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WO2018121678A1 - Prodrug of antiviral nucleoside analogues, and composition and use thereof - Google Patents

Prodrug of antiviral nucleoside analogues, and composition and use thereof 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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WIPO (PCT)
Prior art keywords
alkyl
group
heteroaryl
aryl
butyl
Prior art date
Application number
PCT/CN2017/119448
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French (fr)
Chinese (zh)
Inventor
张英俊
谢洪明
方清洪
罗明
蒋海港
Original Assignee
广东东阳光药业有限公司
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Publication of WO2018121678A1 publication Critical patent/WO2018121678A1/en

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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

The present invention relates to a prodrug of antiviral nucleoside analogues, and a composition and use thereof, and specifically relates to a prodrug of anti-hepatitis C virus nucleoside analogues. The prodrug can be used as an inhibitor for HCV NS5B polymerases and an inhibitor for HCV replication, and for treating infection of hepatitis C in mammals.

Description

一种抗病毒核苷类似物前药及其组合物、用途Antiviral nucleoside analog prodrug, composition and use thereof 技术领域Technical field
本发明属于药物领域，涉及一种抗病毒核苷类似物前药及其组合物、用途，具体的涉及抗丙肝病毒的核苷类似物前药。这些化合物是RNA依赖性RNA病毒复制的抑制剂，并可用作HCV NS5B聚合酶的抑制剂、用作HCV复制的抑制剂和用于治疗哺乳动物中的丙型肝炎感染。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.
背景技术Background technique
丙型肝炎病毒(HCV)感染是导致慢性肝病(如肝硬化和肝细胞癌)的主要健康问题，感染个体估计占世界人口的2-15％。根据世界卫生组织，全世界有超过2亿受感染人口，并且每年有至少300-400万人被感染。一旦被感染，约20％的人可清除病毒，但其余的人在其余生中将携带HCV。10-20％的慢性受感染个体最终发展为肝破坏性肝硬化或癌症。通过污染的血液和血液制品、污染的针或性行为以及从受感染的母亲或携带者母亲垂直地到其后代，胃肠外地传播该病毒性疾病。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. According to the World Health Organization, there are more than 200 million infected people worldwide, and at least 3 to 4 million people are infected every year. Once infected, about 20% of people can get rid of the virus, but the rest will carry HCV in the rest of their lives. 10-20% of chronically infected individuals eventually develop liver-destructive cirrhosis or cancer. 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.
发明内容Summary of the invention
一方面，本发明提供了一种化合物，具有如式(I’)所示的结构，或式(I’)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In one aspect, 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,
Figure PCTCN2017119448-appb-000001
Figure PCTCN2017119448-appb-000001
其中，among them,
G为烷基，芳基取代的烷基，烷氧基羰基取代的烷基，芳基或烷基羰基；G is an alkyl group, an aryl-substituted alkyl group, an alkoxycarbonyl-substituted alkyl group, an aryl group or an alkylcarbonyl group;
Y为芳基、杂芳基或烷基；其中芳基或杂芳基可任意的被卤素或烷基取代；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为F，Cl或Br；X is F, Cl or Br;
R 1为H、氘或烷基； R 1 is H, hydrazine or alkyl;
R 2为-C(＝O)-(CR 6R 7) n-R 3、-C(＝O)-(CH 2OCH 2) n-R 3、-P(＝O)(OR 4)OR 5； R 2 is -C(=O)-(CR 6 R 7 ) n -R 3 , -C(=O)-(CH 2 OCH 2 ) n -R 3 , -P(=O)(OR 4 )OR 5 ;
或R 2为
Figure PCTCN2017119448-appb-000002
Or R 2 is
Figure PCTCN2017119448-appb-000002
R 3为-NR 8R 9、-M-R 10、-C(＝O)OR 10、-C(＝O)OH、-O-N＝CR 14R 15或-N＝CR 14R 15； R 3 is -NR 8 R 9 , -MR 10 , -C(=O)OR 10 , -C(=O)OH, -ON=CR 14 R 15 or -N=CR 14 R 15 ;
R 4和R 5各自独立地为烷基； R 4 and R 5 are each independently an alkyl group;
R 6和R 7各自独立地为H、氘、烷基、杂烷基、芳基、环烷基、杂芳基、杂环基、芳基烷基、杂芳基烷基、环烷基烷基或杂环基烷基； R 6 and R 7 are each independently H, hydrazine, alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylane Or heterocyclylalkyl;
R 8为H或烷基； R 8 is H or an alkyl group;
R 9为H、氘、-C(＝O)R 10、-C(＝O)OR 10、烷基、环烷基、杂环基、杂芳基或芳基； R 9 is H, hydrazine, -C(=O)R 10 , -C(=O)OR 10 , alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;
或R 8和R 9与其相连的N原子一起形成含氮杂环基或含氮杂芳基； Or 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为烷基、杂烷基、芳基、环烷基、芳基烷基、杂芳基烷基、环烷基烷基、杂环基烷基、杂芳基或杂环基； R 10 is alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, heteroaryl or heterocyclic;
M为
Figure PCTCN2017119448-appb-000003
M is
Figure PCTCN2017119448-appb-000003
W为3-8元含氮杂环、含氮C 5-12稠合杂双环或含氮C 5-12螺杂双环； 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为H、烷基、环烷基、杂环基、杂芳基或芳基； R 11 is H, alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;
各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、烷基、卤代烷基、烷氧基烷基、卤代烷氧基烷基、烯基、炔基、烷氧基、卤代烷氧基、烷氧基烷氧基、烷氨基、卤代烷氨基、烷硫基、环烷基、杂环基、芳基、杂芳基、芳氧基、芳氨基、杂芳氧基、羟基取代的烷氧基、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O) 2-、羟基取代的烷基-C(＝O)-、羟基取代的烷基-S(＝O)-或羟基取代的烷基-S(＝O) 2-； Each R 12 is independently H, hydrazine, =O, hydroxy, amino, halogen, cyano, carboxy, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl , alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, heteroaryl Oxyl, hydroxy substituted alkoxy, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy substituted alkyl-C (= O)-, hydroxy-substituted alkyl-S(=O)- or hydroxy-substituted alkyl-S(=O) 2 -;
R 14和R 15各自独立地为烷基、环烷基、杂环基、芳基或杂芳基； R 14 and R 15 are each independently alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
各n独立地为1、2、3、4或5；和Each n is independently 1, 2, 3, 4 or 5; and
m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
其中R 1、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 14或R 15中所述的烷基、杂烷基、芳基、环烷基、芳基烷基、杂芳基烷基、环烷基烷基、杂环基烷基、烯基、炔基、烷氧基、烷氨基、杂芳基或杂环基任选地被1、2、3或4个独立选自羟基、氨基、卤素、氰基、羧基、硝基、烷基、卤代烷基、烷氧基烷基、卤代烷氧基烷基、烯基、炔基、烷氧基、卤代烷氧基、烷氧基烷氧基、烷氨基、卤代烷氨基、烷硫基、环烷基、杂环基、芳基和杂芳基中的取代基所取代。 An alkyl group, a heteroalkyl group, an aryl group, wherein R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 14 or R 15 Cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, alkenyl, alkynyl, alkoxy, alkylamino, heteroaryl or heterocyclyl optionally 1, 2, 3 or 4 independently selected from the group consisting of hydroxyl, amino, halogen, cyano, carboxyl, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, Substituents in alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are substituted.
在一些实施例中，G为C 1-10烷基，C 6-12芳基取代的C 1-10烷基，C 1-10烷氧基羰基取代的C 1-10烷基，C 6-12芳基或C 1-10烷基羰基； In some embodiments, 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为C 6-12芳基、C 1-9杂芳基或C 1-10烷基；其中C 6-12芳基或C 1-9杂芳基可任意的被卤素、C 1-6烷基取代； 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为H、氘或C 1-10烷基； R 1 is H, hydrazine or C 1-10 alkyl;
R 4和R 5各自独立地为C 1-10烷基； R 4 and R 5 are each independently C 1-10 alkyl;
R 6和R 7各自独立地为H、氘、C 1-10烷基、C 1-10杂烷基、C 6-10芳基、C 3-10环烷基、C 1-9杂芳基、C 2-9 杂环基、C 6-10芳基C 1-6烷基、C 2-9杂芳基C 1-6烷基、C 3-6环烷基C 1-6烷基或C 2-9杂环基C 1-6烷基； 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为H或C 1-10烷基； R 8 is H or C 1-10 alkyl;
R 9为H、氘、-C(＝O)R 10、-C(＝O)OR 10、C 1-10烷基、C 3-10环烷基、C 2-8杂环基、C 1-9杂芳基或C 6-12芳基； R 9 is H, 氘, -C(=O)R 10 , -C(=O)OR 10 , C 1-10 alkyl, C 3-10 cycloalkyl, C 2-8 heterocyclic, C 1 -9 heteroaryl or C 6-12 aryl;
或R 8和R 9与其相连的N原子一起形成含氮C 2-8杂环基或含氮C 1-9杂芳基； Or 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为C 1-10烷基、C 1-10杂烷基、C 6-12芳基、C 3-10环烷基、C 6-12芳基C 1-10烷基、C 1-9杂芳基C 1-10烷基、C 3-10环烷基C 1-10烷基、C 2-8杂环基C 1-10烷基、C 1-9杂芳基或C 2-8杂环基； 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为H、C 1-10烷基、C 3-8环烷基、C 2-8杂环基、C 1-9杂芳基或C 6-12芳基； 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;
各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、C 1-10烷基、C 1-10卤代烷基、C 1-10烷氧基C 1-10烷基、卤代C 1-10烷氧基C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基、C 1-10卤代烷氧基、C 1-10烷氧基C 1-10烷氧基、C 1-10烷氨基、C 1-10卤代烷氨基、C 1-10烷硫基、C 3-10环烷基、C 2-8杂环基、C 6-12芳基、C 1-9杂芳基、C 6-12芳氧基、C 6-12芳氨基、C 1-9杂芳氧基、羟基取代的C 1-10烷氧基、C 1-10烷基-C(＝O)-、C 1-10烷基-S(＝O)-、C 1-10烷基-S(＝O) 2-、羟基取代的C 1-10烷基-C(＝O)-、羟基取代的C 1-10烷基-S(＝O)-或羟基取代的C 1-10烷基-S(＝O) 2-； Each R 12 is independently H, hydrazine, =O, hydroxy, amino, halogen, cyano, carboxy, nitro, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 alkoxy C 1 -10 alkyl, halo C 1-10 alkoxy C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 haloalkoxy , C 1-10 alkoxy C 1-10 alkoxy, C 1-10 alkylamino, C 1-10 haloalkylamino, C 1-10 alkylthio, C 3-10 cycloalkyl, C 2-8 Heterocyclyl, C 6-12 aryl, C 1-9 heteroaryl, C 6-12 aryloxy, C 6-12 arylamino, C 1-9 heteroaryloxy, hydroxy substituted C 1-10 Alkoxy, C 1-10 alkyl-C(=O)-, C 1-10 alkyl-S(=O)-, C 1-10 alkyl-S(=O) 2 -, hydroxy substituted C 1-10 alkyl-C(=O)-, hydroxy-substituted C 1-10 alkyl-S(=O)- or hydroxy-substituted C 1-10 alkyl-S(=O) 2 -;
R 14和R 15各自独立地为C 1-10烷基、C 3-10环烷基、C 2-8杂环基、C 6-12芳基或C 1-9杂芳基； 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;
其中R 1、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 14或R 15中所述的C 1-10烷基、C 1-10杂烷基、C 6-12芳基、C 3-10环烷基、C 6-12芳基C 1-10烷基、C 1-9杂芳基C 1-10烷基、C 3-10环烷基C 1-10烷基、C 2-8杂环基C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基、C 1-10烷氨基、C 1-9杂芳基或C 2-8杂环基任选地被1、2、3或4个独立选自羟基、氨基、卤素、氰基、羧基、硝基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基C 1-6烷基、C 1-6卤代烷氧基C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷氨基、C 1-6卤代烷氨基、C 1-6烷硫基、C 3-6环烷基、C 1-10杂环基、C 1-10芳基和C 1-10杂芳基中的取代基所取代。 Wherein C 1 1-10 alkyl, C 1- wherein R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 14 or R 15 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 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1- 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, C 1-6 haloalkoxy C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkylamino, C Substituents in the 1-6 alkylthio group, the C 3-6 cycloalkyl group, the C 1-10 heterocyclic group, the C 1-10 aryl group and the C 1-10 heteroaryl group are substituted.
在一些实施例中，本发明提供了一种化合物，具有如式(II’)、(III’)、(IV’)、(V’)、(VI’)、(VII’)、(VIII’)、(IX’)、(IIa’)、(IIIa’)、(IVa’)、(Va’)、(VIa’)、(VIIa’)、(VIIIa’)或(IXa’)所式的结构、或式(II’)、(III’)、(IV’)、(V’)、(VI’)、(VII’)、(VIII’)、(IX’)、(IIa’)、(IIIa’)、(IVa’)、(Va’)、(VIa’)、(VIIa’)、(VIIIa’)或(IXa’)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000004
Figure PCTCN2017119448-appb-000004
Figure PCTCN2017119448-appb-000005
Figure PCTCN2017119448-appb-000005
在一些实施例中，本发明提供了一种化合物，具有如式(I)所示的结构，或式(I)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000006
Figure PCTCN2017119448-appb-000006
其中，among them,
R 1为H、氘或烷基； R 1 is H, hydrazine or alkyl;
R 2为-C(＝O)-(CR 6R 7) n-R 3、-C(＝O)-(CH 2OCH 2) n-R 3、-P(＝O)(OR 4)OR 5； R 2 is -C(=O)-(CR 6 R 7 ) n -R 3 , -C(=O)-(CH 2 OCH 2 ) n -R 3 , -P(=O)(OR 4 )OR 5 ;
或R 2为
Figure PCTCN2017119448-appb-000007
Or R 2 is
Figure PCTCN2017119448-appb-000007
R 3为-NR 8R 9、-M-R 10、-C(＝O)OR 10、-C(＝O)OH、-O-N＝CR 14R 15或-N＝CR 14R 15； R 3 is -NR 8 R 9 , -MR 10 , -C(=O)OR 10 , -C(=O)OH, -ON=CR 14 R 15 or -N=CR 14 R 15 ;
R 4和R 5各自独立地为烷基； R 4 and R 5 are each independently an alkyl group;
R 6和R 7各自独立地为H、氘、烷基、杂烷基、芳基、环烷基、杂芳基、杂环基、芳基烷基、杂芳基烷基、环烷基烷基或杂环基烷基； R 6 and R 7 are each independently H, hydrazine, alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylane Or heterocyclylalkyl;
R 8为H或烷基； R 8 is H or an alkyl group;
R 9为H、氘、-C(＝O)R 10、-C(＝O)OR 10、烷基、环烷基、杂环基、杂芳基或芳基； R 9 is H, hydrazine, -C(=O)R 10 , -C(=O)OR 10 , alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;
或R 8和R 9与其相连的N原子一起形成含氮杂环基或含氮杂芳基； Or 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为烷基、杂烷基、芳基、环烷基、芳基烷基、杂芳基烷基、环烷基烷基、杂环基烷基、杂芳基或杂环基； R 10 is alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, heteroaryl or heterocyclic;
M为
Figure PCTCN2017119448-appb-000008
M is
Figure PCTCN2017119448-appb-000008
W为3-8元含氮杂环、含氮C 5-12稠合杂双环或含氮C 5-12螺杂双环； 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为H、烷基、环烷基、杂环基、杂芳基或芳基； R 11 is H, alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;
各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、烷基、卤代烷基、烷氧基烷基、卤代烷氧基烷基、烯基、炔基、烷氧基、卤代烷氧基、烷氧基烷氧基、烷氨基、卤代烷氨基、烷硫基、环烷基、杂环基、芳基、杂芳基、芳氧基、芳氨基、杂芳氧基、羟基取代的烷氧基、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O) 2-、羟基取代的烷基-C(＝O)-、羟基取代的烷基-S(＝O)-或羟基取代的烷基-S(＝O) 2-； Each R 12 is independently H, hydrazine, =O, hydroxy, amino, halogen, cyano, carboxy, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl , alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, heteroaryl Oxyl, hydroxy substituted alkoxy, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy substituted alkyl-C (= O)-, hydroxy-substituted alkyl-S(=O)- or hydroxy-substituted alkyl-S(=O) 2 -;
R 14和R 15各自独立地为烷基、环烷基、杂环基、芳基或杂芳基； R 14 and R 15 are each independently alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
各n独立地为1、2、3、4或5；和Each n is independently 1, 2, 3, 4 or 5; and
m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
其中R 1、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 14或R 15中所述的烷基、杂烷基、芳基、环烷基、芳基烷基、杂芳基烷基、环烷基烷基、杂环基烷基、烯基、炔基、烷氧基、烷氨基、杂芳基、杂环基任选地被1、2、3或4个独立选自羟基、氨基、卤素、氰基、羧基、硝基、烷基、卤代烷基、烷氧基烷基、卤代烷氧基烷基、烯基、炔基、烷氧基、卤代烷氧基、烷氧基烷氧基、烷氨基、卤代烷氨基、烷硫基、环烷基、杂环基、芳基和杂芳基中的取代基所取代。 An alkyl group, a heteroalkyl group, an aryl group, wherein R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 14 or R 15 Cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, alkenyl, alkynyl, alkoxy, alkylamino, heteroaryl, heterocyclyl optionally 1, 2, 3 or 4 independently selected from the group consisting of hydroxyl, amino, halogen, cyano, carboxyl, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, Substituents in alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are substituted.
在一些实施例中，本发明提供了一种化合物，具有如式(Ia)所示的结构，或式(Ia)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000009
Figure PCTCN2017119448-appb-000009
在一些实施例中，其中，In some embodiments, wherein
R 1为H、氘或C 1-6烷基； R 1 is H, hydrazine or C 1-6 alkyl;
R 4和R 5各自独立地为C 1-6烷基； R 4 and R 5 are each independently C 1-6 alkyl;
R 6和R 7各自独立地为H、氘、C 1-4烷基、C 1-4杂烷基、C 6-10芳基、C 3-6环烷基、C 1-9杂芳基、C 2-9杂环基、C 6-10芳基C 1-6烷基、C 2-9杂芳基C 1-6烷基、C 3-6环烷基C 1-6烷基或C 2-9杂环基C 1-6烷基； 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为H或C 1-6烷基； R 8 is H or C 1-6 alkyl;
R 9为H、氘、-C(＝O)R 10、-C(＝O)OR 10、C 1-6烷基、C 3-6环烷基、C 2-6杂环基、C 1-9杂芳基或C 6-10芳基； R 9 is H, 氘, -C(=O)R 10 , -C(=O)OR 10 , C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 heterocyclic, C 1 -9 heteroaryl or C 6-10 aryl;
或R 8和R 9与其相连的N原子一起形成含氮C 2-6杂环基或含氮C 1-9杂芳基； Or 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为C 1-6烷基、C 1-4杂烷基、C 6-10芳基、C 3-6环烷基、C 6-12芳基C 1-6烷基、C 1-9杂芳基C 1-6烷基、C 3-10环烷基C 1-6烷基、C 2-8杂环基C 1-6烷基、C 1-9杂芳基或C 2-9杂环基；和 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和R 15各自独立地为C 1-6烷基、C 3-6环烷基、C 2-9杂环基、C 6-10芳基或C 1-9杂芳基； 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;
其中R 1、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 14或R 15中所述的C 1-4烷基、C 1-6烷基、C 1-4杂烷基、C 6-10芳基、C 3-6环烷基、C 2-6杂环基、C 6-12芳基C 1-6烷基、C 1-9杂芳基C 1-6烷基、C 3-10环烷基C 1-6烷基、C 2-8杂环基C 1-6烷基、C 1-9杂芳基或C 2-9杂环基任选被1、2、3或4个选自羟基、氨基、F、Cl、Br、I、氰基、羧基、硝基、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基C 1-4烷基、C 1-4卤代烷氧基C 1-4烷基、C 1-4烯基、C 1-4炔基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4烷氨基、C 1-4卤代烷氨基、C 1-4烷硫基、C 3-6环烷基、C 2-9杂环基、C 6-10芳基和C 1-9杂芳基中的取代基所取代。 Wherein C 1 1-4 alkyl, C 1-6 alkyl, C 1 described in R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 14 or R 15 -4 heteroalkyl, C 6-10 aryl, C 3-6 cycloalkyl, C 2-6 heterocyclyl, 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 heterocyclic C 1-6 alkyl, C 1-9 heteroaryl or C 2-9 heterocyclic 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 alkenyl, C 1-4 alkynyl, C 1-4 alkoxy, C 1-4 Haloalkoxy, C 1-4 alkoxy C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkylamino, C 1-4 alkylthio, C 3-6 cycloalkyl, C Substituents in the 2-9 heterocyclyl, C 6-10 aryl and C 1-9 heteroaryl groups are substituted.
在一些实施例中，其中，In some embodiments, wherein
R 1为H、氘、甲基、乙基、正丙基或异丙基； R 1 is H, hydrazine, methyl, ethyl, n-propyl or isopropyl;
R 4和R 5各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基或仲己基； 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和R 7各自独立地为H、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、甲硫基甲基、甲硫基乙基、甲硫基丙基、甲硫基丁基、苯基、萘基、苯基甲基、苯基乙基、甲氧基、2-甲氧基乙基、环丙基、环丁基、环戊基、环己基、噻唑基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、四氢吡咯基或四氢呋喃基； 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为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基或仲己基； 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 9为H、氘、-C(＝O)R 10、-C(＝O)OR 10、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、仲己基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡 喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基、苯基或萘基； R 9 is H, 氘, -C(=O)R 10 , -C(=O)OR 10 , 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, oxiranyl, nitrogen heterocycle Butyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetra Hydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetra Hydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxoalkyl, dithiaalkyl, thiamethane, homopiperazinyl, homopiperidinyl, oxa Cycloheptyl, thiaheptanyl, oxazepine, diaza, thiazepine, porphyrin, 1,2,3,4-tetrahydroisoquinolinyl, furyl, Imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazole , tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1 , 2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5- Thiodidiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothienyl, fluorenyl, fluorenyl, quinolinyl, isoquinolyl , imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazine , [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl,[1,2,4] Triazolo[1,5-a]pyridinyl, phenyl or naphthyl;
或R 8和R 9与其相连的N原子一起形成氮杂环丁基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、高哌嗪基、1,2,3,4-四氢异喹啉基、咪唑基、吡咯基、四唑基、三唑基、吡唑基、嘧啶基、苯并咪唑基、苯并吡唑基、吲哚基、吲哚啉基、吡啶并咪唑基、吡啶并吡唑基、吡啶并吡咯基、哒嗪并咪唑基、嘌呤基或嘧啶并吡唑基； Or 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为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、仲己基、环丙基、环丁基、环戊基、环己基、四氢吡咯基、四氢呋喃基、苯基、萘基、苄基、萘甲基、噻唑基甲基、咪唑基甲基、环戊基甲基、环己基甲基、四氢吡咯基甲基、四氢呋喃基甲基、 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,
Figure PCTCN2017119448-appb-000010
Figure PCTCN2017119448-appb-000010
R 14和R 15各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、苯甲基、甲硫基乙基、苯基、萘基、环丙基、环丁基、环戊基、环己基、
Figure PCTCN2017119448-appb-000011
Figure PCTCN2017119448-appb-000012
Figure PCTCN2017119448-appb-000013
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,
Figure PCTCN2017119448-appb-000011
Figure PCTCN2017119448-appb-000012
Figure PCTCN2017119448-appb-000013
其中R 1、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 14或R 15中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、苯甲基、甲硫基甲基、甲硫基乙基、甲硫基丙基、甲硫基丁基、苯基、萘基、甲氧基、环丙基、环丁基、环戊基、环己基、噻唑基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、四氢吡咯基或四氢呋喃基任选被1、2、3或4个独立选自羟基、氨基、F、Cl、Br、I、氰基、羧基、硝基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、苯基、萘基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、2-噻唑基、4-噻唑基、5-噻唑基、2-噻吩基、2-噻吩基、3-呋喃基、3-呋喃基、2-吡咯基、3-吡咯基、吡啶基、嘧啶基、四氢吡咯基和四氢呋喃基中的取代基所取代。 Wherein methyl, ethyl, n-propyl, isopropyl, n-butyl as described in R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 14 or R 15 Base, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, n-hexyl, isohexyl, benzyl, methylthiomethyl, methylthioethyl, methyl sulfide Propyl, methylthiobutyl, phenyl, naphthyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, thiazolyl, thienyl, furyl, pyrrolyl, pyridyl, The pyrimidinyl, tetrahydropyrrolyl or tetrahydrofuranyl group is optionally 1, 2, 3 or 4 independently selected from the group consisting of hydroxyl, amino, F, Cl, Br, I, cyano, carboxy, nitro, methyl, ethyl, N-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, n-hexyl, isohexyl, phenyl, naphthyl, methoxy , ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-thienyl, 2-thienyl, 3-furyl , 3-furyl, 2-pyrrolyl, 3-pyrrolyl, pyridyl, pyrimidinyl, tetrahydrogen Substituted pyrrolyl group and the tetrahydrofuryl substituted.
在一些实施例中，其中In some embodiments, wherein
W为
Figure PCTCN2017119448-appb-000014
Figure PCTCN2017119448-appb-000015
W is
Figure PCTCN2017119448-appb-000014
Figure PCTCN2017119448-appb-000015
其中，among them,
t 1为1、2、3或4； t 1 is 1, 2, 3 or 4;
t 2、t 3和t 4各自独立地为1、2或3； t 2 , t 3 and t 4 are each independently 1, 2 or 3;
t 5和t 6各自独立地为1、2、3、4或5； t 5 and t 6 are each independently 1, 2, 3, 4 or 5;
t 7为1或2； t 7 is 1 or 2;
k 1、k 2、k 3和k 4各自独立地为0、1或2；其中k 1和k 2不同时为0；k 3和k 4不同时为0；和 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;
各R 13独立地为H、氘、羧基、烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基。 Each R 13 is independently H, oxime, carboxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
在一些实施例中，其中In some embodiments, wherein
W为
Figure PCTCN2017119448-appb-000016
W is
Figure PCTCN2017119448-appb-000016
Figure PCTCN2017119448-appb-000017
Figure PCTCN2017119448-appb-000017
其中，各R 13独立地为H、氘、羧基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 2-6杂环基、C 6-10芳基或C 1-9杂芳基。 Wherein 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.
在一些实施例中，其中，In some embodiments, wherein
R 11为H、C 1-6烷基、C 3-6环烷基、C 2-6杂环基、C 1-9杂芳基或C 6-10芳基； 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;
各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基C 1-6烷基、卤代C 1-6烷氧基C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷氨基、C 1-6卤代烷氨基、C 1-6烷硫基、C 3-6环烷基、C 2-6杂环基、C 6-10芳基、C 1-9杂芳基、C 6-10芳氧基、C 6-10芳氨基、杂C 1-9芳氧基、羟基取代的C 1-6烷氧基、C 1-6烷基-C(＝O)-、C 1-6烷基-S(＝O)-、C 1-6烷基-S(＝O) 2-、羟基取代的C 1-6烷基-C(＝O)-、羟基取代的C 1-6烷基-S(＝O)-或羟基取代的C 1-6烷基-S(＝O) 2-。 Each R 12 is independently H, hydrazine, =0, hydroxy, amino, halogen, cyano, carboxy, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy C 1 -6 alkyl, halo C 1-6 alkoxy C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkylamino, C 1-6 alkylthio, C 3-6 cycloalkyl, C 2-6 Heterocyclyl, C 6-10 aryl, C 1-9 heteroaryl, C 6-10 aryloxy, C 6-10 arylamino, hetero C 1-9 aryloxy, hydroxy substituted C 1-6 Alkoxy, C 1-6 alkyl-C(=O)-, C 1-6 alkyl-S(=O)-, C 1-6 alkyl-S(=O) 2 -, hydroxy substituted C 1-6 alkyl-C(=O)-, hydroxy-substituted C 1-6 alkyl-S(=O)- or hydroxy-substituted C 1-6 alkyl-S(=O) 2 -.
在一些实施例中，其中，In some embodiments, wherein
R 11为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、环丙基、环丁基、环戊基、环己基、吡咯基、吗啉基、哌嗪基或苯基； R 11 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, Orolinyl, piperazinyl or phenyl;
各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、三氟甲基、甲氧基甲基、二氟甲氧基甲基、三氟甲氧基甲基、乙氧基甲基、乙烯基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、甲氨基、乙氨基、苯基氨基、苯氧基、吡咯基、吗啉基或哌嗪基。 Each R 12 is independently H, hydrazine, =O, hydroxy, amino, halogen, cyano, carboxy, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. Butyl, trifluoromethyl, methoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, ethoxymethyl, vinyl, ethynyl, methoxy, ethoxy, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, phenylamino, phenoxy, pyrrolyl, morpholinyl or piperazinyl.
在一些实施例中，本发明提供了一种化合物具有式(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所式的结构、或式(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)或(IX)所示结构的立体异 构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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) An oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
Figure PCTCN2017119448-appb-000018
Figure PCTCN2017119448-appb-000018
在一些实施例中，本发明提供了一种化合物具有式(IIa)、(IIIa)、(IVa)、(Va)、(VIa)、(VIIa)、(VIIIa)或(IXa)所式的结构、或式(IIa)、(IIIa)、(IVa)、(Va)、(VIa)、(VIIa)、(VIIIa)或(IXa)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000019
Figure PCTCN2017119448-appb-000019
Figure PCTCN2017119448-appb-000020
Figure PCTCN2017119448-appb-000020
在一些实施例中，In some embodiments,
各R 1独立地为H、氘或C 1-6烷基； Each R 1 is independently H, hydrazine or C 1-6 alkyl;
各R 6独立地为H、氘、C 1-6烷基、C 1-6杂烷基、C 6-10芳基、C 3-8环烷基、C 1-9杂芳基、C 2-9杂环基、C 6-10芳基C 1-6烷基、C 1-9杂芳基C 1-6烷基、C 3-8环烷基C 1-6烷基或C 2-9杂环基C 1-6烷基； 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;
各R 8独立地为H或C 1-6烷基； Each R 8 is independently H or C 1-6 alkyl;
各R 9独立地为H、氘、-C(＝O)R 10、-C(＝O)OR 10、C 1-6烷基、C 3-8环烷基、C 2-9杂环基、C 1-9杂芳基或C 6-10芳基； Each R 9 is independently H, 氘, -C(=O)R 10 , -C(=O)OR 10 , C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocyclic group , a C 1-9 heteroaryl group or a C 6-10 aryl group;
或R 8和R 9与其相连的N原子一起形成含氮C 2-9杂环基或含氮C 1-9杂芳基 Or 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
各R 10独立地为C 1-6烷基、C 1-6杂烷基、C 6-10芳基、C 3-8环烷基、C 6-10芳基C 1-6烷基、C 1-9杂芳基C 1-6烷基、C 3-10环烷基C 1-6烷基、C 2-9杂环基C 1-6烷基、C 1-9杂芳基或C 2-9杂环基； 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;
各R 11独立地为H、C 1-6烷基、C 3-8环烷基、C 2-9杂环基、C 1-9杂芳基或C 6-10芳基； 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;
各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基C 1-6烷基、卤代C 1-6烷氧基C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷氨基、C 1-6卤代烷氨基、C 1-6烷硫基、C 3-8环烷基、C 2-9杂环基、C 6-10芳基、C 1-9杂芳基、C 6-10芳氧基、C 6-10芳氨基、C 1-9杂芳氧基、羟基取代的C 1-6烷氧基、C 1-6烷基-C(＝O)-、C 1-6烷基-S(＝O)-、C 1-6烷基-S(＝O) 2-、羟基取代的C 1-6烷基-C(＝O)-、羟基取代的C 1-6烷基-S(＝O)-或羟基取代的C 1-6烷基 -S(＝O) 2-； Each R 12 is independently H, hydrazine, =0, hydroxy, amino, halogen, cyano, carboxy, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy C 1 -6 alkyl, halo C 1-6 alkoxy C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkylamino, C 1-6 alkylthio, C 3-8 cycloalkyl, C 2-9 Heterocyclyl, C 6-10 aryl, C 1-9 heteroaryl, C 6-10 aryloxy, C 6-10 arylamino, C 1-9 heteroaryloxy, hydroxy substituted C 1-6 Alkoxy, C 1-6 alkyl-C(=O)-, C 1-6 alkyl-S(=O)-, C 1-6 alkyl-S(=O) 2 -, hydroxy substituted C 1-6 alkyl-C(=O)-, hydroxy-substituted C 1-6 alkyl-S(=O)- or hydroxy-substituted C 1-6 alkyl-S(=O) 2 -;
其中各R 1、R 6、R 8、R 9、R 10、R 11或R 12中的C 1-6烷基、C 1-6杂烷基、C 6-10芳基、C 3-8环烷基、C 1-9杂芳基、C 2-9杂环基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 1-6烷氨基独立任选地被1、2、3或4个羟基、氨基、F、Cl、Br、氰基、羧基、硝基取代。 Wherein 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.
在一些实施例中，In some embodiments,
各R 1独立地为H、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基； Each R 1 is independently H, hydrazine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl;
各R 6独立地为H、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、甲硫基甲基、1-甲硫基乙基、2-甲硫基乙基、1-甲硫基丙基、2-甲硫基丙基、3-甲硫基丙基、1-甲硫基丁基、2-甲硫基丁基、3-甲硫基丁基、4-甲硫基丁基、甲氧基甲基、1-甲氧基乙基、2-甲氧基乙基、1-甲氧基丙基、2-甲氧基丙基、3-甲氧基丙基、1-甲氧基丁基、2-甲氧基丁基、3-甲氧基丁基、4-甲氧基丁基、苯基、萘基、环丙基、环丁基、环戊基、环己基、噻唑基、噻吩基、噁唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、吡咯基、吡啶基、嘧啶基、吡咯烷基、四氢呋喃基、哒嗪基、吡嗪基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、苯基甲基、苯基乙基、2-噻唑基乙基、2-噻吩基乙基、2-噁唑基乙基、2-咪唑基乙基、2呋喃基乙基、2-吡咯烷基乙基、2-四氢呋喃基乙基、2-吗啉基乙基、2-硫代吗啉基乙基、2-环戊基乙基或2-环己基乙基； 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, cyclohexyl, thiazolyl, thienyl, oxazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrrolidine Base, tetrahydrofuranyl, pyridazinyl, pyrazinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenylmethyl, phenylethyl, 2-thiazole Ethyl ethyl, 2-thienylethyl, 2-oxazolylethyl, 2-imidazolylethyl, 2-furylethyl, 2-pyrrolidinylethyl, 2-tetrahydrofuranylethyl 2-morpholinyl, 2- thiomorpholinyl ethyl, 2-cyclopentylethyl or 2-cyclohexylethyl;
各R 8独立地为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基或仲己基； 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;
各R 9独立地为H、氘、-C(＝O)R 10、-C(＝O)OR 10、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、仲己基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基、苯基或萘基； Each R 9 is independently H, hydrazine, -C(=O)R 10 , -C(=O)OR 10 , 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, oxiranyl, Azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuran Base, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyran , tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxoalkyl, dithiaalkyl, thiamethane, homopiperazinyl, homopiperidinyl , oxetanyl, thiaheptanyl, oxazepine, diaza, thiazepine, porphyrin, 1,2,3,4-tetrahydroisoquinolinyl, Furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazine , thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazole 1,1,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2 , 5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothienyl, fluorenyl, fluorenyl, quinolinyl, iso Quinolinyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b Pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl,[1,2 , 4] triazolo[1,5-a]pyridinyl, phenyl or naphthyl;
或R 8和R 9与其相连的N原子一起形成氮杂环丁基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、高哌嗪基、1,2,3,4-四氢异喹啉基、咪唑基、吡咯基、四唑基、三唑基、吡唑基、嘧啶基、苯并咪唑基、苯并吡唑基、吲哚基、吲哚啉基、吡啶并咪唑 基、吡啶并吡唑基、吡啶并吡咯基、哒嗪并咪唑基、嘌呤基或嘧啶并吡唑基； Or 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;
各R 10独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、仲己基、环丙基、环丁基、环戊基、环己基、四氢吡咯基、四氢呋喃基、苯基、萘基、苄基、萘甲基、噻唑基甲基、咪唑基甲基、环戊基甲基、环己基甲基、四氢吡咯基甲基、四氢呋喃基甲基、
Figure PCTCN2017119448-appb-000021
Figure PCTCN2017119448-appb-000022
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,
Figure PCTCN2017119448-appb-000021
Figure PCTCN2017119448-appb-000022
各R 11独立地为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、环丙基、环丁基、环戊基、环己基、吡咯基、吗啉基、哌嗪基或苯基； 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;
各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、三氟甲基、甲氧基甲基、二氟甲氧基甲基、三氟甲氧基甲基、乙氧基甲基、乙烯基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、甲氨基、乙氨基、苯基氨基、苯氧基、吡咯基、吗啉基或哌嗪基； Each R 12 is independently H, hydrazine, =O, hydroxy, amino, halogen, cyano, carboxy, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. Butyl, trifluoromethyl, methoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, ethoxymethyl, vinyl, ethynyl, methoxy, ethoxy, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, phenylamino, phenoxy, pyrrolyl, morpholinyl or piperazinyl;
其中R 1、R 6、R 8、R 9、R 10、R 11或R 12中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、甲硫基甲基、1-甲硫基乙基、2-甲硫基乙基、1-甲硫基丙基、2-甲硫基丙基、3-甲硫基丙基、1-甲硫基丁基、2-甲硫基丁基、3-甲硫基丁基、4-甲硫基丁基、甲氧基甲基、1-甲氧基乙基、2-甲氧基乙基、1-甲氧基丙基、2-甲氧基丙基、3-甲氧基丙基、1-甲氧基丁基、2-甲氧基丁基、3-甲氧基丁基、4-甲氧基丁基、苯基、萘基、环丙基、环丁基、环戊基、环己基、噻唑基、噻吩基、噁唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、吡咯基、吡啶基、嘧啶基、吡咯烷基、四氢呋喃基、哒嗪基、吡嗪基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、苯基甲基、苯基乙基、2-噻唑基乙基、2-噻吩基乙基、2-噁唑基乙基、2-咪唑基乙基、2呋喃基乙基、2-吡咯烷基乙基、2-四氢呋喃基乙基、2-吗啉基乙基、2-硫代吗啉基乙基、2-环戊基乙基或2-环己基乙基各自独立任选被1、2、3或4个独立选自羟基、氨基、F、Cl、Br、I、氰基、羧基或硝基。 Wherein methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl groups as described in R 1 , R 6 , R 8 , R 9 , R 10 , R 11 or R 12 , methylthiomethyl, 1-methylthioethyl, 2-methylthioethyl, 1-methylthiopropyl, 2-methylthiopropyl, 3-methylthiopropyl, 1-methyl Thiobutyl, 2-methylthiobutyl, 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, cyclohexyl, thiazolyl, thienyl, oxazolyl, imidazolyl, triazolyl, tetrazolyl , furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, pyridazinyl, pyrazinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine Base, phenylmethyl, phenylethyl, 2-thiazolylethyl, 2-thienylethyl, 2-oxazolylethyl, 2-imidazolylethyl, 2-furylethyl, 2-pyrrole alkyl Ethyl ethyl, 2-tetrahydrofuranylethyl, 2-morpholinylethyl, 2-thiomorpholinylethyl, 2-cyclopentylethyl or 2-cyclohexylethyl are each independently optionally 2, 3 or 4 are independently selected from the group consisting of hydroxyl, amino, F, Cl, Br, I, cyano, carboxyl or nitro.
在一些实施例中，本发明提供了一种化合物具有如下结构之一，或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, the invention provides a compound having one of the following structures, or a stereoisomer, tautomer, oxynitride, solvate, metabolite, pharmaceutically acceptable salt or pre- medicine,
Figure PCTCN2017119448-appb-000023
Figure PCTCN2017119448-appb-000023
Figure PCTCN2017119448-appb-000024
Figure PCTCN2017119448-appb-000024
Figure PCTCN2017119448-appb-000025
Figure PCTCN2017119448-appb-000025
Figure PCTCN2017119448-appb-000026
Figure PCTCN2017119448-appb-000026
Figure PCTCN2017119448-appb-000027
Figure PCTCN2017119448-appb-000027
Figure PCTCN2017119448-appb-000028
Figure PCTCN2017119448-appb-000028
Figure PCTCN2017119448-appb-000029
Figure PCTCN2017119448-appb-000029
另一方面，本发明提供了一种药物组合物，其包含本发明所述的化合物，及药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或其组合。In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.
在一些实施例中，本发明所述的药物组合物进一步包含其他抗HCV的药物，其中所述抗HCV的药物为干扰素利巴韦林、白介素2、白介素6、白介素12、促进产生1型辅助性T细胞应答的化合物、干扰RNA、反义RNA、咪喹莫德、肌苷5’-单磷酸脱氢酶抑制剂、金刚烷胺、金刚乙胺、巴维昔单抗、丙型肝炎免疫球蛋白、civacir、波普瑞韦、替拉瑞韦、埃罗替尼、达卡他韦、司美匹韦、阿那匹韦、西鲁瑞韦、丹诺普韦、雷迪帕韦、硝唑尼特、奈韦拉平、阿拉泊韦、依米他韦、vaniprevir、faldaprevir、paritaprevir、sovaprevir、grazoprevir、elbasvir、vedroprevir、narlaprevir、ombitasvir、ravidasvir、velpatasvir、samatasvir、elbasvir、alisporivir、modithromycin、mericitabine、nesbuvir、lomibuvir、setrobuvir、dasabuvir、filibuvir、deleobuvir、tegobuvir、odalasvir、ritonavir、alloferon、nivolumab、multiferon、pibrentasvir、glecaprevir、procvax、miravirsen、EDP239、ANA975、MK-8325、BZF-961、GS-9256、GSK-2336805、PPI-461、ACH-1095、VX-985、IDX-375、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX-316、VBY-376、TMC-649128、INX-189、IDX-184、IDX102、R1479、UNX-08189、PSI-6130、PSI-938、PSI-879、HCV-371、VCH-916、MK-3281、ABT-072、A-837093、JKT-109、Gl-59728、GL-60667、AZD-2795、TMC647055、WF-10、ACH-3422、MK-3682、MK-8408、GS-9857、CD-AdNS3、RG-101、BZF-961、INO-8000、MBL-HCV1、CIGB-230、TG-2349、CB-5300、chronvac-C、MK-1075、ACH-0143422、WS-007、MK-7680、MK-2248、MK-8408、IDX-21459、AV-4025、MK-8876、GSK-2878175、MBX-700、AL-335、JNJ-47910382、AL-704、ABP-560、TD-6450、EDP-239、SB-9200、ITX-5061、ID-12、或其任意组合。In some embodiments, 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, vedroprevir, narlaprevir, ombitasvir, ravidasvir, velpatasvir, samatasvir, elbasvir, alistorivir, modithromycin, mericitabine, nesbuvir , lomibuvir, setrobuvir, dasabuvir, filibuvir, deleobuvir, tegobuvir, odalasvir, ritonavir, alloferon, nivolumab, multiferon, pibrentasvir, glecaprevir, pr Ocvax, miravirsen, EDP239, ANA975, MK-8325, BZF-961, GS-9256, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX- 1766, PHX-2054, IDX-136, IDX-316, VBY-376, TMC-649128, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-371, VCH-916, MK-3281, ABT-072, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, WF-10, ACH-3422, MK-3682, MK-8408, GS-9857, CD-AdNS3, RG-101, BZF-961, INO-8000, MBL-HCV1, CIGB-230, TG-2349, CB-5300, chronvac-C, MK-1075, ACH- 0143422, WS-007, MK-7680, MK-2248, MK-8408, IDX-21459, AV-4025, MK-8876, GSK-2878175, MBX-700, AL-335, JNJ-47910382, AL-704, ABP-560, TD-6450, EDP-239, SB-9200, ITX-5061, ID-12, or any combination thereof.
另一方面，本发明提供了一种本发明所述化合物或药物组合物在制备药物中的用途，所述药物用于预防、处理、治疗或减轻患者的HCV感染或丙型肝炎疾病。In another aspect, 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.
另一方面，本发明提供了一种本发明所述化合物或药物组合物在制备药物中的用途，所述药物用于抑制HCV复制过程和/或抑制HCV病毒蛋白的功能；所述HCV复制过程包括HCV进入、HCV脱壳、HCV 翻译、HCV复制、HCV组装或HCV释放；所述的HCV病毒蛋白选自金属蛋白酶、NS2、NS3、NS4A、NS4B、NS5A或NS5B，以及HCV病毒复制所需要的内部核糖体进入点(IRES)和肌苷单磷酸脱氢酶(IMPDH)。In another aspect, 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).
在一些实施例中，本发明提供了一种本发明所述化合物或药物组合物在制备药物中的用途，所述药物用于抑制HCV病毒蛋白的功能；所述的HCV病毒蛋白为NS5B。In some embodiments, 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.
另一方面，本发明提供了一种本发明所述化合物或药物组合物用于预防、处理、治疗或减轻患者的HCV感染或丙型肝炎疾病的用途。In another aspect, 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.
另一方面，本发明提供了一种本发明所述化合物或药物组合物用于抑制HCV复制过程和/或抑制HCV病毒蛋白的功能；所述HCV复制过程包括HCV进入、HCV脱壳、HCV翻译、HCV复制、HCV组装或HCV释放；所述的HCV病毒蛋白选自金属蛋白酶、NS2、NS3、NS4A、NS4B、NS5A或NS5B，以及HCV病毒复制所需要的内部核糖体进入点(IRES)和肌苷单磷酸脱氢酶(IMPDH)。In another aspect, 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).
在一些实施例中，本发明提供了一种本发明所述化合物或药物组合物用于抑制HCV病毒蛋白的功能；所述的HCV病毒蛋白为NS5B。In some embodiments, 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.
另一方面，本发明提供了一种预防、处理、治疗或减轻患者的HCV感染或丙型肝炎疾病的方法，包括给予患者有效治疗量的本发明所述化合物或药物组合物。In another aspect, 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.
另一方面，本发明提供了一种抑制HCV复制过程和/或抑制HCV病毒蛋白的功能的方法，包括给予患者有效治疗量的本发明所述化合物或药物组合物；所述HCV复制过程包括HCV进入、HCV脱壳、HCV翻译、HCV复制、HCV组装或HCV释放；所述的HCV病毒蛋白选自金属蛋白酶、NS2、NS3、NS4A、NS4B、NS5A或NS5B，以及HCV病毒复制所需要的内部核糖体进入点(IRES)和肌苷单磷酸脱氢酶(IMPDH)。In another aspect, 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).
在一些实施例中，本发明提供了一种抑制HCV病毒蛋白的功能的方法，包括给予患者有效治疗量的本发明所述化合物或药物组合物；所述的HCV病毒蛋白为NS5B。In some embodiments, 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.
本发明另一方面涉及式(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)、(Va)、(VIa)、(VIIa)、(VIIIa)、或(IXa)所包含的化合物的制备、分离和纯化的方法。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).
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他的方面的内容将在下面作更加具体完整的描述。The foregoing description merely summarizes certain aspects of the invention, but is not limited thereto. These and other aspects are described in more detail below.
本发明的详细说明书Detailed description of the invention
定义和一般术语Definitions and general terms
除非另有说明，本发明所用在说明书和权利要求书中的术语具有下述定义。Unless otherwise stated, the terms used in the specification and claims of the invention have the following definitions.
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。Some embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and formulas. The invention is intended to cover all alternatives, modifications, and equivalents, which are within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the invention. The invention is in no way limited to the methods and materials described herein. Where one or more of the incorporated literature, patents, and similar materials are different or inconsistent with the present application (including but not limited to defined terms, terminology applications, described techniques, etc.), The application shall prevail.
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。It will be further appreciated that certain features of the invention are described in the various embodiments of the invention, and may be described in combination in a single embodiment. On the contrary, the various features of the invention are described in a single embodiment for the sake of brevity, but may be provided separately or in any suitable sub-combination.
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。Unless otherwise stated, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art. All patents and publications related to the present invention are hereby incorporated by reference in their entirety.
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考＂Organic Chemistry＂,Thomas Sorrell,University Science Books,Sausalito:1999,和＂March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。The following definitions used herein should be applied unless otherwise stated. For the purposes of the present invention, chemical elements are consistent with the CAS version of the Periodic Table of the Elements, and the Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, the general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007. , the entire contents of which is incorporated herein by reference.
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。The articles "a", "an" and "the" Therefore, the articles used herein are used to refer to the articles of one or more than one (ie, at least one). For example, "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.
本发明所使用的术语“受试对象”是指动物。典型地所述动物是哺乳动物。受试对象，例如也指灵长类动物(例如人类，男性或女性)、牛、绵羊、山羊、马、犬、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中，所述受试对象是灵长类动物。在其他实施方案中，所述受试对象是人。The term "subject" as used herein 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.
本发明说使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中，“患者”是指人。The term "patient" as used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term "comprising" is an open-ended expression that includes the subject matter of the invention, but does not exclude other aspects.
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。"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. .
“手性”是具有与其镜像不能重叠性质的分子；而“非手性”是指与其镜像可以重叠的分子。"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.
“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具 有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。"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.
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。The stereochemical definitions and rules used in the present invention generally follow SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry Of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。在描述光学活性化合物时，使用前缀D和L或R和S来表示分子关于其一个或多个手性中心的绝对构型。前缀d和l或(+)和(-)是用于指定化合物所致平面偏振光旋转的符号，其中(-)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或过程中没有立体选择性或立体特异性时，可出现这种情况。Many organic compounds exist in optically active forms, i.e., they have the ability to rotate a plane of plane polarized light. In describing optically active compounds, 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.
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。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. In certain embodiments, 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.
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对映异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性试剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能有顺式或反式构型。Depending on the choice of starting materials and methods, 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.
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。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.
除非其他方面表明，本发明所描述的结构式包括所有的同分异构形式(如对映异构，非对映异构，和几何异构(或构象异构)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体，和(Z)、(E)的构象异构体。因此，本发明的化合物的单个立体化学异构体或其对映异构体，非对映异构体，或几何异构体(或构象异构体)的混合物都属于本发明的范围。Unless otherwise indicated, 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). Thus, 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.
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible  Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al,Prodrugs：Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。 The term "prodrug" as used in the present invention 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. In the prior invention, 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. For example, 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. For a discussion of the completeness of prodrugs, refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2 nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。 The 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. In particular, 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. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p. 268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。The term "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. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton transfer, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some bonding electrons. A specific example of 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.
本发明所提到的盐为药学上可接受的盐，其中“药学上可接受的盐”在所属领域是为我们所熟知的，如文献：Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmacol Sci,1997,66,1-19所记载的。药学上可接受的非限定性的盐例子包括与氨基基团反应形成的无机酸盐，如有盐酸盐、氢溴酸盐、磷酸盐、偏磷酸盐、硫酸盐、亚硫酸盐、硝酸盐、高氯酸盐，和有机酸盐，如羧酸盐、磺酸盐、亚磺酸盐、硫羧酸盐等，具体的如，但不限于，甲磺酸盐、乙磺酸盐、甲酸盐、乙酸盐、丁二酸盐、苯甲酸盐、琥珀酸盐、双羟萘酸盐、水杨酸盐、半乳糖二酸盐、葡庚酸盐、扁桃酸盐、1,2-乙烷基二磺酸盐、2-萘磺酸盐、碳酸盐、三氟乙酸盐、羟基乙酸盐、羟乙基磺酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐、苯磺酸盐、对甲苯磺酸盐、苹果酸盐、富马酸盐、乳酸盐、乳糖酸盐或草酸，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、葡庚糖酸盐、甘油磷酸盐、萄糖酸盐、半硫酸盐、庚酸盐、己 酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、月桂酸盐、月桂基硫酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、十一酸盐、戊酸盐，等等。此外，药学上可接受的盐还包括通过适当的碱得到的盐，如碱金属、碱土金属、铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。 The 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. Examples of pharmaceutically acceptable non-limiting salts include inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, metaphosphates, sulfates, sulfites, nitrates. , perchlorate, and 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. Other pharmaceutically acceptable 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. Wait. Further, 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 . 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.
可药用的盐可与无机酸和有机酸形成，例如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、氯茶碱盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。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, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalactinate, propionate, stearate, succinate, sulfosalicyrate, tartrate, toluene Acid salts and trifluoroacetate salts.
可以由其衍生得到盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
可以由其衍生得到盐的有机酸包括例如乙酸、丙酸、羟基乙酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、磺基水杨酸等。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.
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。"Solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention. Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" means that the solvent molecule is an association formed by water.
术语“保护基团”或“PG”是指一个取代基与别的官能团起反应的时候，通常用来阻断或保护特殊的功能性。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，合适的氨基保护基团包括乙酰基，三氟乙酰基，叔丁氧羰基(BOC)，苄氧羰基(CBZ)和9-芴亚甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括乙酰基和甲硅烷基。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH 2CH 2SO 2Ph，氰基乙基，2-(三甲基硅烷基)乙基，2-(三甲基硅烷基)乙氧基甲基，2-(对甲苯磺酰基)乙基，2-(对硝基苯磺酰基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。对于保护基团一般的描述可参考文献：T.W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；和P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005。 The term "protecting group" or "PG" refers to a substituent that is typically used to block or protect a particular functionality when reacted with other functional groups. For example, "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). Similarly, 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.
“药物组合物”表示一种或多种本文所述化合物的盐或者其生理学上/药学上可以接受的盐或前体药物与其他化学组分的混合物，其他组分例如生理学上/药学上可以接受的载体或赋形剂。药物组合物的目的是促进化合物对生物体的给药。"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.
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。The term "treating" any disease or condition as used in the present invention, in some embodiments thereof, 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). In other embodiments, "treating" refers to alleviating or ameliorating at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "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. In other embodiments, "treating" refers to preventing or delaying the onset, onset, or exacerbation of a disease or condition.
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构，除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如 2H， 3H， 11C， 13C， 14C， 15N， 17O， 18O， 18F， 31P， 32P， 35S， 36Cl和 125I。 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.
另一方面，本发明所述化合物包括同位素富集的本发明所定义的化合物，例如，其中存在放射性同位素，如 3H， 14C和 18F的那些化合物，或者其中存在非放射性同位素，如 2H和 13C。该类同位素富集的化合物可用于代谢研究(使用 14C)、反应动力学研究(使用例如 2H或 3H)、检测或成像技术，如正电子发射断层扫描术(PET)或包括药物或底物组织分布测定的单光子发射计算机断层成像术(SPECT)，或可用于患者的放疗中。 18F富集的化合物对PET或SPECT研究而言是特别理想的。同位素富集的式(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)、(Va)、(VIa)、(VIIa)、(VIIIa)、或(IXa)所示化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素标记试剂替代原来使用过的未标记试剂来制备。 In another aspect, 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. Such 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. Isotopically enriched 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), (Va) The compound of (VIa), (VIIa), (VIIIa), or (IXa) may be replaced by a suitable isotopically labeled reagent as described by conventional techniques familiar to those skilled in the art or in the examples and preparations of the present invention. Prepared using unlabeled reagents.
此外，较重同位素特别是氘(即， 2H或D)的取代可提供某些治疗优点，这些优点是由代谢稳定性更高带来的。例如，体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。应当理解，本发明中的氘被看做式(I)化合物的取代基。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。本发明所使用的术语“同位素富集因子”是指所指定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物的取代基被指定为氘，该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5％的氘掺入)、至少4000(60％的氘掺入)、至少4500(67.5％的氘掺入)，至少5000(75％的氘掺入)，至少5500(82.5％的氘掺入)、至少6000(90％的氘掺入)、至少6333.3(95％的氘掺入)、至少6466.7(97％的氘掺入)、至少6600(99％的氘掺入)或至少6633.3(99.5％的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D 2O、丙酮-d 6、DMSO-d 6的那些溶剂化物。 In addition, substitution of heavier isotopes, particularly deuterium (i.e., 2 H or D), 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. It should be understood that 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. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotope abundance and the natural abundance of a given isotope. If 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.
如本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者如实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或未取代的”这个术语可以交换使用。一般而言，术语“任选地”不论是否位于术语“取代的”之前，表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表 明，一个任选的取代基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是，但并不限于，氘，羟基，氨基，卤素，氰基，芳基，杂芳基，烷氧基，烷氨基，烷硫基，烷基，烯基，炔基，杂环基，巯基，硝基，芳氧基，杂芳氧基，氧代(＝O)，羧基，羟基取代的烷氧基，羟基取代的烷基-C(＝O)，烷基-C(＝O)，烷基-S(＝O)，烷基-S(＝O) 2-，羟基取代的烷基-S(＝O)，羟基取代的烷基-S(＝O) 2，羧基烷氧基等等。 As described herein, 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. A class of compounds. It should 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. 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. , heterocyclyl, fluorenyl, nitro, aryloxy, heteroaryloxy, oxo (=O), carboxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O), alkyl -C(=O), alkyl-S(=O), alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O) 2 , carboxy alkoxy and the like.
本发明使用的术语“烷基”表示1-20个碳原子，或1-10个碳原子，或1-8个碳原子，或1-6个碳原子，或1-4个碳原子，或1-3个碳原子的饱和直链或支链的单价烃基，其中烷基可以独立且任选地被一个或多个本发明所描述的取代基所取代。烷基的实例包括，但并不限于，甲基(Me，-CH 3)，乙基(Et，-CH 2CH 3)，正丙基(n-Pr，-CH 2CH 2CH 3)，异丙基(i-Pr，-CH(CH 3) 2)，正丁基(n-Bu，-CH 2CH 2CH 2CH 3)，异丁基(i-Bu，-CH 2CH(CH 3) 2)，仲丁基(s-Bu，-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu，-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2，3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3，3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)，正庚基，正辛基，等等。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。术语“烷撑”在此处使用，表示从直链或支链饱和碳氢化物消去两个氢原子得到的饱和二价烃基，这样的实例包括，但并不限于，亚甲基，次乙基，次异丙基等等。 The term "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. Examples of 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(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2- Methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ) , 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2 -butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ) , n-heptyl, Just octyl, and so on. The term "alkyl" and its prefix "alk" are used herein to encompass both straight-chain and branched saturated carbon chains. The term "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.
术语“杂烷基”表示烷基链中间可以插入一个或多个杂原子，其中烷基基团和杂原子具有如本发明所述的含义。除非另外详细说明，杂烷基基团含有1-10个碳原子，另外一些实施方案是，杂烷基基团含有1-8个碳原子，另外一些实施方案是，杂烷基基团含有1-6个碳原子，另外一些实施方案是，杂烷基基团含有1-4个碳原子，另外一些实施方案是，杂烷基基团含有1-3个碳原子。这样的实例包括，但并不限于，CH 3OCH 2-，CH 3CH 2OCH 2-，CH 3SCH 2-，CH 3SCH 2CH 2-，(CH 3) 2NCH 2-，(CH 3) 2CH 2OCH 2-，CH 3OCH 2CH 2-，CH 3CH 2OCH 2CH 2-等。 The term "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. Unless otherwise specified, a heteroalkyl group contains from 1 to 10 carbon atoms, and in other embodiments, a heteroalkyl group contains from 1 to 8 carbon atoms. In still other embodiments, 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.
