WO2018113652A1 - 核苷磷酸类化合物及其制备方法和用途 - Google Patents

核苷磷酸类化合物及其制备方法和用途 Download PDF

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WO2018113652A1
WO2018113652A1 PCT/CN2017/117126 CN2017117126W WO2018113652A1 WO 2018113652 A1 WO2018113652 A1 WO 2018113652A1 CN 2017117126 W CN2017117126 W CN 2017117126W WO 2018113652 A1 WO2018113652 A1 WO 2018113652A1
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group
substituted
unsubstituted
compound
alkyl
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PCT/CN2017/117126
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English (en)
French (fr)
Inventor
蔡家强
宋帅
田强
张毅涛
黄海涛
钟国庆
钟维
郝永佳
赵明亮
曾宏
宋宏梅
周信
刘瑶
谭玉婷
王利春
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to CA3041423A priority Critical patent/CA3041423A1/en
Priority to AU2017378959A priority patent/AU2017378959B2/en
Priority to CN201780065444.5A priority patent/CN109863160B/zh
Priority to EP17882690.5A priority patent/EP3560943A4/en
Priority to JP2019521829A priority patent/JP7151956B2/ja
Priority to US16/344,317 priority patent/US10899786B2/en
Publication of WO2018113652A1 publication Critical patent/WO2018113652A1/zh
Priority to PH12019550069A priority patent/PH12019550069A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine 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
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6524—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having four or more nitrogen atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/02—Phosphorylation
    • 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
    • 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
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a nucleoside phosphate compound, a pharmaceutical composition comprising the same, a process for the preparation thereof, and a NS5B polymerase inhibitor, a DNA polymerase inhibitor or a reverse transcriptase inhibitor for preventing or treating a viral disease or cancer Use in.
  • a virus consists of a nucleic acid molecule (DNA or RNA) or a protein (such as a prion).
  • the virus can cause a variety of infectious diseases. Common diseases caused by viruses include, but are not limited to, viral hepatitis A, hepatitis B, hepatitis C, influenza, herpes and acquired immunodeficiency syndrome. (AIDS).
  • Antiviral drugs currently in clinical use act by inhibiting virus attachment, husking, viral gene duplication, maturation or release, or by affecting the host's immune system, including RNA, DNA polymerase inhibitors, and reverse transcriptase inhibition. Agents and interferons.
  • Hepatitis C virus is a single-stranded, positive-stranded RNA virus belonging to the Flaviviridae family of Hepatitis virus. According to the gene encoding NS5B ribonucleic acid-dependent ribonucleic acid polymerase, hepatitis C virus is divided into 6 genotypes and 50 subtypes. Different genotypes are distributed globally. In North America and Europe, genotypes 1, 2, and 3 were found, with genotype 1 accounting for the majority. There are almost exclusively patients with type 4 and type 5 infections in Africa. Common genotypes in China are 1b and 2a, of which 1b is predominant, and type 6 is mainly found in Hong Kong and Macao (Simmonds, P.
  • genotype 1b of patients with cirrhosis and liver cancer was significantly higher than that of patients with chronic hepatitis.
  • Gene type 1b relapses with hepatitis C, and its liver disease is more severe than other genotypes.
  • the incidence of genotype 1a, 2a with hepatitis B infection was higher, and most (74%) patients with acute hepatitis were genotype 1a.
  • Genotype 4 infection is likely to cause decompensated liver complications.
  • Genotype 3a infection is closely related to fatty liver.
  • the standard treatment regimen is peginterferon plus ribavirin.
  • this therapy is only effective in 40-50% of genotype 1 patients and 75% of genotypes 2 and 3 (Zeuzem, S., et al. Journal of Viral Hepatitis, 2009, 16, 75-90).
  • peginterferon combined with ribavirin is not effective. Therefore, there is an urgent need to develop safe and effective "direct-acting antiviral drugs.”
  • the first generation of hepatitis C virus protease inhibitors, telaprevir and boceprevir, were introduced. The combination of these two drugs with peginterferon/ribavirin can improve the viral clearance rate and shorten the course of treatment in patients with genotype 1.
  • the HCV virion is a spherical single-stranded positive-strand RNA virus containing about 9600 polyproteins encoding and consisting of 3010 amino acids.
  • the genome sequence is: CE1E2/NS1NS2NS3NS4ANS4BNS5ANS5B.
  • the HCV viral polyprotein is cleaved into host independent viral proteins by host cell and viral autoprotease, including three structural proteins (ie, structural protein C, structural protein El and structural protein E2/NS1) and four non-structural proteins ( That is, the non-structural protein NS2, the non-structural protein NS3, the non-structural protein NS4, and the non-structural protein NS5).
  • the structural protein E1 and the structural protein E2/NS1 are glycoproteins, which can produce a neutralizing effect against HCV.
  • the non-structural protein NS provides a catalytic structure for viral replication.
  • the non-structural protein NS3 has helicase activity and is involved in the unwinding of HCV-RNA molecules, which in turn release NS5B, while NS5B is an RNA-dependent RNA polymerase (ie HCV NS5B polymerase) that is involved in the HCV replication cycle.
  • NS5B is an RNA-dependent RNA polymerase (ie HCV NS5B polymerase) that is involved in the HCV replication cycle.
  • the single-stranded viral RNA used as a template for the synthesis of double-stranded RNA. Therefore, if the compound can effectively inhibit the synthesis of double-stranded HCV RNA by inhibiting HCV NS5B polymerase, the HCV virus infection can be effectively controlled.
  • the nucleoside analog must be capable of being converted to a nucleoside triphosphate in order to inhibit the action of the viral polymerase. This process requires the participation of three different kinases.
  • the efficiency of phosphorylation determines the activity of nucleoside analogs as viral polymerase inhibitors. In addition, the activity of the inhibitor also depends on the time of the presence of the nucleoside triphosphate. The longer the nucleoside triphosphate is present, the higher the activity of the inhibitor.
  • nucleoside analogs and their monophosphates, diphosphate metabolites may not be good substrates for the corresponding kinases. Studies have shown that the first kinase is most selective for the substrate during phosphorylation.
  • the first step of phosphorylation is usually the most difficult step.
  • delivery of monophosphate to cells is a necessary means.
  • nucleoside monophosphates are negatively charged, hard to pass through the cell membrane, and are easily degraded by phosphatase.
  • Sofosbuvir is a hepatitis C virus (HCV) NS5B polymerase inhibitor. It is a uracil nucleotide analog having a nucleoside phosphoramidate structure. This structure gives this type of drug good cell permeability and plasma stability.
  • Cerbuvir can be metabolized by hepatocytes to the active component of uridine triphosphate analog, and competes with intracellular uridine triphosphate to insert into the newly generated nucleotide chain, so that the extension of RNA strand is terminated prematurely. Inhibition of the action of RNA polymerase (Journal of Medicinal Chemistry 2010, 53, 7202-7218).
  • nucleoside triphosphate production in the liver directly affects the inhibitory effect of the viral polymerase NS5B.
  • Sofibvir is less effective for patients with hepatitis C genotype 3 infection for 24 weeks; for patients with type 1, 2 and 4 infections, it still takes 12 weeks. Therefore, the invention of a more effective novel nucleoside phosphate derivative has significant significance and application value.
  • Hepatitis B virus a DNA virus belonging to the Hepadnaviridae family, relies on hepatitis B virus DNA polymerase for its DNA synthesis.
  • DNA polymerase inhibitors as anti-HBV drugs has become a very competitive option.
  • Tenofovir (PMPA) is a nucleotide DNA polymerase and a reverse transcriptase inhibitor with anti-HBV and HIV activity. Its phosphoramidate derivative, tenofovir alafenamide (TAF), has been approved by the FDA for the treatment of human immunodeficiency syndrome and hepatitis B virus.
  • TAF forms adenosine triphosphate analogs in hepatocytes by esterase hydrolysis, phosphorylation, etc., which inserts newly generated DNA strands, thereby blocking DNA polymerase-catalyzed DNA synthesis and inhibiting viral replication (WO2013025788A1; Nucleosides Nucleotides) Nucleic Acids, 2001, 20, 1085-1090).
  • Nucleoside anticancer drugs produce nucleoside triphosphates through phosphorylation and metabolism in the body. The latter is inserted into the DNA strand to inhibit DNA synthesis and prevent cell progression from G1 to S phase, resulting in G1 phase arrest of tumor cells. Thereby inhibiting the malignant proliferation of tumor cells (Oncology. 2002, 62(4), 354-362).
  • nucleoside drugs play an active role in the fields of antiviral and anticancer.
  • these drugs are used as nucleoside analogs to be absorbed and metabolized by cells in the body, and prevent RNA or DNA of viruses and tumor cells. synthesis.
  • the nucleoside triphosphate analog is an important active ingredient in the body metabolite, and its production rate, concentration and retention time determine the efficacy.
  • An aspect of the invention provides a nucleoside phosphate compound, a pharmaceutically acceptable salt, ester, solvate, isomer thereof, any crystal form or racemate thereof, a metabolite form thereof, or a mixture.
  • the compound is metabolized by liver tissue to produce a large amount of nucleoside triphosphate metabolites, and is rapidly converted to a nucleoside triphosphate metabolite.
  • the nucleoside phosphate compound of the present invention (hereinafter also referred to as “the compound of the present invention”) can be used as an NS5B polymerase inhibitor, a DNA polymerase inhibitor or a reverse transcriptase inhibitor, for use in, for example, a viral type C Treatment of diseases such as hepatitis (HCV), viral hepatitis B (HBV), viral hepatitis A (HAV), influenza, herpes, and acquired immunodeficiency syndrome (AIDS) or diseases such as cancer.
  • HCV hepatitis
  • HBV viral hepatitis B
  • HAV viral hepatitis A
  • influenza influenza
  • herpes and acquired immunodeficiency syndrome
  • AIDS acquired immunodeficiency syndrome
  • the compounds of the invention can be efficiently metabolized in vivo to be converted to active nucleoside triphosphate metabolites.
  • the compound of the present invention can be more efficiently converted to a nucleoside triphosphate metabolite than an existing (HCV) NS5B polymerase inhibitor, a hepatitis B virus DNA polymerase inhibitor, or a retroviral reverse transcriptase inhibitor. Therefore, it has more excellent activity.
  • the compound of the present invention has a structure represented by the following formula (I):
  • L is selected from a substituted or unsubstituted C 1-12 alkylene group, a C 2-12 alkenylene group, a C 2-12 alkynylene group, optionally an alkylene group, an alkenylene group or an alkynylene group. Interrupted by one or more -O-, -NR 8 - or -S-; or
  • L represents a group represented by the formula (c), the formula (d) or the formula (e), wherein Represents a single bond or a double bond, and is connected to Base at position 1 and to a phosphorus atom (P) at position 2:
  • Base represents a group represented by formula (a) or formula (b):
  • M represents N or NR 8 ;
  • W represents H, NR 8 R 9 , NR 8 , CH 2 , O or S;
  • Q represents O, S, NR 8 or CH 2 ;
  • Z each at a time, independently represents hydrogen, halogen, hydroxy, cyano, nitro, azide, NR 8 R 9 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1 a -6 alkoxy group or a substituted or unsubstituted C 3-8 cycloalkyl group, which may be the same or different if a plurality of Z are present;
  • p 0, 1, 2, 3, 4 or 5;
  • U represents O, S, NR 8 or CR 10 R 11 ;
  • E represents CR 10 , CR 10 R 11 or S, provided that when E is double-bonded, it is CR 10 ;
  • G each independently represents hydrogen, halogen, hydroxy, cyano, nitro, azide, NR 8 R 9 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1 a -6 alkoxy group or a substituted or unsubstituted C 3-8 cycloalkyl group, which may be the same or different if a plurality of G are present;
  • q represents an integer from 0 to 5;
  • Ar 1 represents a C 6-14 aryl group or a 5-14 membered heteroaryl group
  • R 1 each independently represents hydrogen, halogen, -OH, -CN, -NO 2 , -NR 8 R 9 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1 -6 alkoxy, substituted or unsubstituted C 1-6 haloalkyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3 a 10-membered heterocycloalkyl group, a substituted or unsubstituted C 2-10 alkenyl group, or a substituted or unsubstituted C 2-10 alkynyl group, each of which may be the same or different if a plurality of R 1 are present;
  • n an integer from 0 to 7;
  • X represents CH 2 , -S-, -O- or -NR 8 -;
  • R 2 and R 3 each independently represent hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted C 7-20 aralkyl, or substituted or unsubstituted C 3-8 cycloalkyl; or R 2 and R 3 together with the attached carbon atom form a substituted or unsubstituted C a 3-8 cycloalkyl group or a substituted or unsubstituted 3-10 membered heterocycloalkyl group;
  • R 4 and R 5 each independently represent hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted C 7-20 aralkyl, or substituted or unsubstituted C 3-8 cycloalkyl; or R 4 and R 5 together with the attached carbon atom form a substituted or unsubstituted C a 3-8 cycloalkyl group or a substituted or unsubstituted 3-10 membered heterocycloalkyl group;
  • R 3 and R 4 are bonded to each other, together with the carbon atom to which they are attached, to form a substituted or unsubstituted C 3-8 cycloalkyl group or a substituted or unsubstituted 3-10 membered heterocycloalkyl group;
  • R 6 represents hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 6-14 aryl, substituted or unsubstituted C 7- 20 aralkyl or substituted or unsubstituted C 1-6 alkoxy;
  • R 7 each independently represents hydrogen, halogen, -OH, -CN, -NO 2 , -NR 8 R 9 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1 -6 haloalkyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted a C 2-10 alkynyl group, or a substituted or unsubstituted C 1-6 alkoxy group, which may be the same or different if a plurality of R 7 are present; or
  • R 6 and R 7 are bonded to each other together with a carbon atom spaced therebetween to form a substituted or unsubstituted C 3-8 carbocyclic group or a 3-10 membered heterocyclic group;
  • n an integer from 0-7;
  • Ar 2 represents a C 6-14 aryl group or a 5-14 membered heteroaryl group
  • r and s each independently represent 1, 2 or 3;
  • R 8 and R 9 each independently represent hydrogen, a substituted or unsubstituted C 1-6 alkyl group, or a substituted or unsubstituted C 3-8 cycloalkyl group, if present, a plurality of R 8 , R 9 , each of which may be the same or different; and
  • R 10 and R 11 each independently represent hydrogen, a substituted or unsubstituted C 1-6 alkyl group, or a substituted or unsubstituted C 3-8 cycloalkyl group, or R 10 and R 11 are formed together.
  • the C 1-6 alkylene group may be the same or different if a plurality of R 10 and R 11 are present.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, a pharmaceutically acceptable salt, ester, solvate, isomer thereof, any crystal form or racemate thereof, and their metabolism A form, or a mixture thereof, wherein the pharmaceutical composition is in the form of a solid preparation, a semisolid preparation, a liquid preparation, or a gaseous preparation.
  • Another aspect of the invention provides a compound of the invention, a pharmaceutically acceptable salt, ester, solvate, isomer thereof, any crystal form or racemate thereof, a metabolite form thereof, or a mixture thereof, Or the use of a pharmaceutical composition of the invention in the manufacture of a medicament for the prevention or treatment of a NS5B polymerase mediated disease, a DNA polymerase mediated disease or a reverse transcriptase mediated disease.
  • Another aspect of the invention provides a compound of the invention, a pharmaceutically acceptable salt, ester, solvate, isomer thereof, any crystal form or racemate thereof, a metabolite form thereof, or a mixture thereof, Or the use of the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating a viral disease or cancer.
  • Another aspect of the invention provides a compound of the invention, a pharmaceutically acceptable salt, ester, solvate, isomer thereof, any crystal form or racemate thereof, a metabolite form thereof, or a mixture thereof, Or a pharmaceutical composition of the invention for use in preventing or treating a NS5B polymerase mediated disease, a DNA polymerase mediated disease or a reverse transcriptase mediated disease.
  • the compound of the above formula (I) of the present invention a pharmaceutically acceptable salt, ester, solvate, isomer thereof, any crystal form or racemate thereof, or their metabolism A form of the form, or a mixture thereof, or a pharmaceutical composition of the present invention for use in the prevention or treatment of a viral disease or cancer.
  • Another aspect of the invention provides a method of preventing or treating an NS5B polymerase mediated disease, a DNA polymerase mediated disease or a reverse transcriptase mediated disease, comprising administering to an individual in need thereof an effective amount of the present invention
  • a method of preventing or treating a viral disease or cancer which comprises administering to an individual in need thereof an effective amount of a compound of the invention, a pharmaceutically acceptable salt, ester, solvate thereof, isomer thereof Any of their crystal forms or racemates, their metabolite forms, or mixtures thereof, or a pharmaceutical composition of the invention.
  • Another aspect of the invention provides a method of making a compound of the invention comprising the steps of:
  • Step 1 reacting the phosphorus oxyhalide represented by Formula 2 with the compound represented by Formula 1 to obtain a compound represented by Formula 3;
  • Step 2 reacting a compound represented by Formula 3 with a compound represented by Formula 4 to obtain a compound represented by Formula 5;
  • Step 3 reacting a compound represented by Formula 5 with pentafluorophenol represented by Formula 6 to obtain a compound represented by Formula 7;
  • Step 4 reacting a compound represented by Formula 7 with a compound represented by Formula 8 to obtain a compound represented by Formula (I);
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n, s, r, X, Ar 1 , Ar 2 , L and Base are as defined above;
  • Y are the same or different from each other, and are each independently selected from a halogen
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n, s, r, X, Ar 1 , Ar 2 , L and Base are as defined above;
  • the route 3 is a synthesis method of a phosphorus chiral pure compound (I)
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n, s, r, X, Ar 1 , Ar 2 , L and Base are as defined above.
  • the combination of substituents and variables is only allowed if such a combination can bring about a chemically stable compound.
  • substituent itself is substituted by two or more groups, these plural groups may exist in the same carbon or different carbon as long as a stable structure can be produced.
  • the subscript numeral of the carbon atom "C” represents the number of carbon atoms, for example, C 1 represents 1 carbon atom, C 2 represents 2 carbon atoms, and C pq represents pq (0 ⁇ p ⁇ q) carbon atom.
  • the group name attached to the carbon atom "C” indicates the kind of the group.
  • C 1 alkyl represents a methyl group
  • C 2 alkenyl represents a vinyl group
  • C pq alkyl represents an alkyl group having a carbon number of pq.
  • halo or halogen as used herein means fluoro, chloro, bromo or iodo.
  • C 1-6 alkyl refers to a linear or branched aliphatic saturated hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include methyl group, ethyl group, and n-propyl group.
  • Base isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and the like.
  • an alkyl group having 1 to 4 carbon atoms i.e., a C 1-4 alkyl group
  • examples thereof include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, and the like.
  • C 1-6 alkoxy refers to a straight-chain or branched aliphatic saturated hydrocarbonoxy group having an alkyl moiety of the above-mentioned "C 1-6 alkyl group", for example, a Oxyl, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, hexyloxy and the like.
  • Preferred is a C 1-4 alkoxy group.
  • C 1-6 alkylene refers to two formed by the loss of one hydrogen atom from two different carbon atoms of a linear or branched "C 1-6 alkane”.
  • Price group For example, a methylene group (-CH 2 -), an ethylene group (dimethylene group, -CH 2 CH 2 -), a propylene group (trimethylene group, -CH 2 CH 2 CH 2 -), and a butyl group can be cited.
  • isobutylene -CH 2 CH(CH 3 )CH 2 -
  • a C 1-4 alkylene group is preferred, and a C 1-3 alkylene group is more preferred.
  • C1-6 alkylene refers to a divalent radical formed by the loss of two hydrogen atoms from the same carbon atom of a linear or branched " C1-6 alkane”. group.
  • a C 1-4 methylene group is preferred, and a C 1-3 methylene group is more preferred.
  • C 2-10 alkenyl refers to a linear or branched aliphatic hydrocarbon group having 2 to 10 carbon atoms having one or more unsaturated double bonds, and examples thereof include ethylene.
  • Base 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-buten-1-yl, 3-buten-1-yl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 5-hexen-1-yl, 4-hexen-1-yl, 3-hexene- 1-yl, 2-hexen-1-yl, 3-methyl-2-buten-1-yl, 3-methyl-3-penten-1-yl, 3-methyl-2-pentene 1-yl, 4-methyl-3-penten-1-yl, 4-methyl-2-penten-1-yl, 2-methyl-2-penten-1-yl and the like. It is preferred to have one double bond.
  • Preferred is a C 2-6 alkeny
  • C 2-10 alkynyl means a straight or branched aliphatic hydrocarbon group having 2 to 10 carbon atoms having one or more unsaturated triple bonds, and examples thereof include acetylene. , 1-propyn-1-yl, 2-propyn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl, 2-pentyn-1-yl, 3-pentyl Alkyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl, 4-hexyn-1-yl, 3-hexyn-1-yl and 2-hexyn-1-yl Wait. It is preferred to have one triple bond. Preferred is a C 2-6 alkynyl group.
  • C 3-8 cycloalkyl means a cyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. , cycloheptyl and the like. Preferred is a C 3-4 cycloalkyl group, and examples thereof include a cyclopropyl group or a cyclobutyl group.
  • C 4-8 cycloalkyl means a cycloalkyl group having 4 to 8 carbon atoms. In some cases, the cycloalkyl group can be fused to an aryl or heteroaryl group.
  • C 3-8 heterocycloalkyl refers to a group further comprising at least one hetero atom selected from N, O and S on the ring of the above-mentioned "C 3-8 cycloalkyl". Examples thereof include oxetanyl, azetidinyl, thietane, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, dioxoalkyl, piperidinyl, piperazinyl, and tetra. Hydropyranyl and the like. It is preferred to have one hetero atom selected from N, O and S in the C 3-8 cycloalkyl group. Preferred is C 3-6 heterocycloalkyl.
  • C 4-8 heterocycloalkyl means a heterocycloalkyl group having 4 to 8 carbon atoms.
  • the term “3-10 membered heterocycloalkyl” refers to a heterocycloalkyl group having 3 to 10 ring atoms including at least one hetero atom selected from N, O and S; the term “4-10 membered heterocyclic ring""Alkyl” means a heterocycloalkyl group having 4 to 10 ring atoms including at least one hetero atom selected from N, O and S. In some cases, the heterocycloalkyl group is fused to an aryl or heteroaryl group.
  • aralkyl denotes an aryl-substituted alkyl group, wherein the aryl group and the alkyl group are as defined herein.
  • the aryl group can have from 6 to 14 carbon atoms and the alkyl group can have from 1 to 6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl, and the like.
  • alkylthio refers to an alkyl group, as defined above, appended to the parent molecular moiety through a sulfur atom.
  • Representative examples of C1-6 alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, hexylthio, and the like.
  • C 4-8 carbocyclyl refers to a cyclic group having 4 to 8 carbon atoms which may be a saturated ring or an unsaturated ring. In the case of a saturated ring, it corresponds to a cycloalkyl group having 4 to 8 carbon atoms.
  • the unsaturated ring may include a C 4-8 cycloalkenyl group which is a cyclic hydrocarbon group having 4 to 8 carbon atoms having at least one unsaturated double bond in the ring, and examples thereof include a cyclopentenyl group and a ring.
  • the cyclohexynyl group, the cycloheptynyl group and the like may be mentioned; and it may also be an aromatic C 4-8 carbocyclic group such as a phenyl group.
  • C 4-8 heterocyclyl refers to a group further comprising at least one hetero atom selected from N, O and S on the ring of the above C 4-8 carbocyclic group, which may It is a saturated ring or an unsaturated ring. In the case of a saturated ring, it corresponds to a heterocycloalkyl group having 4 to 8 carbon atoms. In the case of the unsaturated ring, it is a group having at least one unsaturated double bond and/or an unsaturated triple bond at any position of the above heterocycloalkyl group having 4 to 8 carbon atoms, and for example, an imidazoline may be mentioned.
  • C 6-10 aryl refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 8 carbon atoms such as phenyl, 1-naphthyl, 2-naphthyl and the like.
  • C 3-10 heteroaryl refers to an aromatic 5- or 5- to 10- membered aromatic ring containing at least one hetero atom selected from N, O and S in at least one ring.
  • Each ring of the hetero atom-containing heteroaryl group may have 1 or 2 oxygen or sulfur atoms and/or 1 to 4 nitrogen atoms, provided that the total number of hetero atoms in each ring is 4 or less and each ring has At least one carbon atom.
  • the nitrogen and sulfur atoms can be optionally oxidized, and the nitrogen atom can optionally be quaternized.
  • Examples of the monocyclic heteroaryl group include a pyrrolyl group, a pyrazolyl group, a pyrazolinyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a furyl group, a thienyl group, a pyridyl group, and the like. Pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.
  • bicyclic heteroaryl group examples include a mercapto group, a benzothiazolyl group, a benzodioxolyl group, a benzoxazolyl group, a benzothienyl group, a quinolyl group, and a tetrahydroisoquinolyl group.
  • the term "5-6 membered heteroaryl” means a heteroaryl group having 5 or 6 ring atoms including at least one hetero atom selected from N, O and S, and examples thereof include pyrrolyl group, pyrazolyl group, Pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, etc.;
  • the "5-14 membered heteroaryl group” means a heteroaryl group having 5 to 14 ring atoms including at least one hetero atom selected from N, O and S.
  • the substituent of the cyclic group, the “C 6-10 aryl group” and the “C 3-10 heteroaryl group” may, for example, be one or more of the same or different groups selected from the group consisting of a cyano group, a hydroxyl group, and a carboxyl group.
  • halogen F, Cl, Br, I
  • C 1-6 alkyl halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy (eg CF 3 O), C 3-6 naphthenic a group (e.g., cyclopropyl), a C 1-6 alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, etc.), a C 2-10 alkenyloxy group (e.g., a vinyloxy group, Allyloxy, etc.), C 1-6 alkoxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), nitro, nitroso, azide, amino, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, aminocarbonyl C 1-6 alkyl, C 1-6 alkylaminocarbonyl C 1-6 alkyl, aminocarbonyloxy, amino C 1-6 alkoxycarbonyl,
  • the above substituent is preferably selected from the group consisting of halogen, cyano, nitro, carboxyl, hydroxy, amino, aminocarbonyl, azide, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy , C 1-6 alkoxycarbonyl, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylaminosulfonyl, C 1- 6 alkylsulfonylamino, C 1-6 alkylamino, C 1-6 alkylcarbonyloxy, C 1-6 alkylaminocarbonyl, aminocarbonylamino, C 1-6 alkylaminocarbonylamino, aminocarbonyl C 1-6 alkyl, C 1-6 alkylaminocarbonylamino, aminocarbonyl C 1-6 alkyl, C 1-6 alkylaminocarbonylamino, aminocarbonyl C 1-6 alkyl
  • the substituents of the substituents may be derived from any suitable position of the substituent, unless otherwise indicated.
  • the invention also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but the atomic mass or mass number differs from the atomic mass prevailing in nature. Or atomic substitution of mass.
  • isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., 2 H, 3 H, preferably 2 H); isotopes of carbon (e.g., 11 C, 13 C, and 14 C); chlorine Isotopes (eg 36 Cl); isotopes of fluorine (eg 18 F); isotopes of iodine (eg 123 I and 125 I); isotopes of nitrogen (eg 13 N and 15 N); isotopes of oxygen (eg 15 O, 17) O and 18 O); phosphorus isotopes (eg 32 P); and sulfur isotopes (eg 35 S).
  • isotopes of hydrogen e.g., 2 H, 3 H, preferably 2 H
  • isotopes of carbon e.g., 11 C, 13 C, and 14 C
  • chlorine Isotopes eg 36 Cl
  • Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies (e.g., assays).
  • the radioisotope ruthenium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose because of their ease of incorporation and ease of detection.
