WO2019129059A1 - 一种具有cd73抑制活性的膦酸衍生物、其制备方法和应用 - Google Patents

一种具有cd73抑制活性的膦酸衍生物、其制备方法和应用 Download PDF

Info

Publication number
WO2019129059A1
WO2019129059A1 PCT/CN2018/123908 CN2018123908W WO2019129059A1 WO 2019129059 A1 WO2019129059 A1 WO 2019129059A1 CN 2018123908 W CN2018123908 W CN 2018123908W WO 2019129059 A1 WO2019129059 A1 WO 2019129059A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
cancer
hydrazine
cycloalkyl
Prior art date
Application number
PCT/CN2018/123908
Other languages
English (en)
French (fr)
Inventor
邓海兵
赵保卫
应海燕
喻红平
陈椎
徐耀昌
Original Assignee
上海和誉生物医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海和誉生物医药科技有限公司 filed Critical 上海和誉生物医药科技有限公司
Priority to CN201880057756.6A priority Critical patent/CN111094317B/zh
Publication of WO2019129059A1 publication Critical patent/WO2019129059A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • 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
    • A61K31/7076—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 containing purines, e.g. adenosine, adenylic acid
    • 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
    • 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
    • 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
    • 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
    • C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of drug synthesis, and in particular relates to a phosphonic acid derivative having CD73 inhibitory activity, a preparation method and application thereof.
  • CD73 also known as Ecto-5'-nucleotidase (eNT) is a 70 kDa protein molecule. Under normal conditions, it is expressed on vascular endothelial cells and a part of blood cells. It is anchored to the cell membrane surface by glycosylphosphatidylinositol (GPI) and, together with CD39, regulates the metabolism of adenosine triphosphate (ATP).
  • GPI glycosylphosphatidylinositol
  • ATP adenosine triphosphate
  • CD39 also known as extra-membrane nucleoside dihydrogenase-NTPDase 1
  • AMP adenosine monophosphate
  • ADP adenosine diphosphate
  • Nucleosides produced by CD73 are considered to be internal regulatory molecules of many different physiological functions.
  • Adenosine regulates the cardiovascular system, the central nervous system, the respiratory system, the kidneys, fat cells, platelets, and the immune system.
  • extracellular adenosine can act on a wide variety of different immune cells and mediate anti-inflammatory responses. In many tissues, adenosine also promotes the process of fibrosis.
  • CD73 The expression of CD73 is found in many tumor cells, including leukemia, bladder cancer, glioma, glioblastoma, ovarian cancer, melanoma, prostate cancer, thyroid cancer, esophageal cancer, and breast cancer. At the same time, expression of CD73 was also found on the surface of immunosuppressive cells including regulatory T cells and myeloid suppressor cells MDSC. High expression of CD73 has also been found to be associated with angiogenesis, infiltration, resistance to chemotherapy, metastasis of tumors, and shorter survival in cancer patients, including breast cancer and melanoma.
  • adenosine a metabolite of ATP
  • A2A adenosine receptors
  • CD73 knockout mice are less likely to develop rejection of organ transplants and spontaneous tumors genetically delete the A2A receptor gene to induce T cell-dependent tumor rejection.
  • treatment with antibodies that bind to mouse CD73 inhibits the growth and migration of breast tumors.
  • targeting CD73 represents a potential therapeutic strategy that enhances the efficacy of anti-tumor immunotherapy and provides a new therapeutic strategy for limiting the further development of tumors.
  • targeting CD73 can also be used to treat other diseases mediated by adenosine, such as enhancing immune response, enhancing immune response, enhancing inflammatory response, and treating diseases including neurological disorders, neurodegeneration, and central nervous system diseases. Such as depression, Parkinson's disease, sleep disorders, fibrosis and other immunoinflammatory diseases.
  • a first aspect of the invention provides a compound of formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof:
  • X 1 and X 2 are each independently selected from N or CH;
  • X 3 and X 4 are each independently selected from N or C;
  • X 5 and X 6 are each independently selected from O, S, C(R 10 ), N or N(R 11 );
  • Y 2 and Y 3 are each independently selected from -O-, -S- or -C(R 17 R 18 )-;
  • Z is selected from -O-, -S- or -NH-;
  • R 1 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl a C 3-10 cycloalkoxy group, a 3-10 membered heterocyclic group, a 3-10 membered heterocyclic oxy group, a C 5-10 aryl group, a C 5-10 aryloxy group, a 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy, -NR 19 R 20 or -C 0-8 -S(O) r R 21 , the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, and nitrate Base, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, C 3-10 cyclo
  • R 2 is selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0 -8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0 -8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 , the above group optionally further one or more selected from the group consisting of hydrazine, halogen,
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 , -C 0-8 - OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 , the above group optionally further selected from one or more selected from Anthracene, halogen, cyan
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 , -C 0-8 - OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 , or R 5 and R 6 and the carbon directly attached thereto The atoms together form a 3-10 membere
  • R 7 , R 8 and R 9 are each independently selected from the group consisting of hydrogen, hydrazine, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3- 10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -S(O) r R 21 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 or -C 0-8 -C(O)NR 24 R 25 , or R 7 together with R 8 or R 9 and a group directly bonded thereto form a 6-10 member hetero a cyclic group, R 8 and R 9 together with a group directly bonded thereto form a 4-10 membered heterocyclic group, the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide
  • Each of R 10 , R 12 , R 13 , R 14 , R 15 , R 17 , R 18 is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, -C 0 -8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0- 8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O R 23 , the above group is optionally
  • R 11 and R 16 is independently selected from the group consisting of hydrogen, hydrazine, C 1-10 alkyl, C 3-10 cycloalkyl C 1-10 alkyl, C 2-10 alkenyl, C 2-10 chain. Alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0- 8 -NR 24 R 25 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 , the above group is optionally further a plurality selected from the group consisting of hydra
  • R 19 and R 20 is independently selected from the group consisting of hydrogen, hydrazine, C 1-10 alkyl, C 3-10 cycloalkyl C 1-10 alkyl, C 2-10 alkenyl, C 2-10 chain. Alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S ( O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(O)NR 24 R 25 or -C 0-8 -N(R 24 )-C(O)R 23 , or And R 19 , R 20 and the directly
  • Each R 21 is selected from the group consisting of hydrogen, hydrazine, hydroxy, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 3-10 cycloalkyl, C 3-10 cycloalkoxy Base, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C 5-10 aryl group, C 5-10 aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group Or -NR 24 R 25 , the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, carbonyl, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl a C 3-10 cycloalkoxy group, a 3-10 membered heterocyclic group, a 3-10 membered heterocyclic oxy group, a C 5-10 aryl group, a C 5-10 aryloxy group, a 5
  • Each R 22 is selected from the group consisting of hydrogen, hydrazine, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl or 5- a 10-membered heteroaryl group, the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, carbonyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 ring Alkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl Substituted by a 5- to 10-membered heteroaryloxy group or a substituent of -NR 24 R 25 ;
  • Each R 23 is selected from the group consisting of hydrogen, hydrazine, hydroxy, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl a C 3-10 cycloalkoxy group, a 3-10 membered heterocyclic group, a 3-10 membered heterocyclic oxy group, a C 5-10 aryl group, a C 5-10 aryloxy group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group or -NR 24 R 25 , the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, cyano, C 1-10 alkyl, C 1-10 alkoxy , C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C 5-10 aryl, C 5-10
  • Each of R 24 and R 25 is independently selected from the group consisting of hydrogen, hydrazine, hydroxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3 -10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, sulfonyl group, methylsulfonyl group, isopropylsulfonyl group, cyclopropylsulfonyl group, p-toluenesulfonyl group, amino group, monoalkyl group An amino group, a dialkylamino group or a C 1-10 alkanoyl group, the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, C 1-8 alkyl, C 1-10 alkoxy, C 3 -10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 member
  • R 24 and R 25 together with the directly bonded nitrogen atom thereof form a 4-10 membered heterocyclic group, and the above group is optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C 5-10 aryl, C Substituted with a substituent of 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C1-10 alkanoyl;
  • Each r is independently 0, 1, or 2.
  • each chiral carbon is independently R or S.
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydrazine, halogen, C 1-4.
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, a C 1-4 alkyl group, a C 2-4 alkenyl group or a C 2-4 alkynyl group, the above group optionally further one or more selected from the group consisting of hydrazine, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, -C 0-4 -OR 22 or -C 0-4 -NR 24 R Substituted by a substituent of 25 , R 22 , R 24 , R 25 , r are as described for the compound of formula (I); preferably, R 3 and R 4 are each independently selected from the group consisting of hydrogen,
  • Y 2 and Y 3 are each independently selected from -C(R 17 R 18 )-
  • R 17 and R 18 is independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C a 3-6 cycloalkyl group, a 3-6 membered heterocyclic group, -C 0-4 -OR 22 or -C 0-4 -OC(O)R 23 , the above group optionally further selected from one or more selected from Anthracene, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -OR 22 or Substituted by
  • R 1 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR 19 R 20 or -C 0-8 -S(O) r R 21 , optionally further Substituted by one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-4 Alkyl, C 3-6 cycloalky
  • R 2 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic ring , C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 or -C 0-8 -NR 24 R 25 Said group optionally further comprising one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , halogen substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O r R 21 ,
  • R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 and r are as defined for the compound of the formula (I).
  • X 3 and X 4 are each independently selected from N or C, and X 3 , X 4 contains at least one N;
  • Y 2 , Y 3 Individually selected from -C(R 17 R 18 )-;
  • R 1 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic ring , 3-10 membered heterocyclooxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR 19 R 20 or - C 0-8 -S(O) r R 21 , wherein the above group is further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2 -4 alkynyl, halo-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0- Sub
  • R 2 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic ring , C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 or -C 0-8 -NR 24 R 25 Said group optionally further comprising one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , halogen substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O Substituting
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, cyano, methyl, vinyl or ethynyl, and the above groups are optionally further substituted by one or more selected from the group consisting of hydrazine, halogen or cyclopropyl. Substituted by
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, methyl, isopropyl, allyl, ethynyl, cyclopropyl, trifluoromethyl, trimethylmethyl, methoxy, and trifluoro. a methoxy group, a trimethyl methoxy group, an amino group or a dimethylamino group;
  • Each of R 12 , R 13 , R 14 , and R 15 is independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3- 6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 21 , -C 0-4 -OR 22 , -C 0-4 -C(O)OR 22 , -C 0-4 -C(O)R 23 , -C 0-4 -OC(O)R 23 , -C 0-4 -NR 24 R 25 And -C 0-4 -C(O)NR 24 R 25 or -C 0-4 -N(R 24 )-C(O)R 23 , wherein the above group is further further selected from one or more selected from the group consisting of Halogen, cyano, C
  • Each R 16 is independently selected from the group consisting of hydrogen, hydrazine, C 1-4 alkyl, C 3-6 cycloalkyl C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 21 , -C 0-4 -OR 22 , -C 0-4 -C(O)OR 22 , -C 0-4 -C(O)R 23 , -C 0-4 -OC(O)R 23 , -C 0-4 -NR 24 R 25 , -C 0-4 -C(O)NR 24 R 25 or -C 0-4 -N(R 24 )-C(O)R 23 , the above groups are optionally further selected by one or more From hydrazine, halogen, cyano,
  • Each of R 17 and R 18 is independently selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, cyano, azido, methyl, vinyl, ethynyl, cyclopropyl, hydroxy, methoxy, ethoxylated or An acetoxy group, the above group optionally further comprising one or more substituents selected from the group consisting of hydrazine, fluorine, cyano, methyl, isopropyl, vinyl, ethynyl, cyclopropyl, hydroxy or methoxy Replace
  • R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 and r are as defined for the compound of the formula (I).
  • the compound of the formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof has the structure of the compound of the formula (IIa) or the compound of the formula (IIb):
  • R 1 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic ring , 3-10 membered heterocyclooxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR 19 R 20 or - C 0-8 -S(O) r R 21 , wherein the above group is further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2 -4 alkynyl, halo-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0- Sub
  • R 2 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic ring , C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 or -C 0-8 -NR 24 R 25 Said group optionally further comprising one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , halogen substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O Substituting
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, hydrazine, cyano, methyl, vinyl or ethynyl, and the above groups are optionally further substituted by one or more substituents selected from the group consisting of hydrazine, fluorine or cyclopropyl.
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydrazine, methyl, cyclopropyl, trifluoromethyl or trimethylmethyl;
  • R 12 , R 13 , R 14 , and R 15 is independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3- 6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -OR 22 , -C 0-4 -C(O)OR 22 , -C 0-4 -NR 24 R 25 , -C 0-4 -C(O)NR 24 R 25 or -C 0-4 -N(R 24 )-C(O)R 23 , optional of the above groups Further further one or more selected from the group consisting of hydrazine, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 aryl Substituted with
  • Each R 16 is independently selected from the group consisting of hydrogen, hydrazine, C 1-4 alkyl, C 3-6 cycloalkyl C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, a C 3-6 cycloalkyl group, a 3-6 membered heterocyclic group or -C 0-4 -C(O)R 23 , the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0- Substituted by a substituent of 4 -OR 22 , -C 0-4 -C(O)OR 22 or -C 0-4 -NR 24 R 25 ;
  • Each of R 17 and R 18 is independently selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, cyano, azido, methyl, vinyl, ethynyl, cyclopropyl, hydroxy, methoxy, ethoxylated or An acetoxy group, the above group optionally further comprising one or more substituents selected from the group consisting of hydrazine, fluorine, cyano, methyl, isopropyl, vinyl, ethynyl, cyclopropyl, hydroxy or methoxy Replace
  • R 7 , R 8 , R 9 , R 10 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 and r are as defined for the compound of the formula (I).
  • X 5 acceptable salt thereof is selected from C (R 10), or a compound of formula N (the I), a stereoisomer, a pharmaceutically acceptable prodrug thereof;
  • X 6 is selected from CH;
  • R 10 is independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 a heterocyclic group, a C 5-8 aryl group, a 5-8 membered heteroaryl group, -C 0-4 -OR 22 , -C 0-4 -OC(O)R 23 , -C 0-4 -NR 24 R 25 or -C 0-4 -N(R 24 )-C(O)R 23 , the above group optionally further one or more selected from the group consisting of hydrazine, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 aryl, 5-8 Substitute
  • R 22 , R 23 , R 24 and R 25 are as defined for the compound of formula (I).
  • the compound of the formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof has the structure of the compound of the formula (IIIa):
  • X 1 and X 2 are each independently selected from N or CH;
  • X 5 is selected from C(R 10 ) or N;
  • Y 1 is selected from -O- or -C(R 12 R 13 )-;
  • R 1 is selected from C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclic, 3-8 membered heterocyclooxy, C 5-8 aryl, C 5-8 aryl An oxy group, a 5-8 membered heteroaryl group, a 5-8 membered heteroaryloxy group or -NR 19 R 20 , the above group optionally further selected from one or more selected from the group consisting of ruthenium, fluorine, chlorine, cyano, methyl , ethyl, vinyl, ethynyl, trifluoromethyl, difluoromethyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazinyl, piperidinyl, phenyl, pyridyl Substituted by a substituent of a hydroxyl group or a methoxy group;
  • R 2 is selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, cyano, methyl, ethyl, propyl, vinyl, ethynyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazinyl , piperidinyl, phenyl, pyridyl, hydroxy, methoxy, amino, methylamino or dimethylamino, the above group optionally further selected from one or more selected from the group consisting of hydrazine, fluorine, chlorine, cyano, methyl , ethyl, propyl, vinyl, trifluoromethyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazinyl, piperidinyl, phenyl, pyridyl, hydroxy or methoxy Substituted by a substitu
  • R 3 is selected from hydrogen, hydrazine, cyano, methyl, vinyl or ethynyl, and the above group is optionally further substituted with one or more substituents selected from the group consisting of hydrazine, fluorine or cyclopropyl;
  • R 12 and R 13 are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, methyl, vinyl, cyclopropyl, hydroxy, trifluoromethyl or cyclopropylmethyl;
  • R 17 and R 18 are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, cyano, azide, methyl, vinyl, ethynyl, cyclopropyl, hydroxy, methoxy, trifluoromethyl, and tri ⁇ Methyl, trifluoromethoxy, trimethylmethoxy, cyclopropylmethyl, methoxymethyl, ethoxylated or acetoxy;
  • R 10 is selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, cyano, methyl, ethyl, propyl, vinyl, ethynyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazinyl , piperidinyl, phenyl, pyridyl, hydroxy, methoxy, amino, methylamino or dimethylamino, the above group optionally further selected from one or more selected from the group consisting of hydrazine, fluorine, chlorine, cyano, methyl , ethyl, propyl, vinyl, trifluoromethyl, cyclopropyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazinyl, piperidinyl, phenyl, pyridyl, hydroxy or methoxy Substituted by a substitu
  • R 19 and R 20 are each independently selected from the group consisting of hydrogen, hydrazine, C 1-4 alkyl, C 3-10 cycloalkyl C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl. , C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, hydroxy, acetyl or —C(O) NH 2 , or R 19 , R 20 and the directly bonded nitrogen atom thereof together form a 4-10 membered heterocyclic group, the above group optionally further selected from one or more selected from the group consisting of ruthenium, fluorine, chlorine, cyano, C 1-4 alkyl, vinyl, trifluoromethyl, cyclopropyl, cyclopentyl, morpholinyl, oxetanyl, tetrahydrofuranyl, piperazinyl,
  • the compound of the formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds:
  • the compound of the formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof has a compound structure of the following formula (IIc):
  • X 5 and X 6 are selected from C (R 10 ) and the other is selected from O or S;
  • R 1 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, C 1-10 alkyl, C 1-10 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic ring , 3-10 membered heterocyclooxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, -NR 19 R 20 or - C 0-8 -S(O) r R 21 , wherein the above group is further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2 -4 alkynyl, halo-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0- Sub
  • R 2 is selected from the group consisting of hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic ring , C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 or -C 0-8 -NR 24 R 25 Said group optionally further comprising one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , halogen substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O Substituting
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, cyano, methyl, vinyl or ethynyl, and the above groups are optionally further substituted by one or more selected from the group consisting of hydrazine, halogen or cyclopropyl. Substituted by
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, methyl, isopropyl, allyl, ethynyl, cyclopropyl, trifluoromethyl, trimethylmethyl, methoxy, and trifluoro. a methoxy group, a trimethyl methoxy group, an amino group or a dimethylamino group;
  • Each R 10 is independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3 -6 cycloalkyl, 3-6 membered heterocyclic, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 21 , -C 0-4 -OR 22 , -C 0-4 -C(O)OR 22 , -C 0-4 -C(O)R 23 , -C 0-4 -OC(O)R 23 , -C 0-4 -NR 24 R 25 , -C 0-4 -C(O)NR 24 R 25 or -C 0-4 -N(R 24 )-C(O)R 23 , the above group optionally further selected from one or more selected from ⁇ , halogen, cyano, nitro, azi
  • Each of R 17 and R 18 is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, azide, methyl, vinyl, ethynyl, cyclopropyl, hydroxy, methoxy or acetoxy.
  • the above group is optionally further substituted with one or more substituents selected from the group consisting of hydrazine, fluorine, cyano, methyl, isopropyl, vinyl, ethynyl, cyclopropyl, hydroxy or methoxy;