本发明中所使用的术语“烷氧基”，涉及烷基，如本发明所定义的，通过氧原子连接到主要的碳链上，这样的实例包括，但并不限于甲氧基，乙氧基，丙氧基，丁氧基等。并且所述烷氧基可以是取代或未取代的，其中取代基可以是，但并不限于，羟基，氨基，卤素，氰基，烷氧基，烷基，烯基，炔基，巯基，硝基等等。The term "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. And 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.
术语“烯基”表示2-12个碳原子，或2-8个碳原子，或2-6个碳原子，或2-4个碳原子的直链或 支链的一价烃基，其中至少一个位置为不饱和状态，即一个C-C为sp 2双键，其中烯基基团可以独立且任选地被一个或多个本发明所描述的取代基所取代，包括基团有“反”，“顺”或“E”，“Z”的定位，其中烯基具体的实例包括，但并不限于，乙烯基(-CH＝CH 2)，烯丙基(-CH 2CH＝CH 2)，等等。 The term "alkenyl" denotes 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, i.e., one CC is a sp 2 double bond, wherein the alkenyl group can be independently and optionally substituted with one or more substituents described herein, including the group having "reverse", The positioning of "S" or "E", "Z", wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), etc. Wait.
术语“炔基”表示2-12个碳原子，或2-8个碳原子，或2-6个碳原子，或2-4个碳原子的直链或支链的一价烃基，其中至少一个位置为不饱和状态，即一个C-C为sp三键，其中炔基基团可以独立且任选地被一个或多个本发明所描述的取代基所取代，其中炔基具体的实例包括，但并不限于，乙炔基(-C≡CH)，炔丙基(-CH 2C≡CH)，等等。 The term "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.
术语“环烷基”是指一价或多价，非芳香族，饱和或部分不饱和的环，且不包含杂原子，其中包括3-12个碳原子的单环或7-12个碳原子的二环。具有7-12个原子的双环碳环可以是二环[4,5]，[5,5]，[5,6]或[6,6]体系，同时具有9或10个原子的双环碳环可以是二环[5,6]或[6,6]体系。合适的环状脂肪族基包括，但并不限于，环烷基，环烯基和环炔基。环状脂肪族基的实例包括，但绝不限于，环丙基，环丁基，环戊基，1-环戊基-1-烯基，1-环戊基-2-烯基，1-环戊基-3-烯基，环己基，1-环己基-1-烯基，1-环己基-2-烯基，1-环己基-3-烯基，环己二烯基，环庚基，环辛基，环壬基，环癸基，环十一烷基，环十二烷基等等。并且所述“环状脂肪族基”或“碳环”、“碳环基”、“环烷基”可以是取代或未取代的，其中取代基可以是，但并不限于，羟基，氨基，卤素，氰基，芳基，杂芳基，烷氧基，烷氨基，烷基，烯基，炔基，杂环基，巯基，硝基，芳氧基，羟基取代的烷氧基，羟基取代的烷基-C(＝O)，烷基-C(＝O)，烷基-S(＝O)，烷基-S(＝O) 2-，羟基取代的烷基-S(＝O)，羟基取代的烷基-S(＝O) 2，羧基烷氧基等等。 The term "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. And the "cyclic aliphatic group" or "carbocyclic ring", "carbocyclic group", "cycloalkyl group" may be substituted or unsubstituted, wherein the substituent may be, but not limited to, a hydroxyl group, an amino group, Halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, fluorenyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted Alkyl-C(=O), alkyl-C(=O), alkyl-S(=O), alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O) a hydroxy-substituted alkyl-S(=O) 2 , a carboxy alkoxy group or the like.
术语“杂环”，“杂环基”，“杂脂环族”或“杂环的”在此处可交换使用，都是指单环，双环，或三环体系，其中环上一个或多个碳原子独立且任选地被杂原子所取代，所述杂原子具有如本发明所述的含义，环可以是完全饱和的或包含一个或多个不饱和度，但绝不是芳香族类，只有一个连接点连接到其他分子上去。一个或多个环上的氢原子独立且任选地被一个或多个本发明所描述的取代基所取代。其中一些实施方案是，“杂环”，“杂环基”，“杂脂环族”或“杂环的”基团是3-7元环的单环(1-6个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到例如SO，SO 2，PO，PO 2的基团，当所述的环为三元环时，其中只有一个杂原子)，或7-10元的双环(4-9个碳原子和选自N，O，P，S的1-3个杂原子，在此S或P任选地被一个或多个氧原子所取代得到例如SO，SO 2，PO，PO 2的基团)。 The terms "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" are used interchangeably herein to refer 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. In some embodiments, 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 ).
杂环基可以是碳基或杂原子基。“杂环基”同样也包括杂环基团与饱和或部分不饱和环或杂环并合所形成的基团。杂环的实例包括，但并不限于，吡咯烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，四氢吡喃基，二氢吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，噻噁烷基，噻唑烷基，噁唑烷基，哌嗪基，高哌嗪基，氮杂环丁基，氧杂环丁基，硫杂环丁基，哌啶基，高哌啶基，环氧丙基，氮杂环庚基，氧杂环庚基，硫杂环庚基，4-甲氧基-哌啶-1-基，1,2,3,6-四氢吡啶-1-基，氧氮杂
Figure PCTCN2017119448-appb-000030
基，二氮杂
Figure PCTCN2017119448-appb-000031
基，硫氮杂
Figure PCTCN2017119448-appb-000032
基，吡咯啉-1-基，2-吡咯啉基，3-吡咯啉基，二氢吲哚基，2H-吡喃基，4H-吡喃基，二氧杂环己基，1,3-二氧戊基，吡唑啉基，二噻烷基，二噻茂烷基，二氢噻吩基，吡唑烷基咪唑啉基，咪唑烷基，1,2,3,4-四氢异喹啉基，1,2,6-噻二嗪烷1,1-二氧代-2-基，4-羟基-1,4-氮杂磷烷4-氧化物-1-基，2-羟基-1-(哌嗪-1-基)乙酮-4-基，2-羟基-1-(5,6-二氢-1,2,4-三嗪-1(4H)-基)乙酮-4-基，5,6-二氢-4H-1,2,4-噁二嗪-4-基，2-羟基-1-(5,6-二氢吡啶-1(2H)-基)乙酮-4-基，3-氮杂双环[3.1.0]己基，3-氮杂双环[4.1.0]庚基，氮杂双环[2.2.2]己基，2-甲基-5,6,7,8-四氢-[1,2,4]三唑[1,5-c]嘧啶-6-基，4,5,6,7-四氢异噁唑[4,3-c]吡啶-5-基，3H-吲哚基2-氧-5-氮杂双环[2.2.1]庚烷-5-基，2-氧-5-氮杂双环[2.2.2]辛烷-5-基，喹嗪基和N-吡啶基尿素。杂环基团的实例还包括，1,1-二氧代硫代吗啉基，和其中环上两个碳原子被氧原子所取代如嘧啶二酮基。并且所述杂环基可以是取代或未取代的，其中取代基可以是，但并不限于，氧代(＝O)，羟基，氨基，卤素，氰基，杂芳基，烷氧基，烷氨基，烷基，烯基，炔基，杂环基，巯基，硝基，芳氧基，羟基取代的烷氧基，羟基取代的烷基-C(＝O)，烷基-C(＝O)，烷基-S(＝O)，烷基-S(＝O) 2-，羟基取代的烷基-S(＝O)，羟基取代的烷基-S(＝O) 2，羧基烷氧基等等。 The 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, oxetanyl, thietyl, 4-methoxy-piperidin-1-yl, 1,2, 3,6-tetrahydropyridin-1-yl, oxaza
Figure PCTCN2017119448-appb-000030
Diaza
Figure PCTCN2017119448-appb-000031
Thioaza
Figure PCTCN2017119448-appb-000032
, pyrroline-1-yl, 2-pyrroline, 3-pyrolinyl, indanyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3- Oxypentyl, pyrazolinyl, dithiaalkyl, dithialimyl, dihydrothienyl, pyrazolidinyl imidazolyl, imidazolidinyl, 1,2,3,4-tetrahydroisoquinoline 1,1,6-thiadiazinidine 1,1-dioxo-2-yl, 4-hydroxy-1,4-azaphosphazene 4-oxide-1-yl, 2-hydroxy-1 -(piperazin-1-yl)ethanone-4-yl, 2-hydroxy-1-(5,6-dihydro-1,2,4-triazin-1(4H)-yl)ethanone-4 -yl,5,6-dihydro-4H-1,2,4-oxadiazin-4-yl, 2-hydroxy-1-(5,6-dihydropyridine-1(2H)-yl)ethanone 4-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-methyl-5,6,7 , 8-tetrahydro-[1,2,4]triazolo[1,5-c]pyrimidin-6-yl,4,5,6,7-tetrahydroisoxazole [4,3-c]pyridine- 5-Based, 3H-indenyl 2-oxo-5-azabicyclo[2.2.1]heptane-5-yl, 2-oxo-5-azabicyclo[2.2.2]octane-5-yl , quinoxazinyl and N-pyridyl urea. Examples of the 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. And the heterocyclic group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, oxo (=O), hydroxy, amino, halogen, cyano, heteroaryl, alkoxy, alkane Amino, alkyl, alkenyl, alkynyl, heterocyclyl, decyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O), alkyl-C(=O ), alkyl-S(=O), alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O) 2 , carboxyalkoxy Base and so on.
具体的，杂环基还可以是以下结构：
Figure PCTCN2017119448-appb-000033
Figure PCTCN2017119448-appb-000034
Specifically, the heterocyclic group may also be the following structure:
Figure PCTCN2017119448-appb-000033
Figure PCTCN2017119448-appb-000034
术语“芳基”可以单独使用或作为“芳烷基”，“芳烷氧基”或“芳氧基烷基”的一大部分，表示共含有6-14元环的单环，双环，和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7元环，且只有一个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用，如芳香环可以包括苯基，萘基和蒽基。并且所述芳基可以是取代或未取代的，其中取代基可以是，但并不限于，羟基，氨基，卤素，氰基，芳基，杂芳基，烷氧基，烷氨基，烷基，烯基，炔基，杂环基，巯基，硝基，芳氧基，羟基取代的烷氧基，羟基取代的烷基-C(＝O)，烷基-C(＝O)，烷基-S(＝O)，烷基-S(＝O) 2-，羟基取代的烷基-S(＝O)，羟基取代的烷基-S(＝O) 2，羧基烷氧基，等等。 The term "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. The term "aryl" may be used interchangeably with the term "aromatic ring", and the aromatic ring may include phenyl, naphthyl and anthracenyl. And the aryl 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, Alkenyl, alkynyl, heterocyclyl, decyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O), alkyl-C(=O), alkyl- S(=O), alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O), hydroxy-substituted alkyl-S(=O) 2 , carboxyalkoxy, and the like.
术语“杂芳基”表示共含有5-14元环的单环，双环，和三环体系，其中至少一个环体系是芳香族的，且至少一个环体系包含一个或多个杂原子，其中杂原子具有本发明所述的含义，其中每一个环体系包含3-7元环，且只有一个附着点与分子其余部分相连。术语“杂芳基”可以与术语“芳杂环”或“杂芳族化合物”交换使用。并且所述杂芳基可以是取代或未取代的，其中取代基可以是，但并不限于，羟基，氨基，卤素，氰基，芳基，杂芳基，烷氧基，烷氨基，烷基，烯基，炔基，杂环基， 巯基，硝基，芳氧基，羟基取代的烷氧基，羟基取代的烷基-C(＝O)-，烷基-C(＝O)-，烷基-S(＝O)-，烷基-S(＝O) 2-，羟基取代的烷基-S(＝O)-，羟基取代的烷基-S(＝O) 2-，羧基烷氧基等等。 The term "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. The term "heteroaryl" can be used interchangeably with the terms "aromatic heterocycle" or "heteroaromatic". And the 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. , alkenyl, alkynyl, heterocyclyl, fluorenyl, nitro, aryloxy, hydroxy substituted alkoxy, hydroxy substituted alkyl-C(=O)-, alkyl-C(=O)-, Alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O) 2 -, carboxyalkane Oxyl and the like.
另外一些实施方案是，杂芳基包括以下的单环，但并不限于这些单环：2-呋喃基，3-呋喃基，N-咪唑基，2-咪唑基，4-咪唑基，5-咪唑基，3-异噁唑基，4-异噁唑基，5-异噁唑基，2-噁唑基，4-噁唑基，5-噁唑基，4-甲基异噁唑-5-基，N-吡咯基，2-吡咯基，3-吡咯基，2-吡啶基，3-吡啶基，4-吡啶基，2-嘧啶基，4-嘧啶基，嘧啶-5-基，哒嗪基(如3-哒嗪基)，2-噻唑基，4-噻唑基，5-噻唑基，四唑基(如5-四唑基)，三唑基(如2-三唑基和5-三唑基)，2-噻吩基，3-噻吩基，吡唑基(如2-吡唑基)，异噻唑基，1,2,3-噁二唑基，1,2,5-噁二唑基，1,2,4-噁二唑基，1,2,3-三唑基，1,2,3-硫代二唑基，1,3,4-硫代二唑基，1,2,5-硫代二唑基，1,3,4-噻二唑-2-基，吡嗪基，吡嗪-2-基，1,3,5-三嗪基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基，苯并呋喃基，苯并噻吩基，吲哚基(如2-吲哚基)，嘌呤基，喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)，和异喹啉基(如1-异喹啉基，3-异喹啉基或4-异喹啉基)，苯并[d]噻唑-2-基，咪唑并[1,5-a]吡啶-6-基。In other embodiments, 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 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (eg 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5- Oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl; also includes the following Bicyclic, but by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, fluorenyl (eg 2-indenyl), hydrazine a quinolinyl group (such as 2-quinolyl, 3-quinolinyl, 4-quinolinyl), and an isoquinolyl group (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-iso) Quinolinyl), benzo[d]thiazol-2-yl, imidazo[1,5-a]pyridin-6-yl.
术语“杂原子”表示一个或多个O，S，N，P和Si原子，包括N，S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(例如3，4-二氢-2H-吡咯基中的N)，NH(例如吡咯烷基中的NH)或NR(例如N-取代的吡咯烷基中的NR)。The term "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.
术语“卤素”是指F，Cl，Br或I。The term "halogen" means F, Cl, Br or I.
本发明所述的“卤代”表示用卤素取代其后接的基团，取代地个数可以是一个或多个。"Halo" as used in the present invention means a group substituted with a halogen followed by one or more.
本发明所述的“羟基取代的”表示用羟基取代其后接的基团，取代地个数可以是一个或多个。The "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.
本发明所述的“取代的”用于两个基团之间时，则其前面为取代基，如“芳基取代的烷基”表示烷基上具有芳基取代基，“烷氧基羰基取代的烷基”表示烷基上具有烷氧基羰基取代基。When the "substituted" of the present invention is used between two groups, it is preceded by a substituent such as "aryl substituted alkyl" means an aryl substituent on the alkyl group, "alkoxycarbonyl" Substituted alkyl" means having an alkoxycarbonyl substituent on the alkyl group.
当本发明多个基团联合使用时，从左到右，依次为取代关系，如“芳基烷基”，表示芳基取代的烷基，“烷氧基烷氧基”，表示烷氧基取代的烷氧基。When a plurality of groups of the present invention are used in combination, from left to right, a substitution relationship, such as "arylalkyl", means an aryl-substituted alkyl group, and an "alkoxyalkoxy group" means an alkoxy group. Substituted alkoxy.
在本发明中所使用的术语“不饱和的”表示结构部分含有一个或多个不饱和度。The term "unsaturated" as used in the present invention means that the moiety contains one or more degrees of unsaturation.
本发明化合物的描述Description of the compounds of the invention
一方面，本发明提供了一种化合物，具有如式(I’)所示的结构，或式(I’)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In one aspect, 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,
Figure PCTCN2017119448-appb-000035
Figure PCTCN2017119448-appb-000035
其中，among them,
G为烷基，芳基取代的烷基，烷氧基羰基取代的烷基，芳基或烷基羰基；G is an alkyl group, an aryl-substituted alkyl group, an alkoxycarbonyl-substituted alkyl group, an aryl group or an alkylcarbonyl group;
Y为芳基、杂芳基或烷基；其中芳基或杂芳基可任意的被卤素或烷基取代；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为F，Cl或Br；X is F, Cl or Br;
R 1为H、氘或烷基； R 1 is H, hydrazine or alkyl;
R 2为-C(＝O)-(CR 6R 7) n-R 3、-C(＝O)-(CH 2OCH 2) n-R 3、-P(＝O)(OR 4)OR 5； R 2 is -C(=O)-(CR 6 R 7 ) n -R 3 , -C(=O)-(CH 2 OCH 2 ) n -R 3 , -P(=O)(OR 4 )OR 5 ;
或R 2为
Figure PCTCN2017119448-appb-000036
Or R 2 is
Figure PCTCN2017119448-appb-000036
R 3为-NR 8R 9、-M-R 10、-C(＝O)OR 10、-C(＝O)OH、-O-N＝CR 14R 15或-N＝CR 14R 15； R 3 is -NR 8 R 9 , -MR 10 , -C(=O)OR 10 , -C(=O)OH, -ON=CR 14 R 15 or -N=CR 14 R 15 ;
R 4和R 5各自独立地为烷基； R 4 and R 5 are each independently an alkyl group;
R 6和R 7各自独立地为H、氘、烷基、杂烷基、芳基、环烷基、杂芳基、杂环基、芳基烷基、杂芳基烷基、环烷基烷基或杂环基烷基； R 6 and R 7 are each independently H, hydrazine, alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylane Or heterocyclylalkyl;
R 8为H或烷基； R 8 is H or an alkyl group;
R 9为H、氘、-C(＝O)R 10、-C(＝O)OR 10、烷基、环烷基、杂环基、杂芳基或芳基； R 9 is H, hydrazine, -C(=O)R 10 , -C(=O)OR 10 , alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;
或R 8和R 9与其相连的N原子一起形成含氮杂环基或含氮杂芳基； Or 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为烷基、杂烷基、芳基、环烷基、芳基烷基、杂芳基烷基、环烷基烷基、杂环基烷基、杂芳基或杂环基； R 10 is alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, heteroaryl or heterocyclic;
M为
Figure PCTCN2017119448-appb-000037
M is
Figure PCTCN2017119448-appb-000037
W为3-8元含氮杂环、含氮C 5-12稠合杂双环或含氮C 5-12螺杂双环； 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为H、烷基、环烷基、杂环基、杂芳基或芳基； R 11 is H, alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;
各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、烷基、卤代烷基、烷氧基烷基、卤代烷氧基烷基、烯基、炔基、烷氧基、卤代烷氧基、烷氧基烷氧基、烷氨基、卤代烷氨基、烷硫基、环烷基、杂环基、芳基、杂芳基、芳氧基、芳氨基、杂芳氧基、羟基取代的烷氧基、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O) 2-、羟基取代的烷基-C(＝O)-、羟基取代的烷基-S(＝O)-或羟基取代的烷基-S(＝O) 2-； Each R 12 is independently H, hydrazine, =O, hydroxy, amino, halogen, cyano, carboxy, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl , alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, heteroaryl Oxyl, hydroxy substituted alkoxy, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy substituted alkyl-C (= O)-, hydroxy-substituted alkyl-S(=O)- or hydroxy-substituted alkyl-S(=O) 2 -;
R 14和R 15各自独立地为烷基、环烷基、杂环基、芳基或杂芳基； R 14 and R 15 are each independently alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
各n独立地为1、2、3、4或5；和Each n is independently 1, 2, 3, 4 or 5; and
m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
其中R 1、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 14或R 15中所述的烷基、杂烷基、芳基、环烷基、芳基烷基、杂芳基烷基、环烷基烷基、杂环基烷基、烯基、炔基、烷氧基、烷氨基、杂芳基或杂环基任选 被1、2、3或4个选自羟基、氨基、卤素、氰基、羧基、硝基、烷基、卤代烷基、烷氧基烷基、卤代烷氧基烷基、烯基、炔基、烷氧基、卤代烷氧基、烷氧基烷氧基、烷氨基、卤代烷氨基、烷硫基、环烷基、杂环基、芳基和杂芳基中的取代基所取代。 An alkyl group, a heteroalkyl group, an aryl group, wherein R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 14 or R 15 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, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are substituted.
在一些实施例中，G为C 1-10烷基，C 6-12芳基取代的C 1-10烷基，C 1-10烷氧基羰基取代的C 1-10烷基，C 6-12芳基或C 1-10烷基羰基。 In some embodiments, 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.
在一些实施例中，G为C 1-6烷基，C 6-10芳基取代的C 1-6烷基，C 1-6烷氧基羰基取代的C 1-6烷基，C 6-10芳基或C 1-6烷基羰基。 In some embodiments, 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.
在一些实施例中，G为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、苯基甲基、苯基乙基、苯基丙基、1-乙氧基羰基乙基、1-丙氧基羰基乙基、1-异丙氧基羰基乙基、苯基、甲基羰基、乙基羰基、正丙基羰基或异丙基羰基。In some embodiments, 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.
在一些实施例中，Y为C 6-12芳基、C 1-9杂芳基或C 1-10烷基；其中C 6-12芳基或C 1-9杂芳基可任意的被卤素、C 1-6烷基取代。 In some embodiments, 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.
在一些实施例中，Y为C 6-10芳基、C 2-9杂芳基或C 1-6烷基；其中C 6-10芳基或C 2-9杂芳基可任意的被卤素、C 1-4烷基取代。 In some embodiments, 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.
在一些实施例中，Y为苯基，萘基、间氯苯基、对氯苯基、间氟苯基、対氟苯基、对甲基苯基。In some embodiments, Y is phenyl, naphthyl, m-chlorophenyl, p-chlorophenyl, m-fluorophenyl, fluorenyl phenyl, p-methylphenyl.
在一些实施例中，X为F，Cl或Br。In some embodiments, X is F, Cl or Br.
在一些实施例中，R 1为H、氘或C 1-10烷基。 In some embodiments, R 1 is H, hydrazine or C 1-10 alkyl.
在一些实施例中，R 1为H、氘或C 1-6烷基。 In some embodiments, R 1 is H, hydrazine or C 1-6 alkyl.
在一些实施例中，R 1为H、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In some embodiments, R 1 is H, hydrazine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
在一些实施例中，R 4和R 5各自独立地为C 1-10烷基。 In some embodiments, R 4 and R 5 are each independently C 1-10 alkyl.
在一些实施例中，R 4和R 5各自独立地为C 1-6烷基。 In some embodiments, R 4 and R 5 are each independently C 1-6 alkyl.
在一些实施例中，R 4和R 5各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In some embodiments, R 4 and R 5 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
在一些实施例中，R 6和R 7各自独立地为H、氘、C 1-10烷基、C 1-10杂烷基、C 6-10芳基、C 3-10环烷基、C 1-9杂芳基、C 2-9杂环基、C 6-10芳基C 1-6烷基、C 2-9杂芳基C 1-6烷基、C 3-6环烷基C 1-6烷基或C 2-9杂环基C 1-6烷基。 In some embodiments, 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.
在一些实施例中，R 6和R 7各自独立地为H、氘、C 1-6烷基、C 1-6杂烷基、C 6-10芳基、C 3-10环烷基、C 1-9杂芳基、C 2-9杂环基、C 6-10芳基C 1-4烷基、C 2-9杂芳基C 1-4烷基、C 3-6环烷基C 1-4烷基或C 2-9杂环基C 1-4烷基。 In some embodiments, R 6 and R 7 are each independently H, 氘, 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.
在一些实施例中，R 6和R 7各自独立地为H、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、苯甲基、甲硫基甲基、甲硫基乙基、甲硫基丙基、甲硫基丁基、苯基、萘基、苯基甲基、苯基乙基、甲氧基、2-甲氧基乙基、环丙基、环丁基、环戊基、环己基、噻唑基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、四氢吡咯基或四氢呋喃基。 In some embodiments, 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.
在一些实施例中，其中In some embodiments, wherein
R 8为H或C 1-10烷基； R 8 is H or C 1-10 alkyl;
R 9为H、氘、-C(＝O)R 10、-C(＝O)OR 10、C 1-10烷基、C 3-10环烷基、C 2-8杂环基、C 1-9杂芳基或C 6-12芳基； R 9 is H, 氘, -C(=O)R 10 , -C(=O)OR 10 , C 1-10 alkyl, C 3-10 cycloalkyl, C 2-8 heterocyclic, C 1 -9 heteroaryl or C 6-12 aryl;
或R 8和R 9与其相连的N原子一起形成含氮C 2-8杂环基或含氮C 1-9杂芳基。 Or 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.
在一些实施例中，其中In some embodiments, wherein
R 8为H或C 1-6烷基； R 8 is H or C 1-6 alkyl;
R 9为H、氘、-C(＝O)R 10、-C(＝O)OR 10、C 1-6烷基、C 3-6环烷基、C 2-8杂环基、C 1-9杂芳基或C 6-12芳基； R 9 is H, 氘, -C(=O)R 10 , -C(=O)OR 10 , C 1-6 alkyl, C 3-6 cycloalkyl, C 2-8 heterocyclic, C 1 -9 heteroaryl or C 6-12 aryl;
或R 8和R 9与其相连的N原子一起形成含氮C 2-8杂环基或含氮C 1-9杂芳基。 Or 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为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基或仲己基； 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 9为H、氘、-C(＝O)R 10、-C(＝O)OR 10、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、仲己基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基、苯基或萘基； R 9 is H, 氘, -C(=O)R 10 , -C(=O)OR 10 , 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, oxiranyl, nitrogen heterocycle Butyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetra Hydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetra Hydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxoalkyl, dithiaalkyl, thiamethane, homopiperazinyl, homopiperidinyl, oxa Cycloheptyl, thiaheptanyl, oxazepine, diaza, thiazepine, porphyrin, 1,2,3,4-tetrahydroisoquinolinyl, furyl, Imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazole , tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1 , 2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5- Thiodidiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothienyl, fluorenyl, fluorenyl, quinolinyl, isoquinolyl , imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazine , [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl,[1,2,4] Triazolo[1,5-a]pyridinyl, phenyl or naphthyl;
或R 8和R 9与其相连的N原子一起形成氮杂环丁基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪 唑啉基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、高哌嗪基、1,2,3,4-四氢异喹啉基、咪唑基、吡咯基、四唑基、三唑基、吡唑基、嘧啶基、苯并咪唑基、苯并吡唑基、吲哚基、吲哚啉基、吡啶并咪唑基、吡啶并吡唑基、吡啶并吡咯基、哒嗪并咪唑基、嘌呤基或嘧啶并吡唑基。 Or 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.
在一些实施例中，R 10为C 1-10烷基、C 1-10杂烷基、C 6-12芳基、C 3-10环烷基、C 6-12芳基C 1-10烷基、C 1-9杂芳基C 1-10烷基、C 3-10环烷基C 1-10烷基、C 2-8杂环基C 1-10烷基、C 1-9杂芳基或C 2-8杂环基。 In some embodiments, 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.
在一些实施例中，R 10为C 1-6烷基、C 1-6杂烷基、C 6-12芳基、C 3-6环烷基、C 6-12芳基C 1-6烷基、C 1-9杂芳基C 1-6烷基、C 3-6环烷基C 1-6烷基、C 2-8杂环基C 1-6烷基、C 1-9杂芳基或C 2-8杂环基。 In some embodiments, 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.
在一些实施例中，R 10为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、仲己基、环丙基、环丁基、环戊基、环己基、四氢吡咯基、四氢呋喃基、苯基、萘基、苄基、萘甲基、噻唑基甲基、咪唑基甲基、环戊基甲基、环己基甲基、四氢吡咯基甲基、四氢呋喃基甲基、
Figure PCTCN2017119448-appb-000038
Figure PCTCN2017119448-appb-000039
In some embodiments, 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,
Figure PCTCN2017119448-appb-000038
Figure PCTCN2017119448-appb-000039
在一些实施例中，R 11为H、C 1-10烷基、C 3-8环烷基、C 2-8杂环基、C 1-9杂芳基或C 6-12芳基。 In some embodiments, 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.
在一些实施例中，R 11为H、C 1-6烷基、C 3-8环烷基、C 2-8杂环基、C 1-9杂芳基或C 6-12芳基。 In some embodiments, 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.
在一些实施例中，R 11为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、环丙基、环丁基、环戊基、环己基、吡咯基、吗啉基、哌嗪基或苯基。 In some embodiments, R 11 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, pyrrolyl, morpholinyl, piperazinyl or phenyl.
在一些实施例中，各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、C 1-10烷基、C 1-10卤代烷基、C 1-10烷氧基C 1-10烷基、卤代C 1-10烷氧基C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基、C 1-10卤代烷氧基、C 1-10烷氧基C 1-10烷氧基、C 1-10烷氨基、C 1-10卤代烷氨基、C 1-10烷硫基、C 3-10环烷基、C 2-8杂环基、C 6-12芳基、C 1-9杂芳基、C 6-12芳氧基、C 6-12芳氨基、C 1-9杂芳氧基、羟基取代的C 1-10烷氧基、C 1-10烷基-C(＝O)-、C 1-10烷基-S(＝O)-、C 1-10烷基-S(＝O) 2-、羟基取代的C 1-10烷基-C(＝O)-、羟基取代的C 1-10烷基-S(＝O)-或羟基取代的C 1-10烷基-S(＝O) 2-。 In some embodiments, each R 12 is independently H, hydrazine, =0, hydroxy, amino, halo, cyano, carboxy, nitro, C 1-10 alkyl, C 1-10 haloalkyl, C 1- 10 alkoxy C 1-10 alkyl, halo C 1-10 alkoxy C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 alkoxy C 1-10 alkoxy, C 1-10 alkylamino, C 1-10 haloalkylamino, C 1-10 alkylthio, C 3-10 naphthenic , C 2-8 heterocyclic group, C 6-12 aryl group, C 1-9 heteroaryl group, C 6-12 aryloxy group, C 6-12 arylamino group, C 1-9 heteroaryloxy group, hydroxy group Substituted C 1-10 alkoxy, C 1-10 alkyl-C(=O)-, C 1-10 alkyl-S(=O)-, C 1-10 alkyl-S(=O) 2 -Hydroxy-substituted C 1-10 alkyl-C(=O)-, hydroxy-substituted C 1-10 alkyl-S(=O)- or hydroxy-substituted C 1-10 alkyl-S (= O) 2 -.
在一些实施例中，各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基C 1-6烷基、卤代C 1-6烷氧基C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷氨基、C 1-6卤代烷氨基、C 1-6烷硫基、C 3-6环烷基、C 2-8杂环基、C 6-10芳基、C 1-9杂芳基、C 6-10芳氧基、C 6-10芳氨基、C 1-9杂芳氧基、羟基取代的C 1-6烷氧基、C 1-10烷基-C(＝O)-、C 1-6烷基-S(＝O)-、C 1-6烷基-S(＝O) 2-、羟基取代的C 1-6烷基-C(＝O)-、羟基取代的C 1-6烷基-S(＝O)-或羟基取代的C 1-6烷基-S(＝O) 2-。 In some embodiments, each R 12 is independently H, hydrazine, =0, hydroxy, amino, halo, cyano, carboxy, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxy C 1-6 alkyl, halo C 1-6 alkoxy C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkylamino, C 1-6 alkylthio, C 3-6 naphthenic , C 2-8 heterocyclic group, C 6-10 aryl group, C 1-9 heteroaryl group, C 6-10 aryloxy group, C 6-10 arylamino group, C 1-9 heteroaryloxy group, hydroxy group Substituted C 1-6 alkoxy, C 1-10 alkyl-C(=O)-, C 1-6 alkyl-S(=O)-, C 1-6 alkyl-S(=O) 2- , hydroxy-substituted C 1-6 alkyl-C(=O)-, hydroxy-substituted C 1-6 alkyl-S(=O)- or hydroxy substituted C 1-6 alkyl-S (= O) 2 -.
在一些实施例中，各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、三氟甲基、甲氧基甲基、二氟甲氧基甲基、三氟甲氧基甲基、乙氧基甲基、乙烯基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、甲氨基、乙氨基、苯基、萘基、苯氨基、苯氧基、吡咯基、吗啉基或哌嗪基。 In some embodiments, each R 12 is independently H, hydrazine, =0, hydroxy, amino, halo, cyano, carboxy, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl, trifluoromethyl, methoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, ethoxymethyl, vinyl, ethynyl, methoxy Base, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, phenyl, naphthyl, phenylamino, phenoxy, pyrrolyl, morpholinyl or piperazinyl .
在一些实施例中，R 14和R 15各自独立地为C 1-10烷基、C 3-10环烷基、C 2-8杂环基、C 6-12芳基或C 1-9杂芳基。 In some embodiments, 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.
在一些实施例中，R 14和R 15各自独立地为C 1-6烷基、C 3-6环烷基、C 2-8杂环基、C 6-10芳基或C 1-9杂芳基。 In some embodiments, 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.
在一些实施例中，R 14和R 15各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、苯甲基、甲硫基乙基、苯基、萘基、环丙基、环丁基、环戊基、环己基、
Figure PCTCN2017119448-appb-000040
Figure PCTCN2017119448-appb-000041
In some embodiments, 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,
Figure PCTCN2017119448-appb-000040
Figure PCTCN2017119448-appb-000041
在一些实施例中，本发明提供了一种化合物，具有如式(II’)、(III’)、(IV’)、(V’)、(VI’)、(VII’)、(VIII’)或(IX’)所式的结构、或式(II’)、(III’)、(IV’)、(V’)、(VI’)、(VII’)、(VIII’)或(IX’)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000042
Figure PCTCN2017119448-appb-000042
在一些实施例中，本发明提供了一种化合物，具有如式(II’)、(V’)、(VIII’)或(IX’)所式的结构、或式(II’)、(V’)、(VIII’)或(IX’)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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'),
Figure PCTCN2017119448-appb-000043
Figure PCTCN2017119448-appb-000043
Figure PCTCN2017119448-appb-000044
Figure PCTCN2017119448-appb-000044
在一些实施例中，本发明提供了一种化合物，具有如式(IIa’)、(IIIa’)、(IVa’)、(Va’)、(VIa’)、(VIIa’)、(VIIIa’)或(IXa’)所式的结构、或式(IIa’)、(IIIa’)、(IVa’)、(Va’)、(VIa’)、(VIIa’)、(VIIIa’)或(IXa’)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000045
Figure PCTCN2017119448-appb-000045
在一些实施例中，本发明提供了一种化合物，具有如式(IIa’)、(Va’)、(VIIIa’)或(IXa’)所式的结构、或式(IIa’)、(Va’)、(VIIIa’)或(IXa’)所示结构的立体异构体、互变异构体、氮氧化物、溶剂 化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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'),
Figure PCTCN2017119448-appb-000046
Figure PCTCN2017119448-appb-000046
在一些实施例中，本发明提供了一种化合物，具有如式(I)或(Ia)所示的结构，或式(I)或(Ia)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000047
Figure PCTCN2017119448-appb-000047
其中，among them,
R 1为H、氘或烷基； R 1 is H, hydrazine or alkyl;
R 2为-C(＝O)-(CR 6R 7) n-R 3、-C(＝O)-(CH 2OCH 2) n-R 3、-P(＝O)(OR 4)OR 5； R 2 is -C(=O)-(CR 6 R 7 ) n -R 3 , -C(=O)-(CH 2 OCH 2 ) n -R 3 , -P(=O)(OR 4 )OR 5 ;
或R 2为
Figure PCTCN2017119448-appb-000048
Or R 2 is
Figure PCTCN2017119448-appb-000048
R 3为-NR 8R 9、-M-R 10、-C(＝O)OR 10、-C(＝O)OH、-O-N＝CR 14R 15或-N＝CR 14R 15； R 3 is -NR 8 R 9 , -MR 10 , -C(=O)OR 10 , -C(=O)OH, -ON=CR 14 R 15 or -N=CR 14 R 15 ;
R 4和R 5各自独立地为烷基； R 4 and R 5 are each independently an alkyl group;
R 6和R 7各自独立地为H、氘、烷基、杂烷基、芳基、环烷基、杂芳基、杂环基、芳基烷基、杂芳基烷基、环烷基烷基或杂环基烷基； R 6 and R 7 are each independently H, hydrazine, alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylane Or heterocyclylalkyl;
R 8为H或烷基； R 8 is H or an alkyl group;
R 9为H、氘、-C(＝O)R 10、-C(＝O)OR 10、烷基、环烷基、杂环基、杂芳基或芳基； R 9 is H, hydrazine, -C(=O)R 10 , -C(=O)OR 10 , alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;
或R 8和R 9与其相连的N原子一起形成含氮杂环基或含氮杂芳基； Or 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为烷基、杂烷基、芳基、环烷基、芳基烷基、杂芳基烷基、环烷基烷基、杂环基烷基、杂芳基或杂环基； R 10 is alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, heteroaryl or heterocyclic;
M为
Figure PCTCN2017119448-appb-000049
M is
Figure PCTCN2017119448-appb-000049
W为3-8元含氮杂环、含氮C 5-12稠合杂双环或含氮C 5-12螺杂双环； 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为H、烷基、环烷基、杂环基、杂芳基或芳基； R 11 is H, alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;
各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、烷基、卤代烷基、烷氧基烷基、卤代烷氧基烷基、烯基、炔基、烷氧基、卤代烷氧基、烷氧基烷氧基、烷氨基、卤代烷氨基、烷硫基、环烷基、杂环基、芳基、杂芳基、芳氧基、芳氨基、杂芳氧基、羟基取代的烷氧基、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O) 2-、羟基取代的烷基-C(＝O)-、羟基取代的烷基-S(＝O)-或羟基取代的烷基-S(＝O) 2-； Each R 12 is independently H, hydrazine, =O, hydroxy, amino, halogen, cyano, carboxy, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl , alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, heteroaryl Oxyl, hydroxy substituted alkoxy, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy substituted alkyl-C (= O)-, hydroxy-substituted alkyl-S(=O)- or hydroxy-substituted alkyl-S(=O) 2 -;
R 14和R 15各自独立地为烷基、环烷基、杂环基、芳基或杂芳基； R 14 and R 15 are each independently alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
各n独立地为1、2、3、4或5；和Each n is independently 1, 2, 3, 4 or 5; and
m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
其中R 1、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 14或R 15中所述的烷基、杂烷基、芳基、环烷基、芳基烷基、杂芳基烷基、环烷基烷基、杂环基烷基、烯基、炔基、烷氧基、烷氨基、杂芳基或杂环基任选被1、2、3或4个独立选自羟基、氨基、卤素、氰基、羧基、硝基、烷基、卤代烷基、烷氧基烷基、卤代烷氧基烷基、烯基、炔基、烷氧基、卤代烷氧基、烷氧基烷氧基、烷氨基、卤代烷氨基、烷硫基、环烷基、杂环基、芳基和杂芳基的取代基所取代。 An alkyl group, a heteroalkyl group, an aryl group, wherein R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 14 or R 15 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, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted.
在一些实施例中，W为
Figure PCTCN2017119448-appb-000050
Figure PCTCN2017119448-appb-000051
In some embodiments, W is
Figure PCTCN2017119448-appb-000050
Figure PCTCN2017119448-appb-000051
其中，among them,
t 1为1、2、3或4； t 1 is 1, 2, 3 or 4;
t 2、t 3和t 4各自独立地为1、2或3； t 2 , t 3 and t 4 are each independently 1, 2 or 3;
t 5和t 6各自独立地为1、2、3、4或5； t 5 and t 6 are each independently 1, 2, 3, 4 or 5;
t 7为1或2； t 7 is 1 or 2;
k 1、k 2、k 3和k 4各自独立地为0、1或2；其中k 1和k 2不同时为0；k 3和k 4不同时为0；和 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;
各R 13独立地为H、氘、羧基、烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基。 Each R 13 is independently H, oxime, carboxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
在一些实施例中，R 1为H、氘或C 1-6烷基。 In some embodiments, R 1 is H, hydrazine or C 1-6 alkyl.
在一些实施例中，R 4和R 5各自独立地为C 1-6烷基。 In some embodiments, R 4 and R 5 are each independently C 1-6 alkyl.
在一些实施例中，R 6和R 7各自独立地为H、氘、C 1-4烷基、C 1-4杂烷基、C 6-10芳基、C 3-6环烷基、C 1-9杂芳基、C 2-9杂环基、C 6-10芳基C 1-6烷基、C 2-9杂芳基C 1-6烷基、C 3-6环烷基C 1-6烷基或C 2-9杂环基C 1-6烷基。 In some embodiments, R 6 and R 7 are each independently H, 氘, 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.
在一些实施例中，R 8为H或C 1-6烷基。 In some embodiments, R 8 is H or C 1-6 alkyl.
在一些实施例中，R 9为H、氘、-C(＝O)R 10、-C(＝O)OR 10、C 1-6烷基、C 3-6环烷基、C 2-6杂环基、C 1-9杂芳基或C 6-10芳基；或R 8和R 9与其相连的N原子一起形成含氮C 2-6杂环基或含氮C 1-9杂芳基。 In some embodiments, R 9 is H, hydrazine, -C(=O)R 10 , -C(=O)OR 10 , C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 a heterocyclic group, a C 1-9 heteroaryl group or a C 6-10 aryl group; or 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; base.
在一些实施例中，R 10为C 1-6烷基、C 1-4杂烷基、C 6-10芳基、C 3-6环烷基、C 6-12芳基C 1-6烷基、C 1-9杂芳基C 1-6烷基、C 3-10环烷基C 1-6烷基、C 2-8杂环基C 1-6烷基、C 1-9杂芳基或C 2-9杂环基。 In some embodiments, 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.
在一些实施例中，R 11为H、C 1-6烷基、C 3-6环烷基、C 2-6杂环基、C 1-9杂芳基或C 6-10芳基。 In some embodiments, 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.
在一些实施例中，各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基C 1-6烷基、卤代C 1-6烷氧基C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷氨基、C 1-6卤代烷氨基、C 1-6烷硫基、C 3-6环烷基、C 2-6杂环基、C 6-10芳基、C 1-9杂芳基、C 6-10芳氧基、C 6-10芳氨基、杂C 1-9芳氧基、羟基取代的C 1-6烷氧基、C 1-6烷基-C(＝O)-、C 1-6烷基-S(＝O)-、C 1-6烷基-S(＝O) 2-、羟基取代的C 1-6烷基-C(＝O)-、羟基取代的C 1-6烷基-S(＝O)-或羟基取代的C 1-6烷基-S(＝O) 2-。 In some embodiments, each R 12 is independently H, hydrazine, =0, hydroxy, amino, halo, cyano, carboxy, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxy C 1-6 alkyl, halo C 1-6 alkoxy C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkylamino, C 1-6 alkylthio, C 3-6 naphthenic , C 2-6 heterocyclyl, C 6-10 aryl, C 1-9 heteroaryl, C 6-10 aryloxy, C 6-10 arylamino, hetero C 1-9 aryloxy, hydroxy Substituted C 1-6 alkoxy, C 1-6 alkyl-C(=O)-, C 1-6 alkyl-S(=O)-, C 1-6 alkyl-S(=O) 2- , hydroxy-substituted C 1-6 alkyl-C(=O)-, hydroxy-substituted C 1-6 alkyl-S(=O)- or hydroxy substituted C 1-6 alkyl-S (= O) 2 -.
在一些实施例中，R 14和R 15各自独立地为C 1-6烷基、C 3-6环烷基、C 2-9杂环基、C 6-10芳基或C 1-9杂芳基。 In some embodiments, 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.
在一些实施例中，R 1、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 14或R 15中所述的C 1-4烷基、C 1-6烷基、C 1-4杂烷基、C 6-10芳基、C 3-6环烷基、C 2-6杂环基、C 6-12芳基C 1-6烷基、C 1-9杂芳基C 1-6烷基、C 3-10环烷基C 1-6烷基、C 2-8杂环基C 1-6烷基、C 1-9杂芳基或C 2-9杂环基任选被1、2、3或4个选自羟基、氨基、F、Cl、Br、I、氰基、羧基、硝基、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基C 1-4烷基、C 1-4卤代烷氧基C 1-4烷基、C 1-4烯基、C 1-4炔基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4烷氨基、C 1-4卤代烷氨基、C 1-4烷硫基、C 3-6环烷基、C 2-9杂环基、C 6-10芳基和C 1-9杂芳基中的取代基所取代。 In some embodiments, C 1-4 alkyl, C 1-6 as described in R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 14 or R 15 Alkyl, C 1-4 heteroalkyl, C 6-10 aryl, C 3-6 cycloalkyl, C 2-6 heterocyclyl, 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- 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 alkenyl, C 1-4 alkynyl, C 1-4 alkoxy , C 1-4 haloalkoxy, C 1-4 alkoxy C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkylamino, C 1-4 alkylthio, C 3-6 Substituted by a substituent in a cycloalkyl group, a C 2-9 heterocyclic group, a C 6-10 aryl group and a C 1-9 heteroaryl group.
在另一些实施例中，R 1为H、氘、甲基、乙基、正丙基或异丙基。 In other embodiments, R 1 is H, hydrazine, methyl, ethyl, n-propyl or isopropyl.
在另一些实施例中，R 4和R 5各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基或仲己基。 In other embodiments, 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.
在另一些实施例中，R 6和R 7各自独立地为H、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、苯甲基、甲硫基甲基、甲硫基乙基、甲硫基丙基、甲硫基丁基、苯基、萘基、苯基甲基、苯基乙基、甲氧基、2-甲氧基乙基、环丙基、环丁基、环戊基、环己基、噻唑基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、四氢吡咯基或四氢呋喃基。 In other embodiments, 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.
在另一些实施例中，R 8为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基或仲己基。 In other embodiments, 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.
在另一些实施例中，R 9为H、氘、-C(＝O)R 10、-C(＝O)OR 10、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、仲己基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基、苯基或萘基； In other embodiments, R 9 is H, hydrazine, -C(=O)R 10 , -C(=O)OR 10 , 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, epoxy Ethyl, azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl , dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxoalkyl, dithiaalkyl, thiamethane, homopiperazinyl, High piperidinyl, oxetanyl, thiaheptanyl, oxazepine, diaza, thiazepine, porphyrin, 1,2,3,4-tetrahydroiso Quinolinyl, furyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidine , pyridazinyl, thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazole 1,1,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothienyl, fluorenyl, fluorenyl, Quinolinyl, isoquinolyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[ 1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl,[1,2,4]triazolo[1,5-a]pyrimidinyl , [1,2,4]triazolo[1,5-a]pyridinyl, phenyl or naphthyl;
或R 8和R 9与其相连的N原子一起形成氮杂环丁基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、高哌嗪基、1,2,3,4-四氢异喹啉基、咪唑基、吡咯基、四唑基、三唑基、吡唑基、嘧啶基、苯并咪唑基、苯并吡唑基、吲哚基、吲哚啉基、吡啶并咪唑基、吡啶并吡唑基、吡啶并吡咯基、哒嗪并咪唑基、嘌呤基或嘧啶并吡唑基。 Or 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.
在另一些实施例中，R 10为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、仲己基、环丙基、环丁基、环戊基、环己基、四氢吡咯基、四氢呋喃基、苯基、萘基、苄基、萘甲基、噻唑基甲基、咪唑基甲基、环戊基甲基、环己基甲基、四氢吡咯基甲基、四氢呋喃基甲基、
Figure PCTCN2017119448-appb-000052
Figure PCTCN2017119448-appb-000053
Figure PCTCN2017119448-appb-000054
In other embodiments, 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,
Figure PCTCN2017119448-appb-000052
Figure PCTCN2017119448-appb-000053
Figure PCTCN2017119448-appb-000054
在另一些实施例中，R 11为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、环丙基、环丁基、环戊基、环己基、吡咯基、吗啉基、哌嗪基或苯基。 In other embodiments, R 11 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, pyrrolyl, morpholinyl, piperazinyl or phenyl.
在另一些实施例中，各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、三氟甲基、甲氧基甲基、二氟甲氧基甲基、三氟甲氧基甲基、乙氧基甲基、乙烯基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、甲氨基、乙氨基、苯基、萘基、苯氨基、苯氧基、吡咯基、吗啉基或哌嗪基。 In other embodiments, each R 12 is independently H, hydrazine, =0, hydroxy, amino, halo, cyano, carboxy, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl, sec-butyl, trifluoromethyl, methoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, ethoxymethyl, vinyl, ethynyl, A Oxyl, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, phenyl, naphthyl, phenylamino, phenoxy, pyrrolyl, morpholinyl or piperazine base.
在另一些实施例中，R 14和R 15各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、苯甲基、甲硫基乙基、苯基、萘基、环丙基、环丁基、环戊基、环己基、
Figure PCTCN2017119448-appb-000055
Figure PCTCN2017119448-appb-000056
In other embodiments, 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,
Figure PCTCN2017119448-appb-000055
Figure PCTCN2017119448-appb-000056
在另一些实施例中，R 1、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 14或R 15中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、苯甲基、甲硫基甲基、甲硫基乙基、甲硫基丙基、甲硫基丁基、苯基、萘基、甲氧基、环丙基、环丁基、环戊基、环己基、噻唑基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、四氢吡咯基或四氢呋喃基任选被1、2、3或4个选自羟基、氨基、F、Cl、Br、I、氰基、羧基、硝基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、苯基、萘基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、2-噻唑基、4-噻唑基、5-噻唑基、2-噻吩基、2-噻吩基、3-呋喃基、3-呋喃基、2-吡咯基、3-吡咯基、吡啶基、嘧啶基、四氢吡咯基和四氢呋喃基中的取代基所取代。 In other embodiments, 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, tetrahydropyrrolyl or tetrahydrofuranyl is optionally 1, 2, 3 or 4 selected from the group consisting of hydroxyl, amino, F, Cl, Br, I, cyano, carboxyl, nitro, A Base, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, n-hexyl, isohexyl, phenyl, Naphthyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-thienyl, 2-thienyl , 3-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, pyridyl, pyrimidine Substituent group, tetrahydrofuranyl group, and pyrrolidine in the substitution.
在另一些实施例中，W为
Figure PCTCN2017119448-appb-000057
Figure PCTCN2017119448-appb-000058
In other embodiments, W is
Figure PCTCN2017119448-appb-000057
Figure PCTCN2017119448-appb-000058
在另一些实施例中，各R 13独立地为H、氘、羧基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 2-6杂环基、C 6-10芳基或C 1-9杂芳基。 In other embodiments, 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.
在另一些实施例中，各R 13独立地为H、氘、羧基、甲基、乙基、丙基、乙烯基、乙炔基、环丙基、环戊基、环己基、吗啉基、苯基或吡啶基。 In other embodiments, each R 13 is independently H, hydrazine, carboxyl, methyl, ethyl, propyl, vinyl, ethynyl, cyclopropyl, cyclopentyl, cyclohexyl, morpholinyl, benzene Base or pyridyl.
在一些实施例中，本发明提供了一种化合物具有式(II)所式的结构、或式(II)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000059
Figure PCTCN2017119448-appb-000059
在一些实施例中，本发明提供了一种化合物具有式(IIa)所式的结构、或式(IIa)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000060
Figure PCTCN2017119448-appb-000060
在一些实施例中，本发明提供了一种化合物具有式(III)所示的结构、或式(III)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000061
Figure PCTCN2017119448-appb-000061
在一些实施例中，本发明提供了一种化合物具有式(IIIa)所示的结构、或式(IIIa)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000062
Figure PCTCN2017119448-appb-000062
在一些实施例中，本发明提供了一种化合物具有式(IV)所示的结构、或式(IV)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000063
Figure PCTCN2017119448-appb-000063
在一些实施例中，本发明提供了一种化合物具有式(IVa)所示的结构、或式(IVa)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000064
Figure PCTCN2017119448-appb-000064
在一些实施例中，本发明提供了一种化合物具有式(V)所示的结构、或式(V)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000065
Figure PCTCN2017119448-appb-000065
在一些实施例中，本发明提供了一种化合物具有式(Va)所示的结构、或式(Va)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000066
Figure PCTCN2017119448-appb-000066
在一些实施例中，本发明提供了一种化合物具有式(VI)所示的结构、或式(VI)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000067
Figure PCTCN2017119448-appb-000067
在一些实施例中，本发明提供了一种化合物具有式(VIa)所示的结构、或式(VIa)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000068
Figure PCTCN2017119448-appb-000068
在一些实施例中，本发明提供了一种化合物具有式(VII)所示的结构、或式(VII)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000069
Figure PCTCN2017119448-appb-000069
在一些实施例中，本发明提供了一种化合物具有式(VIIa)所示的结构、或式(VIIa)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000070
Figure PCTCN2017119448-appb-000070
在一些实施例中，本发明提供了一种化合物具有式(VIII)所示的结构、或式(VIII)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000071
Figure PCTCN2017119448-appb-000071
在一些实施例中，本发明提供了一种化合物具有式(VIIIa)所示的结构、或式(VIIIa)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000072
Figure PCTCN2017119448-appb-000072
在一些实施例中，本发明提供了一种化合物具有式(IX)所示的结构、或式(IX)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000073
Figure PCTCN2017119448-appb-000073
在一些实施例中，本发明提供了一种化合物具有式(IXa)所示的结构、或式(IXa)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000074
Figure PCTCN2017119448-appb-000074
在一些实施例中，本发明提供了一种化合物具有式(II)、(IIa)、(III)、(IIIa)、(IV)、(IVa)、(V)、(Va)、(VI)、(VIa)、(VII)、(VIIa)、(VIII)、(VIIIa)、(IX)或(IXa)所式的结构、或式(II)、(IIa)、(III)、(IIIa)、(IV)、(IVa)、(V)、(Va)、(VI)、(VIa)、(VII)、(VIIa)、(VIII)、(VIIIa)、(IX)或(IXa)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，In some embodiments, 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,
Figure PCTCN2017119448-appb-000075
Figure PCTCN2017119448-appb-000075
Figure PCTCN2017119448-appb-000076
Figure PCTCN2017119448-appb-000076
在一些实施例中，各R 1独立地为H、氘或C 1-6烷基。 In some embodiments, each R 1 is independently H, oxime or C 1-6 alkyl.
在一些实施例中，各R 6独立地为H、氘、C 1-6烷基、C 1-6杂烷基、C 6-10芳基、C 3-8环烷基、C 1-9杂芳基、C 2-9杂环基、C 6-10芳基C 1-6烷基、C 1-9杂芳基C 1-6烷基、C 3-8环烷基C 1-6烷基或C 2-9杂环基C 1-6烷基。 In some embodiments, 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.
在一些实施例中，In some embodiments,
各R 8独立地为H或C 1-6烷基； Each R 8 is independently H or C 1-6 alkyl;
各R 9独立地为H、氘、-C(＝O)R 10、-C(＝O)OR 10、C 1-6烷基、C 3-8环烷基、C 2-9杂环基、C 1-9杂芳基或C 6-10芳基； Each R 9 is independently H, 氘, -C(=O)R 10 , -C(=O)OR 10 , C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocyclic group , a C 1-9 heteroaryl group or a C 6-10 aryl group;
或R 8和R 9与其相连的N原子一起形成含氮C 2-9杂环基或含氮C 1-9杂芳基。 Or 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.
在一些实施例中，各R 10独立地为C 1-6烷基、C 1-6杂烷基、C 6-10芳基、C 3-8环烷基、C 6-10芳基C 1-6烷基、C 1-9杂芳基C 1-6烷基、C 3-10环烷基C 1-6烷基、C 2-9杂环基C 1-6烷基、C 1-9杂芳基或C 2-9杂环基。 In some embodiments, 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.
在一些实施例中，各R 11独立地为H、C 1-6烷基、C 3-8环烷基、C 2-9杂环基、C 1-9杂芳基或C 6-10芳基。 In some embodiments, 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.
在一些实施例中，各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基C 1-6烷基、卤代C 1-6烷氧基C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷氨基、C 1-6卤代烷氨基、C 1-6烷硫基、C 3-8环烷基、C 2-9杂环基、C 6-10芳基、C 1-9杂芳基、C 6-10芳氧基、C 6-10芳氨基、C 1-9杂芳氧基、羟基取代的C 1-6烷氧基、C 1-6烷基-C(＝O)-、C 1-6烷基-S(＝O)-、C 1-6烷基-S(＝O) 2-、羟基取代的C 1-6烷基-C(＝O)-、羟基取代的C 1-6烷基-S(＝O)-或羟基取代的C 1-6烷基-S(＝O) 2-。 In some embodiments, each R 12 is independently H, hydrazine, =0, hydroxy, amino, halo, cyano, carboxy, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxy C 1-6 alkyl, halo C 1-6 alkoxy C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkylamino, C 1-6 alkylthio, C 3-8 naphthenic , C 2-9 heterocyclyl, C 6-10 aryl, C 1-9 heteroaryl, C 6-10 aryloxy, C 6-10 arylamino, C 1-9 heteroaryloxy, hydroxy Substituted C 1-6 alkoxy, C 1-6 alkyl-C(=O)-, C 1-6 alkyl-S(=O)-, C 1-6 alkyl-S(=O) 2- , hydroxy-substituted C 1-6 alkyl-C(=O)-, hydroxy-substituted C 1-6 alkyl-S(=O)- or hydroxy substituted C 1-6 alkyl-S (= O) 2 -.
在一些实施例中，其中各R 1、R 6、R 8、R 9、R 10、R 11或R 12中的C 1-6烷基、C 1-6杂烷基、C 6-10芳基、C 3-8环烷基、C 1-9杂芳基、C 2-9杂环基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 1-6烷氨基独立任选地被1、2、3或4个羟基、氨基、F、Cl、Br、氰基、羧基、硝基取代。 In some embodiments, wherein 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.
在一些实施例中，各R 1独立地为H、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基； In some embodiments, each R 1 is independently H, hydrazine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl;
在一些实施例中，各R 6独立地为H、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、甲硫基甲基、1-甲硫基乙基、2-甲硫基乙基、1-甲硫基丙基、2-甲硫基丙基、3-甲硫基丙基、1-甲硫基丁基、2-甲硫基丁基、3-甲硫基丁基、4-甲硫基丁基、甲氧基甲基、1-甲氧基乙基、2-甲氧基乙基、1-甲氧基丙基、2-甲氧基丙基、3-甲氧基丙基、1-甲氧基丁基、2-甲氧基丁基、3-甲氧基丁基、4-甲氧基丁基、苯基、萘基、环丙基、环丁基、环戊基、环己基、噻唑基、噻吩基、噁唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、吡咯基、吡啶基、嘧啶基、吡咯烷基、四氢呋喃基、哒嗪基、吡嗪基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、苯基甲基、苯基乙基、2-噻唑基乙基、2-噻吩基乙基、2-噁唑基乙基、2-咪唑基乙基、2呋喃基乙基、2-吡咯烷基乙基、2-四氢呋喃基乙基、2-吗啉基乙基、2-硫代吗啉基乙基、2-环戊基乙基或2-环己基乙基。 In some embodiments, 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, cyclohexyl, thiazolyl, thienyl, oxazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, pyrrolyl, pyridyl , pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, pyridazinyl, pyrazinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenylmethyl, phenyl Ethyl, 2-thiazolylethyl, 2-thienylethyl, 2-oxazolylethyl, 2-imidazolylethyl, 2-furylethyl, 2-pyrrolidinylethyl, 2 - tetrahydrofuranylethyl, 2-morpholinylethyl, 2-thiomorpholinylethyl, 2-cyclopentylethyl or 2-cyclohexylethyl.
