WO2024008178A1 - Kras g12d inhibitor and application thereof in medicine - Google Patents

Kras g12d inhibitor and application thereof in medicine Download PDF

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Publication number
WO2024008178A1
WO2024008178A1 PCT/CN2023/106296 CN2023106296W WO2024008178A1 WO 2024008178 A1 WO2024008178 A1 WO 2024008178A1 CN 2023106296 W CN2023106296 W CN 2023106296W WO 2024008178 A1 WO2024008178 A1 WO 2024008178A1
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Prior art keywords
compound
cycloalkyl
alkyl
alkylene
halogen
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PCT/CN2023/106296
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French (fr)
Chinese (zh)
Inventor
吴颢
路渊
徐人奇
杨晓峰
邹正耀
夏洪峰
何将旗
李波燕
张洪波
赵志昌
田凯
高锜
杨翔
匡翠文
周全
兰宏
王家炳
丁列明
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贝达药业股份有限公司
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Publication of WO2024008178A1 publication Critical patent/WO2024008178A1/en

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to the field of medical technology, specifically to the compound of formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutical salt, its preparation method, pharmaceutical composition containing the compound, and its use as Uses of drugs to treat cancer.
  • RAS is the gene with the highest mutation rate in human tumors. About 20-30% of all tumors have RAS mutations, about 98% of pancreatic cancer, 52% of colon cancer, and 43% of multiple myeloma. And RAS gene mutations are present in 32% of lung adenocarcinomas.
  • the most common mutation mode of RAS is point mutation, which often occurs in codons 12, 13, and 61. Among them, mutations in codon 12 are the most common, such as G12C, G12D or G12V.
  • KRAS G12C inhibitors AMG510 (WO2018217651A1) and MRTX849 (WO2019099524A1) have entered the late clinical stage; while MIRATI is leading the research and development of G12D inhibitor (WO2021041671A1).
  • KRAS has always been a target of concern for drug developers. Although progress has been made in this field, there is still a need for improved KRAS G12D mutant protein inhibitors to meet additional clinical needs.
  • the technical problem to be solved by the present invention is to overcome the problem of lack of KRAS G12D mutant protein inhibitors in the prior art, and provide a compound represented by the general formula (I) and its application.
  • the general formula (I) provided by the present invention The compound shown in I) has a good inhibitory effect on KRAS G12D mutant protein.
  • the present invention provides a compound represented by general formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt:
  • X is selected from bond, NH, O or S;
  • L is selected from bond, -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene- , the -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene-optional Further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
  • the ring A is selected from C 5-14 cycloalkyl, 5-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, and the C 5-14 cycloalkyl or 5-14
  • the membered heterocyclyl group is selected from a single ring, a condensed ring, a spiro ring or a bridged ring, and the C 5-14 cycloalkyl group, 5-14 membered heterocyclyl group, C 6-18 aryl group or 5-18 membered heteroaryl group
  • Selected from in is a double bond, Selected from Z configuration or E configuration;
  • R 2 is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, and the C 3-14 cycloalkyl, 3-14 membered heterocyclyl Ring group, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a ;
  • R 3 or R 4 are independently selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1 -6 haloalkyl, C 1-6 haloalkoxy, hydroxyl or hydroxyalkyl, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, haloalkyl or The hydroxyalkyl group is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxy;
  • R 5 is selected from H, halogen, -C 0-3 alkylenecyano, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl;
  • R 6 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, the C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocycle group, C 6-18 aryl or 5-18 membered heteroaryl, optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy replaced;
  • n is selected from 0, 1, 2, 3 or 4.
  • X in formula (I) is O.
  • L in formula (I) is selected from -C 1-3 alkylene- or -C 3-14 cycloalkyl-C 0-3 alkylene-.
  • Ring A in formula (I) is selected from C 5-14 cycloalkyl or 5-14 membered heterocyclyl.
  • the 5-14 membered heterocyclyl group in formula (I) is a fused ring.
  • the fused ring in formula (I) is selected from
  • R 6 in formula (I) is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogens , hydroxyl, cyano, amino, nitro or C 1-6 alkyl substituted.
  • R 2 in formula (I) is selected from C 6-18 aryl or 5-18 membered heteroaryl, and the C 6-18 aryl or 5-18 membered heteroaryl is optionally further Substituted by one or more R a , R a independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 Alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
  • R in formula (I) is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkene base, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
  • R in formula (I) is selected from
  • R 3 in formula (I) is selected from H, hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy or C 3-14 cycloalkyl-O-.
  • R3 in formula (I) is selected from H, hydroxyl, methyl,
  • R 4 in formula (I) is selected from H, halogen, C 1-6 alkoxy or C 1-6 haloalkoxy, preferably F.
  • R5 in formula (I) is H.
  • formula (I) is selected from (IA) or (IB):
  • formula (I) is selected from (IA-1) and (IB-1):
  • the compound of formula (I) is selected from (IA-1) and (IB-1), wherein:
  • R 2 is selected from C 6-18 aryl or 5-18 membered heteroaryl, and the C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a ;
  • the R a is independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl , -C 0-3 alkylene -C 3-14 cycloalkyl, -C 0-3 alkylene - (3-14 membered heterocyclyl), -C 0-3 alkylene -C 6-18 Aryl or -C 0-3 alkylene-(5-18 membered heteroaryl);
  • R 3 or R 4 are independently selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1 -6 haloalkyl, C 1-6 haloalkoxy, hydroxyl or hydroxyalkyl, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, haloalkyl or The hydroxyalkyl group is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxy;
  • X is selected from bond, NH, O or S;
  • L is selected from bond or -C 1-3 alkylene-
  • R 6 is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl are optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro or Substituted with C 1-6 alkyl.
  • the present invention provides a compound represented by general formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt:
  • X is selected from bond, NH, O or S;
  • L is selected from bond, -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene- , the -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene-optional Further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
  • the ring A is selected from C 5-14 cycloalkyl, 5-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, and the C 5-14 cycloalkyl or 5-14
  • the membered heterocyclyl group is selected from a single ring, a condensed ring, a spiro ring or a bridged ring, and the C 5-14 cycloalkyl group, 5-14 membered heterocyclyl group, C 6-18 aryl group or 5-18 membered heteroaryl group
  • Selected from in is a double bond, Selected from Z configuration or E configuration;
  • R 2 is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, and the C 3-14 cycloalkyl, 3-14 membered heterocyclyl Ring group, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a ;
  • R 3 or R 4 are independently selected from H, halogen, cyano, amino, -NHR a , -N(R a ) 2 , nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl or hydroxyalkyl, the C 1-6 alkyl, C 1-6 alkoxy , C 3 -14 Cycloalkyl-O-, haloalkyl or hydroxyalkyl is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or substituted by hydroxyl;
  • R 5 is selected from H, halogen, -C 0-3 alkylenecyano, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl;
  • R 6 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, the C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18
  • the heteroaryl group is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy;
  • n is selected from 0, 1, 2, 3 or 4.
  • X in formula (I) is O.
  • L in formula (I) is selected from -C 1-3 alkylene- or -C 3-14 cycloalkyl-C 0-3 alkylene-.
  • Ring A in formula (I) is selected from C 5-14 cycloalkyl or 5-14 membered heterocyclyl.
  • the 5-14 membered heterocyclyl group in formula (I) is a fused ring.
  • the fused ring in formula (I) is selected from
  • R 6 in formula (I) is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogens , hydroxyl, cyano, amino, nitro or C 1-6 alkyl substituted.
  • R 2 in formula (I) is selected from C 6-18 aryl or 5-18 membered heteroaryl, and the C 6-18 aryl or 5-18 membered heteroaryl is optionally further Substituted by one or more R a , R a independently selected from H, hydroxyl, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 -6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
  • R in formula (I) is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
  • R in formula (I) is selected from
  • R 3 in formula (I) is selected from H, hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 3-14 Cycloalkyl-O-.
  • R in formula (I) is selected from H, halogen, hydroxyl, methyl, methoxy,
  • R 4 in formula (I) is selected from H, halogen, C 1-6 alkoxy or C 1-6 haloalkoxy, preferably F.
  • R5 in formula (I) is H.
  • formula (I) is selected from (IA) or (IB):
  • formula (I) is selected from (IA-1) or (IB-1):
  • the compound of formula (I) is selected from (IA-1) and (IB-1), wherein:
  • R 2 is selected from C 6-18 aryl or 5-18 membered heteroaryl, and the C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a ;
  • the R a is independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl , -C 0-3 alkylene -C 3-14 cycloalkyl, -C 0-3 alkylene - (3-14 membered heterocyclyl), -C 0-3 alkylene -C 6-18 Aryl or -C 0-3 alkylene-(5-18 membered heteroaryl);
  • R 3 or R 4 are independently selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1 -6 haloalkyl, C 1-6 haloalkoxy, hydroxyl or hydroxyalkyl, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, haloalkyl or The hydroxyalkyl group is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxy;
  • X is selected from bond, NH, O or S;
  • L is selected from bond or -C 1-3 alkylene-
  • R 6 is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl are optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro or Substituted with C 1-6 alkyl.
  • formula (I) is selected from (IA-1-1) or (IB-1-1):
  • the R 2 is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl;
  • the R 4 is selected from hydrogen or halogen
  • the R 6 is selected from hydrogen or halogen
  • the R 7 is selected from alkyl, haloalkyl or cycloalkyl, preferably methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.
  • the present invention provides a compound represented by general formula (I), or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt:
  • X is selected from bond, NR a , O or S;
  • L is selected from bond, -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene- ;
  • the ring A is selected from C 5-14 cycloalkyl, 5-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 5-14 cycloalkyl, 5-14
  • the one-membered heterocyclyl group, C 6-18 aryl group or 5-18 membered heteroaryl group is optionally further substituted by one or more halogen, C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, cyano group, Amino, nitro, hydroxyl, replaced;
  • the two R 6 in can together form a C 3-8 cycloalkyl group or a 3-8 membered heterocyclyl group with the atoms to which they are connected.
  • the C 3-8 cycloalkyl group and 3-8 membered heterocyclyl group are optional ground is further replaced by one or more R a ;
  • R 2 is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 3-14 cycloalkyl, 3-14 membered heterocyclyl
  • the ring group, C 6-18 aryl group or 5-18 membered heteroaryl group is optionally further substituted by one or more R a ;
  • R 3 or R 4 are independently selected from H, halogen, cyano, amino, -NHR a , -N(R a ) 2 , nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy or hydroxyl; the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl
  • the base -O-, C 1-6 haloalkyl or C 1-6 haloalkoxy is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , cyano, amino, nitro or hydroxyl substituted;
  • R 5 is selected from H, halogen, -C 0-3 alkylenecyano, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl;
  • R 6 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18
  • the heteroaryl group is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy;
  • Each R b is independently H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl;
  • n is selected from 0, 1, 2, 3 or 4.
  • X in formula (I) is O.
  • L in formula (I) is selected from -C 1-3 alkylene- or -C 3-14 cycloalkyl-C 0-3 alkylene-.
  • Ring A in formula (I) is selected from C 5-14 cycloalkyl or 5-14 membered heterocyclyl.
  • the 5-14 membered heterocyclyl group in formula (I) is a fused ring.
  • the fused ring in formula (I) is selected from
  • R 6 in formula (I) is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogens , hydroxyl, cyano, amino, nitro or C 1-6 alkyl substituted.
  • formula (I) Selected from in Indicates Z configuration or E configuration.
  • R 2 in formula (I) is selected from C 6-18 aryl or 5-18 membered heteroaryl; the C 6-18 aryl or 5-18 membered heteroaryl is optionally further Substituted by one or more R a , R a independently selected from H, hydroxyl, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 -6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
  • R in formula (I) is selected from Among them, the
  • Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
  • R in formula (I) is selected from
  • R 3 in formula (I) is selected from H, hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 3-14 Cycloalkyl-O-.
  • R in formula (I) is selected from H, halogen, hydroxyl, methyl, methoxy,
  • R 4 in formula (I) is selected from H, halogen, C 1-6 alkoxy or C 1-6 haloalkoxy; preferably F.
  • R5 in formula (I) is H.
  • formula (I) is selected from (IA) or (IB):
  • formula (I) is selected from (IA-1) or (IB-1):
  • formula (I) is selected from (IA-1') or (IB-1'):
  • the compound of formula (I) is selected from (IA-1), (IB-1), (IA-1') or (IB-1'), wherein:
  • the R 2 is selected from C 6-18 aryl or 5-18 membered heteroaryl; wherein, the C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a Substituted, the R a is independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 -6 alkynyl, -C 0-3 alkylene -C 3-14 cycloalkyl, -C 0-3 alkylene - (3-14 membered heterocyclyl), -C 0-3 alkylene - C 6-18 aryl or -C 0-3 alkylene-(5-18 membered heteroaryl);
  • the R 3 or R 4 are independently selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy or hydroxyl; wherein, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1- 6 haloalkyl or C 1-6 haloalkoxy is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl ;
  • the X is selected from bond, NH, O or S;
  • the L is selected from bond or -C 1-3 alkylene-;
  • the R 6 is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, so The C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro substituted by C 1-6 alkyl group.
  • formula (I) is selected from (IA-1-1) or (IB-1-1):
  • the R 2 is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl;
  • the R 4 is selected from hydrogen or halogen
  • the R 6 is selected from hydrogen or halogen
  • the R 7 is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-14 cycloalkyl; preferably it is methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.
  • formula (I) is selected from (IA-1'-1) or (IB-1'-1):
  • the R 2 is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl;
  • the R 4 is selected from hydrogen or halogen
  • the R 6 is selected from hydrogen or halogen
  • the R 7 is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-14 cycloalkyl, preferably methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.
  • the present invention provides a compound represented by general formula (I), or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt:
  • X is selected from bond, NR a , O or S;
  • L is selected from bond, -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene- ;
  • the ring A is selected from C 5-14 cycloalkyl, 5-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 5-14 cycloalkyl, 5-14
  • the one-membered heterocyclyl group, C 6-18 aryl group or 5-18 membered heteroaryl group is optionally further substituted by one or more halogen, C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, cyano group, Amino, nitro, hydroxyl, replaced;
  • the two R 6 in can together form a C 3-8 cycloalkyl group or a 3-8 membered heterocyclyl group with the atoms to which they are connected.
  • the C 3-8 cycloalkyl group and 3-8 membered heterocyclyl group are optional ground is further replaced by one or more R a ;
  • R 2 is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 3-14 cycloalkyl, 3-14 membered heterocyclyl
  • the ring group, C 6-18 aryl group or 5-18 membered heteroaryl group is optionally further substituted by one or more R a ;
  • R 3 is independently selected from C 1-6 alkoxy, C 3-14 cycloalkyl-O- or C 1-6 haloalkoxy; the C 1-6 alkoxy, C 3-14 cycloalkyl -O- or C 1-6 haloalkoxy is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, cyano, amino, nitro or substituted by hydroxyl;
  • R 4 is independently selected from H, halogen, cyano, amino, -NHR a , -N(R a ) 2 , nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 ring Alkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy or hydroxyl; the C 1-6 alkyl, C 1-6 alkoxy, C 3- 14 cycloalkyl-O-, C 1-6 haloalkyl or C 1-6 haloalkoxy is optionally further substituted by one or more halogens, C 1-6 alkyl, C 1-6 alkoxy, C 1- 6 substituted by haloalkyl, cyano, amino, nitro or hydroxyl;
  • R 5 is selected from H, halogen, -C 0-3 alkylenecyano, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl;
  • R 6 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18
  • the heteroaryl group is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy;
  • n is selected from 0, 1, 2, 3 or 4.
  • each R b in formula (I) is independently H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl.