  • R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 and r are as defined for the compound of the formula (I).
  • one of X 5 and X 6 in the compound of the formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof is selected from C(R 10 ), and the other is selected. From O;
  • R 3 and R 4 are each independently selected from hydrogen or hydrazine
  • R 5 and R 6 are each independently selected from hydrogen, hydrazine, methyl or cyclopropyl
  • Each R 10 is independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl;
  • R 17 and R 18 are independently selected from the group consisting of hydrogen, hydrazine, fluorine, methyl or hydroxy, and the above group is optionally further substituted with one or more substituents selected from hydrazine or fluorine.
  • the compound of the formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds:
  • a process for the preparation of a compound of the above formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof comprising the steps of:
  • Pg is hydrogen, a hydroxy protecting group, a thiol protecting group or an amino protecting group, preferably hydrogen, tert-butoxycarbonyl or p-toluenesulfonyl;
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y 1 , Y 2 , Y 3 , Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined for the compound of formula (I).
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the above formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a fourth aspect of the invention provides a compound of the above formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for the preparation of a cancer or tumor which is at least partially mediated by CD73, Application in medicines related to immune-related diseases and disorders, metabolic diseases.
  • the cancer or tumor is selected from the group consisting of prostate cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, and head.
  • Cancer neck cancer, skin cancer (including melanoma and basal cell carcinoma), mesenchymal carcinoma, white blood cell carcinoma (including lymphoma and leukemia), esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, lung cancer (including Small cell lung cancer and non-small cell carcinoma), adrenal cancer, thyroid cancer, kidney cancer, bone cancer, brain tumor, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma (including Kaposi's sarcoma), villi Membrane cancer, epidermal basal cell carcinoma, testicular seminoma.
  • skin cancer including melanoma and basal cell carcinoma
  • mesenchymal carcinoma including white blood cell carcinoma (including lymphoma and leukemia)
  • esophageal cancer breast cancer
  • muscle cancer connective tissue cancer
  • lung cancer including Small cell lung cancer and non-small cell carcinoma
  • adrenal cancer thyroid cancer
  • kidney cancer bone cancer
  • brain tumor glioblastoma
  • the cancer or tumor is selected from the group consisting of melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer, and Kaposi's sarcoma.
  • the immune-related diseases and disorders are selected from the group consisting of rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergy, fibrosis, anemia fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infection, Crohn's disease, ulcerative colitis, allergic contact dermatitis and eczema, system Sclerosing and multiple sclerosis.
  • a fifth aspect of the invention provides a compound of the above formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for use in the treatment of a cancer or tumor mediated at least in part by CD73, A drug for autoimmune diseases and disorders, metabolic diseases.
  • a sixth aspect of the invention provides a compound of the above formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for use in the treatment of prostate cancer, colon cancer, rectal cancer, pancreatic cancer , gastric cancer, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, head cancer, neck cancer, skin cancer (including melanoma and basal cell carcinoma), mesothelial cancer, white Blood cell carcinoma (including lymphoma and leukemia), esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, small cell lung cancer (lung cancer and non-small cell carcinoma), adrenal cancer, thyroid cancer, kidney cancer, bone cancer, brain tumor, Glioblastoma, mesothelioma, renal cell carcinoma, sarcoma (including Kaposi's sarcoma), choriocarcinoma, epidermal basal cell carcinoma, testicular seminom
  • a seventh aspect of the invention provides a method of treating cancer or a tumor, an immune-related disease and a disorder, a metabolic disease mediated at least in part by CD73, comprising administering to a patient a compound of the above formula (I), a stereoisomer thereof, A medicament or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.
  • the cancer or tumor is selected from the group consisting of prostate cancer, colon cancer, rectal cancer, pancreatic cancer, gastric cancer, endometrial cancer, cervical cancer, brain cancer, liver cancer, bladder cancer, ovarian cancer, testicular cancer, and head.
  • Cancer neck cancer, skin cancer (including melanoma and basal cell carcinoma), mesenchymal carcinoma, white blood cell carcinoma (including lymphoma and leukemia), esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, small cell lung cancer (lung cancer and non-small cell carcinoma), adrenal cancer, thyroid cancer, kidney cancer, bone cancer, brain tumor, glioblastoma, mesothelioma, renal cell carcinoma, sarcoma (including Kaposi's sarcoma), chorion Cancer, epidermal basal cell carcinoma, testicular seminoma; the immune-related diseases and metabolic diseases selected from rheumatoid arthritis, renal failure, lupus erythematosus, asthma, psoriasis, ulcerative colitis, pancreatitis, allergies , fibrosis, anemia fibromyalgia, Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis
  • An eighth aspect of the invention provides the use of the compound of the first aspect as a CD73 inhibitor.
  • the inventors of the present application have extensively and intensively studied for the first time to develop a phosphonic acid derivative having a CD73 inhibitory activity of the following formula (I), a preparation method thereof, and a pharmaceutical use.
  • the series of compounds of the invention have strong inhibitory effect on CD73 enzyme activity, and can be widely applied to prepare drugs for treating cancer or tumor, immune related diseases and disorders, metabolic diseases mediated at least partially by CD73, especially for treating melanoma.
  • Drugs for colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumor, lymphoma, ovarian cancer and Kaposi's sarcoma are expected to be developed into a new generation of CD73 inhibitor drugs. On the basis of this, the present invention has been completed.
  • Alkyl means a straight-chain or branched-chain saturated aliphatic hydrocarbon group, for example, "C 1-10 alkyl” means a straight-chain alkyl group having from 1 to 10 carbon atoms and a branched alkyl group, including but Not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2- Dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropane 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethyl Butyl, 2-ethylbutyl, 2-methyl
  • Alkyl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from deuterium, halogen, cyano, nitro, azido group, C 1 -10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0 -8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(O)NR 24 R 25 or- Substituents of C 0-8 -N(R 24 R 25
  • Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, for example, "C 3-10 cycloalkyl” refers to a cycloalkyl group of 3 to 10 carbon atoms, which is divided into a single ring. a cycloalkyl, polycyclic cycloalkyl group, wherein:
  • Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl and the like.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • “Spirocycloalkyl” refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group depending on the number of common spiro atoms between the ring and the ring, and the spirocycloalkyl group includes, but is not limited to:
  • fused cycloalkyl refers to an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but None of the rings have a fully conjugated ⁇ -electron system. Depending on the number of constituent rings, it may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, and fused cycloalkyl groups include, but are not limited to:
  • Bridge cycloalkyl refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system . According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, and bridged cycloalkyl groups include but are not limited to:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group including, but not limited to, indanyl, tetrahydronaphthyl , benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • S(O) r where r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms
  • Monocyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer) The heteroatoms of 0, 1, 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspiroheterocyclic group depending on the number of common spiro atoms between the ring and the ring.
  • Spiroheterocyclyl includes, but is not limited to:
  • “Fused heterocyclyl” refers to a polycyclic heterocyclic group in which each ring of the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none
  • the ring has a fully conjugated pi-electron system in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, the remaining ring atoms being carbon.
  • the bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl group may be classified according to the number of constituent rings, and the fused heterocyclic group includes but is not limited to:
  • Bridge heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly bonded, and these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, One or more of the ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon.
  • the bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group may be classified according to the number of constituent rings, and the bridged heterocyclic group includes but is not limited to:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group including, but not limited to:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C.
  • Aryl means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a polycyclic ring of a conjugated ⁇ -electron system (ie, having a ring adjacent to a carbon atom) a group, for example, "C 5-10 aryl” means an all-carbon aryl group having 5 to 10 carbons, and "5-10 membered aryl group” means an all-carbon aryl group having 5 to 10 carbons, including It is not limited to phenyl and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring including, but not limited to:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(O)NR 24 R 25 or -C 0 Substituted
  • Heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen and a hetero atom of S(O)r (wherein r is an integer of 0, 1, 2), for example, 5-10 membered heteroaryl refers to a heteroaromatic system containing 5 to 10 ring atoms, and 5-8 membered heteroaryl refers to a heteroaromatic system containing 5 to 8 ring atoms, including but not limited to furyl, thiophene.
  • Base pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring including, but not limited to:
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C.
  • Alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, C 2-10 alkenyl refers to a straight or branched chain containing from 2 to 10 carbons. Alkenyl. These include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(O)NR 24 R 25 or -C 0 Substituted
  • Alkynyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, for example, C 2-10 alkynyl refers to a straight or branched chain containing from 2 to 10 carbons. Alkynyl. These include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-10.
  • Alkyl C 2-10 alkenyl, C 2-10 alkynyl, halo substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 , -C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(O)NR 24 R 25 or -C 0 Substituted by a substituent of -8- N(R 24 )-C(O)R 23 .
  • Alkoxy means -O-(alkyl) wherein alkyl is as defined above, for example, "C 1-10 alkoxy” refers to an alkyloxy group containing from 1 to 10 carbons, including but not It is limited to methoxy, ethoxy, propoxy, butoxy and the like.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent, preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic, C 5 -10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 ,- C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(O)NR 24 R 25 , -C 0-8
  • Cycloalkoxy refers to and -O-cycloalkyl, wherein cycloalkyl is as defined above, for example, "C 3-10 cycloalkoxy” refers to a cycloalkyloxy group containing from 3 to 10 carbons. Including, but not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • the cycloalkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic, C 5 -10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 ,- C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(O)NR 24 R 25 , -C
  • Heterocyclyloxy means a -O-heterocyclic group, wherein the meaning of the heterocyclic group is as defined above, for example, "C 3-10 heterocyclooxy” refers to a heterocyclic oxy group having 3 to 10 carbons. These include, but are not limited to, azetidinyloxy, oxetanyloxy, azacyclopentyloxy, nitrogen, oxetanyloxy and the like.
  • the heterocyclic oxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic, C 5 -10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 21 , -C 0-8 -OR 22 , -C 0-8 -C(O)OR 22 ,- C 0-8 -C(O)R 23 , -C 0-8 -OC(O)R 23 , -C 0-8 -NR 24 R 25 , -C 0-8 -C(O)NR 24 R 25 , -C 0-8
  • C 1-10 alkanoyl means a monovalent atomic group remaining after the C 1-10 alkyl acid has been removed from the hydroxy group, and is also usually expressed as "C 0-9 -C(O)-", for example, "C 1 -C"(O)-” means acetyl; “C 2 -C(O)-” means propionyl; “C 3 -C(O)-” means butyryl or isobutyryl.
  • -C 0-8 -OR 22 means that the oxygen atom in -OR 22 is attached to a C 0-8 alkyl group, wherein the C 0 alkyl group means a bond, and the C 1-8 alkyl group is as defined above.
  • -C 0-8 -C(O)R 23 means that the carbonyl group in -C(O)R 23 is attached to a C 0-8 alkyl group, wherein a C 0 alkyl group means a bond, a C 1-8 alkyl group
  • the definition is as described above.
  • -C 0-8 -NR 24 R 25 means that the nitrogen atom in -NR 24 R 25 is attached to a C 0-8 alkyl group, wherein the C 0 alkyl group means a bond, and the C 1-8 alkyl group is as defined above. Said.
  • Halo-substituted C 1-10 alkyl means a hydrogen atom on the alkyl group optionally substituted with fluoro, chloro, bromo or iodo, 1-10, including but not limited to difluoromethyl, Chloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.
  • the hydrogen on the "halo-substituted C 1-8 alkoxy" alkyl group is optionally a 1-8 carbon alkoxy group substituted with a fluorine, chlorine, bromine or iodine atom.
  • fluorine chlorine, bromine or iodine atom.
  • these include, but are not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.
  • Halogen means fluoro, chloro, bromo or iodo.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted means that one or more hydrogen atoms in the group are each independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond such as an olefin.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in parts per million (ppm).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ).
  • the internal standard was four.
  • Methyl silane (TMS) Methyl silane
  • LC-MS was determined by LC-MS using an Agilent 6120 mass spectrometer.
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification for TLC is 0.15mm ⁇ 0.20mm, and the specification for separation and purification of thin layer chromatography is 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • Second step Synthesis of 7-bromo-2-chloro-N-cyclopentyl-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine
  • Step 5 (2S, 3R, 4S, 5R)-2-(2-chloro-4-(cyclopentyl(methyl)amino)pyrrolo[2,1-f][1,2,4] Synthesis of azine-7-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol
  • the preparation of the intermediate 2-4 is prepared by referring to the synthesis method of the intermediate 1:
  • Second step 7-((2S,3S,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-yl)-2-chloro- Synthesis of N-cyclopentylpyrrolo[2,1-f][1,2,4]triazin-4-amine
  • Step 2 Synthesis of tert-butyl-7-bromoimidazo[2,1-f][1,2,4]triazin-4-ylcyclopentylcarbamate
  • tert-Butyl-7-bromoimidazo[2,1-f][1,2,4]triazin-4-yl-carbamate (0.90 g, 2.9 mmol) in tetrahydrofuran (15 mL) at 0 ° C
  • cyclopentanol (0.62 g, 7.2 mmol)
  • triphenylphosphine (1.88 g, 7.2 mmol)
  • diisopropyl azodicarboxylate (1.45 g, 7.2 mmol) was added dropwise. After completion, the mixture was allowed to react to room temperature for 10 minutes and then raised to 45 ° C.
  • Step 3 tert-Butyl-7-(3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-hydroxytetrahydrofuran-2-ylimidazole Synthesis of [2,1-f][1,2,4]triazin-4-ylcyclopentylcarbamate
  • n-Butyllithium 1.0 mL, 2.5 M, 2.5 mmol was added dropwise to a solution of methyltetrahydrofuran (2.5 mL). After the addition was completed, the reaction was kept for 20 minutes, and 2,3,5-tribenzyloxy-D was added dropwise again.
  • Step 5 (2S, 3R, 4S, 5R)-2-(4-(cyclopentylamino)imidazo[2,1-f][1,2,4]triazin-7-yl)-5 Synthesis of -(hydroxymethyl)tetrahydrofuran-3,4-diol
  • Step 2 Synthesis of tert-butyl(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)(cyclopentyl)carbamate
  • Step 2 Synthesis of tert-butyl (7-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)(cyclopentyl)carbamate
  • tert-Butyl (7-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)(cyclopentyl)carbamate (10 g, 24.1 mmol) Dissolve in 2-methyltetrahydrofuran (60 mL), add n-butyl lithium (11.55 mL, 2.5 M, 28.8 mmol) dropwise at -78 ° C under nitrogen, stir for 1 hour, add dropwise at this temperature (3R, 4R) , 5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)dihydrofuran-2(3H)-one (11.09 g, 26.5 mmol) of 2-methyltetrahydrofuran ( The solution was stirred and stirred for 1 hour, and the mixture was stirred with a saturated aqueous solution of ammonium chloride.
  • tert-Butyl (7-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)(cyclopentyl)carbamate (730 mg, 1.75 mmol) Soluble in 2-methyltetrahydrofuran (20 mL), add n-butyllithium (1 mL, 2.5 M, 2.5 mmol) dropwise at -78 ° C under nitrogen, stir and react for 1 hour, add dropwise at this temperature (3aR, 6R) ,6aR)-6-(tert-butoxymethyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxazol-4-one (600mg , 2.46 mmol) of a solution of 2-methyltetrahydrofuran (5 mL), stirring with stirring for 1 hour, quenched with saturated aqueous ammonium chloride, and then taken to room temperature and then extracted twice with ethyl acetate.
  • the third step (3S, 4R, 5R)-2-(2-chloro-4-(cyclopentyl(methyl)amino)pyrrolo[2,1-f][1,2,4]triazine- 7-yl)-3-fluoro-4-((triisopropylsilyl)oxy)-5-(((triisopropylsilyl)oxy)methyl)tetrahydrofuran-2-ol synthesis
  • the fourth step 2-chloro-N-cyclopentyl-7-((2S,3R,4R,5R)-3-fluoro-4-((triisopropylsilyl)oxy)-5-(( Synthesis of (triisopropylsilyl)oxo)methyl)tetrahydrofuran-2-yl)-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine
  • Step 5 (2R, 3R, 4S, 5S)-5-(2-chloro-4-(cyclopentyl(methyl)amino)pyrrolo[2,1-f][1,2,4] Synthesis of azine-7-yl)-4-fluoro-2-(hydroxymethyl)tetrahydrofuran-3-ol
  • Second step 2-chloro-N-cyclopentyl-7-((2S,4R,5R)-3,3-difluoro-4-((triisopropylsilyl)oxy)-5- (((Triisopropylsilyl)oxy)methyl)tetrahydrofuran-2-yl)-N-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine Synthesis
  • the preparation of the intermediate 31-34 was prepared by the synthesis method of the intermediate 30:
  • Second step 4-(cyclopentyl (methyl)amino)-7-((2S,3S,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl Synthesis of pyrrolo[2,1-f][1,2,4]triazine-2-carbonitrile
  • the fourth step ((2R, 3R, 4S)-5-(2,4-dichloropyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoro- Synthesis of 5-hydroxy-3-((triisopropylsilyl)oxo)tetrahydrofuran-2-yl)methylbenzoate
  • EtOAc (2R,3R,4S)-5-(2,4-dichloropyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoro-5-hydroxy-3 -((Triisopropylsilyl)oxo)tetrahydrofuran-2-yl)methylbenzoate (1.8 g, yield 45%).
  • Step 5 ((2R,3R,4R,5S)-5-(2,4-Dichloropyrrolo[2,1-f][1,2,4]triazin-7-yl)-4- Synthesis of Fluor-3-((triisopropylsilyl)oxo)tetrahydrofuran-2-yl)methylbenzoate
  • EtOAc EtOAc EtOAc (2R,3R,4R,5S)-5-(2,4-dichloropyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoro-3-( (Triisopropylsilyl)oxo)tetrahydrofuran-2-yl)methylbenzoate (1.3 g, yield 74%).
  • Step 6 ((2R,3R,4R,5S)-5-(2-chloro-4-((R)-1-(2-fluorophenyl)ethyl)amino)pyrrolo[2,1 Synthesis of -f][1,2,4]triazin-7-yl)-4-fluoro-3-((triisopropylsilyl)oxo)tetrahydrofuran-2-yl)methylbenzoate
  • Step 7 ((2R,3R,4R,5S)-5-(2-chloro-4-((R)-1-(2-fluorophenyl)ethyl)amino)pyrrolo[2,1 Synthesis of -f][1,2,4]triazin-7-yl)-4-fluoro-3-((triisopropylsilyl)oxo)tetrahydrofuran-2-yl)methanol
  • Step 8 ((2R,3R,4R,5S)-5-(2-chloro-4-((R)-1-(2-fluorophenyl)ethyl)amino)pyrrolo[2,1 -f][1,2,4]triazin-7-yl)-4-fluoro-3-((triisopropylsilyl)oxo)tetrahydrofuran-2-yl)methyl 4-methylbenzene Synthesis of sulfonate
  • Step 9 ((2R,3R,4S,5S)-5-(2-chloro-4-((R)-1-(2-fluorophenyl)ethyl)amino)pyrrolo[2,1 Synthesis of -f][1,2,4]triazin-7-yl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate
  • Examples 2-29 were prepared by referring to the synthesis method of Example 1:
  • nuclear magnetic data prepared by the above compounds 2 to 29 are listed as follows:
  • Examples 32 to 51 were prepared by referring to the synthesis method of Example 31:
  • the present invention employs a malachite green test of CD73 in a soluble state synthesized in vitro to determine the properties of a compound against CD73 inhibitory activity.
  • the experimental process is as follows:
  • the enzymatic reaction of this experiment was carried out in a 384-well plate at a concentration of 36 ng/ml of CD73 (R&D systems #5795-EN-010) and various concentrations of compound and 50 ⁇ M of AMP in a 40 ⁇ l reaction system (25 mM Tris pH). 7.5, 5 mM MgCl 2 , 0.005% Tween-20) incubation reaction at 25 ° C for 30 minutes;
  • CD73 enzyme activity is calculated by the concentration of the product, and then using non-linear regression analysis of percent inhibition at various concentrations of compounds of the present invention is the value measured 50 IC.
  • the present invention employs human breast cancer cell line MDA-MB-231 which endogenously expresses CD73 to evaluate the inhibitory effect of the compound on the cell surface-expressed CD73 enzyme activity.
  • the cells used were derived from the cell bank of the Chinese Academy of Sciences. The experimental process is as follows:
  • RPMI1640 10% fetal bovine serum (Gibco, 10099-141), cultured overnight at 37 ° C in a 5% CO 2 incubator (the cells were washed 3 times with serum-free RPMI medium during the test);
  • the inhibitory effect of the compound of the present invention and the positive compound on the cell surface CD73 enzyme activity was then evaluated by quantitatively determining the ratio of the decrease in the substrate AMP level in the cell culture supernatant after the reaction.
  • the series of compounds of the present invention have a strong inhibitory effect on CD73 enzyme activity.

