, granules and tablets.
  • formulations also include other ingredients commonly used in the art in connection with the type of formulation, such as those suitable for oral administration, which may include flavoring agents.
  • the present invention provides the use of a compound of the present invention or a pharmaceutical composition thereof for the preparation of a medicament which can be used for inhibiting the HCV replication process and/or inhibiting HCV viral protein function.
  • the HCV replication process is selected from the complete viral cycle of HCV entry, husking, translation, replication, assembly or release of HCV.
  • the HCV viral protein is selected from the group consisting of metalloproteinases, NS2, NS3, NS4A, NS4B, NS5A, NS5B; and the internal ribosome entry point (IRES) and inosine monophosphate dehydrogenase (IMPDH) required for HCV viral replication.
  • Any of the compounds or pharmaceutical compositions of the present invention can be used for the treatment of hepatitis C virus (HCV) infection or hepatitis C disease, in particular, it has a good inhibitory effect on the HCV NS5B protein.
  • a method of treatment comprising administration of a compound or pharmaceutical composition of the invention, further comprising administering to the patient an additional HCV drug, whereby the compound of the invention may be administered in combination with other anti-HCV agents, wherein the anti-HCV drug is Interferon, ribavirin, interleukin 2, interleukin 6, interleukin 12, compounds that promote type 1 helper T cell response, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenation enzyme inhibitors, amantadine, rimantadine, Bavi infliximab (Bavituximab), hepatitis C immune globulin (Civacir TM), boceprevir (of boceprevir), telaprevir (of telaprevir), Herault Erlotinib, daclatasvir, simeprevir, asunaprevir, vaniprevir, faldaprevir, paritaprevir (ABT-450), dan
  • interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha-2a, complex alpha interferon, interferon gamma or a combination thereof .
  • a method of treatment comprising administration of a compound or pharmaceutical composition of the invention, further comprising administration of another anti-HCV drug, wherein the other anti-HCV drug can be administered in combination with a compound of the invention or a pharmaceutical composition thereof, a compound or drug of the invention
  • the composition is presented as a single dosage form, or as a separate compound or pharmaceutical composition as part of a multiple dosage form.
  • Other anti-HCV drugs can be administered simultaneously or not simultaneously with the compounds of the invention. In the latter case, the administration can be carried out by staggering, for example, 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.
  • an “effective amount” or “effective amount” of a compound or pharmaceutically acceptable composition of the invention refers to an effective amount to treat or ameliorate the severity of one or more of the conditions mentioned herein.
  • the compounds and compositions thereof can be used in any dosage and in any route of administration to effectively treat or reduce the severity of the disease. The exact amount required will vary depending on the patient's condition, depending on race, age, general condition of the patient, severity of infection, specific factors, mode of administration, and the like.
  • the compounds or compositions of this invention may be administered in combination with one or more other therapeutic agents, as discussed herein.
  • the compounds of the invention can be prepared by the methods described herein.
  • the following reaction schemes and examples are provided to further illustrate the contents of the present invention.
  • the reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated.
  • the general reagents were purchased from Shantou Xiqiao Chemical Plant, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.
  • Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by refluxing with sodium metal.
  • Anhydrous dichloromethane and chloroform were obtained by reflux drying of calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were previously dried over anhydrous sodium sulfate.
  • reaction is generally carried out under a positive pressure of nitrogen or argon or on a dry solvent (unless otherwise indicated), the reaction bottle is stoppered with a suitable rubber stopper, and the substrate is driven through a syringe.
  • the glassware is dry.
  • the column is a silica gel column.
  • Silica gel 300-400 mesh
  • the nuclear magnetic resonance spectrum was measured by CDC1 3 , d 6 -DMSO, CD 3 OD or d 6 -acetone (reported in ppm) using TMS (0 ppm) or chloroform (7.25 ppm) as a reference standard.