在一些实施例中，In some embodiments,
各R 8独立地为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基或仲己基； 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;
各R 9独立地为H、氘、-C(＝O)R 10、-C(＝O)OR 10、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、仲己基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、 二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基、苯基或萘基； Each R 9 is independently H, hydrazine, -C(=O)R 10 , -C(=O)OR 10 , 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, oxiranyl, Azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuran Base, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyran , tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxoalkyl, dithiaalkyl, thiamethane, homopiperazinyl, homopiperidinyl , oxetanyl, thiaheptanyl, oxazepine, diaza, thiazepine, porphyrin, 1,2,3,4-tetrahydroisoquinolinyl, Furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazine , thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadi Azyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1, 2,5-Thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothienyl, fluorenyl, fluorenyl, quinolyl, Isoquinolinyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2- b] pyrazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1, 2,4]triazolo[1,5-a]pyridinyl, phenyl or naphthyl;
或R 8和R 9与其相连的N原子一起形成氮杂环丁基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、高哌嗪基、1,2,3,4-四氢异喹啉基、咪唑基、吡咯基、四唑基、三唑基、吡唑基、嘧啶基、苯并咪唑基、苯并吡唑基、吲哚基、吲哚啉基、吡啶并咪唑基、吡啶并吡唑基、吡啶并吡咯基、哒嗪并咪唑基、嘌呤基或嘧啶并吡唑基。 Or 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.
在一些实施例中，各R 10独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、仲己基、环丙基、环丁基、环戊基、环己基、四氢吡咯基、四氢呋喃基、苯基、萘基、苄基、萘甲基、噻唑基甲基、咪唑基甲基、环戊基甲基、环己基甲基、四氢吡咯基甲基、四氢呋喃基甲基、
Figure PCTCN2017119448-appb-000077
Figure PCTCN2017119448-appb-000078
In some embodiments, 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,
Figure PCTCN2017119448-appb-000077
Figure PCTCN2017119448-appb-000078
在一些实施例中，各R 11独立地为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、环丙基、环丁基、环戊基、环己基、吡咯基、吗啉基、哌嗪基或苯基。 In some embodiments, 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.
在一些实施例中，各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、三氟甲基、甲氧基甲基、二氟甲氧基甲基、三氟甲氧基甲基、乙氧基甲基、乙烯基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、甲氨基、乙氨基、苯基氨基、苯氧基、吡咯基、吗啉基或哌嗪基。 In some embodiments, each R 12 is independently H, hydrazine, =0, hydroxy, amino, halo, cyano, carboxy, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl, trifluoromethyl, methoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, ethoxymethyl, vinyl, ethynyl, methoxy Base, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, phenylamino, phenoxy, pyrrolyl, morpholinyl or piperazinyl.
在一些实施例中，其中R 1、R 6、R 8、R 9、R 10、R 11或R 12中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、甲硫基甲基、1-甲硫基乙基、2-甲硫基乙基、1-甲硫基丙基、2-甲硫基丙基、3-甲硫基丙基、1-甲硫基丁基、2-甲硫基丁基、3-甲硫基丁基、4-甲硫基丁基、甲氧基甲基、1-甲氧基乙基、 2-甲氧基乙基、1-甲氧基丙基、2-甲氧基丙基、3-甲氧基丙基、1-甲氧基丁基、2-甲氧基丁基、3-甲氧基丁基、4-甲氧基丁基、苯基、萘基、环丙基、环丁基、环戊基、环己基、噻唑基、噻吩基、噁唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、吡咯基、吡啶基、嘧啶基、吡咯烷基、四氢呋喃基、哒嗪基、吡嗪基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、苯基甲基、苯基乙基、2-噻唑基乙基、2-噻吩基乙基、2-噁唑基乙基、2-咪唑基乙基、2呋喃基乙基、2-吡咯烷基乙基、2-四氢呋喃基乙基、2-吗啉基乙基、2-硫代吗啉基乙基、2-环戊基乙基或2-环己基乙基各自独立任选被1、2、3或4个独立选自羟基、氨基、F、Cl、Br、I、氰基、羧基或硝基。 In some embodiments, wherein 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, cyclobutyl, cyclopentyl, cyclohexyl, thiazolyl, thienyl, oxazolyl, imidazolyl, triazole , tetrazolyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, pyridazinyl, pyrazinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholine Base, thiomorpholinyl, phenylmethyl, phenylethyl, 2-thiazolylethyl, 2-thienylethyl, 2-oxazolylethyl, 2-imidazolylethyl, 2fur Ethyl ethyl, 2-pyrrolidinylethyl, 2-tetrahydrofuranylethyl, 2-morpholinylethyl, 2-thiomorpholinylethyl, 2-cyclopentylethyl or 2-cyclohexyl The groups are each independently optionally 1, 2, 3 or 4 independently selected from the group consisting of hydroxyl, amino, F, Cl, Br, I, cyano, carboxyl or nitro.
本发明化合物的组合物，制剂和给药Composition, formulation and administration of a compound of the invention
所述药物组合物包含任何一种本发明的化合物。该药物组合物还可以进一步包含药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或其组合。所述药物组合物可以用于治疗丙型肝炎病毒(HCV)感染或丙型肝炎疾病，特别地，其对HCV NS5B蛋白有很好的抑制作用。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.
可作为药学上可接受载体的物质包括，但并不限于，离子交换剂，铝，硬脂酸铝，卵磷脂，血清蛋白，如人血清蛋白，缓冲物质如磷酸盐，甘氨酸，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶体硅，三硅酸镁，聚乙烯吡咯烷酮，聚丙烯酸脂，蜡，聚乙烯-聚氧丙烯-阻断聚合体，羊毛脂，糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇，磷酸缓冲溶液，和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁，着色剂，释放剂，包衣衣料，甜味剂，调味剂和香料，防腐剂和抗氧化剂。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 butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed acid Pyrogen-free water; isotonic salt; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings Clothing, sweeteners, flavorings and fragrances, preservatives and antioxidants.
所述药物组合物进一步包含抗HCV的药物。所述抗HCV的药物可以为任何已知的不同于本发明化合物的其他用于抗HCV的药物。例如，可以为干扰素、利巴韦林、白介素2、白介素6、白介素12、促进产生1型辅助性T细胞应答的化合物、干扰RNA、反义RNA、咪喹莫德、肌苷5’-单磷酸脱氢酶抑制剂、金刚烷胺、金刚乙胺、巴维昔单抗(Bavituximab)、丙型肝炎免疫球蛋白(Civacir TM)、波普瑞韦(boceprevir)、替拉瑞韦(telaprevir)、埃罗替尼(erlotinib)、达卡他韦(daclatasvir)、司美匹韦(simeprevir)、阿那匹韦(asunaprevir)、vaniprevir、faldaprevir、paritaprevir(ABT-450)、丹诺普韦(danoprevir)、sovaprevir、grazoprevir(MK-5172)、vedroprevir、BZF-961、GS-9256、narlaprevir、ANA975、ombitasvir(ABT-267)、EDP239、ravidasvir(PPI-668)、velpatasvir(GS-5816)、samatasvir(IDX-719)、elbasvir(MK-8742)、MK-8325、GSK-2336805、PPI-461、TMC-435、MK-7009、BI-2013335、西鲁瑞韦(ciluprevir)、BMS-650032、sovaprevir (ACH-1625)、ACH-1095、VX-985、IDX-375、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX-316、modithromycin(EP-013420)、VBY-376、TMC-649128、mericitabine(R-7128)、依米他韦、INX-189、IDX-184、IDX102、R1479、UNX-08189、PSI-6130、PSI-938、PSI-879、nesbuvir(HCV-796)、HCV-371、VCH-916、lomibuvir(VCH-222)、setrobuvir(ANA-598)、MK-3281、dasabuvir(ABT-333)、ABT-072、filibuvir(PF-00868554)、deleobuvir(BI-207127)、tegobuvir(GS-9190)、A-837093、JKT-109、Gl-59728、GL-60667、AZD-2795、TMC647055、雷迪帕韦(ledipasvir)、odalasvir、ritonavir、alloferon、nivolumab、WF-10、硝唑尼特、multiferon、奈韦拉平、ACH-3422、阿拉泊韦、MK-3682、MK-8408、GS-9857、CD-AdNS3、pibrentasvir、RG-101、glecaprevir、BZF-961、INO-8000、MBL-HCV1、CIGB-230、TG-2349、procvax、CB-5300、miravirsen、chronvac-C、MK-1075、ACH-0143422、WS-007、MK-7680、MK-2248、MK-8408、IDX-21459、AV-4025、MK-8876、GSK-2878175、MBX-700、AL-335、JNJ-47910382、AL-704、ABP-560、TD-6450、EDP-239、SB-9200、ITX-5061、ID-12、或其组合。其中，所述干扰素为干扰素α-2b、聚乙二醇化的干扰素α、干扰素α-2a、聚乙二醇化的干扰素α-2a、复合α-干扰素、干扰素γ或其组合。所述药物组合物，进一步包含至少一种HCV抑制剂，所述HCV抑制剂用于抑制HCV复制过程和/或抑制HCV病毒蛋白功能，其中所述HCV复制过程选自HCV进入、脱壳、翻译、复制、组装、释放的HCV的完整病毒周期；所述的HCV病毒蛋白选自金属蛋白酶、NS2、NS3、NS4A、NS4B、NS5A、NS5B；以及HCV病毒复制所需要的内部核糖体进入点(IRES)和肌苷单磷酸脱氢酶(IMPDH)。 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. For example, 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), dannoprevir ( Danoprevir), sovaprevir, grazoprevir (MK-5172), vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ombitasvir (ABT-267), EDP239, ravidasvir (PPI-668), velpatasvir (GS-5816), samatasvir (IDX-719), elbasvir (MK-8742), MK-8325, GSK-2336805, PPI-461, TMC-435, MK-7009, BI-2013335, ciluprevir, BMS-650032, sovaprevir (ACH-1625), ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithr Omycin (EP-013420), VBY-376, TMC-649128, mericitabine (R-7128), imiviride, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938 , PSI-879, nesbuvir (HCV-796), HCV-371, VCH-916, lomibuvir (VCH-222), setrobuvir (ANA-598), MK-3281, dasabuvir (ABT-333), ABT-072, filibuvir (PF-00868554), deleobuvir (BI-207127), tegobuvir (GS-9190), A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, ledipasvir, Odalasvir, ritonavir, alloferon, nivolumab, WF-10, nitazoxanide, multiferon, nevirapine, ACH-3422, alisporivir, MK-3682, MK-8408, GS-9857, CD-AdNS3, pibrentasvir, RG-101 , glecaprevir, BZF-961, INO-8000, MBL-HCV1, CIGB-230, TG-2349, provax, CB-5300, mimirirsen, chronvac-C, MK-1075, ACH-0143422, WS-007, MK-7680 , MK-2248, MK-8408, IDX-21459, AV-4025, MK-8876, GSK-2878175, MBX-700, AL-335, JNJ-47910382, AL-704, ABP-560, TD-6450, EDP - 239, SB-9200, ITX-5061, ID-12, or a combination thereof. Wherein the 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).
当可用于治疗时，治疗有效量的本发明化合物，可作为未加工的化学药品给予，还可作为药物组合物的活性成分提供。因此，本发明内容还提供药物组合物，该药物组合物包括治疗有效量的本发明化合物和一种或多种药学上可接受的载体、稀释剂或赋形剂。本文所使用的术语“治疗有效量”是指足以显示出有意义的患者益处(例如病毒负荷减少)的各活性组分的总量。当使用单独的活性成分单独给药时，该术语仅指该成分。当组合应用时，该术语则是指不论组合，依次或同时给药时，都引起治疗效果的活性成分的组合量。从与制剂其他成分相容以及对其接受者无害的意义上来讲，载体、稀释剂或赋形剂必须是可接受的。根据本发明内容的另一方面，还提供用于制备药物制剂的方法，该方法包括将本发明化合物与一种或多种药学上可接受的载体、稀释剂或赋形剂混匀。本发明所使用的术语“药学上可接受的”是指本发明化合物、原料、组合物和/或剂型，它们在合理医学判断的范围内，适用于与患者组织接触而无过度毒性、刺激性、变态反应或与合理的利益/风险比相对称的其他问题和并发症，并有效用于既定用途。When useful in therapy, 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. Accordingly, 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. The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to exhibit a meaningful patient benefit, such as a reduction in viral load. When administered alone as a separate active ingredient, the term refers only to that ingredient. When used in combination, 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. According to another aspect of the invention, there is also provided 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. The term "pharmaceutically acceptable" as used in the present invention 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.
当本发明内容的组合物包含本发明内容的化合物和一种或多种其他治疗药物或预防药物的组合时，化合物和另外的药物的剂量水平通常在单一疗法方案中，占正常给药剂量的约10-150％，更优选占正常给药剂量的约10-80％。药物制剂适于通过任何合适的途径给药，例如通过口服(包括口腔或舌下)、直肠、鼻、局部(包括口腔、舌下或经皮)、阴道或胃肠外(包括皮下、皮内、肌内、关节内、滑膜内、胸骨内、鞘内、病灶内、静脉内或者真皮下注射或输注)途径。可按药剂学领域的任何已知方法制备这类制剂，例如 通过将活性成分与载体或赋形剂混合。优选口服给药或注射给药。When 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.
适于口服给药的药物制剂按独立的单位提供，例如胶囊剂或片剂；散剂或颗粒剂；水性或非水性液体中的溶液剂或混悬剂；可食用泡沫制剂或起泡制剂(whip)；或水包油乳液剂或油包水乳液剂。Pharmaceutical preparations 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.
举例来说，对于以片剂或胶囊剂形式的口服给药，活性药物组分可与药学上可接受的口服无毒惰性载体(例如乙醇、甘油、水等)相混合。通过将化合物粉碎成合适的微细尺寸，并与被同样粉碎的药用载体(例如淀粉或甘露醇等可食用的糖类)混匀来制备散剂。还可存在矫味剂、防腐剂、分散剂和着色剂。For example, for oral administration in the form of a tablet or capsule, the active drug component can be mixed with 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.
通过制备如上所述的粉状混合物，并装填到成形的明胶壳内，来制备胶囊剂。在装填操作之前，可将助流剂和润滑剂(例如胶态二氧化硅、滑石粉、硬脂酸镁、硬脂酸钙或固态聚乙二醇)加到粉状混合物中。还可加入当服下胶囊剂时将改进药物可利用性的崩解剂或增溶剂(例如琼脂、碳酸钙或碳酸钠)。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.
此外需要或必需时，也可将合适的粘合剂、润滑剂、崩解剂和着色剂掺到混合物中。合适的粘合剂包括淀粉、明胶、天然糖(例如葡萄糖或β-乳糖)、玉米甜味剂、天然和合成树胶(例如阿拉伯树胶、西黄蓍胶或藻酸钠)、羧甲基纤维素、聚乙二醇等。用于这些剂型的润滑剂包括油酸钠、氯化钠等。崩解剂包括但并不限于淀粉、甲基纤维素、琼脂、皂土、黄原胶等。例如，通过制成粉状混合物，制粒或预压片，加入润滑剂和崩解剂，压制成片，从而制成片剂。将适当粉碎的化合物与如上述所述的稀释剂或基料、任选与粘合剂(例如羧甲基纤维素、藻酸盐、明胶或聚乙烯吡咯烷酮)、溶解阻止剂(例如石蜡)、吸收加速剂(季盐)和/或吸收剂(例如皂土、高岭土或磷酸二钙)混合，来制备粉状混合物。可用粘合剂(例如糖浆、淀粉浆、阿拉伯胶浆(acadiamucilage)或纤维素材料或聚合材料溶液)润湿后加压过筛，将粉状混合物制粒。制粒的一个替代方法是，可将粉状混合物通过压片机，结果是将形成不佳的团块再击碎制成颗粒。可通过加入硬脂酸、硬脂酸盐，滑石粉或矿物油使颗粒润滑以防止粘到压片机的冲模上。然后将经润滑的混合物压制成片。本发明内容的化合物还可与自由流动的惰性载体混合，无需通过制粒或预压片步骤便可压制成片。可提供透明或不透明的由虫胶密封衣、糖衣或聚合材料衣和蜡质抛光衣(polish coating of wax)组成的保护性包衣材料。可将染料加到这些包衣材料中以区分不同的单位剂量。In addition, suitable binders, lubricants, disintegrants, and colorants may also be incorporated into the mixture as needed or desired. 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. For example, 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. Suitably comminuted compound with a diluent or binder as described above, optionally with a binder (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. 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 coating or a polymeric material coat and a polish coating of wax may be provided. Dyes can be added to these coating materials to distinguish between different unit doses.
口服液体制剂例如溶液剂、糖浆剂和酏剂可以剂量单位形式制备，从而给定量含有预定量的化合物。糖浆剂可通过将化合物溶于适当调味的水溶液中来制备，而酏剂可通过使用无毒溶媒来制备。还可加入增溶剂和乳化剂(例如乙氧基化异硬脂醇和聚氧乙烯山梨醇醚)、防腐剂、矫味添加剂(例如薄荷油或天然甜味剂或糖精或其他人造甜味剂)等。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, flavoring additives (such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners) may also be added. Wait.
如果适当的话，可将用于口服给药的剂量单位制剂微胶囊化。也可将制剂制成延时或持续释放，例如通过包衣或包埋在聚合物、蜡等微粒材料中。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.
本发明化合物还可以脂质体递药系统给予，例如小单层脂质体、大单层脂质体和多层脂质体。脂质体可由多种磷脂(例如胆固醇、十八烷基胺或磷脂酰胆碱)构成。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.
本发明化合物也可通过使用单克隆抗体作为单独的载体(化合物分子与之偶联)递药。化合物也可与 作为可靶向药物载体的可溶性聚合物偶联。这类聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰胺苯酚、聚羟乙基天冬酰胺苯酚或被棕榈酰残基取代的聚氧化乙烯聚赖氨酸。此外，化合物与一类生物可降解的聚合物偶联，用于达到药物的控释，这类聚合物例如聚乳酸、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝胶的交联共聚物或两亲性嵌段共聚物。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. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenol, polyhydroxyethylaspartamide phenol or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the compounds are coupled to a class of biodegradable polymers for controlled release of such polymers, such as polylactic acid, polyε-caprolactone, polyhydroxybutyrate, polyorthoesters, polycondensation A crosslinked copolymer or an amphiphilic block copolymer of an aldehyde, a polydihydropyran, a polycyanoacrylate, and a hydrogel.
适于经皮给药的药物制剂可作为离散的贴剂(discrete patch)以在长时间内保持与接受者表皮密切接触。例如，活性成分可由通过离子导入贴剂递药，通常可参见Pharmaceutical Research 1986,3(6),318。Pharmaceutical formulations 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. For example, the active ingredient can be delivered by an iontophoretic patch, generally see Pharmaceutical Research 1986, 3(6), 318.
适于局部给药的药物制剂可制成软膏剂、乳膏剂、混悬剂、洗剂、散剂、溶液剂、糊剂、凝胶剂、喷雾剂、气雾剂、油制剂或透皮贴剂。Pharmaceutical preparations suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils or transdermal patches. .
适于直肠给药的药物制剂可作为栓剂或作为灌肠剂提供。Pharmaceutical preparations suitable for rectal administration can be presented as a suppository or as an enemas.
适于经鼻给药的药物制剂(其中载体为固体)包括粒径为例如20-500微米范围的粗粉剂，通过以鼻吸方式给药，即通过鼻通道从接近鼻子的粗粉剂容器中快速吸入。其中载体为液体、适于作为鼻腔喷雾剂或滴鼻剂给药的合适制剂包括活性成分的水性溶液剂或油性溶液剂。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.
适于通过吸入给药的药物制剂包括微细粒子粉剂(dust)或细雾剂(mist)，可用不同类型计量的剂量压缩气溶胶、雾化吸入器、吹入器或其他事宜递送气溶胶喷雾剂的装置中制备。Pharmaceutical preparations suitable for administration by inhalation include 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.
适于阴道给药的药物制剂可以阴道栓、阴道塞、乳膏剂、霜剂、凝胶剂、糊剂、泡沫剂或喷雾剂提供。Pharmaceutical preparations suitable for vaginal administration may be presented as pessaries, pessaries, creams, creams, gels, pastes, foams or sprays.
适于胃肠外给药的药物制剂包括水性和非水性无菌注射溶液剂及水性和非水性无菌混悬剂，水性和非水性无菌注射溶液剂可含有抗氧化剂、缓冲剂、抑菌剂和使所述制剂与待接受者血液等渗的溶质，水性和非水性无菌混悬剂可包括悬浮剂和增稠剂。制剂可以单位剂量或多剂量容器提供，例如密封的安凯和小瓶，并可保存在冷冻干燥(冻干)条件下，只需在临用前加入无菌液体载体，例如注射用水。临用时配置的注射溶液剂和混悬剂可由无菌粉针剂、颗粒剂和片剂制备。Pharmaceutical preparations 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.
应当了解的是，除了以上特别提到的成分以外，制剂还包括与所述制剂类型有关的本领域常用的其它成分，例如适于口服给药的这类制剂可包括矫味剂。It will be appreciated that in addition to the ingredients specifically mentioned above, the 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.
本发明化合物和药物组合物的用途Use of the compounds and pharmaceutical compositions of the invention
本发明提供了本发明的化合物或其药物组合物在制备药物中的用途，所述药物可以用于抑制HCV复制过程和/或抑制HCV病毒蛋白功能。所述HCV复制过程选自HCV进入、脱壳、翻译、复制、组装或释放的HCV的完整病毒周期。所述的HCV病毒蛋白选自金属蛋白酶、NS2、NS3、NS4A、NS4B、NS5A、NS5B；以及HCV病毒复制所需要的内部核糖体进入点(IRES)和肌苷单磷酸脱氢酶(IMPDH)。本发明所述任一化合物或药物组合物可以用于治疗丙型肝炎病毒(HCV)感染或丙型肝炎疾病，特别地，其对HCV NS5B蛋白有很好的抑制作用。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.
包含本发明化合物或药物组合物给药的治疗方法，进一步包括对患者给药其他HCV药物，由此，可 以将本发明的化合物与其他抗HCV药物进行联合治疗，其中所述抗HCV的药物为干扰素、利巴韦林、白介素2、白介素6、白介素12、促进产生1型辅助性T细胞应答的化合物、干扰RNA、反义RNA、咪喹莫德、肌苷5’-单磷酸脱氢酶抑制剂、金刚烷胺、金刚乙胺、巴维昔单抗(Bavituximab)、丙型肝炎免疫球蛋白(Civacir TM)、波普瑞韦(boceprevir)、替拉瑞韦(telaprevir)、埃罗替尼(erlotinib)、达卡他韦(daclatasvir)、司美匹韦(simeprevir)、阿那匹韦(asunaprevir)、vaniprevir、faldaprevir、paritaprevir(ABT-450)、丹诺普韦(danoprevir)、sovaprevir、grazoprevir(MK-5172)、vedroprevir、BZF-961、GS-9256、narlaprevir、ANA975、ombitasvir(ABT-267)、EDP239、ravidasvir(PPI-668)、velpatasvir(GS-5816)、samatasvir(IDX-719)、elbasvir(MK-8742)、MK-8325、GSK-2336805、PPI-461、TMC-435、MK-7009、BI-2013335、西鲁瑞韦(ciluprevir)、BMS-650032、sovaprevir(ACH-1625)、ACH-1095、VX-985、IDX-375、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX-316、modithromycin(EP-013420)、VBY-376、TMC-649128、mericitabine(R-7128)、依米他韦、INX-189、IDX-184、IDX102、R1479、UNX-08189、PSI-6130、PSI-938、PSI-879、nesbuvir(HCV-796)、HCV-371、VCH-916、lomibuvir(VCH-222)、setrobuvir(ANA-598)、MK-3281、dasabuvir(ABT-333)、ABT-072、filibuvir(PF-00868554)、deleobuvir(BI-207127)、tegobuvir(GS-9190)、A-837093、JKT-109、Gl-59728、GL-60667、AZD-2795、TMC647055、雷迪帕韦(ledipasvir)、odalasvir、ritonavir、alloferon、nivolumab、WF-10、硝唑尼特、multiferon、奈韦拉平、ACH-3422、阿拉泊韦、MK-3682、MK-8408、GS-9857、CD-AdNS3、pibrentasvir、RG-101、glecaprevir、BZF-961、INO-8000、MBL-HCV1、CIGB-230、TG-2349、procvax、CB-5300、miravirsen、chronvac-C、MK-1075、ACH-0143422、WS-007、MK-7680、MK-2248、MK-8408、IDX-21459、AV-4025、MK-8876、GSK-2878175、MBX-700、AL-335、JNJ-47910382、AL-704、ABP-560、TD-6450、EDP-239、SB-9200、ITX-5061、ID-12、或其组合。其中所述干扰素为干扰素α-2b、聚乙二醇化的干扰素α、干扰素α-2a、聚乙二醇化的干扰素α-2a、复合α-干扰素、干扰素γ或其组合。 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), danoprevir, sovaprevir , grazoprevir (MK-5172), vedroprevir, BZF-961, GS-9256, narlaprevir, ANA975, ombitasvir (ABT-267), EDP239, ravidasvir (PPI-668), velpatasvir (GS-5816), samatasvir (IDX-719) ), elbasvir (MK-8742), MK-8325, GSK-2336805 , PPI-461, TMC-435, MK-7009, BI-2013335, ciluprevir, BMS-650032, sovaprevir (ACH-1625), ACH-1095, VX-985, IDX-375, VX- 500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin (EP-013420), VBY-376, TMC-649128, mericitabine (R-7128), imiviride, INX -189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, nesbuvir (HCV-796), HCV-371, VCH-916, lomibuvir (VCH-222), setrobuvir (ANA-598), MK-3281, dasabuvir (ABT-333), ABT-072, filibuvir (PF-00868554), deleobuvir (BI-207127), tegobuvir (GS-9190), A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, ledipasvir, odalasvir, ritonavir, alloferon, nivolumab, WF-10, nitazoxanide, multiferon, nevirapine, ACH-3422, alisporide , MK-3682, MK-8408, GS-9857, CD-AdNS3, pibrentasvir, RG-101, glecaprevir, BZF-961, INO-8000, MBL-HCV1, CIGB-230, TG-2349, provax, CB-5300 , miravirsen, chronvac-C, MK-1075, ACH-0143422, WS-007, MK-7680, MK-2248, MK-8408, IDX-21459, AV-4025, MK-8876, GSK-2878175, MBX-700, AL-335, JNJ-47910382, AL-704, ABP-560, TD-6450, EDP- 239, SB-9200, ITX-5061, ID-12, or a combination thereof. Wherein the interferon is interferon alpha-2b, pegylated interferon alpha, interferon alpha-2a, pegylated interferon alpha-2a, complex alpha interferon, interferon gamma or a combination thereof .
并且包含本发明化合物或药物组合物给药的治疗方法，进一步包含其他抗HCV药物的给药，其中，其他抗HCV药物可以和本发明化合物或其药物组合物联合给药，本发明化合物或药物组合物作为单个剂型，或分开的化合物或药物组合物作为多剂型的一部分。其他抗HCV药物可以与本发明化合物的同时给药或不同时给药。后者的情况，给药可以错开进行如6小时、12小时、1天、2天、3天、1周、2周、3周、1个月或2个月进行。And 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.
本发明的化合物或药学上可接受的组合物的“有效量”或“有效剂量”是指处理或减轻一个或多个本发明所提到病症的严重度的有效量。根据本发明的方法，化合物和其组合物可以是任何给药量和任何给药途径来有效地用于处理或减轻疾病的严重程度。必需的准确的量将根据患者的情况而改变，这取决于种族，年龄，患者的一般条件，感染的严重程度、特殊的因素、给药方式，等等。本发明化合物或组合物可以和一个或多个其他治疗剂联合给药，如本发明所讨论的。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. In accordance with the methods of the present invention, 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.
一般合成过程General synthetic process
一般地，本发明的化合物可以通过本发明所描述的方法制备得到。下面的反应方案和实施例用于进一步举例说明本发明的内容。In general, 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.
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare a number of other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by modifications by those skilled in the art, such as appropriate protection of the interfering group, by the use of other known reagents in addition to those described herein, or The reaction conditions are subject to some conventional modifications. Additionally, the reactions or known reaction conditions disclosed herein are also recognized to be suitable for the preparation of other compounds of the invention.
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Inc.,Arco Chemical Company和Alfa Chemical Company，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。The examples described below, unless otherwise indicated, all temperatures are set to degrees Celsius. 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.
无水四氢呋喃、二氧六环、甲苯、乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯、石油醚、正己烷、N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。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.
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。The following 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.
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。核磁共振光谱以CDC1 3、d 6-DMSO、CD 3OD或d 6-丙酮为溶剂(报导以ppm为单位)，用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)、d(doublet，双峰)、t(triplet，三重峰)、q(quartet，四重峰)、m(multiplet，多重峰)、br(broadened，宽峰)、dd(doublet of doublets，双二重峰)、dt(doublet of triplets，双三重峰)。偶合常数，用赫兹(Hz)表示。 The column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. 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. When multiple peaks appear, the following abbreviations are used: s (singlet, unimodal), d (doublet, 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).
低分辨率质谱(MS)数据通过配备G1312A二元泵和a G1316A TCC(柱温保持在30℃)的Agilent 6320系列LC-MS的光谱仪来测定的，G1329A自动采样器和G1315B DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。Low-resolution mass spectrometry (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.
低分辨率质谱(MS)数据通过配备G1311A四元泵和G1316A TCC(柱温保持在30℃)的Agilent 6120系列LC-MS的光谱仪来测定的，G1329A自动采样器和G1315D DAD检测器应用于分析，ESI源应用于LC-MS光谱仪。Low-resolution mass spectrometry (MS) data was measured with a G1311A quaternary pump and G1316A TCC (column temperature maintained at 30 °C) Agilent 6120 Series LC-MS spectrometer, G1329A autosampler and G1315D DAD detector for analysis The ESI source was applied to an LC-MS spectrometer.
以上两种光谱仪都配备了Agilent Zorbax SB-C18柱，规格为2.1×30mm，5μm。注射体积是通过样品浓度来确定；流速为0.6mL/min；HPLC的峰值是通过在210nm和254nm处的UV-Vis波长来记录读取的。 流动相为0.1％的甲酸乙腈溶液(相A)和0.1％的甲酸超纯水溶液(相B)。梯度洗脱条件如表1所示：Both spectrometers are equipped with an Agilent Zorbax SB-C18 column measuring 2.1 x 30 mm, 5 μm. 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:
表1Table 1
时间(min)Time (min) A(CH 3CN，0.1％HCOOH) A (CH 3 CN, 0.1% HCOOH) B(H 2O，0.1％HCOOH) B(H 2 O, 0.1% HCOOH)
0-30-3 5-1005-100 95-095-0
3-63-6 100100 00
6-6.16-6.1 100-5100-5 0-950-95
6.1-86.1-8 55 9595
HPLC制备的工艺条件为：The process conditions for HPLC preparation are:
(1).取含有化合物(II)的非对映异构体混合物适量，用流动相溶解；(1) taking an appropriate amount of the mixture of diastereomers containing the compound (II), and dissolving with a mobile phase;
(2).设置流动相的流速、检测波长和柱温；(2) setting the flow rate, detection wavelength and column temperature of the mobile phase;
(3).取步骤(1)中的样品溶液适量注入高效液相色谱仪，记录色谱图，完成异构体的分离和分析；(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;
色谱柱：表面含有多糖衍生物的硅胶作为固定相的正相手性色谱柱；更具体地，所用的色谱柱为大赛璐AD-H(10*250nm，5um)或大赛璐AD(20*250nm，5um)。Column: A chiral column with a silica derivative containing a polysaccharide derivative as a stationary phase; more specifically, the column used is Daicel 璐AD-H (10*250nm, 5um) or Daicel 璐AD (20*250nm, 5um).
流动相：甲醇、乙醇、异丙醇、乙腈、正己烷、正戊烷、异己烷、正庚烷、二乙胺、三乙胺、三氟乙酸、冰醋酸中的两种以上的混合物；更具体地，流动相的混合物中正己烷、正戊烷、异己烷、正庚烷的体积比例为10～20％，甲醇、乙醇、异丙醇、乙腈的体积比例为20～95％，二乙胺、三乙胺、三氟乙酸、冰醋酸的体积比例为0～2％，流动相中各成分的总和为100％；更具体地，其中所述的流动相的混合物中正己烷的体积比为15～20％，异丙醇的体积比例为80～90％，二乙胺、三乙胺的体积比例为0.5～1％，流动相中各成分的总和为100％。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 volume ratio of isopropyl alcohol is 80 to 90%, the volume ratio of diethylamine and triethylamine is 0.5 to 1%, and the total of the components in the mobile phase is 100%.
检测波长：250nm～320nm；Detection wavelength: 250nm ~ 320nm;
流速：0.5～10mL/min；更具体地为2～5mL/min；Flow rate: 0.5-10 mL/min; more specifically 2-5 mL/min;
柱温：10～35℃。Column temperature: 10 to 35 ° C.
下面简写词的使用贯穿本发明：The following abbreviations are used throughout the invention:
Ac 2OH：醋酸 Ac 2 OH: acetic acid
Boc 2O，BOC酸酐：二碳酸二叔丁酯 Boc 2 O, BOC anhydride: di-tert-butyl dicarbonate
Boc：叔丁基氧羰基Boc: tert-butyloxycarbonyl
Bu 4NHSO 4：四丁基硫酸氢铵 Bu 4 NHSO 4 : tetrabutylammonium hydrogen sulfate
CH 3CN：乙腈 CH 3 CN: acetonitrile
DCM：二氯甲烷DCM: dichloromethane
DIPEA：N,N-二异丙基乙胺DIPEA: N,N-diisopropylethylamine
EA：乙酸乙酯EA: ethyl acetate
HCl：氯化氢HCl: hydrogen chloride
HCl/EA：氯化氢的乙酸乙酯溶液HCl/EA: ethyl acetate solution of hydrogen chloride
H 2O：水 H 2 O: water
NaOH：氢氧化钠NaOH: sodium hydroxide
NaI：碘化钠NaI: sodium iodide
K 2CO 3：碳酸钾 K 2 CO 3 : potassium carbonate
rt，r.t.：室温Rt, r.t.: room temperature
下列合成方案描述了制备本发明公开化合物的步骤。除非另外说明，G、Y、X、R 1、R 2具有如本发明所述的定义。 The following synthetic schemes describe the steps for preparing the compounds disclosed herein. Unless otherwise stated, G, Y, X, R 1 , R 2 have the definitions as described herein.
合成方案Synthetic scheme
方案一Option One
Figure PCTCN2017119448-appb-000079
Figure PCTCN2017119448-appb-000079
式I′所示的化合物可通过方案一所示的过程合成。化合物I′-1可与羟基保护试剂反应，得到呋喃环上羟基保护的化合物I′-2；化合物I′-2与化合物I′-3可在碱作用下反应生成化合物I′-4；化合物I′-4脱保护后得到目标化合物I′。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.
方案二Option II
Figure PCTCN2017119448-appb-000080
Figure PCTCN2017119448-appb-000080
式I所示的化合物可通过方案二所示的过程合成。化合物I-1可与羟基保护试剂反应，得到呋喃环上羟基保护的化合物I-2；化合物I-2与化合物I-3可在碱作用下反应生成化合物I-4；化合物I-4脱保护后得到目标化合物I。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.
实施例Example
中间体的制备Preparation of intermediates
(S)-异丙基2-(((S)-(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-4-甲基-3-((三乙基硅基)氧基)四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基)氨基)丙酸酯(M-2)(S)-Isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2H)) -yl)-4-fluoro-4-methyl-3-((triethylsilyl)oxy)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionate ( M-2)
Figure PCTCN2017119448-appb-000081
Figure PCTCN2017119448-appb-000081
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000082
Figure PCTCN2017119448-appb-000082
将(S)-异丙基2-(((S)-(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基)氨基)丙酸酯(M-1)(100.0g，188.9mmol，1.0eq)加入到无水N，N-二甲 基甲酰胺(500mL)中，在氮气保护下，依次加入咪唑(32.2g,472.2mmol,2.5eq)、4-二甲氨基吡啶(2.3g,19.0mmol，0.1eq)以及三乙基氯硅烷(48mL,286.0mmol，1.5eq)，室温反应过夜。TLC监控反应完成后，将反应液倒入乙酸乙酯(1500mL)中，依次用水(1000mL×3)和饱和食盐水(1000mL)洗涤。有机相用无水硫酸钠干燥后，减压浓缩得到白色油状粗产品，后再溶于无水乙腈(800mL)，并用正庚烷洗涤(800mL×3)后收集乙腈层，减压浓缩得到化合物M-2，白色泡沫状固体74.2g。(S)-Isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidine-1 (2H) )-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionate (M-1) (100.0 g, 188.9 Methanol (1.0 eq) was added to anhydrous N,N-dimethylformamide (500 mL), and then, under nitrogen, imidazole (32.2 g, 472.2 mmol, 2.5 eq), 4-dimethylaminopyridine (2.3) g, 19.0 mmol, 0.1 eq) and triethylchlorosilane (48 mL, 286.0 mmol, 1.5 eq). After the reaction was completed by TLC, the reaction mixture was poured into ethyl acetate (1500 mL), and washed with water (1000 mL×3) and brine (1000 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. M-2, 74.2 g of a white foamy solid.
MS-ESI:m/z 644.20[M+1] +； MS-ESI: m/z 644.20 [M+1] + ;
1H NMR(600MHz,CDCl 3)δ9.12(s,1H),7.56(d,J＝8.1Hz,1H),7.34(t,J＝7.8Hz,2H),7.23(d,J＝8.0Hz,2H),7.19(t,J＝7.3Hz,1H),6.16(d,J＝18.6Hz,1H),5.67(d,J＝8.1Hz,1H),5.09–4.94(m,1H),4.61(dd,J＝11.4,6.1Hz,1H),4.31–4.23(m,1H),4.14(d,J＝8.5Hz,1H),4.00–3.98(m,1H),3.90(t,J＝9.9Hz,1H),1.78(s,1H),1.37(t,J＝13.5Hz,6H),1.24(d,J＝6.2Hz,6H),1.00(t,J＝7.9Hz,9H),0.69(q,J＝7.9Hz,6H)。 1 H NMR (600MHz, CDCl 3 ) δ 9.12 (s, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.34 (t, J = 7.8 Hz, 2H), 7.23 (d, J = 8.0 Hz) , 2H), 7.19 (t, J = 7.3 Hz, 1H), 6.16 (d, J = 18.6 Hz, 1H), 5.67 (d, J = 8.1 Hz, 1H), 5.09 - 4.94 (m, 1H), 4.61 (dd, J=11.4, 6.1 Hz, 1H), 4.31–4.23 (m, 1H), 4.14 (d, J=8.5 Hz, 1H), 4.00–3.98 (m, 1H), 3.90 (t, J=9.9) Hz, 1H), 1.78 (s, 1H), 1.37 (t, J = 13.5 Hz, 6H), 1.24 (d, J = 6.2 Hz, 6H), 1.00 (t, J = 7.9 Hz, 9H), 0.69 ( q, J = 7.9 Hz, 6H).
实施例1Example 1
(3-((2R,3R,4R,5R)-3-氟-4-羟基-5-((((S)-(((S)-1-异丙氧基-1-氧代丙-2-基)氨基)(苯氧基)磷酰基)氧基)甲基)-3-甲基四氢呋喃-2-基)-2,6-二氧代-2,3-二氢嘧啶-1(6H)-基)甲基4-氨基丁酸酯盐酸盐(3-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-((((S)-((()))))) 2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-3-methyltetrahydrofuran-2-yl)-2,6-dioxo-2,3-dihydropyrimidine-1 ( 6H)-yl)methyl 4-aminobutyrate hydrochloride
Figure PCTCN2017119448-appb-000083
Figure PCTCN2017119448-appb-000083
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000084
Figure PCTCN2017119448-appb-000084
1)化合物1-2的合成1) Synthesis of Compound 1-2
Figure PCTCN2017119448-appb-000085
Figure PCTCN2017119448-appb-000085
将氢氧化钠(10g,250mmol,2.5eq)溶于150mL水中，降温到0℃，再加入化合物1-1(10.3g,100mmol,1eq)，0℃下搅拌10分钟，再滴加BOC酸酐(30mL,130mmol,1.3eq)，滴加完后，移到室温反应18h。加硫酸氢钾的水溶液调pH到2-3，再用乙酸乙酯(250mL)萃取，有机相用无水硫酸钠干燥，浓缩，得到20.3g淡黄色油液，收率100％。Sodium hydroxide (10 g, 250 mmol, 2.5 eq) was dissolved in 150 mL of water, cooled to 0 ° C, then compound 1-1 (10.3 g, 100 mmol, 1 eq) was added and stirred at 0 ° C for 10 min. 30 mL, 130 mmol, 1.3 eq), after the addition was completed, the mixture was transferred to room temperature for 18 h. The aqueous solution of potassium hydrogensulfate was adjusted to pH 2-3, and then extracted with ethyl acetate (250 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give 20.3 g of pale yellow oil.
2)化合物1-3的合成2) Synthesis of Compound 1-3
Figure PCTCN2017119448-appb-000086
Figure PCTCN2017119448-appb-000086
将化合物1-2(10g,39.7mmol,1eq)、碳酸钾(22g,158.9mmol,4eq)和四丁基硫酸氢铵(1.35g,3.97mmol,0.1eq)加入到80mL二氯甲烷和80mL水中，降温到0℃，再滴加氯甲基氯磺酸酯(8mL,79.5mmol,2eq)的二氯甲烷(20mL)溶液，滴加完后，室温反应3h。TLC检测反应完全。分液，有机相用无水硫酸钠干燥，浓缩。柱层析纯化，流动相：PE:EA＝8:1，得到9.6g无色油液，收率96％。Compound 1-2 (10 g, 39.7 mmol, 1 eq), potassium carbonate (22 g, 158.9 mmol, 4 eq) and tetrabutylammonium hydrogen sulfate (1.35 g, 3.97 mmol, 0.1 eq) were added to 80 mL dichloromethane and 80 mL water The temperature was lowered to 0 ° C, and a solution of chloromethyl chlorosulfonate (8 mL, 79.5 mmol, 2 eq) in dichloromethane (20 mL) was added dropwise. The reaction was complete by TLC. The organic layer was dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography, mobile phase: PE: EA = 8:1, yielding 9.6 g of colorless oil, yield 96%.
3)化合物1-5的合成3) Synthesis of Compound 1-5
Figure PCTCN2017119448-appb-000087
Figure PCTCN2017119448-appb-000087
将化合物M-2(1.70g,2.64mmol,1eq)、化合物1-3(1.0g,3.96mmol,1.5eq)、碘化钠(1.58g,10.6mmol,4eq)和DIPEA(0.7mL,3.96mmol,1.5eq)加入到15mL乙腈中，室温下反应40h。TLC检测，还有一点点的原料，加入50mL乙酸乙酯和20mL水，分液，有机相用无水硫酸钠干燥，浓缩。柱层析纯化，流动相：DCM:MeOH＝100:1-80:1，得到2.3g黄色油液，收率100％。Compound M-2 (1.70 g, 2.64 mmol, 1 eq), compound 1-3 (1.0 g, 3.96 mmol, 1.5 eq), sodium iodide (1.58 g, 10.6 mmol, 4 eq) and DIPEA (0.7 mL, 3.96 mmol) 1.5 eq) was added to 15 mL of acetonitrile and allowed to react at room temperature for 40 h. TLC, a little bit of the starting material, 50 mL of ethyl acetate and 20 mL of water were added, and the organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography, mobile phase: DCM: MeOH = 100:1 - 80:1 to afforded 2.3 g of yellow oil.
LC-MS:[M+Na] +＝881.2； LC-MS: [M+Na] + = 881.2;
1H NMR(400MHz,CDCl 3)δ7.59(d,J＝8.3Hz,1H),7.34(t,J＝7.9Hz,2H),7.20(dd,J＝17.1,8.0Hz,3H),6.18(d,J＝18.4Hz,1H),5.99–5.91(m,2H),5.70(d,J＝8.3Hz,1H),5.00(hept,J＝6.2Hz,1H),4.74(s,1H),4.67–4.56(m,1H),4.26(ddd,J＝12.0,5.3,2.6Hz,1H),4.13(d,J＝8.8Hz,1H),4.03–3.90(m,2H),3.81–3.71(m,1H),3.15(d,J＝6.3Hz,2H),2.37(t,J＝7.4Hz,2H),1.87(s,1H),1.81(p,J＝7.0Hz,2H),1.43(s,9H),1.35(dd,J＝19.2,8.6Hz,6H),1.23(d,J＝6.3Hz,6H),0.99(dd,J＝9.6,6.2Hz,9H),0.73–0.63(m,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J = 8.3 Hz, 1H), 7.34 (t, J = 7.9 Hz, 2H), 7.20 (dd, J = 17.1, 8.0 Hz, 3H), 6.18 (d, J = 18.4 Hz, 1H), 5.99 - 5.91 (m, 2H), 5.70 (d, J = 8.3 Hz, 1H), 5.00 (hept, J = 6.2 Hz, 1H), 4.74 (s, 1H) , 4.67–4.56 (m, 1H), 4.26 (ddd, J=12.0, 5.3, 2.6 Hz, 1H), 4.13 (d, J=8.8 Hz, 1H), 4.03–3.90 (m, 2H), 3.81–3.71 (m, 1H), 3.15 (d, J = 6.3 Hz, 2H), 2.37 (t, J = 7.4 Hz, 2H), 1.87 (s, 1H), 1.81 (p, J = 7.0 Hz, 2H), 1.43 (s, 9H), 1.35 (dd, J = 19.2, 8.6 Hz, 6H), 1.23 (d, J = 6.3 Hz, 6H), 0.99 (dd, J = 9.6, 6.2 Hz, 9H), 0.73 - 0.63 ( m, 6H).
4)化合物1-6的合成4) Synthesis of Compound 1-6
Figure PCTCN2017119448-appb-000088
Figure PCTCN2017119448-appb-000088
将化合物1-5(2.3g,2.7mmol,1eq)加入到7mL丙酮和6mL水中，室温下加入7mL醋酸和1.5mL三氟乙酸，室温反应2h。TLC检测，反应完全，加入60mL乙酸乙酯，并用水洗涤(20mL×3)、饱和食盐水(20mL)洗涤，有机相用无水硫酸钠干燥，浓缩。柱层析纯化，流动相：DCM:MeOH＝50:1，得到1.12g白色固体，收率56％。Compound 1-5 (2.3 g, 2.7 mmol, 1 eq) was added to 7 mL of acetone and 6 mL of water, and 7 mL of acetic acid and 1.5 mL of trifluoroacetic acid were added at room temperature, and reacted at room temperature for 2 h. The mixture was washed with EtOAc (EtOAc)EtOAc. Purification by column chromatography, EtOAc: EtOAc:EtOAc:
LC-MS:[M+Na] +＝767.3。 LC-MS: [M+Na] + = 767.3.
5)化合物1的合成5) Synthesis of Compound 1
Figure PCTCN2017119448-appb-000089
Figure PCTCN2017119448-appb-000089
将化合物1-6(500mg,0.67mmol,1eq)溶于5mL乙酸乙酯中，室温下加入2mL 4N的HCl/EA，室温下反应。瓶底析出一些油状物，减压浓缩溶剂。加入10mL石油醚，过滤。得到400mg淡黄色固体，收率87％。Compound 1-6 (500 mg, 0.67 mmol, 1 eq) was dissolved in 5 mL of ethyl acetate, and 2 mL of 4N HCl / EA was added at room temperature and allowed to react at room temperature. Some oil was precipitated from the bottom of the bottle, and the solvent was concentrated under reduced pressure. Add 10 mL of petroleum ether and filter. 400 mg of a pale yellow solid were obtained in a yield of 87%.
LC-MS:[M+1] +＝645.3； LC-MS: [M+1] + =645.3;
1H NMR(400MHz,D 2O)δ7.45(d,J＝8.2Hz,1H),7.34(t,J＝7.8Hz,2H),7.17(dd,J＝19.9,7.7Hz,3H),6.09(d,J＝19.5Hz,1H),5.87–5.80(m,2H),5.72(d,J＝8.3Hz,1H),4.85(dp,J＝12.5,6.2Hz,1H),4.51(dd,J＝10.9,6.3Hz,1H),4.37–4.29(m,1H),4.13(t,J＝9.5Hz,1H),4.05(q,J＝7.2Hz,1H),3.88(td,J＝14.3,7.1Hz,1H),2.94(t,J＝7.7Hz,2H),2.44(t,J＝7.2Hz,2H),2.00(d,J＝5.7Hz,1H),1.94–1.81(m,2H),1.32–1.24(m,6H),1.13(d,J＝6.3Hz,6H)。 1 H NMR (400MHz, D 2 O) δ7.45 (d, J = 8.2Hz, 1H), 7.34 (t, J = 7.8Hz, 2H), 7.17 (dd, J = 19.9,7.7Hz, 3H), 6.09 (d, J = 19.5 Hz, 1H), 5.87 - 5.80 (m, 2H), 5.72 (d, J = 8.3 Hz, 1H), 4.85 (dp, J = 12.5, 6.2 Hz, 1H), 4.51 (dd , J = 10.9, 6.3 Hz, 1H), 4.37 - 4.29 (m, 1H), 4.13 (t, J = 9.5 Hz, 1H), 4.05 (q, J = 7.2 Hz, 1H), 3.88 (td, J = 14.3, 7.1 Hz, 1H), 2.94 (t, J = 7.7 Hz, 2H), 2.44 (t, J = 7.2 Hz, 2H), 2.00 (d, J = 5.7 Hz, 1H), 1.94 - 1.81 (m, 2H), 1.32 - 1.24 (m, 6H), 1.13 (d, J = 6.3 Hz, 6H).
实施例2Example 2
(S)-异丙基2-(((S)-(((2R,3R,4R,5R)-4-氟-3-羟基-5-(3-(((R)-2-((甲氧基羰基)氨基)-2-苯基乙酰氧基)甲基)-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-甲基四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基)氨基)丙酸酯(S)-Isopropyl 2-(((S)-(((2R,3R,4R,5R)-4-fluoro-3-hydroxy-5-(3-((()))) Methoxycarbonyl)amino)-2-phenylacetoxy)methyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-methyltetrahydrofuran- 2-yl)methoxy)(phenoxy)phosphoryl)amino)propionate
Figure PCTCN2017119448-appb-000090
Figure PCTCN2017119448-appb-000090
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000091
Figure PCTCN2017119448-appb-000091
Figure PCTCN2017119448-appb-000092
Figure PCTCN2017119448-appb-000092
1)化合物2-2的合成1) Synthesis of Compound 2-2
Figure PCTCN2017119448-appb-000093
Figure PCTCN2017119448-appb-000093
将化合物2-1(5g，24mmol，1.0eq)和四丁基硫酸氢铵(0.8g，2.4mmol，0.1eq)，碳酸钾(13g，95.6mmol，4.0eq)混合于二氯甲烷和水的混合溶液(50mL+50mL)中，在0℃下缓慢滴加氯甲基氯磺酸酯(4.8mL，47.8mmol，2.0eq)，滴完后移至室温反应5小时。TLC监测反应完毕，反应液静置分层，有机相用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，减压浓缩后硅胶柱层析，PE/EA＝10/1做洗脱剂，得白色固体产品4.30g，收率69.8％。Compound 2-1 (5 g, 24 mmol, 1.0 eq) and tetrabutylammonium hydrogen sulfate (0.8 g, 2.4 mmol, 0.1 eq), potassium carbonate (13 g, 95.6 mmol, 4.0 eq) were combined in dichloromethane and water. In the mixed solution (50 mL + 50 mL), chloromethyl chlorosulfonate (4.8 mL, 47.8 mmol, 2.0 eq) was slowly added dropwise at 0 ° C, and the mixture was transferred to room temperature for 5 hours. After the reaction was completed by TLC, the reaction mixture was allowed to stand, and the organic layer was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, silica gel column chromatography, eluting with PE/EA=10/1 The obtained white solid product was 4.30 g, and the yield was 69.8%.
1H NMR(400MHz,CDCl 3)δ7.45–7.33(m,5H),5.73(m,3H),5.44(d,J＝7.2Hz,1H),3.71(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.45 - 7.33 (m, 5H), 5.73 (m, 3H), 5.44 (d, J = 7.2 Hz, 1H), 3.71 (s, 3H).
MS-ESI:m/z＝258.10[M+1] +。 MS-ESI: m/z = 258.10 [M+1] + .
2)化合物2-3的合成2) Synthesis of Compound 2-3
Figure PCTCN2017119448-appb-000094
Figure PCTCN2017119448-appb-000094
将化合物M-2(2.5g，3.9mmol，1.0eq)和化合物2-2(1.5g，5.8mmol，1.5eq)溶于乙腈(25mL)中，室温下加入碘化钠(2.3g，16mmol，4.0eq)和二异丙基乙基胺(1mL，5.8mmol，1.5eq)，室温下反应过夜。TLC检测反应完成后直接减压浓缩反应溶剂，剩余物加入100mL乙酸乙酯和30mL水搅拌至固体完全溶解后静置分液，有机相用水(30mL×2)洗涤，饱和氯化钠溶液(30mL)洗涤，有机相用无水硫酸钠干燥后减压浓缩。以DCM:MeOH＝70:1为洗脱剂柱层析纯化，得到黄色泡沫状固体1.7g，收率50.6％。Compound M-2 (2.5 g, 3.9 mmol, 1.0 eq) and compound 2-2 (1.5 g, 5.8 mmol, 1.5 eq) were dissolved in acetonitrile (25 mL) and sodium iodide (2.3 g, 16 mmol, 4.0 eq) and diisopropylethylamine (1 mL, 5.8 mmol, 1.5 eq) were reacted overnight at room temperature. After the completion of the TLC reaction, the reaction solvent was concentrated under reduced pressure, and the residue was added to 100 mL of ethyl acetate and 30 mL of water, and then the mixture was stirred until the solid was completely dissolved. The organic phase was separated and washed with water (30 mL×2), saturated sodium chloride solution (30 mL) The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography eluting with DCM: MeOH = 70:1 toield
1H NMR(400MHz,CDCl 3)δ7.54(t,J＝8.5Hz,1H),7.44–7.29(m,7H),7.21(dd,J＝14.5,7.5Hz,3H),6.17–5.90(m,3H),5.85–5.57(m,2H),5.44–5.35(m,1H),5.00(dq,J＝12.7,6.3Hz,1H),4.61(dd,J＝10.4,6.5Hz,1H),4.25(ddd,J＝11.7,5.2,2.6Hz,1H),4.14(dd,J＝14.0,7.1Hz,1H),4.04–3.70(m,3H),3.68(d,J＝7.5Hz,3H),1.37(t,J＝6.7Hz,3H),1.29–1.22(m,9H),1.01(t,J＝7.9Hz,9H),0.68(q,J＝7.9Hz,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.54 (t, J = 8.5 Hz, 1H), 7.44 - 7.29 (m, 7H), 7.21. (dd, J = 14.5, 7.5 Hz, 3H), 6.17 - 5.90 ( m,3H), 5.85–5.57 (m, 2H), 5.44–5.35 (m, 1H), 5.00 (dq, J=12.7, 6.3 Hz, 1H), 4.61 (dd, J=10.4, 6.5 Hz, 1H) , 4.25 (ddd, J = 11.7, 5.2, 2.6 Hz, 1H), 4.14 (dd, J = 14.0, 7.1 Hz, 1H), 4.04 - 3.70 (m, 3H), 3.68 (d, J = 7.5 Hz, 3H) ), 1.37 (t, J = 6.7 Hz, 3H), 1.29 - 1.22 (m, 9H), 1.01 (t, J = 7.9 Hz, 9H), 0.68 (q, J = 7.9 Hz, 6H).
MS-ESI:m/z＝865.30[M+1] +。 MS-ESI: m/z = 865.30 [M+1] + .
3)化合物2的合成3) Synthesis of Compound 2
Figure PCTCN2017119448-appb-000095
Figure PCTCN2017119448-appb-000095
将化合物2-3(1.7g，2.0mmol，1eq)溶于丙酮(5mL)，室温下依次加入水(4mL)、三氟乙酸(1mL)和冰乙酸(4mL)后反应3小时。TLC监控反应完全后，往反应液中加入30mL二氯甲烷，搅拌均匀静置分层，有机相依次用水(10mL×3)，饱和氯化钠(10mL)洗涤，无水硫酸钠干燥后减压浓缩，以DCM:MeOH＝70:1为洗脱剂柱层析纯化，得到白色泡沫状固体0.6g,收率40.6％。Compound 2-3 (1.7 g, 2.0 mmol, 1 eq) was dissolved in acetone (5 mL), and water (4 mL), trifluoroacetic acid (1 mL) and EtOAc (4 mL) After the TLC monitoring reaction was completed, 30 mL of dichloromethane was added to the reaction mixture, and the mixture was stirred and allowed to stand for separation. The organic phase was washed successively with water (10 mL×3), saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate Concentration and purification by column chromatography eluting with EtOAc:EtOAc:EtOAc
1H NMR(400MHz,CDCl 3)δ7.43(d,J＝8.1Hz,1H),7.39–7.27(m,7H),7.20(t,J＝8.1Hz,3H),6.05(dt,J＝20.5,17.3Hz,3H),5.71(d,J＝8.2Hz,2H),5.38(d,J＝7.4Hz,1H),5.01(dt,J＝12.5,6.2Hz,1H),4.47(dt,J＝19.2,10.6Hz,2H),4.09(d,J＝9.2Hz,1H),3.97–3.70(m,4H),3.67(s,3H),1.34(d,J＝7.0Hz,3H),1.22(dt,J＝26.9,13.4Hz,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.43 (d, J = 8.1 Hz, 1H), 7.39 - 7.27 (m, 7H), 7.20 (t, J = 8.1 Hz, 3H), 6.05 (dt, J = 20.5, 17.3 Hz, 3H), 5.71 (d, J = 8.2 Hz, 2H), 5.38 (d, J = 7.4 Hz, 1H), 5.01 (dt, J = 12.5, 6.2 Hz, 1H), 4.47 (dt, J = 19.2, 10.6 Hz, 2H), 4.09 (d, J = 9.2 Hz, 1H), 3.97 - 3.70 (m, 4H), 3.67 (s, 3H), 1.34 (d, J = 7.0 Hz, 3H), 1.22 (dt, J = 26.9, 13.4 Hz, 9H).
MS-ESI:m/z＝751.10[M+1] +。 MS-ESI: m/z = 751.10 [M+1] + .