  • X in formula (I) is selected from bonds, NH, O or S;
  • the ring A is selected from C 5-14 cycloalkyl, 5-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, and the C 5-14 cycloalkyl or 5-14
  • the membered heterocyclyl group is selected from a single ring, a condensed ring, a spiro ring or a bridged ring, and the C 5-14 cycloalkyl group, 5-14 membered heterocyclyl group, C 6-18 aryl group or 5-18 membered heteroaryl group
  • Selected from in is a double bond, Selected from Z configuration or E configuration;
  • R 3 is independently selected from C 1-6 alkoxy, C 3-14 cycloalkyl-O- or C 1-6 haloalkoxy, said C 1-6 alkoxy or C 3-14 cycloalkyl- O- is further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
  • R 4 is selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl or hydroxyalkyl, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, haloalkyl or hydroxyalkyl optionally further Substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
  • Each R b is independently H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, or C 1-6 haloalkyl.
  • X in formula (I) is O.
  • L in formula (I) is selected from -C 1-3 alkylene- or -C 3-14 cycloalkyl-C 0-3 alkylene-.
  • Ring A in formula (I) is selected from C 5-14 cycloalkyl or 5-14 membered heterocyclyl.
  • the 5-14 membered heterocyclyl group in formula (I) is a fused ring.
  • the fused ring described in formula (I) is selected from
  • R 6 in formula (I) is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl Or 5-18 membered heteroaryl; the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more Substituted by halogen, hydroxyl, cyano, amino, nitro or C 1-6 alkyl.
  • Formula (I) Selected from described may optionally be further substituted by one or more halogens, C 1-6 alkyl or replaced.
  • Formula (I) Selected from in Indicates Z configuration or E configuration.
  • R 2 in formula (I) is selected from C 6-18 aryl or 5-18 membered heteroaryl; the C 6-18 aryl or 5-18 membered heteroaryl is optionally further One or more R a is substituted, R a is independently selected from H, hydroxyl, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2- 6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
  • R 2 in formula (I) is selected from Among them, the
  • Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
  • R 2 in formula (I) is selected from
  • R 3 in formula (I) is selected from C 1-6 alkoxy or C 3-14 cycloalkyl-O-.
  • R 3 in formula (I) is selected from methoxy
  • R 4 in formula (I) is selected from H, halogen, C 1-6 alkoxy or C 1-6 haloalkoxy; preferably F.
  • R 5 in Formula (I) is H.
  • the compound of formula (I) described in formula (I) is selected from formula (IA) or (IB):
  • the compound of formula (I) is selected from formula (IA-1) or (IB-1):
  • the compound of formula (I) is selected from formula (IA-1') or (IB-1'):
  • the R 2 is selected from C 6-18 aryl or 5-18 yuan Heteroaryl; wherein, the C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a , and the R a is independently selected from H, hydroxyl, cyano, Halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-3 alkylene-C 3- 14- cycloalkyl, -C 0-3 alkylene-(3-14 membered heterocyclyl), -C 0-3 alkylene-C 6-18 aryl or -C 0-3 alkylene-( 5-18 membered heteroaryl);
  • the R 3 is selected from C 1-6 alkoxy, C 3-14 cycloalkyl-O- or C 1-6 haloalkoxy; wherein, the C 1-6 alkoxy, C 3-14 cycloalkyl Alkyl-O- or C 1-6 haloalkoxy is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, cyano, amino, Substituted by nitro or hydroxyl;
  • R 4 is selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy or hydroxyl; wherein, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl or C 1-6 The haloalkoxy group is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, cyano, amino, nitro or hydroxyl;
  • the X is selected from bond, NH, O or S;
  • the L is selected from bond or -C 1-3 alkylene-;
  • the R 6 is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, so The C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogens, hydroxyl groups , cyano, amino, nitro or C 1-6 alkyl substituted.
  • formula (I) is selected from formula (IA-1-1) or (IB-1-1):
  • the R 2 is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl;
  • the R 4 is selected from hydrogen or halogen
  • the R 6 is selected from hydrogen or halogen
  • the R 7 is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-14 cycloalkyl; preferably it is methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.
  • formula (I) is selected from (IA-1'-1) or (IB-1'-1):
  • the R 2 is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl;
  • the R 4 is selected from hydrogen or halogen
  • the R 6 is selected from hydrogen or halogen
  • the R 7 is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-14 cycloalkyl, preferably methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.
  • the compound of formula (I) is selected from:
  • the compound of formula (I) relates to an intermediate compound, and the intermediate compound is selected from:
  • the present invention also provides a method for preparing intermediate compound M13, which includes the following steps: reacting racemate M9 with a chiral acid to generate the corresponding salt, and dissociating it under alkaline conditions to obtain S-configured free base M13.
  • the chiral acid is selected from L-(-)-di-p-toluoyltartaric acid, L-(-)-dibenzoyltartaric acid or L-(-)-dibenzoyltartaric acid.
  • p-Methoxybenzoyltartaric acid is selected from L-(-)-di-p-toluoyltartaric acid, L-(-)-dibenzoyltartaric acid or L-(-)-dibenzoyltartaric acid.
  • the preparation method of intermediate compound M13 includes the following steps:
  • the preparation method of intermediate M13 further includes the following steps:
  • Dissolve M9 in organic solvent 1 raise the temperature and stir to dissolve, to obtain a solution of M9; dissolve L-(-)-di-p-methylbenzoyltartaric acid in organic solvent 2 to form an acid solution; slowly add the acid solution dropwise to In the solution of M9, the acid solution is added dropwise. After heating and dissolving, the organic solvent 3 is added dropwise to the reaction solution. After the dropwise addition is completed, the temperature is slowly cooled and crystallized. The sample is filtered and the filter cake is vacuum dried to obtain (S)- The crude product of DPLT salt, the crude product of (S)-DPLT salt is recrystallized in organic solvent 4 to obtain (S)-DPLT salt M13-1;
  • the organic solvent 1 in step 1) is selected from the group consisting of 2-methyltetrahydrofuran, ethanol, acetonitrile, ethyl ketone, and ethanol.
  • the organic solvent 2 in step 1) is selected from ethyl acetate, ethanol, isopropyl alcohol, ethanone, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran or a mixture thereof.
  • the organic solvent 3 in step 1) is selected from ethyl acetate, isopropyl alcohol, isopropyl acetate, methyl tert-butyl ether, n-heptane or a mixture thereof.
  • the organic solvent 4 in step 1) is selected from isopropyl alcohol/acetonitrile ethanol/acetonitrile/ethyl acetate, methanol/acetonitrile/ethyl acetate, ethanol/ethyl ketone/ethyl acetate, ethanol/methyl tert.
  • the organic solvent 5 in step 2) is selected from dichloromethane/methanol, 2-methyltetrahydrofuran F, ethyl acetate or a mixture thereof.
  • the organic solvent 6 in step 2) is selected from dichloromethane/methanol, 2-methyltetrahydrofuran or ethyl acetate.
  • the present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective amount of at least one compound represented by formula (I), its stereoisomer, tautomer, deuterated product or Medicinal salt.
  • the present invention provides the use of the compound represented by structural formula (I) or its pharmaceutical composition in the preparation of medicines.
  • the application is in the preparation of drugs for the treatment and/or prevention of cancer.
  • the application is the application of preparing drugs for treating diseases mediated by KRAS G12D.
  • the disease is cancer.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, polymorphic lung cancer, ovarian cancer, esophageal cancer Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumors, cholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
  • the present invention also provides a method for treating and/or preventing diseases, which includes administering to the treatment subject a therapeutically effective amount of at least any one compound represented by structural formula (I), its stereoisomer, tautomer, deuterium substitutes or pharmaceutically acceptable salts or pharmaceutical compositions containing them.
  • the present invention also provides a method for treating and/or preventing diseases mediated by KRAS G12D, which includes administering to the treatment subject a therapeutically effective amount of at least any one of the compounds represented by structural formula (I), its stereoisomers, Tautomers, deuterated compounds or pharmaceutically acceptable salts or pharmaceutical compositions containing them.
  • the present invention also provides a method for treating cancer, which includes administering to a treatment subject a therapeutically effective amount of at least any compound represented by structural formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable Salts or pharmaceutical compositions containing them.
  • the KRAS G12D-mediated disease is cancer.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, polymorphic Lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Xuwang cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl includes linear or branched monovalent saturated hydrocarbon groups.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -Pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc.
  • " 1-6 " in "C 1-6 alkyl” refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a linear or branched chain.
  • Alkoxy refers to the oxygen ether form of the aforementioned linear or branched alkyl group, that is, -O-alkyl.
  • alkylene refers to a divalent alkyl linking group. Alkylene formally refers to an alkane in which the two CH bonds are replaced by the alkylene's point of attachment to the rest of the compound. Similarly, “C 1-3 " in C 1-3 alkylene refers to an alkylene group containing 1, 2 or 3 carbon atoms, including but not limited to methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.
  • haloalkyl refers to the aforementioned alkyl group in which one or more H has been replaced by a halogen atom, such as C 1-6 haloalkyl.
  • oxo or "oxo” refers to an oxygen atom in the form of a divalent substituent which, when attached to C, forms a carbonyl group and which, when attached to a heteroatom, forms a sulfoxide or sulfone or N-oxide group group.
  • aromatic ring means having aromatic characteristics (having (4n+2) delocalized ⁇ electrons, where n is Integer) polyunsaturated ring carbocyclic or heterocyclic ring.
  • aryl refers to an unsubstituted or substituted monocyclic or fused ring aromatic group including atoms of a carbocyclic ring.
  • a C 6-18 aryl group is preferred, and a C 6-10 monocyclic or bicyclic aromatic ring group is more preferred.
  • Preferred are phenyl and naphthyl; most preferred are naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, where the ring attached to the parent structure is an aryl ring, non-limiting examples include but are not limited to benzocyclopentyl.
  • heterocyclyl refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heterocyclic atom selected from N, O and/or S.
  • the heterocyclyl group may include monocyclic or polycyclic rings (e.g., having 2, 3 or 4 fused rings, Spiral ring, bridge ring, etc.).
  • Heterocyclyl groups can be connected to other parts of the compound via ring carbon atoms or ring heteroatoms.
  • 3-14-membered heterocyclic groups Preferred are 3-14-membered heterocyclic groups, and the "3-14-membered" in the 3-14-membered heterocyclic groups refers to heterocyclic groups containing 3-14 C, N, O or S ring-forming atoms; more preferably 5-14 membered heterocyclyl and 3-8 membered heterocyclyl, more preferably 3-6 membered heterocyclyl.
  • the nitrogen or sulfur heteroatoms can be selectively oxidized, and the nitrogen heteroatoms can be selectively quaternized.
  • heterocyclyl groups include, but are not limited to Azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxypiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, Tetrahydroxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinylsulfone and tetrahydroxadiazolyl.
  • the heterocyclyl group may be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring attached to the parent structure is the heterocyclyl group.
  • heteroaryl in the present invention, unless otherwise stated, refers to a monocyclic or polycyclic ring with at least one heteroatom (for example, with 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.) Aromatic heterocycle, the heteroatom is selected from N, O and/or S, and wherein the nitrogen or sulfur heteroatom can be selectively oxidized, and the nitrogen heteroatom can be selectively quaternized.
  • heteroaryl groups include but are not limited to thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiodi Azolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolyl or isoquinolyl.
  • the heteroaryl group may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is the heteroaryl ring.
  • cycloalkyl refers to a ring system having at least one cyclized alkyl group.
  • C 3-14 cycloalkyl is preferred, where "C 3-14 " means that the cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms .
  • Cycloalkyl groups can include monocyclic and polycyclic rings (eg, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.).
  • the cycloalkyl group includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group can also be fused to an aryl, heterocyclyl or heteroaryl ring, where it is connected to the parent structure The rings joined together are cycloalkyl.
  • substituted means that one or more hydrogen atoms in the group are replaced by the same or different substituents, respectively.
  • the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy group, tert-butoxy group, -SCH 3 , -SC 2 H 5 , formaldehyde group, -C(OCH 3 ), cyano group, nitro group, -CF 3 , -OCF 3 , amino group, dimethyl group amino, methylthio, sulfonyl and acetyl groups.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low prices), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low prices), potassium, sodium, and zinc. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred.
  • Nontoxic organic bases capable of being derivatized into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines.
  • non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine Acid, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine wait.
  • ion exchange resins and arginine betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylamin
  • the compound provided by the present invention is a base
  • its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
  • acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, parapexic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydriodic acid, perchloric acid, cyclohexane sulfonic acid, salicylic acid, 2-naphthalene sulfonic acid, saccharinic
  • prodrugs of the compounds of the present invention are included in the protection scope of the present invention.
  • the prodrug refers to a functional derivative that is easily converted into the desired compound in the body.
  • any pharmaceutically acceptable salt, ester, ester salt or other derivative of the compound of the present application which can directly or indirectly provide the compound of the present application or its pharmaceutically active metabolite after administration to the recipient; Residues.
  • the compounds described in the present invention may contain one or more asymmetric centers and may thereby give rise to diastereoisomers and Optical isomers.
  • the present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.
  • the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, as well as their mixtures.
  • substitution of compounds of formula (I) with heavier isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.
  • composition refers to a mixture of one or more compounds of the present application or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to an organism of the compounds of the present application.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • the pharmaceutical composition of the present invention can be prepared by combining the compound of the present application with appropriate pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of the compounds of the invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, Subcutaneous and intravenous administration.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • treatment encompasses any treatment of a patient's disease that: (a) inhibits the symptoms of the disease, i.e., prevents their progression; or (b) alleviates the symptoms of the disease, i.e., causes regression of the disease or symptoms.
  • the term "effective amount” means (i) treating or preventing a specified disease, condition, or disorder, (ii) reducing, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying An amount of a compound of the present application that is associated with the onset of one or more symptoms of a particular disease, condition, or disorder described in .
  • the amount of a compound of the present application that constitutes a "therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.
  • the compounds of the present invention have excellent activities in terms of enzymatic activity, cell activity, PK, bioavailability, etc., and can be used to treat and/or prevent diseases mediated by KRAS G12D.
  • the compound of the present invention compared to MART1133 (Compared to Compound D1), the compound of the present invention, has higher whole blood exposure and lower clearance in intravenous administration; it has better PO exposure (AUC) and Oral bioavailability (F%), the oral absorption of the compounds of the present invention is significantly better than that of MART1133.
  • Figure 1 is a stereoscopic polarizing microscope diagram of a single crystal sample of compound M13-1.
  • Figure 2 is an analytical diagram of the single crystal structure of compound M13-1.
  • Figure 3 shows the distribution of compounds in tumor tissues of NCI-H1975 tumor-bearing mice.
  • NIS N-iodosuccinimide
  • PE petroleum ether
  • mCPBA m-chloroperoxybenzoic acid
  • CsF cesium fluoride
  • TBDPSCl tert-butyldiphenylsilyl chloride
  • DPPA diphenylphosphate azide
  • CDI N,N'-carbonyldiimidazole
  • DIEA N,N-diisopropylethylamine
  • CataCXium A Pd G3 methanesulfonate [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II);
  • SphosPdG2 Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) Palladium(II);
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • mCPBA m-chloroperoxybenzoic acid
  • LAH lithium aluminum tetrahydride
  • TFA trifluoroacetic acid
  • BINAP 1,1'-binaphthyl-2,2'-bisdiphenylphosphine
  • compound M1-4 (187g) and difluoromethyl (2-pyridyl) sulfone (184g) were dissolved in anhydrous DMF (1.4L), and potassium tert-butoxide (107g) was added dropwise at -50°C.
  • DMF (460mL) solution after the dropwise addition is completed, control the temperature to react at -40°C for 2 hours.
  • saturated ammonium chloride solution dropwise at -50°C until the solution becomes weakly acidic, and naturally warm to room temperature for 18 hours. , filter to obtain the filtrate, add EA (1.4L) to dilute, filter again to obtain the filtrate, and concentrate.
  • Dissolve compound M2-1 (65.00g) in CH 3 CN (82.00 mL) at room temperature, cool in a water bath, slowly add hydrochloric acid (4M/dioxane) (38.43g), stir and react at room temperature for about 16 hours , a white solid precipitated in a suspended state.
  • the reaction mixture was filtered, and the filter cake was rinsed with a small amount of acetonitrile, drained, and the filtrate was discarded.