  • s singlet, doublet
  • t triplet, triplet
  • q quartet, quadruple
  • m multiplet, Multiple peaks
  • br broadened, broad peaks
  • dd doublet of doublets
  • dt doublet of triplets
  • Coupling constant expressed in Hertz (Hz).
  • MS data was measured with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 °C) Agilent 6320 Series LC-MS spectrometer, G1329A autosampler and G1315B DAD detector applied For analysis, the ESI source was applied to an LC-MS spectrometer.
  • MS mass spectrometry
  • Both spectrometers are equipped with an Agilent Zorbax SB-C18 column measuring 2.1 x 30 mm, 5 ⁇ m.
  • the injection volume was determined by sample concentration; the flow rate was 0.6 mL/min; the peak of HPLC was recorded by UV-Vis wavelengths at 210 nm and 254 nm.
  • the mobile phase was a 0.1% formic acid acetonitrile solution (Phase A) and a 0.1% formic acid ultrapure aqueous solution (Phase B).
  • the gradient elution conditions are shown in Table 1:
  • the process conditions for HPLC preparation are:
  • step (3) Take the appropriate amount of the sample solution in step (1) into a high performance liquid chromatograph, record the chromatogram, and complete the separation and analysis of the isomer;
  • Mobile phase a mixture of two or more of methanol, ethanol, isopropanol, acetonitrile, n-hexane, n-pentane, isohexane, n-heptane, diethylamine, triethylamine, trifluoroacetic acid, glacial acetic acid; Specifically, the volume ratio of n-hexane, n-pentane, isohexane, and n-heptane in the mixture of the mobile phase is 10 to 20%, and the volume ratio of methanol, ethanol, isopropanol, and acetonitrile is 20 to 95%, and diethyl The volume ratio of the amine, triethylamine, trifluoroacetic acid, glacial acetic acid is 0 to 2%, and the sum of the components in the mobile phase is 100%; more specifically, the volume ratio of n-hexane in the mixture of the mobile phases It is 15 to 20%, the
  • Detection wavelength 250nm ⁇ 320nm;
  • Flow rate 0.5-10 mL/min; more specifically 2-5 mL/min;
  • DIPEA N,N-diisopropylethylamine
  • the compound of formula I' can be synthesized by the procedure shown in Scheme 1.
  • Compound I'-1 can be reacted with a hydroxy protecting reagent to obtain a hydroxy-protected compound I'-2 on a furan ring;
  • compound I'-2 and compound I'-3 can be reacted under a base to form compound I'-4;
  • the target compound I' is obtained after deprotection of I'-4.
  • the compound of formula I can be synthesized by the procedure shown in Scheme 2.
  • Compound I-1 can be reacted with a hydroxy protecting reagent to obtain a hydroxy-protected compound 1-2 on a furan ring;
  • compound I-2 and compound 1-3 can be reacted under a base to form compound I-4;
  • compound I-4 is deprotected
  • the target compound I is obtained afterwards.
  • the mixture was extracted with ethyl acetate (200 mL), and the organic phase was washed with water (100 mL ⁇ 2) and saturated sodium chloride solution (100 mL). The mixture was dried over sodium sulfate (MgSO4).
  • reaction mixture was allowed to stand and the organic layer was washed with water (100 mL), saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and evaporated to dryness. The next reaction was directly carried out without further purification.
  • the organic phase was washed with water (30mL) and saturated sodium chloride solution (30mL) and dried over anhydrous sodium sulfate.
  • the mixture was concentrated to give a white solid (10.0 g).
  • reaction mixture was allowed to stand and the organic layer was washed with water (100 mL), saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and evaporated to dryness. The next reaction was directly carried out without further purification.
  • the compound 15-4 (0.50 g, 2.9 mmol, 1.0 eq) was added to a solution of 10 mL of potassium hydroxide (0.243 g, 4.35 mmol, 1.5 eq) in anhydrous ethanol. The residue was dissolved in water (10 mL), EtOAc (EtOAc) (EtOAc) The yield was 95.2%.
  • Potassium hydrogencarbonate (12.8 g, 128.0 mmol, 1.5 eq) was dissolved in 60 mL of water, and compound 18-1 (10 g, 85.4 mmol, 1.0 eq) was added, and phenyl chloroformate (11.8 mL) was slowly added dropwise at -5 °C. 94.1 mmol, 1.1 eq), while adding 50% aqueous NaOH solution (6.5 mL) to control the reaction pH between 8-9, and after 10 minutes of dropwise addition, it was moved to room temperature.
  • aqueous layer was separated and concentrated with hydrochloric acid to adjust to pH 2, ethyl acetate (100 mL) was extracted and the organic layer was washed with water and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure and dried in vacuo to yield 12.5 g, m.