实施例3Example 3
(S)-(3-((2R,3R,4R,5R)-3-氟-4-羟基-5-((((S)-(((S)-1-异丙氧基-1-氧代丙-2-基)氨基)(苯氧基)磷酰基)氧基)甲基)-3-甲基四氢呋喃-2-基)-2,6-二氧代-2,3-二氢嘧啶-1(6H)-基)甲基2-((甲氧基羰基)氨基)-4-(甲硫基)丁酸酯(S)-(3-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-((((S)-((())))) Oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-3-methyltetrahydrofuran-2-yl)-2,6-dioxo-2,3-dihydro Pyrimidine-1(6H)-yl)methyl 2-((methoxycarbonyl)amino)-4-(methylthio)butanoate
Figure PCTCN2017119448-appb-000096
Figure PCTCN2017119448-appb-000096
1)化合物3-2的合成1) Synthesis of compound 3-2
Figure PCTCN2017119448-appb-000097
Figure PCTCN2017119448-appb-000097
将化合物3-1(5g，33.5mmol，1.0eq)和氢氧化钠(4g，100.0mmol，3eq)溶于80mL水中，在-10℃下缓慢滴加氯甲酸甲酯(3.4mL，43.6mmol，1.3eq)，滴完后移至室温反应，TLC监测反应。反应完毕后加入水(100mL)稀释，浓盐酸调pH值至2左右，乙酸乙酯(200mL)萃取后分液，有机相用水(100mL×2)和饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，减压除去溶剂得透明油状产品4.4g。Compound 3-1 (5 g, 33.5 mmol, 1.0 eq) and sodium hydroxide (4 g, 100.0 mmol, 3 eq) were dissolved in water (80 mL), and methyl chloroformate (3.4 mL, 43.6 mmol) was slowly added dropwise at -10 °C. 1.3 eq), after the completion of the dropwise addition, the reaction was carried out to room temperature, and the reaction was monitored by TLC. After the reaction was completed, it was diluted with water (100 mL), and the pH was adjusted to about 2 with concentrated hydrochloric acid. 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).
MS-ESI:m/z 208.20[M+1] +； MS-ESI: m/z 208.20 [M+1] + ;
1H NMR(400MHz,CDCl 3)δ7.54(s,1H),5.49(d,J＝7.6Hz,1H),4.50(d,J＝4.7Hz,1H),3.69(s,3H),2.66–2.39(m,2H),2.18(dd,J＝11.4,6.4Hz,1H),2.10(s,3H),2.03–1.93(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ7.54 (s, 1H), 5.49 (d, J = 7.6Hz, 1H), 4.50 (d, J = 4.7Hz, 1H), 3.69 (s, 3H), 2.66 – 2.39 (m, 2H), 2.18 (dd, J = 11.4, 6.4 Hz, 1H), 2.10 (s, 3H), 2.03 - 1.93 (m, 1H).
2)化合物3-3的合成2) Synthesis of compound 3-3
Figure PCTCN2017119448-appb-000098
Figure PCTCN2017119448-appb-000098
将化合物3-2(4.4g，21mmol，1.0eq)和四丁基硫酸氢铵(0.72g，2.1mmol，0.1eq)，碳酸氢钠(14.4g，170mmol，8.0eq)混合于二氯甲烷和水的混合溶液(40mL+40mL)中，在0℃下缓慢滴加氯甲基氯磺酸酯(4.5mL，42mmol，2.0eq)，滴完后移至室温反应，TLC监测。反应完毕后静置分层，有机相用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，减压除去溶剂后硅胶柱层析，PE/EA＝5/1做洗脱剂，得透明油状液体2.0g。Compound 3-2 (4.4 g, 21 mmol, 1.0 eq) and tetrabutylammonium hydrogen sulfate (0.72 g, 2.1 mmol, 0.1 eq), sodium bicarbonate (14.4 g, 170 mmol, 8.0 eq) Chloromethyl chlorosulfonate (4.5 mL, 42 mmol, 2.0 eq) was slowly added dropwise at 0 ° C in a mixed solution of water (40 mL + 40 mL). After the completion of the reaction, the mixture was separated and the organic layer was washed with saturated sodium chloride solution (100 mL) and dried over anhydrous sodium sulfate, and then evaporated to remove the solvent under silica gel column chromatography, PE/EA=5/1 as eluent. Transparent oily liquid 2.0 g.
1H NMR(400MHz,CDCl 3)δ5.85(d,J＝6.0Hz,1H),5.76–5.61(m,1H),5.43(t,J＝20.4Hz,1H),4.54(t,J＝16.9Hz,1H),3.70(d,J＝7.6Hz,3H),2.68–2.48(m,2H),2.18(dt,J＝12.3,6.8Hz,1H),2.10(d,J＝7.3Hz,3H),2.07–1.95(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ5.85 (d, J = 6.0Hz, 1H), 5.76-5.61 (m, 1H), 5.43 (t, J = 20.4Hz, 1H), 4.54 (t, J = 16.9 Hz, 1H), 3.70 (d, J = 7.6 Hz, 3H), 2.68 - 2.48 (m, 2H), 2.18 (dt, J = 12.3, 6.8 Hz, 1H), 2.10 (d, J = 7.3 Hz, 3H), 2.07–1.95 (m, 1H).
3)化合物3-6的合成3) Synthesis of compound 3-6
Figure PCTCN2017119448-appb-000099
Figure PCTCN2017119448-appb-000099
将化合物M-2(2.75g，4.3mmol，1.0eq)和化合物3-3(1.66g，6.4mmol，1.5eq)溶于乙腈(25mL)中，室温下加入碘化钠(2.56g，17.1mmol，4.0eq)和二异丙基乙基胺(1.1mL，6.4mmol，1.5eq)，-10℃下反应过夜。TLC检测反应完成后直接减压除去反应溶剂，剩余物加入100mL乙酸乙酯和30mL水搅拌至固体完全溶解后静置分液，有机相依次用水(30mL×2)洗涤，饱和氯化钠溶液(30mL)洗涤，有机相用无水硫酸钠干燥后减压除去溶剂。以DCM/MeOH＝100/1为洗脱剂柱层析纯化，得到淡黄色油状液体2.7g。Compound M-2 (2.75 g, 4.3 mmol, 1.0 eq) and compound 3-3 (1.66 g, 6.4 mmol, 1.5 eq) were dissolved in acetonitrile (25 mL) and sodium iodide (2.56 g, 17.1 mmol) , 4.0 eq) and diisopropylethylamine (1.1 mL, 6.4 mmol, 1.5 eq), and reacted at -10 ° C overnight. After the TLC detection reaction was completed, the reaction solvent was directly removed under reduced pressure. The residue was added to 100 mL of ethyl acetate and 30 mL of water and stirred until the solid was completely dissolved, and the mixture was allowed to stand for separation. The organic phase was washed successively with water (30 mL×2) and saturated sodium chloride solution ( After washing with 30 mL), the organic layer was dried over anhydrous sodium sulfate and evaporated. Purification by column chromatography with DCM / MeOH = 100/1 elute
MS-ESI:m/z 863.30[M+1] +； MS-ESI: m/z 863.30 [M+1] + ;
1H NMR(400MHz,CDCl 3)δ7.56(d,J＝8.2Hz,1H),7.27(dd,J＝13.0,5.2Hz,2H),7.17(d,J＝8.3Hz,2H),7.12(t,J＝7.4Hz,1H),6.10(d,J＝16.8Hz,1H),5.96(d,J＝10.0Hz,2H),5.63(dd,J＝24.5,7.8Hz,2H),4.94(dt,J＝12.5,6.3Hz,1H),4.55(dd,J＝11.2,6.3Hz,1H),4.43(d,J＝4.9Hz,1H),4.21(ddd,J＝11.9,5.2,2.6Hz,1H),4.08(d,J＝8.6Hz,1H),3.97–3.85(m,3H),3.61(d,J＝7.2Hz,3H),2.47(t,J＝7.6Hz,2H),2.07–1.99(m,4H),1.90(dt,J＝14.0,6.8Hz,1H),1.33–1.25(m,6H),1.17(d,J＝6.3Hz,6H),0.93(t,J＝8.0Hz,9H),0.62(q,J＝8.0Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.56 (d, J = 8.2Hz, 1H), 7.27 (dd, J = 13.0,5.2Hz, 2H), 7.17 (d, J = 8.3Hz, 2H), 7.12 (t, J = 7.4 Hz, 1H), 6.10 (d, J = 16.8 Hz, 1H), 5.96 (d, J = 10.0 Hz, 2H), 5.63 (dd, J = 24.5, 7.8 Hz, 2H), 4.94 (dt, J = 12.5, 6.3 Hz, 1H), 4.55 (dd, J = 11.2, 6.3 Hz, 1H), 4.43 (d, J = 4.9 Hz, 1H), 4.21 (ddd, J = 11.9, 5.2, 2.6 Hz, 1H), 4.08 (d, J = 8.6 Hz, 1H), 3.97 - 3.85 (m, 3H), 3.61 (d, J = 7.2 Hz, 3H), 2.47 (t, J = 7.6 Hz, 2H), 2.07–1.99 (m, 4H), 1.90 (dt, J=14.0, 6.8 Hz, 1H), 1.33–1.25 (m, 6H), 1.17 (d, J=6.3 Hz, 6H), 0.93 (t, J= 8.0 Hz, 9H), 0.62 (q, J = 8.0 Hz, 6H).
4)化合物3的合成4) Synthesis of Compound 3
Figure PCTCN2017119448-appb-000100
Figure PCTCN2017119448-appb-000100
将化合物3-6(3.63g，4.2mmol，1eq)溶于丙酮(12mL)，室温下依次加入水(9mL)、三氟乙酸(3mL)和冰乙酸(12mL)后反应2小时。TLC监控反应完全后，往反应液中加入30mL二氯甲烷，搅拌均匀静置分层，有机相依次用水(10mL×3)，饱和氯化钠(10mL)洗涤，无水硫酸钠干燥后减压除去溶剂，以DCM:MeOH＝50:1为洗脱剂柱层析纯化，得到白色泡沫状固体2.8g。Compound 3-6 (3.63 g, 4.2 mmol, 1 eq) was dissolved in acetone (12 mL), and water (9 mL), trifluoroacetic acid (3 mL) and EtOAc (EtOAc) After the TLC monitoring reaction was completed, 30 mL of dichloromethane was added to the reaction mixture, and the mixture was stirred and allowed to stand for separation. The organic phase was washed successively with water (10 mL×3), saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate The solvent was removed and purified with EtOAc EtOAc EtOAc EtOAc
MS-ESI:m/z 748.8[M+1] +； MS-ESI: m/z 748.8 [M+1] +
1H NMR(400MHz,CDCl 3)δ7.49(d,J＝8.2Hz,1H),7.34(d,J＝7.6Hz,2H),7.24–7.16(m,3H),6.19(d,J＝17.3Hz,1H),6.07–5.94(m,2H),5.75(d,J＝8.3Hz,1H),5.41(d,J＝7.4Hz,1H),5.07–4.95(m,1H),4.58–4.39(m,3H),4.12(d,J＝8.6Hz,1H),4.02–3.80(m,4H),3.67(s,3H),2.52(t,J＝7.5Hz,2H),2.14–1.90(m,5H),1.37(dd,J＝18.4,14.3Hz,6H),1.24(d,J＝6.3Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.49 (d, J = 8.2Hz, 1H), 7.34 (d, J = 7.6Hz, 2H), 7.24-7.16 (m, 3H), 6.19 (d, J = 17.3 Hz, 1H), 6.07–5.94 (m, 2H), 5.75 (d, J = 8.3 Hz, 1H), 5.41 (d, J = 7.4 Hz, 1H), 5.07–4.95 (m, 1H), 4.58– 4.39 (m, 3H), 4.12 (d, J = 8.6 Hz, 1H), 4.02 - 3.80 (m, 4H), 3.67 (s, 3H), 2.52 (t, J = 7.5 Hz, 2H), 2.14 - 1.90 (m, 5H), 1.37 (dd, J = 18.4, 14.3 Hz, 6H), 1.24 (d, J = 6.3 Hz, 6H).
实施例4Example 4
(S)-2-((3-((2R,3R,4R,5R)-3-氟-4-羟基-5-((((S)-(((S)-1-异丙氧基-1-氧代丙-2-基)氨基)(苯氧基)磷酰基)氧基)甲基)-3-甲基四氢呋喃-2-基)-2,6-二氧代-2,3-二氢嘧啶-1(6H)-基)甲基)1-甲基吡咯烷-1,2-二甲酸酯(S)-2-((3-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-((((S)-(((S)-1-isopropoxy)) -1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-3-methyltetrahydrofuran-2-yl)-2,6-dioxo-2,3 -dihydropyrimidin-1(6H)-yl)methyl)1-methylpyrrolidine-1,2-dicarboxylate
Figure PCTCN2017119448-appb-000101
Figure PCTCN2017119448-appb-000101
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000102
Figure PCTCN2017119448-appb-000102
Figure PCTCN2017119448-appb-000103
Figure PCTCN2017119448-appb-000103
1)化合物4-2的合成1) Synthesis of Compound 4-2
Figure PCTCN2017119448-appb-000104
Figure PCTCN2017119448-appb-000104
将氢氧化钠(10.5g，263mmol，3eq)溶于水(250mL)中，在0℃下加入化合物4-1(10g，86.9mmol，1.0eq)，在此温度下，缓慢滴加氯甲酸甲酯(8.7mL，110mmol，1.3eq)，保持在10min滴加完毕后移至室温。12h后反应完毕，反应液加入浓盐酸调pH值至大约2，乙酸乙酯萃取(300mL×3)，有机相减压浓缩后真空干燥1h得到淡红色透明粘稠液体13.7g，收率91.1％。无进一步纯化投下一步反应。Sodium hydroxide (10.5 g, 263 mmol, 3 eq) was dissolved in water (250 mL), and compound 4-1 (10 g, 86.9 mmol, 1.0 eq) was added at 0 ° C. At this temperature, chloroformic acid was slowly added dropwise. The ester (8.7 mL, 110 mmol, 1.3 eq) was kept at room temperature after 10 min. After 12h, the reaction was completed, and the reaction solution was added with concentrated hydrochloric acid to adjust the pH to about 2, ethyl acetate was extracted (300 mL×3), and the organic phase was concentrated under reduced pressure and dried in vacuo for 1 hour to give a pale red transparent viscous liquid 13.7 g, yield 91.1% . The next reaction was carried out without further purification.
1H NMR(400MHz,CDCl 3)δ8.76(s,1H),4.47–4.17(m,1H),3.74(d,J＝20.8Hz,3H),3.64–3.29(m,2H),2.45–1.70(m,4H) 1 H NMR (400 MHz, CDCl 3 ) δ 8.76 (s, 1H), 4.47 - 4.17 (m, 1H), 3.74 (d, J = 20.8 Hz, 3H), 3.64 - 3.29 (m, 2H), 2.45 - 1.70 (m, 4H)
2)化合物4-3的合成2) Synthesis of compound 4-3
Figure PCTCN2017119448-appb-000105
Figure PCTCN2017119448-appb-000105
将化合物4-2(5g，28.9mmol，1.0eq)和四丁基硫酸氢铵(0.98g，2.9mmol，0.1eq),碳酸钾(16g，115.8mmol，4.0eq)混合于二氯甲烷和水的混合溶液(90mL+90mL)中。在-5℃下缓慢滴加氯甲基氯磺酸酯(5.85mL，57.8mmol，2.0eq)，15min滴完后移至室温反应2小时。TLC监测反应完毕，反应液静置分层，有机相用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，减压浓缩得淡黄色油状液体3.2g，收率50％，无进一步纯化直接投下一步反应。Compound 4-2 (5 g, 28.9 mmol, 1.0 eq) and tetrabutylammonium hydrogen sulfate (0.98 g, 2.9 mmol, 0.1 eq), potassium carbonate (16 g, 115.8 mmol, 4.0 eq) were combined in dichloromethane and water In a mixed solution (90 mL + 90 mL). Chloromethyl chlorosulfonate (5.85 mL, 57.8 mmol, 2.0 eq) was slowly added dropwise at -5 ° C, and after 15 min, the mixture was transferred to room temperature for 2 hours. After the reaction was completed by TLC, the reaction mixture was partitioned. The organic layer was washed with saturated sodium chloride solution (100 mL) and dried over anhydrous sodium sulfate. Directly cast the next reaction.
3)化合物4-4的合成3) Synthesis of compound 4-4
Figure PCTCN2017119448-appb-000106
Figure PCTCN2017119448-appb-000106
将化合物M-2(6g，9.3mmol，1.0eq)和化合物4-3(3.2g，14.3mmol，1.5eq)溶于乙腈(70mL)中，室温下加入碘化钠(5.6g，37mmol，4.0eq)和二异丙基乙基胺(2.12mL，14.0mmol，1.5eq)，50℃下反应过夜。13h后TLC检测反应完成，减压浓缩反应溶剂，剩余物加入乙酸乙酯(200mL)和水(200mL)搅拌至固体完全溶解后静置分液，有机相用水(200mL×2)洗涤，饱和氯化钠溶液(200mL)洗涤，无水硫酸钠干燥后减压浓缩。以DCM:MeOH＝100:1为洗脱剂柱层析纯化，得到乳白色粘稠泡沫固体7.3g，收率94％。Compound M-2 (6 g, 9.3 mmol, 1.0 eq) and compound 4-3 (3.2 g, 14.3 mmol, 1.5 eq) were dissolved in acetonitrile (70 mL) and sodium iodide (5.6 g, 37 mmol, 4.0 Eq) and diisopropylethylamine (2.12 mL, 14.0 mmol, 1.5 eq) were reacted at 50 ° C overnight. After 13 h, the reaction was completed by TLC. The reaction solvent was concentrated under reduced pressure. ethyl acetate (200mL) and water (200mL) were added to the residue. The solid was dissolved and then left to stand. The organic phase was washed with water (200 mL×2). The sodium solution (200 mL) was washed with anhydrous sodium sulfate and evaporated. Purification by column chromatography with DCM: MeOH = 100:1 eluted to afford 7.3 g of viscous white viscous foam solid.
1H NMR(400MHz,CDCl 3)δ7.60(dd,J＝12.9,8.4Hz,1H),7.37(t,J＝7.8Hz,2H),7.22(dd,J＝16.0,7.8Hz,3H),6.21(d,J＝18.4Hz,1H),6.08–5.96(m,2H),5.71(d,J＝8.3Hz,1H),5.02(dt,J＝12.5,6.3Hz,1H),4.63(dd,J＝12.0,6.4Hz,1H),4.42–4.24(m,2H),4.15(d,J＝9.2Hz,1H),4.04–3.91(m,2H),3.68(d,J＝11.0Hz,3H),3.59(dd,J＝12.7,5.1Hz,1H),3.53–3.41(m,1H),2.23(dd,J＝19.9,8.9Hz,1H),2.10–1.85(m,4H),1.37(t,J＝15.4Hz,6H),1.25(d,J＝6.3Hz,6H),1.06–0.97(m,9H),0.69(dt,J＝8.0,5.7Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.60 (dd, J = 12.9,8.4Hz, 1H), 7.37 (t, J = 7.8Hz, 2H), 7.22 (dd, J = 16.0,7.8Hz, 3H) , 6.21 (d, J = 18.4 Hz, 1H), 6.08 - 5.96 (m, 2H), 5.71 (d, J = 8.3 Hz, 1H), 5.02 (dt, J = 12.5, 6.3 Hz, 1H), 4.63 ( Dd, J = 12.0, 6.4 Hz, 1H), 4.42 - 4.24 (m, 2H), 4.15 (d, J = 9.2 Hz, 1H), 4.04 - 3.91 (m, 2H), 3.68 (d, J = 11.0 Hz) , 3H), 3.59 (dd, J = 12.7, 5.1 Hz, 1H), 3.53 - 3.41 (m, 1H), 2.23 (dd, J = 19.9, 8.9 Hz, 1H), 2.10 - 1.85 (m, 4H), 1.37 (t, J = 15.4 Hz, 6H), 1.25 (d, J = 6.3 Hz, 6H), 1.06 - 0.97 (m, 9H), 0.69 (dt, J = 8.0, 5.7 Hz, 6H).
4)化合物4的合成4) Synthesis of Compound 4
Figure PCTCN2017119448-appb-000107
Figure PCTCN2017119448-appb-000107
将化合物4-4(7.3g，8.8mmol，1eq)溶于丙酮(20mL)，室温下依次加入水(15mL)、三氟乙酸(5mL)和冰乙酸(20mL)后反应2小时。TLC监控反应完全后，往反应液中加入二氯甲烷(100mL)和(100mL)水，搅拌均匀静置分层，有机相依次用水(10mL×3)，饱和氯化钠(10mL)洗涤，无水硫酸钠干燥后减压浓缩，以DCM:MeOH＝70:1为洗脱剂柱层析纯化，得到白色泡沫状固体4.3g，收率68％。Compound 4-4 (7.3 g, 8.8 mmol, 1 eq) was dissolved in acetone (20 mL), and water (15 mL), trifluoroacetic acid (5 mL) and EtOAc (20 mL) After the TLC monitoring reaction was completed, dichloromethane (100 mL) and (100 mL) water were added to the reaction mixture, and the mixture was stirred and allowed to stand for separation. The organic phase was washed successively with water (10 mL×3) and saturated sodium chloride (10 mL). The organic layer was dried over anhydrous sodium sulfate (MgSO4).
1H NMR(400MHz,CDCl 3)δ7.55–7.47(m,1H),7.39(s,2H),7.25(d,J＝7.8Hz,3H),6.32–6.17(m,1H),6.04(s,2H),5.81–5.74(m,1H),5.11–4.98(m,1H),4.61–4.43(m,2H),4.42–4.28(m,1H),4.16–4.12(m,1H),4.03–3.88(m,2H),3.81–3.73(m,1H),3.70(d,J＝12.1Hz,3H),3.66–3.36(m,3H),2.29–2.15(m,1H),2.06–1.82(m,3H),1.41(dd,J＝21.1,14.8Hz,6H),1.27(d,J＝6.4Hz,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 - 7.47 (m, 1H), 7.39 (s, 2H), 7.25 (d, J = 7.8 Hz, 3H), 6.32 - 6.17 (m, 1H), 6.04 ( s, 2H), 5.81–5.74 (m, 1H), 5.11–4.98 (m, 1H), 4.61–4.43 (m, 2H), 4.42–4.28 (m, 1H), 4.16–4.12 (m, 1H), 4.03–3.88 (m, 2H), 3.81–3.73 (m, 1H), 3.70 (d, J = 12.1 Hz, 3H), 3.66–3.36 (m, 3H), 2.29–2.15 (m, 1H), 2.06– 1.82 (m, 3H), 1.41 (dd, J = 21.1, 14.8 Hz, 6H), 1.27 (d, J = 6.4 Hz, 6H).
MS-ESI:m/z 715.20[M+1] +。 MS-ESI: m/z 715.20 [M+1] + .
实施例5Example 5
(S)-异丙基2-(((S)-(((2R,3R,4R,5R)-4-氟-3-羟基-5-(3-((2-((甲氧基羰基)氨基)乙酰氧基)甲基)-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-甲基四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基)氨基)丙酸酯(S)-Isopropyl 2-(((S)-(((2R,3R,4R,5R)-4-fluoro-3-hydroxy-5-(3-((2-((methoxycarbonyl))) Amino)acetoxy)methyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-methyltetrahydrofuran-2-yl)methoxy) Phenoxy)phosphoryl)amino)propionate
Figure PCTCN2017119448-appb-000108
Figure PCTCN2017119448-appb-000108
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000109
Figure PCTCN2017119448-appb-000109
1)化合物5-2的合成1) Synthesis of compound 5-2
Figure PCTCN2017119448-appb-000110
Figure PCTCN2017119448-appb-000110
将氢氧化钠(10.5g，263mmol，3eq)溶于水(250mL)中，在0℃下加入化合物5-1(6.5g，87mmol， 1.0eq)，在此温度下，缓慢滴加氯甲酸甲酯(8.7mL，110mmol，1.3eq)，保持在10min滴加完毕后移至室温。12h后反应完毕，反应液加入浓盐酸调pH值至大约2，乙酸乙酯萃取(300mL×3)，有机相减压浓缩后真空干燥1h得无色透明粘稠液体8.5g，收率74％。Sodium hydroxide (10.5 g, 263 mmol, 3 eq) was dissolved in water (250 mL). Compound 5-1 (6.5 g, 87 mmol, 1.0 eq) was added at 0 ° C. At this temperature, chloroformic acid was slowly added dropwise. The ester (8.7 mL, 110 mmol, 1.3 eq) was kept at room temperature after 10 min. After 12h, the reaction was completed, the reaction solution was added with concentrated hydrochloric acid to adjust the pH to about 2, ethyl acetate was extracted (300 mL×3), and the organic phase was concentrated under reduced pressure and dried in vacuo for 1 h to give 8.5 g of colorless transparent viscous liquid, yield 74%. .
1H NMR(400MHz,CDCl 3)12.55(s,1H),7.40(t,J＝5.9Hz,1H),3.63(d,J＝6.1Hz,2H),3.54(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) 12.55 (s, 1H), 7.40 (t,J = 5.9 Hz, 1H), 3.63 (d, J = 6.1 Hz, 2H), 3.54 (s, 3H).
2)化合物5-3的合成2) Synthesis of compound 5-3
Figure PCTCN2017119448-appb-000111
Figure PCTCN2017119448-appb-000111
将化合物5-2(3g，22.5mmol，1.0eq)和四丁基硫酸氢铵(0.77g，2.2mmol，0.1eq)，碳酸钾(12.5g，90.2mmol，4.0eq)混合于二氯甲烷和水的混合溶液(70mL+70mL)中。在-5℃下缓慢滴加氯甲基氯磺酸酯(4.6mL，45.1mmol，2.0eq)，15min滴完后移至室温反应2小时。TLC监测反应完毕，反应液静置分层，有机相用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，减压浓缩得白色泡沫固体2.3g，收率56％，无进一步纯化直接投下一步反应。Compound 5-2 (3 g, 22.5 mmol, 1.0 eq) and tetrabutylammonium hydrogen sulfate (0.77 g, 2.2 mmol, 0.1 eq), potassium carbonate (12.5 g, 90.2 mmol, 4.0 eq) A mixed solution of water (70 mL + 70 mL). Chloromethyl chlorosulfonate (4.6 mL, 45.1 mmol, 2.0 eq) was slowly added dropwise at -5 ° C, and after 15 min, the mixture was transferred to room temperature for 2 hours. After the reaction was completed by TLC, the reaction mixture was partitioned. The organic layer was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and evaporated. Vote for the next step.
3)化合物5-4合成3) Synthesis of compound 5-4
Figure PCTCN2017119448-appb-000112
Figure PCTCN2017119448-appb-000112
将化合物M-2(2.3g，3.6mmol，1.0eq)和化合物5-3(0.85g，4.6mmol，1.3eq)溶于乙腈(30mL)中，室温下加入碘化钠(2.1g，14mmol，4.0eq)和二异丙基乙基胺(0.81mL，5.4mmol，1.5eq)，50℃下反应过夜。15h后TLC检测反应完成，减压浓缩反应溶剂，剩余物加入乙酸乙酯(200mL)和水(200mL)搅拌至固体完全溶解后静置分液，有机相用水(200mL×2)、饱和氯化钠溶液(200mL)洗涤，有机相用无水硫酸钠干燥后减压浓缩。以DCM:MeOH＝100:1为洗脱剂柱层析纯化，得到乳白色粘稠泡沫固体2.1g，收率75％。Compound M-2 (2.3 g, 3.6 mmol, 1.0 eq) and compound 5-3 (0.85 g, 4.6 mmol, 1.3 eq) were dissolved in acetonitrile (30 mL) and sodium iodide (2.1 g, 14 mmol, 4.0 eq) and diisopropylethylamine (0.81 mL, 5.4 mmol, 1.5 eq) were reacted at 50 ° C overnight. After 15 h, the reaction was completed by TLC. The reaction solvent was concentrated under reduced pressure. ethyl acetate (200mL) and water (200mL) were added to the residue and the mixture was stirred and dissolved. The organic phase was partitioned with water (200 mL×2), saturated chlorination The organic layer was dried over anhydrous sodium sulfate and evaporated. Purification by column chromatography with DCM:MeOH = 100:1 elute
4)化合物5合成4) Synthesis of compound 5
Figure PCTCN2017119448-appb-000113
Figure PCTCN2017119448-appb-000113
将化合物5-4(2.12g，2.7mmol，1eq)溶于丙酮(8mL)，室温下依次加入水(6mL)、三氟乙酸(2mL)和冰乙酸(8mL)后反应2小时。TLC监控反应完全后，往反应液中加入二氯甲烷(40mL)和水(40mL)，搅拌均匀静置分层，有机相依次用水(40mL×3)，饱和氯化钠(40mL)洗涤，无水硫酸钠干燥后减压浓缩，以DCM:MeOH＝70:1为洗脱剂柱层析纯化，得到白色泡沫状固体1.3g，收率72％。Compound 5-4 (2.12 g, 2.7 mmol, 1 eq) was dissolved in acetone (8 mL), and water (6 mL), trifluoroacetic acid (2 mL) and EtOAc (EtOAc) After the TLC monitoring reaction was completed, dichloromethane (40 mL) and water (40 mL) were added to the reaction mixture, and the mixture was stirred and left to stand for separation. The organic phase was washed successively with water (40 mL×3) and saturated sodium chloride (40 mL). The organic layer was dried over anhydrous sodium sulfate (MgSO4).
1H NMR(400MHz,CDCl 3)δ7.51(d,J＝8.2Hz,1H),7.38(t,J＝7.9Hz,2H),7.24(dd,J＝8.3,3.2Hz,3H),6.32–6.13(m,1H),6.05(s,2H),5.78(d,J＝8.3Hz,1H),5.30–5.15(m,1H),5.09–4.96(m,1H),4.61–4.41(m,2H),4.14(d,J＝7.3Hz,1H),4.04–3.82(m,6H),3.71(s,3H),1.40(dd,J＝18.1,14.6Hz,6H),1.26(d,J＝6.3Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.51 (d, J = 8.2Hz, 1H), 7.38 (t, J = 7.9Hz, 2H), 7.24 (dd, J = 8.3,3.2Hz, 3H), 6.32 –6.13(m,1H),6.05(s,2H), 5.78(d,J=8.3Hz,1H), 5.30–5.15(m,1H),5.09–4.96(m,1H),4.61–4.41(m) , 2H), 4.14 (d, J = 7.3 Hz, 1H), 4.04 - 3.82 (m, 6H), 3.71 (s, 3H), 1.40 (dd, J = 18.1, 14.6 Hz, 6H), 1.26 (d, J = 6.3 Hz, 6H).
MS-ESI:m/z＝675.10[M+1] +。 MS-ESI: m / z = 675.10 [M + 1] +.
实施例7Example 7
(S)-(3-((2R,3R,4R,5R)-3-氟-4-羟基-5-((((S)-(((S)-1-异丙氧基-1-氧代丙-2-基)氨基)(苯氧基)磷酰基)氧基)甲基)-3-甲基四氢呋喃-2-基)-2,6-二氧代-2,3-二氢嘧啶-1(6H)-基)甲基吡咯烷-2-甲酸酯盐酸盐(S)-(3-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-((((S)-((())))) Oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-3-methyltetrahydrofuran-2-yl)-2,6-dioxo-2,3-dihydro Pyrimidine-1(6H)-yl)methylpyrrolidine-2-carboxylate hydrochloride
Figure PCTCN2017119448-appb-000114
Figure PCTCN2017119448-appb-000114
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000115
Figure PCTCN2017119448-appb-000115
Figure PCTCN2017119448-appb-000116
Figure PCTCN2017119448-appb-000116
1)化合物7-2的合成1) Synthesis of compound 7-2
Figure PCTCN2017119448-appb-000117
Figure PCTCN2017119448-appb-000117
将化合物7-1(3g，13.9mmol，1.0eq)和四丁基硫酸氢铵(0.47g，1.4mmol，0.1eq)，碳酸钾(7.7g，56mmol，4.0eq)混合于二氯甲烷和水的混合溶液(40mL+40mL)中。在-5℃下缓慢滴加氯甲基氯磺酸酯(5.85mL，57.8mmol，2.0eq)，15min滴完后移至室温反应3小时。TLC监测反应完毕，反应液静置分层，有机相用水(100mL)、饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，减压浓缩得淡黄色油状液体3.09g，收率84.1％，无进一步纯化直接投下一步反应。Compound 7-1 (3 g, 13.9 mmol, 1.0 eq) and tetrabutylammonium hydrogen sulfate (0.47 g, 1.4 mmol, 0.1 eq), potassium carbonate (7.7 g, 56 mmol, 4.0 eq) were combined in dichloromethane and water In a mixed solution (40 mL + 40 mL). Chloromethyl chlorosulfonate (5.85 mL, 57.8 mmol, 2.0 eq) was slowly added dropwise at -5 ° C, and after 15 min, the mixture was transferred to room temperature for 3 hours. After the reaction was completed by TLC, the 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.
2)化合物7-3合成2) Synthesis of compound 7-3
Figure PCTCN2017119448-appb-000118
Figure PCTCN2017119448-appb-000118
将化合物M-2(5g，7.8mmol，1.0eq)和化合物7-2(3.1g，11.7mmol，1.5eq)溶于乙腈(50mL)中，室温下加入碘化钠(4.6g，31mmol，4.0eq)和二异丙基乙基胺(1.8mL，11.7mmol，1.5eq)，50℃下反应过夜。13h后TLC检测反应完成，减压浓缩反应溶剂，剩余物加入乙酸乙酯(200mL)和水(200mL)搅拌至固体完全溶解后静置分液，有机相依次用水(200mL×2)，饱和氯化钠溶液(200mL)洗涤，有机相用无水硫酸钠干燥后减压浓缩。以DCM:MeOH＝100:1为洗脱剂柱层析纯化，得到乳白色粘稠泡沫固体 5.5g，收率81％。Compound M-2 (5 g, 7.8 mmol, 1.0 eq) and compound 7-2 (3.1 g, 11.7 mmol, 1.5 eq) were dissolved in acetonitrile (50 mL) and sodium iodide (4.6 g, 31 mmol, 4.0 Eq) and diisopropylethylamine (1.8 mL, 11.7 mmol, 1.5 eq) were reacted at 50 ° C overnight. After 13 h, the reaction was completed by TLC. The reaction solvent was concentrated under reduced pressure. ethyl acetate (200 mL) and water (200 mL) was added to the residue and the mixture was stirred until the solid was completely dissolved. The organic phase was separated by water (200 mL×2), saturated The sodium chloride solution (200 mL) was washed and dried over anhydrous sodium sulfate. Purification by column chromatography with DCM: MeOH = 100:1 eluted to afford pale white viscous foam solids 5.5 g.
3)化合物7-4合成3) Synthesis of compound 7-4
Figure PCTCN2017119448-appb-000119
Figure PCTCN2017119448-appb-000119
将化合物7-3(5.5g，6.3mmol，1eq)溶于丙酮(16mL)，室温下依次加入水(12mL)、三氟乙酸(4mL)和冰乙酸(16mL)后反应2小时。TLC监控反应完全后，往反应液中加入二氯甲烷(40mL)和水(40mL)，搅拌均匀静置分层，有机相依次用水(40mL×3)，饱和氯化钠(40mL)洗涤，无水硫酸钠干燥后减压浓缩，以DCM:MeOH＝70:1为洗脱剂柱层析纯化，得到白色泡沫状固体4.3g，收率80％。纯度98.03％。Compound 7-3 (5.5 g, 6.3 mmol, 1 eq) was dissolved in acetone (16 mL), and water (12 mL), trifluoroacetic acid (4 mL) and EtOAc (16 mL) After the TLC monitoring reaction was completed, dichloromethane (40 mL) and water (40 mL) were added to the reaction mixture, and the mixture was stirred and left to stand for separation. The organic phase was washed successively with water (40 mL×3) and saturated sodium chloride (40 mL). The organic layer was dried over anhydrous sodium sulfate (MgSO4). The purity is 98.03%.
4)化合物7合成4) Synthesis of compound 7
Figure PCTCN2017119448-appb-000120
Figure PCTCN2017119448-appb-000120
将化合物7-4(2.5g，0.13mmol，1eq)溶于盐酸异丙醇溶液(1N，2mL)，室温下搅拌反应，TLC监控。2小时反应完毕，减压浓缩反应溶剂，乙酸乙酯打浆，抽滤得白色固体2.2g，收率96％。Compound 7-4 (2.5 g, 0.13 mmol, 1 eq) was dissolved in EtOAc (1 N, 2 mL). After completion of the reaction for 2 hours, the reaction solvent was concentrated under reduced pressure, and ethyl acetate was evaporated.
1H NMR(600MHz,CDCl 3)δ7.55–7.47(m,1H),7.39(s,2H),7.25(d,J＝7.8Hz,3H),6.32–6.17(m,1H),6.04(s,2H),5.81–5.74(m,1H),5.11–4.98(m,1H),4.61–4.43(m,2H),4.42–4.28(m,1H),4.16–4.12(m,1H),4.03–3.88(m,2H),3.81–3.73(m,1H),3.66–3.36(m,3H),2.29–2.15(m,1H),2.06–1.82(m,4H),1.41(dd,J＝21.1,14.8Hz,6H),1.27(d,J＝6.4Hz,6H)。 1 H NMR (600MHz, CDCl 3 ) δ 7.55 - 7.47 (m, 1H), 7.39 (s, 2H), 7.25 (d, J = 7.8 Hz, 3H), 6.32 - 6.17 (m, 1H), 6.04 ( s, 2H), 5.81–5.74 (m, 1H), 5.11–4.98 (m, 1H), 4.61–4.43 (m, 2H), 4.42–4.28 (m, 1H), 4.16–4.12 (m, 1H), 4.03–3.88 (m, 2H), 3.81–3.73 (m, 1H), 3.66–3.36 (m, 3H), 2.29–2.15 (m, 1H), 2.06–1.82 (m, 4H), 1.41 (dd, J) = 21.1, 14.8 Hz, 6H), 1.27 (d, J = 6.4 Hz, 6H).
MS-ESI:m/z 657.2[M+1] +。 MS-ESI: m/z 657.2 [M+1] + .
实施例8Example 8
4-((3-((2R,3R,4R,5R)-3-氟-4-羟基-5-((((S)-(((S)-1-异丙氧基-1-氧代丙-2-基)氨基)(苯氧基)磷酰基)氧基)甲基)-3-甲基四氢呋喃-2-基)-2,6-二氧代-2,3-二氢嘧啶-1(6H)-基)甲氧基)-4-氧代丁酸4-((3-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-((((S)-((())))) (1,6-dioxo-2,3-dihydropyrimidine) -1(6H)-yl)methoxy)-4-oxobutanoic acid
Figure PCTCN2017119448-appb-000121
Figure PCTCN2017119448-appb-000121
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000122
Figure PCTCN2017119448-appb-000122
1)化合物8-2的合成1) Synthesis of Compound 8-2
Figure PCTCN2017119448-appb-000123
Figure PCTCN2017119448-appb-000123
在100mL单口瓶中加入化合物8-1(5.0g,50.0mmol,1.0eq)和二氯甲烷(40mL)，室温下依次加入苄醇(5.7mL,55.0mmol,1.1eq)，三乙胺(7.6mL,55.0mmol,1.1eq)和4-二甲氨基吡啶(0.6g,0.5mmol,0.1eq)。室温反应过夜，加二氯甲烷(40mL)稀释反应液，有机相用5％的碳酸氢钠(40mL×2)洗涤，收集水相。水相用浓盐酸酸化至pH＝2左右，再用乙酸乙酯萃取(30mL×3)，有机相依次用水(30mL)和饱和氯化钠溶液(30mL)洗涤后经无水硫酸钠干燥，减压浓缩得白色固体10.0g。Compound 8-1 (5.0 g, 50.0 mmol, 1.0 eq) and dichloromethane (40 mL) were added to a 100 mL vial, and benzyl alcohol (5.7 mL, 55.0 mmol, 1.1 eq), triethylamine (7.6) mL, 55.0 mmol, 1.1 eq) and 4-dimethylaminopyridine (0.6 g, 0.5 mmol, 0.1 eq). After reacting at room temperature overnight, the reaction mixture was diluted with dichloromethane (40 mL), and the organic phase was washed with 5% sodium hydrogencarbonate (40 mL×2) and the aqueous phase was collected. The aqueous phase was acidified to pH=2 with concentrated hydrochloric acid and extracted with ethyl acetate (30 mL×3). 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).
1H NMR(400MHz,CDCl 3)δ7.42–7.31(m,5H),5.17(s,2H),2.75–2.67(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.42 - 7.31 (m, 5H), 5.17 (s, 2H), 2.75 - 2.67 (m, 4H).
MS-ESI:m/z 231.0[M+Na] +。 MS-ESI: m/z 231.0 [M+Na] + .
2)化合物8-3的合成2) Synthesis of compound 8-3
Figure PCTCN2017119448-appb-000124
Figure PCTCN2017119448-appb-000124
在100mL单口瓶中依次加入化合物8-2(2.1g,8.0mmol,1.0eq)，四丁基硫酸氢铵(0.33g,0.97mmol,0.1eq)，碳酸氢钠(6.45g,76.8mmol,8.0eq)，二氯甲烷(20mL)和水(20mL)，在-10℃下缓慢滴加氯甲基氯磺酸酯(2.0mL，19.2mmol，2.0eq)，滴完后移至室温反应。5h后TLC监测原料基本反应完全，向反应瓶中加水(20mL)和二氯甲烷(20mL)，静置分液，有机相用水(20mL×3)、饱和氯化钠溶液(20mL)洗涤后经无水硫酸钠干燥，减压浓缩后硅胶柱层析，PE/EA＝5/1做洗脱剂，得无色油状液体2.06g。Compound 8-2 (2.1 g, 8.0 mmol, 1.0 eq), tetrabutylammonium hydrogen sulfate (0.33 g, 0.97 mmol, 0.1 eq), sodium hydrogencarbonate (6.45 g, 76.8 mmol, 8.0) were sequentially added to a 100 mL single-necked flask. Eq), dichloromethane (20 mL) and water (20 mL), chloromethyl chlorosulfonate (2.0 mL, 19.2 mmol, 2.0 eq) was slowly added dropwise at -10 °C. After 5 h, the basic reaction of the starting material was completely monitored by TLC. Water (20 mL) and dichloromethane (20 mL) were added to the reaction flask, and the mixture was separated, and the organic phase was washed with water (20 mL×3) and saturated sodium chloride solution (20 mL). The organic layer was dried over anhydrous sodium sulfate, and evaporated.
3)化合物8-4合成3) Synthesis of compound 8-4
Figure PCTCN2017119448-appb-000125
Figure PCTCN2017119448-appb-000125
在100mL单口瓶中加入化合物M-2(2.8g，4.3mmol，1.0eq)，化合物8-3(2.06g，8.0mmol，1.5eq)和乙腈(30mL)，搅拌溶解。室温下依次加入碘化钠(3.1g，21mmol，4.0eq)和二异丙基乙基胺(1.3mL，7.9mmol，1.5eq)，50℃反应过夜，22h后TLC检测原料反应完全。减压浓缩溶剂后残渣加入乙酸乙酯(50mL)稀释反应液，有机相依次用水洗(25mL×3)，饱和氯化钠溶液(25mL)洗涤后经无水硫酸钠干燥，粗产品用DCM/MeOH＝50/1为洗脱剂柱层析纯化，得到淡黄色油状液体2.85g，收率76％。Compound M-2 (2.8 g, 4.3 mmol, 1.0 eq), compound 8-3 (2.06 g, 8.0 mmol, 1.5 eq), and acetonitrile (30 mL) were added to a 100 mL vial. Sodium iodide (3.1 g, 21 mmol, 4.0 eq) and diisopropylethylamine (1.3 mL, 7.9 mmol, 1.5 eq) were sequentially added at room temperature, and reacted at 50 ° C overnight. After 22 h, the starting material was completely reacted by TLC. The solvent was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc m. Purification by column chromatography eluting with EtOAc = EtOAc (EtOAc)
1H NMR(400MHz,CDCl 3)δ7.57(d,J＝8.3Hz,1H),7.36–7.31(m,7H),7.24–7.15(m,3H),6.18(d,J＝18.4Hz,1H),5.97(d,J＝2.2Hz,2H),5.69(d,J＝8.3Hz,1H),5.12(s,2H),5.05–4.94(m,1H),4.59(s,1H),4.26(s,1H),3.95(dd,J＝15.3,6.9Hz,2H),3.73–3.64(m,1H),2.68(d,J＝6.5Hz,5H),1.34(t,J＝14.2Hz,6H),1.22(d,J＝6.3Hz,6H),1.01–0.96(m,9H),0.66(dt,J＝8.0,6.1Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.57 (d, J = 8.3Hz, 1H), 7.36-7.31 (m, 7H), 7.24-7.15 (m, 3H), 6.18 (d, J = 18.4Hz, 1H), 5.97 (d, J = 2.2 Hz, 2H), 5.69 (d, J = 8.3 Hz, 1H), 5.12 (s, 2H), 5.05 - 4.94 (m, 1H), 4.59 (s, 1H), 4.26 (s, 1H), 3.95 (dd, J = 15.3, 6.9 Hz, 2H), 3.73 - 3.64 (m, 1H), 2.68 (d, J = 6.5 Hz, 5H), 1.34 (t, J = 14.2 Hz) , 6H), 1.22 (d, J = 6.3 Hz, 6H), 1.01 - 0.96 (m, 9H), 0.66 (dt, J = 8.0, 6.1 Hz, 6H).
MS-ESI:m/z 864.30[M+1] +。 MS-ESI: m/z 864.30 [M+1] + .
4)化合物8-5合成4) Synthesis of compound 8-5
Figure PCTCN2017119448-appb-000126
Figure PCTCN2017119448-appb-000126
在25mL单口瓶中依次加入化合物8-4(1.2g，1.4mmol，1.0eq)，4ml丙酮，3ml水，4ml冰乙酸和1ml三氟乙酸，室温下搅拌反应。3小时后TLC检测原料反应完全，向反应瓶中加入二氯甲烷(40mL)稀释，有机相依次用水(20mL×2)和饱和氯化钠(20mL)洗涤后旋除溶剂，粗产品用DCM:MeOH＝50:1为洗脱剂柱层析纯化，得到白色发泡固体0.7g,收率70％。Compound 8-4 (1.2 g, 1.4 mmol, 1.0 eq), 4 ml of acetone, 3 ml of water, 4 ml of glacial acetic acid and 1 ml of trifluoroacetic acid were sequentially added to a 25 mL one-necked flask, and the mixture was stirred at room temperature. After 3 hours, TLC detected the reaction of the starting material completely, and diluted with dichloromethane (40 mL). The organic phase was washed with water (20 mL×2) and saturated sodium chloride (20 mL) and then solvent was evaporated. Purification by column chromatography eluting with MeOH = 50:1 afforded white foamy solid 0.7 g, yield 70%.
1H NMR(400MHz,CDCl 3)δ7.47(d,J＝8.2Hz,1H),7.38–7.32(m,7H),7.25–7.17(m,3H),6.30–6.11(m,1H),5.98(d,J＝4.4Hz,2H),5.75(d,J＝8.3Hz,1H),5.13(s,2H),5.02(s,1H),4.59–4.38(m,2H),4.14–4.07(m,1H),3.82(s,3H),2.68(d,J＝5.4Hz,5H),1.38(dd,J＝18.5,14.7Hz,6H),1.24(d,J＝6.3Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.47 (d, J = 8.2Hz, 1H), 7.38-7.32 (m, 7H), 7.25-7.17 (m, 3H), 6.30-6.11 (m, 1H), 5.98 (d, J = 4.4 Hz, 2H), 5.75 (d, J = 8.3 Hz, 1H), 5.13 (s, 2H), 5.02 (s, 1H), 4.59 - 4.38 (m, 2H), 4.14 - 4.07 (m, 1H), 3.82 (s, 3H), 2.68 (d, J = 5.4 Hz, 5H), 1.38 (dd, J = 18.5, 14.7 Hz, 6H), 1.24 (d, J = 6.3 Hz, 6H) .
MS-ESI:m/z＝750.3[M+1] +。 MS-ESI: m/z = 750.3 [M+1] + .
5)化合物8合成5) Synthesis of compound 8
Figure PCTCN2017119448-appb-000127
Figure PCTCN2017119448-appb-000127
在25mL单口瓶中依次加入化合物8-5(0.65g,0.87mmol,1.0eq)，钯碳(0.06g)和乙酸乙酯(10mL)，氢气氛围下，室温反应过夜。TLC检测原料反应完，向反应瓶中加入乙酸乙酯(20mL)稀释，有机相饱和碳酸氢钠洗涤(15mL×2)，收集水相。水相用浓盐酸酸化至pH＝2左右，再用乙酸乙酯萃取(10mL×3)，得到的有机相依次用水(10mL)和饱和氯化钠溶液(10mL)洗涤后经无水硫酸钠干燥，减压浓缩得灰白色固体0.5g，收率90％。Compound 8-5 (0.65 g, 0.87 mmol, 1.0 eq), palladium on carbon (0.06 g) and ethyl acetate (10 mL) were successively added to a 25-mL one-necked flask, and allowed to react overnight at room temperature under a hydrogen atmosphere. After the reaction of the TLC was started, the reaction mixture was diluted with ethyl acetate (20 mL) and the organic phase was washed with saturated sodium hydrogen carbonate (15 mL×2), and the aqueous phase was collected. The aqueous phase was acidified to pH=2 with concentrated hydrochloric acid and extracted with ethyl acetate (10 mL×3). The organic phase was washed with water (10mL) and saturated sodium chloride (10mL) and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give a white solid (yield: 0.5 g).
1H NMR(400MHz,CDCl 3)δ7.53–7.41(m,1H),7.36(d,J＝7.8Hz,2H),7.24(d,J＝8.5Hz,3H),6.02(s,2H),5.79(d,J＝8.2Hz,1H),5.10–4.96(m,1H),4.61–4.40(m,2H),4.14(d,J＝7.2Hz,3H),4.07–3.88(m,2H),2.67(d,J＝11.6Hz,5H),1.40(dd,J＝19.8,14.8Hz,6H),1.26(d,J＝6.2Hz,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.53 - 7.41 (m, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 8.5 Hz, 3H), 6.02 (s, 2H) , 5.79 (d, J = 8.2 Hz, 1H), 5.10 - 4.96 (m, 1H), 4.61 - 4.40 (m, 2H), 4.14 (d, J = 7.2 Hz, 3H), 4.07 - 3.88 (m, 2H) ), 2.67 (d, J = 11.6 Hz, 5H), 1.40 (dd, J = 19.8, 14.8 Hz, 6H), 1.26 (d, J = 6.2 Hz, 6H).
MS-ESI:m/z＝660.3[M+1] +。 MS-ESI: m/z = 660.3 [M+1] + .
实施例9Example 9
(3-((2R,3R,4R,5R)-3-氟-4-羟基-5-((((S)-(((S)-1-异丙氧基-1-氧代丙-2-基)氨基)(苯氧基)磷酰基)氧基)甲基)-3-甲基四氢呋喃-2-基)-2,6-二氧代-2,3-二氢嘧啶-1(6H)-基)甲基4-((甲氧基羰基)氨基)丁酸甲酯(3-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-((((S)-((()))))) 2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-3-methyltetrahydrofuran-2-yl)-2,6-dioxo-2,3-dihydropyrimidine-1 ( 6H)-yl)methyl 4-((methoxycarbonyl)amino)butyric acid methyl ester
Figure PCTCN2017119448-appb-000128
Figure PCTCN2017119448-appb-000128
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000129
Figure PCTCN2017119448-appb-000129
1)化合物9-2的合成1) Synthesis of compound 9-2
Figure PCTCN2017119448-appb-000130
Figure PCTCN2017119448-appb-000130
在100mL单口瓶中依次加入氢氧化钠(3g,73.3mmol,3eq)和水(60mL)，置于-10℃下搅拌10分钟。再加入4-氨基丁酸(2.52g,24.4mmol,1eq)，滴加氯甲酸甲酯(2.5mL,31.8mmol,1.3eq)。继续低温搅拌半小时，转移至室温反应过夜。加水稀释，水相浓盐酸酸化至PH＝2左右，乙酸乙酯萃取3次，有机相无水硫 酸钠干燥，减压浓缩得透明油状液体2.2g,收率56％。Sodium hydroxide (3 g, 73.3 mmol, 3 eq) and water (60 mL) were sequentially added to a 100 mL single-mouth flask, and stirred at -10 ° C for 10 minutes. Further, 4-aminobutyric acid (2.52 g, 24.4 mmol, 1 eq) was added, and methyl chloroformate (2.5 mL, 31.8 mmol, 1.3 eq) was added dropwise. Stirring was continued for half an hour and transferred to room temperature overnight. After dilution with water, the aqueous phase was acidified to pH = 2, ethyl acetate was extracted three times, and the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude oily liquid 2.2 g, yield 56%.
1H NMR(400MHz,CDCl 3)δ4.94(s,1H),3.68(s,3H),3.27(m,2H),2.42(t,J＝7.2Hz,2H),1.86(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ4.94 (s, 1H), 3.68 (s, 3H), 3.27 (m, 2H), 2.42 (t, J = 7.2Hz, 2H), 1.86 (m, 2H) .
2)化合物9-3的合成2) Synthesis of compound 9-3
Figure PCTCN2017119448-appb-000131
Figure PCTCN2017119448-appb-000131
将化合物9-2(2.2g,14mmol,1eq)和四丁基硫酸氢铵(0.45g,1.3mmol,0.1eq),碳酸钾(7.26g，52.6mmol，4eq)混合于二氯甲烷和水的混合溶液(20mL+20mL)中，在0℃下缓慢滴加氯甲基氯磺酸酯(2.8mL,27mmol,2eq)，滴完后移至室温反应，3小时后TLC监测原料反应完全。静置分层，有机相依次用水和饱和氯化钠溶液洗涤后经无水硫酸钠干燥，减压浓缩后硅胶柱层析，PE/EA＝5/1做洗脱剂，得透明油状液体2.13g，收率74％。Compound 9-2 (2.2 g, 14 mmol, 1 eq) and tetrabutylammonium hydrogen sulfate (0.45 g, 1.3 mmol, 0.1 eq), potassium carbonate (7.26 g, 52.6 mmol, 4 eq) were combined in dichloromethane and water. In the mixed solution (20 mL + 20 mL), chloromethyl chlorosulfonate (2.8 mL, 27 mmol, 2 eq) was slowly added dropwise at 0 ° C. After the dropwise addition, the mixture was allowed to react at room temperature, and after 3 hours, the reaction of the starting material was monitored by TLC. The organic layer was washed successively with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to silica gel column chromatography, PE/EA=5/1 as eluent to obtain a clear oily liquid 2.13. g, yield 74%.
3)化合物9-4的合成3) Synthesis of compound 9-4
Figure PCTCN2017119448-appb-000132
Figure PCTCN2017119448-appb-000132
在100mL单口瓶中加入化合物M-2(4.1g,6.4mmol,1.0eq)，化合物9-3(2.13g,10.2mmol,1.5eq)，碘化钠(3.8g,25mmol,4eq)和二异丙基乙基胺(1.6mL,9.6mmol,1.5eq)和乙腈(30mL)，50℃油浴下反应过夜。16h后TLC检测原料反应完，减压浓缩大部分溶剂，残渣用乙酸乙酯(50mL)稀释，水洗(20mL×3)后无水硫酸钠干燥，减压浓缩。粗产物以DCM/MeOH＝100/1为洗脱剂柱层析纯化，得到淡黄色油状液体4.2g。Compound 100-2 (4.1 g, 6.4 mmol, 1.0 eq), compound 9-3 (2.13 g, 10.2 mmol, 1.5 eq), sodium iodide (3.8 g, 25 mmol, 4 eq) and diiso Propylethylamine (1.6 mL, 9.6 mmol, 1.5 eq) and acetonitrile (30 mL) were reacted in a 50 ° C oil bath overnight. After 16 h, the reaction mixture was purified by EtOAc (EtOAc)EtOAc. The crude product was purified by column chromatography eluting elut elut elut elut
MS-ESI:m/z＝817.30[M+1] +。 MS-ESI: m / z = 817.30 [M + 1] +.
4)化合物9的合成4) Synthesis of Compound 9
Figure PCTCN2017119448-appb-000133
Figure PCTCN2017119448-appb-000133
将化合物9-6(2.6g,3.2mmol,1eq)溶于丙酮(8mL)，室温下依次加入水(6mL)、三氟乙酸(2mL)和冰乙酸(8mL)，搅拌反应2小时。TLC监控反应完全后，往反应液中加入二氯甲烷(30mL)，搅拌均匀静置分层，有机相依次用水(10mL×3)，饱和氯化钠(10mL)洗涤，无水硫酸钠干燥后减压浓缩，以DCM:MeOH＝50:1为洗脱剂柱层析纯化，得到淡黄色泡沫状固体1.7g，收率76％。Compound 9-6 (2.6 g, 3.2 mmol, 1 eq) was dissolved in acetone (8 mL), and water (6 mL), trifluoroacetic acid (2 mL) and EtOAc (EtOAc) After the TLC monitoring reaction was completed, dichloromethane (30 mL) was added to the reaction mixture, and the mixture was stirred and dried, and the organic layer was washed with water (10 mL×3), saturated sodium chloride (10 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure, EtOAc (EtOAc:EtOAc)
1H NMR(400MHz,CDCl 3)δ7.48(d,J＝8.2Hz,1H),7.33(t,J＝7.9Hz,2H),7.18(dd,J＝13.1,7.5Hz,3H),6.18(d,J＝17.4Hz,1H),6.01–5.87(m,2H),5.73(d,J＝8.2Hz,1H),5.03(d,J＝9.0Hz,1H),4.98(dt,J＝12.5,6.3Hz,1H),4.63–4.37(m,2H),4.31–4.04(m,3H),4.02–3.82(m,2H),3.62(s,3H),3.23–3.11(m,2H),2.35(t,J＝7.2Hz,2H),1.82(dd,J＝13.6,6.8Hz,2H),1.40–1.31(m,6H),1.22(d,J＝6.2Hz,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (d, J = 8.2 Hz, 1H), 7.33 (t, J = 7.9 Hz, 2H), 7.18 (dd, J = 13.1, 7.5 Hz, 3H), 6.18 (d, J = 17.4 Hz, 1H), 6.01 - 5.87 (m, 2H), 5.73 (d, J = 8.2 Hz, 1H), 5.03 (d, J = 9.0 Hz, 1H), 4.98 (dt, J = 12.5, 6.3 Hz, 1H), 4.63–4.37 (m, 2H), 4.31–4.04 (m, 3H), 4.02–3.82 (m, 2H), 3.62 (s, 3H), 3.23–3.11 (m, 2H) , 2.35 (t, J = 7.2 Hz, 2H), 1.82 (dd, J = 13.6, 6.8 Hz, 2H), 1.40 - 1.31 (m, 6H), 1.22 (d, J = 6.2 Hz, 6H).
MS-ESI:m/z＝703.20[M+1] +。 MS-ESI: m/z = 703.20 [M + 1] + .
实施例10Example 10
(S)-异丙基2-(((S)-(((2R,3R,4R,5R)-5-(3-((2-氨基乙酰氧基)甲基)-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基)氨基)丙酸酯盐酸盐(S)-Isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(3-((2-aminoacetoxy))methyl)-2,4-di Oxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino Propionate hydrochloride
Figure PCTCN2017119448-appb-000134
Figure PCTCN2017119448-appb-000134
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000135
Figure PCTCN2017119448-appb-000135
Figure PCTCN2017119448-appb-000136
Figure PCTCN2017119448-appb-000136
1)化合物10-2的合成1) Synthesis of compound 10-2
Figure PCTCN2017119448-appb-000137
Figure PCTCN2017119448-appb-000137
将化合物10-1(3g，17.1mmol，1.0eq)和四丁基硫酸氢铵(0.58g，1.7mmol，0.1eq)，碳酸钾(9.5g，68.9mmol，4.0eq)混合于二氯甲烷和水的混合溶液(50mL+50mL)中。在-5℃下缓慢滴加氯甲基氯磺酸酯(7.2mL，71.1mmol，2.0eq)，15min滴完后移至室温反应3小时。TLC监测反应完毕，反应液静置分层，有机相用水(100mL)、饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，减压浓缩得淡黄色油状液体3.3g，收率86.0％，无进一步纯化直接投下一步反应。Compound 10-1 (3 g, 17.1 mmol, 1.0 eq) and tetrabutylammonium hydrogen sulfate (0.58 g, 1.7 mmol, 0.1 eq), potassium carbonate (9.5 g, 68.9 mmol, 4.0 eq) A mixed solution of water (50 mL + 50 mL). Chloromethyl chlorosulfonate (7.2 mL, 71.1 mmol, 2.0 eq) was slowly added dropwise at -5 ° C, and after 15 min, the mixture was transferred to room temperature for 3 hours. After the reaction was completed by TLC, the 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.