  • Substitution with positron emitting isotopes eg, 11 C, 18 F, 15 O, and 13 N
  • PET positron emission tomography
  • Isotopically labeled compounds of the invention can be prepared by replacing the previously employed non-labeled reagents with suitable isotopically labeled reagents by methods analogous to those described in the accompanying routes and/or examples and preparations.
  • the pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be substituted with an isotope, for example, D 2 O, acetone-d 6 or DMSO-d 6 .
  • Solid lines can be used in this article Wavy line Solid wedge Virtual wedge
  • the chemical bonds of the compounds of the invention are depicted.
  • the use of solid lines to delineate linkages to an asymmetric atom is intended to include all possible stereoisomers at the atom (eg, specific enantiomers, racemic mixtures, etc.).
  • Using a wavy line to depict a bond that is bonded to an asymmetric atom the bond is a solid wedge Virtual wedge Any of the keys.
  • the use of a solid or virtual wedge to characterize a bond to an asymmetric atom is intended to indicate that the stereoisomer shown is present. When present in a racemic mixture, solid and virtual wedges are used to define relative stereochemistry rather than absolute stereochemistry.
  • the compounds of the invention are intended to be stereoisomers (including cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof exist.
  • the compounds of the invention may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).
  • the compounds of the present invention contain one or more asymmetric centers, thereby being capable of racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers, and the like. Form exists.
  • the invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which can be directly administered to a patient in need thereof
  • the compound of the invention or a metabolite or residue thereof is provided indirectly or indirectly.
  • a compound of the invention it is also intended to encompass the various derivative forms described above for the compound.
  • the "pharmaceutically acceptable salt” of the compound of the present invention comprises a salt formed with a mineral acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, or nitric acid, or with acetic acid, benzoic acid, oxalic acid, lactic acid, malic acid, tartaric acid, Fumaric acid, maleic acid, citric acid, malonic acid, mandelic acid, gluconic acid, galactonic acid, glucoheptonic acid, glycolic acid, glutamic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, a salt formed of an organic acid such as benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, or naphthalene-2-sulfonic acid, or a lithium ion, a sodium ion, a potassium ion, a calcium ion, a magnesium
  • a salt formed by one or more metal ions or with ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylcyclohexylamine, 2-aminoethanol, benzathine a salt formed by an amine. It is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • the conversion from the free body to the salt can be carried out by existing methods.
  • esters means an ester derived from a compound of the formulae herein, which includes a physiologically hydrolyzable ester (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the invention). Compound).
  • the compounds of the invention may also be esters per se.
  • the compound of the present invention may exist in the form of a solvate (preferably a hydrate) wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • the amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.
  • metabolites of the compounds of the invention i.e., substances formed in vivo upon administration of a compound of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidization, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolic product thereof.
  • the invention further includes within its scope prodrugs of the compounds of the invention which are certain derivatives of the compounds of the invention which may themselves have less or no pharmacological activity, when administered to or into the body It can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by EBRoche, American Pharmaceutical Association).
  • Prodrugs of the invention may, for example, be known by those skilled in the art as “pro-moiety” (e.g., “Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" It is prepared in place of the appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention containing a protecting group.
  • a protecting group In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention. This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protecting groups, which are incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art.
  • L is selected from a substituted or unsubstituted C 1 - 12 alkylene group, a C 2 - 12 alkenylene group, a C 2-12 alkynylene group, optionally an alkylene group, an alkenylene group or an alkynylene group. Interrupted by one or more -O-, -NR 8 - or -S-; or
  • L represents a group represented by the formula (c), the formula (d) or the formula (e), wherein Represents a single bond or a double bond, and is connected to Base at position 1 and to a phosphorus atom (P) at position 2:
  • Base represents a group represented by formula (a) or formula (b):
  • M represents N or NR 8 ;
  • W represents H, NR 8 R 9 , NR 8 , CH 2 , O or S;
  • Q represents O, S, NR 8 or CH 2 ;
  • Z each at a time, independently represents hydrogen, halogen, hydroxy, cyano, nitro, azide, NR 8 R 9 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1 a -6 alkoxy group or a substituted or unsubstituted C 3-8 cycloalkyl group, which may be the same or different if a plurality of Z are present;
  • p 0, 1, 2, 3, 4 or 5;
  • U represents O, S, NR 8 or CR 10 R 11 ;
  • E represents CR 10 , CR 10 R 11 or S, provided that when E is double-bonded, it is CR 10 ;
  • G each independently represents hydrogen, halogen, hydroxy, cyano, nitro, azide, NR 8 R 9 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1 a -6 alkoxy group or a substituted or unsubstituted C 3-8 cycloalkyl group, which may be the same or different if a plurality of G are present;
  • q represents an integer from 0 to 5;
  • Ar 1 represents a C 6-14 aryl group or a 5-14 membered heteroaryl group
  • R 1 each independently represents hydrogen, halogen, -OH, -CN, -NO 2 , -N R 8 R 9 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1 -6 alkoxy, substituted or unsubstituted C 1-6 haloalkyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3 a 10-membered heterocycloalkyl group, a substituted or unsubstituted C 2-10 alkenyl group, or a substituted or unsubstituted C 2-10 alkynyl group, each of which may be the same or different if a plurality of R 1 are present;
  • n an integer from 0 to 7;
  • X represents CH 2 , -S-, -O- or -NR 8 -;
  • R 2 and R 3 each independently represent hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted C 7-20 aralkyl, or substituted or unsubstituted C 3-8 cycloalkyl; or R 2 and R 3 together with the attached carbon atom form a substituted or unsubstituted C a 3-8 cycloalkyl group or a substituted or unsubstituted 3-10 membered heterocycloalkyl group;
  • R 4 and R 5 each independently represent hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted C 7-20 aralkyl, or substituted or unsubstituted C 3-8 cycloalkyl; or R 4 and R 5 together with the attached carbon atom form a substituted or unsubstituted C a 3-8 cycloalkyl group or a substituted or unsubstituted 3-10 membered heterocycloalkyl group;
  • R 3 and R 4 are bonded to each other, together with the carbon atom to which they are attached, to form a substituted or unsubstituted C 3-8 cycloalkyl group or a substituted or unsubstituted 3-10 membered heterocycloalkyl group;
  • R 6 represents hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 6-14 aryl, substituted or unsubstituted C 7- 20 aralkyl or substituted or unsubstituted C 1-6 alkoxy;
  • R 7 each independently represents hydrogen, halogen, -OH, -CN, -NO 2 , -NR 8 R 9 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1 -6 haloalkyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl, substituted or unsubstituted a C 2-10 alkynyl group, or a substituted or unsubstituted C 1-6 alkoxy group, which may be the same or different if a plurality of R 7 are present; or
  • R 6 and R 7 are bonded to each other together with a carbon atom spaced therebetween to form a substituted or unsubstituted C 3-8 carbocyclic group or a 3-10 membered heterocyclic group;
  • n an integer from 0-7;
  • Ar 2 represents a C 6-14 aryl group or a 5-14 membered heteroaryl group
  • r and s each independently represent 1, 2 or 3;
  • R 8 and R 9 each independently represent hydrogen, a substituted or unsubstituted C 1-6 alkyl group, or a substituted or unsubstituted C 3-8 cycloalkyl group, if present, a plurality of R 8 , R 9 , each of which may be the same or different; and
  • R 10 and R 11 each independently represent hydrogen, a substituted or unsubstituted C 1-6 alkyl group, or a substituted or unsubstituted C 3-8 cycloalkyl group, or R 10 and R 11 are formed together.
  • the C 1-6 alkylene group may be the same or different if a plurality of R 10 and R 11 are present.
  • the compound of the invention is a compound of formula (Ia):
  • L-Base represents a group represented by the following formula (f) or formula (g):
  • Base represents a group represented by the following formula (a) or formula (b):
  • M represents N or NR 8 ;
  • W represents NR 8 R 9 or O
  • Q represents O or S
  • Z in each occurrence independently represents hydrogen, halogen, NR 8 R 9 , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy or substituted or unsubstituted C 3-8 cycloalkyl, if there are multiple Z, they may be the same or different;
  • p represents an integer of 0 to 2;
  • U represents O, S or CR 10 R 11 ;
  • E represents CR 10 , CR 10 R 11 or S, provided that when E is double-bonded, it is CR 10 ;
  • G each independently represents hydrogen, halogen, hydroxy, azido, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy or substituted or unsubstituted a C 3-8 cycloalkyl group, which may be the same or different if a plurality of G are present;
  • q represents an integer from 0 to 4.
  • A represents a substituted or unsubstituted C 1-6 alkylene group
  • B represents a substituted or unsubstituted C 1-6 alkylene group
  • D represents O, S or NR 8 ;
  • Ar 1 represents a C 6-10 aryl group or a C 3-10 heteroaryl group
  • R 1 each independently represents hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 3-8 ring
  • n an integer from 0 to 7;
  • X represents -O- or -NR 8 -;
  • R 2 and R 3 each independently represent hydrogen, a substituted or unsubstituted C 1-6 alkyl group, a substituted or unsubstituted C 3-8 cycloalkyl group; or R 2 and R 3 together with the attached carbon atom a substituted or unsubstituted C 3-8 cycloalkyl group or a substituted or unsubstituted C 3-8 heterocycloalkyl group;
  • R 4 and R 5 each independently represent hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-8 cycloalkyl; or R 4 and R 5 are taken together with the attached carbon atom. a substituted or unsubstituted C 3-8 cycloalkyl group or a substituted or unsubstituted C 3-8 heterocycloalkyl group;
  • R 3 and R 4 are bonded to each other, together with the carbon atom to which they are attached, to form a substituted or unsubstituted C 4-8 cycloalkyl group or a substituted or unsubstituted C 4-8 heterocycloalkyl group;
  • R 6 represents hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, or substituted or unsubstituted C 1-6 alkoxy;
  • R 7 each independently represents hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, or substituted or unsubstituted C 1-6 Alkoxy group, if a plurality of R 7 are present, each of them may be the same or different; or
  • R 6 and R 7 are bonded to each other together with a carbon atom spaced therebetween to form a substituted or unsubstituted C 4-8 carbocyclic group or a C 4-8 heterocyclic group;
  • n an integer from 0 to 7;
  • Ar 2 represents a C 6-10 aryl group or a C 3-10 heteroaryl group
  • R 8 and R 9 each independently represent hydrogen, a substituted or unsubstituted C 1-6 alkyl group, or a substituted or unsubstituted C 3-8 cycloalkyl group, if present, a plurality of R 8 , R 9 , each of them can be the same or different.
  • R 10 and R 11 each independently represent hydrogen, a substituted or unsubstituted C 1-6 alkyl group, or a substituted or unsubstituted C 3-8 cycloalkyl group, or R 10 and R 11 are formed together.
  • the C 1-6 alkylene group may be the same or different if a plurality of R 10 and R 11 are present.
  • the present invention provides a compound represented by the above formula (I), a pharmaceutically acceptable salt, ester, solvate, isomer thereof, any crystal form or racemate thereof, or a Metabolite form, or a mixture thereof,
  • Base is selected from:
  • L is selected from C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, optionally substituted by one or more G, said alkylene, alkenylene or alkyne
  • the base is optionally interrupted by one or more -O-, -NR 8 - or -S-;
  • X, U, W, and Q are each independently selected from CH 2 , O, S, and NR 8 at each occurrence;
  • G and Z are each independently selected from the group consisting of halogen, -OH, -CN, -NO 2 , -NR 8 R 9 , -N 3 , C 1-6 alkyl and C 3-6 cycloalkyl;
  • Each occurrence of p, q is independently 0, 1, 2, 3, 4 or 5, provided that p is not greater than the number of positions on the corresponding group that can be substituted and is not greater than the corresponding group can be substituted
  • Ar 1 and Ar 2 are each independently selected from a C 6-14 aryl group and a 5-14 membered heteroaryl group;
  • n are each independently selected from 1, 2, 3, 4 or 5, preferably 1 or 2;
  • R 1 and R 7 are each independently selected from the group consisting of hydrogen, halogen, -OH, -CN, -NO 2 , -NR 8 R 9 , C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 Alkoxy, C 1-6 alkylthio, C 3-6 cycloalkyl, 3-10 membered heterocycloalkyl, and C 2-6 alkynyl;
  • R 8 and R 9 each independently represent hydrogen, C 1-6 alkyl and C 3-6 cycloalkyl at each occurrence;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 6-14 aryl and C 7-20 aralkyl.
  • the alkyl, cycloalkyl, alkoxy, aryl and aralkyl groups are each optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN and -NO 2 ;
  • R 2 and R 3 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group or a 3-10 membered heterocycloalkyl group;
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 6-14 aryl and C 7-20 aralkyl.
  • the alkyl, cycloalkyl, alkoxy, aryl and aralkyl groups are each optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN and -NO 2 ;
  • R 4 and R 5 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group or a 3-10 membered heterocycloalkyl group;
  • R 3 and R 4 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group or a 3-10 membered heterocycloalkyl group;
  • R 6 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 6-14 aryl and C 7-20 aralkyl, said alkyl, ring
  • the alkyl, alkoxy, aryl and aralkyl groups are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -CN and -NO 2 ;
  • R 6 and R 7 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or 3-10 membered heterocycloalkyl fused to Ar 2 ; preferably, R 6 and R 7 are attached thereto
  • R 8 is hydrogen, C 1-6 alkyl or C 3-8 cycloalkyl. In some preferred embodiments, R 8 is hydrogen, methyl, ethyl, propyl or cyclopropyl.
  • R 9 is hydrogen, C 1-6 alkyl or C 3-8 cycloalkyl. In some preferred embodiments, R 9 is hydrogen, methyl, ethyl, propyl or cyclopropyl. In some particularly preferred embodiments, R 9 is hydrogen.
  • Z is each independently hydrogen, halogen, NR 8 R 9 or C 1-6 alkyl at each occurrence.
  • Z is each independently hydrogen, fluorine, chlorine, methyl, ethyl or propyl.
  • p is 0, 1, 2, 3 or 4.
  • R 10 and R 11 are each independently hydrogen, C 1-6 alkyl or C 3-8 cycloalkyl, or R 10 and R 11 together form C 1- 6 alkylene.
  • R 10 and R 11 are each independently hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or R 10 and R, each occurrence. 11 together form a methylene or ethylene group.
  • U is O or S. In some preferred embodiments, U is O.
  • E is CH 2 .
  • each at each occurrence of G is independently hydrogen, halogen, hydroxy, azido or C1-6 alkyl. In some preferred embodiments, each at each occurrence of G is independently hydrogen, fluoro, chloro, hydroxy, methyl, ethyl, propyl, butyl or azide.
  • q is 0, 1, 2, 3 or 4.
  • A is a C 1-3 alkylene group that is unsubstituted or substituted with a C 1-3 alkyl group.
  • A is a methylene, ethylene or isopropenyl group.
  • B is a C 1-3 alkylene group that is unsubstituted or substituted with a C 1-3 alkyl group.
  • B is ethylene or isopropenyl.
  • D is O.
  • Base is a group of the formula:
  • L is selected from the group consisting of:
  • One of the positions is connected to B, and the second position is connected to the phosphorus atom (P).
  • L-Base is a group of the formula:
  • X is NH, NC 1-6 alkyl (eg N-methyl) or O. In some preferred embodiments, X is NH.
  • Ar 1 is phenyl, 1-naphthyl, 2-naphthyl or a 5-6 membered heteroaryl (such as thienyl, pyridyl or pyrazolyl).
  • Ar 2 is phenyl, 1-naphthyl, 2-naphthyl or 5-6 membered heteroaryl (eg thienyl, pyridyl or pyrazolyl).
  • R 1 is each independently hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy at each occurrence.
  • R 1 is each independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl or propyl.
  • m is 0, 1, 2, 3 or 4.
  • R 2 and R 3 are each independently hydrogen or C 1-6 alkyl at each occurrence. In some preferred embodiments, each occurrence of R 2 and R 3 is independently hydrogen, methyl, ethyl or propyl.
  • R 2 and R 3 together with the attached carbon atom form a C 3-8 cycloalkyl group.
  • R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.
  • R 4 and R 5 are each independently hydrogen or C 1-6 alkyl at each occurrence. In some preferred embodiments, each occurrence of R 4 and R 5 is independently hydrogen, methyl, ethyl or propyl.
  • R 6 is hydrogen, C 1-6 alkyl or C 3-8 cycloalkyl. In some preferred embodiments, R 6 is hydrogen, methyl, ethyl, propyl, cyclopropyl or cyclobutyl.
  • each occurrence of R 7 is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl or C 1-6 alkoxy. In some preferred embodiments, each occurrence of R 7 is independently hydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, t-butyl, methoxy, cyclopropyl or cyclobutyl. base.
  • n 0, 1, 2, 3 or 4.
  • the compound of the invention is a compound of formula (II),
  • R 1 , R 2 , R 3 , R 6 , R 7 , m, n, Ar 1 and Ar 2 are as defined above.
  • the compound of the invention is a compound of formula (IIa),
  • R 1 , R 2 , R 3 , R 6 and R 7 and m and n are as defined above.
  • the compound of the invention is a compound of formula (IIb),
  • R 2 , R 3 , R 7 and n are as defined above.
  • the compound of the invention is a compound of formula (III),
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , m, n, s, r, Ar 1 and Ar 2 are as defined above.
  • the compound of the invention is a compound of formula (IIIa),
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , m, n, Ar 1 and Ar 2 are as defined above.
  • the compound of the invention is a compound of formula (IIIb),
  • R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , m, n, Ar 1 and Ar 2 are as defined above.
  • the compound of the invention is a compound of formula (IIIc-1) or formula (IIIc-2),
  • R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , m, n, Ar 1 and Ar 2 are as defined above.
  • the compound of the invention is a compound of formula (IV),
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n, s, r, Ar 1 and Ar 2 are as defined above.
  • the compound of the invention is a compound shown below:
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, a pharmaceutically acceptable salt, ester, solvate, isomer thereof, any crystal form or racemate thereof, or a A metabolite form, or a mixture thereof, in the form of a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation.
  • the pharmaceutical composition of the invention further comprises a pharmaceutically acceptable excipient for forming a pharmaceutical formulation.
  • the excipient can be a carrier, an excipient, a diluent, or a combination thereof.
  • the carrier, excipient, and diluent refer to an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to the organism and does not interfere with the biological activity of the administered compound.
  • the carrier, excipient and diluent include water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gel, alginate, calcium silicate, calcium phosphate , cellulose, aqueous syrup, methyl cellulose, polyvinyl pyrrolidone, alkyl p-hydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, and including sesame oil, olive oil, soybean oil, etc.
  • an additive such as an extender, a binder, a disintegrant, a pH adjuster, or a dissolving agent which are generally used may be blended in the above-mentioned carrier, excipient or diluent as needed.
  • the pharmaceutical composition of the present invention can be prepared into tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, ointments, creams, injections by conventional formulation techniques.
  • Oral or non-oral preparation forms such as skin patches.
  • the pharmaceutical composition of the invention comprises from 0.01 to 1000 mg, suitably from 0.5 to 800 mg, preferably from 1 to 400 mg, more preferably from 5 to 200 mg, particularly preferably from 10 to 100 mg, most preferably from 15 to 50 mg, for example
  • the pharmaceutical composition of the present invention may be in unit dosage form, and the unit dose may contain 0.01 to 1000 mg, suitably 0.5 to 800 mg, preferably 1 to 400 mg, more preferably 5 to 200 mg, particularly preferably 10 to 100 mg, most preferably 15 to 50 mg.
  • 0.01 to 1000 mg suitably 0.5 to 800 mg, preferably 1 to 400 mg, more preferably 5 to 200 mg, particularly preferably 10 to 100 mg, most preferably 15 to 50 mg.
  • a compound of the present invention a pharmaceutically acceptable salt, ester, solvate, isomer thereof, any crystal form or racemate thereof, a metabolite form thereof, or a mixture thereof It can be used in combination with one or more other active ingredients to treat, prevent, inhibit or ameliorate a disease or condition, wherein the combined use of the drug is safer or more effective than the separate use of any of the drugs.
  • Such other drugs may be administered simultaneously or sequentially with the compounds of the present invention in the routes and amounts conventionally used for this purpose.
  • a compound of the present invention a pharmaceutically acceptable salt, ester, solvate, isomer thereof, any crystal form or racemate thereof, a metabolite form thereof, or a mixture thereof, and one or more other
  • a pharmaceutical composition containing the other drug and the compound of the present invention in a unit dosage form is preferred, especially in combination with a pharmaceutically acceptable carrier.
  • combination therapy can also include administering a pharmaceutically acceptable salt, ester, solvate, isomer, any crystalline form or racemate thereof, or a metabolite form thereof, of a compound of the invention in a different overlapping schedule. , or a mixture thereof and treatment of one or more other drugs.
  • the compounds of the invention and the other active ingredients may be employed in lower doses than when each is used alone.
  • the pharmaceutical compositions of the invention may also comprise one or more additional active ingredients.
  • the additional active ingredients include, but are not limited to, interferon, ribavirin or the like, HCV NS3 protease inhibitor, alpha-glucosidase 1 inhibitor, hepatoprotectant, HCV NS5B polymerase Non-nucleoside inhibitors, HCV NS5A inhibitors, TLR-7 agonists, cyclophilin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers, and other drugs or therapeutic agents for the treatment of HCV, or a combination thereof.
  • the interferon is selected from PEGylated PEGylated Interferon alpha (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon, subbalin), interferon Interferon ⁇ -n1 (Wellferon), interferon Interferon beta (Avonex DL-8234), interferon- ⁇ ( ⁇ Biomed510), IFN ⁇ -2bXL, DA-3021, glycosylated interferon alpha 2b (AVI-005), PEG-Infergen, PEGylated interferon lambda-1 (PEGylated IL-29) and
  • the ribavirin and its analogue are selected from ribavirin And Talivilin
  • the HCV NS3 protease inhibitor is selected from the group consisting of boceprevir (SCH-503034, SCH-7), telaprevir (VX-950), TMC435350, BI-1335, BI-1230, MK-7009, VBY-376, VX-500, GS-9256, GS-9451, BMS-605339, PHX-1766, AS-101, YH-5258, YH5530, YH5531, ABT-450, ACH-1625, ITMN-191, MK5172 MK6325 and MK2748.
  • the alpha-glucosidase 1 inhibitor is selected from the group consisting of celgosivir (MX-3253), miglitol and UT-231B.
  • the hepatoprotective agent is selected from the group consisting of americana (IDN-6556), ME-3738, GS-9450 (LB-84451), silibilin and MitoQ.
  • the non-nucleoside inhibitor of the HCV NS5B polymerase is selected from the group consisting of PF-868554, VCH-759, VCH-916, JTK-652, MK-3281, GS-9190, VBY-708, VCH-222, A848837, ANA-598 GL60667, GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (nesbuvir), GSK625433, BILN-1941, XTL-2125, ABT-072, ABT-333, GS-9669, PSI-7792 and GS-9190.
  • the HCV NS5A inhibitor is selected from the group consisting of ABT-267 (ombitasvir), AZD-2836 (A-831), BMS-790052, ACH-3102, ACH-2928, GS-5885, GS-5816, MK8325, MK4882, MK8742. PSI-461, IDX719 and A-689.
  • the TLR-7 agonist is selected from the group consisting of imiquimod, 852A, GS-9620, ANA-773, ANA-975, AZD-8848 (DSP-3025) and SM-360320.
  • the cyclophilin inhibitor is selected from the group consisting of DEBIO-025, SCY-635, and NIM811.
  • the HCV IRES inhibitor is selected from the group consisting of MCI-067.
  • the pharmacokinetic enhancer is selected from the group consisting of BAS-100, SPI-452, PF-4194477, TMC-41629, GS-9350, GS-9585, and roxithromycin.
  • the other drugs for treating HCV are selected from the group consisting of thymosin ⁇ 1 (Zadaxin), nitazoxanide (Alinea, NTZ), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002 , actilon (CPG-10101), GS-9525, KRN-7000, civacir, GI-5005, XTL-6865, BIT225, PTX-111, TX2865, TT-033i, ANA971, NOV-205, tarvacin, EHC-18, VGX-410C, EMZ-702, AVI4065, BMS-650032, BMS-791325, Bavituximab, MDX-1106 (ONO-4538), Oglufanide and VX-497 (merimepodib).
  • the compound of the present invention a pharmaceutically acceptable salt, ester, solvate, isomer thereof, any crystal form or racemate thereof, a metabolite form thereof, or a mixture thereof can inhibit NS5B polymerase, DNA polymerization Enzyme or reverse transcriptase.
  • the compounds of the present invention, their pharmaceutically acceptable salts, esters, solvates, isomers, any of their crystal forms or racemates, their metabolite forms, or mixtures thereof can be used as NS5B polymerase.
  • Inhibitor, DNA polymerase inhibitor or reverse transcriptase inhibitor can be used as NS5B polymerase.
  • Another object of the present invention is to provide a compound of the present invention, a pharmaceutically acceptable salt, ester, solvate, isomer thereof, any crystal form or racemate thereof, a metabolite form thereof, or a mixture thereof Or the use of a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of a NS5B polymerase mediated disease, a DNA polymerase mediated disease or a reverse transcriptase mediated disease.
  • Another object of the present invention is to provide a compound of the present invention, a pharmaceutically acceptable salt, ester, solvate, isomer thereof, any crystal form or racemate thereof, a metabolite form thereof, or a mixture thereof Or the use of a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment of a viral disease or cancer.
  • Another object of the present invention is to provide a compound of the present invention, a pharmaceutically acceptable salt, ester, solvate, isomer thereof, any crystal form or racemate thereof, a metabolite form thereof, or a mixture thereof, Or a pharmaceutical composition of the invention for use in the treatment of a NS5B polymerase mediated disease, a DNA polymerase mediated disease or a reverse transcriptase mediated disease.
  • Another object of the present invention is to provide a compound of the present invention, a pharmaceutically acceptable salt, ester, solvate, isomer thereof, any crystal form or racemate thereof, a metabolite form thereof, or a mixture thereof, Or a pharmaceutical composition of the invention for use in the treatment of a viral disease or cancer.
  • Another object of the invention is to provide a method of treating a NS5B polymerase mediated disease, a DNA polymerase mediated disease or a reverse transcriptase mediated disease comprising administering to an individual in need thereof an effective amount of the invention
  • Another object of the present invention is to provide a method of treating a viral disease or cancer which comprises administering to a subject in need thereof an effective amount of a compound of the present invention, a pharmaceutically acceptable salt, ester, solvate or isomer thereof. And any of their crystalline forms or racemates, their metabolite forms, or mixtures thereof, or the pharmaceutical compositions of the invention.
  • viral diseases which can be prevented or treated using the compounds of the invention include, but are not limited to, viral hepatitis A, hepatitis B virus, hepatitis C virus, influenza, herpes and Acquired immunodeficiency syndrome (AIDS), and related symptoms or diseases caused by the above diseases (such as inflammation, liver fibrosis, cirrhosis, liver cancer, etc.).
  • viral hepatitis A hepatitis B virus
  • hepatitis C virus influenza
  • AIDS Acquired immunodeficiency syndrome
  • the compound of the present invention can be administered orally or parenterally, in a total dose of 0.001 to 1500 mg/day, preferably 0.01 to 1000 mg/day, once or divided into several times a day. It is more preferably 0.1 to 800 mg/day, particularly preferably 1-600 mg/day, such as 250 mg/day, 400 mg/day, 500 mg/day or 600 mg/day.
  • the dose of the compound of the present invention can be appropriately increased or decreased depending on the type of the disease to be treated, the age, body weight, symptoms, and the like of the patient.
  • Another object of the present invention is to provide a process for the preparation of a compound of the above formula (I) which can be carried out according to Scheme 1 below:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n, s, r, X, Ar 1 , Ar 2 , L-Base and Base are as defined above;
  • Y are the same or different from each other and are each independently selected from halogen, preferably chlorine.
