WO2019129059A1 - Dérivé d'acide phosphonique présentant une activité inhibitrice de cd73, procédé de préparation et utilisation associés - Google Patents

Dérivé d'acide phosphonique présentant une activité inhibitrice de cd73, procédé de préparation et utilisation associés Download PDF

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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
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group
alkyl
cancer
hydrazine
cycloalkyl
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PCT/CN2018/123908
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Chinese (zh)
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邓海兵
赵保卫
应海燕
喻红平
陈椎
徐耀昌
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上海和誉生物医药科技有限公司
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Priority to CN201880057756.6A priority Critical patent/CN111094317B/zh
Publication of WO2019129059A1 publication Critical patent/WO2019129059A1/fr

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    • 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.

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Abstract

La présente invention concerne un dérivé d'acide phosphonique ayant une activité inhibitrice de CD73 et une structure de formule (I), ainsi qu'un procédé de préparation et une utilisation associés. La série de composés selon la présente invention peut être largement utilisée dans la préparation de médicaments pour le traitement de cancers ou de tumeurs, de maladies auto-immunes, de troubles et de maladies métaboliques à médiation au moins partiellement par CD73, en particulier des médicaments pour traiter les mélanomes, le cancer du côlon, le cancer du pancréas, le cancer du sein, le cancer de la prostate, le cancer du poumon, la leucémie, les tumeurs cérébrales, le lymphome, le cancer de l'ovaire et le sarcome de Kaposi, et sont supposés être développés en une nouvelle génération de médicaments inhibiteurs de CD73. (I)
PCT/CN2018/123908 2017-12-29 2018-12-26 Dérivé d'acide phosphonique présentant une activité inhibitrice de cd73, procédé de préparation et utilisation associés WO2019129059A1 (fr)

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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 (fr) * 2019-08-23 2021-03-04 Kainos Medicine, Inc. C-nucléosides, c-nucléotides et leurs analogues, équivalents et promédicaments de ceux-ci pour l'inhibition de l'ectonucléotidase
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 (fr) * 2021-12-01 2023-06-08 The Scripps Research Institute Promédicaments antiviraux et formulations correspondantes
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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 (fr) * 2019-04-16 2020-10-22 Bioardis Llc Inhibiteurs de cd73
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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 (fr) * 2019-04-28 2020-11-05 上海和誉生物医药科技有限公司 Inhibiteur de cd73, son procédé de préparation et son utilisation
AU2020264642B2 (en) * 2019-04-28 2023-05-25 Abbisko Therapeutics Co., Ltd. CD73 inhibitor, preparation method therefor and application thereof
EP4272836A3 (fr) * 2019-04-28 2023-11-22 Abbisko Therapeutics Co., Ltd. Inhibiteur de cd73, son procédé de préparation et son utilisation
WO2021040356A1 (fr) * 2019-08-23 2021-03-04 Kainos Medicine, Inc. C-nucléosides, c-nucléotides et leurs analogues, équivalents et promédicaments de ceux-ci pour l'inhibition de l'ectonucléotidase
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
US12030903B2 (en) 2021-02-17 2024-07-09 Gilead Sciences, Inc. Antiviral compounds
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
WO2023102472A1 (fr) * 2021-12-01 2023-06-08 The Scripps Research Institute Promédicaments antiviraux et formulations correspondantes
WO2023201267A1 (fr) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Polythérapie pour le traitement de cancers exprimant trop-2

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