2)化合物10-3的合成2) Synthesis of compound 10-3
Figure PCTCN2017119448-appb-000138
Figure PCTCN2017119448-appb-000138
将化合物M-2(3.2g，5mmol，1.0eq)和化合物10-2(1.7g，7.6mmol，1.5eq)溶于乙腈(25mL)中，室温下加入碘化钠(3g，20mmol，4.0eq)和二异丙基乙基胺(1.2mL，7.3mmol，1.5eq)，50℃下反应过夜。18h后TLC检测反应完成，减压浓缩反应溶剂，剩余物加入乙酸乙酯(200mL)和水(200mL)搅拌至固体完全溶解后静置分液，有机相依次用水(200mL×2)洗涤，饱和氯化钠溶液(200mL)洗涤，有机相用无水硫酸钠干燥后减压浓缩。以DCM:MeOH＝100:1为洗脱剂柱层析纯化，得到乳白色粘稠泡沫固体3.1g，收率75％。Compound M-2 (3.2 g, 5 mmol, 1.0 eq) and compound 10-2 (1.7 g, 7.6 mmol, 1.5 eq) were dissolved in acetonitrile (25 mL) and sodium iodide (3 g, 20 mmol, 4.0 eq. And diisopropylethylamine (1.2 mL, 7.3 mmol, 1.5 eq), and allowed to react at 50 ° C overnight. After 18 h, the reaction was completed by TLC. The solvent was concentrated under reduced pressure. ethyl acetate (200mL) and water (200mL) was added to the residue. The solid was dissolved and then left to stand. The organic phase was washed with water (200 mL×2) and saturated. The organic layer was dried over anhydrous sodium sulfate and evaporated. Purification by column chromatography with DCM:MeOH = 100:1 elute
1H NMR(600MHz,CDCl 3)δ7.58(d,J＝8.3Hz,1H),7.34(t,J＝7.9Hz,2H),7.24–7.15(m,3H),6.23–6.09(m,1H),6.02(d,J＝1.8Hz,2H),5.69(d,J＝8.3Hz,1H),5.08–4.92(m,2H),4.64–4.55(m,1H),4.30–4.20(m,1H),4.16–4.09(m,1H),3.95(dd,J＝15.6,6.7Hz,4H),3.73–3.60(m,1H),1.44(s,9H),1.34(t,J＝14.5Hz,6H),1.23(d,J＝6.3Hz,6H),0.98(t,J＝7.9Hz,9H),0.67(q,J＝7.9Hz,6H)。 1 H NMR (600MHz, CDCl 3 ) δ7.58 (d, J = 8.3Hz, 1H), 7.34 (t, J = 7.9Hz, 2H), 7.24-7.15 (m, 3H), 6.23-6.09 (m, 1H), 6.02 (d, J = 1.8 Hz, 2H), 5.69 (d, J = 8.3 Hz, 1H), 5.08 - 4.92 (m, 2H), 4.64 - 4.55 (m, 1H), 4.30 - 4.20 (m) , 1H), 4.16–4.09 (m, 1H), 3.95 (dd, J=15.6, 6.7 Hz, 4H), 3.73–3.60 (m, 1H), 1.44 (s, 9H), 1.34 (t, J=14.5) Hz, 6H), 1.23 (d, J = 6.3 Hz, 6H), 0.98 (t, J = 7.9 Hz, 9H), 0.67 (q, J = 7.9 Hz, 6H).
MS-ESI:m/z 853.2[M+Na] + MS-ESI: m/z 853.2 [M+Na] +
3)化合物10-4的合成3) Synthesis of Compound 10-4
Figure PCTCN2017119448-appb-000139
Figure PCTCN2017119448-appb-000139
将化合物10-3(3.1g，3.7mmol，1eq)溶于丙酮(12mL)，室温下依次加入水(9mL)、三氟乙酸(3mL)和冰乙酸(12mL)后反应2小时。TLC监控反应完全后，往反应液中加入二氯甲烷(40mL)和水(40mL)，搅拌均匀静置分层，有机相依次用水(40mL×3)，饱和氯化钠(40mL)洗涤，无水硫酸钠干燥后减压浓缩，以DCM:MeOH＝70:1为洗脱剂柱层析纯化，得到白色泡沫状固体2g，收率75％。Compound 10-3 (3.1 g, 3.7 mmol, 1 eq) was dissolved in acetone (12 mL), and water (9 mL), trifluoroacetic acid (3 mL) and EtOAc (EtOAc) After the TLC monitoring reaction was completed, dichloromethane (40 mL) and water (40 mL) were added to the reaction mixture, and the mixture was stirred and left to stand for separation. The organic phase was washed successively with water (40 mL×3) and saturated sodium chloride (40 mL). The organic layer was dried over anhydrous sodium sulfate (MgSO4).
1H NMR(600MHz,CDCl 3)δ7.51(d,J＝8.2Hz,1H),7.38(t,J＝7.9Hz,2H),7.27–7.20(m,3H),6.22(d,J＝19.2Hz,1H),6.09–6.00(m,2H),5.79(d,J＝8.2Hz,1H),5.04(dt,J＝12.4,6.2Hz,2H),4.60–4.51(m,1H),4.51–4.40(m,1H),4.14(d,J＝9.3Hz,1H),3.90(ddd,J＝47.5,17.9,9.4Hz,6H),1.47(s,9H),1.46–1.35(m,6H),1.28–1.25(m,6H)。 1 H NMR (600MHz, CDCl 3 ) δ 7.51 (d, J = 8.2 Hz, 1H), 7.38 (t, J = 7.9 Hz, 2H), 7.27 - 7.20 (m, 3H), 6.22 (d, J = 19.2 Hz, 1H), 6.09 - 6.00 (m, 2H), 5.79 (d, J = 8.2 Hz, 1H), 5.04 (dt, J = 12.4, 6.2 Hz, 2H), 4.60 - 4.51 (m, 1H), 4.51–4.40 (m, 1H), 4.14 (d, J=9.3 Hz, 1H), 3.90 (ddd, J=47.5, 17.9, 9.4 Hz, 6H), 1.47 (s, 9H), 1.46–1.35 (m, 6H), 1.28–1.25 (m, 6H).
MS-ESI:m/z＝739.2[M+Na] + MS-ESI: m/z = 739.2. [M+Na] +
4)化合物10的合成4) Synthesis of Compound 10
Figure PCTCN2017119448-appb-000140
Figure PCTCN2017119448-appb-000140
将化合物10-4(1.4g，1.3mmol，1eq)溶于盐酸异丙醇(1N，20mL)，室温下搅拌反应，TLC监控。2小时反应完毕，减压浓缩反应溶剂，乙酸乙酯打浆，抽滤得白色固体1.2g，收率95％。Compound 10-4 (1.4 g, 1.3 mmol, 1 eq) was dissolved in isopropyl alcohol (1N, 20 mL). After completion of the reaction for 2 hours, the reaction solvent was concentrated under reduced pressure, and ethyl acetate was evaporated.
1H NMR(600MHz,CDCl 3)δ7.51(d,J＝8.2Hz,1H),7.38(t,J＝7.9Hz,2H),7.27–7.20(m,3H),6.22(d,J＝19.2Hz,1H),6.09–6.00(m,2H),5.79(d,J＝8.2Hz,1H),5.04(dt,J＝12.4,6.2Hz,2H),4.60–4.51(m,1H),4.51–4.40(m,1H),4.14(d,J＝9.3Hz,1H),3.90(ddd,J＝47.5,17.9,9.4Hz,7H),1.46–1.35(m,6H),1.28–1.25(m,6H)。 1 H NMR (600MHz, CDCl 3 ) δ 7.51 (d, J = 8.2 Hz, 1H), 7.38 (t, J = 7.9 Hz, 2H), 7.27 - 7.20 (m, 3H), 6.22 (d, J = 19.2 Hz, 1H), 6.09 - 6.00 (m, 2H), 5.79 (d, J = 8.2 Hz, 1H), 5.04 (dt, J = 12.4, 6.2 Hz, 2H), 4.60 - 4.51 (m, 1H), 4.51–4.40 (m, 1H), 4.14 (d, J=9.3 Hz, 1H), 3.90 (ddd, J=47.5, 17.9, 9.4 Hz, 7H), 1.46–1.35 (m, 6H), 1.28–1.25 ( m, 6H).
MS-ESI:m/z＝739.2[M+Na] + MS-ESI: m/z = 739.2. [M+Na] +
实施例11Example 11
(S)-(3-((2R,3R,4R,5R)-3-氟-4-羟基-5-((((S)-(((S)-1-异丙氧基-1-氧代丙-2-基)氨基)(苯氧基)磷酰基)氧基)甲基)-3-甲基四氢呋喃-2-基)-2,6-二氧代-2,3-二氢嘧啶-1(6H)-基)甲基2-((甲氧基羰基)氨基)-3-苯基丙酸酯(S)-(3-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-((((S)-((())))) Oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-3-methyltetrahydrofuran-2-yl)-2,6-dioxo-2,3-dihydro Pyrimidine-1(6H)-yl)methyl 2-((methoxycarbonyl)amino)-3-phenylpropionate
Figure PCTCN2017119448-appb-000141
Figure PCTCN2017119448-appb-000141
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000142
Figure PCTCN2017119448-appb-000142
1)化合物11-2的合成1) Synthesis of Compound 11-2
Figure PCTCN2017119448-appb-000143
Figure PCTCN2017119448-appb-000143
在250mL单口瓶中依次加入氢氧化钠(5.63g,141.0mmol,3eq)和水(120mL)，置于-10℃下搅拌10分钟。再加入L-苯丙氨酸(7.75g,46.9mmol,1eq)，滴加氯甲酸甲酯(4.76mL,61.0mmol,1.3eq)。继续低 温搅拌半小时，转移至室温反应过夜。反应液用浓盐酸酸化至pH＝2左右，再用乙酸乙酯萃取(30mL×3)，有机相无水硫酸钠干燥，减压浓缩得透明油状液体8.6g，收率82％。无进一步纯化直接投下一步反应。Sodium hydroxide (5.63 g, 141.0 mmol, 3 eq) and water (120 mL) were sequentially added to a 250 mL single-necked flask, and stirred at -10 ° C for 10 minutes. Further, L-phenylalanine (7.75 g, 46.9 mmol, 1 eq) was added, and methyl chloroformate (4.76 mL, 61.0 mmol, 1.3 eq) was added dropwise. Stir at low temperature for half an hour and transfer to room temperature overnight. The reaction mixture was acidified to pH=2 with EtOAc (EtOAc)EtOAc. The next reaction was directly carried out without further purification.
2)化合物11-3的合成2) Synthesis of Compound 11-3
Figure PCTCN2017119448-appb-000144
Figure PCTCN2017119448-appb-000144
在250mL单口瓶中依次加入化合物11-2(4.1g,18.0mmol,1eq)，四丁基硫酸氢铵(0.62g,1.8mmol,0.1eq)，碳酸氢钠(12g，143mmol，8eq)，二氯甲烷(40mL)和水(40mL)，在0℃下缓慢滴加氯甲基氯磺酸酯(4.0mL,38.7mmol,2eq)，滴完后移至室温反应，3小时后TLC检测原料反应完全。静置分层，有机相用水(20mL×3)洗涤后无水硫酸钠干燥，减压浓缩后硅胶柱层析，PE/EA＝5/1做洗脱剂，得白色晶体4.0g，收率80％。Compound 11-2 (4.1 g, 18.0 mmol, 1 eq), tetrabutylammonium hydrogen sulfate (0.62 g, 1.8 mmol, 0.1 eq), sodium bicarbonate (12 g, 143 mmol, 8 eq), Methyl chloride (40 mL) and water (40 mL) were slowly added dropwise with chloromethyl chlorosulfonate (4.0 mL, 38.7 mmol, 2 eq) at 0 ° C. After the dropwise addition, the mixture was reacted to room temperature. After 3 hours, TLC was used to detect the reaction of the starting materials. complete. The organic layer was washed with water (20 mL×3), dried over anhydrous sodium sulfate, and evaporated. 80%.
3)化合物11-4的合成3) Synthesis of Compound 11-4
Figure PCTCN2017119448-appb-000145
Figure PCTCN2017119448-appb-000145
在100mL单口瓶中依次加入化合物M-2(5.8mL,9.0mmol,1.0eq)，化合物11-3(3.7g,14mmol,1.5eq)，碘化钠(5.4g,36mmol,4eq)，二异丙基乙基胺(2.2mL,14mmol,1.5eq)和乙腈(50mL)，50℃油浴下反应过夜。12h后TLC检测原料反应完，乙酸乙酯萃取(20mL×3)，有机相水洗后经无水硫酸钠干燥，旋除溶剂。粗产物以DCM/MeOH＝50/1为洗脱剂柱层析纯化，得到白色发泡油状物6.9g，收率87％。Compound M-2 (5.8 mL, 9.0 mmol, 1.0 eq), compound 11-3 (3.7 g, 14 mmol, 1.5 eq), sodium iodide (5.4 g, 36 mmol, 4 eq), two different Propylethylamine (2.2 mL, 14 mmol, 1.5 eq) and acetonitrile (50 mL) were reacted in a 50 ° C oil bath overnight. After 12 h, the reaction mixture was purified by TLC, ethyl acetate (20 mL×3), and the organic phase was washed with water and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography eluting elut elut elut elut eluting
4)化合物11的合成4) Synthesis of Compound 11
Figure PCTCN2017119448-appb-000146
Figure PCTCN2017119448-appb-000146
在250mL单口瓶中依次加入化合物11-4(6.9g,8.0mmol,1eq)，丙酮(24mL)，水(6mL)，三氟乙酸(2mL)和冰乙酸(8mL)，室温搅拌反应2小时。TLC检测原料反应完全，加入饱和碳酸氢钠溶液(50mL)萃灭反应，向反应瓶中加入二氯甲烷(50mL)，静置分层，有机相依次用水(20mL×2)和饱和氯化钠(20mL)洗涤后经无水硫酸钠干燥，旋除溶剂，粗产品用DCM:MeOH＝50:1为洗脱剂柱层析纯化，得到白色发泡固体4.5g，收率74％。Compound 11-4 (6.9 g, 8.0 mmol, 1 eq), acetone (24 mL), water (6 mL), trifluoroacetic acid (2 mL) and EtOAc (EtOAc) The reaction mixture was completely reacted by TLC. The reaction was extracted with saturated sodium hydrogen carbonate solution (50 mL), dichloromethane (50 mL) was added to the reaction flask, and the mixture was allowed to stand for separation. The organic phase was sequentially washed with water (20 mL×2) and saturated sodium chloride. After washing (20 mL), dried over anhydrous sodium sulfate and evaporated, evaporated.
1H NMR(400MHz,CDCl 3)δ7.49(d,J＝8.2Hz,1H),7.36(t,J＝7.9Hz,2H),7.28(dd,J＝10.4,3.5Hz,2H),7.18(dd,J＝28.6,7.6Hz,6H),6.30–6.11(m,1H),6.00(s,2H),5.76(d,J＝8.3Hz,1H),5.17(d,J＝8.2Hz,1H),5.08–4.95(m,1H),4.72–4.61(m,1H),4.60–4.39(m,2H),4.13(d,J＝9.4Hz,1H),4.05–3.82(m,3H),3.65(s,3H),3.08(t,J＝5.6Hz,2H),2.07(s,1H),1.38(t,J＝14.7Hz,6H),1.24(d,J＝6.3Hz,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.49 (d, J = 8.2 Hz, 1H), 7.36 (t, J = 7.9 Hz, 2H), 7.28 (dd, J = 10.4, 3.5 Hz, 2H), 7.18 (dd, J = 28.6, 7.6 Hz, 6H), 6.30 - 6.11 (m, 1H), 6.00 (s, 2H), 5.76 (d, J = 8.3 Hz, 1H), 5.17 (d, J = 8.2 Hz, 1H), 5.08–4.95 (m, 1H), 4.72–4.61 (m, 1H), 4.60–4.39 (m, 2H), 4.13 (d, J=9.4 Hz, 1H), 4.05–3.82 (m, 3H) , 3.65 (s, 3H), 3.08 (t, J = 5.6 Hz, 2H), 2.07 (s, 1H), 1.38 (t, J = 14.7 Hz, 6H), 1.24 (d, J = 6.3 Hz, 6H) .
MS-ESI:m/z＝765.2[M+1] +。 MS-ESI: m/z = 765.2 [M+1] + .
实施例12Example 12
(丁酰氧基)甲基((3-((2R,3R,4R,5R)-3-氟-4-羟基-5-((((S)-(((S)-1-异丙氧基-1-氧代丙-2-基)氨基)(苯氧基)磷酰基)氧基)甲基)-3-甲基四氢呋喃-2-基)-2,6-二氧代-2,3-二氢嘧啶-1(6H)-基)甲基)琥珀酸酯(butyryloxy)methyl ((3-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-((((S)-((()))) Oxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-3-methyltetrahydrofuran-2-yl)-2,6-dioxo-2 ,3-dihydropyrimidin-1(6H)-yl)methyl)succinate
Figure PCTCN2017119448-appb-000147
Figure PCTCN2017119448-appb-000147
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000148
Figure PCTCN2017119448-appb-000148
Figure PCTCN2017119448-appb-000149
Figure PCTCN2017119448-appb-000149
1)化合物12-4的合成1) Synthesis of compound 12-4
Figure PCTCN2017119448-appb-000150
Figure PCTCN2017119448-appb-000150
将化合物12-3(10g，113.5mmol，1.0eq)，四丁基硫酸氢铵(3.85g，11.35mmol，0.1eq)，碳酸氢钠(38g，454mmol，4.0eq)混合于DCM(100mL)和水(100mL)中，降温至0℃，滴加氯甲基氯磺酸酯(23mL，227mmol，2.0eq)，滴完后室温反应。5h后反应完后，反应液静置分液，有机相用水(30mL)洗涤，无水硫酸钠干燥，减压浓缩得到无色液体4g，收率26％。Compound 12-3 (10 g, 113.5 mmol, 1.0 eq), tetrabutylammonium hydrogen sulfate (3.85 g, 11.35 mmol, 0.1 eq), sodium bicarbonate (38 g, 454 mmol, 4.0 eq) In water (100 mL), the mixture was cooled to 0 ° C, and chloromethyl chlorosulfonate (23 mL, 227 mmol, 2.0 eq) was added dropwise. After the completion of the reaction for 5 h, the reaction mixture was evaporated, evaporated, evaporated, evaporated.
2)化合物12-5的合成2) Synthesis of compound 12-5
Figure PCTCN2017119448-appb-000151
Figure PCTCN2017119448-appb-000151
将化合物8-2(3g，14.4mmol，1.0eq)、化合物12-4(2.9g，21.6mmol，1.5eq)溶于乙腈中(30mL)，室温下加入碘化钠(8.6g，57.6mmol，4.0eq)和DIPEA(3.6mL，21.6mmol，1.5eq)，加热至50℃反应；TLC监测，12h后基本反应完全，减压浓缩大部分乙腈，剩余物加入乙酸乙酯(50mL)和水(20mL)，摇匀，分液，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩，柱层析纯化，洗脱剂PE:EA＝10:1，得到淡黄色油状物3.4g。Compound 8-2 (3 g, 14.4 mmol, 1.0 eq), compound 12-4 (2.9 g, 21.6 mmol, 1.5 eq) was dissolved in acetonitrile (30 mL) and sodium iodide (8.6 g, 57.6 mmol, 4.0 eq) and DIPEA (3.6 mL, 21.6 mmol, 1.5 eq), heated to 50 ° C. The reaction was carried out by TLC. After 12 h, the basic reaction was completed, and most of the acetonitrile was concentrated under reduced pressure and ethyl acetate (50 mL) and water. 20 mL), shaken, and the organic layer is washed with brine, dried over anhydrous sodium sulfate .
1H NMR(400MHz,CDCl3)δ7.42–7.30(m,5H),5.76(s,2H),5.15(s,2H),2.71(s,4H),2.35(t,J＝7.4Hz,2H),1.74–1.61(m,2H),0.97(t,J＝7.4Hz,3H)。 1 H NMR (400MHz, CDCl3) δ7.42-7.30 (m, 5H), 5.76 (s, 2H), 5.15 (s, 2H), 2.71 (s, 4H), 2.35 (t, J = 7.4Hz, 2H ), 1.74 - 1.61 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H).
3)化合物12-6的合成3) Synthesis of compound 12-6
Figure PCTCN2017119448-appb-000152
Figure PCTCN2017119448-appb-000152
将化合物12-5(3.3g，11mmol，1eq)溶于乙酸乙酯中，加入钯碳(330mg)置换氢气，室温反应；TLC监测，反应完全，反应液过滤，滤渣用EA(20mL)洗涤，滤液减压浓缩，直接投下一步。The compound 12-5 (3.3 g, 11 mmol, 1 eq) was dissolved in EtOAc. EtOAc (EtOAc) The filtrate was concentrated under reduced pressure and directly taken to the next step.
4)化合物12-7的合成4) Synthesis of compound 12-7
Figure PCTCN2017119448-appb-000153
Figure PCTCN2017119448-appb-000153
将化合物12-6(2.3g，11mmol，1.0eq)，四丁基硫酸氢铵(0.36g，1.1mmol，0.1eq)，碳酸钾(5.8g，42mmol，4.0eq)混合于DCM(20mL)和水(20mL)中，降温至0℃，滴加氯甲基氯磺酸酯(2.1mL，21mmol，2.0eq)，滴完后移至室温反应；TLC监测。3h后反应基本完全，反应液加入DCM(50mL)和水(10mL)，静置分液，有机相用饱和氯化钠洗涤，干燥，减压浓缩，柱层析纯化PE:EA＝10:1，得到无色油状物2.5g。Compound 12-6 (2.3 g, 11 mmol, 1.0 eq), tetrabutylammonium hydrogen sulfate (0.36 g, 1.1 mmol, 0.1 eq), potassium carbonate (5.8 g, 42 mmol, 4.0 eq) In water (20 mL), the mixture was cooled to 0 ° C, and chloromethyl chlorosulfonate (2.1 mL, 21 mmol, 2.0 eq) was added dropwise. After 3 h, the reaction was almost complete. The reaction mixture was added with DCM (50 mL) and water (10 mL), and the mixture was partitioned. The organic phase was washed with saturated sodium chloride, dried, concentrated under reduced pressure and purified by column chromatography: EA=10:1 , 2.5 g of a colorless oil was obtained.
5)化合物12-8的合成5) Synthesis of compound 12-8
Figure PCTCN2017119448-appb-000154
Figure PCTCN2017119448-appb-000154
将化合物M-2(4g，6.2mmol，1.0eq)、化合物12-7(2.5g，9.3mmol，1.5eq)溶于乙腈(20mL)中，室温下加入碘化钠(3.7g，24.9mmol，4.0eq)和DIPEA(1.6mL，9.3mmol，1.5eq)，加热至50℃反应；TLC监测，有少量原料剩余，直接后处理，反应液降至室温，减压浓缩乙腈，剩余物加入乙酸乙酯(100mL)和水(20mL)搅拌至固体完全溶解，静置分液，有机相继续用水(20mL)洗涤，饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩，柱层析纯化，洗脱剂DCM:MeOH＝100:1，得到淡黄色油状物4.8g，收率88％。Compound M-2 (4 g, 6.2 mmol, 1.0 eq), compound 12-7 (2.5 g, 9.3 mmol, 1.5 eq) was dissolved in acetonitrile (20 mL), and sodium iodide (3.7 g, 24.9 mmol, 4.0eq) and DIPEA (1.6mL, 9.3mmol, 1.5eq), heated to 50 ° C reaction; TLC monitoring, a small amount of raw materials remaining, direct post-treatment, the reaction solution was cooled to room temperature, acetonitrile was concentrated under reduced pressure, and the residue was added to acetic acid The ester (100 mL) and water (20 mL) were stirred until the solid was dissolved. The organic layer was washed with water (20 mL), washed with saturated sodium chloride, dried over anhydrous sodium sulfate The eluent DCM: MeOH = 100:1 afforded 4.8 g of pale yellow oil.
6)化合物12的合成6) Synthesis of Compound 12
Figure PCTCN2017119448-appb-000155
Figure PCTCN2017119448-appb-000155
将化合物12-8(4.8g，5.5mmol，1eq)溶于丙酮(15mL)中，室温下依次加入水(10mL)、三氟乙酸(3mL)和冰乙酸(10mL)，室温反应；TLC监测，反应完全，往反应液中加入EA(100mL)，搅拌均匀，静置分液，有机相用水(20mL×3)继续洗涤，饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩，柱层析纯化，洗脱剂DCM:MeOH＝70:1，得到淡黄色油状物2.9g，纯度94.76％，收率69％。Compound 12-8 (4.8 g, 5.5 mmol, 1 eq) was dissolved in acetone (15 mL). Water (10 mL), trifluoroacetic acid (3 mL) and EtOAc (10 mL) The reaction was completed, and EA (100 mL) was added to the reaction mixture, and the mixture was stirred, and the mixture was separated. The organic phase was washed with water (20 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate The oil was purified by chromatography eluting with EtOAc EtOAc:EtOAc:
1H NMR(400MHz,CDCl 3)δ7.53–7.41(m,1H),7.36(d,J＝7.8Hz,2H),7.24(d,J＝8.5Hz,3H),6.02(s,2H),5.79(d,J＝8.2Hz,1H),5.35(s,2H)，5.10–4.96(m,1H),4.61–4.40(m,2H),4.14(d,J＝7.2Hz,3H),4.07–3.88(m,2H),2.67(d,J＝11.6Hz,5H),2.35(t,J＝7.4Hz,2H),1.74–1.61(m,2H),1.40(dd,J＝19.8,14.8Hz,6H),1.26(d,J＝6.2Hz,6H)，0.97(t,J＝7.4Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.53 - 7.41 (m, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 8.5 Hz, 3H), 6.02 (s, 2H) , 5.79 (d, J = 8.2 Hz, 1H), 5.35 (s, 2H), 5.10 - 4.96 (m, 1H), 4.61 - 4.40 (m, 2H), 4.14 (d, J = 7.2 Hz, 3H), 4.07–3.88 (m, 2H), 2.67 (d, J = 11.6 Hz, 5H), 2.35 (t, J = 7.4 Hz, 2H), 1.74 - 1.61 (m, 2H), 1.40 (dd, J = 19.8, 14.8 Hz, 6H), 1.26 (d, J = 6.2 Hz, 6H), 0.97 (t, J = 7.4 Hz, 3H).
MS-ESI:m/z＝760.3[M+1] +。 MS-ESI: m/z = 760.3 [M+1] + .
实施例13Example 13
(S)-(3-((2R,3R,4R,5R)-3-氟-4-羟基-5-((((S)-(((S)-1-异丙氧基-1-氧代丙-2-基)氨基)(苯氧基)磷酰基)氧基)甲基)-3-甲基四氢呋喃-2-基)-2,6-二氧代-2,3-二氢嘧啶-1(6H)-基)甲基2-((甲氧基羰基)氨基)-3-甲基丁酸甲酯(S)-(3-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-((((S)-((())))) Oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-3-methyltetrahydrofuran-2-yl)-2,6-dioxo-2,3-dihydro Pyrimidine-1(6H)-yl)methyl 2-((methoxycarbonyl)amino)-3-methylbutanoate
Figure PCTCN2017119448-appb-000156
Figure PCTCN2017119448-appb-000156
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000157
Figure PCTCN2017119448-appb-000157
1)化合物13-2的合成1) Synthesis of compound 13-2
Figure PCTCN2017119448-appb-000158
Figure PCTCN2017119448-appb-000158
将化合物13-1(10g，57mmol，1.0eq)，四丁基硫酸氢铵(1.9g，5.7mmol，0.1eq)，碳酸氢钠(19g，228mmol，4.0eq)混合于DCM(100mL)和水(100mL)中，降温至0℃，滴加氯甲基氯磺酸酯(11.5mL，114mmol，2.0eq)，滴完后移至室温反应；TLC监测，反应完全，反应液静置分液，有机相用饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩，柱层析纯化PE:EA＝10:1，得到无色油状物12.5g，收率98％。纯度97.27％。Compound 13-1 (10 g, 57 mmol, 1.0 eq), tetrabutylammonium hydrogen sulfate (1.9 g, 5.7 mmol, 0.1 eq), sodium bicarbonate (19 g, 228 mmol, 4.0 eq) was combined in DCM (100 mL) and water (100 mL), the temperature was lowered to 0 ° C, and chloromethyl chlorosulfonate (11.5 mL, 114 mmol, 2.0 eq) was added dropwise. After the dropwise addition, the reaction was carried out to room temperature; TLC was monitored, the reaction was completed, and the reaction mixture was allowed to stand for separation. The organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate The purity is 97.27%.
1H NMR(400MHz,CDCl 3)δ5.85(d,J＝6.0Hz,1H),5.64(d,J＝6.0Hz,1H),5.29(d,J＝7.0Hz,1H),4.33(dd,J＝9.0,4.8Hz,1H),3.69(s,3H),2.21(td,J＝13.1,6.6Hz,1H),1.00(d,J＝6.9Hz,3H),0.92(d,J＝6.9Hz,3H)。 1 H NMR (400MHz, CDCl 3 ) δ5.85 (d, J = 6.0Hz, 1H), 5.64 (d, J = 6.0Hz, 1H), 5.29 (d, J = 7.0Hz, 1H), 4.33 (dd , J = 9.0, 4.8 Hz, 1H), 3.69 (s, 3H), 2.21 (td, J = 13.1, 6.6 Hz, 1H), 1.00 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H).
2)化合物13-3合成2) Synthesis of compound 13-3
Figure PCTCN2017119448-appb-000159
Figure PCTCN2017119448-appb-000159
将化合物M-2(5g，7.8mmol，1.0eq)、化合物13-2(2.6g，11.6mmol，1.5eq)溶于乙腈(50mL)中，室温下加入碘化钠(4.7g，31mmol，4.0eq)和DIPEA(2mL，11.6mmol，1.5eq)，加热至50℃反应。12h后TLC监测，反应基本完全，直接后处理，减压浓缩乙腈，剩余物加入乙酸乙酯(100mL)和水(50mL)搅拌至固体完全溶解，静置分液，有机相继续用水(80mL)洗涤，饱和氯化钠(80mL)洗涤，无水硫酸钠干燥，减压浓缩，柱层析纯化，洗脱剂DCM:MeOH＝70:1，得到黄色油状物6.4g，收率98％。Compound M-2 (5 g, 7.8 mmol, 1.0 eq), compound 13-2 (2.6 g, 11.6 mmol, 1.5 eq) was dissolved in acetonitrile (50 mL) and sodium iodide (4.7 g, 31 mmol, 4.0 Eq) and DIPEA (2 mL, 11.6 mmol, 1.5 eq), heated to 50 °C. After 12 h, the reaction was completed by TLC, and the reaction was taken to complete. The mixture was directly worked-up, and acetonitrile was concentrated under reduced pressure. The residue was added ethyl acetate (100 mL) and water (50 mL) and stirred until the solid was completely dissolved, and the mixture was allowed to stand for separation. The organic phase was continued with water (80 mL) The mixture was washed with EtOAc EtOAc EtOAc.
1H NMR(400MHz,CDCl 3)δ7.54(d,J＝8.2Hz,1H),7.25(dd,J＝10.8,4.9Hz,2H),7.17–7.06(m,3H),6.06(dd,J＝17.3,11.9Hz,1H),5.91(s,1H),5.64(d,J＝8.3Hz,1H),5.41(t,J＝13.4Hz,1H),4.95–4.85(m,1H),4.52(dd,J＝11.1,6.3Hz,1H),4.19(ddd,J＝8.2,6.8,3.8Hz,2H),4.09–3.83(m,5H),3.58(s,3H),2.12–1.97(m,1H),1.27(dd,J＝14.4,11.3Hz,6H),1.14(d,J＝6.2Hz,6H),0.89(dt,J＝11.2,7.5Hz,12H),0.80(d,J＝6.8Hz,3H),0.64–0.54(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.54 (d, J = 8.2Hz, 1H), 7.25 (dd, J = 10.8,4.9Hz, 2H), 7.17-7.06 (m, 3H), 6.06 (dd, J = 17.3, 11.9 Hz, 1H), 5.91 (s, 1H), 5.64 (d, J = 8.3 Hz, 1H), 5.41 (t, J = 13.4 Hz, 1H), 4.95 - 4.85 (m, 1H), 4.52 (dd, J = 11.1, 6.3 Hz, 1H), 4.19 (ddd, J = 8.2, 6.8, 3.8 Hz, 2H), 4.09 - 3.83 (m, 5H), 3.58 (s, 3H), 2.12 - 1.97 ( m,1H), 1.27 (dd, J = 14.4, 11.3 Hz, 6H), 1.14 (d, J = 6.2 Hz, 6H), 0.89 (dt, J = 11.2, 7.5 Hz, 12H), 0.80 (d, J) = 6.8 Hz, 3H), 0.64 - 0.54 (m, 6H).
MS-ESI:m/z＝831.3[M+1] +。 MS-ESI: m/z = 831.3 [M+1] + .
3)化合物13的合成3) Synthesis of Compound 13
Figure PCTCN2017119448-appb-000160
Figure PCTCN2017119448-appb-000160
将化合物13-3(6.4g，7.7mmol，1eq)溶于丙酮(20mL)中，室温下依次加入水(15mL)、三氟乙酸(4mL)和冰乙酸(17mL)，室温反应；TLC监测，反应完全，往反应液中加入DCM(100mL)，搅拌均匀，静置分液，有机相用水(20mL×3)继续洗涤，饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩，柱层析纯化，洗脱剂DCM:MeOH＝70:1，得到白色泡沫状固体4.3g，收率78％。Compound 13-3 (6.4 g, 7.7 mmol, 1 eq) was dissolved in EtOAc (20 mL). Water (15 mL), trifluoroacetic acid (4 mL) and EtOAc (EtOAc) After the reaction was completed, DCM (100 mL) was added to the reaction mixture, and the mixture was stirred, and the mixture was separated. The organic phase was washed with water (20 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate Purification and purification, eluent DCM: MeOH = 70:1.
1H NMR(400MHz,CDCl 3)δ7.49(d,J＝8.2Hz,1H),7.35(t,J＝7.9Hz,2H),7.25–7.15(m,3H),6.30–6.11(m,1H),6.00(d,J＝3.9Hz,2H),5.75(d,J＝8.3Hz,1H),5.28–5.15(m,1H),5.07–4.96(m,1H),4.59– 4.38(m,2H),4.37–4.22(m,1H),4.12(d,J＝8.5Hz,1H),3.92(dd,J＝9.6,5.2Hz,4H),3.67(s,3H),2.19–2.05(m,1H),1.37(dd,J＝17.8,14.3Hz,6H),1.24(d,J＝6.3Hz,6H),0.95(d,J＝6.8Hz,3H),0.88(d,J＝6.8Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.49 (d, J = 8.2 Hz, 1H), 7.35 (t, J = 7.9 Hz, 2H), 7.25 - 7.15 (m, 3H), 6.30 - 6.11 (m, 1H), 6.00 (d, J = 3.9 Hz, 2H), 5.75 (d, J = 8.3 Hz, 1H), 5.28 - 5.15 (m, 1H), 5.07 - 4.96 (m, 1H), 4.59 - 4.38 (m , 2H), 4.37–4.22 (m, 1H), 4.12 (d, J=8.5 Hz, 1H), 3.92 (dd, J=9.6, 5.2 Hz, 4H), 3.67 (s, 3H), 2.19–2.05 ( m,1H), 1.37 (dd, J = 17.8, 14.3 Hz, 6H), 1.24 (d, J = 6.3 Hz, 6H), 0.95 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8) Hz, 3H).
MS-ESI:m/z＝717.2[M+1] +。 MS-ESI: m/z = 717.2 [M+1] + .
实施例14Example 14
(S)-(3-((2R,3R,4R,5R)-3-氟-4-羟基-5-((((S)-(((S)-1-异丙氧基-1-氧代丙-2-基)氨基)(苯氧基)磷酰基)氧基)甲基)-3-甲基四氢呋喃-2-基)-2,6-二氧代-2,3-二氢嘧啶-1(6H)-基)甲基2-((甲氧基羰基)氨基)丙酸酯(S)-(3-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-((((S)-((())))) Oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-3-methyltetrahydrofuran-2-yl)-2,6-dioxo-2,3-dihydro Pyrimidine-1(6H)-yl)methyl 2-((methoxycarbonyl)amino)propionate
Figure PCTCN2017119448-appb-000161
Figure PCTCN2017119448-appb-000161
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000162
Figure PCTCN2017119448-appb-000162
1)化合物14-2的合成1) Synthesis of Compound 14-2
Figure PCTCN2017119448-appb-000163
Figure PCTCN2017119448-appb-000163
将NaOH(6.7g，168.4mmol，3eq)溶于水(170mL)，降温至0℃，加入化合物14-1(5g，56mmol，1eq)，缓慢滴加氯甲酸甲酯(5.65mL，73mmol，1.3eq)，滴完后继续搅拌20min，移至室温反应；TLC监测，用溴甲酚绿显色，有产物点，反应液用浓盐酸调pH至到3左右，用乙酸乙酯(100mL×3)萃取，合并有机相，饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩，得到无色油状物3g。NaOH (6.7 g, 168.4 mmol, 3 eq) was dissolved in water (170 mL), cooled to 0 ° C, Compound 14-1 (5 g, 56 mmol, 1 eq) was added, and methyl chloroformate (5.65 mL, 73 mmol, 1.3) was slowly added dropwise. Eq), stirring was continued for 20 min after the completion of the dropwise addition, and the reaction was carried out to room temperature; TLC monitoring, color development with bromocresol green, product point, pH of the reaction mixture was adjusted to about 3 with concentrated hydrochloric acid, and ethyl acetate (100 mL×3) The organic phase was combined, washed with saturated sodium chloride and dried over anhydrous sodium sulfate.
MS-ESI:m/z＝148.1[M+1] +。 MS-ESI: m/z = 148.1 [M+1] + .
2)化合物14-3的合成2) Synthesis of compound 14-3
Figure PCTCN2017119448-appb-000164
Figure PCTCN2017119448-appb-000164
将化合物14-2(3g，20.4mmol，1.0eq)，四丁基硫酸氢铵(0.7g，2.0mmol，0.1eq)，碳酸钾(11.3g，81mmol，4.0eq)混合于DCM(20mL)和水(20mL)中，降温至0℃，滴加氯甲基氯磺酸酯(4.1mL，40.8mmol，2.0eq)，滴完后移至室温反应；TLC监测，16h反应基本完全，反应液加入DCM(50mL)和水(10mL)，静置分液，有机相用饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩，柱层析纯化PE:EA＝10:1，得到无色油状物1.7g，收率43％。Compound 14-2 (3 g, 20.4 mmol, 1.0 eq), tetrabutylammonium hydrogen sulfate (0.7 g, 2.0 mmol, 0.1 eq), potassium carbonate (11.3 g, 81 mmol, 4.0 eq) In water (20 mL), the temperature was lowered to 0 ° C, and chloromethyl chlorosulfonate (4.1 mL, 40.8 mmol, 2.0 eq) was added dropwise. After the completion of the dropwise addition, the reaction was carried out to room temperature; TLC was monitored, the reaction was substantially complete in 16 h, and the reaction mixture was added. DCM (50 mL) and water (10 mL), EtOAc (EtOAc m. 1.7 g, yield 43%.
1H NMR(400MHz,CDCl 3)δ5.81(d,J＝6.0Hz,1H),5.65(d,J＝6.0Hz,1H),5.27(s,1H),4.52–4.29(m,1H),3.68(s,3H),1.43(d,J＝7.3Hz,3H)。 1 H NMR (400MHz, CDCl 3 ) δ5.81 (d, J = 6.0Hz, 1H), 5.65 (d, J = 6.0Hz, 1H), 5.27 (s, 1H), 4.52-4.29 (m, 1H) , 3.68 (s, 3H), 1.43 (d, J = 7.3 Hz, 3H).
3)化合物14-4的合成3) Synthesis of compound 14-4
Figure PCTCN2017119448-appb-000165
Figure PCTCN2017119448-appb-000165
将化合物M-2(3.8g，5.9mmol，1.0eq)、化合物14-3(1.7g，8.9mmol，1.5eq)溶于乙腈中(20mL)，室温下加入碘化钠(3.5g，24mmol，4.0eq)和DIPEA(1.5mL，8.9mmol，1.5eq)，加热至50℃反应。3h后TLC监测，有少量原料剩余，直接后处理，反应液降至室温，减压浓缩乙腈，剩余物加入乙酸乙酯(100mL)和水(20mL)搅拌至固体完全溶解，静置分液，有机相继续用水(20mL)洗涤，饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩，柱层析纯化，洗脱剂DCM:MeOH＝100:1，得到淡黄色油状物4.7g，收率98％。 1H NMR(400MHz,CDCl 3)δ7.57(d,J＝8.3Hz,1H),7.33(t,J＝7.9Hz,2H),7.18(dd,J＝16.7,7.9Hz,3H),6.15(d,J＝18.4Hz,1H),5.99(t,J＝5.9Hz,2H),5.69(d,J＝8.3Hz,1H),5.02–4.94(m,1H),4.59(dd,J＝10.5,6.5Hz,1H),4.37(s,1H),4.24(ddd,J＝12.0,5.4,2.7Hz,1H),4.01–3.88(m,2H),3.79–3.66(m,3H),3.66(d,J＝4.8Hz,3H),1.39–1.29(m,9H),1.22(d,J＝6.3Hz,6H),0.97(t,J＝7.9Hz,9H),0.66(q,J＝7.9Hz,6H)。 Compound M-2 (3.8 g, 5.9 mmol, 1.0 eq), compound 14-3 (1.7 g, 8.9 mmol, 1.5 eq) was dissolved in acetonitrile (20 mL) and sodium iodide (3.5 g, 24 mmol, 4.0 eq) and DIPEA (1.5 mL, 8.9 mmol, 1.5 eq), heated to 50 ° C. After 3 hours, TLC was monitored, a small amount of raw material remained, and the mixture was directly worked up. The reaction mixture was cooled to room temperature, and acetonitrile was concentrated under reduced pressure. The residue was added ethyl acetate (100 mL) and water (20 mL) and stirred until the solid was completely dissolved. The organic phase was washed with water (20 mL), EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The rate is 98%. 1 H NMR (400MHz, CDCl 3 ) δ7.57 (d, J = 8.3Hz, 1H), 7.33 (t, J = 7.9Hz, 2H), 7.18 (dd, J = 16.7,7.9Hz, 3H), 6.15 (d, J = 18.4 Hz, 1H), 5.99 (t, J = 5.9 Hz, 2H), 5.69 (d, J = 8.3 Hz, 1H), 5.02 - 4.94 (m, 1H), 4.59 (dd, J = 10.5, 6.5 Hz, 1H), 4.37 (s, 1H), 4.24 (ddd, J = 12.00, 5.4, 2.7 Hz, 1H), 4.01 - 3.88 (m, 2H), 3.79 - 3.66 (m, 3H), 3.66 (d, J = 4.8 Hz, 3H), 1.39 - 1.29 (m, 9H), 1.22 (d, J = 6.3 Hz, 6H), 0.97 (t, J = 7.9 Hz, 9H), 0.66 (q, J = 7.9 Hz, 6H).
MS-ESI:m/z＝803.2[M+1] +。 MS-ESI: m/z = 803.2 [M+1] + .
4)化合物14的合成4) Synthesis of Compound 14
Figure PCTCN2017119448-appb-000166
Figure PCTCN2017119448-appb-000166
将化合物14-4(4.7g，5.9mmol，1eq)溶于丙酮(15mL)中，室温下依次加入水(10mL)、三氟乙酸(3mL)和冰乙酸(10mL)，室温反应；TLC监测，20h反应完全，往反应液中加入EA(100mL)，搅拌均匀，静置分液，有机相用水(60mL×3)、饱和氯化钠(60mL)洗涤，干燥，减压浓缩，柱层析纯化，洗脱剂DCM:MeOH＝70:1，得到白色泡沫状固体2.3g，收率57％。Compound 14-4 (4.7 g, 5.9 mmol, 1 eq) was dissolved in acetone (15 mL), water (10 mL), trifluoroacetic acid (3 mL) and glacial acetic acid (10 mL) After 20h, the reaction was completed. EA (100 mL) was added to the reaction mixture, and the mixture was stirred, and the mixture was separated. The organic phase was washed with water (60 mL×3) and saturated sodium chloride (60 mL). The eluent DCM: MeOH = 70:1 afforded 2.3 g as a white foamy solid.
1H NMR(400MHz,CDCl 3)δ7.51(d,J＝8.2Hz,1H),7.38(t,J＝7.9Hz,2H),7.27–7.19(m,3H),6.23(d,J＝16.1Hz,1H),6.04(q,J＝9.4Hz,2H),5.78(d,J＝8.3Hz,1H),5.26(s,1H),5.04(dt,J＝12.5,6.3Hz,1H),4.61–4.52(m,1H),4.52–4.35(m,2H),4.14(d,J＝9.2Hz,1H),3.96(td,J＝16.3,7.1Hz,2H),3.86–3.76(m,1H),3.70(d,J＝6.7Hz,3H),1.67(s,1H),1.51–1.33(m,9H),1.27(d,J＝6.2Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.51 (d, J = 8.2Hz, 1H), 7.38 (t, J = 7.9Hz, 2H), 7.27-7.19 (m, 3H), 6.23 (d, J = 16.1 Hz, 1H), 6.04 (q, J = 9.4 Hz, 2H), 5.78 (d, J = 8.3 Hz, 1H), 5.26 (s, 1H), 5.04 (dt, J = 12.5, 6.3 Hz, 1H) , 4.61–4.52 (m, 1H), 4.52–4.35 (m, 2H), 4.14 (d, J=9.2 Hz, 1H), 3.96 (td, J = 16.3, 7.1 Hz, 2H), 3.86–3.76 (m) , 1H), 3.70 (d, J = 6.7 Hz, 3H), 1.67 (s, 1H), 1.51 - 1.33 (m, 9H), 1.27 (d, J = 6.2 Hz, 6H).
MS-ESI:m/z＝689.3[M+1] +。 MS-ESI: m/z =689.3 [M+1] + .
实施例15Example 15
3-((2R,3R,4R,5R)-3-氟-4-羟基-5-((((S)-(((S)-1-异丙氧基-1-氧代丙-2-基)氨基)(苯氧基)磷酰基)氧基)甲基)-3-甲基四氢呋喃-2-基)-2,6-二氧代-2,3-二氢嘧啶-1(6H)-基)甲基3-((丙-2-亚基氨基)氧基)丙酸酯3-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-((((S)-((())-1-isopropoxy-1-oxopropan-2-) -yl)amino)(phenoxy)phosphoryl)oxy)methyl)-3-methyltetrahydrofuran-2-yl)-2,6-dioxo-2,3-dihydropyrimidin-1 (6H )-yl)methyl 3-((propan-2-ylideneamino)oxy)propionate
Figure PCTCN2017119448-appb-000167
Figure PCTCN2017119448-appb-000167
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000168
Figure PCTCN2017119448-appb-000168
1)化合物15-2的合成1) Synthesis of compound 15-2
Figure PCTCN2017119448-appb-000169
Figure PCTCN2017119448-appb-000169
将碳酸钠(4.0g，38mmol，1.5eq)，丙酮(1.8mL,25mmol，1.0eq)，盐酸羟胺(2.6g，37.5mmol，1.5eq)溶于水(10mL)中，室温反应16h。反应液用乙酸乙酯萃取(20mL×3)有机相用无水硫酸钠干 燥，减压浓缩得白色固体产品1.3g，收率71.5％。Sodium carbonate (4.0 g, 38 mmol, 1.5 eq), acetone (1.8 mL, 25 mmol, 1.0 eq), EtOAc (EtOAc, EtOAc. The reaction mixture was extracted with EtOAc EtOAc.
1H NMR(400MHz,CDCl 3)δ1.89(s,3H),1.87(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 1.89 (s, 3H), 1.87 (s, 3H).
2)化合物15-4的合成2) Synthesis of compound 15-4
Figure PCTCN2017119448-appb-000170
Figure PCTCN2017119448-appb-000170
将化合物15-2(1.2g，16.4mmol，1.0eq)和化合物15-3(1.32g，13.2mmol，0.8eq)加入到无水乙醇(20mL)中，再加入氢氧化钾(0.147g，2.6mmol，0.16eq)的无水乙醇溶液(3mL)，加完室温反应24h，反应完毕，减压浓缩，剩余物用乙醚(20mL)溶解，依次用的氢氧化钠溶液(10％，10mL)和水(10mL)洗，有机相无水硫酸钠干燥，减压浓缩后，柱分离，PE:EA＝10：1做洗脱剂，得无色液体产品0.52g，收率22.8％。Compound 15-2 (1.2 g, 16.4 mmol, 1.0 eq) and compound 15-3 (1.32 g, 13.2 mmol, 0.8 eq) were added to dry ethanol (20 mL) and then potassium hydroxide (0.147 g, 2.6 Ethyl alcohol (0.16 eq) in anhydrous ethanol (3 mL), EtOAc EtOAc (EtOAc) (EtOAc) The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
1H NMR(400MHz,CDCl 3)δ4.6(t,J＝7.2Hz,2H),4.13(m,2H),2.60(t,J＝7.0Hz,2H),1.90(s,3H),1.88(s,3H),1.30(t,J＝8.0Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 4.6 (t, J = 7.2 Hz, 2H), 4.13 (m, 2H), 2.60 (t, J = 7.0 Hz, 2H), 1.90 (s, 3H), 1.88 (s, 3H), 1.30 (t, J = 8.0 Hz, 3H).
3)化合物15-5的合成3) Synthesis of compound 15-5
Figure PCTCN2017119448-appb-000171
Figure PCTCN2017119448-appb-000171
将化合物15-4(0.50g，2.9mmol，1.0eq)加入到10mL氢氧化钾(0.243g，4.35mmol，1.5eq)的无水乙醇溶液,加完室温反应24h，反应完毕，减压浓缩，剩余物用水(10mL)溶解，用20％的磷酸溶液调节pH在4-5，再用乙醚萃取(10mL×3)，有机相无水硫酸钠干燥，减压浓缩得无色油状产品0.40g，收率95.2％。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%.
1H NMR(400MHz,CDCl 3)δ4.58(t,J＝7.2Hz,2H),2.62(t,J＝7.0Hz,2H),1.92(s,3H),1.90(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 4.58 (t, J = 7.2 Hz, 2H), 2.62 (t, J = 7.0 Hz, 2H), 1.92 (s, 3H), 1.90 (s, 3H).
4)化合物15-6的合成4) Synthesis of compound 15-6
Figure PCTCN2017119448-appb-000172
Figure PCTCN2017119448-appb-000172
将化合物15-5(0.40g，2.8mmol，1.0eq)和四丁基硫酸氢铵(0.094g，0.28mmol，0.1eq)，碳酸钾(1.54g，11.2mmol，4.0eq)混合于二氯甲烷和水的混合溶液(15mL+15mL)中。在-5℃下缓慢滴加氯甲基氯磺酸酯(0.924g，5.6mmol，2.0eq)，15min滴完后移至室温反应5小时。TLC监测反应完毕，反应液静置分层，有机相用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，减压浓缩得淡黄色油状液体0.35g，收率64.8％，无进一步纯化，直接投下一步反应。Compound 15-5 (0.40 g, 2.8 mmol, 1.0 eq) and tetrabutylammonium hydrogen sulfate (0.094 g, 0.28 mmol, 0.1 eq), potassium carbonate (1.54 g, 11.2 mmol, 4.0 eq) In a mixed solution with water (15 mL + 15 mL). Chloromethyl chlorosulfonate (0.924 g, 5.6 mmol, 2.0 eq) was slowly added dropwise at -5 ° C, and after 15 min, the mixture was transferred to room temperature for 5 hours. After the reaction was completed by TLC, the reaction mixture was partitioned. The organic layer was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and evaporated to dryness. , directly vote for the next reaction.
5)化合物15-7的合成5) Synthesis of compound 15-7
Figure PCTCN2017119448-appb-000173
Figure PCTCN2017119448-appb-000173
将化合物M-2(0.89g，1.4mmol，1.0eq)和化合物15-6(0.35g，1.8mmol，1.3eq)溶于丙酮(10mL)中，室温下加入碘化钠(0.96g，6.4mmol，4.0eq)和二异丙基乙基胺(0.27g，2.1mmol，1.5eq)，-10℃下反应过夜。TLC检测反应完成后直接减压浓缩反应溶剂，剩余物加入20mL乙酸乙酯和15mL水搅拌至固体完全溶解后静置分液，有机相依次用水(30mL×2)洗涤，饱和氯化钠溶液(30mL)洗涤，有机相用无水硫酸钠干燥后减压浓缩。以DCM/MeOH＝100/1为洗脱剂柱层析纯化，得到淡黄色油状液体0.85g，收率75.9％。Compound M-2 (0.89 g, 1.4 mmol, 1.0 eq) and compound 15-6 (0.35 g, 1.8 mmol, 1.3 eq) were dissolved in acetone (10 mL) and sodium iodide (0.96 g, 6.4 mmol) , 4.0 eq) and diisopropylethylamine (0.27 g, 2.1 mmol, 1.5 eq), and reacted at -10 ° C overnight. After the completion of the TLC reaction, the reaction solvent was concentrated under reduced pressure, and the residue was added to 20 mL of ethyl acetate and 15 mL of water, and the mixture was stirred until the solid was completely dissolved, and then the mixture was separated, and the organic phase was washed with water (30 mL×2) and saturated sodium chloride solution ( The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography eluting with DCM / MeOH = 100/1 affords:
1H NMR(400MHz,CDCl 3)δ7.56(d,J＝8.1Hz,1H),7.27(t,J＝7.8Hz,2H),7.22(d,J＝8.0Hz,2H),7.20(t,J＝7.3Hz,1H),6.16(d,J＝18.6Hz,1H),5.90(s,2H)5.67(d,J＝8.1Hz,1H),5.09–4.94(m,1H),4.61(dd,J＝11.4,6.1Hz,1H),4.56(t,J＝8.2Hz,2H),4.31–4.23(m,1H),4.14(d,J＝8.5Hz,1H),4.00–3.98(m,1H),3.90(t,J＝9.9Hz,1H),2.16(t,J＝8.2Hz,2H),1.90(s,3H),1.88(s,3H),1.78(s,1H),1.37(t,J＝13.5Hz,6H),1.24(d,J＝6.2Hz,6H),1.00(t,J＝7.9Hz,9H),0.69(q,J＝7.9Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.56 (d, J = 8.1Hz, 1H), 7.27 (t, J = 7.8Hz, 2H), 7.22 (d, J = 8.0Hz, 2H), 7.20 (t , J = 7.3 Hz, 1H), 6.16 (d, J = 18.6 Hz, 1H), 5.90 (s, 2H) 5.67 (d, J = 8.1 Hz, 1H), 5.09 - 4.94 (m, 1H), 4.61 ( Dd, J = 11.4, 6.1 Hz, 1H), 4.56 (t, J = 8.2 Hz, 2H), 4.31 - 4.23 (m, 1H), 4.14 (d, J = 8.5 Hz, 1H), 4.00 - 3.98 (m) , 1H), 3.90 (t, J = 9.9 Hz, 1H), 2.16 (t, J = 8.2 Hz, 2H), 1.90 (s, 3H), 1.88 (s, 3H), 1.78 (s, 1H), 1.37 (t, J = 13.5 Hz, 6H), 1.24 (d, J = 6.2 Hz, 6H), 1.00 (t, J = 7.9 Hz, 9H), 0.69 (q, J = 7.9 Hz, 6H).
MS-ESI:m/z＝801.33[M+1] +。 MS-ESI: m / z = 801.33 [M + 1] +.
6)化合物15合成6) Synthesis of compound 15
Figure PCTCN2017119448-appb-000174
Figure PCTCN2017119448-appb-000174
将化合物15-7(0.84g，1.05mmol，1eq)溶于水(2mL)和冰乙酸(6mL)，室温反应5小时。TLC监控反应完全后，往反应液中加入二氯甲烷(15mL)，搅拌均匀静置分层，有机相依次用水(10mL×3)，饱和氯化钠(10mL)洗涤，无水硫酸钠干燥后减压浓缩，以DCM:MeOH＝50:1为洗脱剂柱层析纯化，得到无色油状物0.56g，收率77.8％。Compound 15-7 (0.84 g, 1.05 mmol, 1 eq) was dissolved in water (2 mL) and EtOAc (EtOAc) After the reaction was completed by TLC, methylene chloride (15 mL) was added to the reaction mixture, and the mixture was stirred and dried. The organic phase was washed with water (10 mL×3), saturated sodium chloride (10 mL) and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure and purified tolululululululululu
1H NMR(400MHz,CDCl 3)δ7.50(d,J＝8.1Hz,1H),7.34(t,J＝7.8Hz,2H),7.22(d,J＝8.0Hz,2H),7.20(t,J＝7.3Hz,1H),6.16(d,J＝18.6Hz,1H),5.90(s,2H)5.67(d,J＝8.1Hz,1H),5.09–4.94(m,1H),4.61 (dd,J＝11.4,6.1Hz,1H),4.56(t,J＝8.2Hz,2H)4.31–4.23(m,1H),4.14(d,J＝8.5Hz,1H),4.00–3.98(m,1H),3.90(t,J＝9.9Hz,1H),3.57(d,J＝8.3Hz,1H)2.16(t,J＝8.2Hz,2H),1.90(s,3H),1.88(s,3H),1.78(s,1H),1.37(t,J＝13.5Hz,6H),1.24(d,J＝6.2Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.50 (d, J = 8.1Hz, 1H), 7.34 (t, J = 7.8Hz, 2H), 7.22 (d, J = 8.0Hz, 2H), 7.20 (t , J = 7.3 Hz, 1H), 6.16 (d, J = 18.6 Hz, 1H), 5.90 (s, 2H) 5.67 (d, J = 8.1 Hz, 1H), 5.09 - 4.94 (m, 1H), 4.61 ( Dd, J = 11.4, 6.1 Hz, 1H), 4.56 (t, J = 8.2 Hz, 2H) 4.31 - 4.23 (m, 1H), 4.14 (d, J = 8.5 Hz, 1H), 4.00 - 3.98 (m, 1H), 3.90 (t, J = 9.9 Hz, 1H), 3.57 (d, J = 8.3 Hz, 1H) 2.16 (t, J = 8.2 Hz, 2H), 1.90 (s, 3H), 1.88 (s, 3H) ), 1.78 (s, 1H), 1.37 (t, J = 13.5 Hz, 6H), 1.24 (d, J = 6.2 Hz, 6H).
MS-ESI:m/z＝687.24[M+1] +。 MS-ESI: m / z = 687.24 [M + 1] +.