  • Step 1 The phosphorus oxyhalide represented by Formula 2 is reacted with the compound of Formula 1 to give a compound of Formula 3.
  • step one is carried out in the presence of an organic base.
  • step one comprises: dissolving the phosphorus oxyhalide in an organic solvent, cooling to -80 ° C to -20 ° C, and adding the compound of formula 1 and an organic base.
  • the reaction solution is heated to 15 to 40 ° C, preferably 20 to 35 ° C, more preferably 25 to 30 ° C, and stirred for 1 to 8 hours, preferably 2 to 6 hours, to obtain a crude compound of the formula 3.
  • the molar ratio of the compound of formula 1, phosphorus oxyhalide and organic base is 1: (0.5 to 2): (0.5 to 2), preferably 1: (0.8 to 2): 0.8 to 2), more preferably 1: (1 to 1.5): (1 to 1.5).
  • the weight-to-volume ratio (g/ml) of the compound of Formula 1 to the organic solvent is from 1:5 to 30, preferably from 1:10 to 25, more preferably from 1:15 to 20.
  • the weight ratio by weight of the phosphorus oxyhalide to the organic solvent is from 1:5 to 30, preferably from 1:10 to 25, more preferably from 1:10 to 20.
  • the weight to volume ratio (grams per milliliter) of the organic base to the organic solvent is from 1:15 to 30, preferably from 1:20 to 25.
  • Step 2 A compound represented by Formula 3 is reacted with a compound represented by Formula 4 to give a compound represented by Formula 5.
  • the second step comprises: dissolving the compound of the formula 3 obtained in the first step in an organic solvent, cooling the reaction solution to -80 ° C - 20 ° C, adding the compound represented by the formula 4 and Organic base.
  • the reaction solution is heated to 15 to 40 ° C, preferably 20 to 35 ° C, more preferably 25 to 30 ° C, and stirred for 1 to 8 hours, preferably 2 to 6 hours.
  • a crude compound of the formula 5 is obtained.
  • the molar ratio of the compound of Formula 3, the compound of Formula 4, and the organic base is 1: (0.5-1.5): (1.0-3.5), preferably 1: (0.9-1.1) :(1.4-3).
  • the weight-to-volume ratio (g/ml) of the compound of Formula 4 to the organic solvent is 1: (5-30), preferably 1: (10-25).
  • the weight to volume ratio (grams per milliliter) of the organic base to the organic solvent is 1: (3-25), preferably 1: (5-20).
  • Step 3 A compound represented by Formula 5 is reacted with pentafluorophenol represented by Formula 6 to give a compound represented by Formula 7.
  • the third step comprises: dissolving the compound of the formula 5 obtained in the second step in an organic solvent, cooling the reaction solution to -80 ° C - 20 ° C, and sequentially adding the formula 6 thereto.
  • Compounds and organic bases The reaction solution is heated to 15 to 40 ° C, preferably 20 to 35 ° C, more preferably 25 to 30 ° C, and stirred for 1 to 8 hours, preferably 2 to 6 hours, to obtain a compound of the formula 7.
  • the molar ratio of the compound of Formula 5, the compound of Formula 6 and the organic base is 1: (0.5-2): (0.5-2.5), preferably 1: (0.7-1.5) :(1.0-2.0).
  • the weight-to-volume ratio (g/ml) of the compound of Formula 6 to the organic solvent is 1: (5-30), preferably 1: (10-25).
  • the weight to volume ratio (grams per milliliter) of the organic base to the organic solvent is 1: (10-30), preferably 1: (15-25).
  • Step 4 A compound represented by Formula 7 is reacted with a compound represented by Formula 8 to give a compound represented by Formula (I).
  • the fourth step comprises: dissolving the compound of the formula 8 in an organic solvent, adding a format reagent to the reaction solution at a temperature of 0 ° C to 25 ° C under the protection of an inert gas, and stirring appropriately. After 1-3 hours, the temperature was lowered to -20 ° C - 10 ° C, and the compound of the formula 7 obtained in the third step was added.
  • the reaction solution is heated to 1 ° C to 40 ° C, preferably 10 ° C to 30 ° C, and stirred for 5-20 hours, preferably 10-15 hours, to give a compound of formula I.
  • the molar ratio of the compound of Formula 7, the compound of Formula 8 and the Grignard reagent is 1: (0.8-2): (1.5-4), preferably 1: (1-1.5) ): (2-3.5).
  • the weight-to-volume ratio (g/ml) of the compound of Formula 7 to the organic solvent is 1: (30-70).
  • the weight-to-volume ratio (g/ml) of the compound of Formula 8 to the organic solvent is 1: (90-120).
  • the organic bases used in the above steps 1, 2, and 3 include, but are not limited to, sodium t-butoxide, triethylamine, DIPEA, pyridine or DMAP.
  • the organic solvent used in the above steps 1, 2, 3, and 4 is a solvent commonly used in the art, such as, but not limited to, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and saturation.
  • Hydrocarbons such as cyclohexane, hexane, etc.
  • halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • ethers such as tetrahydrofuran, diethyl ether, dioxane, 1, 2-dimethoxyethane or the like
  • a nitrile for example, acetonitrile or the like
  • a mixed solvent thereof and the like.
  • the method can be performed according to the following route 2:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n, s, r, X, Ar 1 , Ar 2 , L and Base are as defined above.
  • step one'
  • step one' is carried out in the presence of an organic base or an inorganic base and/or a condensation reagent.
  • the organic base includes, but is not limited to, sodium t-butoxide, triethylamine, DIPEA, pyridine or DMAP.
  • the inorganic base includes, but is not limited to, NaH, NaOH, Na 2 CO 3 or K 2 CO 3 .
  • the condensation reagents include, but are not limited to, DCC, DIC, EDC, BOP, PyAOP, and PyBOP.
  • the compound of Formula 1 is phenol or naphthol.
  • step one&apos is carried out at a temperature of from 60 °C to 150 °C, preferably from 70 °C to 130 °C, more preferably from 80 °C to 110 °C.
  • the molar ratio of the compound of Formula 8 to the compound of Formula 1 is 1: (0.5-2), preferably 1: (0.8-2), more preferably 1: (1-1.5).
  • the molar ratio of the compound of Formula 8, the compound of Formula 1 to the organic or inorganic base is 1: (0.5-2): (0.5-2), preferably 1: (0.8-2): (0.8-2), more preferably 1: (1-1.5): (1-1.5).
  • the molar ratio of the compound of formula 8 to the condensing agent is 1: (1.5-3), preferably 1: (1.8-2.5).
  • the halogenating agent is a chlorinating or brominating agent, preferably a chlorinating agent, more preferably SOCl 2 .
  • step two&apos is carried out at a temperature of from -20 °C to 150 °C, preferably from 50 °C to 110 °C, further preferably from 50 °C to 90 °C, more preferably from 60 to 80 °C.
  • the molar ratio of the compound of formula 9 to the halogenating agent is 1: (2-10), preferably 1: (3-10), more preferably 1: (4-8).
  • step three' is carried out in the presence of an organic or inorganic base.
  • the organic base includes, but is not limited to, sodium t-butoxide, triethylamine, DIPEA, pyridine or DMAP.
  • the inorganic base includes, but is not limited to, NaH, NaOH, Na 2 CO 3 or K 2 CO 3 .
  • step three&apos is carried out at a temperature of from -78 °C to 25 °C, preferably from -40 °C to 0 °C, more preferably from -30 °C to 10 °C.
  • the molar ratio of the compound of Formula 10 to the compound of Formula 4 is 1: (1-10), preferably 1: (1-3), more preferably 1: (1.5-2.5).
  • the molar ratio of the compound of formula 10, the compound of formula 4 to the organic or inorganic base is 1: (1-10): (5-20), preferably 1: (1-3): (5-20), more preferably 1: (1.5-2.5): (8-15).
  • the above steps one, two, and three can be carried out in an organic solvent.
  • the organic solvent may be a reaction solvent commonly used in the art, such as, but not limited to, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, saturated hydrocarbons (such as cyclohexane, hexane).
  • Etc. halogenated hydrocarbons (such as dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (such as tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) , nitriles (such as acetonitrile, etc.) and their mixed solvents.
  • halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • ethers such as tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • nitriles such as acetonitrile, etc.
  • the present invention also provides a method for synthesizing a phosphorus chiral pure compound of the formula (I"), which can be carried out according to the following Scheme 3:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n, s, r, X, Ar 1 , Ar 2 , L and Base are as defined above.
  • Step one halogenation of the compound of formula 9 to form a compound of formula 11.
  • the halogenating agent is thionyl chloride, oxalyl chloride, phosphorus trichloride, chlorotriphenylphosphine salt, brominated sulfoxide, oxalyl bromide, phosphorus tribromide or bromotriphenyl.
  • the phosphine salt is preferably thionyl chloride.
  • step one" is carried out at a temperature of from -20 °C to 150 °C, preferably from 25 °C to 120 °C, more preferably from 50 to 110 °C.
  • the reaction time of step one" is from 12 h to 96 h, preferably from 36 h to 72 h.
  • the molar ratio of the compound of formula 9 to the halogenating agent is 1: (2-10), preferably 1: (3-6).
  • Step two reacting a compound of formula 11 with a compound of formula 4 to form a compound of formula (I").
  • step two is carried out at a temperature of from -78 °C to 25 °C, preferably from -40 °C to 0 °C.
  • the molar ratio of the compound of Formula 12 to the compound of Formula 4 is 1: (1-10), preferably 1: (1-5).
  • the above steps “" and “2” can be carried out in an organic solvent.
  • the organic solvent may be a reaction solvent commonly used in the art, such as, but not limited to, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, and esters (eg, methyl acetate, ethyl acetate).
  • saturated hydrocarbons such as cyclohexane, hexane, etc.
  • halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • ethers such as tetrahydrofuran, Ethyl ether, diisopropyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • benzenes e.g., toluene, xylene
  • nitriles e.g., acetonitrile, etc.
  • the compound of the formula (I) obtained above can be isolated by preparative high performance liquid chromatography to give an isomer.
  • the resulting isomers may be in the form of enantiomers, diastereomers and the like.
  • the structure of the compound described in the following examples was determined by 1 H NMR or MS.
  • the 1 H NMR measuring instrument used a JEOL Eclipse 400 nuclear magnetic instrument; the measuring solvent was CD 3 OD, CDCl 3 or DMSO-d6; the internal standard substance was TMS. All ⁇ values are expressed in ppm.
  • the mass spectrometer (MS) assay instrument used an Agilent (ESI) mass spectrometer, model Agilent 6120B.
  • the mixture of diastereomers prepared in the examples can be separated by preparative high performance liquid chromatography to give the pure isomer.
  • the preparative high performance liquid chromatography separation can be carried out according to methods known in the art. For example, under the following separation conditions: using octadecyl bonded silica as a filler, column temperature 30 ° C -50 ° C, flow rate 5.0-20.0 mL / min, detection wavelength 200-400 nm, using mobile phase A (for example, Water), mobile phase B (for example, methanol or acetonitrile), with a linear gradient elution.
  • mobile phase A for example, Water
  • mobile phase B for example, methanol or acetonitrile
  • Step 1 to Step 3 (S)-pentafluorophenyl-phenyl-(1-(2-methylbenzyloxy)propan-2-yl)phosphoramidate (Compound f-1)
  • the reaction system was further cooled to -70 ° C, and a solution of pentafluorophenol (Compound e, 1.66 g, 9 mmol) in dichloromethane (10 mL) was added dropwise, followed by dropwise addition of triethylamine (1.52 g, 15 mmol) in dichloromethane. (10 mL). After the addition was completed, the cold bath was removed, the temperature was raised to 25 ° C, and the mixture was stirred overnight. After the reaction was completed, the reaction system was poured into ice water and extracted with dichloromethane.
  • Step 4 ((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4 -methyltetrahydrofuran-2-yl)methyl-phenyl-((S)-1-(2-methylbenzyloxy)propan-2-yl)phosphoramidate
  • Step 1 to Step 3 (R)-pentafluorophenyl-phenyl-(1-(2-methylbenzyloxy)propan-2-yl)phosphoramidate (Compound f-2)
  • Phosphorus oxychloride (475 mg, 3.1 mmol) was added to dichloromethane (10 mL), and the temperature was lowered to -70 ° C under nitrogen, and phenol (Compound a, 292 mg, 3.1 mmol) and triethylamine (314 mg, 3.1 mmol) of dichloromethane solution. After completion of the dropwise addition, the mixture was reacted at -70 ° C for 5 minutes, then warmed to room temperature, and stirred for 2 hours to obtain a standby reaction solution. Add methylene chloride (20 mL) to (R)-1-(2-methylbenzyloxy)propan-2-ylamine hydrochloride (Compound C-2, 500 mg, 2.79 mmol).
  • Step 4 ((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4 -methyltetrahydrofuran-2-yl)methyl-phenyl-((R)-1-(2-methylbenzyloxy)propan-2-yl)phosphoramidate
  • Step 1 Synthesis of N-Boc-2-amino-2-methyl-1-propanol (Compound b-3)
  • Step 2 Synthesis of N-Boc-(2-methyl-1-((2-methylbenzyloxy)propan-2-yl))amine (Compound c-3)
  • Step 4 Synthesis of pentafluorophenyl-phenyl-(2-methyl-1-(2-methylbenzyloxy)propan-2-yl)phosphoramidate (Compound f-3)
  • Phosphorus oxychloride (459 mg) was added to dichloromethane (10 mL) and the temperature was lowered to -70 °C under nitrogen. A solution of phenol (282 mg, 3 mmol) and triethylamine (303 mg, 3 mmol) in dichloromethane (3 mL) was added dropwise, and the mixture was stirred at -70 ° C for 5 min. Then, the temperature was raised to room temperature, and the mixture was stirred for 2 hours to obtain a standby reaction solution. Dichloromethane (20 mL) was added to 2-methyl-1-(2-methylbenzyloxy)propan-2-ylamine (Compound d-3, 588 mg, 3.03 mmol). 70 ° C.
  • Step 5 (2R, 3R, 4R, 5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4- Synthesis of methyltetrahydrofuran-2-yl)methyl-phenyl-(2-methyl-1-(2-methylbenzyloxy)propan-2-yl)phosphoramidate
  • Step 1 Preparation of ((1R)-2-(6-amino-9H-fluoren-9-yl)-1-methyl-ethoxy)methyl)phosphoric acid monophenyl ester
  • the reaction was incubated at 100 ° C overnight, and the reaction solution was cooled to room temperature and allowed to stand for 2 h. After filtration, the filtrate was concentrated and dissolved in dichloromethane, and a small amount of white insoluble material was observed. Filtration again, the filtrate was concentrated, and the residue was crystallijjjjj
  • 2-(Benzyloxy)ethylamine (46.82 g, 309.65 mmol) was dissolved in dry dichloromethane (200 mL) at room temperature, cooled to -35 ° C under nitrogen, and then added to 22-A-1 (30 g, A crude toluene (200 mL) solution with a controlled temperature of less than -10 °C. After the addition, the temperature was maintained at -10 ° C and reacted for 1 h. A 15% aqueous potassium hydrogenphosphate solution (400 mL) was added, stirred well, allowed to stand, and layered.
  • the organic phase was washed successively with 15% potassium hydrogen phosphate (200 mL ⁇ 2), deionized water (200 mL ⁇ 2), and dried.
  • the insoluble material was filtered out, and the filtrate was evaporated to ethylamine.
  • the retention time (R t ) of the obtained product was the same as that of the compound 22 isomer A obtained in the first preparation method of this example by chiral HPLC.
  • the purity of the diastereomer was 94.6%.
  • Example 12 The synthesis of Example 12 was followed except that (R)-1-((2-methylbenzyloxy)-2-amino-propane was replaced by 2-(2,4-dimethylbenzyloxy)ethylamine. The title compound (58 mg) was obtained eluted elut elut elut elut elut
  • Example 20 Preparation of Example 20 - Isomer A and Example 20 - Isomer B
  • Step 1 Synthesis of ((R)-1-(6-amino-9H-fluoren-9-yl)propan-2-yl)oxy)methyl)phosphoric mono-1-naphthyl ester
  • Step 2 Synthesis of (((R)-1-(6-amino-9H-fluoren-9-yl)propan-2-yl)oxy)methyl)-1-naphthalenyloxy-phosphoryl chloride
  • Step 3 (R)-((((R)-1-(6-Amino-9H-indol-9-yl)propan-2-yl)oxy)methyl)-naphthalen-1-yloxy-N Synthesis of -(2-(2-methylbenzyloxy)ethyl)-phosphoramide
  • Example 12 The synthesis method of Example 12 was followed except that (R)-1-((2-methylbenzyloxy)-2-amino-propane was replaced by (R)-1-(benzyloxy)-2-propanamine.
  • the title compound (370 mg) was
  • Example 23 Example 23 - Preparation of Isomer A, Example 23 - Isomer B
  • Example 12 The synthesis method of Example 12 was followed except that (R)-1-((2-methylbenzyloxy)-2-amino-propane was replaced by (S)-2-(benzyloxy)-1-propanamine. The title compound (205 mg) was obtained.
  • Example 12 The synthesis method of Example 12 was followed except that (R)-1-((2-methylbenzyloxy)-2-amino-propane was replaced by (R)-2-(benzyloxy)-1-propanamine.
  • the title compound (260 mg) was
  • Example 12 The synthesis of Example 12 was followed except that (R)-1-((2-methylbenzyloxy)-2-amino-propane was replaced by 1-(benzyloxy)-2-methyl-2-propylamine.
  • the title compound (30 mg) was obtained after purified by preparative chromatography.
  • Step 1 Synthesis of (((R)-1-(6-amino-9H-fluoren-9-yl)propan-2-yl)oxy)methyl)phosphate mono-p-fluorophenyl ester
  • Step 2 Synthesis of 4-fluorophenoxy-((((R)-1-(6-amino-9H-fluoren-9-yl)propan-2-yl)oxy)methyl)phosphoryl chloride
  • Step 3 ((((R)-1-(6-Amino-9H-indol-9-yl)propan-2-yl)oxy)methyl)-4-fluorophenoxy-N-(2- Synthesis of (benzyloxy)ethyl)-phosphoramide
  • Example 12 The synthesis method of Example 12 was followed except that (R)-1-((2-methylbenzyloxy)-2-amino-propane was replaced by (S)-2-(benzyloxy)-1-propanamine. The title compound (173 mg) was obtained.
  • Example 12 The synthesis of Example 12 was followed except that (R)-1-((2-methylbenzyloxy)-2-amino-propane was replaced by 2-(2,6-dimethylbenzyloxy)ethylamine.
  • the title compound (21 mg) was obtained after purified by chromatography.
  • nucleoside triphosphate metabolites (3P) produced by nucleosides in human primary hepatocytes
  • Human primary hepatocytes (batch MMN, 10 donor mixed sex) were purchased from Bioreclamation IVT, an in vitro technology company.
  • a human primary hepatocyte solution at a concentration of 6 ⁇ 10 5 cells/mL and a test compound solution having a concentration of 50 ⁇ M were prepared. 250 ⁇ L of human primary hepatocyte solution and 250 ⁇ L of the test compound solution were mixed and added to a 24-well plate so that the final concentration of the test compound was 25 ⁇ M. After incubating for 6 hours at 37 ° C in a water bath, the sample was transferred to a test tube and the medium was removed. After washing the cells with phosphate buffer, the supernatant was removed. 180 ⁇ L of 70% methanol was added, vortexed, and allowed to stand at -20 ° C overnight. After centrifugation at 15000 rpm and 4 ° C for 10 min, 150 ⁇ L of the supernatant was transferred to a sample tube, and the amount of 3P product was detected by LC-MS/MS to calculate the 3P production rate.
  • 3P generation rate (3P production amount * 150 ⁇ L) / (6 ⁇ 10 5 cells / mL * 250 ⁇ L * 6h).
  • the amount of 3P compound produced and the rate of formation of the test substance are shown in the table below.
  • the compound of the present invention can be smoothly metabolized in hepatocytes to produce an active nucleoside triphosphate metabolite, and the production amount of the nucleoside triphosphate metabolite is large, and the production rate is fast. Therefore, the compound of the present invention has a good inhibitory effect on hepatitis C, hepatitis B, human immunodeficiency syndrome and the like.
  • the compound was dissolved in DMSO and formulated into a 10 mM stock solution.
  • the substrate was separately dissolved in DMSO to prepare a stock solution of the corresponding concentration.
  • the specific concentrations are shown in the table below:
  • Substrate Stock concentration (mM) Concentration in the incubation system ( ⁇ M) Phenacetin (1A2) 20 10 Diclofenac (2C9) 10 5 Mefentoxin (2C19) 20 30 Dextromethorphan (2D6) 20 5 Midazolam (3A4) 10 2 Testosterone (3A4) 40 50 Amodiaquine (2C8) 10 10 Bupropion (2B6) 80 80
  • the positive control was separately dissolved in DMSO to prepare a stock solution of the corresponding concentration. It was then diluted with methanol to the corresponding concentration of working solution.
  • the specific stock solution concentration is shown in the following table:
  • Inhibitor Stock concentration (mM) Working fluid concentration ( ⁇ M) Naphthoflavone (1A2) 3 300 Sulfaphenazole (2C9) 10 300 Phenylcyclopropylamine (2C19) 10 300 Quinidine (2D6) 3 300 Ketoconazole (3A4) 3 300 Quercetin (2C8) 3 300 Ticlopidine (2B6) 3 300
  • the protein concentration of liver microsomes in the reaction system was 0.2 mg/mL, and the coenzyme NADPH was 1.0 mM.
  • the incubation reaction was carried out in a 37 ° C water bath. The reaction was terminated and subjected to conventional procedures for LC-MS/MS analysis.
  • an IC 50 >10 ⁇ L indicates that the drug has no inhibitory effect on CYP450 enzyme or has a low inhibitory effect. From the above data, the compound of Example 15 in the present invention has no inhibitory effect on eight CYP450 enzymes, and the risk of drug interaction is small, and thus has higher safety. Other compounds of the invention all have similar safety.
  • HBV hepatitis B virus
  • HepG2.2.15 cells in logarithmic growth phase were seeded in 96-well plates at a cell concentration of 40/ ⁇ L. Incubate for 3 days at 37 ° C in a 5% CO 2 incubator. Replace with new medium (200 ⁇ L/well) before adding the compound.
  • the mother liquor concentration of each of the examples was 200 ⁇ M. The highest concentration was 200 ⁇ M and diluted to a number of different concentrations in DMSO. 1 ⁇ L of the test compound was placed in the corresponding medium well, and the final test concentrations of the compounds were 0.06, 0.24, 0.98, 3.9, 15.6, 62.5, 250, 1000 nM (for calculating the half effective concentration (EC 50 )).
  • the tested compounds have strong inhibitory activity against hepatitis B virus (HBV).
  • Nucleoside analogs are phosphorylated by thymidine kinase produced by the virus, metabolized into a potent monophosphate, and then metabolized into active forms of diphosphate and triphosphate to achieve antiviral action. Therefore, the production of active metabolites of monophosphate is fundamental to the efficacy of nucleoside analogs.
  • Example 16 - Compound 22 Isomer B Male ICR mice were administered by intragastric administration
  • Example 16 - Compound 22 Isomer B and Example 16 - Compound 22 Isomer B and Metabolites were determined in vivo (Example 16 - Compound Isomer B Metabolism)
  • the drug and liver drug concentrations of substance 1) were investigated for the pharmacokinetic properties of the compounds.
  • the dose for intragastric administration was 10 mg/kg, and the vehicle system was 0.5% MC.
  • Blood and liver tissue were collected at different time points after intragastric administration for PK studies. Plasma samples and liver homogenates were processed by precipitation protein and analyzed by LC-MS/MS.
  • LC-MS/MS Mass spectrum was API 5500 and liquid phase was Shimadz [mu] LC-30AD system.
  • the column to be tested is Hypersil GOLD C18, 3 ⁇ m particle size, 100 ⁇ 4.6mm, Thermo Company, USA; mobile phase: A phase is 5mA ammonium formate + 0.5% formic acid, phase B is methanol; flow rate is 0.8mL/min; column The temperature is 40 °C.
  • the ion source is used as the ESI source positive ion mode, and the scanning mode is multiple reaction monitoring (MRM).
  • MRM multiple reaction monitoring
  • Example 16 - Compound 22 Isomer B in the present invention can be rapidly metabolized in plasma and liver to produce Example 16 - Compound 22 Isomer B metabolite 1.
  • the concentration of metabolite 1 in the liver was 21 times the plasma concentration, i.e., Example 16 - Compound 22 isomer B had significant liver targeting.
  • Test compound Example 16-isomer B; Dosage: 10 mg/kg, 30 mg/kg; mode of administration: gavage; frequency of dosing: once daily; total duration: day 1 to day 7.
  • Example 16 - Compound 22 isomer B in the present invention has a significant inhibitory effect on mouse plasma and liver HBV DNA in a dose-dependent manner. It is foreseen that Example 16 - Compound 22 isomer B has a significant therapeutic effect on hepatitis B. Therefore, the compound of the present invention can be used as an effective hepatitis B virus reverse transcriptase inhibitor.
  • the compound of the present invention is an inhibitor of hepatitis C virus (HCV) NS5B polymerase, a hepatitis B virus DNA polymerase inhibitor, and a retroviral reverse transcriptase inhibitor, which can be efficiently metabolized in vivo and converted into a high content.