Abstract

本发明涉及一种式(Ⅰ)结构具有CD73抑制活性的膦酸衍生物、其制备方法和应用。本发明系列化合物可广泛应用于制备治疗至少部分由CD73介导的癌症或肿瘤、自身免疫性疾病及紊乱、代谢性疾病的药物，特别是治疗黑色素瘤、结肠癌、胰腺癌、乳腺癌、***癌、肺癌、白血病、脑瘤、淋巴瘤、卵巢癌和卡波西氏肉瘤的药物，有望开发成新一代CD73抑制剂药物。(I)

Description

一种具有CD73抑制活性的膦酸衍生物、其制备方法和应用 技术领域
本发明属于药物合成领域，具体涉及一种具有CD73抑制活性的膦酸衍生物、其制备方法和应用。
背景技术
CD73又被称为胞外-5'-核苷酸酶(Ecto-5'-nucleotidase,eNT)，是一个70kDa的蛋白分子。在正常的情况下会在血管内皮细胞和一部分的血细胞上表达。它通过糖基磷脂酰肌醇(GPI)锚定于细胞膜表面，和CD39一起，调节三磷酸腺苷(ATP)的代谢。其中，CD39(又被称为膜外二三磷酸核苷水解酶-NTPDase 1)可以催化ATP生成单磷酸腺苷(AMP)，只产生少量的双磷酸腺苷(ADP)而CD73的主要功能催化胞外的核苷酸(比如5’AMP)转化为他们相应的核苷(比如腺苷)
CD73所催化产生的核苷，特别是腺苷，被认为是很多种不同生理功能的内部调节分子。腺苷能调节心血管***，中枢神经神经***，呼吸***，肾脏，脂肪细胞，血小板以及免疫***。在免疫***中，胞外腺苷能对很多种不同的免疫细胞产生作用，并介导抗炎性反应。在很多组织里，腺苷还能促进纤维化的过程。
在很多肿瘤细胞中都发现了CD73的表达，包括白血病，膀胱癌，神经胶质瘤，神经胶质母细胞瘤，卵巢癌，黑色素瘤，***癌，甲状腺癌，食管癌和乳腺癌。同时，在免疫抑制细胞(包括调节性T细胞Treg和髓系抑制细胞MDSC)的表面也发现了CD73的表达。CD73的高表达也已经被发现在包括乳腺癌和黑色素瘤在内的多种肿瘤的血管生成，浸润，对于化疗的抗性，肿瘤的转移以及癌症病人的较短生存期相关。
基于机制的研究表明，恶性肿瘤细胞在化疗和其他压力作用下，会释放大量的ATP，并会被迅速转化为腺苷，在肿瘤微环境里积累。由于细胞死亡或者胞内压力带来的胞外ATP的释放会激活免疫反应。但是ATP的代谢物腺苷却有免疫抑制的活性。其中很重要的一点就是肿瘤内的腺苷通过活化腺苷受体(比如A2A)，来抑制浸润的效应T淋巴细胞，从而促进肿瘤的发展。因此肿瘤组织中胞外腺苷的积累是肿瘤免疫逃逸的重要机制。
用干扰RNA降低CD73表达或者在肿瘤细胞里过表达CD73都能够调节肿瘤的生长和迁移。CD73敲除的小鼠会更不容易产生器官移植的排斥以及自发性的肿瘤用遗传学的手段删除A2A受体的基因能诱导依赖于T细胞的肿瘤排斥。而在小鼠模型里，用能和小鼠CD73结合的抗体治疗能抑制乳腺肿瘤的生长和迁移。
因此，靶向CD73代表了一种潜在的治疗策略，能增强抗肿瘤免疫治疗的药效，并为限制肿瘤的进一步发展提供了新的治疗策略。同时，靶向CD73还可以被用来治疗被腺苷所介导的其他疾病，比如增强免疫反应，增强免疫效果，增强炎性反应以及治疗包括神经性紊乱，神经退行性以及中枢神经疫病在内的，例如抑郁症，帕金森症，睡眠障碍，纤维化和其他免疫炎性疾病。
因此，研发靶向CD73的可作为良好药物候选物将可以满足治疗癌症和其他相关疾病中靶向药物的需求，并带来安全性好和特异性强的优点。
发明内容
本发明的目的在于提供一种具有CD73抑制活性的化合物。
本发明第一方面提供一种式(I)化合物、其立体异构体、前药或其药学上可接受盐：
Figure PCTCN2018123908-appb-000001
其中，
X 1、X 2各自独立的选自N或CH；
X 3、X 4各自独立的选自N或C；
X 5、X 6各自独立的选自O、S、C(R 10)、N或N(R 11)；
Y 1选自-O-、-S-、-C(R 12R 13)-、-(C＝CR 14R 15)-或-N(R 16)-；
Y 2、Y 3各自独立的选自-O-、-S-或-C(R 17R 18)-；
Z选自-O-、-S-或-NH-；
R 1选自氢、氘、卤素、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、-NR 19R 20或-C 0-8-S(O) rR 21，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代；
R 2选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代；
R 3、R 4各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、 -C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代；
R 5、R 6各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23，或者，R 5与R 6和其直接相连的碳原子一起形成3-10元环烷基、3-10元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代；
R 7、R 8、R 9各自独立的选自氢、氘、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23或-C 0-8-C(O)NR 24R 25，或者，R 7与R 8或R 9和其直接相连的基团一起形成6-10元杂环基，R 8与R 9和其直接相连的基团一起形成4-10元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代；
每个R 10、R 12、R 13、R 14、R 15、R 17、R 18各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代；
每个R 11、R 16各自独立的选自氢、氘、C 1-10烷基、C 3-10环烷基C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、 -C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代；
每个R 19、R 20各自独立的选自氢、氘、C 1-10烷基、C 3-10环烷基C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、C 3-10环烯基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23，或者，R 19、R 20和其直接相连的氮原子一起形成4-10元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代；
每个R 21选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 24R 25，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 24R 25的取代基所取代；
每个R 22选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-10环烷基、3-10元杂环基、C 5-10芳基或5-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 24R 25的取代基所取代；
每个R 23选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 24R 25，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 24R 25的取代基所取代；
每个R 24、R 25各自独立的选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-8烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代；
或者，R 24、R 25和其直接相连的氮原子一起形成4-10元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代；
每个r独立为0、1或2。
对于式(I)化合物或其药学上可接受的盐，各手性碳的构型独立为R型或S型。
作为优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 5、R 6各自独立的选自氢、氘、卤素、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-C 0-4-O-R 22或-C 0-4-NR 24R 25，或者，R 5与R 6和其直接相连的碳原子一起形成3-6元环烷基、3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-C 0-4-O-R 22或-C 0-4-NR 24R 25的取代基所取代，R 22、R 24、R 25、r如式(I)化合物所述；优选的，R 5、R 6各自独立的选自氢、氘、氟、甲基、异丙基、烯丙基、乙炔基、环丙基、三氟甲基、三氘甲基、甲氧基、三氟甲氧基、三氘甲氧基、氨基或二甲基氨基，或者，R 5与R 6和其直接相连的碳原子一起形成3-4元环烷基、4-5元杂环基。
作为进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 3、R 4各自独立的选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基或C 2-4链炔基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-C 0-4-O-R 22或-C 0-4-NR 24R 25的取代基所取代，R 22、R 24、R 25、r如式(I)化合物所述；优选的，R 3、R 4各自独立的选自氢、氘、氟、氰基、甲基、乙烯基或乙炔基，上述基团任选进一步被一个或多个选自氘、卤素或环丙基的取代基所取代。
作为进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中Y 2、Y 3各自独立的选自-C(R 17R 18)-；每个R 17、R 18各自独立的选自氢、氘、卤素、氰基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-C 0-4-O-R 22或-C 0-4-O-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-O-R 22或-O-C(O)R 23的取代基所取代，R 22、R 23如式(I)化合物所述；优选的，每个R 17、R 18各自独立的选自氢、氘、氟、氯、氰基、叠氮基、甲基、乙烯基、乙炔基、环丙基、羟基、甲氧基或乙酰氧基，上述基团任选进一步被一个或多个选自氘、氟、氰基、甲基、异丙基、乙烯基、乙炔基、环丙基、羟基或甲氧基的取代基所取代。
作为进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中R 1选自氢、氘、卤素、羟基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、-NR 19R 20或-C 0-8-S(O) rR 21，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22、-C 0-4-C(O)OR 22、-C 0-4-C(O)R 23、-C 0-4-O-C(O)R 23、-C 0-4-NR 24R 25、-C 0-4-C(O)NR 24R 25或-C 0-4-N(R 24)-C(O)R 23的取代基所取代；
R 2选自氢、氘、卤素、氰基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22或-C 0-8-NR 24R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22、-C 0-4-C(O)OR 22、-C 0-4-C(O)R 23、-C 0-4-O-C(O)R 23、-C 0-4-NR 24R 25、-C 0-4-C(O)NR 24R 25或-C 0-4-N(R 24)-C(O)R 23的取代基所取代；
R 19、R 20、R 21、R 22、R 23、R 24、R 25、r如式(I)化合物所述。
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中X 3、X 4各自独立的选自N或C，且X 3、X 4中至少包含一个N；Y 1选自-O-、-C(R 12R 13)-、-(C＝CR 14R 15)-或-N(R 16)-；Y 2、Y 3各自独立的选自-C(R 17R 18)-；
R 1选自氢、氘、卤素、羟基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、-NR 19R 20或-C 0-8-S(O) rR 21，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21或-C 0-4-O-R 22的取代基所取代；
R 2选自氢、氘、卤素、氰基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22或-C 0-8-NR 24R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22或-C 0-4-NR 24R 25、的取代基所取代；
R 3、R 4各自独立的选自氢、氘、氟、氰基、甲基、乙烯基或乙炔基，上述基团任选进一步被一个或多个选自氘、卤素或环丙基的取代基所取代；
R 5、R 6各自独立的选自氢、氘、氟、甲基、异丙基、烯丙基、乙炔基、环丙基、三氟甲基、三氘甲基、甲氧基、三氟甲氧基、三氘甲氧基、氨基或二甲基氨基；
每个R 12、R 13、R 14、R 15各自独立的选自氢、氘、卤素、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22、-C 0-4-C(O)OR 22、-C 0-4-C(O)R 23、-C 0-4-O-C(O)R 23、-C 0-4-NR 24R 25、-C 0-4-C(O)NR 24R 25或-C 0-4-N(R 24)-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22、-C 0-4-C(O)OR 22、-C 0-4-C(O)R 23、-C 0-4-O-C(O)R 23、-C 0-4-NR 24R 25、-C 0-4-C(O)NR 24R 25或-C 0-4-N(R 24)-C(O)R 23的取代基所取代；
每个R 16各自独立的选自氢、氘、C 1-4烷基、C 3-6环烷基C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22、-C 0-4-C(O)OR 22、-C 0-4-C(O)R 23、-C 0-4-O-C(O)R 23、-C 0-4-NR 24R 25、-C 0-4-C(O)NR 24R 25或-C 0-4-N(R 24)-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、 -C 0-4-O-R 22、-C 0-4-C(O)OR 22、-C 0-4-C(O)R 23、-C 0-4-O-C(O)R 23、-C 0-4-NR 24R 25、-C 0-4-C(O)NR 24R 25或-C 0-4-N(R 24)-C(O)R 23的取代基所取代；
每个R 17、R 18各自独立的选自氢、氘、氟、氯、氰基、叠氮基、甲基、乙烯基、乙炔基、环丙基、羟基、甲氧基、乙氧酰基或乙酰氧基，上述基团任选进一步被一个或多个选自氘、氟、氰基、甲基、异丙基、乙烯基、乙炔基、环丙基、羟基或甲氧基的取代基所取代；
R 19、R 20、R 21、R 22、R 23、R 24、R 25、r如式(I)化合物所述。
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐具有如下式(Ⅱa)化合物或式(Ⅱb)化合物结构：
Figure PCTCN2018123908-appb-000002
其中，X 1、X 2各自独立的选自N或CH；X 5、X 6各自独立的选自C(R 10)或N；Y 1选自-O-、-C(R 12R 13)-、-(C＝CR 14R 15)-或-N(R 16)-；Z选自-O-或-NH-；
R 1选自氢、氘、卤素、羟基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、-NR 19R 20或-C 0-8-S(O) rR 21，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21或-C 0-4-O-R 22的取代基所取代；
R 2选自氢、氘、卤素、氰基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22或-C 0-8-NR 24R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22或-C 0-4-NR 24R 25、的取代基所取代；
R 3、R 4各自独立的选自氢、氘、氰基、甲基、乙烯基或乙炔基，上述基团任选进一步被一个或多个选自氘、氟或环丙基的取代基所取代；
R 5、R 6各自独立的选自氢、氘、甲基、环丙基、三氟甲基或三氘甲基；
每个R 12、R 13、R 14、R 15各自独立的选自氢、氘、卤素、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-O-R 22、-C 0-4-C(O)OR 22、-C 0-4-NR 24R 25、-C 0-4-C(O)NR 24R 25或-C 0-4-N(R 24)-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、C 1-4烷基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-O-R 22或-C 0-4-NR 24R 25的取代基所取代；
每个R 16各自独立的选自氢、氘、C 1-4烷基、C 3-6环烷基C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基或-C 0-4-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-O-R 22、-C 0-4-C(O)OR 22或-C 0-4-NR 24R 25、的取代基所取代；
每个R 17、R 18各自独立的选自氢、氘、氟、氯、氰基、叠氮基、甲基、乙烯基、乙炔基、环丙基、羟基、甲氧基、乙氧酰基或乙酰氧基，上述基团任选进一步被一个或多个选自氘、氟、氰基、甲基、异丙基、乙烯基、乙炔基、环丙基、羟基或甲氧基的取代基所取代；
R 7、R 8、R 9、R 10、R 19、R 20、R 21、R 22、R 23、R 24、R 25、r如式(I)化合物所述。
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中X 5选自C(R 10)或N；X 6选自CH；
R 10各自独立的选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-O-R 22、-C 0-4-O-C(O)R 23、-C 0-4-NR 24R 25或-C 0-4-N(R 24)-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-O-R 22或-C 0-4-NR 24R 25的取代基所取代；
R 22、R 23、R 24、R 25如式(I)化合物所述。
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐具有如下式(Ⅲa)化合物结构：
Figure PCTCN2018123908-appb-000003
其中，X 1、X 2各自独立的选自N或CH；X 5选自C(R 10)或N；Y 1选自-O-或-C(R 12R 13)-；
R 1选自C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基或-NR 19R 20，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、乙烯基、乙炔基、三氟甲基、二氟甲基、环丙基、吗啉基、氧杂环丁基、四氢呋喃基、哌嗪基、哌啶基、苯基、吡啶基、羟基或甲氧基的取代基所取代；
R 2选自氢、氘、氟、氯、氰基、甲基、乙基、丙基、乙烯基、乙炔基、环丙基、吗啉基、氧杂环丁基、四氢呋喃基、哌嗪基、哌啶基、苯基、吡啶基、羟基、甲氧基、氨基、甲氨基或二甲氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、丙基、乙烯基、三氟甲基、环丙基、吗啉基、氧杂环丁基、四氢呋喃基、哌嗪基、哌啶基、苯基、吡啶基、羟基或甲氧基的取代基所取代；
R 3选自氢、氘、氰基、甲基、乙烯基或乙炔基，上述基团任选进一步被一个或多个选自氘、氟或环丙基的取代基所取代；
R 12、R 13各自独立的选自氢、氘、氟、氯、甲基、乙烯基、环丙基、羟基、三氟甲基或环丙甲基；
R 17、R 18各自独立的选自氢、氘、氟、氯、氰基、叠氮基、甲基、乙烯基、乙炔基、环丙基、羟基、甲氧基、三氟甲基、三氘甲基、三氟甲氧基、三氘甲氧基、环丙甲基、甲氧甲基、乙氧酰基或乙酰氧基；
R 10选自氢、氘、氟、氯、氰基、甲基、乙基、丙基、乙烯基、乙炔基、环丙基、吗啉基、氧杂环丁基、四氢呋喃基、哌嗪基、哌啶基、苯基、吡啶基、羟基、甲氧基、氨基、甲氨基或二甲氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、丙基、乙烯基、三氟甲基、环丙基、吗啉基、氧杂环丁基、四氢呋喃基、哌嗪基、哌啶基、苯基、吡啶基、羟基或甲氧基的取代基所取代；
R 19、R 20各自独立的选自氢、氘、C 1-4烷基、C 3-10环烷基C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-10环烷基、C 4-10环烯基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、羟基、乙酰基或-C(O)NH 2，或者，R 19、R 20和其直接相连的氮原子一起形成4-10元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、C 1-4烷基、乙烯基、三氟甲基、环丙基、环戊基、吗啉基、氧杂环丁基、四氢呋喃基、哌嗪基、哌啶基、苯基、吡啶基、羟基或甲氧基的取代基所取代。
作为最优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐包括但不限于如下化合物：
Figure PCTCN2018123908-appb-000004
Figure PCTCN2018123908-appb-000005
Figure PCTCN2018123908-appb-000006
Figure PCTCN2018123908-appb-000007
Figure PCTCN2018123908-appb-000008
Figure PCTCN2018123908-appb-000009
作为进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐具有如下式(Ⅱc)化合物结构：
Figure PCTCN2018123908-appb-000010
其中，X 5、X 6中一个选自C(R 10)，另一个选自O或S；
R 1选自氢、氘、卤素、羟基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、-NR 19R 20或-C 0-8-S(O) rR 21，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21或-C 0-4-O-R 22的取代基所取代；
R 2选自氢、氘、卤素、氰基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22或-C 0-8-NR 24R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22或-C 0-4-NR 24R 25的取代基所取代；
R 3、R 4各自独立的选自氢、氘、氟、氰基、甲基、乙烯基或乙炔基，上述基团任选进一步被一个或多个选自氘、卤素或环丙基的取代基所取代；
R 5、R 6各自独立的选自氢、氘、氟、甲基、异丙基、烯丙基、乙炔基、环丙基、三氟甲基、三氘甲基、甲氧基、三氟甲氧基、三氘甲氧基、氨基或二甲基氨基；
每个R 10各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22、-C 0-4-C(O)OR 22、-C 0-4-C(O)R 23、-C 0-4-O-C(O)R 23、-C 0-4-NR 24R 25、-C 0-4-C(O)NR 24R 25或-C 0-4-N(R 24)-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22、-C 0-4-C(O)OR 22、-C 0-4-C(O)R 23、-C 0-4-O-C(O)R 23、-C 0-4-NR 24R 25、-C 0-4-C(O)NR 24R 25或-C 0-4-N(R 24)-C(O)R 23的取代基所取代；
每个R 17、R 18各自独立的选自氢、氘、氟、氯、氰基、叠氮基、甲基、乙烯基、乙炔基、环丙基、羟基、甲氧基或乙酰氧基，上述基团任选进一步被一个或多个选自氘、氟、氰基、甲基、异丙基、乙烯基、乙炔基、环丙基、羟基或甲氧基的取代基所取代；
R 19、R 20、R 21、R 22、R 23、R 24、R 25、r如式(I)化合物所述。
作为更进一步优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐中X 5、X 6中一个选自C(R 10)，另一个选自O；
R 3、R 4各自独立的选自氢或氘；
R 5、R 6各自独立的选自氢、氘、甲基或环丙基；
每个R 10各自独立的选自氢、氘、卤素、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基；
每个R 17、R 18各自独立的选自氢、氘、氟、甲基或羟基，上述基团任选进一步被一个或多个选自氘或氟的取代基所取代。
作为最优选的方案，所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐包括但不限于如下化合物：
Figure PCTCN2018123908-appb-000011
本发明第二方面提供一种前述式(I)化合物、其立体异构体、前药或其药学上可接受盐的制备方法，包括如下步骤：
Figure PCTCN2018123908-appb-000012
其中，Pg为氢、羟基保护基、巯基保护基或氨基保护基，优选为氢、叔丁氧羰基或对甲苯磺酰基；X 1、X 2、X 3、X 4、X 5、X 6、Y 1、Y 2、Y 3、Z、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9如式(I)化合物所述。
本发明第三方面提供一种药物组合物，其包括前述式(I)化合物、其立体异构体、前药或其药学上可接受盐及可药用的载体。
本发明第四方面提供一种前述式(I)化合物、其立体异构体、前药或其药学上可接受盐，或前述药物组合物在制备治疗至少部分由CD73介导的癌症或肿瘤、免疫相关疾病及紊乱、代谢性疾病药物中的应用。
作为优选的方案，所述的癌症或肿瘤选自***癌、结肠癌、直肠癌、胰腺癌、胃癌、子宫内膜癌、***、脑癌、肝癌、膀胱癌、卵巢癌、睾丸癌、头癌、颈癌、皮肤癌(包括黑色素瘤和基底细胞癌)、间皮内衬癌、白血细胞癌(包括淋巴瘤和白血病)、食管癌、乳腺癌，肌肉癌、***癌、肺癌(包括小细胞肺癌和非小细胞癌)、肾上腺癌、甲状 腺癌、肾脏癌、骨癌、脑瘤、胶质母细胞瘤、间皮瘤、肾细胞癌、肉瘤(包括卡波西氏肉瘤)、绒毛膜癌、表皮基底细胞癌、睾丸***瘤。
作为进一步优选的方案，所述的癌症或肿瘤选自黑色素瘤、结肠癌、胰腺癌、乳腺癌、***癌、肺癌、白血病、脑瘤、淋巴瘤、卵巢癌和卡波西氏肉瘤。
作为优选的方案，所述的免疫相关疾病及紊乱选自类风湿性关节炎、肾衰竭、红斑狼疮、哮喘、牛皮癣、溃疡性结肠炎、胰腺炎、过敏、纤维化、贫血纤维肌痛症、阿尔茨海默病、充血性心力衰竭、中风、主动脉瓣狭窄、动脉硬化、骨质疏松症、帕金森病、感染、克隆氏病、溃疡性结肠炎、过敏性接触性皮炎和湿疹、***性硬化症和多发性硬化症。
本发明第五方面提供一种前述式(I)化合物、其立体异构体、前药或其药学上可接受盐，或前述药物组合物用作治疗至少部分由CD73介导的癌症或肿瘤、自身免疫性疾病及紊乱、代谢性疾病的药物。