  • compound M2-2 (36.00g) was dissolved in acetonitrile (180.00mL), NIS (66.32g) and p-toluenesulfonic acid (2.12g) were added, and the reaction was heated and kept at 70°C under nitrogen protection. Cool the reaction solution to 50°C, add 900 mL of water, and a pinkish-white solid powder will precipitate. Beat for half an hour; filter, rinse the filter cake with water, and drain it.
  • compound M2-3 (57.50g) was dissolved in DMF (22.00mL), zinc cyanide (32.22g), tetrakis triphenylphosphine palladium (12.19g) and powdered Molecular sieve (20.00 mL) was added, and the reaction was heated and kept at 100°C for about 7 hours in a nitrogen atmosphere. Remove the oil bath, cool to room temperature naturally, and wait for post-processing. Use diatomaceous earth to assist filtration, filter the reaction mixture, and drain it; collect the filtrate and concentrate at 60-70°C to obtain a pale yellow solid crude product.
  • Rinse the filter residue with 500 mL of ethyl acetate and drain it; collect the rinse liquid, combine it with the crude product, and concentrate again until no liquid is distilled; add 700 mL of ethyl acetate to dissolve and concentrate the solid crude product obtained, and then use 250 mL of saturated sodium chloride each time , washed 3 times and separated. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate to obtain a light yellow solid. Add 160 mL of PE/EA 3/1 mixture, beat for half an hour, filter, and drain.
  • M10-1 (54g) was added to a 1L three-necked flask, 500mL ACN was added, NIS (80g) and TsOH (5.1g) were added. After raising the temperature to 70°C and reacting for 1 hour, add 2.5L of water dropwise, filter, and dissolve the filter cake with EA. After liquid separation, the organic phase was concentrated to obtain the target compound M10-2 (94g).
  • M10-2 (88g) was added to a 1L three-necked flask, 500mL DMF was added, and CuCN (31g) was added. After raising the temperature to 125°C and reacting for 16 hours, add 2L of water dropwise, then add it to 2L of water, filter, wash the filter cake with water, and dissolve EA. The aqueous phase was extracted twice with EA, the organic phases were collected and combined, and concentrated to obtain the target product M10-3 (55.4g). ESI-MS m/z:207.0[M] - .
  • Single crystal culture and identification Weigh compound M13-1, dissolve it with 1 ml of butanone/water (19/1, v/v) mixed solvent, transfer the clarified sample to a butanone atmosphere for gas-liquid diffusion overnight, and obtain a single crystal sample.
  • the stereoscopic polarizing microscope picture of the single crystal sample is shown in Figure 1
  • the single crystal structure analysis is shown in Figure 2
  • the single crystal structure information table is as follows.
  • ratio solvent 200ml, stir for 20 minutes, separate and extract, repeat twice; combine the organic phases, wash the organic phase with 200ml of pure water, and then wash with 200ml of saturated brine, and finally dry the organic phase with anhydrous sodium sulfate.
  • the organic phase was filtered, and the filtrate was concentrated. After concentration, it was evaporated twice with an ACN jacket to obtain 5.17g (S)-(2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol M13, R/S The isomer ratio is 0.8%:99.2%.
  • Example 1 Compound 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2-(difluoromethylene) Tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2- Synthesis of alcohol
  • compound 1-1 (0.3g), cataCXium A Pd G3 (40mg), ((2-fluoro-6-(methoxymethoxy)-8-(4,4, 5,5-Tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (0.53g) and potassium phosphate (0.33g) were dissolved in THF (6 mL) and water (1 mL) were heated to 70°C and reacted for 3 hours.
  • Dissolve compound 1-2 (0.31g) in DMF (3mL), add cesium fluoride (0.5g) in batches at room temperature, after the reaction is completed, drop 15mL of water into the reaction liquid, a large amount of solid precipitates, and filter to obtain The solid is dried to obtain the product 1-3 (0.31 g, 76% yield).
  • ESI-MS m/z 775.1[M+H] + .
  • Dissolve compound 1-3 (0.31g) in DCM (3mL) at room temperature, add trifluoroacetic acid (1mL) thereto, after the reaction is completed, add the reaction solution dropwise to the protective sodium bicarbonate solution at 0°C. , add DCM to separate the layers to obtain the organic layer, wash with saturated brine once, dry over anhydrous sodium sulfate, and concentrate.
  • the concentrate was preparatively purified by Pre-HPLC to give product 1 (31 mg, 13% yield).
  • Example 2 Compound 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2-(difluoromethylene) Tetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)-8-fluoro-5-isopropoxypyridine[4,3-d]pyrimidin-7-yl)-5-ethynyl- Synthesis of 6-fluoronaphthalene-2-ol
  • Example 3 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-isopropoxy-2- ((2-Methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene -Synthesis of 2-alcohol
  • Example 5 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethoxy-8-fluoro-2-(( 2-Methyltetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2 -Synthesis of alcohol
  • Example 6 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2-(difluoromethylene)) Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-ethoxy-8-fluoropyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-6- Synthesis of fluoronaphthalene-2-ol
  • Example 7 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-5-methoxy-2- ((2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyne-6-fluoronaphthalene- Synthesis of 2-alcohols
  • Example 8 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2-(difluoromethylene)) Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-5-methoxypyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-6- Synthesis of fluoronaphthalene-2-ol
  • Example 9 Compound 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-cyclopropoxy-8-fluoro-2- (2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene -Synthesis of 2-alcohol
  • Example 39 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-methoxy-2-( (2-Methyltetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene- Synthesis of 2-alcohols
  • Dissolve compound 39-1 (300 mg) in the previous step in 5 mL of methanol, then add Pd/C (50 mg), replace with hydrogen 5 times, react at room temperature for 20 min, filter through diatomaceous earth, and concentrate the filtrate under reduced pressure. The concentrate is passed through a column Purification by chromatography gave the target compound 39-2 (208 mg).
  • Dissolve compound 39-3 (330mg) in DCM (5mL), then add TBSCl (800mg) and imidazole (550mg) in sequence, react at room temperature for 0.5h, extract the reaction solution with DCM and water, retain the organic phase, and add anhydrous sodium sulfate Dry, filter, and concentrate under reduced pressure. The concentrate is purified by column chromatography to obtain target compound 39-4 (270 mg).
  • Dissolve compound 39-4 (270mg) in DCM (5mL), then add m-CPBA (270mg), react at room temperature for 0.5h, add an appropriate amount of saturated sodium sulfite solution and stir for 20min to quench, extract the reaction solution with DCM and water, and retain The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain target compound 39-5 (150 mg).
  • Example 55 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-methoxy-2-( (2-Methyltetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2- Synthesis of alcohol
  • Example 109 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((2-(difluoro methylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6- Synthesis of fluoronaphthyl-2-amine
  • Step 1 Synthesis of Compound 109-1
  • Example 110 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((2-methyltetrakis) Synthesis of hydrogen-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine
  • Dissolve 110-1 (760mg) and intermediate M8 (980mg) in a mixed solvent of 1,4-dioxane (15mL) and water (3mL), add potassium phosphate (888mg), and add cataCXium A under nitrogen protection Pd G3 (101 mg), heat to 100°C and react for 3 hours. Stop heating, cool to room temperature, add water to dilute (40 mL), extract twice with dichloromethane, 40 ml each time, combine the organic phases, wash the organic phases twice with water, dry over anhydrous sodium sulfate, and concentrate. The concentrate was separated and purified by column chromatography (DCM:MeOH 20:1) to obtain 760 mg of compound 110-2.
  • Dissolve 110-3 (635mg), benzophenone imine (234mg) and cesium carbonate (631mg) in 1,4-dioxane (15mL), add BINAP (40mg) and palladium acetate (15mg) under nitrogen protection ), rise to 100°C and react for 1 hour.
  • Dissolve 110-4 (450 mg) in a mixed solution of hydrochloric acid solution (5 mL, 2 mol/L) and THF (10 mL), and stir at room temperature for 15 min. Quench the reaction solution in saturated sodium carbonate solution, extract with DCM twice, 30 ml each time, combine the organic phases, wash with water twice, dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain crude product 110-5, which can be directly used without purification. Cast the next reaction.
  • Example 112 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((2-methyltetrakis) Synthesis of Hydrogen-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-1,6-difluoronaphthalene-2-amine
  • Example 120 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-2-((2-(di Fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3-d]pyrimidin-7-yl)-5-ethynyl6-fluoro Synthesis of naphthalene-2-ol
  • Example 121 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2-(difluoroalkyl) Methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyridin[4,3d]pyrimidin-7-yl)-5-ethynyl-1,6-difluoro Synthesis of naphthalene-2-ol
  • Step 1 Synthesis of Compound 121-1
  • Example 122 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2-(difluoromethylene)) Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-5-(2,2,2-trifluoroethoxy)pyrido[4,3d]pyrimidine-7- Synthesis of 5-ethynyl-6-fluoronaphthalene-2-ol
  • Step 8 Synthesis of Compound 122
  • Example 123 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((2-methyltetrakis) Hydrogen-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(2,2,2-trifluoroethoxy)pyridine[4,3d]pyrimidin-7-yl)-5-ethyne Synthesis of 6-fluoronaphthalene-2-ol
  • Step 1 Synthesis of Compound 123-1
  • Example 125 Compound 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-methoxy-2-( (2-Methyltetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol Synthesis
  • reaction solution was poured into saturated NH 4 Cl solution, and extracted twice with EA.
  • the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE/EA, 5% EA) to obtain compound 125. -1 (1.8g yield 79.6%).
  • Example 141 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-methoxy-2-( (2-Methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- Synthesis of 2-amines
  • Step 1 Synthesis of Compound 141-1
  • Example 143 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2-(difluoromethylene)) Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-5-methoxypyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-6- Synthesis of fluoronaphthyl-2-amine
  • Step 1 Synthesis of Compound 143-1
  • Example 180 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2,6-dimethylenetetrakis) Hydrogen-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Synthesis of fluoronaphthalen-2-ol
  • Example 181 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-methoxy-2-( (2-Methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-vinylnaphthalene- Synthesis of 2-alcohols
  • Dissolve compound 181-2 (95 mg) in DCM (2 mL), then add TBSCl (220 mg) and imidazole (150 mg) in sequence, react at room temperature for 0.5 h, extract the reaction solution with DCM and water, retain the organic phase, and add anhydrous sodium sulfate Dry, filter, and concentrate under reduced pressure, and the concentrate is purified by column chromatography to obtain target compound 181-3 (90 mg).
  • Dissolve compound 181-3 (90 mg) in DCM (2 mL), then add m-CPBA (90 mg), react at room temperature for 0.5 h, add an appropriate amount of saturated sodium sulfite solution and stir for 20 min to quench, extract the reaction solution with DCM and water, and retain The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain target compound 181-4 (60 mg).
  • Example 214 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-methoxy-2-( ((S)-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Synthesis of fluoronaphthalen-2-ol
  • Step 1 Synthesis of Compound 214-1
  • Dissolve compound 214-1 (19.75g 22.41mmol) in DMF, add CsF (34.05g 224.14mmol), and react in a 35°C oil bath for 4 hours. After the reaction is complete, use an ice bath to cool down the temperature to 10°C. Water (800 ml) is slowly added dropwise to produce a large amount of solid, which is filtered to obtain a filter cake. Dissolve it in EA (200 ml), wash it once with saturated brine (100 ml), separate the liquids to obtain the organic phase, and purify it by column chromatography (DCM:MeOH 20:1) to obtain compound 214-2 (14.82g) .
  • KRAS G12D mutant tumor cells AGS ( CRL-1739 TM ) was plated in a low-adsorption 96-well plate at a cell density of 1 ⁇ 10 3 /well, and placed in a cell culture incubator for overnight culture. After the cells adhere to the wall, add the compound to be tested according to the final concentration Add 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.025, 0nM (the final concentration of DMSO is 0.5%) into the 96-well plate, incubate at 37°C for 96 hours, and then add 50 ⁇ L Cell-titer GLO to each well. solution, shake and mix well, incubate at room temperature for 10 minutes, read the Luminescence value on a multifunctional microplate reader, and calculate and convert the luminescence value data into an inhibition percentage. And calculate the percentage of cell proliferation inhibition according to the following formula:
  • Inhibition percentage (maximum value - measured value) / (maximum value - Blank) ⁇ 100
  • KRAS G12D mutant tumor cells AGS ( CRL-1739 TM ) at a cell density of 4 ⁇ 10 4 /well Spread in a 96-well plate and culture in a cell culture incubator overnight. After the cells are adhered, the compound to be tested is added to the 96-well plate at the final concentration of 3000nM, 600nM, 120nM, 24nM, 4.8nM, 0.96nM, 0.19nM, and 0.5% DMSO. After culturing for 3 hours, use pERK HTRF Kit (Cisbio) Lyse each treated cell sample (40ul/well) in the 96-well plate with the lysis buffer in the 96-well plate.
  • Inhibition percentage (maximum value - measured value) / (maximum value - Blank) ⁇ 100
  • KRAS G12D mutant tumor cells HPAC, A427, Aspc-1, LS180, and Panc04.03 were spread in a low-adsorption 96-well plate at a cell density of 1 ⁇ 10 3 /well and placed in a cell culture incubator for overnight culture. After the cells are adhered, the compound to be tested is added to the 96-well plate according to the final concentration of 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.025, 0nM (the final DMSO concentration is 0.5%), and cultured at 37°C. After 96 hours, add 50 ⁇ L of Cell-titer GLO working solution to each well, shake and mix, and incubate at room temperature for 10 minutes. Read the Luminescence value on a multifunctional microplate reader, and calculate and convert the luminescence value data into an inhibition percentage. And calculate the percentage of cell proliferation inhibition according to the following formula:
  • Inhibition percentage (maximum value - measured value) / (maximum value - Blank) ⁇ 100
  • KRAS G12D mutant tumor cells HPAC, A427, Aspc-1, LS180, and Panc04.03 were spread in a 96-well plate at a cell density of 4 ⁇ 10 4 /well and placed in a cell culture incubator for overnight culture. After the cells are adhered, the compound to be tested is added to the 96-well plate at the final concentration of 3000nM, 600nM, 120nM, 24nM, 4.8nM, 0.96nM, 0.19nM, and 0.5% DMSO. After culturing for 3 hours, use pERK HTRF Kit (Cisbio) Lyse each treated cell sample (40ul/well) in the 96-well plate with the lysis buffer in the 96-well plate.
  • Inhibition percentage (maximum value - measured value) / (maximum value - Blank) ⁇ 100
  • Intravenous administration investigation Mix the compound with the solvent 10% DMSO/5% Solutol/85% physiological saline, vortex and sonicate to prepare a 0.2 mg/ml clear intravenous injection solution.
  • Balbc female mice aged 6 to 7 weeks were selected and intravenously administered compounds 7, 110, 141 and D1, and whole blood samples were collected at 5min, 15min, 30min, 1h, 2h, 4h, 7h and 24h.
  • the drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNolin software (Pharsight Company, USA).
  • the dosage and experimental protocol are shown in Table 5 below, and the results are shown in Table 6.
  • the tested mouse PK data are as follows in Table 6:
  • mice the oral exposure (AUC) and oral bioavailability (F%) of compound 110 are higher than those of compound D1; the oral exposure (AUC) and oral bioavailability (F%) of compound 109 are higher than Compound D1.
  • Pharmacological experiment 7 PK investigation of compounds in beagle dogs
  • Pharmacological experiment 8 PK investigation of compounds in tumor tissues of NCI-H1975 tumor-bearing mice
  • a Balbc nude nude mouse model of subcutaneous xenograft tumor of human lung adenocarcinoma cell NCI-H1975 was constructed. After the tumor volume reached 200 mm, 21 tumor-bearing mice were selected and administered Compound 7 and D1 1mpk IV Cassette. The solvent was 10% DMSO/5% Solutol/85% saline. Mouse whole blood samples and tumor tissue samples were collected at 0.5h, 4h, 7h, 24h, 48h, 72h, and 96h after administration. The drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNolin software (Pharsight Company, USA). The results are shown in Table 12.
  • Tumor tissue was collected at 0.5h, 4h, 7h, 24h, 48h, 72h, and 96h after administration, and the concentrations of compound 7 and D1 in the tumor tissue were detected.
  • the detection results are as shown in Figure 3.