  • HCV hepatitis C virus
  • a hepatitis B virus DNA polymerase inhibitor a retroviral reverse transcriptase inhibitor

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Abstract

本发明提供式（I）所示的化合物、包含其的药物组合物、其制备方法及其作为NS5B聚合酶抑制剂、DNA聚合酶抑制剂或逆转录酶抑制剂在预防或治疗病毒性疾病或癌症中的用途。

Description

核苷磷酸类化合物及其制备方法和用途
相关申请的交叉引用
本申请要求2016年12月23日提交的中国专利申请201611204909.4、2017年1月24日提交的中国专利申请201710059345.8以及2017年10月23日提交的中国专利申请201710991293.8的优先权，所述申请的公开内容以其整体援引加入本文。
发明领域
本发明涉及一种核苷磷酸类化合物、包含其的药物组合物、其制备方法及其作为NS5B聚合酶抑制剂、DNA聚合酶抑制剂或逆转录酶抑制剂在预防或治疗病毒性疾病或癌症中的用途。
发明背景
病毒由一种核酸分子(DNA或RNA)与蛋白质构成或仅由蛋白质构成(如朊病毒)。病毒可引起多种传染性疾病，常见的由病毒引起的疾病包括但不限于甲型病毒性肝炎、乙型病毒性肝炎、丙型病毒性肝炎、流行性感冒、疱疹和获得性免疫缺陷综合征(AIDS)。
目前临床使用的抗病毒药物通过抑制病毒的附着、脱壳、病毒基因复制、成熟或释放，或者通过影响宿主的免疫系统来发挥作用，其主要包括RNA、DNA聚合酶抑制剂，逆转录酶抑制剂和干扰素等。
丙型肝炎病毒(HCV)是一种单链、正链RNA病毒，属于肝炎病毒属黄病毒科。根据编码NS5B核糖核酸依赖型核糖核酸聚合酶的基因不同，丙型肝炎病毒分为6个基因型，50个亚型。不同基因型在全球的分布都不一样。在北美和欧洲，发现了基因型1、2、3，其中基因型1占大多数。非洲几乎只存在基因4型、5型感染的病人。中国常见的基因型为1b和2a，其中以1b为主，6型主要见于港澳地区(Simmonds，P.Journal of General Virology,2004，85，3173–3188)。其中，肝硬化及肝癌患者基因型1b明显高于慢性肝炎患者。基因1b型复发丙型肝炎，其肝病较其他基因型要严重。基因型1a，2a合并乙肝感染的发生率较高，大部分(74％)急性肝炎患者为基因型1a。基因型4感染易引起失代偿性肝脏并发症。基因型3a感染与脂肪肝的关系较为密切。
现有技术中，标准的治疗方案是聚乙二醇干扰素联合利巴韦林。然而该疗法仅对40-50％的基因型1病人和75％的基因型2、3病人有效(Zeuzem，S.，et al.Journal of Viral Hepatitis，2009，16，75-90)。对某些亚人群，聚乙二醇干扰素联合利巴韦林的疗效不佳。因此，迫切需要发展安全有效的“直接作用抗病毒药物”。第一代丙型肝炎病毒蛋白酶抑制剂特拉匹韦和波西普韦相继面世。这两种药物与聚乙二醇干扰素/利巴韦林联用，可以提高基因1型病人的病毒清除率，缩短疗程。但是这种新的三联组合疗法带来新的问题，例如更多的副作用，给药方案复杂，易发生耐药，并且仅对感染基因型1病毒的病人有效(Kwong，A.D.et al.Current Opinion in Pharmacology，2008，8，522-531)。新的“直接作用抗病毒药物”需要满足以下三点要求：1)可以口服给药；2)对所有基因型均有效；3)无需和聚乙二醇干扰素联合利巴韦林联用。
HCV病毒体为呈球形的单股正链RNA病毒，约含9600个编码并由3010个氨基酸组成的多聚蛋白，其基因组排列顺序为:CE1E2/NS1NS2NS3NS4ANS4BNS5ANS5B。HCV病毒多聚蛋白经宿主细胞和病毒自身蛋白酶作用，裂解成各自独立的病毒蛋白，包括三种结构蛋白(即结构蛋白C、结构蛋白El和结构蛋白E2/NS1)和四种非结构蛋白(即非结构蛋白NS2、非结构蛋白NS3、非结构蛋白NS4和非结构蛋白NS5)。其中，结构蛋白El和结构蛋白E2/NS1为糖蛋白，能产生抗HCV的中和作用。非结构蛋白NS为病毒复制提供催化结构。目前，还不清楚非结构蛋白NS2和非结构蛋白NS4的功能。非结构蛋白NS3具有螺旋酶活性，并参与解旋HCV-RNA分子，进而释放NS5B，而NS5B为依赖于RNA的RNA聚合酶(即HCV NS5B聚合酶)，该聚合酶参与HCV复制周期中由用作模板的单链病毒RNA合成双链RNA的反应。因此，若化合物可有效地抑制HCV NS5B聚合酶就能阻断双链HCV RNA合成，则可有效地控制HCV病毒感染。
核苷类似物必须能够转化为三磷酸核苷，才能起到抑制病毒聚合酶的作用。这一过程需要三种不同激酶的参与。磷酸化的效率决定了核苷类似物作为病毒聚合酶抑制剂的活性。另外，抑制剂的活性也取决于三磷酸核苷的存在时间。三磷酸核苷的存在时间越长，抑制剂的活性也 越高。在磷酸化的过程中，核苷类似物及其单磷酸，二磷酸代谢物可能并不是相应激酶的良好底物。研究表明在磷酸化过程中，第一个激酶对底物的选择性最强。因此第一步磷酸化通常是最困难的步骤。为了克服这一困难，将单磷酸输送到细胞内是必要的手段。但是，单磷酸核苷带负电荷，很难通过细胞膜，而且容易被磷酸酯酶降解。
索菲布韦(sofosbuvir)是一种丙型肝炎病毒(HCV)NS5B聚合酶抑制剂。它是尿嘧啶核苷酸类似物，具有核苷磷酰胺酯结构。这种结构赋予该类型药物具有良好的细胞通透性和血浆稳定性。索菲布韦可经肝细胞代谢为尿苷三磷酸类似物活性成分，并与胞内的尿苷三磷酸竞争，插入到新产生的核苷酸链中，使RNA链的延伸提前终止,达到抑制RNA聚合酶的作用(Journal of Medicinal Chemistry 2010,53,7202-7218)。
核苷三磷酸在肝脏中的生成量和存在时间直接影响病毒聚合酶NS5B的抑制效果。索菲布韦对丙肝的基因3型感染者的药效较差，疗程24周；而对于基因1、2和4型感染者的疗程仍然需要12周。因此，发明更有效的新型核苷磷酸类衍生物具有显著意义和应用价值。
乙型肝炎病毒，是一种DNA病毒，属于嗜肝DNA病毒科，其DNA的合成依赖于乙肝病毒DNA聚合酶。利用DNA聚合酶抑制剂作为抗乙肝病毒药物已经成为一个极具竞争力的选择。替诺福韦(tenofovir，PMPA)，是一种核苷酸类DNA聚合酶和逆转录酶抑制剂，具有抗HBV和HIV的活性。其磷酰胺酯类衍生物替诺福韦艾拉酚胺(TAF)已被FDA批准用于治疗人类免疫缺陷综合征和乙型病毒肝炎。TAF在肝细胞内通过酯酶水解、磷酸化等作用生成腺苷三磷酸类似物，后者插入新产生的DNA链，从而阻断DNA聚合酶催化的DNA合成，抑制病毒复制(WO2013025788A1；Nucleosides Nucleotides Nucleic Acids,2001,20,1085-1090)。核苷类抗癌药物，在体内通过磷酸化代谢过程生成核苷三磷酸，后者插入DNA链，抑制DNA的合成，阻止细胞由G1期向S期的进展，造成肿瘤细胞G1期周期阻滞，从而抑制肿瘤细胞的恶性增殖(Oncology.2002,62(4),354-362)。
综上所述，许多核苷类药物在抗病毒和抗癌等领域发挥积极作用，关键之处在于这些药物是作为核苷类似物被体内细胞吸收代谢，并阻止病毒、肿瘤细胞的RNA或DNA合成。其中，核苷三磷酸类似物作为体内代谢物是重要的活性成分，其生成速率、浓度和存留时间决定了药效。
发明概述
本发明的一方面提供一种核苷磷酸类化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物。所述化合物经肝组织代谢后产生的三磷酸核苷代谢物质的量多，并且被代谢转化为三磷酸核苷代谢物质的速度快。因此，本发明的核苷磷酸类化合物(下文中也称为“本发明的化合物”)可作为NS5B聚合酶抑制剂、DNA聚合酶抑制剂或逆转录酶抑制剂，用于诸如丙型病毒性肝炎(HCV)、乙型病毒性肝炎(HBV)、甲型病毒性肝炎(HAV)、流行性感冒、疱疹和获得性免疫缺陷综合征(AIDS)的病毒性疾病或癌症等疾病的治疗。本发明的化合物可以在体内进行有效地代谢，从而转化为具有活性的三磷酸核苷代谢物质。与现有的(HCV)NS5B聚合酶抑制剂、乙型肝炎病毒DNA聚合酶抑制剂、逆转录病毒逆转录酶抑制剂相比，本发明的化合物可以更有效地转化为三磷酸核苷代谢物质，因而具有更为优异的活性。
具体而言，本发明的化合物具有以下式(I)所示的结构：
Figure PCTCN2017117126-appb-000001
其中，L选自取代或未取代的C 1-12亚烷基、C 2-12亚烯基、C 2-12亚炔基，所述亚烷基、亚烯基或亚炔基任选地被一个或多个-O-、-NR 8-或-S-间断；或者
L表示式(c)、式(d)或式(e)所示的基团，其中
Figure PCTCN2017117126-appb-000002
表示单键或双键，并且1位置处与Base连接，2位置处与磷原子(P)连接：
Figure PCTCN2017117126-appb-000003
Base表示式(a)或式(b)所示的基团：
Figure PCTCN2017117126-appb-000004
Figure PCTCN2017117126-appb-000005
表示单键或双键；
M表示N或NR 8；
W表示H、NR 8R 9、NR 8、CH 2、O或S；
Q表示O、S、NR 8或CH 2；
Z在每次出现时各自独立地表示氢、卤素、羟基、氰基、硝基、叠氮基、NR 8R 9、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基或者取代或未取代的C 3-8环烷基，如果存在多个Z，则其各自可以相同也可以不同；
p表示0、1、2、3、4或5；
条件是，当M被双键连接时，则W被单键连接；当M被单键连接时，则W被双键连接；
U表示O、S、NR 8或CR 10R 11；
E表示CR 10、CR 10R 11或S，条件是，当E被双键连接时，其为CR 10；
G在每次出现时各自独立地表示氢、卤素、羟基、氰基、硝基、叠氮基、NR 8R 9、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基或者取代或未取代的C 3-8环烷基，如果存在多个G，则其各自可以相同也可以不同；
q表示0-5的整数；
Ar 1表示C 6-14芳基或5-14元杂芳基；
R 1在每次出现时各自独立地表示氢、卤素、-OH、-CN、-NO 2、-NR 8R 9、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基、取代或未取代的C 1-6卤代烷基、取代或未取代的C 1-6烷硫基、取代或未取代的C 3-8环烷基、取代或未取代的3-10元杂环烷基、取代或未取代的C 2-10烯基、或者取代或未取代的C 2-10炔基，如果存在多个R 1，则其各自可以相同也可以不同；
m表示0-7的整数；
X表示CH 2、-S-、-O-或-NR 8-；
R 2和R 3在每次出现时各自独立地表示氢、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基、取代或未取代的C 6-14芳基、取代或未取代的C 7-20芳烷基、或者取代或未取代的C 3-8环烷基；或者R 2和R 3与所连接的碳原子一起形成取代或未取代的C 3-8环烷基或者取代或未取代 的3-10元杂环烷基；
R 4和R 5在每次出现时各自独立地表示氢、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基、取代或未取代的C 6-14芳基、取代或未取代的C 7-20芳烷基、或者取代或未取代的C 3-8环烷基；或者R 4和R 5与所连接的碳原子一起形成取代或未取代的C 3-8环烷基或者取代或未取代的3-10元杂环烷基；或者
R 3和R 4彼此连接、与它们各自所连接的碳原子一起形成取代或未取代的C 3-8环烷基或者取代或未取代的3-10元杂环烷基；
R 6表示氢、取代或未取代的C 1-6烷基、取代或未取代的C 3-8环烷基、取代或未取代的C 6-14芳基、取代或未取代的C 7-20芳烷基或者取代或未取代的C 1-6烷氧基；
R 7在每次出现时各自独立地表示氢、卤素、-OH、-CN、-NO 2、-NR 8R 9、取代或未取代的C 1-6烷基、取代或未取代的C 1-6卤代烷基、取代或未取代的C 1-6烷硫基、取代或未取代的C 3-8环烷基、取代或未取代的3-10元杂环烷基、取代或未取代的C 2-10炔基、或者取代或未取代的C 1-6烷氧基，如果存在多个R 7，则其各自可以相同也可以不同；或者
R 6和R 7彼此连接、与它们之间间隔的碳原子一起形成取代或未取代的C 3-8碳环基或3-10元杂环基；
n表示0-7的整数；
Ar 2表示C 6-14芳基或5-14元杂芳基；
r和s各自独立地表示1、2或3；
R 8和R 9在每次出现时各自独立地表示氢、取代或未取代的C 1-6烷基、或者取代或未取代的C 3-8环烷基，如果存在多个R 8、R 9，则其各自可以相同，也可以不同；并且
R 10和R 11在每次出现时各自独立地表示氢、取代或未取代的C 1-6烷基、或者取代或未取代的C 3-8环烷基，或者R 10和R 11一起形成C 1-6亚烷基，如果存在多个R 10、R 11，则其各自可以相同，也可以不同。
本发明的另一方面提供一种药物组合物，其包含本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，其中所述药物组合物是固体制剂、半固体制剂、液体制剂、气态制剂的形式。
本发明的另一方面提供本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，或者本发明的药物组合物在制备用于预防或治疗NS5B聚合酶介导的疾病、DNA聚合酶介导的疾病或逆转录酶介导的疾病的药物中的用途。
本发明的另一方面提供本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，或者本发明的药物组合物在制备用于预防或治疗病毒性疾病或癌症的药物中的用途。
本发明的另一方面提供本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，或者本发明的药物组合物，其用于预防或治疗NS5B聚合酶介导的疾病、DNA聚合酶介导的疾病或逆转录酶介导的疾病。
本发明提供的另一方面上述本发明的式(I)所示的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，或者本发明的药物组合物，其用于预防或治疗病毒性疾病或癌症。
本发明的另一方面提供预防或治疗NS5B聚合酶介导的疾病、DNA聚合酶介导的疾病或逆转录酶介导的疾病的方法，其包括向有此需要的个体给药有效量的本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，或者本发明的药物组合物。
本发明的另一方面预防或治疗病毒性疾病或癌症的方法，其包括向有此需要的个体给药有效量的本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，或者本发明的药物组合物。
本发明的另一方面提供制备本发明的化合物的方法，其包括以下步骤：
路线1
Figure PCTCN2017117126-appb-000006
步骤一：使式2所示的三卤氧磷与式1所示的化合物反应，得到式3所示的化合物；
步骤二：使式3所示的化合物与式4所示的化合物反应，得到式5所示的化合物；
步骤三：使式5所示的化合物与式6所示的五氟苯酚反应，得到式7所示的化合物；和
步骤四：使式7所示的化合物与式8所示的化合物反应，得到式(I)所示的化合物；
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、m、n、s、r、X、Ar 1、Ar 2、L和Base如上文所定义；并且
Y彼此相同或不同，且各自独立地选自卤素；
或者
路线2
Figure PCTCN2017117126-appb-000007
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、m、n、s、r、X、Ar 1、Ar 2、L和Base如上文所定义；
或者：
路线3
Figure PCTCN2017117126-appb-000008
所述路线3是磷手性纯化合物(I″)的合成方法，
其中，
Figure PCTCN2017117126-appb-000009
表示实楔形
Figure PCTCN2017117126-appb-000010
或虚楔形
Figure PCTCN2017117126-appb-000011
化学键中的任意一种；且
R 1、R 2、R 3、R 4、R 5、R 6、R 7、m、n、s、r、X、Ar 1、Ar 2、L和Base如上文所定义。
发明详述
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
在本发明中，取代基以及变量的组合只在这种组合可以带来化学上稳定的化合物的情况下才被允许。在取代基自身被2个以上基团取代的情况下，只要可以产生稳定的结构，那么这些复数个基团可以存在于相同的碳或者不同的碳。
如本文中所使用，术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
在本发明中，碳原子“C”的下标数字表示碳原子的数目，例如，C 1表示1个碳原子，C 2表示2个碳原子，C p-q表示p-q(0＜p＜q)个碳原子。碳原子“C”后所附基团名称表明该基团的种类，例如，C 1烷基表示甲基，C 2烯基表示乙烯基，C p-q烷基表示碳原子数为p-q的烷基。
如本文中所使用，术语“卤代”或“卤素”意指氟、氯、溴或碘。
如本文中所使用，术语“C 1-6烷基”是指碳原子数为1～6个的直链状或支链状的脂肪族饱和烃基，例如可以列举甲基、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、新戊基、正己基、异己基等。优选碳原子数为1～4的烷基(即C 1-4烷基)，可以列举例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基等。
如本文中所使用，术语“C 1-6烷氧基”是指烷基部分为上述“C 1-6烷基”的直链、或者支链的脂肪族饱和烃氧基，例如可以列举甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、戊氧基、异戊氧基、己氧基等。优选的是C 1-4烷氧基。
如本文中所使用，术语“C 1-6烷撑基”是指从直链状或支链状的“C 1-6烷烃”的两个不同碳原子上各失去一个氢原子而形成的二价基团。例如可以列举甲撑基(-CH 2-)、乙撑基(二亚甲基，-CH 2CH 2-)、丙撑基(三亚甲基，-CH 2CH 2CH 2-)、丁撑基(四亚甲基，-CH 2CH 2CH 2CH 2-)、异丁撑基(-CH 2CH(CH 3)CH 2-)等。其中优选C 1-4烷撑基，更优选C 1-3烷撑基。
如本文中所使用，术语“C 1-6亚烷基”是指从直链状或支链状的“C 1-6烷烃”的相同碳原子上失去两个氢原子而形成的二价基团。例如可以列举亚甲基(CH 2＝)、亚乙基(CH 3CH＝)、亚丙基(CH 3CH 2CH＝)、亚丁基(CH 3CH 2CH 2CH＝)等。其中优选C 1-4亚甲基，更优选C 1-3亚甲基。
如本文中所使用，术语“C 2-10烯基”是指具有1个以上不饱和双键的碳原子数为2～10个的 直链或者支链状的脂肪族烃基，例如可以列举乙烯基、1-丙烯基、2-丙烯基、2-甲基-1-丙烯基、2-甲基-2-丙烯基、2-丁烯-1-基、3-丁烯-1-基、2-戊烯-1-基、3-戊烯-1-基、4-戊烯-1-基、5-己烯-1-基、4-己烯-1-基、3-己烯-1-基、2-己烯-1-基、3-甲基-2-丁烯-1-基、3-甲基-3-戊烯-1-基、3-甲基-2-戊烯-1-基、4-甲基-3-戊烯-1-基、4-甲基-2-戊烯-1-基和2-甲基-2-戊烯-1-基等。优选的是具有一个双键。优选的是C 2-6烯基。
如本文中所使用，术语“C 2-10炔基”是指具有1个以上不饱和三键的碳原子数为2～10个的直链或者支链状的脂肪族烃基，例如可以列举乙炔基、1-丙炔-1-基、2-丙炔-1-基、2-丁炔-1-基、3-丁炔-1-基、2-戊炔-1-基、3-戊炔-1-基、4-戊炔-1-基、5-己炔-1-基、4-己炔-1-基、3-己炔-1-基和2-己炔-1-基等。优选的是具有一个三键。优选的是C 2-6炔基。
如本文中所使用，术语“C 3-8环烷基”是指碳原子数为3～8个的环状脂肪族烃基，例如可以列举环丙基、环丁基、环戊基、环己基、环庚基等。优选的是C 3-4环烷基，可以列举例如环丙基或环丁基。与此相应地，“C 4-8环烷基”是指碳原子数为4～8个的环烷基。在某些情况下，所述环烷基可以与芳基或杂芳基稠合。
如本文中所使用，术语“C 3-8杂环烷基”是指在上述“C 3-8环烷基”的环上进一步包含至少一个选自N、O和S的杂原子的基团，例如可以列举氧杂环丁烷基、氮杂环丁烷基、硫杂环丁烷基、四氢呋喃基、吡咯烷基、咪唑烷基、二噁烷基、哌啶基、哌嗪基、四氢吡喃基等。优选的是在C 3-8环烷基中具有一个选自N、O和S的杂原子。优选的是C 3-6杂环烷基。与此相应地，“C 4-8杂环烷基”是指碳原子数为4～8个的杂环烷基。术语“3-10元杂环烷基”是指具有3至10个环原子(其中包括至少一个选自N、O和S的杂原子)的杂环烷基；术语“4-10元杂环烷基”是指具有4至10个环原子(其中包括至少一个选自N、O和S的杂原子)的杂环烷基。在某些情况下，所述杂环烷基与芳基或杂芳基稠合。
如本文中所使用，术语“芳烷基”表示芳基取代的烷基，其中所述芳基和所述烷基如本文中所定义。通常，所述芳基可具有6-14个碳原子，并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、苯基乙基、苯基丙基、苯基丁基等。
如本文中所使用，术语“烷硫基”意指通过硫原子连接至母体分子部分的如上文所定义的烷基。C 1-6烷硫基的代表性实例包括但不限于甲硫基、乙硫基、叔丁硫基、己硫基等。
如本文中所使用，术语“C 4-8碳环基”是指碳原子数为4～8个的环状基团，其可以是饱和环，也可以是不饱和环。饱和环的情况即相当于碳原子数为4～8个的环烷基。不饱和环的情况可以包括C 4-8环烯基，其是在环上具有至少一个不饱和双键的碳原子数为4～8个的环状烃基，例如可以列举环戊烯基、环己烯基、环庚烯基、环辛烯基等；C 4-8环炔基，其是在环上具有至少一个不饱和三键的碳原子数为4～8个的环状烃基，例如可以列举环己炔基、环庚炔基等；还可以是具有芳香性的C 4-8碳环基，例如苯基。
如本文中所使用，术语“C 4-8杂环基”是指在上述C 4-8碳环基的环上进一步包含至少一个选自N、O和S的杂原子的基团，其可以是饱和环，也可以是不饱和环。饱和环的情况即相当于碳原子数为4～8个的杂环烷基。不饱和环的情况是指在上述碳原子数为4～8个的杂环烷基的任意位置具有至少一个不饱和双键和/或不饱和三键而成的基团，例如可以列举咪唑啉基、异噁唑啉基、吡咯基、吡唑基、吡唑啉基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、噻吩基、噁二唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基等。
如本文中所使用，术语“C 6-10芳基”是指具有6～8个碳原子的单环或双环芳烃基，如苯基、1-萘基、2-萘基等。
如本文中所使用，术语“C 3-10杂芳基”是指在至少一个环中含有至少一个选自N、O和S的杂原子的碳原子数为3-10的芳族5-或6-元单环基团或者9-或10-元双环基团，所述含杂原子的环优选具有1、2或3个选自O、S和N的杂原子。含杂原子的杂芳基的各环可含有1个或2个氧或硫原子和/或1至4个氮原子，条件是各环中的杂原子总数为4个或更少且各环具有至少一个碳原子。氮和硫原子可任选被氧化，且氮原子可任选被季铵化。作为单环杂芳基，例如可以列举吡咯基、吡唑基、吡唑啉基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基等。作为双环杂芳基，例如可以列举吲哚基、苯并噻唑基、苯并间二氧杂环戊烯基、苯并噁唑基、苯并噻吩基、喹啉基、四氢异喹啉基、异喹啉基、苯并咪唑基、苯并吡喃基、吲嗪基、苯并呋喃基、色酮基、香豆素基、苯并吡喃基、噌啉基、喹喔啉基、吲唑基、吡咯并吡啶基、呋喃并吡啶基、二氢异吲哚基、四氢喹啉基等。 术语“5-6元杂芳基”是指具有5或6个环原子(其中包括至少一个选自N、O和S的杂原子)的杂芳基，例如可以列举吡咯基、吡唑基、吡唑啉基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基等；术语“5-14元杂芳基”是指具有5至14个环原子(其中包括至少一个选自N、O和S的杂原子)的杂芳基。
在本发明中，上述“C 1-6烷基”、“C 1-6烷氧基”、“C 1-6烷撑基”、“C 1-6亚烷基”、“C 2-10烯基”、“C 2-10炔基”、“C 3-8环烷基”、“C 3-8杂环烷基”、“C 4-8碳环基”、“C 4-8杂环基”、“C 6-10芳基”和“C 3-10杂芳基”的取代基例如可以列举一种或多种选自以下的相同或不同的基团：氰基、羟基、羧基、卤素(F、Cl、Br、I)、C 1-6烷基、卤代C 1-6烷基、卤代C 1-6烷氧基(例如CF 3O)、C 3-6环烷基(例如环丙基)、C 1-6烷氧基(例如甲氧基、乙氧基、丙氧基、丁氧基等)、C 2-10烯基氧基(例如乙烯基氧基、烯丙基氧基等)、C 1-6烷氧羰基(例如甲氧羰基、乙氧羰基、叔丁氧羰基等)、硝基、亚硝基、叠氮基、氨基、氨基羰基氨基、C 1-6烷基氨基羰基氨基、氨基羰基C 1-6烷基、C 1-6烷基氨基羰基C 1-6烷基、氨基羰基氧基、氨基C 1-6烷氧羰基、C 1-6烷氧羰基氨基、C 1-6烷氧基C 1-6烷基氨基、C 2-10烯基、C 2-10炔基、C 1-6烷基氨基(例如甲基氨基、乙基氨基、二甲基氨基等)、酰基氨基(例如乙酰氨基、苯甲酰氨基等)、C 6-10芳基烷基氨基(例如苄基氨基、三苯甲基氨基)、羟基氨基、C 1-6烷基磺酰基氨基(例如甲基磺酰基氨基)、C 1-6烷基亚磺酰基氨基(例如甲基亚磺酰基氨基)、亚氨基、羟基亚氨基、C 1-6烷基亚氨基(例如甲基亚氨基、乙基亚氨基、二甲基亚氨基等)、C 1-6烷氧基亚氨基(例如甲氧基亚氨基、乙氧基亚氨基等)、酰基亚氨基(例如乙酰基亚氨基、苯甲酰基亚氨基等)、叠氮基、C 6-10芳基(例如苯基等)、C 6-10芳基C 1-6烷基(例如苄基、苯基乙基等)、C 6-10芳基C 1-6烷氧基(例如苄基氧基)、C 1-6烷基羰基氧基、C 4-8杂环基(包含脂族杂环基和杂芳基)、非芳族C 4-8杂环基(例如吡咯啉基、哌啶基、哌嗪基、吡咯烷基、吗啉基、吗啉代等)、C 3-10杂芳基(例如呋喃基、噻吩基、吡啶基、异噁唑基、噻唑基、噻二唑基、噁唑基、噁二唑基、四唑基、吲哚基、苯并呋喃基等)、C 3-10杂芳基C 1-6烷基(吡啶基甲基、吡啶基乙基等)、氰基、异氰基、异氰酸根合、硫代氰酸根合、异硫代氰酸根合、巯基、C 1-6烷硫基(例如甲硫基等)、C 1-6烷基磺酰基(例如甲基磺酰基、乙基磺酰基)、C 1-6烷基亚磺酰基、氨基羰基、C 1-6烷基氨基羰基、(例如甲基氨基羰基、乙基氨基羰基、二甲基氨基羰基等)、氨磺酰基、烷基氨基羰基烷基氨磺酰基、酰基(例如甲酰基、乙酰基等)、甲酰氧基、硫代甲酰基、硫代羧基、二硫代羧基、硫代氨基甲酰基、亚磺基、磺基、肼基、叠氮基、脲基、脒基、胍基、苯二甲酰亚胺基、三C 1-6烷基甲硅烷基(三甲基甲硅烷基等)、氧代基等。上述取代基优选地选自：卤素、氰基、硝基、羧基、羟基、氨基、氨基羰基、叠氮基、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 1-6烷氧羰基、C 1-6烷硫基、C 1-6烷基亚磺酰基、C 1-6烷基磺酰基、C 1-6烷基氨基磺酰基、C 1-6烷基磺酰胺基、C 1-6烷基氨基、C 1-6烷基羰基氧基、C 1-6烷基氨基羰基、氨基羰基氨基、C 1-6烷基氨基羰基氨基、氨基羰基C 1-6烷基、C 1-6烷基氨基羰基C 1-6烷基、氨基羰基氧基、氨基C 1-6烷氧羰基、C 1-6烷氧羰基氨基、C 1-6烷氧基C 1-6烷基氨基、C 2-10烯基、C 2-10炔基、C 6-10芳基和C 4-8杂环基(包含脂族杂环基和杂芳基)；特别优选地选自：羟基、卤素、叠氮基、甲基、乙基、丙基、丁基、卤代甲基、卤代乙基、卤代丙基、卤代丁基、羧基、氰基和硝基。