本发明第六方面提供一种前述式(I)化合物、其立体异构体、前药或其药学上可接受盐，或前述药物组合物用作治疗***癌、结肠癌、直肠癌、胰腺癌、胃癌、子宫内膜癌、***、脑癌、肝癌、膀胱癌、卵巢癌、睾丸癌、头癌、颈癌、皮肤癌(包括黑色素瘤和基底细胞癌)、间皮内衬癌、白血细胞癌(包括淋巴瘤和白血病)、食管癌、乳腺癌、肌肉癌、***癌、小细胞肺癌(肺癌和非小细胞癌)、肾上腺癌、甲状腺癌、肾脏癌、骨癌、脑瘤、胶质母细胞瘤、间皮瘤、肾细胞癌、肉瘤(包括卡波西氏肉瘤)、绒毛膜癌、表皮基底细胞癌、睾丸***瘤、类风湿性关节炎、肾衰竭、红斑狼疮、哮喘、牛皮癣、溃疡性结肠炎、胰腺炎、过敏、纤维化、贫血纤维肌痛症、阿尔茨海默病、充血性心力衰竭、中风、主动脉瓣狭窄、动脉硬化、骨质疏松症、帕金森病、感染、克隆氏病、溃疡性结肠炎、过敏性接触性皮炎和湿疹、***性硬化症和多发性硬化症的药物。
本发明第七方面提供一种治疗至少部分由CD73介导的癌症或肿瘤、免疫相关疾病及紊乱、代谢性疾病的方法，包括对患者施用前述式(I)化合物、其立体异构体、前药或其药学上可接受盐，或前述药物组合物。
作为优选的方案，所述的癌症或肿瘤选自***癌、结肠癌、直肠癌、胰腺癌、胃癌、子宫内膜癌、***、脑癌、肝癌、膀胱癌、卵巢癌、睾丸癌、头癌、颈癌、皮肤癌(包括黑色素瘤和基底细胞癌)、间皮内衬癌、白血细胞癌(包括淋巴瘤和白血病)、食管癌、乳腺癌、肌肉癌、***癌、小细胞肺癌(肺癌和非小细胞癌)、肾上腺癌、甲状腺癌、肾脏癌、骨癌、脑瘤、胶质母细胞瘤、间皮瘤、肾细胞癌、肉瘤(包括卡波西氏肉瘤)、绒毛膜癌、表皮基底细胞癌、睾丸***瘤；所述的免疫相关疾病和代谢性疾病选自类风湿性关节炎、肾衰竭、红斑狼疮、哮喘、牛皮癣、溃疡性结肠炎、胰腺炎、过敏、纤维化、贫血纤维肌痛症、阿尔茨海默病、充血性心力衰竭、中风、主动脉瓣狭窄、动脉硬化、骨质疏松症、帕金森病、感染、克隆氏病、溃疡性结肠炎、过敏性接触性皮炎和湿疹、***性硬化症和多发性硬化症。
本发明第八方面提供第一方面所述化合物的用途，用作CD73抑制剂。
具体实施方式
本申请的发明人经过广泛而深入地研究，首次研发出一种如下式(Ⅰ)结构的具有CD73抑制活性的膦酸衍生物、其制备方法和在药学上的应用。本发明系列化合物具有对CD73酶活性具有很强的抑制作用，可广泛应用于制备治疗至少部分由CD73介导的癌症或肿瘤、免疫相关疾病及紊乱、代谢性疾病的药物，特别是治疗黑色素瘤、结肠癌、胰腺癌、乳腺癌、***癌、肺癌、白血病、脑瘤、淋巴瘤、卵巢癌和卡波西氏肉瘤的药物，有望开发成新一代CD73抑制剂药物。在此基础上，完成了本发明。
详细说明：除非有相反陈述，下列用在说明书和权利要求书中的术语具有下述含义。
“烷基”指直链或含支链的饱和脂族烃基团，例如，“C 1-10烷基”指包括1至10个碳原子的直链烷基和含支链烷基，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，3-二甲基戊基、2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体等。
烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代。
“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，例如，“C 3-10环烷基”指包括3至10个碳原子的环烷基，分为单环环烷基、多环环烷基，其中：
单环环烷基包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，螺环烷基包括但不限于：
Figure PCTCN2018123908-appb-000013
“稠环烷基”指***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，稠环烷基包括但不限于：
Figure PCTCN2018123908-appb-000014
“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥环烷基包括但不限于：
Figure PCTCN2018123908-appb-000015
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，包括但不限于茚满基、四氢萘基、苯并环庚烷基等。
环烷基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代。
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。例如，“4-10元杂环基”指包含4至10个环原子的环基，“3-6元杂环基”指包含3至6个环原子的环基。
单环杂环基包括但不限于吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。
多环杂环基包括螺环、稠环和桥环的杂环基。“螺杂环基”指单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基。螺杂环基包括但不限于：
Figure PCTCN2018123908-appb-000016
“稠杂环基”指***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，稠杂环基包括但不限于：
Figure PCTCN2018123908-appb-000017
“桥杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子选自氮、氧或S(O) r(其中r是整数0、1、2)的杂原子，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，桥杂环基包括但不限于：
Figure PCTCN2018123908-appb-000018
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，包括但不限于：
Figure PCTCN2018123908-appb-000019
杂环基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基 团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代。
“芳基”指全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，具有共轭的π电子体系的多环(即其带有相邻对碳原子的环)基团，例如，“C 5-10芳基”指含有5-10个碳的全碳芳基，“5-10元芳基”指含有5-10个碳的全碳芳基，包括但不限于苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，包括但不限于：
Figure PCTCN2018123908-appb-000020
芳基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代。
“杂芳基”指包含1至4个杂原子的杂芳族体系，所述杂原子包括氮、氧和S(O)r(其中r是整数0、1、2)的杂原子，例如，5-10元杂芳基指含有5-10个环原子的杂芳族体系，5-8元杂芳基指含有5-8个环原子的杂芳族体系，包括但不限于呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，包括但不限于：
Figure PCTCN2018123908-appb-000021
杂芳基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、 -C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代。
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基，例如，C 2-10链烯基指含有2-10个碳的直链或含支链烯基。包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。
烯基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代。
“炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，例如，C 2-10链炔基指含有2-10个碳的直链或含支链炔基。包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-，2-或3-丁炔基等。
炔基可以是取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代。
“烷氧基”指-O-(烷基)，其中烷基的定义如上所述，例如，“C 1-10烷氧基”指含1-10个碳的烷基氧基，包括但不限于甲氧基、乙氧基、丙氧基、丁氧基等。
烷氧基可以是任选取代的或未取代的，当被取代时，取代基，优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代。
“环烷氧基”指和-O-环烷基，其中环烷基的定义如上所述，例如，“C 3-10环烷氧基”指含3-10个碳的环烷基氧基，包括但不限于环丙氧基、环丁氧基、环戊氧基、环己氧基等。
环烷氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代。
“杂环氧基”指和-O-杂环基，其中杂环基的定义如上所述，例如，“C 3-10杂环氧基”指含3-10个碳的杂环基氧基，包括但不限于氮杂环丁基氧基、氧杂环丁氧基、氮杂环戊基氧基、氮、氧杂环己基氧基等。
杂环氧基可以是任选取代的或未取代的，当被取代时，取代基优选为一个或多个以下基团，独立地选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔 基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代。
“C 1-10烷酰基”指C 1-10烷基酸去掉羟基后剩下的一价原子团，通常也表示为“C 0-9-C(O)-”，例如，“C 1-C(O)-”是指乙酰基；“C 2-C(O)-”是指丙酰基；“C 3-C(O)-”是指丁酰基或异丁酰基。
“-C 0-8-S(O) rR 21”指-S(O) rR 21中的硫原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。
“-C 0-8-O-R 22”指-O-R 22中的氧原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。
“-C 0-8-C(O)OR 22”指-C(O)OR 22中的羰基连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。
“-C 0-8-C(O)R 23”指-C(O)R 23中的羰基连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。
“-C 0-8-O-C(O)R 23”指-O-C(O)R 23中的氧原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。
“-C 0-8-NR 24R 25”指-NR 24R 25中的氮原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。
“-C 0-8-C(O)NR 24R 25”指-C(O)NR 24R 25中的羰基连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。
“-C 0-8-N(R 24)-C(O)R 23”指-N(R 24)-C(O)R 23中的氮原子连接在C 0-8烷基上，其中C 0烷基是指键，C 1-8烷基的定义如上所述。
“卤取代C 1-10烷基”指烷基上的氢任选的被氟、氯、溴、碘原子取代的1-10个碳烷基基团，包括但不限于二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。
“卤取代C 1-8烷氧基”烷基上的氢任选的被氟、氯、溴、碘原子取代的1-8个碳烷氧基基团。包括但不限于二氟甲氧基、二氯甲氧基、二溴甲氧基、三氟甲氧基、三氯甲氧基、三溴甲氧基等。
“卤素”指氟、氯、溴或碘。
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和键的碳原子(如烯烃)结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体 药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
下面结合实施例对本发明做进一步详细、完整地说明，但决非限制本发明，本发明也并非仅局限于实施例的内容。
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代甲醇(CD 3OD)和氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。
液质联用色谱LC-MS的测定用Agilent 6120质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度(℃)。
一、中间体的合成
1、(2S,3R,4S,5R)-2-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-(羟甲基)四氢呋喃-3,4-二醇的制备
Figure PCTCN2018123908-appb-000022
第一步：2-氯-N-环戊基-N-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺的合成
Figure PCTCN2018123908-appb-000023
将2,4-二氯吡咯并[2,1-f][1,2,4]三嗪(1.51g,8.0mmol)溶于1,4-二氧六环(20mL)，室温下加入N,N-二异丙基乙基胺(2.08g,16.1mmol)，再加入N-甲基环戊胺(1.44g,66wt％,9.6mmol)，在室温下搅拌反应1小时，然后浓缩，加入乙酸乙酯，依次用水、饱和氯化铵溶液、饱和碳酸氢钠溶液、饱和食盐水洗涤各一次后用硫酸钠干燥后浓缩得到2-氯-N-环戊基-N-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺(1.97g,产率96％)。MS m/z(ESI):251.2 [M+H] +。
1H NMR(400MHz,CDCl 3)δ7.52(dd,J＝2.7,1.5Hz,1H),6.78(dd,J＝4.6,1.6Hz,1H),6.58(dd,J＝4.6,2.7Hz,1H),3.28(s,3H),2.09–1.92(m,2H),1.87–1.57(m,7H)。
第二步：7-溴-2-氯-N-环戊基-N-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺的合成
Figure PCTCN2018123908-appb-000024
将2-氯-N-环戊基-N-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺(2.66g,10.6mmol)溶于二氯甲烷(20mL)，在-10℃下加入N-溴代琥珀酰亚胺(1.89g,10.6mmol)，保温搅拌10分钟后升至室温反应15.5小时，加入N,N-二甲基甲酰胺(0.5mL)搅拌10分钟，依次用饱和碳酸氢钠洗涤三次、饱和食盐水洗涤一次，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚～石油醚/二氯甲烷(2.5:1)]得到7-溴-2-氯-N-环戊基-N-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺(2.90g,产率82％)。MS m/z(ESI):329.2和331.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ6.82(d,J＝4.8Hz,1H),6.63(d,J＝4.8Hz,1H),3.27(s,3H),2.05–1.92(m,2H),1.85–1.59(m,7H)。
第三步：(3R,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)-2-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)四氢呋喃-2-醇的合成
Figure PCTCN2018123908-appb-000025
将7-溴-2-氯-N-环戊基-N-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺(2.90g,8.8mmol)溶于2-甲基四氢呋喃(20mL)，氮气下保温-78℃滴加正丁基锂(4.95mL,2.5M,12.4mmol)，保温搅拌反应1小时，在该温度下滴加(3R,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)二氢呋喃-2(3H)-酮(3.68g,8.8mmol)的2-甲基四氢呋喃(5mL)溶液，继续保温搅拌反应1小时，用饱和氯化铵溶液淬灭，升至室温后乙酸乙酯萃取两次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥后，浓缩后柱层析分离[洗脱剂:石油醚～石油醚/乙酸乙酯(2.5:1)]得到(3R,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)-2-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)四氢呋喃-2-醇(3.80g,产率64％)。MS m/z(ESI):651.6[M+H-H 2O] +,oxonium。
第四步：7-((2S,3S,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-基)-2-氯-N-环戊基-N-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺的合成
Figure PCTCN2018123908-appb-000026
将(3R,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)-2-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)四氢呋喃-2-醇(3.80g,5.7mmol)，三乙基硅烷(9.07mL,56.8mmol)溶于二氯甲烷/乙腈混合溶液(30mL,1:1)，在-20℃滴加三氟化硼***(3.50mL,28.4mmol)，保温搅拌反应1小时后加入饱和碳酸氢钠淬灭反应，升至室温，用二氯甲烷萃取两次，合并有机相，无水硫酸钠干燥，浓缩后分离[洗脱剂:石油醚～石油醚/乙酸乙酯(2.5:1)]得到7-((2S,3S,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-基)-2-氯-N-环戊基-N-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺(2.35g,产率63％)。MS m/z(ESI):653.5[M+H] +。
1H NMR(400MHz,CDCl 3)δ7.41–7.35(m,2H),7.28–7.15(m,13H),6.67–6.57(m,2H),5.58(d,J＝2.5Hz,1H),4.86–4.72(m,2H),4.62–4.46(m,2H),4.44–4.20(m,3H),4.12(dd,J＝4.8,2.6Hz,1H),4.00(dd,J＝7.8,4.7Hz,1H),3.80(dd,J＝10.8,3.1Hz,1H),3.63(dd,J＝10.8,4.2Hz,1H),3.19(s,3H),1.97–1.88(m,2H),1.77–1.50(m,7H)。
第五步：(2S,3R,4S,5R)-2-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-(羟甲基)四氢呋喃-3,4-二醇的合成
Figure PCTCN2018123908-appb-000027
将7-((2S,3S,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-基)-2-氯-N-环戊基-N-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺(0.70g,1.1mmol)，氯苯(0.12g,1.1mmol)溶于四氢呋喃溶液(10mL)，加入氢氧化钯(0.14g,15wt％)，氢气置换三次后室温常压搅拌反应13小时，过滤，浓缩后柱层析分离[洗脱剂:二氯甲烷～二氯甲烷/甲醇(9:1)]得到(2S,3R,4S,5R)-2-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-(羟甲基)四氢呋喃-3,4-二醇(0.33g,产率80％)。MS m/z(ESI):383.4[M+H] +。
1H NMR(400MHz,CDCl 3)δ6.77(d,J＝4.7Hz,1H),6.64(d,J＝4.6Hz,1H),5.07(d,J＝8.0Hz,1H),4.71(dd,J＝8.1,5.5Hz,1H),4.35(dd,J＝5.6,2.2Hz,1H),4.20(q,J＝2.4Hz,1H),3.90(dd,J＝12.1,2.5Hz,1H),3.73(dd,J＝12.2,2.5Hz,1H),3.27(s,3H),1.97(d,J＝11.9Hz,2H),1.66(s,7H)。
中间体2-4的制备参照中间体1的合成方法制备得到：
Figure PCTCN2018123908-appb-000028
Figure PCTCN2018123908-appb-000029
5、7-((2S,3S,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-基)-2-氯-N-环戊基吡咯并[2,1-f][1,2,4]三嗪-4-胺的制备
Figure PCTCN2018123908-appb-000030
第一步：(3R,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)-2-(2-氯-4-(环戊基氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)四氢呋喃-2-醇的合成
Figure PCTCN2018123908-appb-000031
将7-溴-2-氯-N-环戊基吡咯并[2,1-f][1,2,4]三嗪-4-胺(2.20g,6.97mmol)溶于2-甲基四氢呋喃(20mL)，氮气下保温-78℃滴加正丁基锂(6.41mL,2.5M,16.0mmol)，保温搅拌1小时，在该温度下滴加三甲基氯硅烷(752mg,6.97mmol)，保温搅拌反应1小时，再在该温度下滴加(3R,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)二氢呋喃-2(3H)-酮(3.47g,8.3mmol)的2-甲基四氢呋喃(5mL)溶液，继续保温搅拌反应1小时，用饱和氯化铵溶液淬灭，升至室温后乙酸乙酯萃取两次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚～石油醚/乙酸乙酯(2:1)]得到(3R,4R,5R)-3,4-二(苄氧 基)-5-((苄氧基)甲基)-2-(2-氯-4-(环戊基氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)四氢呋喃-2-醇(1.50g,产率32％)。MS m/z(ESI):637.6[M+H-H 2O] +,oxonium。
第二步：7-((2S,3S,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-基)-2-氯-N-环戊基吡咯并[2,1-f][1,2,4]三嗪-4-胺的合成
Figure PCTCN2018123908-appb-000032
将(3R,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)-2-(2-氯-4-(环戊基氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)四氢呋喃-2-醇(1.50g,2.29mmol)，三乙基硅烷(1.06g,9.16mmol)溶于二氯甲烷/乙腈混合溶液(30mL,1:1)，在-20℃滴加三氟化硼***(1.62g,11.45mmol)，保温反应1小时后加入饱和碳酸氢钠淬灭反应，升至室温，用二氯甲烷萃取两次，合并有机相，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚～石油醚/乙酸乙酯(2:1)]得到7-((2S,3S,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-基)-2-氯-N-环戊基吡咯并[2,1-f][1,2,4]三嗪-4-胺(1g,产率68％)。MS m/z(ESI):639.6[M+H] +。
6、(2S,3R,4S,5R)-2-(4-(环戊基氨基)-2-甲基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-(羟甲基)四氢呋喃-3,4-二醇的制备
Figure PCTCN2018123908-appb-000033
第一步：7-((2S,3S,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-基)-N-环戊基-2-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺的合成
Figure PCTCN2018123908-appb-000034
在微波反应管中氮气保护下在7-((2S,3S,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-基)-2-氯-N-环戊基吡咯并[2,1-f][1,2,4]三嗪-4-胺(0.30g,0.48mmol)和三甲基环三硼氧烷(0.12g,0.94mmol)的二氧六环(4mL)/水(1mL)溶液中依次加入碳酸钾(0.20g,1.4mmol)和四三苯基膦钯(0.22g,0.19mmol)，微波保温130℃反应6小时，加入乙酸乙酯，依次用水、饱和食盐水洗涤，有机相合并，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚～石油醚/乙酸乙酯(4:1)]得到7-((2S,3S,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-基)-N-环戊基-2-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺(0.12g,产率40％)。MS  m/z(ESI):619.8[M+H] +。
第二步：(2S,3R,4S,5R)-2-(4-(环戊基氨基)-2-甲基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-(羟甲基)四氢呋喃-3,4-二醇的合成
Figure PCTCN2018123908-appb-000035
将7-((2S,3S,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-基)-N-环戊基-2-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺(0.11g,0.18mmol)溶于四氢呋喃溶液(5mL)，加入氢氧化钯(66mg,15wt％)，氢气置换三次后保温30℃反应48小时，过滤，浓缩后柱层析分离[洗脱剂:二氯甲烷～二氯甲烷/甲醇(9:1)]得到(2S,3R,4S,5R)-2-(4-(环戊基氨基)-2-甲基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-(羟甲基)四氢呋喃-3,4-二醇(50mg,产率79％)。MS m/z(ESI):349.2[M+H] +。
1H NMR(400MHz,MeOH-d 4)δ6.81(d,J＝4.5Hz,1H),6.61(d,J＝4.4Hz,1H),5.14(d,J＝7.6Hz,1H),4.65–4.55(m,2H),4.21(dd,J＝5.3,3.0Hz,1H),4.06(q,J＝3.1Hz,1H),3.80(dd,J＝12.0,3.1Hz,1H),3.69(dd,J＝12.1,3.3Hz,1H),2.34(s,3H),2.13–1.58(m,8H)。
中间体7-9的制备参照中间体6方法制备得到：