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Abstract

Provided are a compound of formula (I), and a stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt thereof, a preparation method therefor, a pharmaceutical composition containing the compound, and an application thereof as a medicament for the treatment and/or prevention of diseases mediated by KRAS.

Description

KRAS G12D抑制剂及其在医药上的应用KRAS G12D inhibitors and their applications in medicine 技术领域Technical field
本发明涉及医药技术领域，具体涉及式(I)化合物、其立体异构体、互变异构体、氘代物或药用盐，其制备方法，含有该化合物的药用组合物，及其作为治疗癌症药物的用途。The present invention relates to the field of medical technology, specifically to the compound of formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutical salt, its preparation method, pharmaceutical composition containing the compound, and its use as Uses of drugs to treat cancer.
背景技术Background technique
临床数据显示，RAS是人类肿瘤中发生突变率最高的基因，所有肿瘤中，约20-30％有RAS突变，大约98％的胰腺癌，52％的结肠癌,43％的多发性骨髓瘤，及32％的肺腺癌中存在RAS基因突变。RAS最常见的突变方式是点突变，经常发生在12、13、61密码子，其中又以第12位密码子突变最常见，例如G12C、G12D或G12V。Clinical data show that RAS is the gene with the highest mutation rate in human tumors. About 20-30% of all tumors have RAS mutations, about 98% of pancreatic cancer, 52% of colon cancer, and 43% of multiple myeloma. And RAS gene mutations are present in 32% of lung adenocarcinomas. The most common mutation mode of RAS is point mutation, which often occurs in codons 12, 13, and 61. Among them, mutations in codon 12 are the most common, such as G12C, G12D or G12V.
目前针对KRAS突变的药物研发是当前新药研究热点之一。KRAS G12C抑制剂AMG510(WO2018217651A1)和MRTX849(WO2019099524A1)已进入后期临床阶段；而MIRATI在G12D抑制剂(WO2021041671A1)研发上进展领先。Currently, drug development targeting KRAS mutations is one of the current hot spots in new drug research. KRAS G12C inhibitors AMG510 (WO2018217651A1) and MRTX849 (WO2019099524A1) have entered the late clinical stage; while MIRATI is leading the research and development of G12D inhibitor (WO2021041671A1).
基于KRAS异常激活在癌症进展中的重要性和KRAS基因突变在人类癌症中的普遍性，KRAS一直是药物研发人员关注的靶点。尽管己在这个领域中取得进展，但在本领域中仍需要改进的KRAS G12D突变蛋白抑制剂，以满足更多的临床需求。Based on the importance of abnormal activation of KRAS in cancer progression and the prevalence of KRAS gene mutations in human cancers, KRAS has always been a target of concern for drug developers. Although progress has been made in this field, there is still a need for improved KRAS G12D mutant protein inhibitors to meet additional clinical needs.
发明内容Contents of the invention
本发明所要解决的技术问题是为了克服现有技术中基于KRAS G12D突变蛋白抑制剂缺乏的问题，而提供了一种通式(I)所示的化合物及其应用，本发明提供的通式(I)所示的化合物对KRAS G12D突变蛋白具有良好的抑制作用。The technical problem to be solved by the present invention is to overcome the problem of lack of KRAS G12D mutant protein inhibitors in the prior art, and provide a compound represented by the general formula (I) and its application. The general formula (I) provided by the present invention The compound shown in I) has a good inhibitory effect on KRAS G12D mutant protein.
本发明提供一种通式(I)所示的化合物、其立体异构体、互变异构体、氘代物或药用盐：
The present invention provides a compound represented by general formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt:
其中，in,
X选自键、NH、O或S； X is selected from bond, NH, O or S;
选自单键或双键； Selected from single or double bonds;
L选自键、-C1-3亚烷基-、-C3-14环烷基-C0-3亚烷基-或-3-14元杂环基-C0-3亚烷基-，所述-C1-3亚烷基-、-C3-14环烷基-C0-3亚烷基-或-3-14元杂环基-C0-3亚烷基-任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基或羟基所取代；L is selected from bond, -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene- , the -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene-optional Further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
所述环A选自C5-14环烷基、5-14元杂环基、C6-18芳基或5-18元杂芳基，所述C5-14环烷基或5-14元杂环基选自单环、稠环、螺环或桥环，所述C5-14环烷基、5-14元杂环基、C6-18芳基或5-18元杂芳基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基或羟基所取代；The ring A is selected from C 5-14 cycloalkyl, 5-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, and the C 5-14 cycloalkyl or 5-14 The membered heterocyclyl group is selected from a single ring, a condensed ring, a spiro ring or a bridged ring, and the C 5-14 cycloalkyl group, 5-14 membered heterocyclyl group, C 6-18 aryl group or 5-18 membered heteroaryl group Optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
选自其中，为双键，选自Z构型或E构型； Selected from in, is a double bond, Selected from Z configuration or E configuration;
R2选自C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基，所述C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选地进一步被一个或多个Ra取代；Ra独立地选自H、羟基、氰基、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、-C0-3亚烷基-ORb、-OC(＝O)C1-6烷基、-C0-3亚烷基-SRb、-C0-3亚烷基-N(Rb)2、-C0-3亚烷基-S(＝O)Rb、-C0-3亚烷基-S(＝O)2Rb、-C0-3亚烷基-SRb、-C0-3亚烷基-S(Rb)5、-C0-3亚烷基-C(＝O)Rb、-C0-3亚烷基-C(＝O)ORb、-C0-3亚烷基-C(＝O)N(Rb)2、C2-6烯基、C2-6炔基、-C0-3亚烷基-C3-14环烷基、-C0- 3亚烷基-(3-14元杂环基)、-C0-3亚烷基-C6-18芳基或-C0-3亚烷基-(5-18元杂芳基)，所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-C0-3亚烷基-C3-14环烷基、-C0-3亚烷基-(3-14元杂环基)、-C0-3亚烷基-C6-18芳基或-C0-3亚烷基-(5-18元杂芳基)任选地进一步被一个或多个Rb取代，每个Rb独立地为H、卤素、羟基、氰基、C1-6烷基、C3-6环烷基或C1-6卤代烷基；R 2 is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, and the C 3-14 cycloalkyl, 3-14 membered heterocyclyl Ring group, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a ; R a is independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkane group, C 1-6 haloalkyl group, C 1-6 alkoxy group, -C 0-3 alkylene group -OR b , -OC(=O)C 1-6 alkyl group, -C 0-3 alkylene group -SR b , -C 0-3 alkylene-N(R b ) 2 , -C 0-3 alkylene -S(=O)R b , -C 0-3 alkylene -S(=O ) 2 R b , -C 0-3 alkylene -SR b , -C 0-3 alkylene -S(R b ) 5 , -C 0-3 alkylene -C(=O)R b , -C 0-3 alkylene-C(=O)OR b , -C 0-3 alkylene-C(=O)N(R b ) 2 , C 2-6 alkenyl, C 2-6 alkyne base, -C 0-3 alkylene -C 3-14 cycloalkyl, -C 0- 3 alkylene - (3-14 membered heterocyclyl), -C 0-3 alkylene -C 6- 18 aryl or -C 0-3 alkylene-(5-18 membered heteroaryl), the C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl, -C 0-3 alkylene -C 3-14 cycloalkyl, -C 0-3 alkylene - (3-14 membered heterocyclyl), -C 0 -3 alkylene-C 6-18 aryl or -C 0-3 alkylene-(5-18 membered heteroaryl) is optionally further substituted by one or more R b , each R b independently is H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl;
R3或R4分别独立的选自H、卤素、氰基、氨基、硝基、C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、C1-6卤代烷基、C1-6卤代烷氧基、羟基或羟基烷基，所述C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、卤代烷基或羟基烷基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基或羟基所取代；R 3 or R 4 are independently selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1 -6 haloalkyl, C 1-6 haloalkoxy, hydroxyl or hydroxyalkyl, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, haloalkyl or The hydroxyalkyl group is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxy;
R5选自H、卤素、-C0-3亚烷基氰基、C1-6烷基、C1-6烷氧基或C1-6卤代烷基；R 5 is selected from H, halogen, -C 0-3 alkylenecyano, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl;
R6选自H、卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基，所述C1-6烷基、C1-6卤代烷基、C3-14环烷基、3-14元杂环 基、C6-18芳基或5-18元杂芳基任选进一步被一个或多个卤素、羟基、氰基、氨基、硝基、C1-6烷基或C1-6烷氧基所取代；R 6 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, the C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocycle group, C 6-18 aryl or 5-18 membered heteroaryl, optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy replaced;
m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.
一些实施方式中，式(I)中的X为O。In some embodiments, X in formula (I) is O.
一些实施方式中，式(I)中的L选自-C1-3亚烷基-或-C3-14环烷基-C0-3亚烷基-。In some embodiments, L in formula (I) is selected from -C 1-3 alkylene- or -C 3-14 cycloalkyl-C 0-3 alkylene-.
一些实施方式中，式(I)中的环A选自C5-14环烷基或5-14元杂环基。In some embodiments, Ring A in formula (I) is selected from C 5-14 cycloalkyl or 5-14 membered heterocyclyl.
一些实施方式中，式(I)中的5-14元杂环基为稠环。In some embodiments, the 5-14 membered heterocyclyl group in formula (I) is a fused ring.
一些实施方式中，式(I)中的稠环选自 In some embodiments, the fused ring in formula (I) is selected from
一些实施方式中，式(I)中的选自 In some embodiments, in formula (I) Selected from
一些实施方式中，式(I)中的R6独立选自H、卤素、C1-6烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基，所述C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选地进一步被一个或多个卤素、羟基、氰基、氨基、硝基或C1-6烷基所取代。In some embodiments, R 6 in formula (I) is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogens , hydroxyl, cyano, amino, nitro or C 1-6 alkyl substituted.
一些实施方式中，式(I)中的选自 In some embodiments, in formula (I) Selected from
一些实施方式中，式(I)中的选自 In some embodiments, in formula (I) Selected from
一些实施方式中，式(I)中的R2选自C6-18芳基或5-18元杂芳基，所述C6-18芳基或5-18元杂芳基任选地进一步被一个或多个Ra取代，Ra独立地选自H、羟基、氰基、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基或-C0-3亚烷基-C3-14环烷基。In some embodiments, R 2 in formula (I) is selected from C 6-18 aryl or 5-18 membered heteroaryl, and the C 6-18 aryl or 5-18 membered heteroaryl is optionally further Substituted by one or more R a , R a independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 Alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
一些实施方式中，式(I)中的R2选自 所述 任选地进一步被一个或多个Ra取代，所述Ra独立地选自H、羟基、氰基、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基或-C0-3亚烷基-C3-14环烷基。In some embodiments, R in formula (I) is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkene base, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
一些实施方式中，式(I)中的R2选自 In some embodiments, R in formula (I) is selected from
一些实施方式中，式(I)中的R3选自H、羟基、卤素、氰基、C1-6烷基、C1-6烷氧基或C3-14环烷基-O-。 In some embodiments, R 3 in formula (I) is selected from H, hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy or C 3-14 cycloalkyl-O-.
一些实施方式中，式(I)中的R3选自H、羟基、甲基、 In some embodiments, R3 in formula (I) is selected from H, hydroxyl, methyl,
一些实施方式中，式(I)中的R4选自H、卤素、C1-6烷氧基或C1-6卤代烷氧基，优选为F。In some embodiments, R 4 in formula (I) is selected from H, halogen, C 1-6 alkoxy or C 1-6 haloalkoxy, preferably F.
一些实施方式中，式(I)中的R5为H。In some embodiments, R5 in formula (I) is H.
一些实施方式中，式(I)选自(IA)或(IB)：
In some embodiments, formula (I) is selected from (IA) or (IB):
其中，所述X，L，R2，R3，R4及R6的定义如式(I)所述。Wherein, the definitions of X, L, R 2 , R 3 , R 4 and R 6 are as described in formula (I).
一些实施方式中，式(I)选自(IA-1)和(IB-1)：
In some embodiments, formula (I) is selected from (IA-1) and (IB-1):
其中，所述X，L，R2，R3，R4及R6的定义如式(I)所述。Wherein, the definitions of X, L, R 2 , R 3 , R 4 and R 6 are as described in formula (I).
一些实施方式中，式(I)化合物选自(IA-1)和(IB-1)，其中：In some embodiments, the compound of formula (I) is selected from (IA-1) and (IB-1), wherein:
R2选自C6-18芳基或5-18元杂芳基，所述C6-18芳基或5-18元杂芳基任选地进一步被一个或多个Ra取代；所述Ra独立地选自H、羟基、氰基、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-C0-3亚烷基-C3-14环烷基、-C0-3亚烷基-(3-14元杂环基)、-C0-3亚烷基-C6-18芳基或-C0-3亚烷基-(5-18元杂芳基)；R 2 is selected from C 6-18 aryl or 5-18 membered heteroaryl, and the C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a ; the R a is independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl , -C 0-3 alkylene -C 3-14 cycloalkyl, -C 0-3 alkylene - (3-14 membered heterocyclyl), -C 0-3 alkylene -C 6-18 Aryl or -C 0-3 alkylene-(5-18 membered heteroaryl);
R3或R4分别独立的选自H、卤素、氰基、氨基、硝基、C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、C1-6卤代烷基、C1-6卤代烷氧基、羟基或羟基烷基，所述C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、卤代烷基或羟基烷基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基或羟基所取代；R 3 or R 4 are independently selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1 -6 haloalkyl, C 1-6 haloalkoxy, hydroxyl or hydroxyalkyl, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, haloalkyl or The hydroxyalkyl group is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxy;
X选自键、NH、O或S；X is selected from bond, NH, O or S;
L选自键或-C1-3亚烷基-； L is selected from bond or -C 1-3 alkylene-;
R6独立选自H、卤素、C1-6烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基，所述C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选地进一步被一个或多个卤素、羟基、氰基、氨基、硝基或C1-6烷基所取代。R 6 is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl are optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro or Substituted with C 1-6 alkyl.