除非另外指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如 2H、 3H，优选 2H)；碳的同位素(例如 11C、 13C及 14C)；氯的同位素(例如 36Cl)；氟的同位素(例如 18F)；碘的同位素(例如 123I及 125I)；氮的同位素(例如 13N及 15N)；氧的同位素(例如 15O、 17O及 18O)；磷的同位素(例如 32P)；及硫的同位素(例如 35S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即 3H)及碳-14(即 14C)因易于掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如 11C、 18F、 15O及 13N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些，例如，D 2O、丙酮-d 6或DMSO-d 6。
本文中可使用实线
Figure PCTCN2017117126-appb-000012
波浪线
Figure PCTCN2017117126-appb-000013
实楔形
Figure PCTCN2017117126-appb-000014
或虚楔形
Figure PCTCN2017117126-appb-000015
描绘本发明的化合物的化学键。使用实线以描绘键连至不对称原子的键欲表明，包括该原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用波浪线以描绘键连至不对称原子的键欲表明，该键为实楔形
Figure PCTCN2017117126-appb-000016
或虚楔形
Figure PCTCN2017117126-appb-000017
键中的任意一种。使用实或虚楔形以描绘键连至不对称原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。
本发明的化合物含有一个或多个不对称中心，由此能够以外消旋物、外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体等的形式存在。
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于：药学上可接受的盐、酯、溶剂合物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本发明的化合物的“药物上可接受的盐”包含与硫酸、盐酸、氢溴酸、磷酸、或硝酸等无机酸形成的盐，或者与乙酸、苯甲酸、草酸、乳酸、苹果酸、酒石酸、富马酸、马来酸、柠檬酸、丙二酸、扁桃酸、葡萄糖酸、半乳糖二酸、葡庚糖酸、乙醇酸、谷氨酸、三氟醋酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、樟脑磺酸、或萘-2-磺酸等有机酸形成的盐，或者与锂离子、钠离子、钾离子、钙离子、镁离子、锌离子、铝离子等1种或多种金属离子形成的盐，或者与氨、精氨酸、赖氨酸、哌嗪、胆碱、二乙基胺、4-苯基环己基胺、2-氨基乙醇、苄星青霉素等胺形成的盐。只要是药学上可接受的盐即可，没有特别限定。由游离体向该盐的转换可以用现有的方法来进行
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、脱脂化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)及“Bioreversible Carriers in Drug Design,”Pergamon Press,1987(E.B.Roche编辑，American Pharmaceutical Association)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973；和T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,1991中所述的那些保护基，这些参考文献通过援 引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。
术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。
化合物
本发明的一个目的在于提供式(I)所示的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，
Figure PCTCN2017117126-appb-000018
其中，L选自取代或未取代的C 1- 12亚烷基、C 2- 12亚烯基、C 2-12亚炔基，所述亚烷基、亚烯基或亚炔基任选地被一个或多个-O-、-NR 8-或-S-间断；或者
L表示式(c)、式(d)或式(e)所示的基团，其中
Figure PCTCN2017117126-appb-000019
表示单键或双键，并且1位置处与Base连接，2位置处与磷原子(P)连接：
Figure PCTCN2017117126-appb-000020
Base表示式(a)或式(b)所示的基团：
Figure PCTCN2017117126-appb-000021
Figure PCTCN2017117126-appb-000022
表示单键或双键；
M表示N或NR 8；
W表示H、NR 8R 9、NR 8、CH 2、O或S；
Q表示O、S、NR 8或CH 2；
Z在每次出现时各自独立地表示氢、卤素、羟基、氰基、硝基、叠氮基、NR 8R 9、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基或者取代或未取代的C 3-8环烷基，如果存在多个Z，则其各自可以相同也可以不同；
p表示0、1、2、3、4或5；
条件是，当M被双键连接时，则W被单键连接；当M被单键连接时，则W被双键连接；
U表示O、S、NR 8或CR 10R 11；
E表示CR 10、CR 10R 11或S，条件是，当E被双键连接时，其为CR 10；
G在每次出现时各自独立地表示氢、卤素、羟基、氰基、硝基、叠氮基、NR 8R 9、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基或者取代或未取代的C 3-8环烷基，如果存在多个G，则其各自可以相同也可以不同；
q表示0-5的整数；
Ar 1表示C 6-14芳基或5-14元杂芳基；
R 1在每次出现时各自独立地表示氢、卤素、-OH、-CN、-NO 2、-N R 8R 9、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基、取代或未取代的C 1-6卤代烷基、取代或未取代的C 1-6烷硫基、取代或未取代的C 3-8环烷基、取代或未取代的3-10元杂环烷基、取代或未取代的C 2-10烯基、或者取代或未取代的C 2-10炔基，如果存在多个R 1，则其各自可以相同也可以不同；
m表示0-7的整数；
X表示CH 2、-S-、-O-或-NR 8-；
R 2和R 3在每次出现时各自独立地表示氢、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基、取代或未取代的C 6-14芳基、取代或未取代的C 7-20芳烷基、或者取代或未取代的C 3-8环烷基；或者R 2和R 3与所连接的碳原子一起形成取代或未取代的C 3-8环烷基或者取代或未取代的3-10元杂环烷基；
R 4和R 5在每次出现时各自独立地表示氢、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基、取代或未取代的C 6-14芳基、取代或未取代的C 7-20芳烷基、或者取代或未取代的C 3-8环烷基；或者R 4和R 5与所连接的碳原子一起形成取代或未取代的C 3-8环烷基或者取代或未取代的3-10元杂环烷基；或者
R 3和R 4彼此连接、与它们各自所连接的碳原子一起形成取代或未取代的C 3-8环烷基或者取代或未取代的3-10元杂环烷基；
R 6表示氢、取代或未取代的C 1-6烷基、取代或未取代的C 3-8环烷基、取代或未取代的C 6-14芳基、取代或未取代的C 7-20芳烷基或者取代或未取代的C 1-6烷氧基；
R 7在每次出现时各自独立地表示氢、卤素、-OH、-CN、-NO 2、-NR 8R 9、取代或未取代的C 1-6烷基、取代或未取代的C 1-6卤代烷基、取代或未取代的C 1-6烷硫基、取代或未取代的C 3-8环烷基、取代或未取代的3-10元杂环烷基、取代或未取代的C 2-10炔基、或者取代或未取代的C 1-6烷氧基，如果存在多个R 7，则其各自可以相同也可以不同；或者
R 6和R 7彼此连接、与它们之间间隔的碳原子一起形成取代或未取代的C 3-8碳环基或3-10元杂环基；
n表示0-7的整数；
Ar 2表示C 6-14芳基或5-14元杂芳基；
r和s各自独立地表示1、2或3；
R 8和R 9在每次出现时各自独立地表示氢、取代或未取代的C 1-6烷基、或者取代或未取代的C 3-8环烷基，如果存在多个R 8、R 9，则其各自可以相同，也可以不同；并且
R 10和R 11在每次出现时各自独立地表示氢、取代或未取代的C 1-6烷基、或者取代或未取代的C 3-8环烷基，或者R 10和R 11一起形成C 1-6亚烷基，如果存在多个R 10、R 11，则其各自可以相同，也可以不同。
根据本发明的一些实施方案，本发明的化合物为式(Ia)的化合物：
Figure PCTCN2017117126-appb-000023
其中，
L-Base表示下式(f)或式(g)所示的基团：
Figure PCTCN2017117126-appb-000024
Base表示下式(a)或式(b)所示的基团：
Figure PCTCN2017117126-appb-000025
其中，
Figure PCTCN2017117126-appb-000026
表示单键或双键，
M表示N或NR 8；
W表示NR 8R 9或O；
Q表示O或S；
Z在每次出现时各自独立地表示氢、卤素、NR 8R 9、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基或者取代或未取代的C 3-8环烷基，如果存在多个Z，则其各自可以相同也可以不同；
p表示0～2的整数；
条件是，当M被双键连接时，则W被单键连接，M表示N，W表示NR 8R 9；当M被单键连接时，则W被双键连接，M表示NR 8，W表示O；
U表示O、S或CR 10R 11；
E表示CR 10、CR 10R 11或S，条件是，当E被双键连接时，则其为CR 10；
G在每次出现时各自独立地表示氢、卤素、羟基、叠氮基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基或者取代或未取代的C 3-8环烷基，如果存在多个G，则其各自可以相同也可以不同；
q表示0～4的整数；
A表示取代或未取代的C 1-6烷撑基；
B表示取代或未取代的C 1-6烷撑基；
D表示O、S或NR 8；
Ar 1表示C 6-10芳基或C 3-10杂芳基；
R 1在每次出现时各自独立地表示氢、卤素、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基、取代或未取代的C 3-8环烷基、取代或未取代的C 3-8杂环烷基、取代或未取代的C 2-10烯基、或者取代或未取代的C 2-10炔基如果存在多个R 1，则其各自可以相同也可以不同；
m表示0～7的整数；
X表示-O-或-NR 8-；
R 2和R 3各自独立地表示氢、取代或未取代的C 1-6烷基、取代或未取代的C 3-8环烷基；或者R 2和R 3与所连接的碳原子一起形成取代或未取代的C 3-8环烷基或取代或未取代的C 3-8杂环烷基；
R 4和R 5各自独立地表示氢、取代或未取代的C 1-6烷基、取代或未取代的C 3-8环烷基；或者R 4和R 5与所连接的碳原子一起形成取代或未取代的C 3-8环烷基或者取代或未取代的C 3-8杂环烷基；或者
R 3和R 4彼此连接、与它们各自所连接的碳原子一起形成取代或未取代的C 4-8环烷基或者取代或未取代的C 4-8杂环烷基；
R 6表示氢、取代或未取代的C 1-6烷基、取代或未取代的C 3-8环烷基、或者取代或未取代的C 1-6烷氧基；
R 7在每次出现时各自独立地表示氢、卤素、取代或未取代的C 1-6烷基、取代或未取代的C 3-8环烷基、或者取代或未取代的C 1-6烷氧基，如果存在多个R 7，则其各自可以相同也可以不同；或者
R 6和R 7彼此连接、与它们之间间隔的碳原子一起形成取代或未取代的C 4-8碳环基或C 4-8杂环基；
n表示0～7的整数；
Ar 2表示C 6-10芳基或C 3-10杂芳基；
R 8和R 9在每次出现时各自独立地表示氢、取代或未取代的C 1-6烷基、或者取代或未取代的C 3-8环烷基，如果存在多个R 8、R 9，则其各自可以相同，也可以不同，
R 10和R 11在每次出现时各自独立地表示氢、取代或未取代的C 1-6烷基、或者取代或未取代的C 3-8环烷基，或者R 10和R 11一起形成C 1-6亚烷基，如果存在多个R 10、R 11，则其各自可以相同，也可以不同。
根据本发明的一些实施方案，本发明提供上述式(I)所示的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，
其中，
r、s均为1；
Base选自：
Figure PCTCN2017117126-appb-000027
L选自任选地被一个或多个G取代的C 1-6亚烷基、C 2-6亚烯基、C 2-6亚炔基，所述亚烷基、亚烯基或亚炔基任选地被一个或多个-O-、-NR 8-或-S-间断；
或者L选自下列基团：
Figure PCTCN2017117126-appb-000028
其中
Figure PCTCN2017117126-appb-000029
表示单键或双键，并且1位置处与Base连接，2位置处与磷原子(P)连接；
X、U、W、Q在每次出现时各自独立地选自CH 2、O、S和NR 8；
G和Z在每次出现时各自独立地选自卤素、-OH、-CN、-NO 2、-NR 8R 9、-N 3、C 1-6烷基和C 3-6环烷基；
p、q在每次出现时各自独立地为0、1、2、3、4或5，条件是p不大于对应基团上可被取代的位置的数目且不大于对应基团上可被取代的位置的数目；当p大于1时，每个Z可以相同或不同；当q大于1时，每个G可以相同或不同；
Ar 1和Ar 2各自独立地选自C 6-14芳基和5-14元杂芳基；
m、n各自独立地选自1、2、3、4或5，优选1或2；
R 1、R 7各自独立地选自氢、卤素、-OH、-CN、-NO 2、-NR 8R 9、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 3-6环烷基、3-10元杂环烷基和C 2-6炔基；
R 8、R 9在每次出现时各自独立地表示氢、C 1-6烷基和C 3-6环烷基；
R 2、R 3各自独立地选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 6-14芳基和C 7-20芳烷基，所述烷基、环烷基、烷氧基、芳基和芳烷基各自任选地被一个或多个选自卤素、-OH、-CN和-NO 2的取代基取代；
或者R 2和R 3连同其所连接的碳原子共同形成C 3-6环烷基或3-10元杂环烷基；
R 4、R 5各自独立地选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 6-14芳基和C 7-20芳烷基，所述烷基、环烷基、烷氧基、芳基和芳烷基各自任选地被一个或多个选自卤素、-OH、-CN和-NO 2的取代基取代；
或者R 4和R 5连同其所连接的碳原子共同形成C 3-6环烷基或3-10元杂环烷基；
或者R 3和R 4连同其所连接的碳原子共同形成C 3-6环烷基或3-10元杂环烷基；且
R 6选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 6-14芳基和C 7-20芳烷基，所述烷基、环烷基、烷氧基、芳基和芳烷基各自任选地被一个或多个选自卤素、-OH、-CN和-NO 2的取代基取代；
或者R 6和R 7连同其所连接的碳原子共同形成与Ar 2稠合的C 3-6环烷基或3-10元杂环烷基；优选地，R 6和R 7连同其所连接的碳原子共同形成与Ar 2稠合的C 4-6环烷基或4-10元杂环烷基。
根据本发明的一些实施方案，R 8为氢、C 1-6烷基或C 3-8环烷基。在一些优选的实施方案中，R 8为氢、甲基、乙基、丙基或环丙基。
根据本发明的一些实施方案，R 9为氢、C 1-6烷基或C 3-8环烷基。在一些优选的实施方案中，R 9为氢、甲基、乙基、丙基或环丙基。在一些特别优选的实施方案中，R 9为氢。
根据本发明的一些实施方案，Z在每次出现时各自独立地为氢、卤素、NR 8R 9或C 1-6烷基。在一些优选的实施方案中，Z在每次出现时各自独立地为氢、氟、氯、甲基、乙基或丙基。
根据本发明的一些实施方案，p为0、1、2、3或4。
根据本发明的一些实施方案，R 10和R 11在每次出现时各自独立地为氢、C 1-6烷基或C 3-8环烷基，或者R 10和R 11一起形成C 1-6亚烷基。在一些优选的实施方案中，R 10和R 11在每次出现时各自独立地为氢、甲基、乙基、丙基、环丙基、环丁基、环戊基，或者R 10和R 11一起形成亚甲基或亚乙基。
根据本发明的一些实施方案，U为O或S。在一些优选的实施方案中，U为O。
根据本发明的一些实施方案，E为CH 2。
根据本发明的一些实施方案，G在每次出现时各自独立地为氢、卤素、羟基、叠氮基或C 1-6烷基。在一些优选的实施方案中，G在每次出现时各自独立地为氢、氟、氯、羟基、甲基、乙基、丙基、丁基或叠氮基。
根据本发明的一些实施方案，q为0、1、2、3或4。
根据本发明的一些实施方案，A为未取代的或被C 1-3烷基取代的C 1-3烷撑基。在一些优选的实施方案中，A为甲撑基、乙撑基或异丙撑基。
根据本发明的一些实施方案，B为未取代的或被C 1-3烷基取代的C 1-3烷撑基。在一些优选的实施方案中，B为乙撑基或异丙撑基。
根据本发明的一些实施方案，D为O。
根据本发明的一些实施方案，Base为下式所示的基团：
Figure PCTCN2017117126-appb-000030
根据本发明的一个实施方案，L选自：
Figure PCTCN2017117126-appb-000031
其中1位置处与B连接，2位置处与磷原子(P)连接。
根据本发明的一些实施方案，L-Base为下式所示的基团：
Figure PCTCN2017117126-appb-000032
根据本发明的一些实施方案，X为NH、N-C 1-6烷基(例如N-甲基)或O。在一些优选的实施方案中，X为NH。
根据本发明的一些实施方案，Ar 1为苯基、1-萘基、2-萘基或5-6元杂芳基(例如噻吩基、吡啶基或吡唑基)。
根据本发明的一些实施方案，Ar 2为苯基、1-萘基、2-萘基或5-6元杂芳基(例如噻吩基、吡啶基或吡唑基)。
根据本发明的一些实施方案，R 1在每次出现时各自独立地为氢、卤素、C 1-6烷基或C 1-6烷 氧基。在一些优选的实施方案中，R 1在每次出现时各自独立地为氢、氟、氯、溴、甲基、乙基或丙基。
根据本发明的一些实施方案，m为0、1、2、3或4。
根据本发明的一些实施方案，R 2和R 3在每次出现时各自独立地为氢或C 1-6烷基。在一些优选的实施方案中，R 2和R 3在每次出现时各自独立地为氢、甲基、乙基或丙基。
根据本发明的一些实施方案，R 2和R 3与所连接的碳原子一起形成C 3-8环烷基。在一些优选的实施方案中，R 2和R 3与所连接的碳原子一起形成环丙基、环丁基、环戊基或环己基。
根据本发明的一些实施方案，R 4和R 5在每次出现时各自独立地为氢或C 1-6烷基。在一些优选的实施方案中，R 4和R 5在每次出现时各自独立地为氢、甲基、乙基或丙基。
根据本发明的一些实施方案，R 6为氢、C 1-6烷基或C 3-8环烷基。在一些优选的实施方案中，R 6为氢、甲基、乙基、丙基、环丙基或环丁基。
根据本发明的一些实施方案，R 7在每次出现时各自独立地为氢、C 1-6烷基、C 3-8环烷基或C 1-6烷氧基。在一些优选的实施方案中，R 7在每次出现时各自独立地为氢、氟、氯、溴、甲基、乙基、丙基、叔丁基、甲氧基、环丙基或环丁基。
根据本发明的一些实施方案，n为0、1、2、3或4。
在本发明中，如果在同一化学式中存在多个G、Z、R 1、R 2、R 3、R 4、R 5、R 7、R 8、R 9、R 10，则各个基团的选择是独立的。即，在同一化学式中，相同符号表示的基团可以相同，也可以不同。
根据本发明的一些实施方案，本发明的化合物为式(II)所示的化合物，
Figure PCTCN2017117126-appb-000033
其中，R 1、R 2、R 3、R 6、R 7、m、n、Ar 1和Ar 2如上文所定义。
在一些优选的实施方案中，本发明的化合物为式(IIa)所示的化合物，
Figure PCTCN2017117126-appb-000034
其中，R 1、R 2、R 3、R 6和R 7以及m和n如上文所定义。
在一些特别优选的实施方案中，本发明的化合物为式(IIb)所示的化合物，
Figure PCTCN2017117126-appb-000035
其中，R 2、R 3、R 7和n如上文所定义。
根据本发明的一些实施方案，本发明的化合物为式(III)所示的化合物，
Figure PCTCN2017117126-appb-000036
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、m、n、s、r、Ar 1和Ar 2如上文所定义。
在一些优选的实施方案中，本发明的化合物为式(IIIa)所示的化合物，
Figure PCTCN2017117126-appb-000037
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、m、n、Ar 1和Ar 2如上文所定义。
在一些特别优选的实施方案中，本发明的化合物为式(IIIb)所示的化合物，
Figure PCTCN2017117126-appb-000038
其中，R 1、R 2、R 3、R 6、R 7、R 8、m、n、Ar 1和Ar 2如上文所定义。
在一些特别优选的实施方案中，本发明的化合物为式(IIIc-1)或式(IIIc-2)所示的化合物，
Figure PCTCN2017117126-appb-000039
其中，R 1、R 2、R 3、R 6、R 7、R 8、m、n、Ar 1和Ar 2如上文所定义。
根据本发明的一些实施方案，本发明的化合物为式(IV)所示的化合物，
Figure PCTCN2017117126-appb-000040
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、m、n、s、r、Ar 1和Ar 2如上文所定义。
根据本发明的一些实施方案，本发明的化合物为以下所示的化合物：
Figure PCTCN2017117126-appb-000041
Figure PCTCN2017117126-appb-000042
Figure PCTCN2017117126-appb-000043
药物组合物
本发明的另一目的在于提供一种药物组合物，其包含本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，所述药物组合物是固体制剂、半固体制剂、液体制剂或气态制剂的形式。
根据本发明的一些实施方案，本发明的药物组合物进一步包含药学上可接受的辅料，用来形成药物制剂。所述辅料可以为载体、赋形剂、稀释剂或其组合。所述载体、赋形剂和稀释剂指的是对有机体不引起明显的刺激性和不干扰所给药化合物的生物活性的性质的药物组合物中的非活性成分。所述载体、赋形剂和稀释剂包括水、乳糖、葡萄糖、果糖、蔗糖、山梨糖醇、甘露醇、聚乙二醇、丙二醇、淀粉、凝胶、藻酸盐、硅酸钙、磷酸钙、纤维素、水性糖浆、甲基纤维素、聚乙烯基吡咯烷酮、对羟基苯并山梨酸烷基酯、滑石、硬脂酸镁、硬脂酸、甘油、以及包括芝麻油、橄榄油、大豆油等在内的各种油等。另外，根据需要可在上述载体、赋形剂或稀释剂中混合一般使用的增量剂、粘合剂、崩解剂、pH调节剂、溶解剂等添加剂。
根据本发明的一些实施方案，本发明的药物组合物可以利用常用的制剂技术制备成片剂、丸剂、胶囊剂、颗粒剂、散剂、溶液剂、乳剂、悬浮剂、软膏剂、乳膏剂、注射剂、皮肤贴剂等口服或非口服制剂形式。
根据本发明的一些实施方案，本发明的药物组合物包含0.01-1000mg，适宜地0.5-800mg，优选1-400mg，更优选为5-200mg，特别优选10-100mg，最优选15-50mg，例如20mg、25mg、30mg的量的本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物。本发明药物组合物可以是单位剂量形式，所述单位剂量可含有0.01-1000mg，适宜地0.5-800mg，优选1-400mg，更优选5-200mg，特别优选10-100mg，最优选15-50mg，例如20mg、25mg、30mg的本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物。
根据本发明的一些实施方案，本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物可以与一种或多种其它活性成分联合用于治疗、预防、抑制或者改善疾病或者病状，其中药物的联合使用比任何一种药物的单独使用更为安全或者更为有效。这种其它药物可以以对此通常使用的途径和量与本发明的化合物同时或者依次给药。当本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物与一种或者多种其它药物同时使用时，在单位剂型中含有该其它药物和本发明的化合物的药物组合物是优选的，特别是与药学可接受的载体联合。然而，联合治疗还可以包括在不同重叠日程中给药本发明的化合物其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物和一种或者多种其它药物的治疗。还可以预期，当与一种或者多种其它活性成分联合使用时，本发明化合物和其它活性成分可以以比各自单独使用时更低的剂量使用。因此，除 了本发明的化合物外，本发明药物组合物还可以包含一种或者多种其它活性成分。
在一些优选的实施方案中，所述其它活性成分包括但不限于干扰素、病毒唑或其类似物、HCV NS3蛋白酶抑制剂、α-葡糖苷酶1抑制剂、肝保护剂、HCV NS5B聚合酶的非核苷抑制剂、HCV NS5A抑制剂、TLR-7激动剂、亲环素抑制剂、HCV IRES抑制剂、药物动力学增加剂和用于治疗HCV的其它药物或治疗剂，或其组合。
所述干扰素选自PEG化的
Figure PCTCN2017117126-appb-000044
PEG化的
Figure PCTCN2017117126-appb-000045
Figure PCTCN2017117126-appb-000046
Figure PCTCN2017117126-appb-000047
干扰素α(MOR-22、OPC-18、Alfaferone、Alfanative、Multiferon、subalin)、干扰素
Figure PCTCN2017117126-appb-000048
干扰素α-n1(Wellferon)、干扰素
Figure PCTCN2017117126-appb-000049
干扰素β(Avonex DL-8234)、干扰素-ω(ω
Figure PCTCN2017117126-appb-000050
Biomed510)、
Figure PCTCN2017117126-appb-000051
IFNα-2bXL、
Figure PCTCN2017117126-appb-000052
DA-3021、糖基化的干扰素α2b(AVI-005)、PEG-Infergen、PEG化的干扰素λ-1(PEG化的IL-29)和
Figure PCTCN2017117126-appb-000053
所述病毒唑及其类似物选自病毒唑
Figure PCTCN2017117126-appb-000054
和塔利韦林(taribavirin)
Figure PCTCN2017117126-appb-000055
Figure PCTCN2017117126-appb-000056
所述HCV NS3蛋白酶抑制剂选自波普瑞韦(SCH-503034、SCH-7)、替拉瑞韦(telaprevir)(VX-950)、TMC435350、BI-1335、BI-1230、MK-7009、VBY-376、VX-500、GS-9256、GS-9451、BMS-605339、PHX-1766、AS-101、YH-5258、YH5530、YH5531、ABT-450、ACH-1625、ITMN-191、MK5172、MK6325和MK2748。
所述α-葡糖苷酶1抑制剂选自西戈韦(celgosivir)(MX-3253)、米格列醇和UT-231B。
所述肝保护剂选自emericasan(IDN-6556)、ME-3738、GS-9450(LB-84451)、silibilin和MitoQ。