Figure PCTCN2018123908-appb-000036
10、(2S,3R,4S,5R)-2-(2-氯-4-(环戊基氨基)-5-氟吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-(羟甲基)四氢呋喃-3,4-二醇的制备
Figure PCTCN2018123908-appb-000037
第一步：7-((2S,3S,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-基)-2-氯-N-环戊基-5-氟吡咯并[2,1-f][1,2,4]三嗪-4-胺的合成
Figure PCTCN2018123908-appb-000038
将7-((2S,3S,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-基)-2-氯-N-环戊基吡咯并[2,1-f][1,2,4]三嗪-4-胺(0.20g,0.31mmol)溶于乙腈(1.5mL)，室温下加入Selectfluor(0.28g,0.78mmol),保温反应2小时，浓缩后柱层析分离[洗脱剂:石油醚～石油醚/乙酸乙酯(2:1)]得到7-((2S,3S,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-基)-2-氯-N-环戊基-5-氟吡咯并[2,1-f][1,2,4]三嗪-4-胺(53mg,产率32％)。
1H NMR(400MHz,CDCl 3)δ7.43–7.25(m,15H),6.37(s,1H),5.58–5.55(m,1H),4.80(s,2H),4.63–4.45(m,4H),4.39–4.29(m,2H),4.17–4.03(m,2H),3.83(dd,J＝10.9,3.2Hz,1H),3.64(dd,J＝10.7,3.7Hz,1H),2.20–2.10(m,2H),1.82–1.60(m,6H).MS m/z(ESI):657.7[M+H] +。
第二步：(2S,3R,4S,5R)-2-(2-氯-4-(环戊基氨基)-5-氟吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-(羟甲基)四氢呋喃-3,4-二醇的合成
Figure PCTCN2018123908-appb-000039
将7-((2S,3S,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-基)-2-氯-N-环戊基-5-氟吡咯并[2,1-f][1,2,4]三嗪-4-胺(67mg,0.10mmol)、氯苯(22mg,0.20mmol)溶于四氢呋喃溶液(2mL)，加入氢氧化钯(34mg,15wt％)，氢气置换三次后保温35℃搅拌反应16小时，过滤，浓缩后柱层析分离[洗脱剂:二氯甲烷～二氯甲烷/甲醇(9:1)]得到(2S,3R,4S,5R)-2-(2-氯-4-(环戊基氨基)-5-氟吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-(羟甲基)四氢呋喃-3,4-二醇(18mg,产率44％)。MS m/z(ESI):387.4[M+H] +。
1H NMR(400MHz,MeOH-d 4)δ6.50(s,1H),5.17(d,J＝6.3Hz,1H),4.62–4.53(m,1H),4.42–4.26(m,1H),4.19–4.10(m,1H),4.05–3.95(m,1H),3.82–3.64(m,2H),2.15–2.04(m,2H),1.83–1.61(m,6H)。
11、(2S,3R,4S,5R)-2-(4-(环戊基氨基)咪唑并[2,1-f][1,2,4]三嗪-7-基)-5-(羟甲基)四氢呋喃-3,4-二醇的制备
Figure PCTCN2018123908-appb-000040
第一步：叔丁基-7-溴咪唑并[2,1-f][1,2,4]三嗪-4-基-氨基甲酸酯的合成
Figure PCTCN2018123908-appb-000041
在100mL三颈瓶中依次加入7-溴咪唑并[2,1-f][1,2,4]三嗪-4-胺(1.76g,68.1％,6.4mmol)、乙腈(15mL)、二碳酸二叔丁酯(1.81g,8.4mmol)、4-二甲氨基吡啶(79mg,0.64mmol)和N,N-二异丙基乙胺(2.06g,16.0mmol)，保温30℃搅拌反应13.5小时，反应完全后加入乙酸乙酯稀释，依次用水、饱和氯化铵溶液、水、饱和碳酸氢钠溶液、饱和食盐水溶液洗涤，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚～石油醚/乙酸乙酯(2:1)]得到叔丁基-7-溴咪唑并[2,1-f][1,2,4]三嗪-4-基-氨基甲酸酯(0.90g,产率58％)。MS m/z(ESI):314.2和316.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.60(s,1H),8.51(s,1H),7.68(s,1H),1.56(s,9H)。
第二步：叔丁基-7-溴咪唑并[2,1-f][1,2,4]三嗪-4-基环戊基氨基甲酸酯的合成
Figure PCTCN2018123908-appb-000042
0℃下在叔丁基-7-溴咪唑并[2,1-f][1,2,4]三嗪-4-基-氨基甲酸酯(0.90g,2.9mmol)的四氢呋喃(15mL)溶液中加入环戊醇(0.62g,7.2mmol)和三苯基膦(1.88g,7.2mmol)，保温反应5分钟后滴加偶氮二甲酸二异丙酯(1.45g,7.2mmol)，加完后升至室温反应10分钟然后再升至45℃搅拌反应2小时，LCMS监控反应，反应完全后浓缩，然后柱层析分离[洗脱剂:石油醚～石油醚/乙酸乙酯(9:1)]得到叔丁基-7-溴咪唑并[2,1-f][1,2,4]三嗪-4-基环戊基氨基甲酸酯(0.74g,产率67％)。MS m/z(ESI):382.4和384.4[M+H] +。
1H NMR(400MHz,CDCl 3)δ8.59(s,1H),7.78(s,1H),4.90(p,J＝8.7Hz,1H),2.00(dt,J＝8.3,5.7Hz,4H),1.81(dh,J＝11.4,4.9Hz,2H),1.63–1.51(m,2H),1.41(s,9H)。
第三步：叔丁基-7-(3R,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)-2-羟基四氢呋喃-2-基咪唑并[2,1-f][1,2,4]三嗪-4-基环戊基氨基甲酸酯的合成
Figure PCTCN2018123908-appb-000043
-70℃下在叔丁基-7-溴咪唑并[2,1-f][1,2,4]三嗪-4-基环戊基氨基甲酸酯(0.74g,1.9mmol)的2-甲基四氢呋喃(2.5mL)溶液中滴加正丁基锂(1.0mL,2.5M,2.5mmol)，加完后保温反应20分钟，再次滴加2,3,5-三苄氧基-D-核糖酸-1,4-内酯(0.89g,2.1mmol)的2-甲基四氢呋喃(1.5mL)，保温搅拌反应2小时，LCMS监控反应，加入饱和氯化铵淬灭反应，然后用乙酸乙酯萃取，依次用饱和氯化铵溶液、水、饱和食盐水洗涤，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚～石油醚/乙酸乙酯(1:1)]得到叔丁基-7-(3R,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)-2-羟基四氢呋喃-2-基咪唑并[2,1-f][1,2,4]三嗪-4-基环戊基氨基甲酸酯(0.36g,产率12％)。MS m/z(ESI):722.8[M+H] +。
第四步：7-((2S,3S,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-基)-N-环戊基咪唑并[2,1-f][1,2,4]三嗪-4-胺的合成
Figure PCTCN2018123908-appb-000044
-20℃下在叔丁基-7-(3R,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)-2-羟基四氢呋喃-2-基咪唑并[2,1-f][1,2,4]三嗪-4-基环戊基氨基甲酸酯(0.36g,45.4％,0.23mmol)的二氯甲烷(5mL)溶液中加入三乙基硅烷(0.26g,2.3mmol)，然后再滴加三氟化硼***(0.16g,1.1mmol)，保温搅拌反应2小时，升至室温反应2.5小时，LCMS监控反应，加入饱和碳酸氢钠溶液淬灭反应，然后用二氯甲烷萃取，依次用饱和碳酸氢钠溶液、水、饱和食盐水洗涤，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚～石油醚/乙酸乙酯(2:1)]得到7-((2S,3S,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-基)-N-环戊基咪唑并[2,1-f][1,2,4]三嗪-4-胺(0.19g,产率61％)。MS m/z(ESI):606.8[M+H] +。
第五步：(2S,3R,4S,5R)-2-(4-(环戊基氨基)咪唑并[2,1-f][1,2,4]三嗪-7-基)-5-(羟甲基)四氢呋喃-3,4-二醇的合成
Figure PCTCN2018123908-appb-000045
将7-((2S,3S,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)四氢呋喃-2-基)-N-环戊基咪唑并[2,1-f][1,2,4]三嗪-4-胺(0.19g,0.31mmol)溶于四氢呋喃溶液(5mL)，加入氢氧化钯(0.19g,15wt％)，氢气置换三次后保温30℃搅拌反应22小时，过滤，浓缩后柱层析分离[洗脱剂: 二氯甲烷～二氯甲烷/甲醇(9:1)]得到(2S,3R,4S,5R)-2-(4-(环戊基氨基)咪唑并[2,1-f][1,2,4]三嗪-7-基)-5-(羟甲基)四氢呋喃-3,4-二醇(78mg,产率73％)。MS m/z(ESI):336.4[M+H] +。
1H NMR(400MHz,MeOH-d 4)δ8.09(s,1H),7.60(s,1H),5.19(d,J＝6.8Hz,1H),4.54(td,J＝7.6,6.9,5.5Hz,2H),4.20(dd,J＝5.3,3.9Hz,1H),4.04(q,J＝3.7Hz,1H),3.80(dd,J＝12.1,3.3Hz,1H),3.77–3.64(m,2H),2.18–2.05(m,2H),1.88–1.66(m,6H)。
12、(2R,3R,4S,5R)-2-(2-氯-4-(环戊基氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-甲腈的制备
Figure PCTCN2018123908-appb-000046
第一步：2-氯-N-环戊基吡咯并[2,1-f][1,2,4]三嗪-4-胺的合成
Figure PCTCN2018123908-appb-000047
将2,4-二氯吡咯并[2,1-f][1,2,4]三嗪(5.0g,26.6mmol)溶于1,4-二氧六环(50mL)，室温下加入N,N-二异丙基乙基胺(9.73g,79.7mmol)，再加入环戊胺(4.53g,53.2mmol)，在室温下搅拌反应1小时，然后浓缩，加入乙酸乙酯，依次用水、饱和氯化铵溶液、饱和碳酸氢钠溶液、饱和食盐水洗涤各一次，无水硫酸钠干燥后浓缩得到2-氯-N-环戊基吡咯并[2,1-f][1,2,4]三嗪-4-胺(5.60g,产率89％)。MS m/z(ESI):237.2[M+H] +。
第二步：叔-丁基(2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯的合成
Figure PCTCN2018123908-appb-000048
将2-氯-N-环戊基吡咯并[2,1-f][1,2,4]三嗪-4-胺(5.0g,26.6mmol)溶于四氢呋喃(50mL)，室温下加入N,N-二异丙基乙基胺(6.49g,53.2mmol)，N,N-二甲基吡啶-4-胺(317mg,2.6mmol)，再加入二碳酸二叔丁酯(8.69g,39.9mmol)，在室温下搅拌反应16小时，浓缩后柱层析分离[洗脱剂:石油醚～石油醚/乙酸乙酯(5:1)]得到叔-丁基(2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯(7.20g,产率90％)。MS m/z(ESI):337.2[M+H] +。
第二步：叔-丁基(7-溴-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯的合成
Figure PCTCN2018123908-appb-000049
将叔-丁基(2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯(7.20g,21.4mmol)溶于二氯甲烷(50mL)，在-10℃下加入N-溴代琥珀酰亚胺(3.81g,21.4mmol)，保温搅拌10分钟后升至室温反应15.5小时，加入N,N-二甲基甲酰胺(0.5mL)搅拌10分钟，依次用饱和碳酸氢钠洗涤三次、饱和食盐水洗涤一次，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚～石油醚/二氯甲烷(5:1)]得到叔-丁基(7-溴-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯(8.0g,产率89％)。MS m/z(ESI):415.2和417.2[M+H] +。
第三步：叔-丁基(7-((3R,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)-2-羟基四氢呋喃-2-基)-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯的合成
Figure PCTCN2018123908-appb-000050
将叔-丁基(7-溴-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯(10g,24.1mmol)溶于2-甲基四氢呋喃(60mL)，氮气下保温-78℃滴加正丁基锂(11.55mL,2.5M,28.8mmol)，保温搅拌1小时，在该温度下滴加(3R,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)二氢呋喃-2(3H)-酮(11.09g,26.5mmol)的2-甲基四氢呋喃(20mL)溶液，保温搅拌反应1小时，用饱和氯化铵溶液淬灭，升至室温后乙酸乙酯萃取两次，合并有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚～石油醚/乙酸乙酯(4:1)]得到叔-丁基(7-((3R,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)-2-羟基四氢呋喃-2-基)-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯(12g,产率65％)。MS m/z(ESI):737.2[M+H-H 2O] +,oxonium。
第四步：(3R,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)-2-(2-氯-4-(环戊基氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)四氢呋喃-2-甲腈的合成
Figure PCTCN2018123908-appb-000051
将叔-丁基(7-((3R,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)-2-羟基四氢呋喃-2-基)-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯(9.0g,12mmol)，三甲基氰硅烷(3.78g,48mmol)，三氟甲磺酸铟(13.47g,24mmol)溶于乙腈溶液(300mL)，在70℃搅拌反应16小时，加入饱和碳酸氢钠淬灭反应，升至室温，用乙酸乙酯萃取两次，合并有机相，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚～石油醚/乙酸乙酯(2.5:1)]得到(3R,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)-2-(2-氯-4-(环戊基氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)四氢呋喃-2-甲腈(7.2g,产率90％)。MS m/z(ESI):664.2[M+H] +。
第五步：(2R,3R,4S,5R)-2-(2-氯-4-(环戊基氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-3,4-二羟基 -5-(羟甲基)四氢呋喃-2-甲腈的合成
Figure PCTCN2018123908-appb-000052
将(3R,4R,5R)-3,4-二(苄氧基)-5-((苄氧基)甲基)-2-(2-氯-4-(环戊基氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)四氢呋喃-2-甲腈(9.6g,14.4mmol)溶于二氯甲烷溶液(400mL)，在0℃加入三氯化硼(72mL,1M,72mmol)，在该温度下搅拌反应4小时，加入甲醇淬灭反应，升至室温，浓缩后反相柱层析分离[洗脱剂:水～水/乙腈(7:3)]得到(2R,3R,4S,5R)-2-(2-氯-4-(环戊基氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-3,4-二羟基-5-(羟甲基)四氢呋喃-2-甲腈(1g,产率17％)。MS m/z(ESI):394.2[M+H] +。
1H NMR(400MHz,MeOH-d 4)δ6.96(d,J＝4.8Hz,1H),6.91(d,J＝4.4Hz,1H),4.88–4.85(m,1H),4.59–4.54(m,1H),4.27–4.22(m,1H),3.89–3.85(m,1H),3.76–3.72(m,1H),2.11–2.06(m,2H),1.80–1.77(m,2H),1.71–1.61(m,4H)。
13、(1R,2S,3S,5R)-3-(2-氯-4-(环戊基氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-(羟甲基)环戊烷-1,2-二醇的制备
Figure PCTCN2018123908-appb-000053
第一步：叔-丁基(7-((3aR,6R,6aR)-6-(叔-丁氧基甲基)-4-羟基-2,2-二甲基四氢-4H-环戊二烯并[d][1,3]二噁唑-4-基)-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯的合成
Figure PCTCN2018123908-appb-000054
将叔-丁基(7-溴-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯(730mg,1.75mmol)溶于2-甲基四氢呋喃(20mL)，氮气下保温-78℃滴加正丁基锂(1mL,2.5M,2.5mmol)，保温搅拌反应1小时，在该温度下滴加(3aR,6R,6aR)-6-(叔-丁氧基甲基)-2,2-二甲基四氢-4H-环戊二烯并[d][1,3]二噁唑-4-酮(600mg,2.46mmol)的2-甲基四氢呋喃(5mL)溶液，继续保温搅拌反应1小时，用饱和氯化铵溶液淬灭，升至室温后乙酸乙酯萃取两次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚～ 石油醚/乙酸乙酯(2.5:1)]得到叔-丁基(7-((3aR,6R,6aR)-6-(叔-丁氧基甲基)-4-羟基-2,2-二甲基四氢-4H-环戊二烯并[d][1,3]二噁唑-4-基)-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯(550mg,产率54％)。
第二步：叔-丁基(7-((3aR,4R,6aS)-4-(叔-丁氧基甲基)-2,2-二甲基-3a,6a-二氢-4H-环戊二烯并[d][1,3]二噁唑-6-基)-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯的合成
Figure PCTCN2018123908-appb-000055
将叔-丁基(7-((3aR,6R,6aR)-6-(叔-丁氧基甲基)-4-羟基-2,2-二甲基四氢-4H-环戊二烯并[d][1,3]二噁唑-4-基)-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯(580mg,1.00mmol)溶于四氢呋喃(10mL)，室温下加入伯吉斯试剂(1000mg,4mmol)，在80℃搅拌反应16小时，浓缩后柱层析分离[石油醚～石油醚/乙酸乙酯(10:1)]得到叔-丁基(7-((3aR,4R,6aS)-4-(叔-丁氧基甲基)-2,2-二甲基-3a,6a-二氢-4H-环戊二烯并[d][1,3]二噁唑-6-基)-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯(440mg,产率78％)。MS m/z(ESI):561.6[M+H] +。
第三步：叔-丁基(7-((3aS,4S,6R,6aR)-6-(叔-丁氧基甲基)-2,2-二甲基四氢-4H-环戊二烯并[d][1,3]二噁唑-4-基)-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯的合成
Figure PCTCN2018123908-appb-000056
将叔-丁基(7-((3aR,4R,6aS)-4-(叔-丁氧基甲基)-2,2-二甲基-3a,6a-二氢-4H-环戊二烯并[d][1,3]二噁唑-6-基)-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯(440mg,0.78mmol)溶于四氢呋喃(20mL)，室温下加入氢氧化钯/碳(400mg)，在氢气条件下室温搅拌反应4小时，过滤后柱层析分离[石油醚～石油醚/乙酸乙酯(10:1)]得到叔-丁基(7-((3aS,4S,6R,6aR)-6-(叔-丁氧基甲基)-2,2-二甲基四氢-4H-环戊二烯并[d][1,3]二噁唑-4-基)-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯(280mg,产率63％)。MS m/z(ESI):563.6[M+H] +。
第四步：(1R,2S,3S,5R)-3-(2-氯-4-(环戊基氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-(羟甲基)环戊烷-1,2-二醇的合成
Figure PCTCN2018123908-appb-000057
将叔-丁基(7-((3aS,4S,6R,6aR)-6-(叔-丁氧基甲基)-2,2-二甲基四氢-4H-环戊二烯并[d][1,3]二噁唑-4-基)-2-氯吡咯并[2,1-f][1,2,4]三嗪-4-基)(环戊基)氨基甲酸酯(260mg,0.46mmol)溶于乙腈(0.5mL)，室温下加入浓盐酸(0.5mL)，在室温下搅拌反应16小时，浓缩后柱层析分离[洗脱剂:水～乙腈(10～100)]得到(1R,2S,3S,5R)-3-(2-氯-4-(环戊基氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-(羟甲基)环戊烷-1,2-二醇(140mg,产率83％)。MS m/z(ESI):367.2[M+H] +。
14、(2R,3R,4S,5S)-5-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-2-(羟甲基)四氢呋喃-3-醇的制备
Figure PCTCN2018123908-appb-000058
第一步：(4S,5R)-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)二氢呋喃-2(3H)-酮的合成
Figure PCTCN2018123908-appb-000059
将(4S,5R)-4-羟基-5-(羟甲基)二氢呋喃-2(3H)-酮(25.0g,0.189mol)溶于DMF(230mL)中，加入咪唑(77.3g,1.14mol)，在0℃下缓慢滴加三异丙基硅基氯(146g,0.757mol)，滴加完成后室温搅拌过夜。反应完成后用饱和碳酸氢钠水溶液(1L)淬灭，乙酸乙酯萃取三次后，有机相合并，依次用水和饱和食盐水分别洗涤，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚/乙酸乙酯(19:1)]得到(4S,5R)-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)二氢呋喃-2(3H)-酮(80.0g,产率95％)。
第二步：(3S,4R,5R)-3-氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)二氢呋喃-2(3H)-酮的合成
Figure PCTCN2018123908-appb-000060
将(4S,5R)-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)二氢呋喃-2(3H)-酮(10.0g,22.5mmol)溶于无水四氢呋喃(100mL)中，加入N-氟代双苯磺酰胺(10.6g, 33.7mmol)，在-78℃下缓慢滴加双三甲基硅基胺基锂(1.0M四氢呋喃溶液,29.2mL,29.2mmol)，滴加完成后在-78℃下搅拌反应2小时，反应完成后用饱和氯化铵溶液淬灭。乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚/乙酸乙酯(40/1)]得到(3S,4R,5R)-3-氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)二氢呋喃-2(3H)-酮(7.0g,产率67％)。
第三步：(3S,4R,5R)-2-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-3-氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)四氢呋喃-2-醇的合成
Figure PCTCN2018123908-appb-000061
将7-溴-2-氯-N-环戊基-N-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺(1.50g,4.55mmol)溶于无水2-甲基四氢呋喃(15mL)后冷却至-78℃，缓慢滴加正丁基锂(2.5M四氢呋喃溶液,2.7mL,6.37mmol)，滴加完成后在-78℃下搅拌反应1小时后，缓慢加入(3S,4R,5R)-3-氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)二氢呋喃-2(3H)-酮(2.32g,5.01mmol)的2-甲基四氢呋喃溶液(10mL)，滴加完成后继续搅拌反应1小时。反应完成后用饱和氯化铵淬灭，乙酸乙酯萃取三次。有机相合并，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚/乙酸乙酯(8/1)]得到(3S,4R,5R)-2-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-3-氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)四氢呋喃-2-醇(2.0g,产率61％)。
第四步 2-氯-N-环戊基-7-((2S,3R,4R,5R)-3-氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)四氢呋喃-2-基)-N-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺的合成
Figure PCTCN2018123908-appb-000062
将(3S,4R,5R)-2-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-3-氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)四氢呋喃-2-醇(2.0g,2.8mmol)，溶于二氯甲烷(30mL)中，在-20℃下加入三氟化硼***溶液(2.0g,14.0mmol)，搅拌五分钟后缓慢加入三乙基硅烷(3.3g,28.0mmol)，滴加完成后在-20℃下继续搅拌反应2小时，反应完成后加入饱和碳酸氢钠水溶液淬灭，二氯甲烷萃取三次。有机相合并，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚/乙酸乙酯(10/1)]得到2-氯-N-环戊基-7-((2S,3R,4R,5R)-3-氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)四氢呋喃-2-基)-N-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺(1.6g,产率82％)。