本发明提供一种通式(I)所示的化合物、其立体异构体、互变异构体、氘代物或药用盐：
The present invention provides a compound represented by general formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt:
其中，in,
X选自键、NH、O或S；X is selected from bond, NH, O or S;
选自单键或双键； Selected from single or double bonds;
L选自键、-C1-3亚烷基-、-C3-14环烷基-C0-3亚烷基-或-3-14元杂环基-C0-3亚烷基-，所述-C1-3亚烷基-、-C3-14环烷基-C0-3亚烷基-或-3-14元杂环基-C0-3亚烷基-任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基或羟基所取代；L is selected from bond, -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene- , the -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene-optional Further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
所述环A选自C5-14环烷基、5-14元杂环基、C6-18芳基或5-18元杂芳基，所述C5-14环烷基或5-14元杂环基选自单环、稠环、螺环或桥环，所述C5-14环烷基、5-14元杂环基、C6-18芳基或5-18元杂芳基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基或羟基所取代；The ring A is selected from C 5-14 cycloalkyl, 5-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, and the C 5-14 cycloalkyl or 5-14 The membered heterocyclyl group is selected from a single ring, a condensed ring, a spiro ring or a bridged ring, and the C 5-14 cycloalkyl group, 5-14 membered heterocyclyl group, C 6-18 aryl group or 5-18 membered heteroaryl group Optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
选自其中，为双键，选自Z构型或E构型； Selected from in, is a double bond, Selected from Z configuration or E configuration;
R2选自C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基，所述C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选地进一步被一个或多个Ra取代；Ra独立地选自H、羟基、氰基、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、-C0-3亚烷基-ORb、-OC(＝O)C1-6烷基、-C0-3亚烷基-SRb、-C0-3亚烷基-N(Rb)2、-C0-3亚烷基-S(＝O)Rb、-C0-3亚烷基-S(＝O)2Rb、-C0-3亚烷基-SRb、-C0-3亚烷基-S(Rb)5、-C0-3亚烷基-C(＝O)Rb、-C0-3亚烷基-C(＝O)ORb、-C0-3亚烷基-C(＝O)N(Rb)2、C2-6烯基、C2-6炔基、-C0-3亚烷基-C3-14环烷基、-C0- 3亚烷基-(3-14元杂环基)、-C0-3亚烷基-C6-18芳基或-C0-3亚烷基-(5-18元杂芳基)，所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-C0-3亚烷基-C3-14环烷基、-C0-3亚烷基-(3-14元杂环基)、-C0-3亚烷基-C6-18芳基或-C0-3亚烷基-(5-18元杂芳基)任选地进一步被一个或多个Rb取代，每个Rb独立地为H、卤素、羟基、氰基、C1-6烷基、C3-6环烷基或C1-6卤代烷基；R 2 is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, and the C 3-14 cycloalkyl, 3-14 membered heterocyclyl Ring group, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a ; R a is independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkane group, C 1-6 haloalkyl group, C 1-6 alkoxy group, -C 0-3 alkylene group -OR b , -OC(=O)C 1-6 alkyl group, -C 0-3 alkylene group -SR b , -C 0-3 alkylene-N(R b ) 2 , -C 0-3 alkylene -S(=O)R b , -C 0-3 alkylene -S(=O ) 2 R b , -C 0-3 alkylene -SR b , -C 0-3 alkylene -S(R b ) 5 , -C 0-3 alkylene -C(=O)R b , -C 0-3 alkylene-C(=O)OR b , -C 0-3 alkylene-C(=O)N(R b ) 2 , C 2-6 alkenyl, C 2-6 alkyne Base, -C 0-3 alkylene -C 3-14 cycloalkyl, -C 0- 3 alkylene-(3-14 membered heterocyclyl), -C 0-3 alkylene-C 6-18 aryl or -C 0-3 alkylene-(5-18 membered heteroaryl), The C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 2-6 alkenyl group, C 2-6 alkynyl group, -C 0-3 alkylene group -C 3- 14- cycloalkyl, -C 0-3 alkylene-(3-14 membered heterocyclyl), -C 0-3 alkylene-C 6-18 aryl or -C 0-3 alkylene-( 5-18 membered heteroaryl) optionally further substituted by one or more R b , each R b is independently H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl base or C 1-6 haloalkyl;
R3或R4分别独立的选自H、卤素、氰基、氨基、-NHRa、-N(Ra)2、硝基、C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、C1-6卤代烷基、C1-6卤代烷氧基、羟基或羟基烷基，所述C1- 6烷基、C1-6烷氧基、C3-14环烷基-O-、卤代烷基或羟基烷基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基或羟基所取代；R 3 or R 4 are independently selected from H, halogen, cyano, amino, -NHR a , -N(R a ) 2 , nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl or hydroxyalkyl, the C 1-6 alkyl, C 1-6 alkoxy , C 3 -14 Cycloalkyl-O-, haloalkyl or hydroxyalkyl is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or substituted by hydroxyl;
R5选自H、卤素、-C0-3亚烷基氰基、C1-6烷基、C1-6烷氧基或C1-6卤代烷基；R 5 is selected from H, halogen, -C 0-3 alkylenecyano, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl;
R6选自H、卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基，所述C1-6烷基、C1-6卤代烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选进一步被一个或多个卤素、羟基、氰基、氨基、硝基、C1-6烷基或C1-6烷氧基所取代；R 6 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, the C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 The heteroaryl group is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy;
m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.
一些实施方式中，式(I)中的X为O。In some embodiments, X in formula (I) is O.
一些实施方式中，式(I)中的L选自-C1-3亚烷基-或-C3-14环烷基-C0-3亚烷基-。In some embodiments, L in formula (I) is selected from -C 1-3 alkylene- or -C 3-14 cycloalkyl-C 0-3 alkylene-.
一些实施方式中，式(I)中的环A选自C5-14环烷基或5-14元杂环基。In some embodiments, Ring A in formula (I) is selected from C 5-14 cycloalkyl or 5-14 membered heterocyclyl.
一些实施方式中，式(I)中的5-14元杂环基为稠环。In some embodiments, the 5-14 membered heterocyclyl group in formula (I) is a fused ring.
一些实施方式中，式(I)中的稠环选自 In some embodiments, the fused ring in formula (I) is selected from
一些实施方式中，式(I)中的选自 In some embodiments, in formula (I) Selected from
一些实施方式中，式(I)中的R6独立选自H、卤素、C1-6烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基，所述C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选地进一步被一个或多个卤素、羟基、氰基、氨基、硝基或C1-6烷基所取代。 In some embodiments, R 6 in formula (I) is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogens , hydroxyl, cyano, amino, nitro or C 1-6 alkyl substituted.
一些实施方式中，式(I)中的选自 In some embodiments, in formula (I) Selected from
一些实施方式中，式(I)中的选自 In some embodiments, in formula (I) Selected from
一些实施方式中，式(I)中的R2选自C6-18芳基或5-18元杂芳基，所述C6-18芳基或5-18元杂芳基任选地进一步被一个或多个Ra取代，Ra独立地选自H、羟基、氰基、氨基、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基或-C0-3亚烷基-C3-14环烷基。In some embodiments, R 2 in formula (I) is selected from C 6-18 aryl or 5-18 membered heteroaryl, and the C 6-18 aryl or 5-18 membered heteroaryl is optionally further Substituted by one or more R a , R a independently selected from H, hydroxyl, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 -6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
一些实施方式中，式(I)中的R2选自 所述 任选地进一步被一个或多个Ra取代，所述Ra独立地选自H、羟基、氰基、氨基、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基或-C0-3亚烷基-C3-14环烷基。In some embodiments, R in formula (I) is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
一些实施方式中，式(I)中的R2选自 In some embodiments, R in formula (I) is selected from
一些实施方式中，式(I)中的R3选自H、羟基、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C3-14环烷基-O-。In some embodiments, R 3 in formula (I) is selected from H, hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 3-14 Cycloalkyl-O-.
一些实施方式中，式(I)中的R3选自H、卤素、羟基、甲基、甲氧基、 In some embodiments, R in formula (I) is selected from H, halogen, hydroxyl, methyl, methoxy,
一些实施方式中，式(I)中的R4选自H、卤素、C1-6烷氧基或C1-6卤代烷氧基，优选为F。In some embodiments, R 4 in formula (I) is selected from H, halogen, C 1-6 alkoxy or C 1-6 haloalkoxy, preferably F.
一些实施方式中，式(I)中的R5为H。In some embodiments, R5 in formula (I) is H.
一些实施方式中，式(I)选自(IA)或(IB)：
In some embodiments, formula (I) is selected from (IA) or (IB):
其中，所述X，L，R2，R3，R4及R6的定义如式(I)所述。Wherein, the definitions of X, L, R 2 , R 3 , R 4 and R 6 are as described in formula (I).
一些实施方式中，式(I)选自(IA-1)或(IB-1)：
In some embodiments, formula (I) is selected from (IA-1) or (IB-1):
其中，所述X，L，R2，R3，R4及R6的定义如式(I)所述。Wherein, the definitions of X, L, R 2 , R 3 , R 4 and R 6 are as described in formula (I).
一些实施方式中，式(I)化合物选自(IA-1)和(IB-1)，其中：In some embodiments, the compound of formula (I) is selected from (IA-1) and (IB-1), wherein:
R2选自C6-18芳基或5-18元杂芳基，所述C6-18芳基或5-18元杂芳基任选地进一步被一个或多个Ra取代；所述Ra独立地选自H、羟基、氰基、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-C0-3亚烷基-C3-14环烷基、-C0-3亚烷基-(3-14元杂环基)、-C0-3亚烷基-C6-18芳基或-C0-3亚烷基-(5-18元杂芳基)；R 2 is selected from C 6-18 aryl or 5-18 membered heteroaryl, and the C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a ; the R a is independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl , -C 0-3 alkylene -C 3-14 cycloalkyl, -C 0-3 alkylene - (3-14 membered heterocyclyl), -C 0-3 alkylene -C 6-18 Aryl or -C 0-3 alkylene-(5-18 membered heteroaryl);
R3或R4分别独立的选自H、卤素、氰基、氨基、硝基、C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、C1-6卤代烷基、C1-6卤代烷氧基、羟基或羟基烷基，所述C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、卤代烷基或羟基烷基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基或羟基所取代；R 3 or R 4 are independently selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1 -6 haloalkyl, C 1-6 haloalkoxy, hydroxyl or hydroxyalkyl, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, haloalkyl or The hydroxyalkyl group is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxy;
X选自键、NH、O或S；X is selected from bond, NH, O or S;
L选自键或-C1-3亚烷基-；L is selected from bond or -C 1-3 alkylene-;
R6独立选自H、卤素、C1-6烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基，所述C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选地进一步被一个或多个卤素、羟基、氰基、氨基、硝基或C1-6烷基所取代。R 6 is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl are optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro or Substituted with C 1-6 alkyl.
一些实施方式中，式(I)选自(IA-1-1)或(IB-1-1)：
In some embodiments, formula (I) is selected from (IA-1-1) or (IB-1-1):
所述R2选自所述任选地进一步被一个或多个Ra取代，所述Ra独立地选自H、羟基、氰基、氨基、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基或-C0-3亚烷基-C3-14环烷基；The R 2 is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl;
所述R4选自氢或卤素；The R 4 is selected from hydrogen or halogen;
所述R6选自氢或卤素；The R 6 is selected from hydrogen or halogen;
所述R7选自烷基、卤代烷基或环烷基，优选为甲基、乙基、异丙基、三氟乙基或环丙基。The R 7 is selected from alkyl, haloalkyl or cycloalkyl, preferably methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.
本发明提供一种通式(I)所示的化合物，或其立体异构体、互变异构体、氘代物或药用盐：
The present invention provides a compound represented by general formula (I), or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt:
其中，in,
X选自键、NRa、O或S；X is selected from bond, NR a , O or S;
选自单键或双键； Selected from single or double bonds;
L选自键、-C1-3亚烷基-、-C3-14环烷基-C0-3亚烷基-或-3-14元杂环基-C0-3亚烷基-；所述-C1-3亚烷基-、-C3-14环烷基-C0-3亚烷基-或-3-14元杂环基-C0-3亚烷基-任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基或羟基所取代；L is selected from bond, -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene- ;The -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene-optional Further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
所述环A选自C5-14环烷基、5-14元杂环基、C6-18芳基或5-18元杂芳基；所述C5-14环烷基、5-14元杂环基、C6-18芳基或5-18元杂芳基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基、羟基、所取代； The ring A is selected from C 5-14 cycloalkyl, 5-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 5-14 cycloalkyl, 5-14 The one-membered heterocyclyl group, C 6-18 aryl group or 5-18 membered heteroaryl group is optionally further substituted by one or more halogen, C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, cyano group, Amino, nitro, hydroxyl, replaced;
选自其中，中的两个R6可与其所连接的原子一起形成C3-8的环烷基或3-8元杂环基，所述C3-8环烷基、3-8元杂环基任选地进一步被一个或多个Ra所取代； Selected from in, The two R 6 in can together form a C 3-8 cycloalkyl group or a 3-8 membered heterocyclyl group with the atoms to which they are connected. The C 3-8 cycloalkyl group and 3-8 membered heterocyclyl group are optional ground is further replaced by one or more R a ;
R2选自C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基；所述C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选地进一步被一个或多个Ra取代；R 2 is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 3-14 cycloalkyl, 3-14 membered heterocyclyl The ring group, C 6-18 aryl group or 5-18 membered heteroaryl group is optionally further substituted by one or more R a ;
R3或R4分别独立的选自H、卤素、氰基、氨基、-NHRa、-N(Ra)2、硝基、C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、C1-6卤代烷基、C1-6卤代烷氧基或羟基；所述C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、C1-6卤代烷基或C1-6卤代烷氧基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、氰基、氨基、硝基或羟基所取代；R 3 or R 4 are independently selected from H, halogen, cyano, amino, -NHR a , -N(R a ) 2 , nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy or hydroxyl; the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl The base -O-, C 1-6 haloalkyl or C 1-6 haloalkoxy is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , cyano, amino, nitro or hydroxyl substituted;
R5选自H、卤素、-C0-3亚烷基氰基、C1-6烷基、C1-6烷氧基或C1-6卤代烷基；R 5 is selected from H, halogen, -C 0-3 alkylenecyano, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl;
R6选自H、卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基；所述C1-6烷基、C1-6卤代烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选进一步被一个或多个卤素、羟基、氰基、氨基、硝基、C1-6烷基或C1-6烷氧基所取代；R 6 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 The heteroaryl group is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy;
Ra各自独立地选自H、羟基、氰基、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、-C0- 3亚烷基-ORb、-OC(＝O)C1-6烷基、-C0-3亚烷基-SRb、-C0-3亚烷基-N(Rb)2、-C0-3亚烷基-S(＝O)Rb、-C0-3亚烷基-S(＝O)2Rb、-C0-3亚烷基-SRb、-C0-3亚烷基-S(Rb)5、-C0-3亚烷基-C(＝O)Rb、-C0-3亚烷基-C(＝O)ORb、-C0-3亚烷基-C(＝O)N(Rb)2、C2-6烯基、C2-6炔基、-C0-3亚烷基-C3-14环烷基、-C0-3亚烷基-(3-14元杂环基)、-C0-3亚烷基-C6-18芳基或-C0-3亚烷基-(5-18元杂芳基)；所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-C0-3亚烷基-C3-14环烷基、-C0-3亚烷基-(3-14元杂环基)、-C0-3亚烷基-C6-18芳基或-C0-3亚烷基-(5-18元杂芳基)任选地进一步被一个或多个Rb取代； R a is each independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -C 0-3 alkylene -OR b , -OC(=O)C 1-6 alkyl, -C 0-3 alkylene -SR b , -C 0-3 alkylene -N(R b ) 2 , -C 0-3 alkylene- S(=O)R b , -C 0-3 alkylene -S(=O) 2 R b , -C 0-3 alkylene -SR b , -C 0-3 alkylene -S(R b ) 5 , -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b , -C 0-3 alkylene-C(= O)N(R b ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-3 alkylene -C 3-14 cycloalkyl, -C 0-3 alkylene -( 3-14 membered heterocyclyl), -C 0-3 alkylene-C 6-18 aryl or -C 0-3 alkylene-(5-18 membered heteroaryl); the C 1-6 Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-3 alkylene -C 3-14 cycloalkyl, - C 0-3 alkylene-(3-14 membered heterocyclyl), -C 0-3 alkylene-C 6-18 aryl or -C 0-3 alkylene-(5-18 membered heteroaryl radical) optionally further substituted by one or more R b ;
每个Rb独立地为H、卤素、羟基、氰基、C1-6烷基、C3-6环烷基或C1-6卤代烷基；Each R b is independently H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl;
m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.
一些实施方式中，式(I)中的X为O。In some embodiments, X in formula (I) is O.
一些实施方式中，式(I)中的L选自-C1-3亚烷基-或-C3-14环烷基-C0-3亚烷基-。In some embodiments, L in formula (I) is selected from -C 1-3 alkylene- or -C 3-14 cycloalkyl-C 0-3 alkylene-.
一些实施方式中，式(I)中的环A选自C5-14环烷基或5-14元杂环基。In some embodiments, Ring A in formula (I) is selected from C 5-14 cycloalkyl or 5-14 membered heterocyclyl.
一些实施方式中，式(I)中的5-14元杂环基为稠环。 In some embodiments, the 5-14 membered heterocyclyl group in formula (I) is a fused ring.
一些实施方式中，式(I)中的稠环选自 In some embodiments, the fused ring in formula (I) is selected from
一些实施方式中，式(I)中的选自 In some embodiments, in formula (I) Selected from
一些实施方式中，式(I)中的R6独立选自H、卤素、C1-6烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基；所述C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选地进一步被一个或多个卤素、羟基、氰基、氨基、硝基或C1-6烷基所取代。In some embodiments, R 6 in formula (I) is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogens , hydroxyl, cyano, amino, nitro or C 1-6 alkyl substituted.
一些实施方式中，式(I)中的选自所述 可任选地进一步被一个或多个卤素、C1-6烷基或所取代。In some embodiments, in formula (I) Selected from described may optionally be further substituted by one or more halogens, C 1-6 alkyl or replaced.