所述HCV NS5B聚合酶的非核苷抑制剂选自PF-868554、VCH-759、VCH-916、JTK-652、MK-3281、GS-9190、VBY-708、VCH-222、A848837、ANA-598、GL60667、GL59728、A-63890、A-48773、A-48547、BC-2329、VCH-796(nesbuvir)、GSK625433、BILN-1941、XTL-2125、ABT-072、ABT-333、GS-9669、PSI-7792和GS-9190。
所述HCV NS5A抑制剂选自ABT-267(ombitasvir)、AZD-2836(A-831)、BMS-790052、ACH-3102、ACH-2928、GS-5885、GS-5816、MK8325、MK4882、MK8742、PSI-461、IDX719和A-689。
所述TLR-7激动剂选自咪喹莫特、852A、GS-9620、ANA-773、ANA-975、AZD-8848(DSP-3025)和SM-360320。
所述亲环素抑制剂选自DEBIO-025、SCY-635和NIM811。
所述HCV IRES抑制剂选自MCI-067。
所述药物动力学增强剂选自BAS-100、SPI-452、PF-4194477、TMC-41629、GS-9350、GS-9585和罗红霉素。
所述用于治疗HCV的其他药物选自胸腺肽α1(日达仙(Zadaxin))、硝唑尼特(nitazoxanide)(Alinea、NTZ)、BIVN-401(virostat)、PYN-17(altirex)、KPE02003002、actilon(CPG-10101)、GS-9525、KRN-7000、civacir、GI-5005、XTL-6865、BIT225、PTX-111、TX2865、TT-033i、ANA971、NOV-205、tarvacin、EHC-18、VGX-410C、EMZ-702、AVI4065、BMS-650032、BMS-791325、Bavituximab、MDX-1106(ONO-4538)、Oglufanide和VX-497(merimepodib)。
治疗方法和用途
本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物可以抑制NS5B聚合酶、DNA聚合酶或逆转录酶。因此，本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物可以用作NS5B聚合酶抑制剂、DNA聚合酶抑制剂或逆转录酶抑制剂。
本发明的另一目的在于提供本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，或者本发明的药物组合物在制备用于治疗NS5B聚合酶介导的疾病、DNA聚合酶介导的疾病或逆转录酶介导的疾病的药物中的用途。
本发明的另一目的在于提供本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、 它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，或者本发明的药物组合物在制备用于治疗病毒性疾病或癌症的药物中的用途。
本发明另一目的在于提供本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，或者本发明的药物组合物，其用于治疗NS5B聚合酶介导的疾病、DNA聚合酶介导的疾病或逆转录酶介导的疾病。
本发明另一目的在于提供本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，或者本发明的药物组合物，其用于治疗病毒性疾病或癌症。
本发明另一目的在于提供治疗NS5B聚合酶介导的疾病、DNA聚合酶介导的疾病或逆转录酶介导的疾病的方法，其包括向有此需要的个体给药有效量的本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，或者本发明的药物组合物。
本发明另一目的在于提供治疗病毒性疾病或癌症的方法，其包括向有此需要的个体给药有效量的本发明的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，或者本发明的药物组合物。
根据本发明的一些实施方案，可使用本发明的化合物进行预防或治疗的病毒性疾病包括但不限于甲型病毒性肝炎、乙型病毒性肝炎、丙型病毒性肝炎、流行性感冒、疱疹和获得性免疫缺陷综合征(AIDS)，以及由上述疾病引发的相关症状或疾病(例如炎症、肝纤维化、肝硬化和肝癌等)。
一般对于成人患者而言，本发明的化合物可以以口服或非口服形式来进行给药，1天1次或分为数次来给药总剂量0.001～1500mg/天，优选0.01-1000mg/天，更优选0.1-800mg/天，特别优选1-600mg/天，例如250mg/天、400mg/天、500mg/天或600mg/天。应予说明，本发明的化合物的给药量可根据作为治疗对象的疾病的种类、患者的年龄、体重、症状等而适当增减。
制备方法
本发明的另一目的在于提供上述式(I)的化合物的制备方法，所述方法可以按照以下路线1来进行：
路线1
Figure PCTCN2017117126-appb-000057
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、m、n、s、r、X、Ar 1、Ar 2、L-Base和Base如上文所定义；并且
Y彼此相同或不同，且各自独立地选自卤素，优选为氯。
步骤一：使式2所示的三卤氧磷与式1所示的化合物反应，得到式3所示的化合物。
根据本发明的一些实施方案，步骤一是在有机碱的存在下进行的。
根据本发明的一些实施方案，步骤一包括：将三卤氧磷溶于有机溶剂，冷却至-80℃～-20 ℃，加入式1所示的化合物和有机碱。将反应液升温至15～40℃，优选20℃～35℃，更优选25～30℃，并搅拌1-8小时，优选2-6小时，得到式3所示的化合物粗品。
根据本发明的一些实施方案，式1所示的化合物、三卤氧磷和有机碱的摩尔比为1:(0.5～2):(0.5～2)，优选1:(0.8～2):(0.8～2)，更优选1:(1～1.5):(1～1.5)。
根据本发明的一些实施方案，式1所示的化合物与有机溶剂的重量体积比(克/毫升)为1:5～30，优选1:10～25，更优选1:15～20。
根据本发明的一些实施方案，三卤氧磷与有机溶剂的重量体积比(克/毫升)为1:5-30，优选1:10-25，更优选1:10-20。
根据本发明的一些实施方案，有机碱与有机溶剂的重量体积比(克/毫升)为1:15-30，优选1:20-25。
步骤二：使式3所示的化合物与式4所示的化合物反应，得到式5所示的化合物。
根据本发明的一些实施方案，步骤二包括：将步骤一所得的式3所示的化合物溶于有机溶剂中，将反应液冷却到-80℃--20℃，加入式4所示的化合物和有机碱。将反应液升温至15-40℃，优选20℃-35℃，更优选25-30℃，并搅拌1-8小时，优选2-6小时。得到式5所示的化合物粗品。
根据本发明的一些实施方案，式3所示的化合物、式4所示的化合物和有机碱的摩尔比为1:(0.5-1.5):(1.0-3.5)，优选1:(0.9-1.1):(1.4-3)。
根据本发明的一些实施方案，式4所示的化合物与有机溶剂的重量体积比(克/毫升)为1:(5-30)，优选1:(10-25)。
根据本发明的一些实施方案，有机碱与有机溶剂的重量体积比(克/毫升)为1:(3-25)，优选1:(5-20)。
步骤三：使式5所示的化合物与式6所示的五氟苯酚反应，得到式7所示的化合物。
根据本发明的一些实施方案，步骤三包括：将步骤二所得的式5所示的化合物溶于有机溶剂中，将反应液冷却到-80℃--20℃，依次向其中加入式6所示的化合物和有机碱。将反应液升温至15-40℃，优选20℃-35℃，更优选25-30℃，并搅拌1-8小时，优选2-6小时，得到得到式7所示的化合物。
根据本发明的一些实施方案，式5所示的化合物、式6所示的化合物和有机碱的摩尔比为1:(0.5-2):(0.5-2.5)，优选1:(0.7-1.5):(1.0-2.0)。
根据本发明的一些实施方案，式6所示的化合物与有机溶剂的重量体积比(克/毫升)为1:(5-30)，优选1:(10-25)。
根据本发明的一些实施方案，有机碱与有机溶剂的重量体积比(克/毫升)为1:(10-30)，优选1:(15-25)。
步骤四：使式7所示的化合物与式8所示的化合物反应，得到式(I)所示的化合物。
根据本发明的一些实施方案，步骤四包括：将式8所示的化合物溶于有机溶剂中，在惰性气体置换保护下，在0℃-25℃温度下向反应液中加入格式试剂，适当搅拌1-3小时后，降温至-20℃--10℃，加入步骤三得到的式7所示的化合物。将反应液升温至1℃-40℃，优选10℃-30℃，并搅拌5-20小时，优选10-15小时，得到式I所示化合物。
根据本发明的一些实施方案，式7所示的化合物、式8所示的化合物和格氏试剂的摩尔比为1:(0.8-2):(1.5-4)，优选1:(1-1.5):(2-3.5)。
根据本发明的一些实施方案，式7所示的化合物与有机溶剂的重量体积比(克/毫升)为1:(30-70)。
根据本发明的一些实施方案，式8所示的化合物与有机溶剂的重量体积比(克/毫升)为1:(90-120)。
在上述步骤一、二、三中所使用的有机碱包括但不限于叔丁醇钠、三乙胺、DIPEA、吡啶或DMAP。
在上述步骤一、二、三、四中所使用的有机溶剂是本领域常用的溶剂，例如但不限于N,N-二甲基甲酰胺、二甲基亚砜、N-甲基吡咯烷酮、饱和烃类(例如环己烷、己烷等)、卤代烃类(例如二氯甲烷、氯仿、1,2-二氯乙烷等)、醚类(例如四氢呋喃、乙醚、二噁烷、1,2-二甲氧基乙烷等)、腈类(例如乙腈等)和它们的混合溶剂等。
或者，所述方法可以按照以下路线2来进行：
路线2
Figure PCTCN2017117126-appb-000058
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、m、n、s、r、X、Ar 1、Ar 2、L和Base如上文所定义。
步骤一’：
根据本发明的一些实施方案，步骤一’是在有机碱或无机碱和/或缩合试剂的存在下进行的。所述有机碱包括但不限于叔丁醇钠、三乙胺、DIPEA、吡啶或DMAP。所述无机碱包括但不限于NaH、NaOH、Na 2CO 3或K 2CO 3。所述缩合试剂包括但不限于DCC、DIC、EDC、BOP、PyAOP和PyBOP。
根据本发明的一些实施方案，式1的化合物为苯酚或萘酚。
根据本发明的一些实施方案，步骤一’是在60℃-150℃，优选70℃-130℃，更优选80℃-110℃的温度下进行的。
根据本发明的一些实施方案，式8的化合物与式1的化合物的摩尔比为1:(0.5-2)，优选1:(0.8-2)，更优选1:(1-1.5)。
根据本发明的一些实施方案，式8的化合物、式1的化合物与有机碱或无机碱的摩尔比为1:(0.5-2):(0.5-2)，优选1:(0.8-2):(0.8-2)，更优选1:(1-1.5):(1-1.5)。
根据本发明的一些实施方案，式8的化合物与缩合剂的摩尔比为1:(1.5-3)，优选1:(1.8-2.5)。
步骤二’：
根据本发明的一些实施方案，所述卤化剂为氯化剂或溴化剂，优选为氯化剂，更优选为SOCl 2。
根据本发明的一些实施方案，步骤二’是在-20℃-150℃，优选50℃-110℃，进一步优选50℃-90℃，更优选60-80℃的温度下进行的。
根据本发明的一些实施方案，式9的化合物与卤化剂的摩尔比为1:(2-10)，优选1:(3-10)，更优选1:(4-8)。
步骤三’：
根据本发明的一些实施方案，步骤三’是在有机碱或无机碱的存在下进行的。所述有机碱包括但不限于叔丁醇钠、三乙胺、DIPEA、吡啶或DMAP。所述无机碱包括但不限于NaH、NaOH、Na 2CO 3或K 2CO 3。
根据本发明的一些实施方案，步骤三’是在-78℃-25℃，优选-40℃-0℃，更优选-30℃-10℃的温度下进行的。
根据本发明的一些实施方案，式10的化合物与式4的化合物的摩尔比为1:(1-10)，优选1:(1-3)，更优选1:(1.5-2.5)。
根据本发明的一些实施方案，式10的化合物、式4的化合物与有机碱或无机碱的摩尔比为1:(1-10):(5-20)，优选1:(1-3):(5-20)，更优选1:(1.5-2.5):(8-15)。
以上步骤一’、二’和三’均可在有机溶剂中进行。所述有机溶剂可以是本领域常用的反应溶剂，例如但不限于N,N-二甲基甲酰胺、二甲基亚砜、N-甲基吡咯烷酮、饱和烃类(例如环己烷、己烷等)、卤代烃类(例如二氯甲烷、氯仿、1,2-二氯乙烷等)、醚类(例如四氢呋喃、乙醚、二噁烷、1,2-二甲氧基乙烷等)、腈类(例如乙腈等)和它们的混合溶剂等。
本发明还提供了式(I″)的磷手性纯化合物的合成方法，所述方法可以按照以下路线3来进行：
路线3
Figure PCTCN2017117126-appb-000059
其中，
Figure PCTCN2017117126-appb-000060
表示实楔形
Figure PCTCN2017117126-appb-000061
或虚楔形
Figure PCTCN2017117126-appb-000062
化学键中的任意一种；且
R 1、R 2、R 3、R 4、R 5、R 6、R 7、m、n、s、r、X、Ar 1、Ar 2、L和Base如上文所定义。
步骤一”：使式9的化合物发生卤化反应生成式11的化合物。
根据本发明的一些实施方案，所述卤化剂为氯化亚砜、草酰氯、三氯化磷、氯三苯基膦盐、溴化亚砜、草酰溴、三溴化磷或溴三苯基膦盐，优选为氯化亚砜。
根据本发明的一些实施方案，步骤一”是在-20℃-150℃，优选25℃-120℃，更优选50-110℃的温度下进行的。
根据本发明的一些实施方案，步骤一”的反应时间为12h-96h，优选36h-72h。
根据本发明的一些实施方案，式9的化合物与卤化剂的摩尔比为1:(2-10)，优选1:(3-6)。
步骤二”：使式11的化合物与式4的化合物反应生成式(I”)的化合物。
根据本发明的一些实施方案，步骤二”是在-78℃-25℃，优选-40℃-0℃的温度下进行的。
根据本发明的一些实施方案，式12的化合物与式4的化合物的摩尔比为1:(1-10)，优选1:(1-5)。
以上步骤一”和二”均可在有机溶剂中进行。所述有机溶剂可以是本领域常用的反应溶剂，例如但不限于N,N-二甲基甲酰胺、二甲基亚砜、N-甲基吡咯烷酮、酯类(例如乙酸甲酯、乙酸乙酯、乙酸丙酯等)、饱和烃类(例如环己烷、己烷等)、卤代烃类(例如二氯甲烷、氯仿、1,2-二氯乙烷等)、醚类(例如四氢呋喃、乙醚、异丙醚、二噁烷、1,2-二甲氧基乙烷等)、苯类(例如甲苯、二甲苯)和腈类(例如乙腈等)和它们的混合溶剂等。
如上所得的式(I)化合物可以通过制备高效液相色谱进行分离，得到异构体。所得到的异构体可以是对映异构体，非对映异构体等形式。
Figure PCTCN2017117126-appb-000063
实施例
为了使本发明的目的和技术方案更加清楚，以下结合具体实施例进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。并且，下列实施例中未提及的具体实验方法，均按照常规实验方法进行。在本发明中用于合成的起始物质和反应试剂均可以在商业上得到。
本文中的缩写具有以下含义：
表1.英文缩写含义
缩写 含义
DMAP 4-二甲氨基吡啶
DIPEA N,N-二异丙基乙胺
DCC 二环己基碳二亚胺
DIC N,N-二异丙基碳二亚胺
EDC 1-(3-二甲氨基丙基)-3-乙基碳二亚胺
BOP 苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐
PyAOP (3H-1,2,3-三唑并[4,5-b]吡啶-3-氧基)三-1-吡咯烷基磷鎓六氟磷酸盐
PyBOP 1H-苯并三唑-1-基-氧基三吡咯烷基磷鎓六氟磷酸盐
CD 3OD 氘代甲醇
CDCl 3 氘代氯仿
DMSO-d 6 六氘代二甲基亚砜
TMS 四甲基硅烷
NMR 核磁共振
MS 质谱
IPA 异丙醇
TEA 三乙胺
s 单峰(singlet)
s 单峰(singlet)
d 二重峰(doublet)
t 三重峰(triplet)
q 四重峰(quartet)
dd 双二重峰(double doublet)
qd 四二重峰(quartet doublet)
ddd 双双二重峰(double double doublet)
ddt 双双三重峰(double double triplet)
dddd 双双双二重峰(double double double doublet)
m 多重峰(multiplet)
br 宽峰(broad)
J 偶合常数
Hz 赫兹
Rt 在液相色谱中的保留时间
MC 二氯甲烷
LC-MS 液质联用
以下的实施例中记载的化合物的结构通过 1H NMR或MS来确定。 1H NMR的测定仪器使用JEOL Eclipse 400核磁仪；测定溶剂为CD 3OD、CDCl 3或DMSO-d6；内标物质为TMS。全部δ值用ppm值表示。质谱(MS)的测定仪器使用Agilent(ESI)质谱仪，型号为Agilent 6120B。
实施例中制备的非对映异构体混合物可以通过制备高效液相色谱进行分离，从而得到纯的异构体。所述制备高效液相色谱分离可以按照本领域已知的方法来进行。例如在以下分离条件下进行：以十八烷基键合硅胶为填充剂，柱温30℃-50℃，流速5.0-20.0mL/min，检测波长200-400nm，使用流动相A(例如可以为水)，流动相B(例如可以为甲醇或乙腈)，进行线性梯度洗脱。
实施例1.((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)甲基-苯基-((S)-1-(2-甲基苄氧基)丙-2-基)氨基磷酸酯(化合物2-1)
Figure PCTCN2017117126-appb-000064
步骤一至步骤三：(S)-五氟苯基-苯基-(1-(2-甲基苄氧基)丙-2-基)氨基磷酸酯(化合物f-1)
将三氯氧磷(1.53g，10mmol)溶于二氯甲烷(10mL)，冷却到-70℃，滴加苯酚(化合物a，0.94g,10mmol)和三乙胺(1.01g，10mmol)的二氯甲烷溶液(10mL)。滴加完毕后，撤去冷浴，将温度升至室温，并搅拌2小时得到备用反应液。向(S)-1-(2-甲基苄氧基)丙-2基胺盐酸盐(化合物c-1，2.16g，10mmol)中加入二氯甲烷(40mL)，在氮气保护下降温至-70℃。向反应体系中滴加三乙胺(1.01g,10mmol)的二氯甲烷(10mL)溶液，滴加完毕后，将上述备用反应液滴加到上述反应体系中。滴加完毕后，在-70℃下搅拌90分钟，撤去冷浴，升温至20℃，并搅拌3小时。进一步将反应体系冷却到-70℃，滴加五氟苯酚(化合物e，1.66g，9mmol)的二氯甲烷溶液(10mL)，再滴加三乙胺(1.52g，15mmol)的二氯甲烷溶液(10mL)。滴加完毕后，撤去冷浴，升温至25℃，搅拌过夜。反应完全后，将反应体系倒入冰水中，用二氯甲烷萃取。合并有机相，并用饱和食盐水溶液洗涤，干燥，过滤浓缩，得到(S)-五氟苯基-苯基-(1-(2-甲基苄氧基)丙-2-基)氨基磷酸酯(化合物f-1)。
步骤四：((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)甲基-苯基-((S)-1-(2-甲基苄氧基)丙-2-基)氨基磷酸酯
在氩气保护下，将1-((2R,3R,4R,5R)-3-氟-4-羟基-5-羟甲基-3-甲基四氢呋喃-2-基)嘧啶-2,4-(1H,3H)-二酮(化合物g，260mg，1mmol)溶于无水四氢呋喃(20mL)中。于0℃滴加叔丁基氯化镁(1.0mol/L，2.5mL，2.5mmol)，升温至30℃，反应1小时。降温至0℃，滴加化合物f-1(502mg，1mmol)的无水四氢呋喃(10mL)溶液。滴加完毕后，升温至25℃，反应10小时。将反应体系降温至-5℃，用2M盐酸调至pH4-5，再倒入冰水中。将反应体系用乙酸乙酯萃取，合并有机相，并分别用饱和碳酸氢钠水溶液和饱和食盐水洗涤，干燥，过滤浓缩，经纯化得标题化合物2-1(440mg，收率76％)。
其结构表征如下：
1H NMR(CDCl 3,400MHz)δ9.06(s,1H),7.42–7.12(m,10H),6.15(d,J＝18.8Hz,1H),5.52(dd,J＝8.3,3.3Hz,1H),4.58–4.29(m,4H),4.04(d,J＝9.4Hz,1H),3.53–3.47(m,2H),3.45–3.35(m,2H),2.31(s,3H),1.38(d,J＝3.6Hz,3H),1.29–1.10(d,J＝3.2Hz,3H)。
31P NMR(CDCl 3,162MHz)δ4.36。
ESI-MS：m/z 578.2[M+H] +。
实施例2.((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)甲基-苯基-((R)-1-(2-甲基苄氧基)丙-2-基)氨基磷酸酯(化合物2-2)
Figure PCTCN2017117126-appb-000065
步骤一至步骤三：(R)-五氟苯基-苯基-(1-(2-甲基苄氧基)丙-2-基)氨基磷酸酯(化合物f-2)
将三氯氧磷(475mg，3.1mmol)加入到二氯甲烷(10mL)中，在氮气保护下降温至-70℃，滴加苯酚(化合物a，292mg,3.1mmol)和三乙胺(314mg,3.1mmol)的二氯甲烷溶液。滴加完毕后，在-70℃下反应5分钟，然后升温至室温，搅拌2小时得到备用反应液。在(R)-1-(2-甲基苄氧基)丙-2基胺盐酸盐(化合物c-2，500mg,2.79mmol)中加入二氯甲烷(20mL)，在氮气保护下降温至-70℃。向反应体系中滴加三乙胺(314mg,3.1mmol)的二氯甲烷(3mL)溶液，滴加完毕后搅拌5分钟得到反应体系。将上述备用反应液滴加到上述反应体系中，滴加完毕后，在-70℃搅拌90分钟。然后升温至0℃，并搅拌2小时，最后再将反应体系降温至-70℃。向反应体系中滴加五氟苯酚(化合物e，514mg，2.79mmol)的二氯甲烷(5mL)溶液，滴加完毕后，搅拌5分钟。滴加三乙胺(374mg，3.7mmol)的二氯甲烷(5mL)溶液，滴加完毕后搅拌5分钟。升温至室温，搅拌过夜。将水(30mL)加入反应液中，分层。将水相用二氯甲烷萃取，合并有机相，用饱和氯化钠溶液清洗两次，干燥，过滤浓缩，得到(R)-五氟苯基-苯基-(1-(2-甲基苄氧基)丙-2-基)氨基磷酸酯(化合物f-2)。
步骤四：((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)甲基-苯基-((R)-1-(2-甲基苄氧基)丙-2-基)氨基磷酸酯
将1-((2R,3R,4R,5R)-3-氟-4-羟基-5-羟甲基-3-甲基四氢呋喃-2-基)嘧啶-2,4-(1H,3H)-二酮(化合物g，605mg，2.3mmol)溶于四氢呋喃(30mL)中，在氮气保护下降温至-20℃。在-20℃下滴加叔丁基氯化镁(4.9mL，4.9mmol)，滴加完毕后，在-20℃搅拌30分钟。移除冷浴，将反应体系自然升温至室温，搅拌2小时，然后降温至-5℃。向反应体系中滴加化合物f-2(671mg，3.1mmol)的四氢呋喃(10mL)溶液，滴加完毕后在-5℃搅拌1小时。移除冷浴，升温至室温，并搅拌过夜。将反应体系降温至-5℃，用2M盐酸调节至PH＝4-5，再倒入冰水中，加入乙酸乙酯，搅拌，分液。将水相用乙酸乙酯萃取，合并有机相，并分别用饱和碳酸氢钠水溶液和饱和食盐水洗涤，干燥，浓缩，纯化得标题化合物2-2(460mg，收率28.5％)。
其结构表征如下：
1H NMR(400MHz,Chloroform-d)δ8.63(s,1H),7.54–7.29(m,3H),7.24–7.11(m,6H),6.13(d,J＝18.77Hz,1H),5.59(d,J＝8.10Hz,1H),4.45(dd,J＝16.62,10.12Hz,4H),4.18–3.17(m,6H),2.31(d,J＝10.07Hz,3H),1.52–1.09(m,6H)。
ESI-MS(m/z)：578.2[M+H] +
实施例3.((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)甲基-苯基-(2-甲基-1-(2-甲基苄氧基)丙-2-基)氨基磷酸酯(化合物3)
Figure PCTCN2017117126-appb-000066
步骤一：N-Boc-2-氨基-2-甲基-1-丙醇(化合物b-3)的合成
将碳酸钾(31.5g,225mmol)加入到水(150mL)中，经搅拌后溶解，得到反应液。将2-氨基-2-甲基-1-丙醇(化合物a-3，13.35g,150mmol)溶于四氢呋喃(50mL)中，并将所得溶液加入到上述反应液中。然后滴加二碳酸二叔丁酯(32.7g,150mmol)的四氢呋喃溶液，在室温下搅拌过夜。加入乙酸乙酯(50mL)，分层，将水相用乙酸乙酯萃取两次，合并有机相，用饱和氯化钠溶液洗涤，干燥，浓缩得到化合物b-3(28g，收率99％)。
步骤二：N-Boc-(2-甲基-1-((2-甲基苄氧基)丙-2-基))胺(化合物c-3)的合成
将化合物b-3(5.67g,30mmol)溶于N,N-二甲基甲酰胺(60mL)中，在氮气保护下降温至5℃。加入氢化钠(1.8g,45mmol)，在5℃下搅拌30分钟。在保持5℃温度的情况下，向反应体系中滴加邻甲基苄溴(5.83g,31.5mmol)。滴加完毕后，在5℃下搅拌30分钟。移除冷浴，缓慢升温至室温，搅拌过夜。将反应体系倒入冰水中，用甲基叔丁基醚萃取2次，将有机相用饱和食盐水洗涤，干燥浓缩，纯化得化合物c-3(2g，收率23％)。
步骤三：2-甲基-1-(2-甲基苄氧基)丙-2-基胺(化合物d-3)的合成
将化合物c-3(2g，6.8mmol)加入到三口瓶中，加入二氯甲烷(30mL)，降温至0℃。滴加三氟乙酸(4.9g，34mmol)，滴加完毕后自然升温至室温，搅拌过夜。停止反应，将反应液倒入冰的饱和碳酸氢钠溶液中，用固体氯化钠饱和，分液，用DCM萃取，干燥浓缩，得到化合物d-3(1.2g，收率76％)。
步骤四：五氟苯基-苯基-(2-甲基-1-(2-甲基苄氧基)丙-2-基)氨基磷酸酯(化合物f-3)的合成
将三氯氧磷(459mg)加入到二氯甲烷(10mL)中，在氮气保护下降温至-70℃。滴加苯酚(282mg,3mmol)和三乙胺(303mg,3mmol)的二氯甲烷(3mL)溶液，滴加完毕后，在-70℃下反应5分钟。然后升温至室温，搅拌2小时，得到备用反应液。在2-甲基-1-(2-甲基苄氧基)丙-2-基胺(化合物d-3，588mg,3.03mmol)中加入二氯甲烷(20mL)，在氮气保护下降温至-70℃。向其中滴加三乙胺(318mg,3.15mmol)的二氯甲烷(3mL)溶液，滴加完毕后搅拌5分钟得到反应体系。将上述备用反应液滴加到上述反应体系中，滴加完毕后，在-70℃下搅拌90分钟。然后升温至0℃，搅拌2小时。最后再将反应体系降温至-70℃，在-70℃下向反应体系中滴加五氟苯酚(496mg，2.7mmol)的二氯甲烷(5mL)溶液。滴加完毕后，搅拌5分钟，滴加三乙胺(363mg，3.6mmol)的二氯甲烷(5mL)溶液。滴加完毕后，搅拌5分钟，自然升温至室温，搅拌过夜。将水(30mL)加入反应液中，分层，将水相用二氯甲烷萃取，合并有机相，用饱和氯化钠溶液清洗，干燥，浓缩得到化合物f-3，将其直接用于下一步反应。
步骤五：(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)甲基-苯基-(2-甲基-1-(2-甲基苄氧基)丙-2-基)氨基磷酸酯的合成
将1-((2R,3R,4R,5R)-3-氟-4-羟基-5-羟甲基-3-甲基四氢呋喃-2基)嘧啶-2,4(1H,3H)-二酮(化合物g，650mg，2.5mmol)溶于四氢呋喃(30mL)中，在氮气保护下降温至-20℃。在-20℃下滴加叔丁基氯化镁(5.25mL 5.25mmol)，滴加完毕后，在-20℃下搅拌30分钟。将移除冷浴，反应体系自然升温至室温，搅拌2小时。然后降温至-5℃，向反应体系中缓慢滴加化合物f-3(1.5g,3.0mmol)的四氢呋喃(20mL)溶液，滴加完毕后在-5℃下搅拌1小时。移除冷浴，缓慢升温至室温，搅拌过夜。将反应体系降温至-5℃，用2M盐酸调节至PH＝4-5，再倒入冰水中，加入乙酸乙酯搅拌5分钟，分液，将水相用乙酸乙酯萃取，合并有机相，先后用饱和碳酸氢钠和饱和食盐水洗涤，干燥浓缩，纯化得到标题化合物3(100mg，收率5.5％)。
其结构表征如下：
1H NMR(400MHz,Chloroform-d)δ8.80(s,1H),7.44(d,J＝8.2Hz,1H),7.32(dd,J＝8.6,7.2Hz,2H),7.20(m,7H),6.15(d,J＝18.8Hz,1H),5.59(dd,J＝8.1,1.9Hz,1H),4.60–4.35(m,4H),4.07(d,J＝9.3Hz,1H),3.90(dd,J＝23.1,9.4Hz,1H),3.65(d,J＝9.4Hz,1H),3.32–3.18(m,2H),2.31(s,3H),1.43–1.24(m,9H).