第五步：(2R,3R,4S,5S)-5-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-2-(羟甲基)四氢呋喃-3-醇的合成
Figure PCTCN2018123908-appb-000063
将2-氯-N-环戊基-7-((2S,3R,4R,5R)-3-氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)四氢呋喃-2-基)-N-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺(600mg,0.86mmol)溶于四氢呋喃(15mL)中，室温下加入四丁基氟化铵(1M四氢呋喃溶液,2.6mL,2.6mmol)，室温搅拌过夜，浓缩后反相柱层析分离[洗脱剂:乙腈/水(40/60)]得到(2R,3R,4S,5S)-5-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-2-(羟甲基)四氢呋喃-3-醇(300mg,产率91％)。MS m/z(ESI):385.4[M+H] +。
中间体15-29的制备参照中间体14的合成方法制备得到：
Figure PCTCN2018123908-appb-000064
Figure PCTCN2018123908-appb-000065
Figure PCTCN2018123908-appb-000066
30、(2R,3R,5S)-5-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4,4-二氟-2-(羟甲基)四氢呋喃-3-醇的制备
Figure PCTCN2018123908-appb-000067
第一步：((4R,5R)-2-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-3,3-二氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)四氢呋喃-2-醇的合成
Figure PCTCN2018123908-appb-000068
将7-溴-2-氯-N-环戊基-N-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺(2.90g,8.8mmol)溶于2-甲基四氢呋喃(20mL)，氮气下保温-78℃滴加正丁基锂(4.95mL,2.5M,12.4mmol)，保温搅拌反应1小时，在该温度下滴加(4R,5R)-3,3-二氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)二氢呋喃-2(3H)-酮(4.23g,8.8mmol)的2-甲基四氢呋喃(5mL)溶液，继续保温搅拌反应1小时，用饱和氯化铵溶液淬灭，升至室温，乙酸乙酯萃取两次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚～石油醚/乙酸乙酯(2.5:1)]得到((4R,5R)-2-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-3,3-二氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)四氢呋喃-2-醇(3.15g,产率50％)。
第二步：2-氯-N-环戊基-7-((2S,4R,5R)-3,3-二氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)四氢呋喃-2-基)-N-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺的合成
Figure PCTCN2018123908-appb-000069
将((4R,5R)-2-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-3,3-二氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)四氢呋喃-2-醇(3.15g,4.4mmol)，三乙基硅烷(7.03mL,44.0mmol)溶于二氯甲烷/乙腈混合溶液(30mL,1:1)，在-20℃滴加三氟化硼***(2.78mL，22.0mmol)，保温搅拌反应1小时，加入饱和碳酸氢钠淬灭反应，升至室温，二氯甲烷萃取两次，合并有机相，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚～石油醚/乙酸乙酯(2.5:1)]得到2-氯-N-环戊基-7-((2S,4R,5R)-3,3-二氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)四氢呋喃-2-基)-N-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺(1.88g,产率60％)。
第三步：(2R,3R,5S)-5-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4,4-二氟-2-(羟甲基)四氢呋喃-3-醇的合成
Figure PCTCN2018123908-appb-000070
将2-氯-N-环戊基-7-((2S,4R,5R)-3,3-二氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)四氢呋喃-2-基)-N-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺(0.71g,1.0mmol)，溶于四氢呋喃溶液(10mL)，加入TBAF(2mL,1M/L)，然后室温搅拌反应12小时，浓缩后柱层析分离[洗脱剂:二氯甲烷～二氯甲烷/甲醇(9:1)]得到(2R,3R,5S)-5-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4,4-二氟-2-(羟甲基)四氢呋喃-3-醇(0.30g,产率75％)。MS m/z(ESI):403.4[M+H] +。
中间体31-34的制备参照中间体30的合成方法制备得到：
Figure PCTCN2018123908-appb-000071
35、4-(环戊基(甲基)氨基)-7-((2S,3S,4R,5R)-3-氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)吡咯并[2,1-f][1,2,4]三嗪-2-甲腈的制备
Figure PCTCN2018123908-appb-000072
第一步：4-(环戊基(甲基)氨基)-7-((2S,3R,4R,5R)-3-氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)四氢呋喃-2-基)吡咯并[2,1-f][1,2,4]三嗪-2-甲腈的合成
Figure PCTCN2018123908-appb-000073
将2-氯-N-环戊基-7-((2S,3R,4R,5R)-3-氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)四氢呋喃-2-基)-N-甲基吡咯并[2,1-f][1,2,4]三嗪-4-胺(880mg,1.26mmol)溶于无水N,N-二甲基甲酰胺(10mL)中，加入四(三苯基膦)钯(580mg,0.51mmol)和氰化锌(444mg,3.78mmol)。反应在微波条件下于130℃搅拌反应9小时，过滤，滤液加水(100mL)后用乙酸乙酯萃取三次，有机相合并，依次用水和饱和食盐水洗涤，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚/乙酸乙酯(10/1)]得到4-(环戊基(甲基)氨基)-7-((2S,3R,4R,5R)-3-氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)四氢呋喃-2-基)吡咯并[2,1-f][1,2,4]三嗪-2-甲腈(690mg,产率79％)。
第二步：4-(环戊基(甲基)氨基)-7-((2S,3S,4R,5R)-3-氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)吡咯并[2,1-f][1,2,4]三嗪-2-甲腈的合成
Figure PCTCN2018123908-appb-000074
将4-(环戊基(甲基)氨基)-7-((2S,3R,4R,5R)-3-氟-4-((三异丙基甲硅烷基)氧代)-5-(((三异丙基甲硅烷基)氧代)甲基)四氢呋喃-2-基)吡咯并[2,1-f][1,2,4]三嗪-2-甲腈(690mg,1.0mmol)溶于四氢呋喃(15mL)中，室温下加入四丁基氟化铵(1M四氢呋喃溶液,3.0mL,3.0mmol)，室温条件下搅拌过夜，浓缩后反相柱层析分离[洗脱剂:乙腈/水(75/25)]得到4-(环戊基(甲基)氨基)-7-((2S,3S,4R,5R)-3-氟-4-羟基-5-(羟甲基)四氢呋喃-2-基)吡咯并[2,1-f][1,2,4]三嗪-2-甲腈(350mg,产率93％)。MS m/z(ESI):376.4[M+H] +。
中间体36-37的制备参照中间体35的合成方法制备得到：
Figure PCTCN2018123908-appb-000075
38、((2R,3R,4S,5S)-5-(2-氯-4-(((R)-1-(2-氟苯基)乙基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-3-羟基四氢呋喃-2-基)甲基4-甲基苯磺酸酯的制备
Figure PCTCN2018123908-appb-000076
第一步((2R,3S)-3-羟基-5-羰基四氢呋喃-2-基)甲基苯酸酯的合成
Figure PCTCN2018123908-appb-000077
将(4S,5R)-4-羟基-5-(羟甲基)二氢呋喃-2(3H)-酮(10g,75.7mmol)溶于干燥的二氯甲烷(100mL)中，加入吡啶(18g,227mmol)，降至-20℃后滴加苯甲酰氯(11.7g,83.3mmol)的二氯甲烷(50mL)溶液。反应在-20℃下搅拌反应2小时，然后用饱和碳酸氢钠水溶液(150mL)淬灭，分出有机相，依次用饱和碳酸氢钠水溶液、水、稀盐酸洗涤，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚/乙酸乙酯(2/1)]得到((2R,3S)-3-羟基-5-羰基四氢呋喃-2-基)甲基苯酸酯(13.3g,产率74％)。MS m/z(ESI):237.0[M+H] +。
第二步((2R,3S)-5-羰基-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲基苯酸酯的合成
Figure PCTCN2018123908-appb-000078
将((2R,3S)-3-羟基-5-羰基四氢呋喃-2-基)甲基苯酸酯(13.3g,56.3mmol)溶于N,N- 二甲基甲酰胺(100mL)中，加入咪唑(11.5g,169mmol)，在0℃下缓慢滴加三异丙基硅基氯(16.3g,84.5mmol)，逐渐升至室温搅拌过夜，用饱和碳酸氢钠水溶液(500mL)淬灭反应，乙酸乙酯萃取三次，有机相合并，依次用水和饱和食盐水洗涤。无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:石油醚/乙酸乙酯(15/1)]得到((2R,3S)-3-羟基-5-羰基四氢呋喃-2-基)甲基苯酸酯(20.0g，收率90.5％)。MS m/z(ESI):393.2[M+H] +。
第三步((2R,3R,4S)-4-氟-5-羰基-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲基苯酸酯的合成
Figure PCTCN2018123908-appb-000079
将((2R,3S)-3-羟基-5-羰基四氢呋喃-2-基)甲基苯酸酯(12.0g,30.6mmol)溶于无水四氢呋喃(150mL)，加入N-氟-N-(苯磺酰)苯磺酰胺(14.5g,45.9mmol)。在-78℃下逐滴加入二(三甲基甲硅烷基)氨基锂(1M四氢呋喃溶液,39.4mL,39.4mmol)，滴加完成后在-78℃下继续搅拌反应2小时，用饱和氯化铵水溶液(500mL)淬灭，乙酸乙酯萃取三次，有机相合并，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:乙酸乙酯/石油醚(1/20)]得到((2R,3R,4S)-4-氟-5-羰基-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲基苯酸酯(9.5g,产率75.7％)。
第四步：((2R,3R,4S)-5-(2,4-二氯吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-5-羟基-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲基苯酸酯的合成
Figure PCTCN2018123908-appb-000080
将7-溴-2,4-二氯吡咯并[2,1-f][1,2,4]三嗪(1.77g,6.64mmol)溶于无水2-甲基四氢呋喃(25mL)中，在-78℃下缓慢滴加正丁基锂(2.5M四氢呋喃溶液,3.45mL,8.63mmol)，滴加完成后在-78℃下搅拌1小时，缓慢滴加((2R,3R,4S)-4-氟-5-羰基-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲基苯酸酯(3.0g,7.31mmol)的2-甲基四氢呋喃(7mL)溶液。滴加完成后继续搅拌反应2小时。加入饱和氯化铵溶液淬灭，乙酸乙酯萃取三次，有机相合并，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:乙酸乙酯/石油醚(1/10)]得到((2R,3R,4S)-5-(2,4-二氯吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-5-羟基-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲基苯酸酯(1.8g,产率45％)。
第五步：((2R,3R,4R,5S)-5-(2,4-二氯吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲基苯酸酯的合成
Figure PCTCN2018123908-appb-000081
将((2R,3R,4S)-5-(2,4-二氯吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-5-羟基-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲基苯酸酯(1.8g,3.0mmol)溶于二氯甲烷(30mL)后，在-20℃下加入三氟化硼***溶液(2.1g,15.0mmol)，搅拌5分钟后缓慢加入三乙基硅烷(1.4g,12.0mmol)，滴加完毕继续搅拌反应2小时。加入饱和碳酸氢钠水溶液淬灭，二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:乙酸乙酯/石油醚(1/15)]得到((2R,3R,4R,5S)-5-(2,4-二氯吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲基苯酸酯(1.3g,产率74％)。
第六步：((2R,3R,4R,5S)-5-(2-氯-4-(((R)-1-(2-氟苯基)乙基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲基苯酸酯的合成
Figure PCTCN2018123908-appb-000082
将((2R,3R,4R,5S)-5-(2,4-二氯吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲基苯酸酯(300mg,0.51mmol)溶于1,4-二氧六环(20mL)中，加入(R)-1-(2-氟苯基)乙烷-1-胺(108mg,0.77mmol)和N,N-二异丙基乙胺(200mg,1.54mmol)。在室温下搅拌反应1小时，浓缩后柱层析分离[洗脱剂:乙酸乙酯/石油醚(1/10)]得到((2R,3R,4R,5S)-5-(2-氯-4-(((R)-1-(2-氟苯基)乙基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲基苯酸酯(330mg,产率93％)。
第七步：((2R,3R,4R,5S)-5-(2-氯-4-(((R)-1-(2-氟苯基)乙基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲醇的合成
Figure PCTCN2018123908-appb-000083
将((2R,3R,4R,5S)-5-(2-氯-4-(((R)-1-(2-氟苯基)乙基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲基苯酸酯(330mg,0.48mmol)溶于甲醇/四氢呋喃/水(10mL/10mL/5mL)中，加入碳酸钾(665mg,4.82mmol)，室温下搅拌反应2小时，浓缩后柱层析分离[洗脱剂:乙酸乙酯/二氯甲烷(1/3)]得到((2R,3R,4R,5S)-5-(2- 氯-4-(((R)-1-(2-氟苯基)乙基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲醇(280mg,产率100％)。
第八步：((2R,3R,4R,5S)-5-(2-氯-4-(((R)-1-(2-氟苯基)乙基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲基4-甲基苯磺酸酯的合成
Figure PCTCN2018123908-appb-000084
将((2R,3R,4R,5S)-5-(2-氯-4-(((R)-1-(2-氟苯基)乙基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲醇(280mg,0.48mmol)溶于无水二氯甲烷(15mL)中，加入4-二甲氨基吡啶(147mg,1.20mmol)和N,N-二异丙基乙胺(249mg,1.93mmol)，在0℃下缓慢滴加对甲苯磺酰氯(138mg,0.72mmol)的二氯甲烷(1mL)溶液，滴加完毕后缓慢升至室温，继续搅拌反应2小时。反应完成后用饱和碳酸氢钠淬灭，二氯甲烷萃取三次，有机相合并，无水硫酸钠干燥，浓缩后柱层析分离[洗脱剂:乙酸乙酯/石油醚(1/10)]得到((2R,3R,4R,5S)-5-(2-氯-4-(((R)-1-(2-氟苯基)乙基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲基4-甲基苯磺酸酯(330mg,产率93％)。
第九步：((2R,3R,4S,5S)-5-(2-氯-4-(((R)-1-(2-氟苯基)乙基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-3-羟基四氢呋喃-2-基)甲基4-甲基苯磺酸酯的合成
Figure PCTCN2018123908-appb-000085
将((2R,3R,4R,5S)-5-(2-氯-4-(((R)-1-(2-氟苯基)乙基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-3-((三异丙基甲硅烷基)氧代)四氢呋喃-2-基)甲基4-甲基苯磺酸酯(330mg,0.45mmol)溶于四氢呋喃(15mL)中，室温下加入四丁基氟化铵(1M四氢呋喃溶液,0.9mL,0.9mmol)。在室温下搅拌反应2小时，浓缩后柱层析分离[洗脱剂:乙酸乙酯/二氯甲烷(1/10)]得到((2R,3R,4S,5S)-5-(2-氯-4-(((R)-1-(2-氟苯基)乙基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-3-羟基四氢呋喃-2-基)甲基4-甲基苯磺酸酯(250mg,产率96％)。MS m/z(ESI):579.0[M+H] +。
中间体39-59参照中间体38的合成方法制备得到：
Figure PCTCN2018123908-appb-000086
Figure PCTCN2018123908-appb-000087
Figure PCTCN2018123908-appb-000088
Figure PCTCN2018123908-appb-000089
Figure PCTCN2018123908-appb-000090
二、具体实施例化合物的制备
实施例1(((((2R,3S,4R,5S)-5-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-3,4-二羟基四氢呋喃-2-基)甲氧基)(羟基)磷基)甲基)膦酸的制备
Figure PCTCN2018123908-appb-000091
将(2S,3R,4S,5R)-2-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-(羟甲基)四氢呋喃-3,4-二醇(100mg,0.26mmol)溶于磷酸三甲酯(2.5mL)，在0℃下滴加亚甲基双氯化磷(0.33g,1.3mmol)的磷酸三甲酯(0.5mL)溶液，加完保温搅拌反应3小时，然后加入0.5N碳酸氢三乙胺溶液淬灭反应，冻干后反相柱层析分离[C 18柱，洗脱剂:水～水/乙腈(9:1)+0.1％氨水]得到(((((2R,3S,4R,5S)-5-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-3,4-二羟基四氢呋喃-2-基)甲氧基)(羟基)磷基)甲基)膦酸(5.1mg,产率3.6％)。MS m/z(ESI):541.4[M+H] +。
1H NMR(400MHz,D 2O)δ6.97(d,J＝4.9Hz,1H),6.81(d,J＝4.8Hz,1H),5.25(d,J＝6.6Hz,1H),5.18–5.01(m,1H),4.54(dd,J＝6.6,5.4Hz,1H),4.35(t,J＝4.9Hz,1H),4.20(q,J＝4.2Hz,1H),4.01(t,J＝5.0Hz,2H),3.20(s,3H),2.11(t,J＝19.9Hz,2H),1.96–1.84(m,2H),1.78–1.61(m,6H)。
实施例2-29参照实施例1的合成方法制备得到：
Figure PCTCN2018123908-appb-000092
Figure PCTCN2018123908-appb-000093
Figure PCTCN2018123908-appb-000094
Figure PCTCN2018123908-appb-000095
Figure PCTCN2018123908-appb-000096
Figure PCTCN2018123908-appb-000097
其中，上述实施例化合物2～29制备得到的核磁数据列举如下：
Figure PCTCN2018123908-appb-000098
Figure PCTCN2018123908-appb-000099
Figure PCTCN2018123908-appb-000100
实施例31(((((2R,3S,4R,5S)-5-(2-氯-4-(环己基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-3,4-二羟基四氢呋喃-2-基)甲氧基)(羟基)磷基)甲基)膦酸的制备
Figure PCTCN2018123908-appb-000101
将((2R,3R,4S,5S)-5-(2-氯-4-(环己基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-3-羟基四氢呋喃-2-基)甲基4-甲基苯磺酸酯(250mg,0.45mmol)，亚甲基二(膦酸)三正丁基胺(1.97g,2.26mmol)溶于N,N-二甲基甲酰胺(5mL)，在室温下搅拌反应16小时，然后反相柱层析分离[C 18柱，洗脱剂:水～水/乙腈(9:1)+0.1％甲酸]得到(((((2R,3S,4R,5S)-5-(2-氯-4-(环戊基(甲基)氨基)吡咯并[2,1-f][1,2,4]三嗪-7-基)-3,4-二羟基四氢呋喃-2-基)甲氧基)(羟基)磷基)甲基)膦酸(12mg,产率5％)。MS m/z(ESI):557.4[M+H] +。
1H NMR(400MHz,D 2O)δ7.39–7.38(m,1H),6.82–6.81(m,1H),5.61–5.53(m,1H),5.30–5.17(m,1H),4.67–4.63(m,1H),4.51–4.37(m,1H),4.11–4.10(m,1H),4.04–4.01(m,2H),3.30–3.13(m,3H),2.12–2.08(m,2H),1.80–1.73(m,2H),1.72-1.65(m,2H),1.65–1.50(m,4H),1.42–1.31(m,2H)。
实施例32～51参照实施例31的合成方法制备得到：
Figure PCTCN2018123908-appb-000102
Figure PCTCN2018123908-appb-000103
Figure PCTCN2018123908-appb-000104
Figure PCTCN2018123908-appb-000105
其中，上述实施例32～51制备得到的化合物核磁数据列举如下：
Figure PCTCN2018123908-appb-000106
Figure PCTCN2018123908-appb-000107
Figure PCTCN2018123908-appb-000108
生物学测试评价
一、CD73体外酶活性评价
本发明采用体外合成的可溶性状态的CD73的孔雀绿测试来测定化合物对CD73抑制活性的特性。实验过程如下：
1、本实验的酶反应在384孔板中进行，浓度为36ng/ml的CD73(R&D systems#5795-EN-010)和不同浓度的化合物以及50μM的AMP在40μl的反应体系中(25mM Tris pH 7.5,5mM MgCl 2,0.005％Tween-20)25℃下孵育反应30分钟；
2、然后通过每孔添加10μL孔雀绿溶液(malachite green solution,Sigma)来终止反应；
3、根据试剂生产厂商的说明书来测定所产生的非有机磷酸(inorganic phosphate)的浓度。
4、通过产物的浓度计算CD73酶活性，然后采用非线性回归分析本发明化合物不同浓度下的抑制百分比来测定IC 50值。
本发明实施例化合物的实验结果如表1。
二、细胞表面的CD73酶活性评价(Cell Titer Glo(CTG)实验)
本发明采用内源性表达CD73的人乳腺癌细胞MDA-MB-231来评价化合物对细胞表面表达的CD73酶活性的抑制作用。所用细胞来源于中科院细胞库。实验过程如下：
1、测试前将20000/孔的MDA-MB231细胞接种到96孔板中；
2、在RPMI1640,10％胎牛血清(Gibco,10099-141)，置于37℃，5％CO 2培养箱中培养培养过夜(测试时应用无血清的RPMI培养基清洗细胞3次)；
3、将50μl的包含不同浓度稀释的化合物的无血清培养基加入到细胞中，孵育15分钟；
4、加入25μl 1.2mM AMP，在37℃孵育2小时，从细胞中取出25μl的上清液和25μl100μM的ATP混合，然后通过CTG(Promega，#G7573)的方法测定AMP在样品中的浓度。
5、然后通过对反应之后细胞培养上清液里底物AMP水平减少比例的定量测定来评价本发明实施例化合物和阳性化合物对于细胞表面CD73酶活性的抑制作用。
6、最后使用Graphpad Prism中四参数曲线拟合来测定导致绝对半数酶活性抑制的化合物浓度(IC 50)。
本发明实施例化合物的实验结果如表1。
表1：生物学测试结果
Figure PCTCN2018123908-appb-000109
Figure PCTCN2018123908-appb-000110
从具体实施例化合物体外酶学或细胞活性数据来看，本发明系列化合物对CD73酶活性具有很强的抑制作用。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (22)