一些实施方式中，式(I)中的选自所述 任选地进一步被一个或多个所取代。In some embodiments, in formula (I) Selected from described optionally further by one or more replaced.
一些实施方式中，式(I)中的选自 其中，表示Z构型或E构型。In some embodiments, in formula (I) Selected from in, Indicates Z configuration or E configuration.
一些实施方式中，式(I)中的选自 In some embodiments, in formula (I) Selected from
一些实施方式中，式(I)中的R2选自C6-18芳基或5-18元杂芳基；所述C6-18芳基或5-18元杂芳基任选地进一步被一个或多个Ra取代，Ra独立地选自H、羟基、氰基、氨基、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基或-C0-3亚烷基-C3-14环烷基。In some embodiments, R 2 in formula (I) is selected from C 6-18 aryl or 5-18 membered heteroaryl; the C 6-18 aryl or 5-18 membered heteroaryl is optionally further Substituted by one or more R a , R a independently selected from H, hydroxyl, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 -6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
一些实施方式中，式(I)中的R2选自 其中，所述 In some embodiments, R in formula (I) is selected from Among them, the
任选地进一步被一个或多个Ra取代，所述Ra独立地选自H、羟基、氰基、氨基、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基或-C0-3亚烷基-C3-14环烷基。Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
一些实施方式中，式(I)中的R2选自 In some embodiments, R in formula (I) is selected from
一些实施方式中，式(I)中的R3选自H、羟基、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C3-14环烷基-O-。In some embodiments, R 3 in formula (I) is selected from H, hydroxyl, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 3-14 Cycloalkyl-O-.
一些实施方式中，式(I)中的R3选自H、卤素、羟基、甲基、甲氧基、 In some embodiments, R in formula (I) is selected from H, halogen, hydroxyl, methyl, methoxy,
一些实施方式中，式(I)中的R4选自H、卤素、C1-6烷氧基或C1-6卤代烷氧基；优选为F。In some embodiments, R 4 in formula (I) is selected from H, halogen, C 1-6 alkoxy or C 1-6 haloalkoxy; preferably F.
一些实施方式中，式(I)中的R5为H。In some embodiments, R5 in formula (I) is H.
一些实施方式中，式(I)选自(IA)或(IB)：
In some embodiments, formula (I) is selected from (IA) or (IB):
其中，所述环A，X，L，R2，R3，R4及R6的定义如式(I)所述。Wherein, the definitions of ring A, X, L, R 2 , R 3 , R 4 and R 6 are as described in formula (I).
一些实施方式中，式(I)选自(IA-1)或(IB-1)：
In some embodiments, formula (I) is selected from (IA-1) or (IB-1):
其中，所述X，L，R2，R3，R4及R6的定义如式(I)所述。Wherein, the definitions of X, L, R 2 , R 3 , R 4 and R 6 are as described in formula (I).
一些实施方式中，式(I)选自(IA-1’)或(IB-1’)：
In some embodiments, formula (I) is selected from (IA-1') or (IB-1'):
其中，所述X，L，R2，R3，R4、R6和Ra的定义如式(I)所述。Wherein, the definitions of X, L, R 2 , R 3 , R 4 , R 6 and R a are as described in formula (I).
一些实施方式中，式(I)化合物选自(IA-1)、(IB-1)、(IA-1’)或(IB-1’)，其中：In some embodiments, the compound of formula (I) is selected from (IA-1), (IB-1), (IA-1') or (IB-1'), wherein:
所述R2选自C6-18芳基或5-18元杂芳基；其中，所述C6-18芳基或5-18元杂芳基任选地进一步被一个或多个Ra取代，所述Ra独立地选自H、羟基、氰基、卤素、C1-6烷基、C1- 6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-C0-3亚烷基-C3-14环烷基、-C0-3亚烷基-(3-14元杂环基)、-C0-3亚烷基-C6-18芳基或-C0-3亚烷基-(5-18元杂芳基)；The R 2 is selected from C 6-18 aryl or 5-18 membered heteroaryl; wherein, the C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a Substituted, the R a is independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 -6 alkynyl, -C 0-3 alkylene -C 3-14 cycloalkyl, -C 0-3 alkylene - (3-14 membered heterocyclyl), -C 0-3 alkylene - C 6-18 aryl or -C 0-3 alkylene-(5-18 membered heteroaryl);
所述R3或R4分别独立的选自H、卤素、氰基、氨基、硝基、C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、C1-6卤代烷基、C1-6卤代烷氧基或羟基；其中，所述C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、C1-6卤代烷基或C1-6卤代烷氧基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基或羟基所取代；The R 3 or R 4 are independently selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy or hydroxyl; wherein, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1- 6 haloalkyl or C 1-6 haloalkoxy is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl ;
所述X选自键、NH、O或S；The X is selected from bond, NH, O or S;
所述L选自键或-C1-3亚烷基-；The L is selected from bond or -C 1-3 alkylene-;
所述R6独立选自H、卤素、C1-6烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基，所述C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选地进一步被一个或多个卤素、羟基、氰基、氨基、硝基或C1-6烷基所取代。The R 6 is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, so The C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro substituted by C 1-6 alkyl group.
一些实施方式中，式(I)选自(IA-1-1)或(IB-1-1)：
In some embodiments, formula (I) is selected from (IA-1-1) or (IB-1-1):
所述R2选自所述任选地进一步被一个或多个Ra取代，所述Ra独立地选自H、羟基、氰基、氨基、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基或-C0-3亚烷基-C3-14环烷基；The R 2 is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl;
所述R4选自氢或卤素；The R 4 is selected from hydrogen or halogen;
所述R6选自氢或卤素；The R 6 is selected from hydrogen or halogen;
所述R7选自C1-6烷基、C1-6卤代烷基或C3-14环烷基；优选为甲基、乙基、异丙基、三氟乙基或环丙基。The R 7 is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-14 cycloalkyl; preferably it is methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.
一些实施方式中，式(I)选自(IA-1’-1)或(IB-1’-1)：
In some embodiments, formula (I) is selected from (IA-1'-1) or (IB-1'-1):
所述R2选自所述任选地进一步被一个或多个Ra取代，所述Ra独立地选自H、羟基、氰基、氨基、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基或-C0-3亚烷基-C3-14环烷基；The R 2 is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl;
所述R4选自氢或卤素；The R 4 is selected from hydrogen or halogen;
所述R6选自氢或卤素；The R 6 is selected from hydrogen or halogen;
所述R7选自C1-6烷基、C1-6卤代烷基或C3-14环烷基，优选为甲基、乙基、异丙基、三氟乙基或环丙基。 The R 7 is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-14 cycloalkyl, preferably methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.
本发明提供一种通式(I)所示的化合物，或其立体异构体、互变异构体、氘代物或药用盐：
The present invention provides a compound represented by general formula (I), or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt:
其中，in,
X选自键、NRa、O或S；X is selected from bond, NR a , O or S;
选自单键或双键； Selected from single or double bonds;
L选自键、-C1-3亚烷基-、-C3-14环烷基-C0-3亚烷基-或-3-14元杂环基-C0-3亚烷基-；所述-C1-3亚烷基-、-C3-14环烷基-C0-3亚烷基-或-3-14元杂环基-C0-3亚烷基-任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基或羟基所取代；L is selected from bond, -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene- ;The -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene-optional Further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
所述环A选自C5-14环烷基、5-14元杂环基、C6-18芳基或5-18元杂芳基；所述C5-14环烷基、5-14元杂环基、C6-18芳基或5-18元杂芳基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基、羟基、所取代；The ring A is selected from C 5-14 cycloalkyl, 5-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 5-14 cycloalkyl, 5-14 The one-membered heterocyclyl group, C 6-18 aryl group or 5-18 membered heteroaryl group is optionally further substituted by one or more halogen, C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, cyano group, Amino, nitro, hydroxyl, replaced;
选自其中，中的两个R6可与其所连接的原子一起形成C3-8的环烷基或3-8元杂环基，所述C3-8环烷基、3-8元杂环基任选地进一步被一个或多个Ra所取代； Selected from in, The two R 6 in can together form a C 3-8 cycloalkyl group or a 3-8 membered heterocyclyl group with the atoms to which they are connected. The C 3-8 cycloalkyl group and 3-8 membered heterocyclyl group are optional ground is further replaced by one or more R a ;
R2选自C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基；所述C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选地进一步被一个或多个Ra取代；R 2 is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 3-14 cycloalkyl, 3-14 membered heterocyclyl The ring group, C 6-18 aryl group or 5-18 membered heteroaryl group is optionally further substituted by one or more R a ;
R3独立地选自C1-6烷氧基、C3-14环烷基-O-或C1-6卤代烷氧基；所述C1-6烷氧基、C3- 14环烷基-O-或C1-6卤代烷氧基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、C1- 6卤代烷基、氰基、氨基、硝基或羟基所取代；R 3 is independently selected from C 1-6 alkoxy, C 3-14 cycloalkyl-O- or C 1-6 haloalkoxy; the C 1-6 alkoxy, C 3-14 cycloalkyl -O- or C 1-6 haloalkoxy is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, cyano, amino, nitro or substituted by hydroxyl;
R4独立地选自H、卤素、氰基、氨基、-NHRa、-N(Ra)2、硝基、C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、C1-6卤代烷基、C1-6卤代烷氧基或羟基；所述C1-6烷基、C1-6烷氧基、C3- 14环烷基-O-、C1-6卤代烷基或C1-6卤代烷氧基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、氰基、氨基、硝基或羟基所取代；R 4 is independently selected from H, halogen, cyano, amino, -NHR a , -N(R a ) 2 , nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 ring Alkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy or hydroxyl; the C 1-6 alkyl, C 1-6 alkoxy, C 3- 14 cycloalkyl-O-, C 1-6 haloalkyl or C 1-6 haloalkoxy is optionally further substituted by one or more halogens, C 1-6 alkyl, C 1-6 alkoxy, C 1- 6 substituted by haloalkyl, cyano, amino, nitro or hydroxyl;
R5选自H、卤素、-C0-3亚烷基氰基、C1-6烷基、C1-6烷氧基或C1-6卤代烷基；R 5 is selected from H, halogen, -C 0-3 alkylenecyano, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl;
R6选自H、卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基；所述C1-6烷基、C1-6卤代烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选进一步被一个或多个卤素、羟基、氰基、氨基、硝基、C1-6烷基或C1-6烷氧基所取代；R 6 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 The heteroaryl group is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy;
Ra各自独立地选自H、羟基、氰基、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、-C0- 3亚烷基-ORb、-OC(＝O)C1-6烷基、-C0-3亚烷基-SRb、-C0-3亚烷基-N(Rb)2、-C0-3亚烷基-S(＝O)Rb、-C0-3亚烷基-S(＝O)2Rb、-C0-3亚烷基-SRb、-C0-3亚烷基-S(Rb)5、-C0-3亚烷基-C(＝O)Rb、-C0-3亚烷基-C(＝O)ORb、-C0-3亚烷基-C(＝O)N(Rb)2、C2-6烯基、C2-6炔基、-C0-3亚烷基-C3-14环烷基、-C0-3亚烷基-(3-14元杂环基)、-C0-3亚烷基-C6-18芳基或-C0-3亚烷基-(5-18元杂芳基)；所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-C0-3亚烷基-C3-14环烷基、-C0-3亚烷基-(3-14元杂环基)、-C0-3亚烷基-C6-18芳基或-C0-3亚烷基-(5-18元杂芳基)任选地进一步被一个或多个Rb取代； R a is each independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -C 0-3 alkylene -OR b , -OC(=O)C 1-6 alkyl, -C 0-3 alkylene -SR b , -C 0-3 alkylene -N(R b ) 2 , -C 0-3 alkylene- S(=O)R b , -C 0-3 alkylene -S(=O) 2 R b , -C 0-3 alkylene -SR b , -C 0-3 alkylene -S(R b ) 5 , -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b , -C 0-3 alkylene-C(= O)N(R b ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-3 alkylene -C 3-14 cycloalkyl, -C 0-3 alkylene -( 3-14 membered heterocyclyl), -C 0-3 alkylene-C 6-18 aryl or -C 0-3 alkylene-(5-18 membered heteroaryl); the C 1-6 Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-3 alkylene -C 3-14 cycloalkyl, - C 0-3 alkylene-(3-14 membered heterocyclyl), -C 0-3 alkylene-C 6-18 aryl or -C 0-3 alkylene-(5-18 membered heteroaryl radical) optionally further substituted by one or more R b ;
每个Rb独立地为H、卤素、羟基、氰基、C1-6烷基、C3-6环烷基、C1-6卤代烷基、-C(＝O)C1-6烷基或-C(＝O)OC1-6烷基；Each R b is independently H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, -C(=O)C 1-6 alkyl Or -C(=O)OC 1-6 alkyl;
m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.
一些实施方式中，式(I)中所述每个Rb独立地为H、卤素、羟基、氰基、C1-6烷基、C3-6环烷基或C1-6卤代烷基。In some embodiments, each R b in formula (I) is independently H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl.
一些实施方式中，式(I)所述X选自键、NH、O或S；In some embodiments, X in formula (I) is selected from bonds, NH, O or S;
所述环A选自C5-14环烷基、5-14元杂环基、C6-18芳基或5-18元杂芳基，所述C5-14环烷基或5-14元杂环基选自单环、稠环、螺环或桥环，所述C5-14环烷基、5-14元杂环基、C6-18芳基或5-18元杂芳基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基或羟基所取代；The ring A is selected from C 5-14 cycloalkyl, 5-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, and the C 5-14 cycloalkyl or 5-14 The membered heterocyclyl group is selected from a single ring, a condensed ring, a spiro ring or a bridged ring, and the C 5-14 cycloalkyl group, 5-14 membered heterocyclyl group, C 6-18 aryl group or 5-18 membered heteroaryl group Optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
选自其中，为双键，选自Z构型或E构型； Selected from in, is a double bond, Selected from Z configuration or E configuration;
R3独立选自C1-6烷氧基、C3-14环烷基-O-或C1-6卤代烷氧基，所述C1-6烷氧基或C3-14环烷基-O-进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基或羟基所取代；R 3 is independently selected from C 1-6 alkoxy, C 3-14 cycloalkyl-O- or C 1-6 haloalkoxy, said C 1-6 alkoxy or C 3-14 cycloalkyl- O- is further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
R4选自H、卤素、氰基、氨基、硝基、C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、C1-6卤代烷基、C1-6卤代烷氧基、羟基或羟基烷基，所述C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、卤代烷基或羟基烷基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基或羟基所取代；R 4 is selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl or hydroxyalkyl, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, haloalkyl or hydroxyalkyl optionally further Substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
每个Rb独立地为H、卤素、羟基、氰基、C1-6烷基、C3-6环烷基或C1-6卤代烷基。Each R b is independently H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, or C 1-6 haloalkyl.
一些实施方式中，式(I)中所述X为O。In some embodiments, X in formula (I) is O.
一些实施方式中，式(I)中所述L选自-C1-3亚烷基-或-C3-14环烷基-C0-3亚烷基-。In some embodiments, L in formula (I) is selected from -C 1-3 alkylene- or -C 3-14 cycloalkyl-C 0-3 alkylene-.
一些实施方式中，式(I)中所述环A选自C5-14环烷基或5-14元杂环基。In some embodiments, Ring A in formula (I) is selected from C 5-14 cycloalkyl or 5-14 membered heterocyclyl.
一些实施方式中，式(I)中所述5-14元杂环基为稠环。In some embodiments, the 5-14 membered heterocyclyl group in formula (I) is a fused ring.
一些实施方式中，式(I)中所述稠环选自 In some embodiments, the fused ring described in formula (I) is selected from
一些实施方式中，式(I)中所述选自 In some embodiments, as described in Formula (I) Selected from
一些实施方式中，式(I)中所述R6独立选自H、卤素、C1-6烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基；所述C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选地进一步被一个或多个卤素、羟基、氰基、氨基、硝基或C1-6烷基所取代。In some embodiments, R 6 in formula (I) is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl Or 5-18 membered heteroaryl; the C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more Substituted by halogen, hydroxyl, cyano, amino, nitro or C 1-6 alkyl.