ESI-MS(m/z)：592.2[M+H] +
参照实施例1-3的合成方法，可得如下化合物：
Figure PCTCN2017117126-appb-000067
Figure PCTCN2017117126-appb-000068
实施例11.(2S)-((((1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基乙氧基)甲基-苯氧基-磷酰基)氨基)-3-(2-甲基苄氧基)-丙烷(化合物10)的制备
Figure PCTCN2017117126-appb-000069
步骤一：(((1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基)磷酸单苯酯的制备
室温下，将[(1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基]甲基磷酸(PMPA，3.1g，10.8mmol)和苯酚(1.0g,10.8mmol)溶于N-甲基吡咯烷酮(20mL)中，升温至85℃，滴加三乙胺(1.1g，10.8mmol)使反应液由白色浑浊变为澄清。滴加完毕后继续升温至100℃，滴加DCC(4.8g，23.1mmol)的N-甲基吡咯烷酮(10mL)溶液。滴加完毕后在100℃下保温反应过夜后，将反应液降温至室温，放置2h。过滤，将滤液浓缩，用二氯甲烷溶解，观察到有少量白色不溶物析出。再次过滤，将滤液浓缩，将残余物经制备液相色谱纯化得到标题化合物(1.0g)。
ESI-MS(m/z)：364.2[M+H] +。
步骤二：((((R)-1-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基)苯氧基磷酰氯的制备
室温下，将(((1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基)磷酸单苯酯(100mg，0.28mmol)溶于乙腈(0.5mL)中，加入二氯亚砜(1.0mL)。滴加完毕后将反应液升温至70℃，反应3h后，将反应液浓缩，得到标题化合物(110mg)，未经进一步纯化直接用于下一步反应。
ESI-MS(m/z)：378.1[M+H] +。
步骤三：(2S)-((((1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基-苯氧基-磷酰基)氨基)-3-(2-甲基苄氧基)-丙烷的制备
室温下，将((((R)-1-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基)苯氧基磷酰氯(110mg，0.28mmol)溶于干燥二氯甲烷(2mL)中。将反应液降温至-20℃，加入(S)-1-((2-甲基苯基)氧基)-2-氨基-丙烷(99mg，0.55mmol)，并滴加三乙胺(0.5mL)。滴加完毕后在-20℃下反应1h后，将反应液倒入水中终止反应。用二氯甲烷萃取，合并有机相并用水洗涤，干燥，浓缩得到粗品化合物。经制备高效液相色谱纯化得到标题化合物(39mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.20-8.04(m,2H),7.38-7.00(m,11H),5.08-4.81(m,1H),4.44-4.31(m,2H),4.24(dt,J＝14.4,4.0Hz,1H),4.13(dt,J＝14.1,6.8Hz,1H),3.97-3.77(m,2H),3.70(ddd,J＝13.3,9.3,6.8Hz,1H),3.43-3.37(m,1H),3.29-3.08(m,2H),2.23(d,J＝5.8Hz,3H),1.03(dd,J＝22.8,6.2Hz,3H),0.95(t,J＝6.8Hz,3H)。
ESI-MS(m/z)：525.2[M+H] +。
实施例12.(2R)-((((1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基-苯氧基-磷酰基)氨基)-3-(2-甲基苄氧基)-丙烷(化合物11)的制备
Figure PCTCN2017117126-appb-000070
室温下，将((((R)-1-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基)苯氧基磷酰氯(110mg，0.28mmol)溶于干燥二氯甲烷(2mL)中。将反应液降温至-20℃，加入(R)-1-((2-甲基苄氧基)-2-氨基-丙烷(99mg，0.55mmol)。滴加三乙胺(0.5mL)，滴加完毕后在-20℃下反应1h后，将反应液倒入水中终止反应。用二氯甲烷萃取，合并有机相并用水洗涤，干燥，浓缩得到粗品化合物。经制备液相色谱纯化得到标题化合物(56mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.11(dd,J＝16.3,1.3Hz,2H),7.35-7.22(m,3H),7.22-7.09(m,7H),7.09-6.99(m,1H),4.99(td,J＝11.9,11.3,6.3Hz,1H),4.38(d,J＝13.0Hz,2H),4.31-4.09(m,2H),3.93-3.89(m,1H),3.85-3.69(m,2H),3.42-3.39(m,1H),3.23(dd,J＝9.2,5.5Hz,1H),3.11(ddd,J＝30.2,9.2,6.8Hz,1H),2.23(d,J＝2.4Hz,3H),1.03(t,J＝6.8Hz,3H),0.95(dd,J＝10.4,6.6Hz,3H).
ESI-MS(m/z)：525.2[M+H] +。
实施例13.1-((((1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基-苯氧基-磷酰基)氨基)-2-(2-甲基苄氧基)-乙烷(化合物12)的制备
Figure PCTCN2017117126-appb-000071
室温下，将((((R)-1-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基)苯氧基磷酰氯(110mg，0.28mmol)溶于干燥二氯甲烷(2mL)中。将反应液降温至-20℃，加入1-(2-甲基苄氧基)-2-乙胺(100mg,0.56mmol)。滴加三乙胺(0.5mL)，滴加完毕后在-20℃下反应1h后，将反应液倒入水中终止反应。用二氯甲烷萃取，合并有机相并用水洗涤，干燥，浓缩得到粗品化合物。经制备液相色谱纯化得到标题化合物(34mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)8.14(s,1H),8.10(d,J＝5.0Hz,1H),7.37-7.24(m,3H),7.20(s,2H),7.18-7.09(m,5H),7.05(d,J＝8.0Hz,1H),5.22-5.06(m,1H),4.45-4.33(m,2H),4.25(dd,J＝14.4,3.8Hz,1H),4.15(ddd,J＝14.5,8.5,6.4Hz,1H),3.97-3.69(m,3H),3.32-3.23(m,2H),3.01(dd,J＝11.2,6.1Hz,2H),2.23(d,J＝3.1Hz,3H),1.04(dd,J＝13.7,6.2Hz,3H).
ESI-MS(m/z)：511.2[M+H] +。
实施例14.2-甲基-2-((((1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基-苯氧基-磷酰基)氨基)-3-(2-甲基苄氧基)-丙烷(化合物13)的制备
Figure PCTCN2017117126-appb-000072
室温下，将((((R)-1-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基)苯氧基磷酰氯(110mg，0.28mmol)溶于干燥二氯甲烷(2mL)中。将反应液降温至-20℃，加入1-(2-甲基苄氧基)-2,2-二甲基乙胺(108mg,0.56mmol)。滴加三乙胺(0.5mL)，滴加完毕后在-20℃下反应1h后，将反应液倒入水中终止反应。用二氯甲烷萃取，合并有机相并用水洗涤，干燥，浓缩得到粗品化合物。经制备液相色谱纯化得到标题化合物(18mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.19-8.01(m,2H),7.37-7.24(m,3H),7.24-7.02(m,8H),4.74(dd,J＝16.2,9.7Hz,1H),4.42(d,J＝8.3Hz,2H),4.23(dd,J＝14.4,4.0Hz,1H),4.14(dd,J＝14.4,6.2Hz,1H),3.95-3.89(m,1H)，3.85-3.63(m,2H),3.31-3.19(m,2H),2.24(d,J＝3.4Hz,3H),1.16(d,J＝10.2Hz,6H),1.03(t,J＝6.0Hz,3H).
ESI-MS(m/z)：539.3[M+H] +。
实施例15.((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-(2-(苄氧基)乙基)-磷酰胺(化合物22)的制备
Figure PCTCN2017117126-appb-000073
除了将(R)-1-((2-甲基苄氧基)-2-氨基-丙烷替换为2-(苄氧基)乙胺外，参照实施例12的合成方法制备，并经制备高效液相色谱纯化得作为白色固体的标题化合物(1.4g)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.15-8.12(m,2H),7.34-7.26(m,8H),7.14-7.03(m,3H),5.22-5.12(m,1H),4.39-4.24(m,3H),3.95-3.68(m,3H),3.36-3.28(m,1H),3.05-2.95(m,1H),1.29-1.16(m,2H),1.05-0.95(m,3H).ESI-MS(m/z)：497.2[M+H] +。
实施例16.化合物22异构体A和化合物22异构体B的制备
化合物22异构体A和化合物22异构体B的制备方法一：
将实施例15的化合物(400mg)通过手性色谱法分离，分离条件如下：分离柱CHIRALPAKOD-H 0.46cm I.D.×15cm L，流动相：己烷/IPA/TEA＝70/30/0.1(V/V/V)，流速1.0ml/min，波长UV 254nm，温度35℃，分离得到标题两种立体异构体化合物。
化合物22异构体A：R t＝5.846min，198mg，ee％＝98.5％，其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.14(s,1H),8.10(s,1H),7.37-7.18(m,9H),7.17-7.10(m,1H),7.05(dt,J＝8.5,1.2Hz,2H),5.16(dt,J＝11.9,6.9Hz,1H),4.40(s,2H),4.26(dd,J＝14.4,3.7Hz,1H),4.14(dd,J＝14.4,6.6Hz,1H),4.02-3.81(m,2H),3.75(dd,J＝13.5,9.2Hz,1H),3.28(d,J＝5.7Hz,2H),3.05-2.93(m,2H),1.06(d,J＝6.2Hz,3H).ESI-MS(m/z)：497.2[M+H] +。
化合物22异构体B：R t＝7.345min，166mg，ee％＝98.3％，其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.14(s,1H),8.10(s,1H),7.35-7.21(m,9H),7.13(t,J＝7.3Hz,1H),7.05(dt,J＝8.5,1.2Hz,2H),5.16(dt,J＝11.8,6.9Hz,1H),4.40(s,2H),4.26(dd,J＝14.4,3.7Hz,1H),4.14(dd,J＝14.4,6.6Hz,1H),3.97-3.81(m,2H),3.75(dd,J＝13.5,9.2Hz,1H),3.30(d,J＝11.1Hz,2H),3.00(dq,J＝12.5,6.2Hz,2H),1.06(d,J＝6.2Hz,3H).ESI-MS(m/z)：497.2[M+H] +。
化合物22异构体A的制备方法二，其中，
Figure PCTCN2017117126-appb-000074
表示实楔形
Figure PCTCN2017117126-appb-000075
或虚楔形
Figure PCTCN2017117126-appb-000076
化学键中 的任意一种：
Figure PCTCN2017117126-appb-000077
步骤一：中间体22-A-1的合成
室温下，将(((1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基乙氧基)甲基)磷酸单苯酯(25g，68.81mmol)溶于甲苯(250mL)中，加入二氯亚砜(28.65g，240.84mmol)。加毕，将反应液升温至95℃，反应48h。将反应液减压蒸馏，得到标题化合物(30g)。所得产物未经进一步纯化而直接用于下一步反应。
步骤二：化合物22异构体A的合成
室温下，将2-(苄氧基)乙胺(46.82g，309.65mmol)溶于干燥的二氯甲烷(200mL)，在氮气保护下降温至-35℃，加入22-A-1(30g，粗品)的甲苯(200mL)溶液，控制温度小于-10℃。加毕，保持温度在-10℃，反应1h。加入15％的磷酸氢钾水溶液(400mL)，充分搅拌，静置，分层。将有机相依次用15％的磷酸氢钾(200mL×2)、去离子水(200mL×2)洗涤，干燥。滤除不溶物，将滤液浓缩得标题化合物(30g)。经手性HPLC检测，所得产物的保留时间(R t)与本实施例制备方法一获得的化合物22异构体A一致，非对映异构体纯度：94.6％。
实施例17.((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-(2-(4-甲基苄氧基)乙基)-磷酰胺(化合物23)的制备
Figure PCTCN2017117126-appb-000078
除了将(R)-1-((2-甲基苄氧基)-2-氨基-丙烷替换为2-(4-甲基苄氧基)乙胺外，参照实施例12的合成方法制备，并经制备高效液相色谱纯化得标题化合物(65mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.14(s,1H),8.10(d,J＝5.0Hz,1H),7.37-7.24(m,2H),7.20-7.11(m,8H),7.03(d,J＝8.0Hz,1H),5.17-5.08(m,1H),4.45-4.33(m,2H),4.34(s,1H),4.32(s,1H),4.27-4.22(m,1H),4.18-4.11(m,1H),3.93-3.71(m,3H),3.33-3.24(m,2H),3.02-2.91(m,2H),2.24(d,J＝3.1Hz,3H),1.04(dd,J＝13.7,6.2Hz,3H).ESI-MS(m/z)：511.2[M+H] +。
实施例18.((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-(2-(2,4-二甲基苄氧基)乙基)-磷酰胺(化合物26)的制备
Figure PCTCN2017117126-appb-000079
除了将(R)-1-((2-甲基苄氧基)-2-氨基-丙烷替换为2-(2,4-二甲基苄氧基)乙胺外，参照实施例12的合成方法制备，并经制备液相纯化得标题化合物(58mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.14(s,1H),8.09(d,J＝8.0Hz,1H),7.34-7.28(m,2H),7.22(s,2H),7.15-7.03(m,4H),6.95-6.93(m,2H),5.26-5.13(m,1H),4.31-4.11(m,5H),3.88-3.75(m,3H),2.92-2.76(m,2H),2.22(s,3H),2.19(s,3H),1.56-1.53(m,2H),1.04(dd,J＝13.7,6.2Hz,3H).ESI-MS(m/z)：525.2[M+H] +。
实施例19.((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-甲基-N-(2-(2-甲基苄氧基)乙基)-磷酰胺(化合物30)的制备
Figure PCTCN2017117126-appb-000080
除了将(R)-1-((2-甲基苄氧基)-2-氨基-丙烷替换为N-甲基-2-(2-甲基苄氧基)乙胺外，参照实施例12的合成方法制备，并经制备高效液相色谱纯化得标题化合物(7mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.14(s,1H),8.06(s,1H),7.32-7.10(m,10H),7.04-7.02(m,1H),4.38-4.36(m,2H),4.25-4.15(m,2H),3.95-3.68(m,3H),3.39-3.34(m,2H),3.15-3.00(m,2H),2.54-2.48(m,3H),2.22(s,3H),1.08-1.01(m,3H).ESI-MS(m/z)：525.2[M+H] +。
实施例20.实施例20-异构体A和实施例20-异构体B的制备
Figure PCTCN2017117126-appb-000081
步骤一：(((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)磷酸单-1-萘酯的合成
除了将苯酚替换为1-萘酚外，参照实施例11中步骤一的合成方法制备，并经制备液相纯化得到标题化合物(1.2g)。ESI-MS(m/z)：414.1[M+H] +。
步骤二：(((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-1-萘氧基-磷酰氯的合成
除了将(((1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基)磷酸单苯酯替换为(((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)磷酸单-1-萘酯外，参照实施例11中步骤二的合成方法制备得标题化合物(200mg)，将其直接用于下一步反应。ESI-MS(m/z)：432.0[M+H] +。
步骤三：(R)-((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-萘-1-氧基-N-(2-(2-甲基苄氧基)乙基)-磷酰胺的合成
将(((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-1-萘氧基-磷酰氯(200mg，0.46mmol)溶于干燥二氯甲烷(2mL)中。在氮气保护下，将反应液降温至-20℃，加入2-(2-甲基苄氧基)乙胺(153mg，0.92mmol)，滴加三乙胺(1.0mL)，在-20℃下反应1h。将反应液倒入水(20mL)中淬灭，用二氯甲烷萃取(30mL x 3)，合并有机相，水洗，干燥，浓缩得粗品，经制备高效液相色谱纯化分离，得到上述两种标题立体异构体化合物。
实施例20-异构体A：R t＝2.549min，9mg。其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.13-8.10(m,3H),7.95-7.92(m,1H),7.73-7.71(m,1H),7.54-7.52(m,2H),7.43-7.38(m,2H),7.20-7.13(m,6H),5.30-5.27(m,1H),4.31-4.16(m,4H),4.05-3.91(m,3H),3.33-3.25(m,2H),3.05-2.95(m,2H),2.19(s,3H),1.0-0.98(m,3H).ESI-MS(m/z)：561.2[M+H] +。
实施例20-异构体B，R t＝2.486min，35mg。其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.22-8.14(m,3H),8.06-8.04(m,1H),7.73-7.71(m,1H),7.54-7.52(m,2H),7.40-7.36(m,2H),7.19-7.13(m,6H),5.33-5.27(m,1H),4.31-4.18(m,4H), 4.05-3.91(m,3H),3.33-3.25(m,2H),3.05-2.95(m,2H),2.19(s,3H),1.00-0.98(m,3H).ESI-MS(m/z)：561.2[M+H] +。
实施例21.((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-萘-2-氧基-N-(2-(2-甲基苄氧基)乙基)-磷酰胺(化合物31)的制备
Figure PCTCN2017117126-appb-000082
除了将1-萘酚替换为2-萘酚外，参照实施例20的合成方法制备，并经制备高效液相色谱纯化得标题化合物(58mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.17(s,1H),7.92-7.84(m,2H),7.83-7.76(m,1H),7.61(d,J＝15.8Hz,1H),7.49-7.45(m,2H),7.33(d,J＝2.2Hz,1H),7.31-7.22(m,3H),7.18-7.07(m,3H),5.26-5.18(m,1H),4.33(t,J＝3.2Hz,1H),4.29-4.20(m,1H),4.18-3.13(m,1H),3.96-3.77(m,3H),3.33-3.25(m,2H),3.07-2.98(m,2H),2.19(s,3H),1.13-1.02(m,3H).ESI-MS(m/z)：561.2[M+H] +。
实施例22.(((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-((R)-1-(苄氧基)丙-2-基)-磷酰胺(化合物37)的制备
Figure PCTCN2017117126-appb-000083
除了将(R)-1-((2-甲基苄氧基)-2-氨基-丙烷替换为(R)-1-(苄氧基)-2-丙胺外，参照实施例12的合成方法制备，并经制备高效液相色谱纯化得标题化合物(370mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.14(s,1H),8.10(s,1H),7.33-7.20(m,9H),7.13(t,J＝7.4Hz,1H),7.05(dt,J＝8.3,1.3Hz,2H),4.99(dd,J＝12.4,10.2Hz,1H),4.41(s,2H),4.24(dd,J＝14.4,3.8Hz,1H),4.14(dd,J＝14.4,6.4Hz,1H),3.91(td,J＝6.3,3.8Hz,1H),3.86-3.67(m,2H),3.21(dd,J＝9.3,5.8Hz,1H),3.13(dd,J＝9.3,6.7Hz,1H),1.04(d,J＝6.2Hz,3H),0.96(d,J＝6.6Hz,3H).ESI-MS(m/z)：511.2[M+H] +。
实施例23.实施例23-异构体A、实施例23-异构体B的制备
Figure PCTCN2017117126-appb-000084
除了将(R)-1-((2-甲基苄氧基)-2-氨基-丙烷替换为(S)-1-(苄氧基)-2-丙胺外，参照实施例12的合成方法制备，并经制备高效液相色谱纯化分离，得到上述两种标题立体异构体化合物。
实施例23-异构体A：R t＝2.486min，106mg。其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.13(d,J＝2.6Hz,1H),8.04(s,1H),7.38-7.16(m,10H),7.14-7.08(m,1H),7.08-7.01(m,1H),4.46(d,J＝12.9Hz,2H),4.30-4.11(m,4H),4.11-4.01(m,1H),4.01-3.89(m,2H),3.57(ddd,J＝19.5,6.0,3.3Hz,2H),1.07(t,J＝6.6Hz,3H).ESI-MS(m/z)：511.2[M+H] +。
实施例23-异构体B：R t＝2.536min，75mg。其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.14(s,1H),8.12(s,1H),7.36-7.22(m,9H),7.17-7.10(m,3H),4.84(dd,J＝12.4,10.2Hz,1H),4.36(d,J＝4.3Hz,2H),4.29-4.09(m,2H),3.91-3.77(m,2H),3.70(dd,J＝13.3,9.4Hz,1H),3.19-3.07(m,2H),1.00(d,J＝6.2Hz,3H),0.94(d,J＝6.6Hz,3H).ESI-MS(m/z)：511.2[M+H] +。
实施例24.((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-((S)-2-(苄氧基)丙基)-磷酰胺(化合物40)的制备
Figure PCTCN2017117126-appb-000085
除了将(R)-1-((2-甲基苄氧基)-2-氨基-丙烷替换为(S)-2-(苄氧基)-1-丙胺外，参照实施例12的合成方法制备，并经制备高效液相色谱纯化得标题化合物(205mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.13(s,1H),8.09(s,1H),7.35-7.19(m,9H),7.12(t,J＝7.4Hz,1H),7.05(dd,J＝7.5,1.3Hz,2H),5.06(dd,J＝11.8,10.1Hz,1H),4.39(s,2H),4.25(dd,J＝14.4,3.7Hz,1H),4.13(dd,J＝14.4,6.6Hz,1H),3.96-3.79(m,2H),3.71(dd,J＝13.5,9.2Hz,1H),3.26(dd,J＝9.1,5.2Hz,1H),3.09(dd,J＝9.1,7.0Hz,1H),1.05(d,J＝6.2Hz,3H),0.96(d,J＝6.6Hz,3H).ESI-MS(m/z)：511.2[M+H] +。
实施例25.(((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-((R)-2-(苄氧基)丙基)-磷酰胺(化合物41)的制备
Figure PCTCN2017117126-appb-000086
除了将(R)-1-((2-甲基苄氧基)-2-氨基-丙烷替换为(R)-2-(苄氧基)-1-丙胺外，参照实施例12的合成方法制备，并经制备高效液相色谱纯化得标题化合物(260mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.14(s,1H),8.10(s,1H),7.36-7.21(m,9H),7.12(t,J＝7.3Hz,1H),7.06(dt,J＝8.4,1.2Hz,2H),5.08(dt,J＝11.8,7.1Hz,1H),4.44(d,J＝12.0Hz,1H),4.36(d,J＝11.9Hz,1H),4.25(dd,J＝14.4,3.7Hz,1H),4.15(dd,J＝14.4,6.5Hz,1H),3.92-3.72(m,3H),3.33(d,J＝5.9Hz,1H),2.90-2.76(m,2H),1.05(d,J＝6.2Hz,3H),1.02(d,J＝6.2Hz,3H).ESI-MS(m/z)：511.2[M+H] +。
实施例26.((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-(1-(苄氧基)-2-甲基丙-2-基)-磷酰胺(化合物42)的制备
Figure PCTCN2017117126-appb-000087
除了将(R)-1-((2-甲基苄氧基)-2-氨基-丙烷替换为1-(苄氧基)-2-甲基-2-丙胺外，参照实施例12的合成方法制备，并经制备高效液相色谱纯化得标题化合物(30mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.13(s,1H),8.10(s,1H),7.31-7.22(m,9H),7.14-7.11(m,1H),7.06-7.04(m,2H),5.11-5.05(m,1H),4.46-4.43(m,2H),4.37-4.34(m,1H),4.28-4.23(m,1H),3.93-3.90(m,1H),3.75-3.65(m,2H),3.39-3.35(m,1H),1.17-1.15(m,6H),1.05-1.02(m,3H).ESI-MS(m/z)：525.2[M+H] +。
实施例27.((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-4-氟苯氧基-N-(2-(苄氧基)乙基)-磷酰胺(化合物43)的制备
Figure PCTCN2017117126-appb-000088
步骤一：((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)磷酸单对氟苯酯的合成
除了将苯酚替换为4-氟苯酚外，参照实施例11中步骤一的合成方法制备，并经制备高效液相色谱纯化得标题化合物(400mg)。ESI-MS(m/z)：382.1[M+H] +。
步骤二：4-氟苯氧基-((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)磷酰氯的合成
除了将(((1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基-乙氧基)甲基)磷酸单苯酯替换为4-氟苯基-((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)磷酸酯外，参照实施例11中步骤二的合成方法制备得到标题化合物(500mg)，将其直接用于下一步反应。ESI-MS(m/z)：396.1[M+H] +。
步骤三：((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-4-氟苯氧基-N-(2-(苄氧基)乙基)-磷酰胺的合成
除了将(S)-1-((2-甲基苯基)氧基)-2-氨基-丙烷替换为2-(苄氧基)乙胺外，参照实施例11中步骤三的合成方法制备，并经制备高效液相色谱纯化得标题化合物(206mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.14(s,1H),8.11(d,J＝4.9Hz,1H),7.39-7.19(m,8H),7.13(d,J＝6.7Hz,3H),5.16(dt,J＝12.9,6.9Hz,1H),4.38(d,J＝1.5Hz,2H),4.25(dd,J＝14.4,3.9Hz,1H),4.16(dd,J＝14.4,6.2Hz,1H),3.99-3.70(m,3H),3.29-3.18(m,2H),2.98(tq,J＝12.6,6.8Hz,2H),1.03(d,J＝6.2Hz,3H).ESI-MS(m/z)：515.2[M+H] +。
实施例28.2-(苄氧基)乙基-苯基-(((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)磷酸酯(化合物44)的制备
Figure PCTCN2017117126-appb-000089
室温下，将((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)磷酸单苯酯(200mg，0.55mmol)、2-(苄氧基)乙醇(167mg,1.1mmol)溶于干燥N,N-二甲基甲酰胺(2mL)中。将反应液降温至0℃，加入PyBOP(573mg)，滴加N,N-二异丙基乙胺(285mg)。加毕，升温至室温，反应过夜。经制备高效液相色谱纯化，得标题化合物(245mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.13(d,J＝2.6Hz,1H),8.04(s,1H),7.38-7.16(m,10H),7.14-7.08(m,1H),7.08-7.01(m,1H),4.46(d,J＝12.9Hz,2H),4.30-4.11(m,4H),4.11-4.01(m,1H),4.01-3.89(m,2H),3.57(ddd,J＝19.5,6.0,3.3Hz,2H),1.07(t,J＝6.6Hz,3H).ESI-MS(m/z)：498.2 [M+H] +。
实施例29.3-(苄氧基)丙基-苯基-((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)磷酸酯(化合物45)的制备
Figure PCTCN2017117126-appb-000090
除了将2-(苄氧基)乙醇替换为3-(苄氧基)-1-丙醇外，参照实施例28的合成方法制备，并经制备高效液相色谱纯化得到标题化合物(160mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.13(d,J＝1.9Hz,1H),8.03(d,J＝1.9Hz,1H),7.37-7.16(m,10H),7.10(dt,J＝8.5,1.3Hz,1H),7.04(dt,J＝8.4,1.3Hz,1H),4.41(d,J＝6.5Hz,2H),4.31-3.89(m,8H),3.42(dt,J＝14.4,6.2Hz,2H),1.88-1.72(m,2H),1.09(t,J＝6.2Hz,3H).ESI-MS(m/z)：512.2[M+H] +。
实施例30.((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-(3-(苄氧基)丙基)-磷酰胺(化合物46)的制备
Figure PCTCN2017117126-appb-000091
除了将(R)-1-((2-甲基苄氧基)-2-氨基-丙烷替换为(S)-2-(苄氧基)-1-丙胺外，参照实施例12的合成方法制备，并经制备高效液相色谱纯化得标题化合物(173mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.14(s,1H),8.10(d,J＝6.1Hz,1H),7.36-7.20(m,9H),7.17-7.09(m,2H),5.06(td,J＝11.4,5.9Hz,1H),4.37(d,J＝2.2Hz,2H),4.32-4.11(m,2H),4.00-3.70(m,3H),3.36(dd,J＝6.3,2.3Hz,2H),2.87(ddd,J＝10.4,6.3,2.6Hz,2H),1.55(p,J＝6.7Hz,2H),1.07(dd,J＝16.9,6.2Hz,3H).ESI-MS(m/z)：511.2[M+H] +。
实施例31.(((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-(2-(萘-1-基甲氧基)乙基)-磷酰胺(化合物47)的制备
Figure PCTCN2017117126-appb-000092
除了将(R)-1-((2-甲基苄氧基)-2-氨基-丙烷替换为2-(1-萘甲氧基)乙胺外，参照实施例12的合成方法制备，并经制备液相色谱法纯化得标题化合物(33mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.19(s,1H),8.18-8.05(m,2H),7.85-7.79(m,2H),7.49-7.39(m,4H),7.27-7.22(m,2H),7.09-7.06(m,2H),6.96(d,J＝8.0Hz,1H),4.87-4.85(m,1H),4.22-4.20(m,1H),4.10-4.02(m,1H),3.82-3.53(m,3H),3.46-3.43(m,2H),3.22-3.03(m,2H),1.03(dd,J＝16.0,8.0Hz,3H).ESI-MS(m/z)：547.2[M+H] +.