  1. 式(I)化合物、其立体异构体、前药或其药学上可接受盐：
    Figure PCTCN2018123908-appb-100001
    其中，
    X 1、X 2各自独立的选自N或CH；
    X 3、X 4各自独立的选自N或C；
    X 5、X 6各自独立的选自O、S、C(R 10)、N或N(R 11)；
    Y 1选自-O-、-S-、-C(R 12R 13)-、-(C＝CR 14R 15)-或-N(R 16)-；
    Y 2、Y 3各自独立的选自-O-、-S-或-C(R 17R 18)-；
    Z选自-O-、-S-或-NH-；
    R 1选自氢、氘、卤素、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、-NR 19R 20或-C 0-8-S(O) rR 21，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代；
    R 2选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代；
    R 3、R 4各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、 -C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代；
    R 5、R 6各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23，或者，R 5与R 6和其直接相连的碳原子一起形成3-10元环烷基、3-10元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代；
    R 7、R 8、R 9各自独立的选自氢、氘、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23或-C 0-8-C(O)NR 24R 25，或者，R 7与R 8或R 9和其直接相连的基团一起形成6-10元杂环基，R 8与R 9和其直接相连的基团一起形成4-10元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代；
    每个R 10、R 12、R 13、R 14、R 15、R 17、R 18各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代；
    每个R 11、R 16各自独立的选自氢、氘、C 1-10烷基、C 3-10环烷基C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代；
    每个R 19、R 20各自独立的选自氢、氘、C 1-10烷基、C 3-10环烷基C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、C 3-10环烯基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、 -C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23，或者，R 19、R 20和其直接相连的氮原子一起形成4-10元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、卤取代C 1-10烷基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22、-C 0-8-C(O)OR 22、-C 0-8-C(O)R 23、-C 0-8-O-C(O)R 23、-C 0-8-NR 24R 25、-C 0-8-C(O)NR 24R 25或-C 0-8-N(R 24)-C(O)R 23的取代基所取代；
    每个R 21选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 24R 25，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 24R 25的取代基所取代；
    每个R 22选自氢、氘、C 1-10烷基、C 2-10链烯基、C 3-10环烷基、3-10元杂环基、C 5-10芳基或5-10元杂芳基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、羰基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 24R 25的取代基所取代；
    每个R 23选自氢、氘、羟基、C 1-10烷基、C 1-10烷氧基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 24R 25，上述基团任选进一步被一个或多个选自氘、卤素、羟基、氰基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基或-NR 24R 25的取代基所取代；
    每个R 24、R 25各自独立的选自氢、氘、羟基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、磺酰基、甲磺酰基、异丙磺酰基、环丙基磺酰基、对甲苯磺酰基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-8烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代；
    或者，R 24、R 25和其直接相连的氮原子一起形成4-10元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、羟基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、氨基、单烷基氨基、二烷基氨基或C 1-10烷酰基的取代基所取代；
    每个r独立为0、1或2。
  2. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，R 5、R 6各自独立的选自氢、氘、卤素、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-C 0-4-O-R 22或-C 0-4-NR 24R 25，或者，R 5与R 6和其直接相连的 碳原子一起形成3-6元环烷基、3-6元杂环基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-C 0-4-O-R 22或-C 0-4-NR 24R 25的取代基所取代，R 22、R 24、R 25如权利要求1所述；
    优选的，R 5、R 6各自独立的选自氢、氘、氟、甲基、异丙基、烯丙基、乙炔基、环丙基、三氟甲基、三氘甲基、甲氧基、三氟甲氧基、三氘甲氧基、氨基或二甲基氨基，或者，R 5与R 6和其直接相连的碳原子一起形成3-4元环烷基、4-5元杂环基。
  3. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，R 3、R 4各自独立的选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基或C 2-4链炔基，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-C 0-4-O-R 22或-C 0-4-NR 24R 25的取代基所取代，R 22、R 24、R 25如权利要求1所述；优选的，R 3、R 4各自独立的选自氢、氘、氟、氰基、甲基、乙烯基或乙炔基，上述基团任选进一步被一个或多个选自氘、卤素或环丙基的取代基所取代。
  4. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，Y 2、Y 3各自独立的选自-C(R 17R 18)-；
    每个R 17、R 18各自独立的选自氢、氘、卤素、氰基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-C 0-4-O-R 22或-C 0-4-O-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、-O-R 22或-O-C(O)R 23的取代基所取代，R 22、R 23如权利要求1所述；优选的，每个R 17、R 18各自独立的选自氢、氘、氟、氯、氰基、叠氮基、甲基、乙烯基、乙炔基、环丙基、羟基、甲氧基或乙酰氧基，上述基团任选进一步被一个或多个选自氘、氟、氰基、甲基、异丙基、乙烯基、乙炔基、环丙基、羟基或甲氧基的取代基所取代。
  5. 根据权利要求1所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，R 1选自氢、氘、卤素、羟基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、-NR 19R 20或-C 0-8-S(O) rR 21，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22、-C 0-4-C(O)OR 22、-C 0-4-C(O)R 23、-C 0-4-O-C(O)R 23、-C 0-4-NR 24R 25、-C 0-4-C(O)NR 24R 25或-C 0-4-N(R 24)-C(O)R 23的取代基所取代；
    R 2选自氢、氘、卤素、氰基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22或-C 0-8-NR 24R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂 芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22、-C 0-4-C(O)OR 22、-C 0-4-C(O)R 23、-C 0-4-O-C(O)R 23、-C 0-4-NR 24R 25、-C 0-4-C(O)NR 24R 25或-C 0-4-N(R 24)-C(O)R 23的取代基所取代；
    R 19、R 20、R 21、R 22、R 23、R 24、R 25、r如权利要求1所述。
  6. 根据权利要求1-5任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，X 3、X 4各自独立的选自N或C，且X 3、X 4中至少包含一个N；
    Y 1选自-O-、-C(R 12R 13)-、-(C＝CR 14R 15)-或-N(R 16)-；
    Y 2、Y 3各自独立的选自-C(R 17R 18)-；
    R 1选自氢、氘、卤素、羟基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、-NR 19R 20或-C 0-8-S(O) rR 21，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21或-C 0-4-O-R 22的取代基所取代；
    R 2选自氢、氘、卤素、氰基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22或-C 0-8-NR 24R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22或-C 0-4-NR 24R 25、的取代基所取代；
    R 3、R 4各自独立的选自氢、氘、氟、氰基、甲基、乙烯基或乙炔基，上述基团任选进一步被一个或多个选自氘、卤素或环丙基的取代基所取代；
    R 5、R 6各自独立的选自氢、氘、氟、甲基、异丙基、烯丙基、乙炔基、环丙基、三氟甲基、三氘甲基、甲氧基、三氟甲氧基、三氘甲氧基、氨基或二甲基氨基；
    每个R 12、R 13、R 14、R 15各自独立的选自氢、氘、卤素、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22、-C 0-4-C(O)OR 22、-C 0-4-C(O)R 23、-C 0-4-O-C(O)R 23、-C 0-4-NR 24R 25、-C 0-4-C(O)NR 24R 25或-C 0-4-N(R 24)-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22、-C 0-4-C(O)OR 22、-C 0-4-C(O)R 23、-C 0-4-O-C(O)R 23、-C 0-4-NR 24R 25、-C 0-4-C(O)NR 24R 25或-C 0-4-N(R 24)-C(O)R 23的取代基所取代；
    每个R 16各自独立的选自氢、氘、C 1-4烷基、C 3-6环烷基C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22、-C 0-4-C(O)OR 22、-C 0-4-C(O)R 23、-C 0-4-O-C(O)R 23、-C 0-4-NR 24R 25、-C 0-4-C(O)NR 24R 25或-C 0-4-N(R 24)-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22、-C 0-4-C(O)OR 22、-C 0-4-C(O)R 23、-C 0-4-O-C(O)R 23、-C 0-4-NR 24R 25、-C 0-4-C(O)NR 24R 25或-C 0-4-N(R 24)-C(O)R 23的取代基所取代；
    每个R 17、R 18各自独立的选自氢、氘、氟、氯、氰基、叠氮基、甲基、乙烯基、乙炔基、环丙基、羟基、甲氧基、乙氧酰基或乙酰氧基，上述基团任选进一步被一个或多个选自氘、氟、氰基、甲基、异丙基、乙烯基、乙炔基、环丙基、羟基或甲氧基的取代基所取代；
    R 19、R 20、R 21、R 22、R 23、R 24、R 25、r如权利要求1所述。
  7. 根据权利要求6所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，选自式(Ⅱa)化合物或式(Ⅱb)化合物：
    Figure PCTCN2018123908-appb-100002
    其中，X 1、X 2各自独立的选自N或CH；X 5、X 6各自独立的选自C(R 10)或N；Y 1选自-O-、-C(R 12R 13)-、-(C＝CR 14R 15)-或-N(R 16)-；Z选自-O-或-NH-；
    R 1选自氢、氘、卤素、羟基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、-NR 19R 20或-C 0-8-S(O) rR 21，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21或-C 0-4-O-R 22的取代基所取代；
    R 2选自氢、氘、卤素、氰基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22或-C 0-8-NR 24R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22或-C 0-4-NR 24R 25、的取代基所取代；
    R 3、R 4各自独立的选自氢、氘、氰基、甲基、乙烯基或乙炔基，上述基团任选进一步被一个或多个选自氘、氟或环丙基的取代基所取代；
    R 5、R 6各自独立的选自氢、氘、甲基、环丙基、三氟甲基或三氘甲基；
    每个R 12、R 13、R 14、R 15各自独立的选自氢、氘、卤素、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-O-R 22、-C 0-4-C(O)OR 22、-C 0-4-NR 24R 25、-C 0-4-C(O)NR 24R 25或-C 0-4-N(R 24)-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、C 1-4烷基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-O-R 22或-C 0-4-NR 24R 25的取代基所取代；
    每个R 16各自独立的选自氢、氘、C 1-4烷基、C 3-6环烷基C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基或-C 0-4-C(O)R 23，上述基团任选进一步被一个或多个选 自氘、卤素、氰基、C 1-4烷基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-O-R 22、-C 0-4-C(O)OR 22或-C 0-4-NR 24R 25、的取代基所取代；
    每个R 17、R 18各自独立的选自氢、氘、氟、氯、氰基、叠氮基、甲基、乙烯基、乙炔基、环丙基、羟基、甲氧基、乙氧酰基或乙酰氧基，上述基团任选进一步被一个或多个选自氘、氟、氰基、甲基、异丙基、乙烯基、乙炔基、环丙基、羟基或甲氧基的取代基所取代；
    R 7、R 8、R 9、R 10、R 19、R 20、R 21、R 22、R 23、R 24、R 25、r如权利要求1所述。
  8. 根据权利要求7所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，X 5选自C(R 10)或N；X 6选自CH；
    R 10各自独立的选自氢、氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-O-R 22、-C 0-4-O-C(O)R 23、-C 0-4-NR 24R 25或-C 0-4-N(R 24)-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-O-R 22或-C 0-4-NR 24R 25的取代基所取代；
    R 22、R 23、R 24、R 25如权利要求1所述。
  9. 根据权利要求7或8所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，选自式(Ⅲa)化合物：
    Figure PCTCN2018123908-appb-100003
    其中，X 1、X 2各自独立的选自N或CH；X 5选自C(R 10)或N；Y 1选自-O-或-C(R 12R 13)-；
    R 1选自C 3-8环烷基、C 3-8环烷氧基、3-8元杂环基、3-8元杂环氧基、C 5-8芳基、C 5-8芳氧基、5-8元杂芳基、5-8元杂芳氧基或-NR 19R 20，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、乙烯基、乙炔基、三氟甲基、二氟甲基、环丙基、吗啉基、氧杂环丁基、四氢呋喃基、哌嗪基、哌啶基、苯基、吡啶基、羟基或甲氧基的取代基所取代；
    R 2选自氢、氘、氟、氯、氰基、甲基、乙基、丙基、乙烯基、乙炔基、环丙基、吗啉基、氧杂环丁基、四氢呋喃基、哌嗪基、哌啶基、苯基、吡啶基、羟基、甲氧基、氨基、甲氨基或二甲氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、丙基、乙烯基、三氟甲基、环丙基、吗啉基、氧杂环丁基、四氢呋喃基、哌嗪基、哌啶基、苯基、吡啶基、羟基或甲氧基的取代基所取代；
    R 3选自氢、氘、氰基、甲基、乙烯基或乙炔基，上述基团任选进一步被一个或多个选自氘、氟或环丙基的取代基所取代；
    R 10选自氢、氘、氟、氯、氰基、甲基、乙基、丙基、乙烯基、乙炔基、环丙基、吗啉基、氧杂环丁基、四氢呋喃基、哌嗪基、哌啶基、苯基、吡啶基、羟基、甲氧基、氨基、甲氨基或二甲氨基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、甲基、乙基、丙基、乙烯基、三氟甲基、环丙基、吗啉基、氧杂环丁基、四氢呋喃基、哌嗪基、哌啶基、苯基、吡啶基、羟基或甲氧基的取代基所取代；
    R 12、R 13各自独立的选自氢、氘、氟、氯、甲基、乙烯基、环丙基、羟基、三氟甲基或环丙甲基；
    R 17、R 18各自独立的选自氢、氘、氟、氯、氰基、叠氮基、甲基、乙烯基、乙炔基、环丙基、羟基、甲氧基、三氟甲基、三氘甲基、三氟甲氧基、三氘甲氧基、环丙甲基、甲氧甲基、乙氧酰基或乙酰氧基；
    R 19、R 20各自独立的选自氢、氘、C 1-4烷基、C 3-10环烷基C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-10环烷基、C 4-10环烯基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、羟基、乙酰基或-C(O)NH 2，或者，R 19、R 20和其直接相连的氮原子一起形成4-10元杂环基，上述基团任选进一步被一个或多个选自氘、氟、氯、氰基、C 1-4烷基、乙烯基、三氟甲基、环丙基、环戊基、吗啉基、氧杂环丁基、四氢呋喃基、哌嗪基、哌啶基、苯基、吡啶基、羟基或甲氧基的取代基所取代。
  10. 根据权利要求6-9任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，选自如下化合物：
    Figure PCTCN2018123908-appb-100004
    Figure PCTCN2018123908-appb-100005
    Figure PCTCN2018123908-appb-100006
    Figure PCTCN2018123908-appb-100007
    Figure PCTCN2018123908-appb-100008
    Figure PCTCN2018123908-appb-100009
  11. 根据权利要求1-5任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，选自式(Ⅱc)化合物：
    Figure PCTCN2018123908-appb-100010
    其中，X 5、X 6中一个选自C(R 10)，另一个选自O或S；
    R 1选自氢、氘、卤素、羟基、C 1-10烷基、C 1-10烷氧基、C 3-10环烷基、C 3-10环烷氧基、3-10元杂环基、3-10元杂环氧基、C 5-10芳基、C 5-10芳氧基、5-10元杂芳基、5-10元杂芳氧基、-NR 19R 20或-C 0-8-S(O) rR 21，上述基团任选进一步被一个或多个选自氘、卤素、氰基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21或-C 0-4-O-R 22的取代基所取代；
    R 2选自氢、氘、卤素、氰基、C 1-10烷基、C 2-10链烯基、C 2-10链炔基、C 3-10环烷基、3-10元杂环基、C 5-10芳基、5-10元杂芳基、-C 0-8-S(O) rR 21、-C 0-8-O-R 22或-C 0-8-NR 24R 25，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4 链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22或-C 0-4-NR 24R 25、的取代基所取代；
    R 3、R 4各自独立的选自氢、氘、氟、氰基、甲基、乙烯基或乙炔基，上述基团任选进一步被一个或多个选自氘、卤素或环丙基的取代基所取代；
    R 5、R 6各自独立的选自氢、氘、氟、甲基、异丙基、烯丙基、乙炔基、环丙基、三氟甲基、三氘甲基、甲氧基、三氟甲氧基、三氘甲氧基、氨基或二甲基氨基；
    每个R 10各自独立的选自氢、氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22、-C 0-4-C(O)OR 22、-C 0-4-C(O)R 23、-C 0-4-O-C(O)R 23、-C 0-4-NR 24R 25、-C 0-4-C(O)NR 24R 25或-C 0-4-N(R 24)-C(O)R 23，上述基团任选进一步被一个或多个选自氘、卤素、氰基、硝基、叠氮基、C 1-4烷基、C 2-4链烯基、C 2-4链炔基、卤取代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 5-8芳基、5-8元杂芳基、-C 0-4-S(O) rR 21、-C 0-4-O-R 22、-C 0-4-C(O)OR 22、-C 0-4-C(O)R 23、-C 0-4-O-C(O)R 23、-C 0-4-NR 24R 25、-C 0-4-C(O)NR 24R 25或-C 0-4-N(R 24)-C(O)R 23的取代基所取代；
    每个R 17、R 18各自独立的选自氢、氘、氟、氯、氰基、叠氮基、甲基、乙烯基、乙炔基、环丙基、羟基、甲氧基或乙酰氧基，上述基团任选进一步被一个或多个选自氘、氟、氰基、甲基、异丙基、乙烯基、乙炔基、环丙基、羟基或甲氧基的取代基所取代；
    R 19、R 20、R 21、R 22、R 23、R 24、R 25、r如权利要求1所述。
  12. 根据权利要求11所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，X 5、X 6中一个选自C(R 10)，另一个选自O；
    R 3、R 4各自独立的选自氢或氘；
    R 5、R 6各自独立的选自氢、氘、甲基或环丙基；
    每个R 10各自独立的选自氢、氘、卤素、C 1-4烷基、卤取代C 1-4烷基、氘取代C 1-4烷基；
    每个R 17、R 18各自独立的选自氢、氘、氟、甲基或羟基，上述基团任选进一步被一个或多个选自氘或氟的取代基所取代。
  13. 根据权利要求11-12任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，其特征在于，选自如下化合物：
    Figure PCTCN2018123908-appb-100011
  14. 权利要求1-13任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐的制备方法，其特征在于，包括如下步骤：
    Figure PCTCN2018123908-appb-100012
    其中，Pg为氢、羟基保护基、巯基保护基或氨基保护基，优选为氢、叔丁氧羰基或对甲苯磺酰基；X 1、X 2、X 3、X 4、X 5、X 6、Y 1、Y 2、Y 3、Z、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9如权利要求1所述。
  15. 一种药物组合物，其包括权利要求1-13任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐及可药用的载体。
  16. 权利要求1-13任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，或权利要求15所述的药物组合物在制备治疗至少部分由CD73介导的癌症或肿瘤、免疫相关疾病及紊乱、代谢性疾病药物中的应用。
  17. 根据权利要求16所述的应用，其特征在于，所述的癌症或肿瘤选自***癌、结肠癌、直肠癌、胰腺癌、胃癌、子宫内膜癌、***、脑癌、肝癌、膀胱癌、卵巢癌、睾丸癌、头癌、颈癌、皮肤癌(包括黑色素瘤和基底细胞癌)、间皮内衬癌、白血细胞癌(包括淋巴瘤和白血病)、食管癌、乳腺癌，肌肉癌、***癌、肺癌(包括小细胞肺癌和非小细胞癌)、肾上腺癌、甲状腺癌、肾脏癌、骨癌、脑瘤、胶质母细胞瘤、间皮瘤、肾细胞癌、肉瘤(包括卡波西氏肉瘤)、绒毛膜癌、表皮基底细胞癌、睾丸***瘤；
    优选的，在制备治疗黑色素瘤、结肠癌、胰腺癌、乳腺癌、***癌、肺癌、白血病、脑瘤、淋巴瘤、卵巢癌和卡波西氏肉瘤。
  18. 根据权利要求16所述的应用，其特征在于，所述的免疫相关疾病及紊乱选自类风湿性关节炎、肾衰竭、红斑狼疮、哮喘、牛皮癣、溃疡性结肠炎、胰腺炎、过敏、纤维化、贫血纤维肌痛症、阿尔茨海默病、充血性心力衰竭、中风、主动脉瓣狭窄、动脉硬化、骨质疏松症、帕金森病、感染、克隆氏病、溃疡性结肠炎、过敏性接触性皮炎和湿疹、***性硬化症和多发性硬化症。
  19. 根据权利要求1-13任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，或根据权利要求15所述的药物组合物，其用作治疗至少部分由CD73介导的癌症或肿瘤、自身免疫性疾病及紊乱、代谢性疾病的药物。
  20. 根据权利要求1-13任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，或根据权利要求15所述的药物组合物，其用作治疗***癌、结肠癌、直肠癌、胰腺癌、胃癌、子宫内膜癌、***、脑癌、肝癌、膀胱癌、卵巢癌、睾丸癌、头癌、颈癌、皮肤癌(包括黑色素瘤和基底细胞癌)、间皮内衬癌、白血细胞癌(包括淋巴瘤和白血病)、食管癌、乳腺癌、肌肉癌、***癌、小细胞肺癌(肺癌和非小细胞癌)、肾上腺癌、甲状腺癌、肾脏癌、骨癌、脑瘤、胶质母细胞瘤、间皮瘤、肾细胞癌、肉瘤(包括卡波西氏肉瘤)、绒毛膜癌、表皮基底细胞癌、睾丸***瘤、类风湿性关节炎、肾衰竭、红斑狼疮、哮喘、牛皮癣、溃疡性结肠炎、胰腺炎、过敏、纤维化、贫血纤维肌痛症、阿尔茨海默病、充血性心力衰竭、中风、主动脉瓣狭窄、动脉硬化、骨质疏松症、帕金森病、感染、克隆氏病、溃疡性结肠炎、过敏性接触性皮炎和湿疹、***性硬化症和多发性硬化症的药物。
  21. 一种治疗至少部分由CD73介导的癌症或肿瘤、免疫相关疾病及紊乱、代谢性疾病的方法，其特征在于，包括对患者施用权利要求1-13任一所述的式(I)化合物、其立体异构体、前药或其药学上可接受盐，或权利要求15所述的药物组合物。
  22. 根据权利要求21所述的方法，其特征在于，所述的癌症或肿瘤选自***癌、结肠癌、直肠癌、胰腺癌、胃癌、子宫内膜癌、***、脑癌、肝癌、膀胱癌、卵巢癌、睾 丸癌、头癌、颈癌、皮肤癌(包括黑色素瘤和基底细胞癌)、间皮内衬癌、白血细胞癌(包括淋巴瘤和白血病)、食管癌、乳腺癌、肌肉癌、***癌、小细胞肺癌(肺癌和非小细胞癌)、肾上腺癌、甲状腺癌、肾脏癌、骨癌、脑瘤、胶质母细胞瘤、间皮瘤、肾细胞癌、肉瘤(包括卡波西氏肉瘤)、绒毛膜癌、表皮基底细胞癌、睾丸***瘤；所述的免疫相关疾病和代谢性疾病选自类风湿性关节炎、肾衰竭、红斑狼疮、哮喘、牛皮癣、溃疡性结肠炎、胰腺炎、过敏、纤维化、贫血纤维肌痛症、阿尔茨海默病、充血性心力衰竭、中风、主动脉瓣狭窄、动脉硬化、骨质疏松症、帕金森病、感染、克隆氏病、溃疡性结肠炎、过敏性接触性皮炎和湿疹、***性硬化症和多发性硬化症。
PCT/CN2018/123908 2017-12-29 2018-12-26 一种具有cd73抑制活性的膦酸衍生物、其制备方法和应用 WO2019129059A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201880057756.6A CN111094317B (zh) 2017-12-29 2018-12-26 一种具有cd73抑制活性的膦酸衍生物、其制备方法和应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201711469577 2017-12-29
CN201711469577.7 2017-12-29