一些实施方式中，式(I)中所述选自所述 可任选地进一步被一个或多个卤素、C1-6烷基或所取代。 In some embodiments, as described in Formula (I) Selected from described may optionally be further substituted by one or more halogens, C 1-6 alkyl or replaced.
一些实施方式中，式(I)中所述选自所述 任选地进一步被一个或多个所取代。In some embodiments, as described in Formula (I) Selected from described optionally further by one or more replaced.
一些实施方式中，式(I)中所述选自 其中，表示Z构型或E构型。In some embodiments, as described in Formula (I) Selected from in, Indicates Z configuration or E configuration.
一些实施方式中，式(I)中所述选自 In some embodiments, as described in Formula (I) Selected from
一些实施方式中，式(I)中R2选自C6-18芳基或5-18元杂芳基；所述C6-18芳基或5-18元杂芳基任选地进一步被一个或多个Ra取代，Ra独立地选自H、羟基、氰基、氨基、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基或-C0-3亚烷基-C3-14环烷基。In some embodiments, R 2 in formula (I) is selected from C 6-18 aryl or 5-18 membered heteroaryl; the C 6-18 aryl or 5-18 membered heteroaryl is optionally further One or more R a is substituted, R a is independently selected from H, hydroxyl, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2- 6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
一些实施方式中，式(I)中所述R2选自 其中，所述 In some embodiments, R 2 in formula (I) is selected from Among them, the
任选地进一步被一个或多个Ra取代，所述Ra独立地选自H、羟基、氰基、氨基、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基或-C0-3亚烷基-C3-14环烷基。 Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
一些实施方式中，式(I)中所述R2选自 In some embodiments, R 2 in formula (I) is selected from
一些实施方式中，式(I)中所述R3选自C1-6烷氧基或C3-14环烷基-O-。In some embodiments, R 3 in formula (I) is selected from C 1-6 alkoxy or C 3-14 cycloalkyl-O-.
一些实施方式中，式(I)中所述R3选自甲氧基、 In some embodiments, R 3 in formula (I) is selected from methoxy,
一些实施方式中，式(I)中所述R4选自H、卤素、C1-6烷氧基或C1-6卤代烷氧基；优选为F。In some embodiments, R 4 in formula (I) is selected from H, halogen, C 1-6 alkoxy or C 1-6 haloalkoxy; preferably F.
一些实施方式中，式(I)中所述R5为H。In some embodiments, R 5 in Formula (I) is H.
一些实施方式中，式(I)中所述式(I)化合物选自式(IA)或(IB)：
In some embodiments, the compound of formula (I) described in formula (I) is selected from formula (IA) or (IB):
其中，所述环A，X，L，R2，R3，R4及R6的定义如上述通式(I)中所述。Wherein, the definitions of ring A, X, L, R 2 , R 3 , R 4 and R 6 are as described in the above general formula (I).
一些实施方式中，式(I)化合物选自式(IA-1)或(IB-1)：
In some embodiments, the compound of formula (I) is selected from formula (IA-1) or (IB-1):
其中，所述X，L，R2，R3，R4及R6的定义如上述通式(I)中所述。Wherein, the definitions of X, L, R 2 , R 3 , R 4 and R 6 are as described in the above general formula (I).
一些实施方式中，式(I)化合物选自式(IA-1’)或(IB-1’)：
In some embodiments, the compound of formula (I) is selected from formula (IA-1') or (IB-1'):
其中，所述X，L，R2，R3，R4、R6和Ra的定义如上述通式(I)中所述。Wherein, the definitions of X, L, R 2 , R 3 , R 4 , R 6 and R a are as described in the above general formula (I).
一些实施方式中，式(IA-1)、(IB-1)、(IA-1’)或(IB-1’)中，所述R2选自C6- 18芳基或5-18元杂芳基；其中，所述C6-18芳基或5-18元杂芳基任选地进一步被一个或多个Ra取代，所述Ra独立地选自H、羟基、氰基、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-C0-3亚烷基-C3-14环烷基、-C0-3亚烷基-(3-14元杂环基)、-C0-3亚烷基-C6-18芳基或-C0-3亚烷基-(5-18元杂芳基)；In some embodiments, in formula (IA-1), (IB-1), (IA-1') or ( IB -1'), the R 2 is selected from C 6-18 aryl or 5-18 yuan Heteroaryl; wherein, the C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a , and the R a is independently selected from H, hydroxyl, cyano, Halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-3 alkylene-C 3- 14- cycloalkyl, -C 0-3 alkylene-(3-14 membered heterocyclyl), -C 0-3 alkylene-C 6-18 aryl or -C 0-3 alkylene-( 5-18 membered heteroaryl);
所述R3选自C1-6烷氧基、C3-14环烷基-O-或C1-6卤代烷氧基；其中，所述C1-6烷氧基、C3-14环烷基-O-或C1-6卤代烷氧基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、氰基、氨基、硝基或羟基所取代； The R 3 is selected from C 1-6 alkoxy, C 3-14 cycloalkyl-O- or C 1-6 haloalkoxy; wherein, the C 1-6 alkoxy, C 3-14 cycloalkyl Alkyl-O- or C 1-6 haloalkoxy is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, cyano, amino, Substituted by nitro or hydroxyl;
R4选自H、卤素、氰基、氨基、硝基、C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、C1-6卤代烷基、C1-6卤代烷氧基或羟基；其中，所述C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、C1- 6卤代烷基或C1-6卤代烷氧基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、氰基、氨基、硝基或羟基所取代；R 4 is selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy or hydroxyl; wherein, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl or C 1-6 The haloalkoxy group is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, cyano, amino, nitro or hydroxyl;
所述X选自键、NH、O或S；The X is selected from bond, NH, O or S;
所述L选自键或-C1-3亚烷基-；The L is selected from bond or -C 1-3 alkylene-;
所述R6独立选自H、卤素、C1-6烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基，所述C1-6烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选地进一步被一个或多个卤素、羟基、氰基、氨基、硝基或C1-6烷基所取代。The R 6 is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, so The C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogens, hydroxyl groups , cyano, amino, nitro or C 1-6 alkyl substituted.
一些实施方式中，式(I)选自式(IA-1-1)或(IB-1-1)：
In some embodiments, formula (I) is selected from formula (IA-1-1) or (IB-1-1):
所述R2选自所述任选地进一步被一个或多个Ra取代，所述Ra独立地选自H、羟基、氰基、氨基、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基或-C0-3亚烷基-C3-14环烷基；The R 2 is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl;
所述R4选自氢或卤素；The R 4 is selected from hydrogen or halogen;
所述R6选自氢或卤素；The R 6 is selected from hydrogen or halogen;
所述R7选自C1-6烷基、C1-6卤代烷基或C3-14环烷基；优选为甲基、乙基、异丙基、三氟乙基或环丙基。The R 7 is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-14 cycloalkyl; preferably it is methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.
一些实施方式中，式(I)选自(IA-1’-1)或(IB-1’-1)：
In some embodiments, formula (I) is selected from (IA-1'-1) or (IB-1'-1):
所述R2选自所述任选地进一步被一个或多个Ra取代，所述Ra独立地选自H、羟基、氰基、氨基、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基或-C0-3亚烷基-C3-14环烷基；The R 2 is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl;
所述R4选自氢或卤素；The R 4 is selected from hydrogen or halogen;
所述R6选自氢或卤素；The R 6 is selected from hydrogen or halogen;
所述R7选自C1-6烷基、C1-6卤代烷基或C3-14环烷基，优选为甲基、乙基、异丙基、三氟乙基或环丙基。The R 7 is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-14 cycloalkyl, preferably methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.
一些实施方式中，式(I)中的化合物选自：



In some embodiments, the compound of formula (I) is selected from:



一些实施方式中，式(I)化合物涉及的中间体化合物，所述中间体化合物选自：

In some embodiments, the compound of formula (I) relates to an intermediate compound, and the intermediate compound is selected from:

本发明还提供了中间体化合物M13的制备方法，其包括以下步骤：将消旋体M9与手性酸反应生成对应的盐，在碱性条件下游离，得到S构型的游离碱M13。The present invention also provides a method for preparing intermediate compound M13, which includes the following steps: reacting racemate M9 with a chiral acid to generate the corresponding salt, and dissociating it under alkaline conditions to obtain S-configured free base M13.
在本发明的一些实施方式中，所述手性酸选自L-(-)-二对甲基苯甲酰酒石酸、L-(-)-二苯甲酰酒石酸或L-(-)-二对甲氧基苯甲酰酒石酸。In some embodiments of the invention, the chiral acid is selected from L-(-)-di-p-toluoyltartaric acid, L-(-)-dibenzoyltartaric acid or L-(-)-dibenzoyltartaric acid. p-Methoxybenzoyltartaric acid.
在本发明的一些实施方式中，中间体化合物M13的制备方法，包括以下步骤：In some embodiments of the present invention, the preparation method of intermediate compound M13 includes the following steps:
1)将消旋体M9与手性酸L-(-)-二对甲基苯甲酰酒石酸(DPLT)反应生成对应化合物M13-1，1) React racemate M9 with chiral acid L-(-)-di-p-methylbenzoyltartaric acid (DPLT) to generate the corresponding compound M13-1,
2)在碱性条件下游离得到S构型的游离碱M13。
2) Dissociate under alkaline conditions to obtain S-configuration free base M13.
在本发明的一些实施方式中，中间体M13的制备方法，进一步包括以下步骤：In some embodiments of the present invention, the preparation method of intermediate M13 further includes the following steps:
1)M13-1的制备1) Preparation of M13-1
将M9溶于有机溶剂1，升温搅拌溶清，得到M9的溶液；将L-(-)-二对甲基苯甲酰酒石酸溶于有机溶剂2中形成酸液；将酸液缓慢滴加至M9的溶液中，酸液滴加完成，加热溶清后，向反应液中滴加有机溶剂3，滴加完成后缓慢降温，析晶，样品抽滤，滤饼真空干燥，得到(S)-DPLT盐的粗品，将(S)-DPLT盐的粗品在有机溶剂4中重结晶后得到(S)-DPLT盐M13-1；Dissolve M9 in organic solvent 1, raise the temperature and stir to dissolve, to obtain a solution of M9; dissolve L-(-)-di-p-methylbenzoyltartaric acid in organic solvent 2 to form an acid solution; slowly add the acid solution dropwise to In the solution of M9, the acid solution is added dropwise. After heating and dissolving, the organic solvent 3 is added dropwise to the reaction solution. After the dropwise addition is completed, the temperature is slowly cooled and crystallized. The sample is filtered and the filter cake is vacuum dried to obtain (S)- The crude product of DPLT salt, the crude product of (S)-DPLT salt is recrystallized in organic solvent 4 to obtain (S)-DPLT salt M13-1;
2)M13的制备2) Preparation of M13
称取M13-1于反应釜中，加入有机溶剂5，搅拌溶清；向反应液中加入纯化水，碱，调节水相pH至11～12，搅拌；水相用有机溶剂6搅拌后分液萃取；有机相经洗涤，干燥，干燥后的有机相过滤，滤液进行浓缩，得到M13。Weigh M13-1 into the reaction kettle, add organic solvent 5, stir to dissolve; add purified water and alkali to the reaction solution, adjust the pH of the water phase to 11~12, stir; stir the water phase with organic solvent 6 and separate the liquids Extraction; the organic phase is washed, dried, the dried organic phase is filtered, and the filtrate is concentrated to obtain M13.
作为优选，所述步骤1)中有机溶剂1选自2-甲基四氢呋喃、乙醇、乙腈、乙酮、乙 酮/H2O(19/1，体积比)、乙腈/水(30/1，体积比)或其混合物。Preferably, the organic solvent 1 in step 1) is selected from the group consisting of 2-methyltetrahydrofuran, ethanol, acetonitrile, ethyl ketone, and ethanol. Ketone/H 2 O (19/1, volume ratio), acetonitrile/water (30/1, volume ratio) or mixtures thereof.
作为优选，所述步骤1)中有机溶剂2选自乙酸乙酯、乙醇、异丙醇、乙酮、乙酸异丙酯、四氢呋喃、2-甲基四氢呋喃或其混合物。Preferably, the organic solvent 2 in step 1) is selected from ethyl acetate, ethanol, isopropyl alcohol, ethanone, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran or a mixture thereof.
作为优选，所述步骤1)中有机溶剂3选自乙酸乙酯、异丙醇、醋酸异丙酯、甲基叔丁基醚、正庚烷或其混合物。Preferably, the organic solvent 3 in step 1) is selected from ethyl acetate, isopropyl alcohol, isopropyl acetate, methyl tert-butyl ether, n-heptane or a mixture thereof.
作为优选，所述步骤1)中有机溶剂4选自异丙醇/乙腈乙酮/乙腈/乙酸乙酯、甲醇/乙腈/乙酸乙酯、乙醇/乙酮/乙酸乙酯、乙醇/甲基叔丁基醚、异丙醇/2-甲基四氢呋喃F、甲醇/2-甲基四氢呋喃或乙醇/乙腈/乙酸乙酯。作为优选，所述步骤2)中有机溶剂5选自二氯甲烷/甲醇、2-甲基四氢呋喃F、乙酸乙酯或其混合物。Preferably, the organic solvent 4 in step 1) is selected from isopropyl alcohol/acetonitrile ethanol/acetonitrile/ethyl acetate, methanol/acetonitrile/ethyl acetate, ethanol/ethyl ketone/ethyl acetate, ethanol/methyl tert. Butyl ether, isopropyl alcohol/2-methyltetrahydrofuran F, methanol/2-methyltetrahydrofuran or ethanol/acetonitrile/ethyl acetate. Preferably, the organic solvent 5 in step 2) is selected from dichloromethane/methanol, 2-methyltetrahydrofuran F, ethyl acetate or a mixture thereof.
作为优选，所述步骤2)有机溶剂6选自二氯甲烷/甲醇、2-甲基四氢呋喃或乙酸乙酯。Preferably, the organic solvent 6 in step 2) is selected from dichloromethane/methanol, 2-methyltetrahydrofuran or ethyl acetate.
本发明还提供了一种药物组合物，其中，所述药物组合物包含治疗有效量的至少一种式(I)所示的化合物、其立体异构体、互变异构体、氘代物或药用盐。The present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective amount of at least one compound represented by formula (I), its stereoisomer, tautomer, deuterated product or Medicinal salt.
本发明提供了结构式(I)所示化合物或其药物组合物在制备药物中的应用。The present invention provides the use of the compound represented by structural formula (I) or its pharmaceutical composition in the preparation of medicines.
本发明进一步提供了所述应用的优选技术方案：The present invention further provides preferred technical solutions for the application:
作为优选，所述应用为制备治疗和/或预防癌症药物中的应用。Preferably, the application is in the preparation of drugs for the treatment and/or prevention of cancer.
作为优选，所述应用为制备用于治疗由KRAS G12D介导的疾病的药物的应用。作为优选，所述疾病是癌症。Preferably, the application is the application of preparing drugs for treating diseases mediated by KRAS G12D. Preferably, the disease is cancer.
作为优选，所述癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、宫颈癌、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、前列腺癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, polymorphic lung cancer, ovarian cancer, esophageal cancer Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumors, cholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
本发明还提供了一种治疗和/或预防疾病的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物，其立体异构体、互变异构体、氘代物或药用盐或含其的药物组合物。The present invention also provides a method for treating and/or preventing diseases, which includes administering to the treatment subject a therapeutically effective amount of at least any one compound represented by structural formula (I), its stereoisomer, tautomer, deuterium substitutes or pharmaceutically acceptable salts or pharmaceutical compositions containing them.
本发明还提供了一种治疗和/或预防由KRAS G12D介导的疾病的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物，，其立体异构体、互变异构体、氘代物或药用盐或含其的药物组合物。 The present invention also provides a method for treating and/or preventing diseases mediated by KRAS G12D, which includes administering to the treatment subject a therapeutically effective amount of at least any one of the compounds represented by structural formula (I), its stereoisomers, Tautomers, deuterated compounds or pharmaceutically acceptable salts or pharmaceutical compositions containing them.