实施例32.((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-(2-(2,6-二甲基苄氧基)乙基)-磷酰胺(化合物48)的制备
Figure PCTCN2017117126-appb-000093
除了将(R)-1-((2-甲基苄氧基)-2-氨基-丙烷替换为2-(2,6-二甲基苄氧基)乙胺外，参照实施例12的合成方法制备，并经制备高效液相色谱纯化得标题化合物(21mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.14(s,1H),8.08(s,1H),7.32-6.97(m,10H),5.19-5.13(m,1H),4.40(s,2H),4.28-4.23(m,1H),4.17-4.12(m,1H),3.94-3.83(m,2H),3.78-3.72(m,1H),3.31-2.96(m,2H),3.04-2.96(m,2H),2.28(s,6H),1.06-1.01(m,3H).ESI-MS(m/z)：497.2[M+H] +。
实施例33.((((R)-1-(6-氨基-9H-嘌呤-9-基)丙-2-基)氧基)甲基)-苯氧基-N-(3-(2,4-二甲基苄氧基)丙基)-磷酰胺(化合物49)的制备
Figure PCTCN2017117126-appb-000094
除了将(R)-1-((2-甲基苄氧基)-2-氨基-丙烷替换为3-(2,4-二甲基苄氧基)-1-丙胺外，参照实施例12的合成方法制备，并经制备液相纯化得标题化合物(53mg)。
其结构表征如下：
1H NMR(400MHz,DMSO-d 6)δ8.13(s,1H),8.09(d,J＝8.0Hz,1H),7.32-7.26(m,2H),7.21(s,2H),7.15-7.11(m,3H),7.05-6.91(m,3H),5.26-5.13(m,1H),4.34-4.32(m,2H),4.24-4.15(m,2H),3.87-3.63(m,3H),3.31-3.19(m,2H),3.08-2.95(m,2H),2.22(s,3H),2.19(s,3H),1.06(dd,J＝16.0,8.0Hz,3H).ESI-MS(m/z)：539.3[M+H] +.
参照实施例11-33的合成方法，可得如下化合物：
Figure PCTCN2017117126-appb-000095
Figure PCTCN2017117126-appb-000096
生物试验
1.核苷类药物在人原代肝细胞中的三磷酸核苷代谢产物(3P)生成量的体外筛选评价
1.1.测试系统
人原代肝细胞(批号MMN，10个供体混合性别)购买自美国体外技术公司BioreclamationIVT。
1.2.测试方法
配制浓度为6×10 5个细胞/mL的人原代肝细胞溶液和浓度为50μM的待测化合物溶液。将250μL的人原代肝细胞溶液和250μL的待测化合物溶液混合，并加入24-孔板，使得待测化合物的最终浓度为25μM。在37℃下水浴孵育6小时后，将样品转移到试管中，除去培养基。加入磷酸盐缓冲液清洗细胞后，去除上清液。加入180μL 70％甲醇，漩涡混匀，于-20℃下静置过夜。在15000rpm及4℃下离心10min后，取150μL上清液转移到上样管，经LC-MS/MS检测3P产物生成量，计算3P生成速率。
3P生成速率＝(3P生成量*150μL)/(6×10 5个细胞/mL*250μL*6h)。
1.3.实验结果
测试物的3P化合物生成量和生成速率见下表。
表2：测试物的3P化合物生成量和生成速率
Figure PCTCN2017117126-appb-000097
可见，本发明的化合物可以在肝细胞内顺利代谢，生成具有活性的三磷酸核苷代谢物质，并且三磷酸核苷代谢产物的生成量大，生成速率快。因此，本发明的化合物对丙型肝炎、乙型肝炎、人类免疫缺陷综合征等具有很好的抑制效果。
2、CYP抑制实验
2.1.测试方法
2.1.1.待测化合物储备液和工作液的配制
将化合物溶解于DMSO中，将其配制成10mM的储备液。将储备液用DMSO:甲醇＝1:1的混合溶剂进一步稀释成5、1.5、0.5、0.15、0.05、0.015和0.005mM的系列工作溶液。
2.1.2.底物及其配制
将底物分别溶解于DMSO中，配制成相应浓度的储备液。具体浓度见下表：
表3.CYP抑制实验中不同组别底物储备液和孵化体系中的浓度
底物 储备液浓度(mM) 孵化体系中的浓度(μM)
非那西汀(1A2) 20 10
双氯芬酸(2C9) 10 5
美芬妥英(2C19) 20 30
右美沙芬(2D6) 20 5
米达唑仑(3A4) 10 2
睾酮(3A4) 40 50
阿莫地喹(2C8) 10 10
安非他酮(2B6) 80 80
2.1.3.阳性对照品溶液配制
将阳性对照品分别溶解于DMSO中，配制成相应浓度的储备液。再将其用甲醇稀释成相应浓度的工作液。具体储备液浓度见下表：
表4.CYP抑制实验中不同组别阳性对照品储备液和工作液的浓度
抑制剂 储备液浓度(mM) 工作液浓度(μM)
萘黄酮(1A2) 3 300
磺胺苯吡唑(2C9) 10 300
苯环丙胺(2C19) 10 300
奎尼丁(2D6) 3 300
酮康唑(3A4) 3 300
槲皮素(2C8) 3 300
噻氯匹定(2B6) 3 300
2.1.4.肝微粒体孵育
反应体系中肝微粒体的蛋白浓度为0.2mg/mL，辅酶NADPH为1.0mM。在37℃水浴中进行孵育反应。终止反应，经常规步骤处理，对产品进行LC-MS/MS分析。
2.2.实验结果
表5.CYP抑制实验结果
Figure PCTCN2017117126-appb-000098
通常认为，IC 50>10μL即说明药物对CYP450酶无抑制作用或抑制作用低。由以上数据看出，本发明中的实施例15化合物对八种CYP450酶均无抑制作用，产生药物相互作用的风险很小，因而具有更高的安全性。本发明的其他化合物均具有类似的安全性。
3、体外药效实验
测试本发明的化合物对乙型肝炎病毒(HBV)的抑制作用。在病毒-细胞水平测试本发明的化合物的细胞毒性以及对病毒(HBV)核酸(DNA)复制水平的影响。
3.1.测试方法
将对数生长期的HepG2.2.15细胞接种于96孔板中，细胞浓度为40个/μL。于37℃、5％CO 2培养箱中培养3天。加入化合物前用新培养基(200μL/孔)更换。各实施例化合物的母液浓度为200μM。以200μM为最高浓度，用DMSO稀释为多个不同浓度。取1μL待测化合物置于相应培养基孔，化合物的最终测试浓度为0.06、0.24、0.98、3.9、15.6、62.5、250、1000nM(用于计算半数有效浓度(EC 50))。
3.2.实验结果
由表6可见，所测试的化合物对乙型肝炎病毒(HBV)具有较强的抑制活性。
表6
化合物编号 EC 50(nM)
实施例15 54.7±26.4
4、小鼠体内的药物代谢动力学(PK)研究
核苷类似物通过病毒产生的胸腺嘧啶核苷激酶磷酸化，代谢为具有药效的单磷酸，进而代谢为二磷酸、三磷酸活性形式，从而达到抗病毒作用。因此，单磷酸活性代谢物的生成是核苷类似物发挥药效的根本。
以下结构为实施例16-化合物22异构体B代谢物1：
Figure PCTCN2017117126-appb-000099
测定方法：通过灌胃给予雄性ICR小鼠实施例16-化合物22异构体B，测定小鼠体内实施例16-化合物22异构体B及代谢产物(实施例16-化合物异构体B代谢物1)的血药和肝药浓度，考察化合物的药代动力学特性。灌胃给药剂量为10mg/kg，溶媒系统为0.5％MC。灌胃给药后在不同时间点收集血液与肝组织，用于PK研究。血浆样品和肝组织匀浆液经沉淀蛋白处理后进行LC-MS/MS分析。
LC-MS/MS：质谱为API 5500，液相为ShimadzμLC-30AD系统。待测物色谱柱为Hypersil GOLD C18，3μm粒径，100×4.6mm，美国Thermo公司；流动相：A相为5mA甲酸铵+0.5％甲酸，B相为甲醇；流速为0.8mL/min；柱温为40℃。采用离子源为ESI源正离子模式，扫描方式为多重反应监测(MRM)。
表7.小鼠体内PK实验结果
Figure PCTCN2017117126-appb-000100
由以上数据看出，本发明中的实施例16-化合物22异构体B在血浆和肝脏中可快速代谢生成实施例16-化合物22异构体B代谢物1。肝脏中代谢物1的浓度是血浆浓度的21倍，即实施例16-化合物22异构体B具有明显的肝靶向性。
5、小鼠体内药效实验
5.1.测试方法
将动物经尾静脉高压注射HBV质粒DNA当天定为第0天。往后一天为第1天，以此类推。第0天，所有小鼠在5秒内从尾静脉注射(HDI)小鼠体重8％的质粒DNA溶液(注射体积(ml)＝小鼠体重(g)×8％))，每只小鼠注射质粒的质量为10μg。
测试化合物：实施例16-异构体B；给药剂量：10mg/kg、30mg/kg；给药方式：灌胃；给药频率：每天一次；总时长：第1天到第7天。
5.2.实验结果小鼠血浆中以及肝脏中的HBV DNA含量测定结果见下表8及表9。
表8.小鼠血浆中HBV DNA含量测定结果
Figure PCTCN2017117126-appb-000101
表9.小鼠血浆中HBV DNA含量测定结果(第七天)
Figure PCTCN2017117126-appb-000102
由以上数据看出，本发明中的实施例16-化合物22异构体B对小鼠血浆、肝脏HBV DNA有显著的抑制作用并呈剂量依赖关系。可以预见，实施例16-化合物22异构体B对乙肝具有明显的治疗作用。因此，本发明的化合物可以作为有效的乙型肝炎病毒逆转录酶抑制剂。
产业实用性
本发明的化合物作为丙型肝炎病毒(HCV)NS5B聚合酶的抑制剂、乙型肝炎病毒DNA聚合酶抑制剂、逆转录病毒逆转录酶抑制剂，可以在体内进行有效地代谢，转化为高含量的三磷酸核苷代谢物质。由此，本发明的化合物具有更为优异的病毒抑制活性。

Claims (14)

  1. 式(I)所示的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，
    Figure PCTCN2017117126-appb-100001
    其中，
    L选自取代或未取代的C 1-12亚烷基、C 2-12亚烯基、C 2-12亚炔基，所述亚烷基、亚烯基或亚炔基任选地被一个或多个-O-、-NR 8-或-S-间断；或者
    L表示式(c)、式(d)或式(e)所示的基团，其中
    Figure PCTCN2017117126-appb-100002
    表示单键或双键，并且1位置处与Base连接，2位置处与磷原子(P)连接：
    Figure PCTCN2017117126-appb-100003
    Base表示式(a)或式(b)所示的基团：
    Figure PCTCN2017117126-appb-100004
    Figure PCTCN2017117126-appb-100005
    表示单键或双键；
    M表示N或NR 8；
    W表示H、NR 8R 9、NR 8、CH 2、O或S；
    Q表示O、S、NR 8或CH 2；
    Z在每次出现时各自独立地表示氢、卤素、羟基、氰基、硝基、叠氮基、NR 8R 9、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基或者取代或未取代的C 3-8环烷基，优选地，Z在每次出现时各自独立地表示氢、卤素、NR 8R 9或C 1-6烷基，如果存在多个Z，则其各自可以相同也可以不同；
    p表示0、1、2、3、4或5；
    条件是，当M被双键连接时，则W被单键连接；当M被单键连接时，则W被双键连接；
    U表示O、S、NR 8或CR 10R 11；
    E表示CR 10、CR 10R 11或S，条件是，当E被双键连接时，其为CR 10；
    G在每次出现时各自独立地表示氢、卤素、羟基、氰基、硝基、叠氮基、NR 8R 9、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基或者取代或未取代的C 3-8环烷基，优选地，G在每次出现时各自独立地表示氢、卤素、羟基、叠氮基或C 1-6烷基，如果存在多个G，则其各自可以相同也可以不同；
    q表示0-5的整数，优选地，q表示0、1、2、3或4；
    Ar 1表示C 6-14芳基或5-14元杂芳基，优选地，Ar 1表示表示苯基、1-萘基、2-萘基或5-6元杂芳基(例如噻吩基、吡啶基或吡唑基)；
    R 1在每次出现时各自独立地表示氢、卤素、-OH、-CN、-NO 2、-NR 8R 9、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基、取代或未取代的C 1-6卤代烷基、取代或未取代的C 1-6烷硫基、取代或未取代的C 3-8环烷基、取代或未取代的3-10元杂环烷基、取代或未取代的C 2-10烯基、或者取代或未取代的C 2-10炔基，优选地，R 1在每次出现时各自独立地表示氢、卤素、C 1-6烷基或C 1-6烷氧基，更优选地，R 1在每次出现时各自独立地表示氢、氟、氯、溴、甲基、乙基或丙基，如果存在多个R 1，则其各自可以相同也可以不同；
    m表示0-7的整数，优选地，m表示0、1、2、3或4；
    X表示CH 2、-S-、-O-或-NR 8-，优选地，X表示NH、N-C 1-6烷基(例如N-甲基)或O，更优选地，X表示NH；
    R 2和R 3在每次出现时各自独立地表示氢、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基、取代或未取代的C 6-14芳基、取代或未取代的C 7-20芳烷基、或者取代或未取代的C 3-8环烷基；或者R 2和R 3与所连接的碳原子一起形成取代或未取代的C 3-8环烷基或者取代或未取代的3-10元杂环烷基，优选地，R 2和R 3在每次出现时各自独立地表示氢或C 1-6烷基(例如甲基、乙基或丙基)；或者R 2和R 3与所连接的碳原子一起形成环丙基、环丁基、环戊基或环己基；
    R 4和R 5在每次出现时各自独立地表示氢、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基、取代或未取代的C 6-14芳基、取代或未取代的C 7-20芳烷基、或者取代或未取代的C 3-8环烷基；或者R 4和R 5与所连接的碳原子一起形成取代或未取代的C 3-8环烷基或者取代或未取代的3-10元杂环烷基，优选地，R 4和R 5在每次出现时各自独立地表示氢或C 1-6烷基(例如甲基、乙基或丙基)；或者
    R 3和R 4彼此连接、与它们各自所连接的碳原子一起形成取代或未取代的C 3-8环烷基或者取代或未取代的3-10元杂环烷基；
    R 6表示氢、取代或未取代的C 1-6烷基、取代或未取代的C 3-8环烷基、取代或未取代的C 6-14芳基、取代或未取代的C 7-20芳烷基或者取代或未取代的C 1-6烷氧基，优选地，R 6表示氢、C 1-6烷基或C 3-8环烷基，更优选地，R 6表示氢、甲基、乙基、丙基、环丙基或环丁基；
    R 7在每次出现时各自独立地表示氢、卤素、-OH、-CN、-NO 2、-NR 8R 9、取代或未取代的C 1-6烷基、取代或未取代的C 1-6卤代烷基、取代或未取代的C 1-6烷硫基、取代或未取代的C 3-8环烷基、取代或未取代的3-10元杂环烷基、取代或未取代的C 2-10炔基、或者取代或未取代的C 1-6烷氧基，优选地，R 7在每次出现时各自独立地表示氢、氟、氯、溴、甲基、乙基、丙基、叔丁基、甲氧基、环丙基或环丁基，如果存在多个R 7，则其各自可以相同也可以不同；或者
    R 6和R 7彼此连接、与它们之间间隔的碳原子一起形成取代或未取代的C 3-8碳环基或3-10元杂环基；
    n表示0-7的整数，优选地，n表示0、1、2、3或4；
    Ar 2表示C 6-14芳基或5-14元杂芳基，优选地，Ar 2表示苯基、1-萘基、2-萘基或5-6元杂芳基(例如噻吩基、吡啶基或吡唑基)；
    r和s各自独立地表示1、2或3；
    R 8和R 9在每次出现时各自独立地表示氢、取代或未取代的C 1-6烷基、或者取代或未取代的C 3-8环烷基，如果存在多个R 8、R 9，则其各自可以相同，也可以不同，优选地，R 8表示氢、C 1-6烷基或C 3-8环烷基；且R 9表示氢；并且
    R 10和R 11在每次出现时各自独立地表示氢、取代或未取代的C 1-6烷基、或者取代或未取代的C 3-8环烷基，或者R 10和R 11一起形成C 1-6亚烷基，如果存在多个R 10、R 11，则其各自可以相 同，也可以不同。
  2. 权利要求1所述的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，其中，所述化合物为式(Ia)的化合物
    Figure PCTCN2017117126-appb-100006
    其中，
    L-Base表示下式(f)或式(g)所示的基团：
    Figure PCTCN2017117126-appb-100007
    Base表示下式(a)或式(b)所示的基团：
    Figure PCTCN2017117126-appb-100008
    其中，
    Figure PCTCN2017117126-appb-100009
    表示单键或双键，
    M表示N或NR 8；
    W表示NR 8R 9或O；
    Q表示O或S；
    Z在每次出现时各自独立地表示氢、卤素、NR 8R 9、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基或者取代或未取代的C 3-8环烷基，如果存在多个Z，则其各自可以相同也可以不同；
    p表示0～2的整数；
    条件是，当M被双键连接时，则W被单键连接，M表示N，W表示NR 8R 9；当M被单键连接时，则W被双键连接，M表示NR 8，W表示O；
    U表示O、S或CR 10R 11；
    E表示CR 10、CR 10R 11或S，条件是，当E被双键连接时，则其为CR 10；
    G在每次出现时各自独立地表示氢、卤素、羟基、叠氮基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基或者取代或未取代的C 3-8环烷基，如果存在多个G，则其各自可以相同也可以不同；
    q表示0～4的整数；
    A表示取代或未取代的C 1-6烷撑基，优选地，A表示C 1-3烷撑基；
    B表示取代或未取代的C 1-6烷撑基，优选地，B表示未取代的或被C 1-3烷基取代的C 1-3烷撑基；
    D表示O、S或NR 8，优选地，D表示O；
    Ar 1表示C 6-10芳基或C 3-10杂芳基；
    R 1在每次出现时各自独立地表示氢、卤素、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基、取代或未取代的C 3-8环烷基、取代或未取代的C 3-8杂环烷基、取代或未取代的C 2-10烯基、或者取代或未取代的C 2-10炔基，如果存在多个R 1，则其各自可以相同也可以不同；
    m表示0～7的整数；
    X表示-O-或-NR 8-；
    R 2和R 3各自独立地表示氢、取代或未取代的C 1-6烷基、取代或未取代的C 3-8环烷基；或者R 2和R 3与所连接的碳原子一起形成取代或未取代的C 3-8环烷基或取代或未取代的C 3-8杂环烷基；
    R 4和R 5各自独立地表示氢、取代或未取代的C 1-6烷基、取代或未取代的C 3-8环烷基；或者R 4和R 5与所连接的碳原子一起形成取代或未取代的C 3-8环烷基或者取代或未取代的C 3-8杂环烷基；或者
    R 3和R 4彼此连接、与它们各自所连接的碳原子一起形成取代或未取代的C 4-8环烷基或者取代或未取代的C 4-8杂环烷基；
    R 6表示氢、取代或未取代的C 1-6烷基、取代或未取代的C 3-8环烷基、或者取代或未取代的C 1-6烷氧基；
    R 7在每次出现时各自独立地表示氢、卤素、取代或未取代的C 1-6烷基、取代或未取代的C 3-8环烷基、或者取代或未取代的C 1-6烷氧基，如果存在多个R 7，则其各自可以相同也可以不同；或者
    R 6和R 7彼此连接、与它们之间间隔的碳原子一起形成取代或未取代的C 4-8碳环基或C 4-8杂环基；
    n表示0～7的整数；
    Ar 2表示C 6-10芳基或C 3-10杂芳基；
    R 8和R 9在每次出现时各自独立地表示氢、取代或未取代的C 1-6烷基、或者取代或未取代的C 3-8环烷基，如果存在多个R 8、R 9，则其各自可以相同，也可以不同，
    R 10和R 11在每次出现时各自独立地表示氢、取代或未取代的C 1-6烷基、或者取代或未取代的C 3-8环烷基，或者R 10和R 11一起形成C 1-6亚烷基，如果存在多个R 10、R 11，则其各自可以相同，也可以不同。
  3. 权利要求1所述的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，
    其中，
    r、s均为1；
    Base选自：
    Figure PCTCN2017117126-appb-100010
    L选自任选地被一个或多个G取代的C 1-6亚烷基、C 2-6亚烯基、C 2-6亚炔基，所述亚烷基、亚烯基或亚炔基任选地被一个或多个-O-、-NR 8-或-S-间断；
    或者L选自下列基团：
    Figure PCTCN2017117126-appb-100011
    其中
    Figure PCTCN2017117126-appb-100012
    表示单键或双键，并且1位置处与Base连接，2位置处与磷原子(P)连接；
    X、U、W、Q在每次出现时各自独立地选自CH 2、O、S和NR 8；
    G和Z在每次出现时各自独立地选自卤素、-OH、-CN、-NO 2、-NR 8R 9、-N 3、C 1-6烷基和C 3-6环烷基；
    p、q在每次出现时各自独立地为0、1、2、3、4或5，条件是p不大于对应基团上可被取代的位置的数目且不大于对应基团上可被取代的位置的数目；当p大于1时，每个Z可以相同或不同；当q大于1时，每个G可以相同或不同；
    Ar 1和Ar 2各自独立地选自C 6-14芳基和5-14元杂芳基；
    m、n各自独立地选自1、2、3、4或5，优选1或2；
    R 1、R 7各自独立地选自氢、卤素、-OH、-CN、-NO 2、-NR 8R 9、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、C 1-6烷硫基、C 3-6环烷基、3-10元杂环烷基和C 2-6炔基；
    R 8、R 9在每次出现时各自独立地表示氢、C 1-6烷基和C 3-6环烷基；
    R 2、R 3各自独立地选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 6-14芳基和C 7-20芳烷基，所述烷基、环烷基、烷氧基、芳基和芳烷基各自任选地被一个或多个选自卤素、-OH、-CN和-NO 2的取代基取代；
    或者R 2和R 3连同其所连接的碳原子共同形成C 3-6环烷基或3-10元杂环烷基；
    R 4、R 5各自独立地选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 6-14芳基和C 7-20芳烷基，所述烷基、环烷基、烷氧基、芳基和芳烷基各自任选地被一个或多个选自卤素、-OH、-CN和-NO 2的取代基取代；
    或者R 4和R 5连同其所连接的碳原子共同形成C 3-6环烷基或3-10元杂环烷基；
    或者R 3和R 4连同其所连接的碳原子共同形成C 3-6环烷基或3-10元杂环烷基；且
    R 6选自氢、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、C 6-14芳基和C 7-20芳烷基，所述烷基、环烷基、烷氧基、芳基和芳烷基各自任选地被一个或多个选自卤素、-OH、-CN和-NO 2的取代基取代；
    或者R 6和R 7连同其所连接的碳原子共同形成与Ar 2稠合的C 3-6环烷基或3-10元杂环烷基；优选地，R 6和R 7连同其所连接的碳原子共同形成与Ar 2稠合的C 4-6环烷基或4-10元杂环烷基。
  4. 权利要求1至3中任一项所述的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，其中，Base表示下式所示的基团，
    Figure PCTCN2017117126-appb-100013
  5. 权利要求1-4中任一项所述的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，其中，L-Base表示下式所示的基团，
    Figure PCTCN2017117126-appb-100014
  6. 权利要求1-5中任一项所述的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，其中，所述化合物为式(II)所示的化合物，
    Figure PCTCN2017117126-appb-100015
    其中，R 1、R 2、R 3、R 6、R 7、m、n、Ar 1和Ar 2如权利要求1-5中任一项所定义；
    优选地，所述化合物为式(IIa)所示的化合物，
    Figure PCTCN2017117126-appb-100016
    其中，R 1、R 2、R 3、R 6和R 7以及m和n如权利要求1-5中任一项所定义；
    更优选地，所述化合物为式(IIb)所示的化合物，
    Figure PCTCN2017117126-appb-100017
    其中，R 2、R 3、R 7和n如权利要求1-5中任一项所定义。
  7. 权利要求1所述的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，其中，所述化合物为式(III)所示的化合物，
    Figure PCTCN2017117126-appb-100018
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、m、n、s、r、Ar 1和Ar 2如权利要求1所定义；
    优选地，所述化合物为式(IIIa)所示的化合物，
    Figure PCTCN2017117126-appb-100019
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、m、n、Ar 1和Ar 2如权利要求1所定义；
    更优选地，所述化合物为式(IIIb)所示的化合物，
    Figure PCTCN2017117126-appb-100020
    其中，R 1、R 2、R 3、R 6、R 7、R 8、m、n、Ar 1和Ar 2如权利要求1所定义；
    例如，所述化合物为式(IIIc-1)或式(IIIc-2)所示的化合物，
    Figure PCTCN2017117126-appb-100021
    其中，R 1、R 2、R 3、R 6、R 7、R 8、m、n、Ar 1和Ar 2如权利要求1所定义。
  8. 权利要求1所述的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，其中，所述化合物为式(IV)所示的化合物，
    Figure PCTCN2017117126-appb-100022
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、m、n、s、r、Ar 1和Ar 2如权利要求1所定义。
  9. 权利要求1-8中任一项所述的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，其中，所述化合物为
    Figure PCTCN2017117126-appb-100023
    Figure PCTCN2017117126-appb-100024
    Figure PCTCN2017117126-appb-100025
  10. 药物组合物，其包含权利要求1-9中任一项所述的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，优选进一步包含药学上可以接受的辅料，更优选进一步包含可与权利要求1-9中任一项所述的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物联用的其它活性成分，其中所述其它活性成分优选地选自干扰素、病毒唑或其类似物、HCV NS3蛋白酶抑制剂、α-葡糖苷酶1抑制剂、肝保护剂、HCV NS5B聚合酶的非核苷抑制剂、HCV NS5A抑制剂、TLR-7激动剂、亲环素抑制剂、HCV IRES抑制剂、药物动力学增加剂和用于治疗HCV的其它药物或治疗剂，或其组合，所述药物组合物是固体制剂、半固体制剂、液体制剂或气态制剂的形式。
  11. 权利要求10所述的组合物，其中所述组合物所包含的权利要求1-9中任一项所述的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物的量为0.01-1000mg，适宜地为0.5-800mg，优选为1-400mg，更优选为5-200mg，特别优选10-100mg，最优选15-50mg。
  12. 权利要求1-9中任一项所述的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，或者权利要求10或11所述的药物组合物在制备用于预防或治疗NS5B聚合酶介导的疾病、DNA聚合酶介导的疾病或逆转录酶介导的疾病的药物中的用途。
  13. 权利要求1-9中任一项所述的化合物、其药学可接受的盐、酯、溶剂化物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物，或者权利要求10或11所述的药物组合物在制备用于预防或治疗病毒性疾病或癌症的药物中的用途，其中所述病毒性疾病优选地选自甲型病毒性肝炎、乙型病毒性肝炎、丙型病毒性肝炎、流行性感冒、疱疹和获得性免疫缺陷综合征(AIDS)。
  14. 制备权利要求1-9中任一项所述的化合物、其药学可接受的盐、酯、溶剂合物、异构体、它们的任意晶型或消旋物、它们的代谢物形式、或它们的混合物的制备方法，其包括以下步骤：
    Figure PCTCN2017117126-appb-100026
    步骤一：使式2所示的三卤氧磷与式1所示的化合物反应，得到式3所示的化合物；
    步骤二：使式3所示的化合物与式4所示的化合物反应，得到式5所示的化合物；
    步骤三：使式5所示的化合物与式6所示的五氟苯酚反应，得到式7所示的化合物；和
    步骤四：使式7所示的化合物与式8所示的化合物反应，得到式(I)所示的化合物；
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、m、n、s、r、X、Ar 1、Ar 2、L和Base如权利要求1-5中任一项所定义；并且
    Y彼此相同或不同，且各自独立地选自卤素；
    或者
    Figure PCTCN2017117126-appb-100027
    其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、m、n、s、r、X、Ar 1、Ar 2、L和Base如权利要求1-5中任一项所定义；
    或者
    Figure PCTCN2017117126-appb-100028
    其中，
    Figure PCTCN2017117126-appb-100029
    表示实楔形
    Figure PCTCN2017117126-appb-100030
    或虚楔形
    Figure PCTCN2017117126-appb-100031
    化学键中的任意一种；且
    R 1、R 2、R 3、R 4、R 5、R 6、R 7、m、n、s、r、X、Ar 1、Ar 2、L和Base如权利要求1-5中任一项所定义。
PCT/CN2017/117126 2016-12-23 2017-12-19 核苷磷酸类化合物及其制备方法和用途 WO2018113652A1 (zh)

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