实施例16Example 16
(S)-异丙基2-(((S)-(((2R,3R,4R,5R)-4-氟-3-羟基-5-(3-(((S)-2-((甲氧基羰基)氨基)-2-苯基乙酰氧基)甲基)-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-甲基四氢呋喃-2-基)甲氧基)(苯氧基)磷酰基)氨基)丙酸酯(S)-Isopropyl 2-(((S)-(((2R,3R,4R,5R)-4-fluoro-3-hydroxy-5-(3-((()))) Methoxycarbonyl)amino)-2-phenylacetoxy)methyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-methyltetrahydrofuran- 2-yl)methoxy)(phenoxy)phosphoryl)amino)propionate
Figure PCTCN2017119448-appb-000175
Figure PCTCN2017119448-appb-000175
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000176
Figure PCTCN2017119448-appb-000176
1)化合物16-2的合成1) Synthesis of Compound 16-2
Figure PCTCN2017119448-appb-000177
Figure PCTCN2017119448-appb-000177
将化合物16-1(3g，14.34mmol，1.0eq)，四丁基硫酸氢铵(486mg，1.4mmol，0.1eq)，碳酸钾(8g，57.4mmol，4.0eq)混合于DCM(30mL)和水(30mL)中，降温至0℃，滴加氯甲基氯磺酸酯(2.9mL，28.7mmol，2.0eq)，滴完后移至室温反应；TLC监测，3h反应基本完全，反应液加入DCM(50mL)和水(10mL)，静置分液，有机相用饱和氯化钠洗涤，干燥，减压浓缩，柱层析纯化PE:EA＝10:1，得到淡黄色油状物3g,收率81.2％。Compound 16-1 (3 g, 14.34 mmol, 1.0 eq), tetrabutylammonium hydrogen sulfate (486 mg, 1.4 mmol, 0.1 eq), potassium carbonate (8 g, 57.4 mmol, 4.0 eq) was combined in DCM (30 mL) and water (30mL), the temperature was lowered to 0 ° C, chloromethyl chlorosulfonate (2.9 mL, 28.7 mmol, 2.0 eq) was added dropwise. After the completion of the dropwise addition, the reaction was carried out to room temperature; TLC was monitored, the reaction was almost complete in 3 h, and the reaction solution was added to DCM. (50 mL) and water (10 mL), EtOAc (EtOAc) m. 81.2%.
2)化合物16-3的合成2) Synthesis of compound 16-3
Figure PCTCN2017119448-appb-000178
Figure PCTCN2017119448-appb-000178
将化合物M-2(5g，7.8mmol，1.0eq)、化合物16-2(3g，11.7mmol，1.5eq)溶于丙酮中(50mL)，室温下加入碘化钠(4.6g，31mmol，4.0eq)和DIPEA(2mL，11.7mmol，1.5eq)，加完后室温反应。TLC监测20h两个原料都有少量剩余，停止反应直接后处理，减压浓缩丙酮，剩余物加入乙酸乙酯(100mL)和水(60mL)搅拌至固体完全溶解，静置分液，有机相继续用水(60mL)洗涤，饱和氯化钠(60mL)洗涤，无水硫酸钠干燥，减压浓缩，柱层析纯化，洗脱剂DCM:MeOH＝100:1，得到黄色油状物3.8g，收率57％。Compound M-2 (5 g, 7.8 mmol, 1.0 eq), compound 16-2 (3 g, 11.7 mmol, 1.5 eq) was dissolved in acetone (50 mL) and sodium iodide (4.6 g, 31 mmol, 4.0 eq. And DIPEA (2 mL, 11.7 mmol, 1.5 eq), reacted at room temperature after addition. After TLC was monitored for 20 hours, both materials had a small amount of residual. The reaction was stopped and the residue was directly treated. The acetone was concentrated under reduced pressure. The residue was added ethyl acetate (100 mL) and water (60 mL) and stirred until the solid was completely dissolved. Was washed with water (60 mL), EtOAc (EtOAc m. 57%.
1H NMR(400MHz,CDCl 3)δ7.54(t,J＝8.5Hz,1H),7.44–7.29(m,7H),7.21(dd,J＝14.5,7.5Hz,3H),6.17–5.90(m,3H),5.85–5.57(m,2H),5.44–5.35(m,1H),5.00(dq,J＝12.7,6.3Hz,1H),4.61(dd,J＝10.4,6.5Hz,1H),4.25(ddd,J＝11.7,5.2,2.6Hz,1H),4.14(dd,J＝14.0,7.1Hz,1H),4.04–3.70(m,3H),3.68(d,J＝7.5Hz,3H),1.37(t,J＝6.7Hz,3H),1.29–1.22(m,9H),1.01(t,J＝7.9Hz,9H),0.68(q,J＝7.9Hz,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.54 (t, J = 8.5 Hz, 1H), 7.44 - 7.29 (m, 7H), 7.21. (dd, J = 14.5, 7.5 Hz, 3H), 6.17 - 5.90 ( m,3H), 5.85–5.57 (m, 2H), 5.44–5.35 (m, 1H), 5.00 (dq, J=12.7, 6.3 Hz, 1H), 4.61 (dd, J=10.4, 6.5 Hz, 1H) , 4.25 (ddd, J = 11.7, 5.2, 2.6 Hz, 1H), 4.14 (dd, J = 14.0, 7.1 Hz, 1H), 4.04 - 3.70 (m, 3H), 3.68 (d, J = 7.5 Hz, 3H) ), 1.37 (t, J = 6.7 Hz, 3H), 1.29 - 1.22 (m, 9H), 1.01 (t, J = 7.9 Hz, 9H), 0.68 (q, J = 7.9 Hz, 6H).
MS-ESI:m/z＝865.30[M+1] +。 MS-ESI: m/z = 865.30 [M+1] + .
3)化合物16的合成3) Synthesis of Compound 16
Figure PCTCN2017119448-appb-000179
Figure PCTCN2017119448-appb-000179
将化合物16-3(3.8g，4.4mmol，1eq)溶于丙酮(12mL)中，室温下依次加入水(8mL)、三氟乙酸(3mL)和冰乙酸(9mL)，室温反应；TLC监测，反应完全，往反应液中加入DCM(50mL)，搅拌均匀，静置分液，有机相用水(10mL×3)继续洗涤，饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩，柱层析纯化，洗脱剂DCM:MeOH＝70:1，得到浅绿色泡沫状固体1.7g，收率52％。Compound 16-3 (3.8 g, 4.4 mmol, 1 eq) was dissolved in acetone (12 mL). Water (8 mL), trifluoroacetic acid (3 mL) and EtOAc (EtOAc) After the reaction was completed, DCM (50 mL) was added to the reaction mixture, and the mixture was stirred, and the mixture was separated. The organic phase was washed with water (10 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate Purification and purification, eluent DCM: MeOH = 70:1 afforded 1.7 g as a pale green solid.
1H NMR(400MHz,CDCl 3)δ7.43(d,J＝8.1Hz,1H),7.39–7.27(m,7H),7.20(t,J＝8.1Hz,3H),6.05(dt,J＝20.5,17.3Hz,3H),5.71(d,J＝8.2Hz,2H),5.38(d,J＝7.4Hz,1H),5.01(dt,J＝12.5,6.2Hz,1H),4.47(dt,J＝19.2,10.6Hz,2H),4.09(d,J＝9.2Hz,1H),3.97–3.70(m,4H),3.67(s,3H),1.34(d,J＝7.0Hz,3H),1.22(dt,J＝26.9,13.4Hz,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.43 (d, J = 8.1 Hz, 1H), 7.39 - 7.27 (m, 7H), 7.20 (t, J = 8.1 Hz, 3H), 6.05 (dt, J = 20.5, 17.3 Hz, 3H), 5.71 (d, J = 8.2 Hz, 2H), 5.38 (d, J = 7.4 Hz, 1H), 5.01 (dt, J = 12.5, 6.2 Hz, 1H), 4.47 (dt, J = 19.2, 10.6 Hz, 2H), 4.09 (d, J = 9.2 Hz, 1H), 3.97 - 3.70 (m, 4H), 3.67 (s, 3H), 1.34 (d, J = 7.0 Hz, 3H), 1.22 (dt, J = 26.9, 13.4 Hz, 9H).
MS-ESI:m/z＝751.2[M+1] +。 MS-ESI: m/z = 751.2 [M+1] + .
实施例17Example 17
(2S,3S)-(3-((2R,3R,4R,5R)-3-氟-4-羟基-5-((((S)-(((S)-1-异丙氧基-1-氧代丙-2-基)氨基)(苯氧基)磷酰基)氧基)甲基)-3-甲基四氢呋喃-2-基)-2,6-二氧代-2,3-二氢嘧啶-1(6H)-基)甲基3-甲氧基-2-((甲氧基羰基)氨基)丁酸甲酯(2S,3S)-(3-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-((((S)-((())))) 1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-3-methyltetrahydrofuran-2-yl)-2,6-dioxo-2,3- Dihydropyrimidin-1(6H)-yl)methyl 3-methoxy-2-((methoxycarbonyl)amino)butyric acid methyl ester
Figure PCTCN2017119448-appb-000180
Figure PCTCN2017119448-appb-000180
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000181
Figure PCTCN2017119448-appb-000181
Figure PCTCN2017119448-appb-000182
Figure PCTCN2017119448-appb-000182
1)化合物17-2的合成1) Synthesis of Compound 17-2
Figure PCTCN2017119448-appb-000183
Figure PCTCN2017119448-appb-000183
将氢氧化钠(4.5g，110.0mmol，3eq)溶于80mL水中，加入化合物17-1(5g，37.5mmol，1.0eq)，在-5℃下缓慢滴加氯甲酸甲酯(3.8mL，48.8mmol，1.3eq)，保持在10min滴加完毕后移至室温。20h后反应完毕，反应液加入浓盐酸调pH值至大约2，二氯甲烷萃取(150mL×3)，有机相减压减压浓缩后真空干燥1h得到透明油状液体4.3g，收率60％。Sodium hydroxide (4.5 g, 110.0 mmol, 3 eq) was dissolved in water (80 mL), compound 17-1 (5 g, 37.5 mmol, 1.0 eq) was added, and methyl chloroformate (3.8 mL, 48.8) was slowly added dropwise at -5 °C. M, 1.3 eq), kept at room temperature after 10 minutes of dropwise addition. After 20 hours, the reaction was completed, and the reaction mixture was added with concentrated hydrochloric acid to adjust the pH to about 2, and extracted with dichloromethane (150 mL × 3). The organic phase was concentrated under reduced pressure and then dried in vacuo.
1H NMR(400MHz,CDCl 3)δ7.50(s,1H),5.54(d,J＝9.2Hz,1H),4.33(dd,J＝9.3,2.0Hz,1H),3.96(tt,J＝17.3,8.6Hz,1H),3.67(d,J＝4.9Hz,3H),3.30(s,3H),1.19(d,J＝6.3Hz,3H)。 1 H NMR (400MHz, CDCl 3 ) δ7.50 (s, 1H), 5.54 (d, J = 9.2Hz, 1H), 4.33 (dd, J = 9.3,2.0Hz, 1H), 3.96 (tt, J = 17.3, 8.6 Hz, 1H), 3.67 (d, J = 4.9 Hz, 3H), 3.30 (s, 3H), 1.19 (d, J = 6.3 Hz, 3H).
MS-ESI:m/z＝192.1[M+1] +。 MS-ESI: m / z = 192.1 [M + 1] +.
2)化合物17-3的合成2) Synthesis of compound 17-3
Figure PCTCN2017119448-appb-000184
Figure PCTCN2017119448-appb-000184
将化合物17-2(4.3g，22mmol，1.0eq)和四丁基硫酸氢铵(0.76g，2.2mmol，0.1eq)，碳酸钾(12g，86.8mmol，4.0eq)混合于二氯甲烷和水的混合溶液(40mL+40mL)中。在-5℃下缓慢滴加氯甲基氯磺酸酯(4.6mL，45mmol，2.0eq)，15min滴完后移至室温反应5小时。TLC监测反应完毕，反应液静置分层，有 机相用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，减压浓缩得淡黄色油状液体5.2g，收率96％，无进一步纯化直接投下一步反应。Compound 17-2 (4.3 g, 22 mmol, 1.0 eq) and tetrabutylammonium hydrogen sulfate (0.76 g, 2.2 mmol, 0.1 eq), potassium carbonate (12 g, 86.8 mmol, 4.0 eq) were combined in dichloromethane and water In a mixed solution (40 mL + 40 mL). Chloromethyl chlorosulfonate (4.6 mL, 45 mmol, 2.0 eq) was slowly added dropwise at -5 ° C, and after 15 min, the mixture was transferred to room temperature for 5 hours. After the reaction was completed by TLC, the reaction mixture was partitioned, the organic layer was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and evaporated. Directly cast the next reaction.
1H NMR(400MHz,CDCl 3)δ5.86(d,J＝6.1Hz,1H),5.65(d,J＝6.1Hz,1H),5.44(d,J＝8.9Hz,1H),4.35(dd,J＝9.5,2.2Hz,1H),3.94(qd,J＝6.2,2.2Hz,1H),3.69(s,3H),3.27(s,3H),1.21(d,J＝6.3Hz,3H)。 1 H NMR (400MHz, CDCl 3 ) δ5.86 (d, J = 6.1Hz, 1H), 5.65 (d, J = 6.1Hz, 1H), 5.44 (d, J = 8.9Hz, 1H), 4.35 (dd , J=9.5, 2.2 Hz, 1H), 3.94 (qd, J=6.2, 2.2 Hz, 1H), 3.69 (s, 3H), 3.27 (s, 3H), 1.21 (d, J = 6.3 Hz, 3H) .
MS-ESI:m/z＝240.10[M+1] +。 MS-ESI: m/z = 240.10 [M+1] + .
3)化合物17-4的合成3) Synthesis of Compound 17-4
Figure PCTCN2017119448-appb-000185
Figure PCTCN2017119448-appb-000185
将化合物M-2(4g，6.2mmol，1.0eq)和化合物17-3(2.4g，10mmol，1.6eq)溶于丙酮(40mL)中，室温下加入碘化钠(3.73g，24.8mmol，4.0eq)和二异丙基乙基胺(1.85mL，11.2mmol，1.8eq)，-5℃下反应过夜。16h后TLC检测反应完成，减压浓缩反应溶剂，剩余物加入乙酸乙酯(200mL)和水(100mL)搅拌至固体完全溶解后静置分液，有机相依次用水(80mL×2)洗涤，饱和氯化钠溶液(80mL)洗涤，有机相用无水硫酸钠干燥后减压浓缩。以DCM:MeOH＝70:1为洗脱剂柱层析纯化，得到黄色粘稠液体3.8g，收率72.2％。Compound M-2 (4 g, 6.2 mmol, 1.0 eq) and compound 17-3 (2.4 g, 10 mmol, 1.6 eq) were dissolved in acetone (40 mL) and sodium iodide (3.73 g, 24.8 mmol, 4.0 Eq) and diisopropylethylamine (1.85 mL, 11.2 mmol, 1.8 eq) were reacted at -5 °C overnight. After 16 h, the reaction was completed by TLC. The solvent was concentrated under reduced pressure. ethyl acetate (200 mL) and water (100 mL) was added to the residue. The solid was dissolved and then left to stand. The organic phase was washed with water (80 mL×2) and saturated. The organic layer was dried over anhydrous sodium sulfate and evaporated. Purification by column chromatography with DCM: MeOH = 70:1 eluted to afford 3.8 g of yel.
1H NMR(400MHz,CDCl 3)δ7.55(d,J＝8.2Hz,1H),7.28(t,J＝7.9Hz,2H),7.21–7.05(m,3H),6.12(d,J＝18.2Hz,1H),5.95(dd,J＝21.4,9.3Hz,2H),5.66(d,J＝8.2Hz,1H),5.43(d,J＝9.5Hz,1H),4.94(dt,J＝12.5,6.2Hz,1H),4.55(dd,J＝11.1,6.4Hz,1H),4.32–4.13(m,2H),4.08(d,J＝8.3Hz,1H),3.88(ddd,J＝22.5,13.7,5.5Hz,3H),3.62(s,3H),3.22(s,3H),2.16(s,1H),1.30(dd,J＝14.4,9.8Hz,6H),1.17(d,J＝6.2Hz,6H),1.12(d,J＝6.2Hz,3H),0.93(t,J＝7.9Hz,9H),0.62(q,J＝7.9Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.55 (d, J = 8.2Hz, 1H), 7.28 (t, J = 7.9Hz, 2H), 7.21-7.05 (m, 3H), 6.12 (d, J = 18.2 Hz, 1H), 5.95 (dd, J = 21.4, 9.3 Hz, 2H), 5.66 (d, J = 8.2 Hz, 1H), 5.43 (d, J = 9.5 Hz, 1H), 4.94 (dt, J = 12.5, 6.2 Hz, 1H), 4.55 (dd, J = 11.1, 6.4 Hz, 1H), 4.32 - 4.13 (m, 2H), 4.08 (d, J = 8.3 Hz, 1H), 3.88 (ddd, J = 22.5) , 13.7, 5.5 Hz, 3H), 3.62 (s, 3H), 3.22 (s, 3H), 2.16 (s, 1H), 1.30 (dd, J = 14.4, 9.8 Hz, 6H), 1.17 (d, J = 6.2 Hz, 6H), 1.12 (d, J = 6.2 Hz, 3H), 0.93 (t, J = 7.9 Hz, 9H), 0.62 (q, J = 7.9 Hz, 6H).
MS-ESI:m/z＝847.30[M+1] +。 MS-ESI: m/z = 847.30 [M+1] + .
4)化合物17合成4) Synthesis of compound 17
Figure PCTCN2017119448-appb-000186
Figure PCTCN2017119448-appb-000186
将化合物17-4(3.7g，4.4mmol，1eq)溶于丙酮(10mL)，室温下依次加入水(7.5mL)、三氟乙酸 (2.5mL)和冰乙酸(10mL)后反应3小时。TLC监控反应完全后，往反应液中加入二氯甲烷(400mL)和水(400mL)，搅拌均匀静置分层，有机相依次用水(400mL×3)，饱和氯化钠(400mL)洗涤，无水硫酸钠干燥后减压浓缩，以DCM:MeOH＝60:1为洗脱剂柱层析纯化，得到白色泡沫状固体2.2g，收率69％。Compound 17-4 (3.7 g, 4.4 mmol, 1 eq) was dissolved in acetone (10 mL), and water (7.5 mL), trifluoroacetic acid (2.5 mL) and EtOAc (10 mL) After the TLC monitoring reaction was completed, dichloromethane (400 mL) and water (400 mL) were added to the reaction mixture, and the mixture was uniformly stirred and layered. The organic phase was washed successively with water (400 mL×3) and saturated sodium chloride (400 mL). The aqueous solution was dried over anhydrous sodium sulfate (MgSO4).
1H NMR(400MHz,CDCl 3)δ7.48(d,J＝8.2Hz,1H),7.34(t,J＝7.8Hz,2H),7.20(dd,J＝11.4,7.8Hz,3H),6.29–6.10(m,1H),6.01(dd,J＝26.5,9.4Hz,2H),5.75(d,J＝8.2Hz,1H),5.41(d,J＝9.6Hz,1H),5.06–4.94(m,1H),4.48(dd,J＝25.3,8.2Hz,2H),4.32(dd,J＝9.6,1.8Hz,1H),4.11(d,J＝8.8Hz,1H),4.05–3.80(m,4H),3.67(s,3H),3.27(s,3H),2.65(s,1H),1.37(dd,J＝18.6,14.7Hz,6H),1.23(d,J＝6.3Hz,6H),1.17(d,J＝6.2Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (d, J = 8.2 Hz, 1H), 7.34 (t, J = 7.8 Hz, 2H), 7.20 (dd, J = 11.4, 7.8 Hz, 3H), 6.29 –6.10(m,1H), 6.01 (dd, J=26.5, 9.4 Hz, 2H), 5.75 (d, J=8.2 Hz, 1H), 5.41 (d, J=9.6 Hz, 1H), 5.06–4.94 ( m,1H), 4.48 (dd, J=25.3, 8.2 Hz, 2H), 4.32 (dd, J=9.6, 1.8 Hz, 1H), 4.11 (d, J=8.8 Hz, 1H), 4.05–3.80 (m) , 4H), 3.67 (s, 3H), 3.27 (s, 3H), 2.65 (s, 1H), 1.37 (dd, J = 18.6, 14.7 Hz, 6H), 1.23 (d, J = 6.3 Hz, 6H) , 1.17 (d, J = 6.2 Hz, 3H).
MS-ESI:m/z＝733.1[M+1] +。 MS-ESI: m/z = 733.1 [M+1] + .
实施例18Example 18
(S)-(3-((2R,3R,4R,5R)-3-氟-4-羟基-5-((((S)-(((S)-1-异丙氧基-1-氧代丙-2-基)氨基)(苯氧基)磷酰基)氧基)甲基)-3-甲基四氢呋喃-2-基)-2,6-二氧代-2,3-二氢嘧啶-1(6H)-基)甲基2-((乙氧基羰基)氨基)-3-甲基丁酸甲酯(S)-(3-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-((((S)-((())))) Oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-3-methyltetrahydrofuran-2-yl)-2,6-dioxo-2,3-dihydro Pyrimidine-1(6H)-yl)methyl 2-((ethoxycarbonyl)amino)-3-methylbutanoate
Figure PCTCN2017119448-appb-000187
Figure PCTCN2017119448-appb-000187
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000188
Figure PCTCN2017119448-appb-000188
Figure PCTCN2017119448-appb-000189
Figure PCTCN2017119448-appb-000189
1)化合物18-2的合成1) Synthesis of Compound 18-2
Figure PCTCN2017119448-appb-000190
Figure PCTCN2017119448-appb-000190
将氢氧化钠(5.1g，130.0mmol，3eq)溶于水(80mL)中，加入化合物18-1(5g，42.7mmol，1.0eq)，在-5℃下缓慢滴加氯甲酸乙酯(5.3mL，55.5mmol，1.3eq)，保持在10min滴加完毕后移至室温。20h后反应完毕，反应液加入浓盐酸调pH值至大约2，二氯甲烷萃取(150mL×3)，有机相减压减压浓缩后真空干燥1h得到透明油状液体4.7g，收率58％。Sodium hydroxide (5.1 g, 130.0 mmol, 3 eq) was dissolved in water (80 mL). Compound 18-1 (5 g, 42.7 mmol, 1.0 eq) was added, and ethyl chloroformate (5.3) was slowly added dropwise at -5 °C. mL, 55.5 mmol, 1.3 eq), was kept at room temperature after 10 min addition. After 20 hours, the reaction was completed, and the reaction mixture was added with concentrated hydrochloric acid to adjust the pH to about 2, and extracted with dichloromethane (150 mL×3). The organic phase was concentrated under reduced pressure and then dried in vacuo to yield 4.7 g of a clear oily liquid.
1H NMR(400MHz,CDCl 3)δ7.63(s,1H),5.26(d,J＝8.9Hz,1H),4.30(dd,J＝8.8,4.4Hz,1H),4.16–4.08(m,2H),2.21(dd,J＝11.8,6.3Hz,1H),1.27–1.21(m,3H),0.96(dd,J＝27.5,6.8Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.63 (s, 1H), 5.26 (d, J = 8.9Hz, 1H), 4.30 (dd, J = 8.8,4.4Hz, 1H), 4.16-4.08 (m, 2H), 2.21 (dd, J = 11.8, 6.3 Hz, 1H), 1.27 - 1.21 (m, 3H), 0.96 (dd, J = 27.5, 6.8 Hz, 6H).
MS-ESI:m/z＝190.10[M+1] +。 MS-ESI: m / z = 190.10 [M + 1] +.
2)化合物18-3的合成2) Synthesis of Compound 18-3
Figure PCTCN2017119448-appb-000191
Figure PCTCN2017119448-appb-000191
将化合物18-2(4.7g，25mmol，1.0eq)和四丁基硫酸氢铵(0.84g，2.5mmol，0.1eq)，碳酸钾(14g，101.3mmol，4.0eq)混合于二氯甲烷和水的混合溶液(40mL+40mL)中。在-5℃下缓慢滴加氯甲基氯磺酸酯(5mL，49.4mmol，2.0eq)，15min滴完后移至室温反应5小时。TLC监测反应完毕，反应液静置分层，有机相用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，减压浓缩得淡黄色油状液体3.5g，收率59％，无进一步纯化直接投下一步反应。Compound 18-2 (4.7 g, 25 mmol, 1.0 eq) and tetrabutylammonium hydrogen sulfate (0.84 g, 2.5 mmol, 0.1 eq), potassium carbonate (14 g, 101.3 mmol, 4.0 eq) were combined in dichloromethane and water In a mixed solution (40 mL + 40 mL). Chloromethyl chlorosulfonate (5 mL, 49.4 mmol, 2.0 eq) was slowly added dropwise at -5 ° C, and after 15 min, the mixture was transferred to room temperature for 5 hours. After the reaction was completed by TLC, the reaction mixture was partitioned. The organic layer was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and evaporated. Directly cast the next reaction.
1H NMR(400MHz,CDCl 3)δ5.87(d,J＝6.0Hz,1H),5.64(d,J＝6.0Hz,1H),5.19(d,J＝8.0Hz,1H),4.33(dd,J＝8.9,4.7Hz,1H),4.17–4.10(m,2H),2.22(td,J＝13.0,6.6Hz,1H),1.26(t,J＝7.1Hz,3H),0.97(dd,J＝30.6,6.9Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ5.87 (d, J = 6.0Hz, 1H), 5.64 (d, J = 6.0Hz, 1H), 5.19 (d, J = 8.0Hz, 1H), 4.33 (dd , J=8.9, 4.7 Hz, 1H), 4.17–4.10 (m, 2H), 2.22 (td, J=13.0, 6.6 Hz, 1H), 1.26 (t, J=7.1 Hz, 3H), 0.97 (dd, J = 30.6, 6.9 Hz, 6H).
MS-ESI:m/z＝238.30[M+1] +。 MS-ESI: m / z = 238.30 [M + 1] +.
3)化合物18-4的合成3) Synthesis of Compound 18-4
Figure PCTCN2017119448-appb-000192
Figure PCTCN2017119448-appb-000192
将化合物M-2(4g，6.2mmol，1.0eq)和化合物18-3(2.4g，10mmol，1.6eq)溶于丙酮(40mL)中，室温下加入碘化钠(3.73g，25mmol，4.0eq)、DMAP(0.075g，0.61mmol，0.1eq)和二异丙基乙基胺(1.85mL，11.2mmol，1.8eq)，-5℃下反应过夜。15h后TLC检测反应完成，减压浓缩反应溶剂，剩余物加入乙酸乙酯(200mL)和水(100mL)搅拌至固体完全溶解后静置分液，有机相依次用水(80mL×2)洗涤，饱和氯化钠溶液(80mL)洗涤，有机相用无水硫酸钠干燥后减压浓缩。以DCM:MeOH＝100:1为洗脱剂柱层析纯化，得到黄色粘稠液体3.98g，收率75.8％。Compound M-2 (4 g, 6.2 mmol, 1.0 eq) and compound 18-3 (2.4 g, 10 mmol, 1.6 eq) were dissolved in acetone (40 mL) and sodium iodide (3.73 g, 25 mmol, 4.0 eq. DMAP (0.075 g, 0.61 mmol, 0.1 eq) and diisopropylethylamine (1.85 mL, 11.2 mmol, 1.8 eq) were reacted at -5 ° C overnight. After 15 h, the reaction was completed by TLC. The solvent was concentrated under reduced pressure. ethyl acetate (200 mL) and water (100 mL) was added to the residue. The solid was dissolved and then left to stand. The organic phase was washed with water (80 mL×2) and saturated. The organic layer was dried over anhydrous sodium sulfate and evaporated. Purification by column chromatography with DCM: MeOH = 100:1 elute to afford 3.
1H NMR(400MHz,CDCl 3)δ7.57(d,J＝8.2Hz,1H),7.32(t,J＝7.9Hz,2H),7.18(dd,J＝17.0,8.0Hz,3H),6.15(d,J＝18.3Hz,1H),5.98(d,J＝4.5Hz,2H),5.68(d,J＝8.3Hz,1H),5.18(d,J＝9.0Hz,1H),5.04–4.92(m,1H),4.59(dd,J＝10.7,6.5Hz,1H),4.32–4.19(m,2H),4.11(t,J＝7.0Hz,3H),4.00–3.88(m,2H),3.72(t,J＝9.9Hz,1H),2.24–1.96(m,1H),1.32(d,J＝21.6Hz,6H),1.22(dd,J＝6.7,2.8Hz,9H),1.00–0.93(m,12H),0.89–0.85(m,3H),0.72–0.57(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.57 (d, J = 8.2Hz, 1H), 7.32 (t, J = 7.9Hz, 2H), 7.18 (dd, J = 17.0,8.0Hz, 3H), 6.15 (d, J = 18.3 Hz, 1H), 5.98 (d, J = 4.5 Hz, 2H), 5.68 (d, J = 8.3 Hz, 1H), 5.18 (d, J = 9.0 Hz, 1H), 5.04 - 4.92 (m, 1H), 4.59 (dd, J = 10.7, 6.5 Hz, 1H), 4.32 - 4.19 (m, 2H), 4.11 (t, J = 7.0 Hz, 3H), 4.00 - 3.88 (m, 2H), 3.72 (t, J = 9.9 Hz, 1H), 2.24 - 1.96 (m, 1H), 1.32 (d, J = 21.6 Hz, 6H), 1.22 (dd, J = 6.7, 2.8 Hz, 9H), 1.00 - 0.93 (m, 12H), 0.89 - 0.85 (m, 3H), 0.72 - 0.57 (m, 6H).
4)化合物18的合成4) Synthesis of Compound 18
Figure PCTCN2017119448-appb-000193
Figure PCTCN2017119448-appb-000193
将化合物18-4(3.7g，4.4mmol，1eq)溶于丙酮(10mL)，室温下依次加入水(7.5mL)、三氟乙酸(2.5mL)和冰乙酸(10mL)后反应3小时。TLC监控反应完全后，往反应液中加入二氯甲烷(400mL)和水(400mL)，搅拌均匀静置分层，有机相依次用水(400mL×3)，饱和氯化钠(400mL)洗涤，无水硫酸钠干燥后减压浓缩，以DCM:MeOH＝60:1为洗脱剂柱层析纯化，得到白色泡沫状固体2.2g，收率81％。Compound 18-4 (3.7 g, 4.4 mmol, 1 eq) was dissolved in acetone (10 mL), and water (7.5 mL), trifluoroacetic acid (2.5 mL) and EtOAc (10 mL) After the TLC monitoring reaction was completed, dichloromethane (400 mL) and water (400 mL) were added to the reaction mixture, and the mixture was uniformly stirred and layered. The organic phase was washed successively with water (400 mL×3) and saturated sodium chloride (400 mL). The organic layer was dried over anhydrous sodium sulfate (MgSO4).
1H NMR(400MHz,CDCl 3)δ7.48(d,J＝8.2Hz,1H),7.33(t,J＝7.9Hz,2H),7.18(dd,J＝12.3,7.8Hz,3H),6.29–6.07(m,1H),6.05–5.92(m,2H),5.73(d,J＝8.3Hz,1H),5.20(d,J＝9.1Hz,1H),4.99(hept,J＝6.2Hz,1H),4.61–4.34(m,2H),4.28(dd,J＝8.7,4.3Hz,1H),4.10(dd,J＝6.9,3.2Hz,4H),3.90(dt,J＝15.9,7.9Hz,2H),3.04(s,1H),2.10(dd,J＝11.7,6.3Hz,1H),1.35(dd,J＝14.4,12.8Hz,6H),1.23(dd,J＝8.9,3.5 Hz,9H),0.90(dd,J＝27.5,6.8Hz,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (d, J = 8.2 Hz, 1H), 7.33 (t, J = 7.9 Hz, 2H), 7.18 (dd, J = 12.3, 7.8 Hz, 3H), 6.29 –6.07(m,1H), 6.05–5.92(m,2H), 5.73(d,J=8.3Hz,1H), 5.20(d,J=9.1Hz,1H),4.99(hept,J=6.2Hz, 1H), 4.61–4.34 (m, 2H), 4.28 (dd, J=8.7, 4.3 Hz, 1H), 4.10 (dd, J=6.9, 3.2 Hz, 4H), 3.90 (dt, J=15.9, 7.9 Hz) , 2H), 3.04 (s, 1H), 2.10 (dd, J = 11.7, 6.3 Hz, 1H), 1.35 (dd, J = 14.4, 12.8 Hz, 6H), 1.23 (dd, J = 8.9, 3.5 Hz, 9H), 0.90 (dd, J = 27.5, 6.8 Hz, 6H).
MS-ESI:m/z＝731.2[M+1] +。 MS-ESI: m/z = 731.2 [M+1] + .
实施例19Example 19
(S)-异丙基2-(((S)-(((2R,3R,4R,5R)-5-(3-(((S)-2-环己基-2-((乙氧基甲氧基羰基)氨基)乙酰氧基)甲基)-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)乙氧基甲氧基)(苯氧基)磷酰基)氨基)丙酸酯(S)-Isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(3-((()))-cyclohexyl-2-((ethoxy) Methoxycarbonyl)amino)acetoxy)methyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyl Tetrahydrofuran-2-yl)ethoxymethoxy)(phenoxy)phosphoryl)amino)propionate
Figure PCTCN2017119448-appb-000194
Figure PCTCN2017119448-appb-000194
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000195
Figure PCTCN2017119448-appb-000195
1)化合物19-2的合成1) Synthesis of Compound 19-2
Figure PCTCN2017119448-appb-000196
Figure PCTCN2017119448-appb-000196
将化合物19-1(1.5g，7.0mmol，1.0eq)和四丁基硫酸氢铵(0.24g，0.7mmol，0.1eq)，碳酸钾(3.9g，28.0mmol，4.0eq)混合于二氯甲烷和水的混合溶液(10mL+10mL)中。在-5℃下缓慢滴加氯甲基氯磺酸酯(1.4mL，14mmol，2.0eq)，15min滴完后移至室温反应5小时。TLC监测反应完毕，反应液静置分层，有机相用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，减压浓缩得淡黄色透明油状液体1.72g，收率94％，无进一步纯化直接投下一步反应。Compound 19-1 (1.5 g, 7.0 mmol, 1.0 eq) and tetrabutylammonium hydrogen sulfate (0.24 g, 0.7 mmol, 0.1 eq), potassium carbonate (3.9 g, 28.0 mmol, 4.0 eq) Mixed solution with water (10 mL + 10 mL). Chloromethyl chlorosulfonate (1.4 mL, 14 mmol, 2.0 eq) was slowly added dropwise at -5 ° C, and after 15 min, the mixture was transferred to room temperature for 5 hours. After the reaction was completed by TLC, the reaction mixture was partitioned, the organic layer was washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate and evaporated to dryness. Purification is directly administered to the next reaction.
1H NMR(400MHz,CDCl 3)δ5.73(dd,J＝80.5,6.0Hz,2H),5.19(d,J＝8.2Hz,1H),4.31(dd,J＝8.7,5.1Hz,1H),3.68(s,3H),1.69(ddd,J＝32.1,22.3,14.3Hz,7H),1.31–1.13(m,4H)。 1 H NMR (400MHz, CDCl 3 ) δ5.73 (dd, J = 80.5,6.0Hz, 2H), 5.19 (d, J = 8.2Hz, 1H), 4.31 (dd, J = 8.7,5.1Hz, 1H) , 3.68 (s, 3H), 1.69 (ddd, J = 32.1, 22.3, 14.3 Hz, 7H), 1.31 - 1.13 (m, 4H).
2)化合物19-3的合成2) Synthesis of compound 19-3
Figure PCTCN2017119448-appb-000197
Figure PCTCN2017119448-appb-000197
将化合物M-2(2.4g，3.7mmol，1.0eq)和化合物19-2(1.6g，6.1mmol，1.6eq)溶于丙酮(25mL)中，室温下加入碘化钠(2.2g，15mmol，4.0eq)、DMAP(0.046g，0.38mmol，0.1eq)和二异丙基乙基胺(1.1mL，6.7mmol，1.8eq)，-5℃下反应过夜。15h后TLC检测反应基本完成，减压浓缩反应溶剂，剩余物加入乙酸乙酯(200mL)和水(100mL)搅拌至固体完全溶解后静置分液，有机相依次用水(80mL×2)洗涤，饱和氯化钠溶液(80mL)洗涤，有机相用无水硫酸钠干燥后减压浓缩。以DCM:MeOH＝100:1为洗脱剂柱层析纯化，得到黄色粘稠液体2.6g，收率80％。Compound M-2 (2.4 g, 3.7 mmol, 1.0 eq) and compound 19-2 (1.6 g, 6.1 mmol, 1.6 eq) were dissolved in acetone (25 mL) and sodium iodide (2.2 g, 15 mmol, 4.0 eq), DMAP (0.046 g, 0.38 mmol, 0.1 eq) and diisopropylethylamine (1.1 mL, 6.7 mmol, 1.8 eq). After 15 h, the reaction was completely completed by TLC. The solvent was concentrated under reduced pressure. ethyl acetate (200 mL) and water (100 mL) was added to the residue and the mixture was stirred and dissolved. The organic phase was washed with water (80 mL×2). The organic layer was dried over anhydrous sodium sulfate and evaporated. Purification by column chromatography with DCM: MeOH = 100:1 eluted to afford 2.6 g of yel.
1H NMR(400MHz,CDCl 3)δ7.58(d,J＝8.1Hz,1H),7.33(t,J＝7.9Hz,2H),7.23–7.14(m,3H),6.15(d,J＝17.3Hz,1H),5.98(dd,J＝30.3,9.3Hz,2H),5.69(d,J＝8.3Hz,1H),5.23(d,J＝8.9Hz,1H),4.98(dt,J＝12.5,6.2Hz,1H),4.59(dd,J＝11.0,6.3Hz,1H),4.30–4.21(m,2H),4.12–4.08(m,2H),4.00–3.89(m,2H),3.73(dd,J＝11.4,8.4Hz,1H),3.65(s,3H),1.86–1.52(m,10H),1.34(dd,J＝19.6,14.5Hz,6H),1.21(d,J＝6.3Hz,6H),0.97(t,J＝8.0Hz,9H),0.66(q,J＝7.9Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.58 (d, J = 8.1Hz, 1H), 7.33 (t, J = 7.9Hz, 2H), 7.23-7.14 (m, 3H), 6.15 (d, J = 17.3 Hz, 1H), 5.98 (dd, J = 30.3, 9.3 Hz, 2H), 5.69 (d, J = 8.3 Hz, 1H), 5.23 (d, J = 8.9 Hz, 1H), 4.98 (dt, J = 12.5, 6.2 Hz, 1H), 4.59 (dd, J = 11.0, 6.3 Hz, 1H), 4.30 - 4.21 (m, 2H), 4.12 - 4.08 (m, 2H), 4.00 - 3.89 (m, 2H), 3.73 (dd, J = 11.4, 8.4 Hz, 1H), 3.65 (s, 3H), 1.86 - 1.52 (m, 10H), 1.34 (dd, J = 19.6, 14.5 Hz, 6H), 1.21 (d, J = 6.3) Hz, 6H), 0.97 (t, J = 8.0 Hz, 9H), 0.66 (q, J = 7.9 Hz, 6H).
MS-ESI:m/z 871.8[M+1] +。 MS-ESI: m/z 871.8 [M+1] + .
3)化合物19合成3) Synthesis of compound 19
Figure PCTCN2017119448-appb-000198
Figure PCTCN2017119448-appb-000198
将化合物19-3(2.6g，3.0mmol，1eq)溶于丙酮(7mL)，室温下依次加入水(5.5mL)、三氟乙酸(1.7mL)和冰乙酸(7mL)后反应3小时。TLC监控反应完全后，往反应液中加入100mL乙酸乙酯和100mL水，搅拌均匀静置分层，有机相依次用水(100mL×2)，饱和氯化钠(100mL)洗涤，无水硫酸钠干燥后减压浓缩，以DCM:MeOH＝60:1为洗脱剂柱层析纯化，得到白色泡沫状固体1.8g，收率80％。Compound 19-3 (2.6 g, 3.0 mmol, 1 eq) was dissolved in acetone (7 mL), and water (5.5 mL), trifluoroacetic acid (1.7 mL) and EtOAc (7 mL) After the TLC monitoring reaction was completed, 100 mL of ethyl acetate and 100 mL of water were added to the reaction mixture, and the mixture was stirred and allowed to stand for separation. The organic phase was washed successively with water (100 mL×2), saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate After concentration under reduced pressure, the residue was purified tolulululululululululu
1H NMR(400MHz,CDCl 3)δ7.48(d,J＝8.2Hz,1H),7.34(t,J＝7.9Hz,2H),7.24–7.12(m,3H),6.28–6.08(m,1H),5.99(dd,J＝22.9,9.4Hz,2H),5.74(d,J＝8.3Hz,1H),5.24(d,J＝9.0Hz,1H),5.00(dt,J＝12.5,6.3Hz,1H),4.48(dd,J＝26.6,8.2Hz,2H),4.27(dd,J＝8.7,4.8Hz,1H),4.13–4.02(m,2H),3.92(dd,J＝16.2,9.0Hz,2H),3.66(s,3H),1.79–1.53(m,6H),1.37(t,J＝14.7Hz,6H),1.25–0.98(m,12H)。 1 H NMR (400MHz, CDCl 3 ) δ7.48 (d, J = 8.2Hz, 1H), 7.34 (t, J = 7.9Hz, 2H), 7.24-7.12 (m, 3H), 6.28-6.08 (m, 1H), 5.99 (dd, J = 22.9, 9.4 Hz, 2H), 5.74 (d, J = 8.3 Hz, 1H), 5.24 (d, J = 9.0 Hz, 1H), 5.00 (dt, J = 12.5, 6.3) Hz, 1H), 4.48 (dd, J = 26.6, 8.2 Hz, 2H), 4.27 (dd, J = 8.7, 4.8 Hz, 1H), 4.13 - 4.02 (m, 2H), 3.92 (dd, J = 16.2, 9.0 Hz, 2H), 3.66 (s, 3H), 1.79 - 1.53 (m, 6H), 1.37 (t, J = 14.7 Hz, 6H), 1.25 - 0.98 (m, 12H).
MS-ESI:m/z 756.8[M+1] +。 MS-ESI: m/z 756.8 [M+1] + .
实施例20Example 20
(S)-(3-((2R,3R,4R,5R)-3-氟-4-羟基-5-((((S)-(((S)-1-异丙氧基-1-氧代丙-2-基)氨基)(苯氧基)磷酰基)氧基)甲基)-3-甲基四氢呋喃-2-基)-2,6-二氧代-2,3-二氢嘧啶-1(6H)-基)甲基3-甲基-2-((苯氧基羰基)氨基)丁酸甲酯(S)-(3-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-((((S)-((())))) Oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-3-methyltetrahydrofuran-2-yl)-2,6-dioxo-2,3-dihydro Pyrimidine-1(6H)-yl)methyl 3-methyl-2-((phenoxycarbonyl)amino)butanoic acid methyl ester
Figure PCTCN2017119448-appb-000199
Figure PCTCN2017119448-appb-000199
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000200
Figure PCTCN2017119448-appb-000200
Figure PCTCN2017119448-appb-000201
Figure PCTCN2017119448-appb-000201
1)化合物20-2的合成1) Synthesis of Compound 20-2
Figure PCTCN2017119448-appb-000202
Figure PCTCN2017119448-appb-000202
将碳酸氢钾(12.8g，128.0mmol，1.5eq)溶于60mL水中，加入化合物18-1(10g，85.4mmol，1.0eq)，在-5℃下缓慢滴加氯甲酸苯酯(11.8mL，94.1mmol，1.1eq)，同时滴加50％NaOH水溶液(6.5mL)以控制反应pH值为8-9之间，保持在10min滴加完毕后移至室温。3.5h后反应完毕，反应液加甲基叔丁基醚(100mL)，过滤掉不溶物，滤液有机相丢弃，水相用浓盐酸调pH值至大约2，甲基叔丁基醚(100mL)萃取，分层后有机相水洗，无水硫酸钠干燥后减压减压浓缩得到无色透明油状液体12.5g，收率61.7％。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. After 3.5 h, the reaction was completed, methyl t-butyl ether (100 mL) was added to the reaction mixture, the insoluble material was filtered off, the organic phase of the filtrate was discarded, and the aqueous phase was adjusted to pH 2 with concentrated hydrochloric acid, and methyl t-butyl ether (100 mL) After extraction and crystallization, the organic layer was washed with water and dried over anhydrous sodium sulfate.
1H NMR(400MHz,CDCl 3)δ7.70(s,1H),7.35(t,J＝7.8Hz,2H),7.19(t,J＝7.4Hz,1H),7.12(t,J＝10.1Hz,2H),5.73(d,J＝9.0Hz,1H),4.39(dd,J＝9.0,4.5Hz,1H),2.29(td,J＝13.5,6.8Hz,1H),1.08–0.95(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.70 (s, 1H), 7.35 (t, J = 7.8Hz, 2H), 7.19 (t, J = 7.4Hz, 1H), 7.12 (t, J = 10.1Hz , 2H), 5.73 (d, J = 9.0 Hz, 1H), 4.39 (dd, J = 9.0, 4.5 Hz, 1H), 2.29 (td, J = 13.5, 6.8 Hz, 1H), 1.08 - 0.95 (m, 6H).
MS-ESI:m/z＝238.10[M+1] +。 MS-ESI: m / z = 238.10 [M + 1] +.
2)化合物20-3的合成2) Synthesis of Compound 20-3
Figure PCTCN2017119448-appb-000203
Figure PCTCN2017119448-appb-000203
将化合物20-2(6.5g，27mmol，1.0eq)和四丁基硫酸氢铵(0.93g，2.7mmol，0.1eq),碳酸钾(15g，108.5mmol，4.0eq)混合于二氯甲烷和水的混合溶液(45mL+45mL)中。在-5℃下缓慢滴加氯甲基氯磺酸酯(5.5mL，54.0mmol，2.0eq)，15min滴完后移至室温反应4.5小时。TLC监测反应完毕，反应液静置 分层，有机相减压减压浓缩得到淡黄色油状物，乙酸乙酯(100mL)溶解，水洗(100mL×2)，饱和食盐水(100mL)洗涤，分液后有机相减压浓缩，真空干燥得到淡黄色透明油状物5.1g，收率为65％。无进一步纯化后直接投反应。Compound 20-2 (6.5 g, 27 mmol, 1.0 eq) and tetrabutylammonium hydrogen sulfate (0.93 g, 2.7 mmol, 0.1 eq), potassium carbonate (15 g, 108.5 mmol, 4.0 eq) were combined in dichloromethane and water In a mixed solution (45 mL + 45 mL). Chloromethyl chlorosulfonate (5.5 mL, 54.0 mmol, 2.0 eq) was slowly added dropwise at -5 ° C, and after 15 min, the mixture was transferred to room temperature for 4.5 hours. After the reaction was completed by TLC, the reaction mixture was partitioned, and the organic layer was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The organic phase was concentrated under reduced pressure and dried in vacuo to yieldd pale-yellow oil (yield: 5.1 g). The reaction was directly administered without further purification.
1H NMR(400MHz,CDCl 3)δ7.36(t,J＝7.9Hz,2H),7.20(t,J＝7.7Hz,1H),7.17–7.10(m,2H),5.92–5.61(m,2H),5.57(d,J＝8.5Hz,1H),4.41(dd,J＝9.0,4.8Hz,1H),2.28(dt,J＝11.9,6.8Hz,1H),1.02(dq,J＝6.8,3.8Hz,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.36 (t, J = 7.9 Hz, 2H), 7.20 (t, J = 7.7 Hz, 1H), 7.17 - 7.10 (m, 2H), 5.92 - 5.61 (m, 2H), 5.57 (d, J = 8.5 Hz, 1H), 4.41 (dd, J = 9.0, 4.8 Hz, 1H), 2.28 (dt, J = 11.9, 6.8 Hz, 1H), 1.02 (dq, J = 6.8) , 3.8 Hz, 6H).
3)化合物20-4的合成3) Synthesis of Compound 20-4
Figure PCTCN2017119448-appb-000204
Figure PCTCN2017119448-appb-000204
将化合物M-2(3g，4.7mmol，1.0eq)和化合物20-3(2.1g，7.4mmol，1.6eq)溶于丙酮(30mL)中，室温下加入碘化钠(2.8g，19mmol，4.0eq)、DMAP(0.056g，0.46mmol，0.1eq)和二异丙基乙基胺(1.4mL，8.5mmol，1.8eq)，-5℃下反应过夜。15h后TLC检测反应完成，减压浓缩反应溶剂，剩余物加入乙酸乙酯(100mL)和水(100mL)搅拌至固体完全溶解后静置分液，有机相用水(80mL×2)洗涤，饱和氯化钠溶液(80mL)洗涤，有机相用无水硫酸钠干燥后减压浓缩。以DCM:MeOH＝100:1为洗脱剂柱层析纯化，得到黄色粘稠液体1.43g，收率34.5％。Compound M-2 (3 g, 4.7 mmol, 1.0 eq) and compound 20-3 (2.1 g, 7.4 mmol, 1.6 eq) were dissolved in acetone (30 mL) and sodium iodide (2.8 g, 19 mmol, 4.0 Eq), DMAP (0.056 g, 0.46 mmol, 0.1 eq) and diisopropylethylamine (1.4 mL, 8.5 mmol, 1.8 eq). After 15 h, the reaction was completed by TLC. The reaction solvent was concentrated under reduced pressure. ethyl acetate (100 mL) and water (100 mL) was added to the residue. The solid was dissolved and then left to stand. The organic phase was washed with water (80 mL×2). The organic layer was washed with anhydrous sodium sulfate and concentrated. Purification by column chromatography with DCM:MeOH = 100:1 elute
1H NMR(400MHz,CDCl 3)δ7.58(d,J＝8.3Hz,1H),7.34(td,J＝7.8,3.6Hz,4H),7.23–7.11(m,6H),6.22–6.11(m,1H),6.04(q,J＝9.4Hz,2H),5.70(d,J＝8.3Hz,1H),5.59(d,J＝9.1Hz,1H),5.06–4.90(m,1H),4.65–4.54(m,1H),4.38(dd,J＝9.1,4.5Hz,1H),4.25(dd,J＝7.3,4.6Hz,1H),4.13(d,J＝8.7Hz,1H),4.02–3.89(m,2H),3.75–3.60(m,1H),2.21(dd,J＝6.8,2.1Hz,1H),1.34(t,J＝14.9Hz,6H),1.22(d,J＝6.3Hz,6H),1.02–0.93(m,15H),0.66(q,J＝7.9Hz,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 (d, J = 8.3 Hz, 1H), 7.34 (td, J = 7.8, 3.6 Hz, 4H), 7.23 - 7.11 (m, 6H), 6.22 - 6.11 ( m, 1H), 6.04 (q, J = 9.4 Hz, 2H), 5.70 (d, J = 8.3 Hz, 1H), 5.59 (d, J = 9.1 Hz, 1H), 5.06 - 4.90 (m, 1H), 4.65–4.54 (m, 1H), 4.38 (dd, J=9.1, 4.5 Hz, 1H), 4.25 (dd, J=7.3, 4.6 Hz, 1H), 4.13 (d, J=8.7 Hz, 1H), 4.02 –3.89(m,2H), 3.75–3.60 (m,1H), 2.21 (dd, J=6.8, 2.1 Hz, 1H), 1.34 (t, J=14.9 Hz, 6H), 1.22 (d, J=6.3) Hz, 6H), 1.02 - 0.93 (m, 15H), 0.66 (q, J = 7.9 Hz, 6H).
4)化合物20的合成4) Synthesis of Compound 20
Figure PCTCN2017119448-appb-000205
Figure PCTCN2017119448-appb-000205
将化合物20-4(1.43g，1.6mmol，1eq)溶于丙酮(4mL)，室温下依次加入水(3mL)、三氟乙酸(1 mL)和冰乙酸(4mL)后反应3小时。TLC监控反应完全后，往反应液中加入二氯甲烷(40mL)和水(40mL)，搅拌均匀静置分层，有机相依次用水(40mL×3)，饱和氯化钠(40mL)洗涤，无水硫酸钠干燥后减压浓缩，以DCM:MeOH＝60:1为洗脱剂柱层析纯化，得到白色泡沫状固体0.93g，收率75％。Compound 20-4 (1.43 g, 1.6 mmol, 1 eq) was dissolved in acetone (4 mL), and water (3 mL), trifluoroacetic acid (1 mL) and EtOAc (4 mL) After the TLC monitoring reaction was completed, dichloromethane (40 mL) and water (40 mL) were added to the reaction mixture, and the mixture was stirred and left to stand for separation. The organic phase was washed successively with water (40 mL×3) and saturated sodium chloride (40 mL). The organic layer was dried over anhydrous sodium sulfate (MgSO4).
1H NMR(400MHz,CDCl 3)δ7.48(d,J＝8.2Hz,1H),7.36–7.29(m,4H),7.18(dd,J＝14.6,7.5Hz,4H),7.11(d,J＝7.8Hz,2H),6.18(d,J＝15.5Hz,1H),6.09–5.95(m,2H),5.72(t,J＝9.0Hz,2H),4.98(dt,J＝12.5,6.2Hz,1H),4.55–4.38(m,2H),4.36(dd,J＝9.1,4.6Hz,1H),4.30–4.17(m,1H),4.10–4.05(m,1H),3.90(dt,J＝16.1,8.0Hz,2H),3.47(s,1H),2.18(dt,J＝13.7,5.9Hz,1H),1.38–1.30(m,6H),1.21(d,J＝6.4Hz,6H),0.96(dd,J＝26.6,6.8Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.48 (d, J = 8.2Hz, 1H), 7.36-7.29 (m, 4H), 7.18 (dd, J = 14.6,7.5Hz, 4H), 7.11 (d, J = 7.8 Hz, 2H), 6.18 (d, J = 15.5 Hz, 1H), 6.09 - 5.95 (m, 2H), 5.72 (t, J = 9.0 Hz, 2H), 4.98 (dt, J = 12.5, 6.2 Hz, 1H), 4.55–4.38 (m, 2H), 4.36 (dd, J=9.1, 4.6 Hz, 1H), 4.30–4.17 (m, 1H), 4.10–4.05 (m, 1H), 3.90 (dt, J = 16.1, 8.0 Hz, 2H), 3.47 (s, 1H), 2.18 (dt, J = 13.7, 5.9 Hz, 1H), 1.38 - 1.30 (m, 6H), 1.21 (d, J = 6.4 Hz, 6H) ), 0.96 (dd, J = 26.6, 6.8 Hz, 6H).
MS-ESI:m/z＝778.80[M+1] +。 MS-ESI: m / z = 778.80 [M + 1] +.
实施例21Example 21
(S)-异丙基2-(((S)-(((2R,3R,4R,5R)-5-(3-((2-(((苄氧基)羰基)氨基)乙酰氧基)甲基)-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)乙氧基甲氧基)(苯氧基)磷酰基)氨基)丙酸酯(S)-Isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(3-((2-((benzyloxy))carbonyl)amino)acetoxy) )methyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)ethoxy Methoxy)(phenoxy)phosphoryl)amino)propionate
Figure PCTCN2017119448-appb-000206
Figure PCTCN2017119448-appb-000206
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000207
Figure PCTCN2017119448-appb-000207
Figure PCTCN2017119448-appb-000208
Figure PCTCN2017119448-appb-000208
1)化合物21-2的合成1) Synthesis of Compound 21-2
Figure PCTCN2017119448-appb-000209
Figure PCTCN2017119448-appb-000209
将氢氧化钠(4.8g，120.0mmol，3eq)溶于水(80mL)中，加入化合物5-1(3g，40mmol，1.0eq)，在-5℃下缓慢滴加氯甲酸苄酯(7.3mL，52mmol，1.3eq)，保持在10min滴加完毕后移至室温。20h后反应完毕，反应液加100ml乙酸乙酯，分层后水相用浓盐酸调pH值至大约2，乙酸乙酯(100mL)萃取分层后有机相水洗，无水硫酸钠干燥后减压减压浓缩，真空干燥1h得到无色透明油状液体12.5g，收率61.7％。Sodium hydroxide (4.8 g, 120.0 mmol, 3 eq) was dissolved in water (80 mL), Compound 5-1 (3 g, 40 mmol, 1.0 eq) was added, and benzyl chloroformate (7.3 mL) was slowly added dropwise at -5 °C. , 52 mmol, 1.3 eq), kept at room temperature after 10 minutes of dropwise addition. After 20h, the reaction was completed, and 100 ml of ethyl acetate was added to the reaction mixture. The 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.
MS-ESI:m/z＝209.95[M+1] +。 MS-ESI: m / z = 209.95 [M + 1] +.
2)化合物21-3的合成2) Synthesis of Compound 21-3
Figure PCTCN2017119448-appb-000210
Figure PCTCN2017119448-appb-000210
将化合物21-2(6.5g，7.9mmol，1.0eq)和四丁基硫酸氢铵(1.1g，3.2mmol，0.1eq)，碳酸钾(17g，123mmol，4.0eq)混合于二氯甲烷和水的混合溶液(45mL+45mL)中。在-5℃下缓慢滴加氯甲基氯磺酸酯(6.3mL，62mmol，2.0eq)，15min滴完后移至室温反应5小时。TLC监测反应完毕，反应液静置分层，有机相用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，减压浓缩得淡黄色油状液体6.75g，收率84％，无进一步纯化直接投下一步反应。Compound 21-2 (6.5 g, 7.9 mmol, 1.0 eq) and tetrabutylammonium hydrogen sulfate (1.1 g, 3.2 mmol, 0.1 eq), potassium carbonate (17 g, 123 mmol, 4.0 eq) were combined in dichloromethane and water In a mixed solution (45 mL + 45 mL). Chloromethyl chlorosulfonate (6.3 mL, 62 mmol, 2.0 eq) was slowly added dropwise at -5 ° C, and after 15 min, the mixture was transferred to room temperature for 5 hours. After the reaction was completed by TLC, the reaction mixture was partitioned, and the organic layer was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and evaporated. Directly cast the next reaction.
3)化合物21-4合成3) Synthesis of compound 21-4
Figure PCTCN2017119448-appb-000211
Figure PCTCN2017119448-appb-000211
将化合物M-2(3g，4.7mmol，1.0eq)和化合物21-3(1.9g，7.5mmol，1.6eq)溶于丙酮(45mL)中，室温下加入碘化钠(2.8g，8.4mmol，4.0eq)、DMAP(0.056g,0.47mmol,0.1eq)和二异丙基乙基胺(1.4 mL，8.4mmol，1.8eq)，室温下反应过夜。12h后TLC检测反应完成，减压浓缩反应溶剂，剩余物加入乙酸乙酯(200mL)和水(100mL)搅拌至固体完全溶解后静置分液，有机相用水(100mL×2)洗涤，饱和氯化钠溶液(100mL)洗涤，有机相用无水硫酸钠干燥后减压浓缩。以DCM:MeOH＝100:1为洗脱剂柱层析纯化，得到黄色粘稠液体2.25g，收率56％。Compound M-2 (3 g, 4.7 mmol, 1.0 eq) and compound 21-3 (1.9 g, 7.5 mmol, 1.6 eq) were dissolved in acetone (45 mL) and sodium iodide (2.8 g, 8.4 mmol, 4.0 eq), DMAP (0.056 g, 0.47 mmol, 0.1 eq) and diisopropylethylamine (1.4 mL, 8.4 mmol, 1.8 eq). After 12 h, the reaction was completed by TLC. The solvent was evaporated, and the residue was evaporated to ethyl ether (200 mL) and water (100 mL), and the mixture was stirred to dissolve. The solid was dissolved and the organic phase was washed with water (100 mL×2). The sodium salt solution (100 mL) was washed and dried over anhydrous sodium sulfate. Purification by column chromatography with DCM: MeOH = 100:1 elute to afford 2.