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Abstract

La présente invention concerne un promédicament d'analogues nucléosidiques antiviraux, une composition et son utilisation, et concerne particulièrement un promédicament d'analogues nucléosidiques anti-virus de l'hépatite C. Le promédicament peut être utilisé en tant qu'inhibiteur pour des polymérases NS5B du VHC, un inhibiteur de la réplication du VHC ainsi que pour traiter une infection de l'hépatite C chez les mammifères.
PCT/CN2017/119448 2016-12-29 2017-12-28 Promédicament d'analogues nucléosidiques antiviraux, composition et utilisation associées WO2018121678A1 (fr)

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US20220023820A1 (en) * 2018-12-21 2022-01-27 Microsoft Technology Licensing, Llc Regulation of dna synthesis by nucleotides linked to protecting groups
WO2021262826A3 (fr) * 2020-06-24 2022-02-17 Gilead Sciences, Inc. Analogues de 1'-cyano nucléoside et leurs utilisations
US11382926B2 (en) 2015-09-16 2022-07-12 Gilead Sciences, Inc. Methods for treating Arenaviridae and Coronaviridae virus infections
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US11613553B2 (en) 2020-03-12 2023-03-28 Gilead Sciences, Inc. Methods of preparing 1′-cyano nucleosides
US11660307B2 (en) 2020-01-27 2023-05-30 Gilead Sciences, Inc. Methods for treating SARS CoV-2 infections
US11701372B2 (en) 2020-04-06 2023-07-18 Gilead Sciences, Inc. Inhalation formulations of 1'-cyano substituted carba-nucleoside analogs
US11780844B2 (en) 2022-03-02 2023-10-10 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
US11814406B2 (en) 2020-08-27 2023-11-14 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
WO2024032718A1 (fr) * 2022-08-11 2024-02-15 广东东阳光药业股份有限公司 Forme cristalline d'un inhibiteur de l'hépatite c et son utilisation dans un médicament
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CN111118073B (zh) * 2019-12-27 2022-02-15 宜昌东阳光生化制药有限公司 酶法合成依米他韦中间体的方法

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CN105348345A (zh) * 2015-12-15 2016-02-24 杭州和正医药有限公司 一种含有硫普罗宁结构的前药、其制备方法、药物组合物及其用途

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US11382926B2 (en) 2015-09-16 2022-07-12 Gilead Sciences, Inc. Methods for treating Arenaviridae and Coronaviridae virus infections
US12030906B2 (en) 2017-05-01 2024-07-09 Gilead Sciences, Inc. Crystalline forms of (s)-2-ethylbutyl 2-(((s)-(((2r,3s,4r,5r)-5-(4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy) phosphoryl)amino)propanoate
US11597742B2 (en) 2017-05-01 2023-03-07 Gilead Sciences, Inc. Crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy) phosphoryl)amino)propanoate
US11975017B2 (en) 2017-07-11 2024-05-07 Gilead Sciences, Inc. Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections
US20220023820A1 (en) * 2018-12-21 2022-01-27 Microsoft Technology Licensing, Llc Regulation of dna synthesis by nucleotides linked to protecting groups
EP3771711A1 (fr) 2019-07-29 2021-02-03 Bayer Animal Health GmbH Dérivés de pyrazole pour le contrôle des arthropodes
WO2021018849A1 (fr) 2019-07-29 2021-02-04 Bayer Animal Health Gmbh Dérivés de pyrazole pour lutter contre les arthropodes
US11660307B2 (en) 2020-01-27 2023-05-30 Gilead Sciences, Inc. Methods for treating SARS CoV-2 infections
US11613553B2 (en) 2020-03-12 2023-03-28 Gilead Sciences, Inc. Methods of preparing 1′-cyano nucleosides
US12012431B2 (en) 2020-03-12 2024-06-18 Gilead Sciences, Inc. Methods of preparing 1′-cyano nucleosides
US11701372B2 (en) 2020-04-06 2023-07-18 Gilead Sciences, Inc. Inhalation formulations of 1'-cyano substituted carba-nucleoside analogs
US11975012B2 (en) 2020-05-29 2024-05-07 Gilead Sciences, Inc. Remdesivir treatment methods
US11903953B2 (en) 2020-05-29 2024-02-20 Gilead Sciences, Inc. Remdesivir treatment methods
US11491169B2 (en) 2020-05-29 2022-11-08 Gilead Sciences, Inc. Remdesivir treatment methods
US11939347B2 (en) 2020-06-24 2024-03-26 Gilead Sciences, Inc. 1′-cyano nucleoside analogs and uses thereof
WO2021262826A3 (fr) * 2020-06-24 2022-02-17 Gilead Sciences, Inc. Analogues de 1'-cyano nucléoside et leurs utilisations
US11926645B2 (en) 2020-08-27 2024-03-12 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
US11814406B2 (en) 2020-08-27 2023-11-14 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
US12297226B2 (en) 2020-08-27 2025-05-13 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
US11845755B2 (en) 2022-03-02 2023-12-19 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
US11851438B2 (en) 2022-03-02 2023-12-26 Gilead Sciences, Inc. 1′-cyano nucleoside analogs and methods for treatment of viral infections
US11780844B2 (en) 2022-03-02 2023-10-10 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
US12180217B2 (en) 2022-03-02 2024-12-31 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
WO2024032718A1 (fr) * 2022-08-11 2024-02-15 广东东阳光药业股份有限公司 Forme cristalline d'un inhibiteur de l'hépatite c et son utilisation dans un médicament

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