Publications (1)

Publication Number Publication Date
WO2019129059A1 true WO2019129059A1 (zh) 2019-07-04

Family

ID=67066638

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/123908 WO2019129059A1 (zh) 2017-12-29 2018-12-26 一种具有cd73抑制活性的膦酸衍生物、其制备方法和应用

Country Status (2)

Country Link
CN (1) CN111094317B (zh)
WO (1) WO2019129059A1 (zh)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020211672A1 (en) * 2019-04-16 2020-10-22 Bioardis Llc Cd73 inhibitors
WO2020221209A1 (zh) * 2019-04-28 2020-11-05 上海和誉生物医药科技有限公司 一种cd73抑制剂，其制备方法和应用
US10870657B2 (en) 2015-12-22 2020-12-22 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US10933054B2 (en) 2017-06-21 2021-03-02 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
WO2021040356A1 (en) * 2019-08-23 2021-03-04 Kainos Medicine, Inc. C-nucleosides, c-nucleotides and their analogs, equivalents and prodrugs thereof for ectonucleotidase inhibition
CN115667190A (zh) * 2020-06-17 2023-01-31 贝达药业股份有限公司 双环类化合物及其应用
WO2023102472A1 (en) * 2021-12-01 2023-06-08 The Scripps Research Institute Antiviral prodrugs and formulations thereof
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
WO2023201267A1 (en) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Combination therapy for treating trop-2 expressing cancers

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115960106B (zh) * 2022-11-03 2024-03-26 中国药科大学 线粒体rna聚合酶抑制剂及其衍生物、药物组合物和医药用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9029346B1 (en) * 2013-12-13 2015-05-12 The Johns Hopkins University Irreversible inhibitors of DNA polymerase beta
WO2017120508A1 (en) * 2016-01-08 2017-07-13 Arcus Biosciences, Inc. Modulators of 5'-nucleotidase, ecto and the use thereof
WO2018067424A1 (en) * 2016-10-03 2018-04-12 Arcus Biosciences, Inc. Inhibitors of adenosine 5'-nucleotidase
WO2018208980A1 (en) * 2017-05-10 2018-11-15 Oric Pharmaceuticals, Inc. Cd73 inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9029346B1 (en) * 2013-12-13 2015-05-12 The Johns Hopkins University Irreversible inhibitors of DNA polymerase beta
WO2017120508A1 (en) * 2016-01-08 2017-07-13 Arcus Biosciences, Inc. Modulators of 5'-nucleotidase, ecto and the use thereof
WO2018067424A1 (en) * 2016-10-03 2018-04-12 Arcus Biosciences, Inc. Inhibitors of adenosine 5'-nucleotidase
WO2018208980A1 (en) * 2017-05-10 2018-11-15 Oric Pharmaceuticals, Inc. Cd73 inhibitors

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11560390B2 (en) 2015-12-22 2023-01-24 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US10870657B2 (en) 2015-12-22 2020-12-22 SHY Therapeutics LLC Compounds for the treatment of cancer and inflammatory disease
US10933054B2 (en) 2017-06-21 2021-03-02 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11541041B1 (en) 2017-06-21 2023-01-03 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, Rasopathies, and fibrotic disease
US10940139B2 (en) 2017-06-21 2021-03-09 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11000515B2 (en) 2017-06-21 2021-05-11 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11026930B1 (en) 2017-06-21 2021-06-08 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
US11213515B1 (en) 2017-06-21 2022-01-04 SHY Therapeutics LLC Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
WO2020211672A1 (en) * 2019-04-16 2020-10-22 Bioardis Llc Cd73 inhibitors
CN114286824A (zh) * 2019-04-16 2022-04-05 博奥阿迪斯生物科技公司 Cd73抑制剂
JP2022526147A (ja) * 2019-04-28 2022-05-23 アビスコ セラピューティクス カンパニー リミテッド Ｃｄ７３阻害剤、その製造方法と応用
WO2020221209A1 (zh) * 2019-04-28 2020-11-05 上海和誉生物医药科技有限公司 一种cd73抑制剂，其制备方法和应用
AU2020264642B2 (en) * 2019-04-28 2023-05-25 Abbisko Therapeutics Co., Ltd. CD73 inhibitor, preparation method therefor and application thereof
EP4272836A3 (en) * 2019-04-28 2023-11-22 Abbisko Therapeutics Co., Ltd. Cd73 inhibitor, preparation method therefor and application thereof
WO2021040356A1 (en) * 2019-08-23 2021-03-04 Kainos Medicine, Inc. C-nucleosides, c-nucleotides and their analogs, equivalents and prodrugs thereof for ectonucleotidase inhibition
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
CN115667190A (zh) * 2020-06-17 2023-01-31 贝达药业股份有限公司 双环类化合物及其应用
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
WO2023102472A1 (en) * 2021-12-01 2023-06-08 The Scripps Research Institute Antiviral prodrugs and formulations thereof
WO2023201267A1 (en) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Combination therapy for treating trop-2 expressing cancers

Also Published As

Publication number Publication date
CN111094317B (zh) 2023-03-31
CN111094317A (zh) 2020-05-01

Similar Documents

Publication Publication Date Title
WO2019129059A1 (zh) 一种具有cd73抑制活性的膦酸衍生物、其制备方法和应用
JP5913631B2 (ja) Ｐａｒｐ阻害剤としての縮合四環式または縮合五環式ピリドフタラジノン
JP6034877B2 (ja) Ｐａｒｐ阻害剤としての縮合四環式または縮合五環式ジヒドロジアゼピノカルバゾロン
JP5579864B2 (ja) Ｎ−９−置換プリン化合物、組成物及び使用の方法
BR112014007912B1 (pt) Derivados de pirazoloquinolina
TW200940542A (en) Pyrimidyl cyclopentanes as AKT protein kinase inhibitors
CN102858754A (zh) Raf抑制剂化合物及其使用方法
US9156853B2 (en) AKT inhibitor compounds for treatment of cancer
KR20130029756A (ko) Ｎ-7 치환된 퓨린 및 피라졸로피리미딘 화합물, 조성물 및 사용 방법
JP2013503193A (ja) Ｒａｆ阻害剤化合物およびその使用方法
UA116534C2 (uk) Піразолопіримідинілові інгібітори убіквітинактивуючого ферменту
CN117730075A (zh) 一种吡唑衍生物，其制备方法和在药学上的应用
JP2023145547A (ja) Ｃｄ７３阻害剤、その製造方法と応用
WO2019120276A1 (zh) 嘧啶酮化合物及其应用
CN111094314B (zh) 含有葡糖苷酸衍生物jak抑制剂的前药及其制备方法和应用
JP2021504332A (ja) ピラゾロピリジノン化合物
WO2020259703A1 (zh) 一种吡唑酮并嘧啶类化合物、其制备方法及应用
JP2013503189A (ja) Ｒａｆ阻害化合物およびその使用方法
TW202136269A (zh) 稠合二環類衍生物、其製備方法及其在醫藥上的應用
RU2787428C1 (ru) Ингибитор cd73, метод его получения и его применение
TWI633107B (zh) 作為ｐａｒｐ抑制劑的稠合四或五環二氫二氮呯并咔唑酮
TWI794576B (zh) 一類含氟取代的苯并噻吩類化合物及其藥物組合物及應用
JP6541635B2 (ja) Ｐａｒｐ阻害剤としての縮合四環式または縮合五環式ジヒドロジアゼピノカルバゾロン
WO2023030335A1 (zh) 作为tyk2/jak1假激酶结构域抑制剂的化合物及合成和使用方法
M Perron-Sierra et al. Synthesis of cis-fused pyran indolocarbazole derivatives that inhibit FLT3 kinase and the DNA damage kinase, Checkpoint kinase 1

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18897112

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 30/09/2020)

122 Ep: pct application non-entry in european phase

Ref document number: 18897112

Country of ref document: EP

Kind code of ref document: A1