1H NMR(400MHz,CDCl 3)δ7.58(d,J＝8.3Hz,1H),7.32(dt,J＝8.6,4.1Hz,7H),7.18(dd,J＝18.4,7.9Hz,3H),6.15(d,J＝18.3Hz,1H),6.00(d,J＝9.5Hz,2H),5.69(d,J＝8.3Hz,1H),5.36(s,1H),5.11(s,2H),4.98(dt,J＝12.5,6.3Hz,1H),4.58(dd,J＝10.6,6.5Hz,1H),4.24(ddd,J＝12.0,5.3,2.6Hz,1H),4.11(d,J＝8.8Hz,1H),4.03–3.87(m,4H),3.76(dd,J＝18.7,7.9Hz,1H),1.33(t,J＝14.3Hz,6H),1.22(d,J＝6.3Hz,6H),0.98(t,J＝7.9Hz,9H),0.66(q,J＝7.9Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.58 (d, J = 8.3Hz, 1H), 7.32 (dt, J = 8.6,4.1Hz, 7H), 7.18 (dd, J = 18.4,7.9Hz, 3H) , 6.15 (d, J = 18.3 Hz, 1H), 6.00 (d, J = 9.5 Hz, 2H), 5.69 (d, J = 8.3 Hz, 1H), 5.36 (s, 1H), 5.11 (s, 2H) , 4.98 (dt, J = 12.5, 6.3 Hz, 1H), 4.58 (dd, J = 10.6, 6.5 Hz, 1H), 4.24 (ddd, J = 12.00, 5.3, 2.6 Hz, 1H), 4.11 (d, J = 8.8 Hz, 1H), 4.03 - 3.87 (m, 4H), 3.76 (dd, J = 18.7, 7.9 Hz, 1H), 1.33 (t, J = 14.3 Hz, 6H), 1.22 (d, J = 6.3 Hz) , 6H), 0.98 (t, J = 7.9 Hz, 9H), 0.66 (q, J = 7.9 Hz, 6H).
4)化合物21合成4) Synthesis of Compound 21
Figure PCTCN2017119448-appb-000212
Figure PCTCN2017119448-appb-000212
将化合物21-4(2.25g，2.6mmol，1eq)溶于丙酮(6mL)，室温下依次加入水(4.5mL)、三氟乙酸(1.5mL)和冰乙酸(6mL)后反应2小时。TLC监控反应完全后，往反应液中加入100mL二氯甲烷和100mL水，搅拌均匀静置分层，有机相依次用水(100mL×3)，饱和氯化钠(100mL)洗涤，无水硫酸钠干燥后减压浓缩，以DCM:MeOH＝60:1为洗脱剂柱层析纯化，得到白色泡沫状固体1.2g，收率60.9％。Compound 21-4 (2.25 g, 2.6 mmol, 1 eq) was dissolved in acetone (6 mL), and water (4.5 mL), trifluoroacetic acid (1.5 mL) and EtOAc (EtOAc) After the TLC monitoring reaction was completed, 100 mL of dichloromethane and 100 mL of water were added to the reaction mixture, and the mixture was stirred and allowed to stand for separation. The organic phase was washed with water (100 mL×3), saturated sodium chloride (100 mL) and dried over anhydrous sodium sulfate. After concentrating under reduced pressure, the residue was purified eluted eluted elut elut elut elut eluting
1H NMR(400MHz,CDCl 3)δ7.48(d,J＝8.2Hz,1H),7.29(dt,J＝9.8,4.2Hz,7H),7.16(dd,J＝16.5,7.9Hz,3H),6.15(d,J＝17.0Hz,1H),6.00(d,J＝10.3Hz,2H),5.72(d,J＝8.3Hz,1H),5.56(t,J＝5.0Hz,1H),5.08(s,2H),4.96(dt,J＝12.5,6.2Hz,1H),4.56–4.26(m,3H),4.09(q,J＝7.1Hz,2H),3.98–3.89(m,3H),3.49(d,J＝33.0Hz,1H),1.37–1.28(m,6H),1.20(d,J＝6.3Hz,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (d, J = 8.2 Hz, 1H), 7.29 (dt, J = 9.8, 4.2 Hz, 7H), 7.16 (dd, J = 16.5, 7.9 Hz, 3H) , 6.15 (d, J = 17.0 Hz, 1H), 6.00 (d, J = 10.3 Hz, 2H), 5.72 (d, J = 8.3 Hz, 1H), 5.56 (t, J = 5.0 Hz, 1H), 5.08 (s, 2H), 4.96 (dt, J = 12.5, 6.2 Hz, 1H), 4.56 - 4.26 (m, 3H), 4.09 (q, J = 7.1 Hz, 2H), 3.98 - 3.89 (m, 3H), 3.49 (d, J = 33.0 Hz, 1H), 1.37 - 1.28 (m, 6H), 1.20 (d, J = 6.3 Hz, 6H).
MS-ESI:m/z＝750.8[M+1] +。 MS-ESI: m/z = 750.8 [M+1] + .
实施例22Example 22
(S)-(3-((2R,3R,4R,5R)-3-氟-4-羟基-5-((((S)-(((S)-1-异丙氧基-1-氧代丙-2-基)氨基)(苯氧基)磷酰基)氧基)甲基)-3-甲基四氢呋喃-2-基)-2,6-二氧代-2,3-二氢嘧啶-1(6H)-基)甲基2-(((环戊氧基)羰基)氨基)-3-甲基丁酸甲酯(S)-(3-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-((((S)-((())))) Oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-3-methyltetrahydrofuran-2-yl)-2,6-dioxo-2,3-dihydro Pyrimidine-1(6H)-yl)methyl 2-(((cyclopentyloxy)carbonyl)amino)-3-methylbutanoate
Figure PCTCN2017119448-appb-000213
Figure PCTCN2017119448-appb-000213
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000214
Figure PCTCN2017119448-appb-000214
1)化合物22-2的合成1) Synthesis of Compound 22-2
Figure PCTCN2017119448-appb-000215
Figure PCTCN2017119448-appb-000215
将氢氧化钠(8.2g，204.8mmol，3eq)溶于水(120mL)中，加入化合物18-1(8g，68.3mmol，1.0eq)，在-5℃下缓慢滴加氯甲酸环戊酯(9.4mL，75.1mmol，1.1eq)，保持在10min滴加完毕后移至室温。20h后反应完毕，反应液加甲基叔丁基醚(100mL)，分层后水相用浓盐酸调pH值至大约2，甲基叔丁基醚(100mL)萃取分层后有机相水洗，无水硫酸钠干燥后减压减压浓缩，真空干燥1h得到无色透明油状液体3.2g，收率20％。Sodium hydroxide (8.2 g, 204.8 mmol, 3 eq) was dissolved in water (120 mL), compound 18-1 (8 g, 68.3 mmol, 1.0 eq) was added, and cyclopentyl chloroformate was slowly added dropwise at -5 °C ( 9.4 mL, 75.1 mmol, 1.1 eq), was added to room temperature after 10 min addition. After 20 h, the reaction was completed, and the reaction mixture was added with methyl tert-butyl ether (100 mL). After separation, the aqueous phase was adjusted to pH 2 with concentrated hydrochloric acid, and extracted with methyl t-butyl ether (100 mL). After drying over anhydrous sodium sulfate, the mixture was evaporated. evaporated.
MS-ESI:m/z＝228.20[M-1] +。 MS-ESI: m/z = 228.20 [M-1] + .
2)化合物22-3的合成2) Synthesis of Compound 22-3
Figure PCTCN2017119448-appb-000216
Figure PCTCN2017119448-appb-000216
将化合物22-2(3.0g，13mmol，1.0eq)和四丁基硫酸氢铵(0.44g，1.3mmol，0.1eq)，碳酸钾(7.2g，52mmol，4.0eq)混合于二氯甲烷和水的混合溶液(30mL+30mL)中。在-5℃下缓慢滴加氯甲基氯磺酸酯(2.6mL，26mmol，2.0eq)，15min滴完后移至室温反应5小时。TLC监测反应完毕，反应液静置分层，有机相用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，减压浓缩得淡黄色油状液体3.1g，收率85％，无进一步纯化直接投下一步反应。Compound 22-2 (3.0 g, 13 mmol, 1.0 eq) and tetrabutylammonium hydrogen sulfate (0.44 g, 1.3 mmol, 0.1 eq), potassium carbonate (7.2 g, 52 mmol, 4.0 eq). In a mixed solution (30 mL + 30 mL). Chloromethyl chlorosulfonate (2.6 mL, 26 mmol, 2.0 eq) was slowly added dropwise at -5 ° C, and after 15 min, the mixture was transferred to room temperature for 5 hours. After the reaction was completed by TLC, the reaction mixture was partitioned, the organic layer was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and evaporated. Directly cast the next reaction.
1H NMR(400MHz,CDCl 3)δ5.73(dd,J＝92.3,5.9Hz,2H),5.07(s,1H),4.31(dd,J＝8.7,4.7Hz,1H),2.18(dt,J＝12.8,6.5Hz,1H),1.90–1.43(m,9H),1.01–0.89(m,6H)。 1 H NMR (400MHz, CDCl 3 ) δ5.73 (dd, J = 92.3,5.9Hz, 2H), 5.07 (s, 1H), 4.31 (dd, J = 8.7,4.7Hz, 1H), 2.18 (dt, J = 12.8, 6.5 Hz, 1H), 1.90 - 1.43 (m, 9H), 1.01 - 0.89 (m, 6H).
MS-ESI:m/z＝300.50[M+Na] +。 MS-ESI: m/z = 300.50 [M+Na] + .
3)化合物22-4合成3) Synthesis of compound 22-4
Figure PCTCN2017119448-appb-000217
Figure PCTCN2017119448-appb-000217
将化合物M-2(4.5g，7.0mmol，1.0eq)和化合物22-3(3.1g，11mmol，1.6eq)溶于丙酮(45mL)中，室温下加入碘化钠(4.2g，28mmol，4.0eq)、DMAP(0.085g,0.70mmol,0.1eq)和二异丙基乙基胺(2.1mL，13mmol，1.8eq)，室温下反应过夜。18h后TLC检测反应完成，减压浓缩反应溶剂，剩余物加入乙酸乙酯(200mL)和水(100mL)搅拌至固体完全溶解后静置分液，有机相依次用水(80mL×2)洗涤，饱和氯化钠溶液(80mL)洗涤，有机相用无水硫酸钠干燥后减压浓缩。以DCM:MeOH＝100:1为洗脱剂柱层析纯化，得到黄色粘稠液体4.36g，收率70％。Compound M-2 (4.5 g, 7.0 mmol, 1.0 eq) and compound 22-3 (3.1 g, 11 mmol, 1.6 eq) were dissolved in acetone (45 mL) and sodium iodide (4.2 g, 28 mmol, 4.0) Eq), DMAP (0.085 g, 0.70 mmol, 0.1 eq) and diisopropylethylamine (2.1 mL, 13 mmol, 1.8 eq). After 18 h, the reaction was completed by TLC. The solvent was evaporated, and the residue was evaporated to ethyl ether (200mL) and water (100mL), and the mixture was stirred until the solid was completely dissolved. The organic phase was washed with water (80 mL×2) and saturated. The organic layer was dried over anhydrous sodium sulfate and evaporated. Purification by column chromatography with DCM: MeOH = 100:1 elute to afford 4.
1H NMR(400MHz,CDCl 3)δ7.57(d,J＝8.2Hz,1H),7.33(t,J＝7.9Hz,2H),7.18(dd,J＝16.5,8.0Hz,3H),6.16(d,J＝18.3Hz,1H),5.98(q,J＝9.2Hz,2H),5.69(d,J＝8.3Hz,1H),5.13–5.02(m,2H),4.98(dt,J＝12.5,6.3Hz,1H),4.59(dd,J＝10.6,6.4Hz,1H),4.34–4.19(m,2H),4.12(d,J＝8.9Hz,1H),4.02–3.86(m,2H),3.71(dd,J＝13.4,6.4Hz,1H),2.10(d,J＝5.6Hz,1H),1.85–1.79(m,2H),1.69(s,4H),1.55(s,2H),1.33(t,J＝14.3Hz,6H),1.22(d,J＝6.2Hz,6H),0.97(t,J＝7.9Hz,9H),0.94(d,J＝6.9Hz,3H),0.88–0.85(m, 3H),0.66(q,J＝7.9Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.57 (d, J = 8.2Hz, 1H), 7.33 (t, J = 7.9Hz, 2H), 7.18 (dd, J = 16.5,8.0Hz, 3H), 6.16 (d, J = 18.3 Hz, 1H), 5.98 (q, J = 9.2 Hz, 2H), 5.69 (d, J = 8.3 Hz, 1H), 5.13 - 5.02 (m, 2H), 4.98 (dt, J = 12.5, 6.3 Hz, 1H), 4.59 (dd, J = 10.6, 6.4 Hz, 1H), 4.34 - 4.19 (m, 2H), 4.12 (d, J = 8.9 Hz, 1H), 4.02 - 3.86 (m, 2H) ), 3.71 (dd, J = 13.4, 6.4 Hz, 1H), 2.10 (d, J = 5.6 Hz, 1H), 1.85 - 1.79 (m, 2H), 1.69 (s, 4H), 1.55 (s, 2H) , 1.33 (t, J = 14.3 Hz, 6H), 1.22 (d, J = 6.2 Hz, 6H), 0.97 (t, J = 7.9 Hz, 9H), 0.94 (d, J = 6.9 Hz, 3H), 0.88 – 0.85 (m, 3H), 0.66 (q, J = 7.9 Hz, 6H).
4)化合物22合成4) Synthesis of compound 22
Figure PCTCN2017119448-appb-000218
Figure PCTCN2017119448-appb-000218
将化合物22-4(4.6g，5.2mmol，1eq)溶于丙酮(12mL)，室温下依次加入水(9mL)、三氟乙酸(3mL)和冰乙酸(12mL)后反应2小时。TLC监控反应完全后，往反应液中加入二氯甲烷(40mL)和水(40mL)，搅拌均匀静置分层，有机相依次用水(40mL×3)，饱和氯化钠(40mL)洗涤，无水硫酸钠干燥后减压浓缩，以DCM:MeOH＝60:1为洗脱剂柱层析纯化，得到白色泡沫状固体2.8g，收率69％。Compound 22-4 (4.6 g, 5.2 mmol, 1 eq) was dissolved in acetone (12 mL), and water (9 mL), trifluoroacetic acid (3 mL) and EtOAc (EtOAc) After the TLC monitoring reaction was completed, dichloromethane (40 mL) and water (40 mL) were added to the reaction mixture, and the mixture was stirred and left to stand for separation. The organic phase was washed successively with water (40 mL×3) and saturated sodium chloride (40 mL). The organic layer was dried over anhydrous sodium sulfate (MgSO4).
1H NMR(400MHz,CDCl 3)δ7.47(d,J＝8.2Hz,1H),7.32(t,J＝7.9Hz,2H),7.17(dd,J＝11.6,7.9Hz,3H),6.17(d,J＝16.1Hz,1H),6.03–5.88(m,2H),5.71(d,J＝8.3Hz,1H),5.12(t,J＝11.7Hz,1H),5.05(s,1H),4.98(dt,J＝12.5,6.3Hz,1H),4.56–4.36(m,2H),4.27(d,J＝6.7Hz,3H),4.10(d,J＝9.3Hz,1H),3.97–3.83(m,2H),2.07(dt,J＝15.4,6.7Hz,1H),1.79(s,2H),1.68(s,4H),1.54(s,2H),1.39–1.30(m,6H),1.21(d,J＝6.3Hz,6H),0.92(d,J＝6.8Hz,3H),0.85(d,J＝6.7Hz,3H)。 1 H NMR (400MHz, CDCl 3 ) δ7.47 (d, J = 8.2Hz, 1H), 7.32 (t, J = 7.9Hz, 2H), 7.17 (dd, J = 11.6,7.9Hz, 3H), 6.17 (d, J = 16.1 Hz, 1H), 6.03 - 5.88 (m, 2H), 5.71 (d, J = 8.3 Hz, 1H), 5.12 (t, J = 11.7 Hz, 1H), 5.05 (s, 1H) , 4.98 (dt, J = 12.5, 6.3 Hz, 1H), 4.56 - 4.36 (m, 2H), 4.27 (d, J = 6.7 Hz, 3H), 4.10 (d, J = 9.3 Hz, 1H), 3.97 - 3.83 (m, 2H), 2.07 (dt, J = 15.4, 6.7 Hz, 1H), 1.79 (s, 2H), 1.68 (s, 4H), 1.54 (s, 2H), 1.39 - 1.30 (m, 6H) , 1.21 (d, J = 6.3 Hz, 6H), 0.92 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H).
MS-ESI:m/z＝770.8[M+1] +。 MS-ESI: m/z = 770.8 [M+1] + .
实施例23Example 23
(S)-异丙基2-(((S)-(((2R,3R,4R,5R)-5-(2,4-二氧代-3-(((R)-2-苯基-2-(((噻唑-5-基乙氧基甲氧基)羰基)氨基)乙酰氧基)甲基)-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)乙氧基甲氧基)(苯氧基)磷酰基)氨基)丙酸酯(S)-Isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3-((R)-2-phenyl)) -2-(((thiazol-5-ylethoxymethoxy)carbonyl)amino)acetoxy)methyl)-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro- 3-hydroxy-4-methyltetrahydrofuran-2-yl)ethoxymethoxy)(phenoxy)phosphoryl)amino)propionate
Figure PCTCN2017119448-appb-000219
Figure PCTCN2017119448-appb-000219
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000220
Figure PCTCN2017119448-appb-000220
1)化合物23-2的合成1) Synthesis of Compound 23-2
Figure PCTCN2017119448-appb-000221
Figure PCTCN2017119448-appb-000221
250mL单口瓶装依次加入DCM(100mL),吡啶(4.2mL,52mmol,1.5eq)，化合物23-1(3mL,34.88mmol,1eq)，0℃搅拌下缓慢加入三光气(11.4g,38.4mmol,1.1eq)，加完后此温度下反应10min，再移至室温下继续反应，TLC监控。3h后原料基本反应完毕，加入的盐酸(100mL，1N)淬灭反应，水相再用DCM(100mL×2)萃取，合并有机相用饱和食盐水(100mL)洗涤后，无水硫酸钠干燥，减压浓缩得棕褐色固体3.2g，收率51.8％。250 mL of a single-necked bottle was added DCM (100 mL), pyridine (4.2 mL, 52 mmol, 1.5 eq), Compound 23-1 (3 mL, 34.88 mmol, 1 eq), and slowly added to phosgene (11.4 g, 38.4 mmol, 1.1) with stirring at 0 °C. Eq), after the addition, the reaction was carried out at this temperature for 10 min, and then moved to room temperature to continue the reaction, and monitored by TLC. After 3h, the basic reaction was completed, and the reaction was quenched with hydrochloric acid (100 mL, 1 N). The aqueous phase was extracted with DCM (100 mL×2). The organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to give a brown solid (yield: 3.2%).
1H NMR(400MHz,CDCl 3)δ8.81(s,1H),7.86(s,1H),4.84(s,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ 8.81 (s, 1H), 7.86 (s, 1H), 4.84 (s, 2H).
2)化合物23-3的合成2) Synthesis of compound 23-3
Figure PCTCN2017119448-appb-000222
Figure PCTCN2017119448-appb-000222
将NaOH(1.9g,48mmol,3eq)溶解在水(30mL)中，-5℃加入依次加入THF(30mL)、R-苯甘氨酸(2.6g,17.6mmol,1eq)，化合物23-2(3.2g,17.6mmol,1.0eq)，0℃下搅拌过夜。反应液加乙酸乙酯(100mL)萃取，分液后水相用浓盐酸调pH值至大约2，乙酸乙酯(100mL)萃取，分层后有机相水饱和氯化钠(50mL)洗，无水硫酸钠干燥后减压减压浓缩，得到2.5g棕黑色固体，收率50.1％，无进一步纯化直接投下一步反应。NaOH (1.9 g, 48 mmol, 3 eq) was dissolved in water (30 mL), and then added THF (30 mL), R-phenylglycine (2.6 g, 17.6 mmol, 1 eq), compound 23-2 (3.2 g) , 17.6 mmol, 1.0 eq), stirred at 0 ° C overnight. The reaction mixture was extracted with ethyl acetate (100 mL). After the mixture was separated, the aqueous phase was adjusted to pH 2 with concentrated hydrochloric acid, and extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated sodium chloride (50 mL). The organic layer was dried over sodium sulfate and evaporated to dryness.
3)化合物23-4的合成3) Synthesis of compound 23-4
Figure PCTCN2017119448-appb-000223
Figure PCTCN2017119448-appb-000223
将化合物23-3(2.4g，8.2mmol，1.0eq)和四丁基硫酸氢铵(0.27g，0.8mmol，0.1eq)，碳酸钾(4.5g，95.6mmol，4.0eq)混合于二氯甲烷和水的混合溶液(30mL+30mL)中，在0℃下缓慢滴加氯甲基氯磺酸酯(1.6mL，16.4mmol，2.0eq)，滴完后移至室温反应5小时。TLC监测反应完毕，反应液静置分层，有机相用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，减压浓缩后硅胶柱层析，PE/EA＝10/1做洗脱剂，得白色固体产品2.1g,收率75％。Compound 23-3 (2.4 g, 8.2 mmol, 1.0 eq) and tetrabutylammonium hydrogen sulfate (0.27 g, 0.8 mmol, 0.1 eq), potassium carbonate (4.5 g, 95.6 mmol, 4.0 eq) Chloromethyl chlorosulfonate (1.6 mL, 16.4 mmol, 2.0 eq) was slowly added dropwise at 0 ° C in a mixed solution of water and water (30 mL + 30 mL), and the mixture was transferred to room temperature for 5 hours. After the reaction was completed by TLC, the reaction mixture was allowed to stand, and the organic layer was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, silica gel column chromatography, eluting with PE/EA=10/1 The agent obtained 2.1 g of a white solid product, yield 75%.
1H NMR(400MHz,CDCl 3)δ8.81(s,1H),7.86(s,1H),7.45–7.33(m,5H),5.73(m,3H),5.44(d,J＝7.2Hz,1H),4.84(s,2H)。 1 H NMR (400MHz, CDCl 3 ) δ8.81 (s, 1H), 7.86 (s, 1H), 7.45-7.33 (m, 5H), 5.73 (m, 3H), 5.44 (d, J = 7.2Hz, 1H), 4.84 (s, 2H).
4)化合物23-5的合成4) Synthesis of compound 23-5
Figure PCTCN2017119448-appb-000224
Figure PCTCN2017119448-appb-000224
将化合物M-2(2.5g，3.9mmol，1.0eq)和化合物23-5(2.0g，5.8mmol，1.5eq)溶于丙酮(25mL)中，室温下加入碘化钠(2.3g，16mmol，4.0eq)和二异丙基乙基胺(1mL，5.8mmol，1.5eq)，室温下反应过夜。TLC检测反应完成后直接减压浓缩反应溶剂，剩余物加入乙酸乙酯(100mL)和水(30mL)搅拌至固体完全溶解后静置分液，有机相用水(30mL×2)洗涤，饱和氯化钠溶液(30mL)洗涤，有机相用无水硫酸钠干燥后减压浓缩。以DCM:MeOH＝70:1为洗脱剂柱层析纯化，得到黄色泡沫状固体2.88g，收率85％。Compound M-2 (2.5 g, 3.9 mmol, 1.0 eq) and compound 23-5 (2.0 g, 5.8 mmol, 1.5 eq) were dissolved in acetone (25 mL) and sodium iodide (2.3 g, 16 mmol, 4.0 eq) and diisopropylethylamine (1 mL, 5.8 mmol, 1.5 eq) were reacted overnight at room temperature. After the completion of the TLC reaction, the reaction solvent was concentrated under reduced pressure. The residue was added ethyl acetate (100 mL) and water (30 mL), and the mixture was stirred until the solid was completely dissolved. The organic phase was separated and washed with water (30 mL×2). The organic layer was dried over anhydrous sodium sulfate and evaporated. Purification by column chromatography eluting with DCM: MeOH = 70:1 toield
5)化合物23的合成5) Synthesis of Compound 23
Figure PCTCN2017119448-appb-000225
Figure PCTCN2017119448-appb-000225
将化合物23-5(2g，2.6mmol，1eq)溶于丙酮(5mL)，室温下依次加入水(4mL)、三氟乙酸(1mL)和冰乙酸(4mL)后反应3小时。TLC监控反应完全后，往反应液中加入30mL二氯甲烷，搅拌均匀静置分层，有机相依次用水(10mL×3)，饱和氯化钠(10mL)洗涤，无水硫酸钠干燥后减压浓缩，以DCM:MeOH＝70:1为洗脱剂柱层析纯化，得到白色泡沫状固体1.4g，收率80.1％。Compound 23-5 (2 g, 2.6 mmol, 1 eq) was dissolved in acetone (5 mL), and water (4 mL), trifluoroacetic acid (1 mL) and EtOAc (4 mL) After the TLC monitoring reaction was completed, 30 mL of dichloromethane was added to the reaction mixture, and the mixture was stirred and allowed to stand for separation. The organic phase was washed successively with water (10 mL×3), saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate Concentration and purification by column chromatography eluting with EtOAc EtOAc:EtOAc
1H NMR(400MHz,CDCl 3)δ8.81(s,1H),7.86(s,1H)，7.43(d,J＝8.1Hz,1H),7.39–7.27(m,7H),7.20(t,J＝8.1Hz,3H),6.05(dt,J＝20.5,17.3Hz,3H),5.71(d,J＝8.2Hz,2H),5.38(d,J＝7.4Hz,1H),5.01(dt,J＝12.5,6.2Hz,1H),4.84(s,2H)，4.47(dt,J＝19.2,10.6Hz,2H),4.09(d,J＝9.2Hz,1H),3.97–3.70(m,4H),1.34(d,J＝7.0Hz,3H),1.22(dt,J＝26.9,13.4Hz,9H)。 1 H NMR (400MHz, CDCl 3 ) δ8.81 (s, 1H), 7.86 (s, 1H), 7.43 (d, J = 8.1Hz, 1H), 7.39-7.27 (m, 7H), 7.20 (t, J = 8.1 Hz, 3H), 6.05 (dt, J = 20.5, 17.3 Hz, 3H), 5.71 (d, J = 8.2 Hz, 2H), 5.38 (d, J = 7.4 Hz, 1H), 5.01 (dt, J=12.5, 6.2 Hz, 1H), 4.84 (s, 2H), 4.47 (dt, J = 19.2, 10.6 Hz, 2H), 4.09 (d, J = 9.2 Hz, 1H), 3.97 - 3.70 (m, 4H) ), 1.34 (d, J = 7.0 Hz, 3H), 1.22 (dt, J = 26.9, 13.4 Hz, 9H).
MS-ESI:m/z＝834.2[M+1] +。 MS-ESI: m/z = 834.2 [M+1] + .
实施例24Example 24
(S)-异丙基2-(((S)-(((2R,3R,4R,5R)-5-(3-((2-乙酰胺基乙酰氧基)甲基)-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)乙氧基甲氧基)(苯氧基)磷酰基)氨基)丙酸酯(S)-Isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(3-((2-acetamidoacetoxy))methyl)-2,4 -dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)ethoxymethoxy)(phenoxy) Phosphoryl)amino)propionate
Figure PCTCN2017119448-appb-000226
Figure PCTCN2017119448-appb-000226
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000227
Figure PCTCN2017119448-appb-000227
Figure PCTCN2017119448-appb-000228
Figure PCTCN2017119448-appb-000228
1)化合物24-2的合成1) Synthesis of compound 24-2
Figure PCTCN2017119448-appb-000229
Figure PCTCN2017119448-appb-000229
将化合物5-1(5g，66.6mmol，3eq)溶于水(20mL)中，加入乙酸酐(12.6mL，133mmol，2.0eq)，室温下搅拌反应。4h后，反应置于低温下搅拌5min，趁冷抽滤，滤饼用少量冷水洗涤后加入到水(10mL)中低温打浆，抽滤，滤饼55℃下减压蒸出残留溶剂，得到4.4g白色粉末固体，收率55％。Compound 5-1 (5 g, 66.6 mmol, 3 eq) was dissolved in water (20 mL), and acetic acid (12.6 mL, 133 mmol, 2.0 eq) was added and the mixture was stirred at room temperature. After 4h, the reaction was stirred at low temperature for 5 min, and filtered by suction. The filter cake was washed with a small amount of cold water, then added to water (10 mL) for low-temperature beating, suction filtration, and the filter cake was evaporated under reduced pressure at 55 ° C to obtain a solvent. g White powder solid in 55% yield.
1H NMR(400MHz,MeOD)δ3.90(s,2H),2.00(s,3H)。 1 H NMR (400 MHz, MeOH) δ 3.90 (s, 2H), 2.00 (s, 3H).
MS-ESI:m/z＝118.2[M+1] +。 MS-ESI: m/z = 118.2 [M+1] + .
2)化合物24-3的合成2) Synthesis of compound 24-3
Figure PCTCN2017119448-appb-000230
Figure PCTCN2017119448-appb-000230
将化合物24-2(2g，17.1mmol，1.0eq)和四丁基硫酸氢铵(0.47g，1.7mmol，0.1eq),碳酸钾(7.6g，68.3mmol，4.0eq)混合于二氯甲烷和水的混合溶液(15mL+15mL)中。在-5℃下缓慢滴加氯甲基氯磺酸酯(2.8mL，34.1mmol，2.0eq)，15min滴完后移至室温反应5小时。TLC监测反应完毕，反应液静置分层，有机相用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，减压浓缩得淡黄色油状液体2.1g，收率74％，无进一步纯化直接投下一步反应。Compound 24-2 (2 g, 17.1 mmol, 1.0 eq) and tetrabutylammonium hydrogen sulfate (0.47 g, 1.7 mmol, 0.1 eq), potassium carbonate (7.6 g, 68.3 mmol, 4.0 eq) A mixed solution of water (15 mL + 15 mL). Chloromethyl chlorosulfonate (2.8 mL, 34.1 mmol, 2.0 eq) was slowly added dropwise at -5 ° C, and after 15 min, the mixture was transferred to room temperature for 5 hours. After the reaction was completed by TLC, the reaction mixture was partitioned. The organic layer was washed with saturated sodium chloride solution (100 mL) and dried over anhydrous sodium sulfate. Directly cast the next reaction.
1H NMR(400MHz,CDCl 3)δ5.87(d,J＝6.0Hz,1H),5.64(d,J＝6.0Hz,1H),5.19(d,J＝8.0Hz,1H),3.90(s,2H),2.00(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ5.87 (d, J = 6.0Hz, 1H), 5.64 (d, J = 6.0Hz, 1H), 5.19 (d, J = 8.0Hz, 1H), 3.90 (s , 2H), 2.00 (s, 3H).
MS-ESI:m/z＝166.2[M+1] +。 MS-ESI: m/z = 166.2 [M+1] + .
3)化合物24-4的合成3) Synthesis of compound 24-4
Figure PCTCN2017119448-appb-000231
Figure PCTCN2017119448-appb-000231
将化合物M-2(4.6g，7.2mmol，1.0eq)和化合物24-3(0.76g，4.6mmol，1.3eq)溶于丙酮(60mL)中，室温下加入碘化钠(4.2g，28mmol，4.0eq)和二异丙基乙基胺(1.6mL，10.8mmol，1.5eq)，50℃下反应过夜。15h后TLC检测反应完成，减压浓缩反应溶剂，剩余物加入200mL乙酸乙酯和200mL水搅拌至固体完全溶解后静置分液，有机相用水(200mL×2)、饱和氯化钠溶液(200mL)洗涤，有机相用无水硫酸钠干燥后减压浓缩。以DCM:MeOH＝100:1为洗脱剂柱层析纯化，得到乳白色粘稠泡沫固体4.3g，收率75％。Compound M-2 (4.6 g, 7.2 mmol, 1.0 eq) and compound 24-3 (0.76 g, 4.6 mmol, 1.3 eq) were dissolved in acetone (60 mL) and sodium iodide (4.2 g, 28 mmol, 4.0 eq) and diisopropylethylamine (1.6 mL, 10.8 mmol, 1.5 eq) were reacted at 50 ° C overnight. After 15 h, the reaction was completed by TLC. The reaction solvent was concentrated under reduced pressure. The residue was added to ethyl acetate (200 mL) and water (200 mL), and the mixture was stirred until the solid was completely dissolved. The organic phase was partitioned with water (200 mL×2) and saturated sodium chloride solution (200 mL) The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography with DCM: MeOH = 100:1 elute elute
4)化合物24的合成4) Synthesis of Compound 24
Figure PCTCN2017119448-appb-000232
Figure PCTCN2017119448-appb-000232
将化合物24-4(4.0g，5.2mmol，1eq)溶于丙酮(12mL)，室温下依次加入水(9mL)、三氟乙酸(3mL)和冰乙酸(12mL)后反应2小时。TLC监控反应完全后，往反应液中加入二氯甲烷(40mL)和水(40mL)，搅拌均匀静置分层，有机相依次用水(40mL×3)，饱和氯化钠(40mL)洗涤，无水硫酸钠干燥后减压浓缩，以DCM:MeOH＝60:1为洗脱剂柱层析纯化，得到白色泡沫状固体2.45g，收率72％。The compound 24-4 (4.0 g, 5.2 mmol, 1 eq) was dissolved in acetone (12 mL), and water (9 mL), trifluoroacetic acid (3 mL) and EtOAc (EtOAc) After the TLC monitoring reaction was completed, dichloromethane (40 mL) and water (40 mL) were added to the reaction mixture, and the mixture was stirred and left to stand for separation. The organic phase was washed successively with water (40 mL×3) and saturated sodium chloride (40 mL). The organic layer was dried over anhydrous sodium sulfate (MgSO4).
1H NMR(400MHz,CDCl 3)δ7.51(d,J＝8.2Hz,1H),7.38(t,J＝7.9Hz,2H),7.24(dd,J＝8.3,3.2Hz,3H),6.32–6.13(m,1H),6.05(s,2H),5.78(d,J＝8.3Hz,1H),5.30–5.15(m,1H),5.09–4.96(m,1H),4.61–4.41(m,2H),4.14(d,J＝7.3Hz,1H),4.04–3.82(m,6H),1.84(s,3H),1.40(dd,J＝18.1,14.6Hz,6H),1.26(d,J＝6.3Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.51 (d, J = 8.2Hz, 1H), 7.38 (t, J = 7.9Hz, 2H), 7.24 (dd, J = 8.3,3.2Hz, 3H), 6.32 –6.13(m,1H),6.05(s,2H), 5.78(d,J=8.3Hz,1H), 5.30–5.15(m,1H),5.09–4.96(m,1H),4.61–4.41(m) , 2H), 4.14 (d, J = 7.3 Hz, 1H), 4.04 - 3.82 (m, 6H), 1.84 (s, 3H), 1.40 (dd, J = 18.1, 14.6 Hz, 6H), 1.26 (d, J = 6.3 Hz, 6H).
MS-ESI:m/z＝659.1[M+1] +。 MS-ESI: m/z = 659.1 [M+1] + .
实施例25Example 25
(S)-异丙基2-(((S)-(((2R,3R,4R,5R)-5-(3-(((R)-2-(((环己基氧基)羰基)氨基)-2-苯基乙酰氧基)甲基)-2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)乙氧基甲氧基)(苯氧基)磷酰基)氨基)丙酸酯(S)-Isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(3-(((R)))))) Amino)-2-phenylacetoxy)methyl)-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyl Tetrahydrofuran-2-yl)ethoxymethoxy)(phenoxy)phosphoryl)amino)propionate
Figure PCTCN2017119448-appb-000233
Figure PCTCN2017119448-appb-000233
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000234
Figure PCTCN2017119448-appb-000234
1)化合物25-2的合成1) Synthesis of Compound 25-2
Figure PCTCN2017119448-appb-000235
Figure PCTCN2017119448-appb-000235
将氢氧化钠(5.1g，130.0mmol，3eq)溶于水(80mL)中，加入化合物25-1(6.5g，43.3mmol，1.0eq)，在-5℃下缓慢滴加氯甲酸环己酯(6mL，48.1mmol，1.1eq)，保持在10min滴加完毕后移至室温。20h后反应完毕，反应液加甲基叔丁基醚(100mL)，分层后水相用浓盐酸调pH值至大约2，甲基叔丁基醚(100mL)萃取分层后有机相水洗，无水硫酸钠干燥后减压减压浓缩，真空干燥1h得到无色透明油状液体4.32g，收率36％。Sodium hydroxide (5.1 g, 130.0 mmol, 3 eq) was dissolved in water (80 mL), compound 25-1 (6.5 g, 43.3 mmol, 1.0 eq) was added, and cyclohexyl chloroformate was slowly added dropwise at -5 °C. (6 mL, 48.1 mmol, 1.1 eq), was added to room temperature after 10 min. After 20 h, the reaction was completed, and the reaction mixture was added with methyl tert-butyl ether (100 mL). After separation, the aqueous phase was adjusted to pH 2 with concentrated hydrochloric acid, and extracted with methyl t-butyl ether (100 mL). After drying over anhydrous sodium sulfate, the mixture was evaporated.
2)化合物25-3的合成2) Synthesis of compound 25-3
Figure PCTCN2017119448-appb-000236
Figure PCTCN2017119448-appb-000236
将化合物25-2(3.6g，13mmol，1.0eq)和四丁基硫酸氢铵(0.44g，1.3mmol，0.1eq)，碳酸钾(7.2g，52mmol，4.0eq)混合于二氯甲烷和水的混合溶液(30mL+30mL)中。在-5℃下缓慢滴加氯甲基氯磺酸酯(2.6mL，26mmol，2.0eq)，15min滴完后移至室温反应5小时。TLC监测反应完毕，反应液静置分层，有机相用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，减压浓缩得淡黄色油状液体3.6g，收率85.4％，无进一步纯化直接投下一步反应。Compound 25-2 (3.6 g, 13 mmol, 1.0 eq) and tetrabutylammonium hydrogen sulfate (0.44 g, 1.3 mmol, 0.1 eq), potassium carbonate (7.2 g, 52 mmol, 4.0 eq) were combined in dichloromethane and water In a mixed solution (30 mL + 30 mL). Chloromethyl chlorosulfonate (2.6 mL, 26 mmol, 2.0 eq) was slowly added dropwise at -5 ° C, and after 15 min, the mixture was transferred to room temperature for 5 hours. After the reaction was completed by TLC, the reaction mixture was partitioned. The organic layer was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and evaporated. Directly cast the next reaction.
1H NMR(400MHz,CDCl 3)δ7.45–7.33(m,5H),5.73(m,3H),5.44(d,J＝7.2Hz,1H),4.31(dd,J＝8.7,4.7Hz,1H)，1.90–1.43(m,10H)。 1 H NMR (400MHz, CDCl 3 ) δ7.45-7.33 (m, 5H), 5.73 (m, 3H), 5.44 (d, J = 7.2Hz, 1H), 4.31 (dd, J = 8.7,4.7Hz, 1H), 1.90–1.43 (m, 10H).
MS-ESI:m/z＝326.2[M+1] +。 MS-ESI: m/z = 326.2 [M+1] + .
3)化合物25-4的合成3) Synthesis of Compound 25-4
Figure PCTCN2017119448-appb-000237
Figure PCTCN2017119448-appb-000237
将化合物M-2(4.5g，7.0mmol，1.0eq)和化合物25-3(3.58g，11mmol，1.6eq)溶于丙酮(45mL)中，室温下加入碘化钠(4.2g，28mmol，4.0eq)、DMAP(0.085g,0.70mmol,0.1eq)和二异丙基乙基胺(2.1mL，13mmol，1.8eq)，室温下反应过夜。18h后TLC检测反应完成，减压浓缩反应溶剂，剩余物加入乙酸乙酯(200mL)和水(100mL)搅拌至固体完全溶解后静置分液，有机相依次用水(80mL×2)洗涤，饱和氯化钠溶液(80mL)洗涤，有机相用无水硫酸钠干燥后减压浓缩。以DCM:MeOH＝100:1为洗脱剂柱层析纯化，得到黄色粘稠液体4.83g，收率74％。Compound M-2 (4.5 g, 7.0 mmol, 1.0 eq) and compound 25-3 (3.58 g, 11 mmol, 1.6 eq) were dissolved in acetone (45 mL) and sodium iodide (4.2 g, 28 mmol, 4.0 Eq), DMAP (0.085 g, 0.70 mmol, 0.1 eq) and diisopropylethylamine (2.1 mL, 13 mmol, 1.8 eq). After 18 h, the reaction was completed by TLC. The solvent was evaporated, and the residue was evaporated to ethyl ether (200mL) and water (100mL), and the mixture was stirred until the solid was completely dissolved. The organic phase was washed with water (80 mL×2) and saturated. The organic layer was dried over anhydrous sodium sulfate and evaporated. Purification by column chromatography with DCM: MeOH = 100:1 eluted to afford 4.
1H NMR(400MHz,CDCl 3)δ7.54(t,J＝8.5Hz,1H),7.44–7.29(m,7H),7.21(dd,J＝14.5,7.5Hz,3H),6.17–5.90(m,3H),5.85–5.57(m,2H),5.44–5.35(m,1H),5.00(dq,J＝12.7,6.3Hz,1H),4.61(dd,J＝10.4,6.5Hz,1H),4.31(dd,J＝8.7,4.7Hz,1H)，4.25(ddd,J＝11.7,5.2,2.6Hz,1H),4.14(dd,J＝14.0,7.1Hz,1H),4.04–3.70(m,3H),1.90–1.43(m,10H),1.37(t,J＝6.7Hz,3H),1.29–1.22(m,9H),1.01(t,J＝7.9Hz,9H),0.68(q,J＝7.9Hz,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.54 (t, J = 8.5 Hz, 1H), 7.44 - 7.29 (m, 7H), 7.21. (dd, J = 14.5, 7.5 Hz, 3H), 6.17 - 5.90 ( m,3H), 5.85–5.57 (m, 2H), 5.44–5.35 (m, 1H), 5.00 (dq, J=12.7, 6.3 Hz, 1H), 4.61 (dd, J=10.4, 6.5 Hz, 1H) , 4.31 (dd, J=8.7, 4.7 Hz, 1H), 4.25 (ddd, J=11.7, 5.2, 2.6 Hz, 1H), 4.14 (dd, J=14.0, 7.1 Hz, 1H), 4.04–3.70 (m) , 3H), 1.90–1.43 (m, 10H), 1.37 (t, J=6.7 Hz, 3H), 1.29–1.22 (m, 9H), 1.01 (t, J=7.9 Hz, 9H), 0.68 (q, J = 7.9 Hz, 6H).
4)化合物25的合成4) Synthesis of Compound 25
Figure PCTCN2017119448-appb-000238
Figure PCTCN2017119448-appb-000238
将化合物25-4(4.6g，4.9mmol，1eq)溶于丙酮(12mL)，室温下依次加入水(9mL)、三氟乙酸(3mL)和冰乙酸(12mL)后反应2小时。TLC监控反应完全后，往反应液中加入二氯甲烷(40mL)和水(40mL)，搅拌均匀静置分层，有机相依次用水(40mL×3)，饱和氯化钠(40mL)洗涤，无水硫酸钠干燥后减压浓缩，以DCM:MeOH＝60:1为洗脱剂柱层析纯化，得到白色泡沫状固体3.1g，收率76％。Compound 25-4 (4.6 g, 4.9 mmol, 1 eq) was dissolved in acetone (12 mL), and water (9 mL), trifluoroacetic acid (3 mL) and EtOAc (EtOAc) After the TLC monitoring reaction was completed, dichloromethane (40 mL) and water (40 mL) were added to the reaction mixture, and the mixture was stirred and left to stand for separation. The organic phase was washed successively with water (40 mL×3) and saturated sodium chloride (40 mL). The organic layer was dried over anhydrous sodium sulfate (MgSO4).
1H NMR(400MHz,CDCl 3)δ7.43(d,J＝8.1Hz,1H),7.39–7.27(m,7H),7.20(t,J＝8.1Hz,3H),6.05(dt,J＝20.5,17.3Hz,3H),5.71(d,J＝8.2Hz,2H),5.38(d,J＝7.4Hz,1H),5.01(dt,J＝12.5,6.2Hz,1H),4.47(dt,J＝19.2,10.6Hz,2H),4.31(dd,J＝8.7,4.7Hz,1H)，4.09(d,J＝9.2Hz,1H),3.97–3.70(m,4H),1.90–1.43(m,10H),1.34(d,J＝7.0Hz,3H),1.22(dt,J＝26.9,13.4Hz,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.43 (d, J = 8.1 Hz, 1H), 7.39 - 7.27 (m, 7H), 7.20 (t, J = 8.1 Hz, 3H), 6.05 (dt, J = 20.5, 17.3 Hz, 3H), 5.71 (d, J = 8.2 Hz, 2H), 5.38 (d, J = 7.4 Hz, 1H), 5.01 (dt, J = 12.5, 6.2 Hz, 1H), 4.47 (dt, J=19.2, 10.6 Hz, 2H), 4.31 (dd, J=8.7, 4.7 Hz, 1H), 4.09 (d, J=9.2 Hz, 1H), 3.97–3.70 (m, 4H), 1.90–1.43 (m) , 10H), 1.34 (d, J = 7.0 Hz, 3H), 1.22 (dt, J = 26.9, 13.4 Hz, 9H).
MS-ESI:m/z＝819.8[M+1] +。 MS-ESI: m/z = 819.8 [M+1] + .
实施例26Example 26
(S)-异丙基2-(((S)-(((2R,3R,4R,5R)-5-(2,4-二氧代-3-((2-(丙-2-亚基氨基)乙酰氧基)甲基)-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)乙氧基甲氧基)(苯氧基)磷酰基)氨基)丙酸酯(S)-Isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3-((2-(propyl-2-)) Aminoamino)acetoxy)methyl)-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)ethoxymethoxy (phenoxy)phosphoryl)amino)propionate
Figure PCTCN2017119448-appb-000239
Figure PCTCN2017119448-appb-000239
合成路线：synthetic route:
Figure PCTCN2017119448-appb-000240
Figure PCTCN2017119448-appb-000240
1)化合物26-2的合成1) Synthesis of Compound 26-2
Figure PCTCN2017119448-appb-000241
Figure PCTCN2017119448-appb-000241
将化合物5-1(5.0g，66.7mmol，1.0eq)，氢氧化钠(5.34g，133.4mmol，2.0eq)和丙酮(3.87g,66.7mmol，1.0eq)加入到乙醇(50mL)中，回流反应6h。停止反应，冷却到室温，旋除溶剂，剩余物加入水(30mL)溶解，用20％的磷酸调节pH在4-5，再用乙酸乙酯萃取(30mL×3)，有机相用无水硫酸钠干燥，减压浓缩得白色固体产品5.6g，收率73.0％。Compound 5-1 (5.0 g, 66.7 mmol, 1.0 eq), sodium hydroxide (5.34 g, 133.4 mmol, 2.0 eq) and acetone (3.87 g, 66.7 mmol, 1.0 eq) were added to ethanol (50 mL) and reflux Reaction for 6 h. The reaction was stopped, cooled to room temperature, and the solvent was evaporated. The residue was dissolved in water (30 mL), adjusted to pH 4-5 with 20% phosphoric acid, and extracted with ethyl acetate (30 mL×3) The sodium was dried and concentrated under reduced pressure to give 5.6 g of white solid.
1H NMR(400MHz,CDCl 3)δ4.35(s,2H),1.89(s,3H),1.87(s,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 4.35 (s, 2H), 1.89 (s, 3H), 1.87 (s, 3H).
2)化合物26-3的合成2) Synthesis of compound 26-3
Figure PCTCN2017119448-appb-000242
Figure PCTCN2017119448-appb-000242
将化合物26-2(3.22g，28mmol，1.0eq)和四丁基硫酸氢铵(0.94g，2.8mmol，0.1eq)，碳酸钾(15.4g，112mmol，4.0eq)混合于二氯甲烷和水的混合溶液(20mL+20mL)中。在-5℃下缓慢滴加氯甲基氯磺酸酯(9.24g，56mmol，2.0eq)，15min滴完后移至室温反应5小时。TLC监测反应完毕，反应液静置分层，有机 相用饱和氯化钠溶液(100mL)洗涤后无水硫酸钠干燥，减压浓缩得淡黄色油状液体3.0g，收率65.8％，无进一步纯化，直接投下一步反应。Compound 26-2 (3.22 g, 28 mmol, 1.0 eq) and tetrabutylammonium hydrogen sulfate (0.94 g, 2.8 mmol, 0.1 eq), potassium carbonate (15.4 g, 112 mmol, 4.0 eq) were combined in dichloromethane and water In a mixed solution (20 mL + 20 mL). Chloromethyl chlorosulfonate (9.24 g, 56 mmol, 2.0 eq) was slowly added dropwise at -5 ° C, and after 15 min, the mixture was transferred to room temperature for 5 hours. After the reaction was completed by TLC, the reaction mixture was partitioned. The organic layer was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and evaporated to dryness. , directly vote for the next reaction.
3)化合物26-4的合成3) Synthesis of Compound 26-4
Figure PCTCN2017119448-appb-000243
Figure PCTCN2017119448-appb-000243
将化合物M-2(0.89g，1.4mmol，1.0eq)和化合物26-3(0.29g，1.8mmol，1.3eq)溶于丙酮(10mL)中，室温下加入碘化钠(0.96g，6.4mmol，4.0eq)和二异丙基乙基胺(0.27g，2.1mmol，1.5eq)，-10℃下反应过夜。TLC检测反应完成后直接减压浓缩反应溶剂，剩余物加入乙酸乙酯(20mL)和水(15mL)搅拌至固体完全溶解后静置分液，有机相依次用水(30mL×2)洗涤，饱和氯化钠溶液(30mL)洗涤，有机相用无水硫酸钠干燥后减压浓缩。以DCM/MeOH＝100/1为洗脱剂柱层析纯化，得到白色固体0.70g，收率64.8％。Compound M-2 (0.89 g, 1.4 mmol, 1.0 eq) and compound 26-3 (0.29 g, 1.8 mmol, 1.3 eq) were dissolved in acetone (10 mL) and sodium iodide (0.96 g, 6.4 mmol) , 4.0 eq) and diisopropylethylamine (0.27 g, 2.1 mmol, 1.5 eq), and reacted at -10 ° C overnight. After the completion of the TLC reaction, the reaction solvent was concentrated under reduced pressure. The residue was added ethyl acetate (20 mL) and water (15 mL), and the mixture was stirred until the solid was completely dissolved. The organic phase was washed with water (30 mL×2) and saturated The sodium salt solution (30 mL) was washed and dried over anhydrous sodium sulfate. Purification by column chromatography eluting with DCM / MeOH = 100/1 afforded white white solid.
1H NMR(400MHz,CDCl 3)δ7.56(d,J＝8.1Hz,1H),7.27(t,J＝7.8Hz,2H),7.22(d,J＝8.0Hz,2H),7.20(t,J＝7.3Hz,1H),6.16(d,J＝18.6Hz,1H),5.92(s,2H)5.67(d,J＝8.1Hz,1H),5.09–4.94(m,1H),4.61(dd,J＝11.4,6.1Hz,1H),4.37(s,2H),4.31–4.23(m,1H),4.14(d,J＝8.5Hz,1H),4.00–3.98(m,1H),3.90(t,J＝9.9Hz,1H),1.90(s,3H),1.88(s,3H),1.78(s,1H),1.37(t,J＝13.5Hz,6H),1.24(d,J＝6.2Hz,6H),1.00(t,J＝7.9Hz,9H),0.69(q,J＝7.9Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.56 (d, J = 8.1Hz, 1H), 7.27 (t, J = 7.8Hz, 2H), 7.22 (d, J = 8.0Hz, 2H), 7.20 (t , J = 7.3 Hz, 1H), 6.16 (d, J = 18.6 Hz, 1H), 5.92 (s, 2H) 5.67 (d, J = 8.1 Hz, 1H), 5.09 - 4.94 (m, 1H), 4.61 ( Dd, J = 11.4, 6.1 Hz, 1H), 4.37 (s, 2H), 4.31 - 4.23 (m, 1H), 4.14 (d, J = 8.5 Hz, 1H), 4.00 - 3.98 (m, 1H), 3.90 (t, J = 9.9 Hz, 1H), 1.90 (s, 3H), 1.88 (s, 3H), 1.78 (s, 1H), 1.37 (t, J = 13.5 Hz, 6H), 1.24 (d, J = 6.2 Hz, 6H), 1.00 (t, J = 7.9 Hz, 9H), 0.69 (q, J = 7.9 Hz, 6H).
MS-ESI:m/z＝771.33[M+1] +。 MS-ESI: m / z = 771.33 [M + 1] +.
4)化合物26的合成4) Synthesis of Compound 26
Figure PCTCN2017119448-appb-000244
Figure PCTCN2017119448-appb-000244
将化合物26-4(0.60g，0.78mmol，1eq)溶于水(2mL)和冰乙酸(6mL)，室温反应5小时。TLC监控反应完全后，往反应液中加入二氯甲烷(15mL)，搅拌均匀静置分层，有机相依次用水(10mL×3)， 饱和氯化钠(10mL)洗涤，无水硫酸钠干燥后减压浓缩，以DCM:MeOH＝50:1为洗脱剂柱层析纯化，得到无色油状物0.45g，收率88.2％。Compound 26-4 (0.60 g, 0.78 mmol, 1 eq) was dissolved in water (2 mL) and EtOAc (EtOAc) After the TLC monitoring reaction was completed, dichloromethane (15 mL) was added to the reaction mixture, and the mixture was stirred and dried, and the organic phase was washed with water (10 mL×3), saturated sodium chloride (10 mL) and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc.
1H NMR(400MHz,CDCl 3)δ7.54(d,J＝8.1Hz,1H),7.25(t,J＝7.8Hz,2H),7.22(d,J＝8.0Hz,2H),7.20(t,J＝7.3Hz,1H),6.16(d,J＝18.6Hz,1H),5.90(s,2H),5.67(d,J＝8.1Hz,1H),5.09–4.94(m,1H),4.61(dd,J＝11.4,6.1Hz,1H),4.37(s,2H),4.31–4.23(m,1H),4.14(d,J＝8.5Hz,1H),4.12(d,J＝8.6Hz,1H),4.00–3.98(m,1H),3.90(t,J＝9.9Hz,1H),1.90(s,3H),1.88(s,3H),1.78(s,1H),1.37(t,J＝13.5Hz,6H),1.24(d,J＝6.2Hz,6H)。 1 H NMR (400MHz, CDCl 3 ) δ7.54 (d, J = 8.1Hz, 1H), 7.25 (t, J = 7.8Hz, 2H), 7.22 (d, J = 8.0Hz, 2H), 7.20 (t , J = 7.3 Hz, 1H), 6.16 (d, J = 18.6 Hz, 1H), 5.90 (s, 2H), 5.67 (d, J = 8.1 Hz, 1H), 5.09 - 4.94 (m, 1H), 4.61 (dd, J = 11.4, 6.1 Hz, 1H), 4.37 (s, 2H), 4.31 - 4.23 (m, 1H), 4.14 (d, J = 8.5 Hz, 1H), 4.12 (d, J = 8.6 Hz, 1H), 4.00–3.98 (m, 1H), 3.90 (t, J=9.9 Hz, 1H), 1.90 (s, 3H), 1.88 (s, 3H), 1.78 (s, 1H), 1.37 (t, J) =13.5 Hz, 6H), 1.24 (d, J = 6.2 Hz, 6H).
MS-ESI:m/z＝657.23[M+1] +。 MS-ESI: m / z = 657.23 [M + 1] +.
实施例27-实施例35Example 27 - Example 35
Figure PCTCN2017119448-appb-000245
Figure PCTCN2017119448-appb-000245
Figure PCTCN2017119448-appb-000246
Figure PCTCN2017119448-appb-000246
Figure PCTCN2017119448-appb-000247
Figure PCTCN2017119448-appb-000247
实施例36-实施例70Example 36 - Example 70
Figure PCTCN2017119448-appb-000248
Figure PCTCN2017119448-appb-000248
Figure PCTCN2017119448-appb-000249
Figure PCTCN2017119448-appb-000249
Figure PCTCN2017119448-appb-000250
Figure PCTCN2017119448-appb-000250
Figure PCTCN2017119448-appb-000251
Figure PCTCN2017119448-appb-000251
Figure PCTCN2017119448-appb-000252
Figure PCTCN2017119448-appb-000252
Figure PCTCN2017119448-appb-000253
Figure PCTCN2017119448-appb-000253
Figure PCTCN2017119448-appb-000254
Figure PCTCN2017119448-appb-000254
Figure PCTCN2017119448-appb-000255
Figure PCTCN2017119448-appb-000255
生物测试实例Biological test example
HCV复制子活性测试HCV replicon activity test
用DMSO将化合物作3倍稀释11个浓度(200倍最终测试浓度)，双复孔，然后使用Echo 550移液系统加样1μL至96孔板或0.25μL至384孔板。将GT1b、GT2a及GT3a复制子细胞分别稀释至5×10 4/mL和1×10 5/mL浓度，分别加入200μL或50μL稀释好的细胞至含待测化合物的测试板。同时设置HPE和ZPE组，HPE:100％抑制效应,加入100nM HCV-796；ZPE:0％抑制效应,0.5％DMSO。37℃，5％CO 2培养箱孵育2天。GT1b细胞株用萤火虫荧光素酶试剂盒检测活性，GT2a细胞株用海肾荧光素酶试剂盒检测活性，GT13a细胞株用萤火虫荧光素酶试剂盒检测活性。化合物对复制子活性的抑制百分比可通过以下公式计算： Compounds were diluted 3 times (200 times the final test concentration) with DMSO, double wells, and then 1 μL to 96-well plates or 0.25 μL to 384-well plates were loaded using an Echo 550 pipetting system. The GT1b, GT2a and GT3a replicon cells were diluted to a concentration of 5×10 4 /mL and 1×10 5 /mL, respectively, and 200 μL or 50 μL of the diluted cells were added to the test plates containing the test compound. At the same time, HPE and ZPE groups were set up, HPE: 100% inhibition effect, 100 nM HCV-796 was added; ZPE: 0% inhibition effect, 0.5% DMSO. Incubate for 2 days at 37 ° C in a 5% CO 2 incubator. The GT1b cell line was assayed for activity using the firefly luciferase kit, the GT2a cell line was assayed for activity using the Renilla luciferase kit, and the GT13a cell line was assayed for activity using the firefly luciferase kit. The percent inhibition of replicon activity by a compound can be calculated by the following formula:
％inhibition＝100-(检测孔-HPE平均值)/(ZPE平均值-HPE平均值)*100%inhibition=100-(detection hole-HPE average)/(ZPE average-HPE average)*100
然后使用GraphPad Prism 5计算化合物对复制子的EC 50值，测试结果如表2。 Then the compound is calculated using GraphPad Prism 5 50 values replicon EC, the test results shown in Table 2.
表2：Table 2:
Figure PCTCN2017119448-appb-000256
Figure PCTCN2017119448-appb-000256
同时，本发明化合物1、7-10、12、15、17-70具有50-120nM的EC50值。Meanwhile, the compounds 1, 7-10, 12, 15, 17-70 of the present invention have an EC50 value of 50 to 120 nM.
结论：in conclusion:
针对GT1b、GT2a及GT3a复制子，本发明化合物具有与索菲布韦相当的活性。For the GT1b, GT2a and GT3a replicons, the compounds of the invention have comparable activity to solifebluff.
药代动力学参数测试Pharmacokinetic parameter test
雄性SD大鼠，禁食过夜后，分为2组，每组3只，分别静脉注射和灌胃给予本发明化合物，利用LC-MS/MS测定给药后不同时间点大鼠血浆中PSI6206药物浓度，利用WinNonlin 6.3计算药物在SD大鼠中PK参数(表3)。Male SD rats, after fasting overnight, were divided into 2 groups, 3 rats in each group. The compounds of the present invention were administered intravenously and intragastrically, and the plasma PSI6206 drug was measured by LC-MS/MS at different time points after administration. Concentration, PK parameters of the drug in SD rats were calculated using WinNonlin 6.3 (Table 3).
Figure PCTCN2017119448-appb-000257
Figure PCTCN2017119448-appb-000257
表3：table 3:
Figure PCTCN2017119448-appb-000258
Figure PCTCN2017119448-appb-000258
同时，本发明化合物1、7-10、12、15、17-70的代谢产物的暴露量(AUClast)具有2000-5000h*ng/ml， 优选地具有3000-5000h*ng/ml，更优选地具有4000-5000h*ng/ml；它们的T1/2具有3-10h，优选地具有5-10h，更优选地具有6-10h；它们的生物利用度具有30％-70％，优选地具有40-70％，更优选地具有50-70％。结论：Meanwhile, the exposure amount (AUClast) of the metabolite of the compound 1, 7-10, 12, 15, 17-70 of the present invention has 2000-5000 h*ng/ml, preferably 3000-5000 h*ng/ml, more preferably Having 4000-5000 h*ng/ml; their T1/2 has 3-10 h, preferably 5-10 h, more preferably 6-10 h; their bioavailability has 30%-70%, preferably 40 -70%, more preferably 50-70%. in conclusion:
通过对代谢产物PSI6206的检测，本发明化合物具有很好的药代动力学性质，特别是在暴露量、半衰期、生物利用度方面达到了不可预料的效果。By detecting the metabolite PSI6206, the compounds of the present invention have excellent pharmacokinetic properties, particularly in terms of exposure, half-life, and bioavailability.
化合物稳定性研究Compound stability study
高温环境稳定性测试：取一批供试品适量放入扁形称量瓶中，摊成≤5mm厚的薄层，分别在60℃±2℃、40℃±2℃温度下放置，于第5天和第13天取样进行检测。考察外观变化及通过HPLC考察其纯度变化(表4)。High-temperature environmental stability test: Take a batch of test samples into a flat weighing bottle and spread them into thin layers ≤5mm thick, placed at 60°C±2°C and 40°C±2°C respectively. Samples were taken for testing on days and days 13. The change in appearance was examined and the change in purity was examined by HPLC (Table 4).
高湿环境稳定性测试：取一批供试品适量放入扁形称量瓶中，摊成≤5mm厚的薄层，分别在25℃，RH 90％±5％、RH 75％±5％条件下放置，于第5天和第13天取样进行检测。考察外观变化及通过HPLC考察其纯度变化(表5)。High-humidity environment stability test: Take a batch of test samples into a flat weighing bottle and spread them into thin layers ≤5mm thick, respectively at 25°C, RH 90%±5%, RH 75%±5%. Placed underneath and sampled on days 5 and 13 for testing. The change in appearance was examined and the change in purity was examined by HPLC (Table 5).
高效液相(HPLC)检测条件：色谱柱：Agilent ZORBAX SB-C18，4.6*150mm，5μm；流动相：A:0.1％磷酸；B:乙腈；柱温：35℃；流速：1.0mL/min；检测波长：260nm；运行时间：25min，后运行：6min；洗脱程序：梯度洗脱。High performance liquid chromatography (HPLC) detection conditions: column: Agilent ZORBAX SB-C18, 4.6*150 mm, 5 μm; mobile phase: A: 0.1% phosphoric acid; B: acetonitrile; column temperature: 35 ° C; flow rate: 1.0 mL / min; Detection wavelength: 260 nm; running time: 25 min, post-run: 6 min; elution procedure: gradient elution.
表4：Table 4:
Figure PCTCN2017119448-appb-000259
Figure PCTCN2017119448-appb-000259
表5table 5
Figure PCTCN2017119448-appb-000260
Figure PCTCN2017119448-appb-000260
同时，本发明化合物1，4-70在高温或高湿环境下，具有较为稳定的性质，优选地为化合物4、5、7、9-11、13、14、16-25、28-35、37、46-70；进一步优选地为化合物4、5、9、11、13、14、16-25、28-33、 37、46-70；更优选地为化合物11、13、14、16-19、28、33、37、56-70。Meanwhile, the compound 1,4-70 of the present invention has relatively stable properties in a high temperature or high humidity environment, preferably compounds 4, 5, 7, 9-11, 13, 14, 16-25, 28-35, 37, 46-70; further preferably compounds 4, 5, 9, 11, 13, 14, 16-25, 28-33, 37, 46-70; more preferably compounds 11, 13, 14, 16- 19, 28, 33, 37, 56-70.
结论：in conclusion:
本发明化合物具有较为稳定的性质，对于成药性起着不可估量的影响。The compounds of the present invention have relatively stable properties and have an immeasurable effect on the drug-forming properties.
对于本领域技术人员显而易见的是，本发明内容并不限于前述说明性实施例，而且可以体现在其它具体形式中而又不偏离其实质特性。因此，预期各实施例在所有方面都被视作说明性的且非限制性的，应参照所附权利要求书，而不是前述这些实施例，因此，在所附权利要求书等同内容的含义和范围内的所有变化都包括在本文中。It is obvious to those skilled in the art that the present invention is not limited to the foregoing illustrative embodiments, and may be embodied in other specific forms without departing from the essential characteristics. The present embodiments are to be considered in all respects as illustrative and not restrict All changes within the scope are included in this article.
本发明内容的化合物可通过除NS5B抑制以外或不同于NS5B抑制的机制来抑制HCV。在一个实施方案中，本发明内容的化合物抑制HCV复制子，在另一个实施方案中，本发明内容的化合物抑制NS5B。本发明内容的化合物可抑制HCV的多种基因型。Compounds of the present invention may inhibit HCV by a mechanism other than NS5B inhibition or different from NS5B inhibition. In one embodiment, a compound of the invention inhibits HCV replicon, and in another embodiment, a compound of the invention inhibits NS5B. The compounds of the present invention inhibit multiple genotypes of HCV.
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“另一些实施例”、“示例”、“具体示例”或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不一定指的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。In the description of the present specification, the description with reference to the terms "one embodiment", "some embodiments", "another embodiment", "example", "specific example" or "some examples", etc. Particular features, structures, materials or features described in the examples are included in at least one embodiment or example of the invention. In the present specification, the schematic representation of the above terms does not necessarily mean the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in a suitable manner in any one or more embodiments or examples.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在不脱离本发明的原理和宗旨的情况下在本发明的范围内可以对上述实施例进行变化、修改、替换和变型，本发明的范围由权利要求及其等同物限定。Although the embodiments of the present invention have been shown and described, it is understood that the foregoing embodiments are illustrative and not restrictive The scope of the present invention is defined by the appended claims and their equivalents.

Claims (21)

  1. 一种化合物，具有如式(I’)所示的结构，或式(I’)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，a compound having a structure represented by the formula (I'), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, or a pharmaceutically acceptable structure of the structure represented by the formula (I') Accepted salt or prodrug,
    Figure PCTCN2017119448-appb-100001
    Figure PCTCN2017119448-appb-100001
    其中，among them,
    G为烷基，芳基取代的烷基，烷氧基羰基取代的烷基，芳基或烷基羰基；G is an alkyl group, an aryl-substituted alkyl group, an alkoxycarbonyl-substituted alkyl group, an aryl group or an alkylcarbonyl group;
    Y为芳基、杂芳基或烷基；其中芳基或杂芳基可任意的被卤素或烷基取代；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为F，Cl或Br；X is F, Cl or Br;
    R 1为H、氘或烷基； R 1 is H, hydrazine or alkyl;
    R 2为-C(＝O)-(CR 6R 7) n-R 3、-C(＝O)-(CH 2OCH 2) n-R 3、-P(＝O)(OR 4)OR 5； R 2 is -C(=O)-(CR 6 R 7 ) n -R 3 , -C(=O)-(CH 2 OCH 2 ) n -R 3 , -P(=O)(OR 4 )OR 5 ;
    或R 2为
    Figure PCTCN2017119448-appb-100002
    Or R 2 is
    Figure PCTCN2017119448-appb-100002
    R 3为-NR 8R 9、-M-R 10、-C(＝O)OR 10、-C(＝O)OH、-O-N＝CR 14R 15或-N＝CR 14R 15； R 3 is -NR 8 R 9 , -MR 10 , -C(=O)OR 10 , -C(=O)OH, -ON=CR 14 R 15 or -N=CR 14 R 15 ;
    R 4和R 5各自独立地为烷基； R 4 and R 5 are each independently an alkyl group;
    R 6和R 7各自独立地为H、氘、烷基、杂烷基、芳基、环烷基、杂芳基、杂环基、芳基烷基、杂芳基烷基、环烷基烷基或杂环基烷基； R 6 and R 7 are each independently H, hydrazine, alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylane Or heterocyclylalkyl;
    R 8为H或烷基； R 8 is H or an alkyl group;
    R 9为H、氘、-C(＝O)R 10、-C(＝O)OR 10、烷基、环烷基、杂环基、杂芳基或芳基； R 9 is H, hydrazine, -C(=O)R 10 , -C(=O)OR 10 , alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;
    或R 8和R 9与其相连的N原子一起形成含氮杂环基或含氮杂芳基； Or 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为烷基、杂烷基、芳基、环烷基、芳基烷基、杂芳基烷基、环烷基烷基、杂环基烷基、杂芳基或杂环基； R 10 is alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, heteroaryl or heterocyclic;
    M为
    Figure PCTCN2017119448-appb-100003
    M is
    Figure PCTCN2017119448-appb-100003
    W为3-8元含氮杂环、含氮C 5-12稠合杂双环或含氮C 5-12螺杂双环； 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为H、烷基、环烷基、杂环基、杂芳基或芳基； R 11 is H, alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;
    各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、烷基、卤代烷基、烷氧基烷基、卤代烷氧基烷基、烯基、炔基、烷氧基、卤代烷氧基、烷氧基烷氧基、烷氨基、卤代烷氨基、烷硫基、环 烷基、杂环基、芳基、杂芳基、芳氧基、芳氨基、杂芳氧基、羟基取代的烷氧基、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O) 2-、羟基取代的烷基-C(＝O)-、羟基取代的烷基-S(＝O)-或羟基取代的烷基-S(＝O) 2-； Each R 12 is independently H, hydrazine, =O, hydroxy, amino, halogen, cyano, carboxy, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl , alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, heteroaryl Oxyl, hydroxy substituted alkoxy, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy substituted alkyl-C (= O)-, hydroxy-substituted alkyl-S(=O)- or hydroxy-substituted alkyl-S(=O) 2 -;
    R 14和R 15各自独立地为烷基、环烷基、杂环基、芳基或杂芳基； R 14 and R 15 are each independently alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
    各n独立地为1、2、3、4或5；和Each n is independently 1, 2, 3, 4 or 5; and
    m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
    其中R 1、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 14或R 15中所述的烷基、杂烷基、芳基、环烷基、芳基烷基、杂芳基烷基、环烷基烷基、杂环基烷基、烯基、炔基、烷氧基、烷氨基、杂芳基或杂环基任选被1、2、3或4个独立选自羟基、氨基、卤素、氰基、羧基、硝基、烷基、卤代烷基、烷氧基烷基、卤代烷氧基烷基、烯基、炔基、烷氧基、卤代烷氧基、烷氧基烷氧基、烷氨基、卤代烷氨基、烷硫基、环烷基、杂环基、芳基和杂芳基中的取代基所取代。 An alkyl group, a heteroalkyl group, an aryl group, wherein R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 14 or R 15 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 in the oxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are substituted.
  2. 根据权利要求1所述的化合物，其中，The compound according to claim 1, wherein
    G为C 1-10烷基，C 6-12芳基取代的C 1-10烷基，C 1-10烷氧基羰基取代的C 1-10烷基，C 6-12芳基或C 1-10烷基羰基； 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为C 6-12芳基、C 1-9杂芳基或C 1-10烷基；其中C 6-12芳基或C 1-9杂芳基可任意的被卤素、C 1-6烷基取代； 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为H、氘或C 1-10烷基； R 1 is H, hydrazine or C 1-10 alkyl;
    R 4和R 5各自独立地为C 1-10烷基； R 4 and R 5 are each independently C 1-10 alkyl;
    R 6和R 7各自独立地为H、氘、C 1-10烷基、C 1-10杂烷基、C 6-10芳基、C 3-10环烷基、C 1-9杂芳基、C 2-9杂环基、C 6-10芳基C 1-6烷基、C 2-9杂芳基C 1-6烷基、C 3-6环烷基C 1-6烷基或C 2-9杂环基C 1-6烷基； 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为H或C 1-10烷基； R 8 is H or C 1-10 alkyl;
    R 9为H、氘、-C(＝O)R 10、-C(＝O)OR 10、C 1-10烷基、C 3-10环烷基、C 2-8杂环基、C 1-9杂芳基或C 6-12芳基； R 9 is H, 氘, -C(=O)R 10 , -C(=O)OR 10 , C 1-10 alkyl, C 3-10 cycloalkyl, C 2-8 heterocyclic, C 1 -9 heteroaryl or C 6-12 aryl;
    或R 8和R 9与其相连的N原子一起形成含氮C 2-8杂环基或含氮C 1-9杂芳基； Or 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为C 1-10烷基、C 1-10杂烷基、C 6-12芳基、C 3-10环烷基、C 6-12芳基C 1-10烷基、C 1-9杂芳基C 1-10烷基、C 3-10环烷基C 1-10烷基、C 2-8杂环基C 1-10烷基、C 1-9杂芳基或C 2-8杂环基； 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为H、C 1-10烷基、C 3-8环烷基、C 2-8杂环基、C 1-9杂芳基或C 6-12芳基； 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;
    各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、C 1-10烷基、C 1-10卤代烷基、C 1-10烷氧基C 1-10烷基、卤代C 1-10烷氧基C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基、C 1-10卤代烷氧基、C 1-10烷氧基C 1-10烷氧基、C 1-10烷氨基、C 1-10卤代烷氨基、C 1-10烷硫基、C 3-10环烷基、C 2-8杂环基、C 6-12芳基、C 1-9杂芳基、C 6-12芳氧基、C 6-12芳氨基、C 1-9杂芳氧基、羟基取代的C 1-10烷氧基、C 1-10烷基-C(＝O)-、C 1-10烷基-S(＝O)-、C 1-10烷基-S(＝O) 2-、羟基取代的C 1-10烷基-C(＝O)-、羟基取代的C 1-10烷基-S(＝O)-或羟基取代的C 1-10烷基-S(＝O) 2-； Each R 12 is independently H, hydrazine, =O, hydroxy, amino, halogen, cyano, carboxy, nitro, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 alkoxy C 1 -10 alkyl, halo C 1-10 alkoxy C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 haloalkoxy , C 1-10 alkoxy C 1-10 alkoxy, C 1-10 alkylamino, C 1-10 haloalkylamino, C 1-10 alkylthio, C 3-10 cycloalkyl, C 2-8 Heterocyclyl, C 6-12 aryl, C 1-9 heteroaryl, C 6-12 aryloxy, C 6-12 arylamino, C 1-9 heteroaryloxy, hydroxy substituted C 1-10 Alkoxy, C 1-10 alkyl-C(=O)-, C 1-10 alkyl-S(=O)-, C 1-10 alkyl-S(=O) 2 -, hydroxy substituted C 1-10 alkyl-C(=O)-, hydroxy-substituted C 1-10 alkyl-S(=O)- or hydroxy-substituted C 1-10 alkyl-S(=O) 2 -;
    R 14和R 15各自独立地为C 1-10烷基、C 3-10环烷基、C 2-8杂环基、C 6-12芳基或C 1-9杂芳基； 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;
    其中R 1、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 14或R 15中所述的C 1-10烷基、C 1-10杂烷基、C 6-12芳基、C 3-10环烷基、C 6-12芳基C 1-10烷基、C 1-9杂芳基C 1-10烷基、C 3-10环烷基C 1-10烷基、C 2-8杂环基C 1-10烷基、C 2-10烯基、C 2-10炔基、C 1-10烷氧基、C 1-10烷氨基、C 1-9杂芳基或C 2-8杂环基任选地被1、2、3或4个独立选自羟基、氨基、卤素、氰基、羧基、硝基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基C 1-6烷基、C 1-6卤代烷氧基C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷氨基、C 1-6卤代烷氨基、C 1-6烷硫基、C 3-6环烷基、C 1-10杂环基、C 1-10芳基和C 1-10杂芳基中的取代基所取代。 Wherein C 1 1-10 alkyl, C 1- wherein R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 14 or R 15 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 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1- 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, C 1-6 haloalkoxy C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkylamino, C Substituents in the 1-6 alkylthio group, the C 3-6 cycloalkyl group, the C 1-10 heterocyclic group, the C 1-10 aryl group and the C 1-10 heteroaryl group are substituted.
  3. 根据权利要求1或2所述的化合物，具有如式(II’)、(III’)、(IV’)、(V’)、(VI’)、(VII’)、(VIII’)、(IX’)、(IX’)、(IIa’)、(IIIa’)、(IVa’)、(Va’)、(VIa’)、(VIIa’)、(VIIIa’)、(IXa’)或(IXa’)所式的结构、或式(II’)、(III’)、(IV’)、(V’)、(VI’)、(VII’)、(VIII’)、(IX’)、(IX’)、(IIa’)、(IIIa’)、(IVa’)、(Va’)、(VIa’)、(VIIa’)、(VIIIa’)、(IXa’)或(IXa’)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，The compound according to claim 1 or 2, having the formulae (II'), (III'), (IV'), (V'), (VI'), (VII'), (VIII'), ( IX'), (IX'), (IIa'), (IIIa'), (IVa'), (Va'), (VIa'), (VIIa'), (VIIIa'), (IXa') or IXa'), or formula (II'), (III'), (IV'), (V'), (VI'), (VII'), (VIII'), (IX'), (IX'), (IIa'), (IIIa'), (IVa'), (Va'), (VIa'), (VIIa'), (VIIIa'), (IXa') or (IXa') a stereoisomer, tautomer, oxynitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure,
    Figure PCTCN2017119448-appb-100004
    Figure PCTCN2017119448-appb-100004
    Figure PCTCN2017119448-appb-100005
    Figure PCTCN2017119448-appb-100005
  4. 根据权利要求1所述的化合物，具有如式(I)所示的结构，或式(I)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，The compound according to claim 1, having a structure represented by the formula (I), or a stereoisomer, a tautomer, an oxynitride, a solvate, a metabolite, or a structure of the structure represented by the formula (I). a pharmaceutically acceptable salt or prodrug,
    Figure PCTCN2017119448-appb-100006
    Figure PCTCN2017119448-appb-100006
    其中，among them,
    R 1为H、氘或烷基； R 1 is H, hydrazine or alkyl;
    R 2为-C(＝O)-(CR 6R 7) n-R 3、-C(＝O)-(CH 2OCH 2) n-R 3、-P(＝O)(OR 4)OR 5； R 2 is -C(=O)-(CR 6 R 7 ) n -R 3 , -C(=O)-(CH 2 OCH 2 ) n -R 3 , -P(=O)(OR 4 )OR 5 ;
    或R 2为
    Figure PCTCN2017119448-appb-100007
    Or R 2 is
    Figure PCTCN2017119448-appb-100007
    R 3为-NR 8R 9、-M-R 10、-C(＝O)OR 10、-C(＝O)OH、-O-N＝CR 14R 15或-N＝CR 14R 15； R 3 is -NR 8 R 9 , -MR 10 , -C(=O)OR 10 , -C(=O)OH, -ON=CR 14 R 15 or -N=CR 14 R 15 ;
    R 4和R 5各自独立地为烷基； R 4 and R 5 are each independently an alkyl group;
    R 6和R 7各自独立地为H、氘、烷基、杂烷基、芳基、环烷基、杂芳基、杂环基、芳基烷基、杂芳基烷基、环烷基烷基或杂环基烷基； R 6 and R 7 are each independently H, hydrazine, alkyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylane Or heterocyclylalkyl;
    R 8为H或烷基； R 8 is H or an alkyl group;
    R 9为H、氘、-C(＝O)R 10、-C(＝O)OR 10、烷基、环烷基、杂环基、杂芳基或芳基； R 9 is H, hydrazine, -C(=O)R 10 , -C(=O)OR 10 , alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;
    或R 8和R 9与其相连的N原子一起形成含氮杂环基或含氮杂芳基； Or 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为烷基、杂烷基、芳基、环烷基、芳基烷基、杂芳基烷基、环烷基烷基、杂环基烷基、杂芳基或杂环基； R 10 is alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, heteroaryl or heterocyclic;
    M为
    Figure PCTCN2017119448-appb-100008
    M is
    Figure PCTCN2017119448-appb-100008
    W为3-8元含氮杂环、含氮C 5-12稠合杂双环或含氮C 5-12螺杂双环； 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为H、烷基、环烷基、杂环基、杂芳基或芳基； R 11 is H, alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl;
    各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、烷基、卤代烷基、烷氧基烷基、卤代烷氧基烷基、烯基、炔基、烷氧基、卤代烷氧基、烷氧基烷氧基、烷氨基、卤代烷氨基、烷硫基、环烷基、杂环基、芳基、杂芳基、芳氧基、芳氨基、杂芳氧基、羟基取代的烷氧基、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O) 2-、羟基取代的烷基-C(＝O)-、羟基取代的烷基-S(＝O)-或羟基取代的烷基-S(＝O) 2-； Each R 12 is independently H, hydrazine, =O, hydroxy, amino, halogen, cyano, carboxy, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl , alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryloxy, arylamino, heteroaryl Oxyl, hydroxy substituted alkoxy, alkyl-C(=O)-, alkyl-S(=O)-, alkyl-S(=O) 2 -, hydroxy substituted alkyl-C (= O)-, hydroxy-substituted alkyl-S(=O)- or hydroxy-substituted alkyl-S(=O) 2 -;
    R 14和R 15各自独立地为烷基、环烷基、杂环基、芳基或杂芳基； R 14 and R 15 are each independently alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
    各n独立地为1、2、3、4或5；和Each n is independently 1, 2, 3, 4 or 5; and
    m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
    其中R 1、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 14或R 15中所述的烷基、杂烷基、芳基、环烷基、芳基烷基、杂芳基烷基、环烷基烷基、杂环基烷基、烯基、炔基、烷氧基、烷氨基、杂芳基或杂环基任选地被1、2、3或4个独立选自羟基、氨基、卤素、氰基、羧基、硝基、烷基、卤代烷基、烷氧基烷基、卤代烷氧基烷基、烯基、炔基、烷氧基、卤代烷氧基、烷氧基烷氧基、烷氨基、卤代烷氨基、烷硫基、环烷基、杂环基、芳基和杂芳基中的取代基所取代。 An alkyl group, a heteroalkyl group, an aryl group, wherein R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 14 or R 15 Cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, alkenyl, alkynyl, alkoxy, alkylamino, heteroaryl or heterocyclyl optionally 1, 2, 3 or 4 independently selected from the group consisting of hydroxyl, amino, halogen, cyano, carboxyl, nitro, alkyl, haloalkyl, alkoxyalkyl, haloalkoxyalkyl, alkenyl, alkynyl, Substituents in alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, haloalkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are substituted.
  5. 根据权利要求1-4任一项所述的化合物，具有如式(Ia)所示的结构，或式(Ia)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，The compound according to any one of claims 1 to 4, which has a structure represented by the formula (Ia), or a stereoisomer, a tautomer, an oxynitride, a solvent of the structure represented by the formula (Ia). a metabolite, a pharmaceutically acceptable salt or a prodrug,
    Figure PCTCN2017119448-appb-100009
    Figure PCTCN2017119448-appb-100009
  6. 根据权利要求1-5任一项所述化合物，其中，A compound according to any one of claims 1 to 5, wherein
    R 1为H、氘或C 1-6烷基； R 1 is H, hydrazine or C 1-6 alkyl;
    R 4和R 5各自独立地为C 1-6烷基； R 4 and R 5 are each independently C 1-6 alkyl;
    R 6和R 7各自独立地为H、氘、C 1-4烷基、C 1-4杂烷基、C 6-10芳基、C 3-6环烷基、C 1-9杂芳基、C 2-9杂环基、C 6-10芳基C 1-6烷基、C 2-9杂芳基C 1-6烷基、C 3-6环烷基C 1-6烷基或C 2-9杂环基C 1-6烷基； 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为H或C 1-6烷基； R 8 is H or C 1-6 alkyl;
    R 9为H、氘、-C(＝O)R 10、-C(＝O)OR 10、C 1-6烷基、C 3-6环烷基、C 2-6杂环基、C 1-9杂芳基或C 6-10芳基； R 9 is H, 氘, -C(=O)R 10 , -C(=O)OR 10 , C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 heterocyclic, C 1 -9 heteroaryl or C 6-10 aryl;
    或R 8和R 9与其相连的N原子一起形成含氮C 2-6杂环基或含氮C 1-9杂芳基； Or 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为C 1-6烷基、C 1-4杂烷基、C 6-10芳基、C 3-6环烷基、C 6-12芳基C 1-6烷基、C 1-9杂芳基C 1-6烷基、C 3-10环烷基C 1-6烷基、C 2-8杂环基C 1-6烷基、C 1-9杂芳基或C 2-9杂环基；和 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和R 15各自独立地为C 1-6烷基、C 3-6环烷基、C 2-9杂环基、C 6-10芳基或C 1-9杂芳基； 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;
    其中R 1、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 14或R 15中所述的C 1-4烷基、C 1-6烷基、C 1-4杂烷基、C 6-10芳基、C 3-6环烷基、C 2-6杂环基、C 6-12芳基C 1-6烷基、C 1-9杂芳基C 1-6烷基、C 3-10环烷基C 1-6烷基、C 2-8杂环基C 1-6烷基、C 1-9杂芳基或C 2-9杂环基任选被1、2、3或4个选自羟基、氨基、F、Cl、Br、I、氰基、羧基、硝基、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基C 1-4烷基、C 1-4卤代烷氧基C 1-4烷基、C 1-4烯基、C 1-4炔基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4烷氨基、C 1-4卤代烷氨基、C 1-4烷硫基、C 3-6环烷基、C 2-9杂环基、C 6-10芳基和C 1-9杂芳基中的取代基所取代。 Wherein C 1 1-4 alkyl, C 1-6 alkyl, C 1 described in R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 14 or R 15 -4 heteroalkyl, C 6-10 aryl, C 3-6 cycloalkyl, C 2-6 heterocyclyl, 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 heterocyclic C 1-6 alkyl, C 1-9 heteroaryl or C 2-9 heterocyclic 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 alkenyl, C 1-4 alkynyl, C 1-4 alkoxy, C 1-4 Haloalkoxy, C 1-4 alkoxy C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkylamino, C 1-4 alkylthio, C 3-6 cycloalkyl, C Substituents in the 2-9 heterocyclyl, C 6-10 aryl and C 1-9 heteroaryl groups are substituted.
  7. 根据权利要求1-6任一项所述化合物，其中，A compound according to any one of claims 1 to 6, wherein
    R 1为H、氘、甲基、乙基、正丙基或异丙基； R 1 is H, hydrazine, methyl, ethyl, n-propyl or isopropyl;
    R 4和R 5各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基或仲己基； 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和R 7各自独立地为H、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、苯甲基、甲硫基甲基、甲硫基乙基、甲硫基丙基、甲硫基丁基、苯基、萘基、苯基甲基、苯基乙基、甲氧基、2-甲氧基乙基、环丙基、环丁基、环戊基、环己基、噻唑基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、四氢吡咯基或四氢呋喃基； R 6 and R 7 are each independently H, hydrazine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, benzyl, methylthiomethyl, A Thioethyl, methylthiopropyl, methylthiobutyl, phenyl, naphthyl, phenylmethyl, phenylethyl, methoxy, 2-methoxyethyl, cyclopropyl, ring Butyl, cyclopentyl, cyclohexyl, thiazolyl, thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, tetrahydropyrrolyl or tetrahydrofuranyl;
    R 8为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基或仲己基； 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 9为H、氘、-C(＝O)R 10、-C(＝O)OR 10、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、仲己基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基、苯基或萘基； R 9 is H, 氘, -C(=O)R 10 , -C(=O)OR 10 , 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, oxiranyl, nitrogen heterocycle Butyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetra Hydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetra Hydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxoalkyl, dithiaalkyl, thiamethane, homopiperazinyl, homopiperidinyl, oxa Cycloheptyl, thiaheptanyl, oxazepine, diaza, thiazepine, porphyrin, 1,2,3,4-tetrahydroisoquinolinyl, furyl, Imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazinyl, thiazole , tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1 , 2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5- Thiodidiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothienyl, fluorenyl, fluorenyl, quinolinyl, isoquinolyl , imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazine , [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl,[1,2,4] Triazolo[1,5-a]pyridinyl, phenyl or naphthyl;
    或R 8和R 9与其相连的N原子一起形成氮杂环丁基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、高哌嗪基、1,2,3,4-四氢异喹啉基、咪唑基、吡咯基、四唑基、三唑基、吡唑基、嘧啶基、苯并咪唑基、苯并吡唑基、吲哚基、吲哚啉基、吡啶并咪唑基、吡啶并吡唑基、吡啶并吡咯基、哒嗪并咪唑基、嘌呤基或嘧啶并吡唑基； Or 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为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、仲己基、环丙基、环丁基、环戊基、环己基、四氢吡咯基、四氢呋喃基、苯基、萘基、苄基、萘甲基、噻唑基甲基、咪唑基甲基、环戊基甲基、环己基甲基、四氢吡咯基甲基、四氢呋喃基甲基、 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,
    Figure PCTCN2017119448-appb-100010
    Figure PCTCN2017119448-appb-100010
    Figure PCTCN2017119448-appb-100011
    Figure PCTCN2017119448-appb-100011
    R 14和R 15各自独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、苯甲基、甲硫基乙基、苯基、萘基、环丙基、环丁基、环戊基、环己基、
    Figure PCTCN2017119448-appb-100012
    Figure PCTCN2017119448-appb-100013
    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,
    Figure PCTCN2017119448-appb-100012
    Figure PCTCN2017119448-appb-100013
    其中R 1、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 14或R 15中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、苯甲基、甲硫基甲基、甲硫基乙基、甲硫基丙基、甲硫基丁基、苯基、萘基、甲氧基、环丙基、环丁基、环戊基、环己基、噻唑基、噻吩基、呋喃基、吡咯基、吡啶基、嘧啶基、四氢吡咯基或四氢呋喃基任选被1、2、3或4个独立选自羟基、氨基、F、Cl、Br、I、氰基、羧基、硝基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、苯基、萘基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、2-噻唑基、4-噻唑基、5-噻唑基、2-噻吩基、2-噻吩基、3-呋喃基、3-呋喃基、2-吡咯基、3-吡咯基、吡啶基、嘧啶基、四氢吡咯基和四氢呋喃基中的取代基所取代。 Wherein methyl, ethyl, n-propyl, isopropyl, n-butyl as described in R 1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 14 or R 15 Base, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, n-hexyl, isohexyl, benzyl, methylthiomethyl, methylthioethyl, methyl sulfide Propyl, methylthiobutyl, phenyl, naphthyl, methoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, thiazolyl, thienyl, furyl, pyrrolyl, pyridyl, The pyrimidinyl, tetrahydropyrrolyl or tetrahydrofuranyl group is optionally 1, 2, 3 or 4 independently selected from the group consisting of hydroxyl, amino, F, Cl, Br, I, cyano, carboxy, nitro, methyl, ethyl, N-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, n-hexyl, isohexyl, phenyl, naphthyl, methoxy , ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-thienyl, 2-thienyl, 3-furyl , 3-furyl, 2-pyrrolyl, 3-pyrrolyl, pyridyl, pyrimidinyl, tetrahydrogen Substituted pyrrolyl group and the tetrahydrofuryl substituted.
  8. 根据权利要求1-7任一项所述化合物，其中，A compound according to any one of claims 1 to 7, wherein
    W为
    Figure PCTCN2017119448-appb-100014
    Figure PCTCN2017119448-appb-100015
    W is
    Figure PCTCN2017119448-appb-100014
    Figure PCTCN2017119448-appb-100015
    其中，among them,
    t 1为1、2、3或4； t 1 is 1, 2, 3 or 4;
    t 2、t 3和t 4各自独立地为1、2或3； t 2 , t 3 and t 4 are each independently 1, 2 or 3;
    t 5和t 6各自独立地为1、2、3、4或5； t 5 and t 6 are each independently 1, 2, 3, 4 or 5;
    t 7为1或2； t 7 is 1 or 2;
    k 1、k 2、k 3和k 4各自独立地为0、1或2；其中k 1和k 2不同时为0；k 3和k 4不同时为0；和 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;
    各R 13独立地为H、氘、羧基、烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基。 Each R 13 is independently H, oxime, carboxyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
  9. 根据权利要求1-8任一项所述化合物，其中，A compound according to any one of claims 1-8, wherein
    W为
    Figure PCTCN2017119448-appb-100016
    Figure PCTCN2017119448-appb-100017
    W is
    Figure PCTCN2017119448-appb-100016
    Figure PCTCN2017119448-appb-100017
    其中，各R 13独立地为H、氘、羧基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、C 2-6杂环基、C 6-10芳基或C 1-9杂芳基。 Wherein 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.
  10. 根据权利要求1-9任一项所述的化合物，其中A compound according to any one of claims 1-9, wherein
    R 11为H、C 1-6烷基、C 3-6环烷基、C 2-6杂环基、C 1-9杂芳基或C 6-10芳基； 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;
    各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基C 1-6烷基、卤代C 1-6烷氧基C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷氨基、C 1-6卤代烷氨基、C 1-6烷硫基、C 3-6环烷基、C 2-6杂环基、C 6-10芳基、C 1-9杂芳基、C 6-10芳氧基、C 6-10芳氨基、杂C 1-9芳氧基、羟基取代的C 1-6烷氧基、C 1-6烷基-C(＝O)-、C 1-6烷基-S(＝O)-、C 1-6烷基-S(＝O) 2-、羟基取代的C 1-6烷基-C(＝O)-、羟基取代的C 1-6烷基-S(＝O)-或羟基取代的C 1-6烷基-S(＝O) 2-。 Each R 12 is independently H, hydrazine, =0, hydroxy, amino, halogen, cyano, carboxy, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy C 1 -6 alkyl, halo C 1-6 alkoxy C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkylamino, C 1-6 alkylthio, C 3-6 cycloalkyl, C 2-6 Heterocyclyl, C 6-10 aryl, C 1-9 heteroaryl, C 6-10 aryloxy, C 6-10 arylamino, hetero C 1-9 aryloxy, hydroxy substituted C 1-6 Alkoxy, C 1-6 alkyl-C(=O)-, C 1-6 alkyl-S(=O)-, C 1-6 alkyl-S(=O) 2 -, hydroxy substituted C 1-6 alkyl-C(=O)-, hydroxy-substituted C 1-6 alkyl-S(=O)- or hydroxy-substituted C 1-6 alkyl-S(=O) 2 -.
  11. 根据权利要求1-10任一项所述的化合物，其中A compound according to any one of claims 1 to 10, wherein
    R 11为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、环丙基、环丁基、环戊基、环己基、吡咯基、吗啉基、哌嗪基或苯基；和 R 11 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, a phenyl group, a piperazinyl group or a phenyl group;
    各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、三氟甲基、甲氧基甲基、二氟甲氧基甲基、三氟甲氧基甲基、乙氧基甲基、乙烯基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、甲氨基、乙氨基、苯基、萘基、苯氨基、苯氧基、吡咯基、吗啉基或哌嗪基。 Each R 12 is independently H, hydrazine, =O, hydroxy, amino, halogen, cyano, carboxy, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. Butyl, trifluoromethyl, methoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, ethoxymethyl, vinyl, ethynyl, methoxy, ethoxy, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, phenyl, naphthyl, phenylamino, phenoxy, pyrrolyl, morpholinyl or piperazinyl.
  12. 根据权利要求1-11任一项所述的化合物，其具有式(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)或(IX)所式的结构、或式(II)、(III)、(IV)、(V)、(VI)、(VII)、(VIII)、(IX)或(IX)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，A compound according to any one of claims 1 to 11 having formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or IX) a structure of the formula or a stereoscopic structure of the structure represented by formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (IX) a construct, tautomer, oxynitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
    Figure PCTCN2017119448-appb-100018
    Figure PCTCN2017119448-appb-100018
    Figure PCTCN2017119448-appb-100019
    Figure PCTCN2017119448-appb-100019
  13. 根据权利要求1-12任一项所述的化合物，其具有式(IIa)、(IIIa)、(IVa)、(Va)、(VIa)、(VIIa)、(VIIIa)、(IXa)或(IXa)所式的结构、或式(IIa)、(IIIa)、(IVa)、(Va)、(VIa)、(VIIa)、(VIIIa)、(IXa)或(IXa)所示结构的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，A compound according to any one of claims 1 to 12 having the formula (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (IXa) or ( The structure of the formula IXa), or the structure of the formula (IIa), (IIIa), (IVa), (Va), (VIa), (VIIa), (VIIIa), (IXa) or (IXa) a construct, tautomer, oxynitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug,
    Figure PCTCN2017119448-appb-100020
    Figure PCTCN2017119448-appb-100020
  14. 根据权利要求1-5、13任一项所述的化合物，其中A compound according to any one of claims 1 to 5, wherein
    各R 1独立地为H、氘或C 1-6烷基； Each R 1 is independently H, hydrazine or C 1-6 alkyl;
    各R 6独立地为H、氘、C 1-6烷基、C 1-6杂烷基、C 6-10芳基、C 3-8环烷基、C 1-9杂芳基、C 2-9杂环基、C 6-10芳基C 1-6烷基、C 1-9杂芳基C 1-6烷基、C 3-8环烷基C 1-6烷基或C 2-9杂环基C 1-6烷基； 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;
    各R 8独立地为H或C 1-6烷基； Each R 8 is independently H or C 1-6 alkyl;
    各R 9独立地为H、氘、-C(＝O)R 10、-C(＝O)OR 10、C 1-6烷基、C 3-8环烷基、C 2-9杂环基、C 1-9杂芳基或C 6-10芳基； Each R 9 is independently H, 氘, -C(=O)R 10 , -C(=O)OR 10 , C 1-6 alkyl, C 3-8 cycloalkyl, C 2-9 heterocyclic group , a C 1-9 heteroaryl group or a C 6-10 aryl group;
    或R 8和R 9与其相连的N原子一起形成含氮C 2-9杂环基或含氮C 1-9杂芳基； Or 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;
    各R 10独立地为C 1-6烷基、C 1-6杂烷基、C 6-10芳基、C 3-8环烷基、C 6-10芳基C 1-6烷基、C 1-9杂芳基C 1-6烷基、C 3-10环烷基C 1-6烷基、C 2-9杂环基C 1-6烷基、C 1-9杂芳基或C 2-9杂环基； 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;
    各R 11独立地为H、C 1-6烷基、C 3-8环烷基、C 2-9杂环基、C 1-9杂芳基或C 6-10芳基； 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;
    各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基C 1-6烷基、卤代C 1-6烷氧基C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氧基C 1-6烷氧基、C 1-6烷氨基、C 1-6卤代烷氨基、C 1-6烷硫基、C 3-8环烷基、C 2-9杂环基、C 6-10芳基、C 1-9杂芳基、C 6-10芳氧基、C 6-10芳氨基、C 1-9杂芳氧基、羟基取代的C 1-6烷氧基、C 1-6烷基-C(＝O)-、C 1-6烷基-S(＝O)-、C 1-6烷基-S(＝O) 2-、羟基取代的C 1-6烷基-C(＝O)-、羟基取代的C 1-6烷基-S(＝O)-或羟基取代的C 1-6烷基-S(＝O) 2-； Each R 12 is independently H, hydrazine, =0, hydroxy, amino, halogen, cyano, carboxy, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy C 1 -6 alkyl, halo C 1-6 alkoxy C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 alkoxy C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkylamino, C 1-6 alkylthio, C 3-8 cycloalkyl, C 2-9 Heterocyclyl, C 6-10 aryl, C 1-9 heteroaryl, C 6-10 aryloxy, C 6-10 arylamino, C 1-9 heteroaryloxy, hydroxy substituted C 1-6 Alkoxy, C 1-6 alkyl-C(=O)-, C 1-6 alkyl-S(=O)-, C 1-6 alkyl-S(=O) 2 -, hydroxy substituted C 1-6 alkyl-C(=O)-, hydroxy-substituted C 1-6 alkyl-S(=O)- or hydroxy-substituted C 1-6 alkyl-S(=O) 2 -;
    其中各R 1、R 6、R 8、R 9、R 10、R 11或R 12中的C 1-6烷基、C 1-6杂烷基、C 6-10芳基、C 3-8环烷基、C 1-9杂芳基、C 2-9杂环基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 1-6烷氨基独立任选地被1、2、3或4个羟基、氨基、F、Cl、Br、氰基、羧基、硝基取代。 Wherein 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.
  15. 根据权利要求14所述的化合物，其中，The compound according to claim 14, wherein
    各R 1独立地为H、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基； Each R 1 is independently H, hydrazine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl;
    各R 6独立地为H、氘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、甲硫基甲基、1-甲硫基乙基、2-甲硫基乙基、1-甲硫基丙基、2-甲硫基丙基、3-甲硫基丙基、1-甲硫基丁基、2-甲硫基丁基、3-甲硫基丁基、4-甲硫基丁基、甲氧基甲基、1-甲氧基乙基、2-甲氧基乙基、1-甲氧基丙基、2-甲氧基丙基、3-甲氧基丙基、1-甲氧基丁基、2-甲氧基丁基、3-甲氧基丁基、4-甲氧基丁基、苯基、萘基、环丙基、环丁基、环戊基、环己基、噻唑基、噻吩基、噁唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、吡咯基、吡啶基、嘧啶基、吡咯烷基、四氢呋喃基、哒嗪基、吡嗪基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、苯基甲基、苯基乙基、2-噻唑基乙基、2-噻吩基乙基、2-噁唑基乙基、2-咪唑基乙基、2呋喃基乙基、2-吡咯烷基乙基、2-四氢呋喃基乙基、2-吗啉基乙基、2-硫代吗啉基乙基、2-环戊基乙基或2-环己基乙基； 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, cyclohexyl, thiazolyl, thienyl, oxazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrrolidine Base, tetrahydrofuranyl, pyridazinyl, pyrazinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenylmethyl, phenylethyl, 2-thiazole Ethyl ethyl, 2-thienylethyl, 2-oxazolylethyl, 2-imidazolylethyl, 2-furylethyl, 2-pyrrolidinylethyl, 2-tetrahydrofuranylethyl 2-morpholinyl, 2- thiomorpholinyl ethyl, 2-cyclopentylethyl or 2-cyclohexylethyl;
    各R 8独立地为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基或仲己基； 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;
    各R 9独立地为H、氘、-C(＝O)R 10、-C(＝O)OR 10、甲基、乙基、正丙基、异丙基、正丁基、异丁基、 仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、仲己基、环丙基、环丁基、环戊基、环己基、环氧乙烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、吲哚啉基、1,2,3,4-四氢异喹啉基、呋喃基、咪唑基、3-异噁唑基、异噁唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、四唑基、三唑基、2-噻吩基、3-噻吩基、吡唑基、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基、嘌呤基、喹啉基、异喹啉基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基、苯基或萘基； Each R 9 is independently H, hydrazine, -C(=O)R 10 , -C(=O)OR 10 , 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, oxiranyl, Azetidinyl, oxetanyl, thioheterobutyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuran Base, tetrahydrothiophenyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyran , tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxoalkyl, dithiaalkyl, thiamethane, homopiperazinyl, homopiperidinyl , oxetanyl, thiaheptanyl, oxazepine, diaza, thiazepine, porphyrin, 1,2,3,4-tetrahydroisoquinolinyl, Furanyl, imidazolyl, 3-isoxazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridazine , thiazolyl, tetrazolyl, triazolyl, 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadi Azyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1, 2,5-Thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothienyl, fluorenyl, fluorenyl, quinolyl, Isoquinolinyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2- b] pyrazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1, 2,4]triazolo[1,5-a]pyridinyl, phenyl or naphthyl;
    或R 8和R 9与其相连的N原子一起形成氮杂环丁基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、高哌嗪基、1,2,3,4-四氢异喹啉基、咪唑基、吡咯基、四唑基、三唑基、吡唑基、嘧啶基、苯并咪唑基、苯并吡唑基、吲哚基、吲哚啉基、吡啶并咪唑基、吡啶并吡唑基、吡啶并吡咯基、哒嗪并咪唑基、嘌呤基或嘧啶并吡唑基； Or 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;
    各R 10独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、仲戊基、正己基、异己基、仲己基、环丙基、环丁基、环戊基、环己基、四氢吡咯基、四氢呋喃基、苯基、萘基、苄基、萘甲基、噻唑基甲基、咪唑基甲基、环戊基甲基、环己基甲基、四氢吡咯基甲基、四氢呋喃基甲基、
    Figure PCTCN2017119448-appb-100021
    Figure PCTCN2017119448-appb-100022
    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,
    Figure PCTCN2017119448-appb-100021
    Figure PCTCN2017119448-appb-100022
    各R 11独立地为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、环丙基、环丁基、环戊基、环己基、吡咯基、吗啉基、哌嗪基或苯基； 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;
    各R 12独立地为H、氘、＝O、羟基、氨基、卤素、氰基、羧基、硝基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、三氟甲基、甲氧基甲基、二氟甲氧基甲基、三氟甲氧基甲基、乙氧基甲基、乙烯基、乙炔基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、甲氨基、乙氨基、苯基氨基、苯氧 基、吡咯基、吗啉基或哌嗪基； Each R 12 is independently H, hydrazine, =O, hydroxy, amino, halogen, cyano, carboxy, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. Butyl, trifluoromethyl, methoxymethyl, difluoromethoxymethyl, trifluoromethoxymethyl, ethoxymethyl, vinyl, ethynyl, methoxy, ethoxy, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylamino, ethylamino, phenylamino, phenoxy, pyrrolyl, morpholinyl or piperazinyl;
    其中R 1、R 6、R 8、R 9、R 10、R 11或R 12中所述的甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、甲硫基甲基、1-甲硫基乙基、2-甲硫基乙基、1-甲硫基丙基、2-甲硫基丙基、3-甲硫基丙基、1-甲硫基丁基、2-甲硫基丁基、3-甲硫基丁基、4-甲硫基丁基、甲氧基甲基、1-甲氧基乙基、2-甲氧基乙基、1-甲氧基丙基、2-甲氧基丙基、3-甲氧基丙基、1-甲氧基丁基、2-甲氧基丁基、3-甲氧基丁基、4-甲氧基丁基、苯基、萘基、环丙基、环丁基、环戊基、环己基、噻唑基、噻吩基、噁唑基、咪唑基、三氮唑基、四氮唑基、呋喃基、吡咯基、吡啶基、嘧啶基、吡咯烷基、四氢呋喃基、哒嗪基、吡嗪基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、苯基甲基、苯基乙基、2-噻唑基乙基、2-噻吩基乙基、2-噁唑基乙基、2-咪唑基乙基、2呋喃基乙基、2-吡咯烷基乙基、2-四氢呋喃基乙基、2-吗啉基乙基、2-硫代吗啉基乙基、2-环戊基乙基或2-环己基乙基各自独立任选被1、2、3或4个独立选自羟基、氨基、F、Cl、Br、I、氰基、羧基或硝基。 Wherein methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl groups as described in R 1 , R 6 , R 8 , R 9 , R 10 , R 11 or R 12 , methylthiomethyl, 1-methylthioethyl, 2-methylthioethyl, 1-methylthiopropyl, 2-methylthiopropyl, 3-methylthiopropyl, 1-methyl Thiobutyl, 2-methylthiobutyl, 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, cyclohexyl, thiazolyl, thienyl, oxazolyl, imidazolyl, triazolyl, tetrazolyl , furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrrolidinyl, tetrahydrofuranyl, pyridazinyl, pyrazinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine Base, phenylmethyl, phenylethyl, 2-thiazolylethyl, 2-thienylethyl, 2-oxazolylethyl, 2-imidazolylethyl, 2-furylethyl, 2-pyrrole alkyl Ethyl ethyl, 2-tetrahydrofuranylethyl, 2-morpholinylethyl, 2-thiomorpholinylethyl, 2-cyclopentylethyl or 2-cyclohexylethyl are each independently optionally 2, 3 or 4 are independently selected from the group consisting of hydroxyl, amino, F, Cl, Br, I, cyano, carboxyl or nitro.
  16. 根据权利要求1-15任一项所述的化合物，其具有如下结构之一，或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或前药，The compound according to any one of claims 1 to 15, which has one of the following structures, or a stereoisomer, tautomer, oxynitride, solvate, metabolite, pharmaceutically acceptable salt thereof Or a prodrug,
    Figure PCTCN2017119448-appb-100023
    Figure PCTCN2017119448-appb-100023
    Figure PCTCN2017119448-appb-100024
    Figure PCTCN2017119448-appb-100024
    Figure PCTCN2017119448-appb-100025
    Figure PCTCN2017119448-appb-100025
    Figure PCTCN2017119448-appb-100026
    Figure PCTCN2017119448-appb-100026
    Figure PCTCN2017119448-appb-100027
    Figure PCTCN2017119448-appb-100027
    Figure PCTCN2017119448-appb-100028
    Figure PCTCN2017119448-appb-100028
    Figure PCTCN2017119448-appb-100029
    Figure PCTCN2017119448-appb-100029
  17. 一种药物组合物，其包含权利要求1-16任一项所述的化合物，及药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或其组合。A pharmaceutical composition comprising a compound of any of claims 1-16, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.
  18. 根据权利要求17所述的药物组合物，其进一步包含其他抗HCV的药物，其中所述抗HCV的药物为干扰素利巴韦林、白介素2、白介素6、白介素12、促进产生1型辅助性T细胞应答的化合物、干扰RNA、反义RNA、咪喹莫德、肌苷5’-单磷酸脱氢酶抑制剂、金刚烷胺、金刚乙胺、巴维昔单抗、丙型肝炎免疫球蛋白、civacir、波普瑞韦、替拉瑞韦、埃罗替尼、达卡他韦、司美匹韦、阿那匹韦、西 鲁瑞韦、丹诺普韦、雷迪帕韦、硝唑尼特、奈韦拉平、阿拉泊韦、依米他韦、vaniprevir、faldaprevir、paritaprevir、sovaprevir、grazoprevir、elbasvir、vedroprevir、narlaprevir、ombitasvir、ravidasvir、velpatasvir、samatasvir、elbasvir、alisporivir、modithromycin、mericitabine、nesbuvir、lomibuvir、setrobuvir、dasabuvir、filibuvir、deleobuvir、tegobuvir、odalasvir、ritonavir、alloferon、nivolumab、multiferon、pibrentasvir、glecaprevir、procvax、miravirsen、EDP239、ANA975、MK-8325、BZF-961、GS-9256、GSK-2336805、PPI-461、ACH-1095、VX-985、IDX-375、VX-500、VX-813、PHX-1766、PHX-2054、IDX-136、IDX-316、VBY-376、TMC-649128、INX-189、IDX-184、IDX102、R1479、UNX-08189、PSI-6130、PSI-938、PSI-879、HCV-371、VCH-916、MK-3281、ABT-072、A-837093、JKT-109、Gl-59728、GL-60667、AZD-2795、TMC647055、WF-10、ACH-3422、MK-3682、MK-8408、GS-9857、CD-AdNS3、RG-101、BZF-961、INO-8000、MBL-HCV1、CIGB-230、TG-2349、CB-5300、chronvac-C、MK-1075、ACH-0143422、WS-007、MK-7680、MK-2248、MK-8408、IDX-21459、AV-4025、MK-8876、GSK-2878175、MBX-700、AL-335、JNJ-47910382、AL-704、ABP-560、TD-6450、EDP-239、SB-9200、ITX-5061、ID-12、或其任意组合。The pharmaceutical composition according to claim 17, which further comprises other anti-HCV drugs, wherein the anti-HCV drug is interferon ribavirin, interleukin 2, interleukin 6, interleukin 12, promotes the production of type 1 auxiliary T cell-responsive compounds, interfering RNA, antisense RNA, imiquimod, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, baviximab, hepatitis C immunoglobulin Protein, civacir, boceprevir, telaprevir, erlotinib, dacaviride, simipiride, anapyvir, cilostry, dannoprevir, radipavir, nitrate Zobenid, nevirapine, alisporivir, imivirvir, vaniprevir, faldaprevir, paritaprevir, sovaprevir, grazoprevir, elbasvir, vedroprevir, narlaprevir, ombitasvir, ravidasvir, velpatasvir, samatasvir, elbasvir, alistorivir, modithromycin, mericitabine, nesbuvir, lomibuvir , setrobuvir, dasabuvir, filibuvir, deleobuvir, tegobuvir, odalasvir, ritonavir, alloferon, nivolumab, multiferon, pibrentasvir, glecaprevir, provax Miravirsen, EDP239, ANA975, MK-8325, BZF-961, GS-9256, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, VBY-376, TMC-649128, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV- 371, VCH-916, MK-3281, ABT-072, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC647055, WF-10, ACH-3422, MK-3682, MK- 8408, GS-9857, CD-AdNS3, RG-101, BZF-961, INO-8000, MBL-HCV1, CIGB-230, TG-2349, CB-5300, chronvac-C, MK-1075, ACH-0143422, WS-007, MK-7680, MK-2248, MK-8408, IDX-21459, AV-4025, MK-8876, GSK-2878175, MBX-700, AL-335, JNJ-47910382, AL-704, ABP- 560, TD-6450, EDP-239, SB-9200, ITX-5061, ID-12, or any combination thereof.
  19. 权利要求1-16中任一项所述的化合物或权利要求17-18中任一项所述的药物组合物在制备药物中的用途，所述药物用于预防、处理、治疗或减轻患者的HCV感染或丙型肝炎疾病。Use of a compound according to any one of claims 1 to 16 or a pharmaceutical composition according to any one of claims 17 to 18 for the preparation of a medicament for the prevention, treatment, treatment or alleviation of a patient HCV infection or hepatitis C disease.
  20. 权利要求1-16中任一项所述的化合物或权利要求17-18中任一项所述的药物组合物用于预防、处理、治疗或减轻患者的HCV感染或丙型肝炎疾病的用途。Use of a compound according to any one of claims 1 to 16 or a pharmaceutical composition according to any one of claims 17 to 18 for the prevention, treatment, treatment or alleviation of HCV infection or hepatitis C disease in a patient.
  21. 一种预防、处理、治疗或减轻患者的HCV感染或丙型肝炎疾病的方法，包括给予患者有效治疗量的权利要求1-16中任一项所述的化合物或权利要求17-18中任一项所述的药物组合物。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 according to any one of claims 1 to 16 or any one of claims 17-18 The pharmaceutical composition described in the above.
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Publication number Priority date Publication date Assignee Title
EP3771711A1 (en) 2019-07-29 2021-02-03 Bayer Animal Health GmbH Pyrazole derivatives for controlling arthropods
US20220023820A1 (en) * 2018-12-21 2022-01-27 Microsoft Technology Licensing, Llc Regulation of dna synthesis by nucleotides linked to protecting groups
WO2021262826A3 (en) * 2020-06-24 2022-02-17 Gilead Sciences, Inc. 1'-cyano nucleoside analogs and uses thereof
US11382926B2 (en) 2015-09-16 2022-07-12 Gilead Sciences, Inc. Methods for treating Arenaviridae and Coronaviridae virus infections
JP2022532520A (en) * 2019-05-03 2022-07-15 ターンズ・ファーマシューティカルズ・インコーポレイテッド Compounds for treating cancer
US11491169B2 (en) 2020-05-29 2022-11-08 Gilead Sciences, Inc. Remdesivir treatment methods
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
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 (en) * 2022-08-11 2024-02-15 广东东阳光药业股份有限公司 Crystal form of hepatitis c inhibitor and use thereof in drug
US11975017B2 (en) 2017-07-11 2024-05-07 Gilead Sciences, Inc. Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections
US12357577B1 (en) 2024-02-02 2025-07-15 Gilead Sciences, Inc. Pharmaceutical formulations and uses thereof
US12398412B2 (en) 2019-08-16 2025-08-26 Microsoft Technology Licensing, Llc Regulation of polymerase using cofactor oxidation states

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110003171B (en) * 2019-04-12 2020-11-06 清华大学 Small molecule reversible BTK inhibitors for the treatment of rheumatoid arthritis
CN111118073B (en) * 2019-12-27 2022-02-15 宜昌东阳光生化制药有限公司 Method for synthesizing intermediate of ezetimivir by enzyme method
CN116947947A (en) * 2022-04-20 2023-10-27 中国科学院上海药物研究所 Antiviral nucleoside analogs and pharmaceutical compositions and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105348345A (en) * 2015-12-15 2016-02-24 杭州和正医药有限公司 Prodrug containing tiopronin structure, preparation method of prodrug, pharmaceutical composition and application of pharmaceutical composition
CN106188193A (en) * 2015-05-07 2016-12-07 苏州旺山旺水生物医药有限公司 (2`R)-2`-deoxidation-2`-halo-2`-MU glycoside derivates, Preparation Method And The Use

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015054465A1 (en) * 2013-10-11 2015-04-16 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106188193A (en) * 2015-05-07 2016-12-07 苏州旺山旺水生物医药有限公司 (2`R)-2`-deoxidation-2`-halo-2`-MU glycoside derivates, Preparation Method And The Use
CN105348345A (en) * 2015-12-15 2016-02-24 杭州和正医药有限公司 Prodrug containing tiopronin structure, preparation method of prodrug, pharmaceutical composition and application of pharmaceutical composition

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* Cited by examiner, † Cited by third party
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US11382926B2 (en) 2015-09-16 2022-07-12 Gilead Sciences, Inc. Methods for treating Arenaviridae and Coronaviridae virus infections
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
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
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
US12415171B2 (en) * 2018-12-21 2025-09-16 Microsoft Technology Licensing, Llc Regulation of DNA synthesis by nucleotides linked to protecting groups
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US12012431B2 (en) 2020-03-12 2024-06-18 Gilead Sciences, Inc. Methods of preparing 1′-cyano nucleosides
US11613553B2 (en) 2020-03-12 2023-03-28 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
US11491169B2 (en) 2020-05-29 2022-11-08 Gilead Sciences, Inc. Remdesivir treatment methods
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