本发明还提供了一种治疗癌症的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物，其立体异构体、互变异构体、氘代物或药用盐或含其的药物组合物。The present invention also provides a method for treating cancer, which includes administering to a treatment subject a therapeutically effective amount of at least any compound represented by structural formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable Salts or pharmaceutical compositions containing them.
作为优选，在上述方法中，所述KRAS G12D介导的疾病是癌症。Preferably, in the above method, the KRAS G12D-mediated disease is cancer.
作为优选，在上述方法中，所述的癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、宫颈癌、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、前列腺癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。Preferably, in the above method, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, polymorphic Lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Xuwang cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
除非另有说明，所述结构通式中使用的一般化学术语具有通常的含义。Unless otherwise stated, general chemical terms used in the structural formulas have their ordinary meanings.
例如，除非另有说明，本发明所用的术语“卤素”是指氟、氯、溴或碘。For example, unless otherwise stated, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.
在本发明中，除非另有说明，“烷基”包括直链或支链的一价饱和烃基。例如，烷基包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、正己基、2-己基、2-甲基戊基等。类似的，“C1-6烷基”中的“1-6”是指包含有1、2、3、4、5或6个碳原子的直链或支链形式排列的基团。In the present invention, unless otherwise stated, "alkyl" includes linear or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -Pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, " 1-6 " in "C 1-6 alkyl" refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a linear or branched chain.
“烷氧基”是指前述的直链或支链烷基的氧醚形式，即-O-烷基。"Alkoxy" refers to the oxygen ether form of the aforementioned linear or branched alkyl group, that is, -O-alkyl.
术语“亚烷基”是指二价烷基连接基团。亚烷基在形式上是指两个C-H键替换为亚烷基与化合物其余部分的连接点的烷烃。类似的，C1-3亚烷基中的“C1-3”是指含有1、2或3个碳原子的亚烷基，包括但不限于亚甲基、1,2-亚乙基、1,3-亚丙基或1,2-亚异丙基。The term "alkylene" refers to a divalent alkyl linking group. Alkylene formally refers to an alkane in which the two CH bonds are replaced by the alkylene's point of attachment to the rest of the compound. Similarly, "C 1-3 " in C 1-3 alkylene refers to an alkylene group containing 1, 2 or 3 carbon atoms, including but not limited to methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.
术语“卤代烷基”是指一个或多个H已经被卤素原子置换的前述烷基，如C1-6卤代烷基。The term "haloalkyl" refers to the aforementioned alkyl group in which one or more H has been replaced by a halogen atom, such as C 1-6 haloalkyl.
术语“氧代”或“氧代基”是指呈二价取代基形式的氧原子，其与C连接时形成羰基，其与杂原子连接时形成亚砜基或砜基或N-氧化物基团。The term "oxo" or "oxo" refers to an oxygen atom in the form of a divalent substituent which, when attached to C, forms a carbonyl group and which, when attached to a heteroatom, forms a sulfoxide or sulfone or N-oxide group group.
本发明中，除另有说明，术语“芳香环”、“芳香族环”或“芳香族杂环”即为具有芳香族特征(具有(4n+2)个非定域π电子，其中n为整数)的多不饱和环的碳环或杂环。In the present invention, unless otherwise stated, the term "aromatic ring", "aromatic ring" or "aromatic heterocycle" means having aromatic characteristics (having (4n+2) delocalized π electrons, where n is Integer) polyunsaturated ring carbocyclic or heterocyclic ring.
术语“芳基”，在本发明中，除非另有说明，是指未取代或取代的包括碳环的原子的单环或稠环芳香基团。优选C6-18芳基，更优选芳基为C6-10的单环或双环的芳香环基团。优选为苯基、萘基；最优选为萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基上，其中与母体结构连接在一起的环为芳基环，非限制性实例包括但不限于苯并环戊基。The term "aryl", as used herein, unless otherwise stated, refers to an unsubstituted or substituted monocyclic or fused ring aromatic group including atoms of a carbocyclic ring. A C 6-18 aryl group is preferred, and a C 6-10 monocyclic or bicyclic aromatic ring group is more preferred. Preferred are phenyl and naphthyl; most preferred are naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, where the ring attached to the parent structure is an aryl ring, non-limiting examples include but are not limited to benzocyclopentyl.
术语“杂环基”是指具有至少一个含有杂环子的环化烷基或环化烯基的环系统，所述杂原子选自N、O和/或S。所述杂环基可以包括单环或多环(例如具有2、3或4个稠合环、 螺环、桥环等)。杂环基可以经由成环碳原子或成环杂原子与化合物其他部分相连接。优选3-14元杂环基，3-14元杂环基中的“3-14元”是指含有3-14个C、N、O或S的成环原子组成的杂环基；更优选5-14元杂环基和3-8元杂环基，更更优选3-6元杂环基。其中氮或硫杂原子可以选择性地被氧化，并且氮杂原子可以选择性地被季铵化。这些杂环基的实例包括但不限于 氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、氧代哌嗪基、氧代哌啶基、四氢呋喃基、二氧戊环基、四氢咪唑基、四氢噻唑基、四氢恶唑基、四氢吡喃基、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜基和四氢恶二唑基。所述杂环基可以稠合于芳基、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。The term "heterocyclyl" refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heterocyclic atom selected from N, O and/or S. The heterocyclyl group may include monocyclic or polycyclic rings (e.g., having 2, 3 or 4 fused rings, Spiral ring, bridge ring, etc.). Heterocyclyl groups can be connected to other parts of the compound via ring carbon atoms or ring heteroatoms. Preferred are 3-14-membered heterocyclic groups, and the "3-14-membered" in the 3-14-membered heterocyclic groups refers to heterocyclic groups containing 3-14 C, N, O or S ring-forming atoms; more preferably 5-14 membered heterocyclyl and 3-8 membered heterocyclyl, more preferably 3-6 membered heterocyclyl. Wherein the nitrogen or sulfur heteroatoms can be selectively oxidized, and the nitrogen heteroatoms can be selectively quaternized. Examples of these heterocyclyl groups include, but are not limited to Azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxypiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, Tetrahydroxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinylsulfone and tetrahydroxadiazolyl. The heterocyclyl group may be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring attached to the parent structure is the heterocyclyl group.
术语“杂芳基”，在本发明中，除非另有说明，是指具有至少一个杂原子的单环或多环(例如具有2、3或4个稠合环、螺环、桥环等)芳香族杂环，所述杂原子选自N、O和/或S，并且其中所述氮或硫杂原子可以选择性地被氧化，所述氮杂原子可以选择性地被季铵化。优选5-18元杂芳基，其中5-18元杂芳基中的“5-18元”是指含有5-18个C、N、O或S的成环原子组成的杂芳基，更优选的是5-10元杂芳基，杂芳基的实例包括但不限于噻吩基、呋喃基、咪唑基、异恶唑基、恶唑基、吡唑基、吡咯基、噻唑基、噻二唑基、三唑基、吡啶基、哒嗪基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并异恶唑基、苯并噻唑基、苯并噻唑基、苯并噻二唑基、苯并三唑基腺嘌呤、喹啉基或异喹啉基。所述杂芳基可以稠合于芳基、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。The term "heteroaryl" in the present invention, unless otherwise stated, refers to a monocyclic or polycyclic ring with at least one heteroatom (for example, with 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.) Aromatic heterocycle, the heteroatom is selected from N, O and/or S, and wherein the nitrogen or sulfur heteroatom can be selectively oxidized, and the nitrogen heteroatom can be selectively quaternized. Preferred are 5-18-membered heteroaryl groups, wherein the "5-18-membered" in 5-18-membered heteroaryl groups refers to heteroaryl groups containing 5-18 C, N, O or S ring-forming atoms, and more Preferred are 5-10 membered heteroaryl groups. Examples of heteroaryl groups include but are not limited to thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiodi Azolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolyl or isoquinolyl. The heteroaryl group may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is the heteroaryl ring.
术语“环烷基”是指具有至少一个环化烷基的环系统。优选C3-14环烷基，其中的“C3-14”是指环烷基可以具有3、4、5、6、7、8、9、10、11、12、13或14个成环原子。环烷基可以包括单环和多环(例如具有2、3或4个稠合环、螺环、桥环等)。一些实施例中环烷基包括但不限于环丙基、环丁基、环戊基等；所述环烷基还可以稠合于芳基、杂环基或杂芳基环上，其中与母体结构连接在一起的环为环烷基。The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. C 3-14 cycloalkyl is preferred, where "C 3-14 " means that the cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms . Cycloalkyl groups can include monocyclic and polycyclic rings (eg, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). In some embodiments, the cycloalkyl group includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group can also be fused to an aryl, heterocyclyl or heteroaryl ring, where it is connected to the parent structure The rings joined together are cycloalkyl.
术语“取代的”是指基团中的一个或多个氢原子分别被相同的或者不同的取代基所取代。典型的取代基包括但不限于卤素(F、Cl、Br或I)、C1-8烷基、C3-12环烷基、-OR1、-SR1、 ＝O、＝S、-C(O)R1、-C(S)R1、＝NR1、-C(O)OR1、-C(S)OR1、-NR1R2、-C(O)NR1R2、氰基、硝基、-S(O)2R1、-O-S(O2)OR1、-O-S(O)2R1、-OP(O)(OR1)(OR2)；其中R1和R2独立地选自-H、C1-6烷基、C1-6卤代烷基或C3-6环烷基。在一些实施例中，取代基独立地选自包含-F、-Cl、-Br、-I、-OH、三氟甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、-SCH3、-SC2H5、甲醛基、-C(OCH3)、氰基、硝基、-CF3、-OCF3、氨基、二甲基氨基、甲硫基、磺酰基和乙酰基的基团。The term "substituted" means that one or more hydrogen atoms in the group are replaced by the same or different substituents, respectively. Typical substituents include but are not limited to halogen (F, Cl, Br or I), C 1-8 alkyl, C 3-12 cycloalkyl, -OR 1 , -SR 1 , =O, =S, -C(O)R 1 , -C(S)R 1 , =NR 1 , -C(O)OR 1 , -C(S)OR 1 , -NR 1 R 2 , -C (O)NR 1 R 2 , cyano, nitro, -S(O) 2 R 1 , -OS(O 2 )OR 1 , -OS(O) 2 R 1 , -OP(O)(OR 1 ) (OR 2 ); wherein R 1 and R 2 are independently selected from -H, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl. In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy group, tert-butoxy group, -SCH 3 , -SC 2 H 5 , formaldehyde group, -C(OCH 3 ), cyano group, nitro group, -CF 3 , -OCF 3 , amino group, dimethyl group amino, methylthio, sulfonyl and acetyl groups.
当一个连接基团的数量为0时，比如-(CH2)0-表示该连接基团为键。When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
术语“药用盐”是指从药学上可接受的无毒的碱或酸制备的盐。The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
当本发明提供的化合物是酸时，可以从药学上可接受的无毒的碱，包括无机碱和有机碱，方便地制得其相应的盐。从无机碱衍生的盐包括铝、铵、钙、铜(高价和低价)、三价铁、亚铁、锂、镁、锰(高价和低价)、钾、钠、锌之类的盐。特别优选铵、钙、镁、钾和钠的盐。能够衍生成药学上可接受的盐的无毒有机碱包括伯胺、仲胺和叔胺，也包括环胺及含有取代基的胺，如天然存在的和合成的含取代基的胺。能够成盐的其他药学上可接受的无毒有机碱，包括离子交换树脂以及精氨酸、甜菜碱、咖啡因、胆碱、N',N'-二苄乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡萄糖胺、氨基葡萄糖、组氨酸、异丙胺、赖氨酸，甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、氯普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。When the compound provided by the present invention is an acid, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low prices), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low prices), potassium, sodium, and zinc. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. Nontoxic organic bases capable of being derivatized into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine Acid, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine wait.
当本发明提供的化合物是碱时，可以从药学上可接受的无毒的酸，包括无机酸和有机酸，方便制得其相应的盐。这样的酸包括，如，醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、甲酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、黏酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、草酸、丙酸、乙醇酸、氢碘酸、高氯酸、环己氨磺酸、水杨酸、2-萘磺酸、糖精酸、三氟乙酸、酒石酸和对甲苯磺酸等。较优地，柠檬酸、氢溴酸、甲酸、盐酸、马来酸、磷酸、硫酸和酒石酸。更优地，甲酸和盐酸。When the compound provided by the present invention is a base, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, parapexic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydriodic acid, perchloric acid, cyclohexane sulfonic acid, salicylic acid, 2-naphthalene sulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid, etc. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid.
本发明化合物的药物前体包含在本发明的保护范围内。通常，所述药物前体是指很容易在体内转化成所需化合物的功能性衍生物。例如，本申请化合物的任何药学上可接受的盐、酯、酯的盐或其它衍生物，其在向受体施用后能够直接或间接地提供本申请的化合物或其具有药学活性的代谢物或残基。The prodrugs of the compounds of the present invention are included in the protection scope of the present invention. Generally, the prodrug refers to a functional derivative that is easily converted into the desired compound in the body. For example, any pharmaceutically acceptable salt, ester, ester salt or other derivative of the compound of the present application, which can directly or indirectly provide the compound of the present application or its pharmaceutically active metabolite after administration to the recipient; Residues.
本发明所述化合物可能含有一个或多个不对称中心，并可能由此产生非对映异构体和 光学异构体。本发明包括所有可能的非对映异构体及其外消旋混合物、其基本上纯的拆分对映异构体、所有可能的几何异构体及其药用盐。The compounds described in the present invention may contain one or more asymmetric centers and may thereby give rise to diastereoisomers and Optical isomers. The present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.
当式(I)所示化合物存在互变异构体时，除非特别声明，本发明包括任何可能的互变异构体和其药用盐，及它们的混合物。When there are tautomers of the compound represented by formula (I), unless otherwise stated, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, as well as their mixtures.
当式(I)所示化合物用较重的同位素(例如氘)替代可能提供某些治疗优势，这是由于更大的代谢稳定性，例如增加体内半衰期或减少剂量要求。Substitution of compounds of formula (I) with heavier isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.
术语“药物组合物”是指一种或多种本申请的化合物或其药用盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. The purpose of pharmaceutical compositions is to facilitate administration to an organism of the compounds of the present application.
在本发明中，“一”、“一个”、“该”、“至少一个”和“一个或多个”可互换使用。因此，例如，包含“一种”药学上可接受的辅料组成的混合物可以被解释为表示该药物组合物包括“一种或多种”药学上可接受的辅料。In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a mixture consisting of "a" pharmaceutically acceptable excipient may be interpreted to mean that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "pharmaceutically acceptable excipients" refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
本发明的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。The pharmaceutical composition of the present invention can be prepared by combining the compound of the present application with appropriate pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
给予本发明化合物或其药用盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。Typical routes of administration of the compounds of the invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, Subcutaneous and intravenous administration.
术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。The term "treatment" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a patient's disease that: (a) inhibits the symptoms of the disease, i.e., prevents their progression; or (b) alleviates the symptoms of the disease, i.e., causes regression of the disease or symptoms.
术语“有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。The term "effective amount" means (i) treating or preventing a specified disease, condition, or disorder, (ii) reducing, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying An amount of a compound of the present application that is associated with the onset of one or more symptoms of a particular disease, condition, or disorder described in . The amount of a compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.
本发明的优异效果：本发明的化合物在酶学活性、细胞活性、PK、生物利用度等方面具有优异的活性，可以用于治疗和/或预防由KRAS G12D所介导的疾病。特别是，相比 MART1133(对比化合物D1)，本发明化合物，在静脉给药中，具有更高的全血暴露量和更低的清除率；在口服给药中，其具有更优的PO暴露量(AUC)以及口服生物利用度(F％)，本发明化合物的口服吸收显著优于MART1133。Excellent effects of the present invention: The compounds of the present invention have excellent activities in terms of enzymatic activity, cell activity, PK, bioavailability, etc., and can be used to treat and/or prevent diseases mediated by KRAS G12D. In particular, compared to MART1133 (Compared to Compound D1), the compound of the present invention, has higher whole blood exposure and lower clearance in intravenous administration; it has better PO exposure (AUC) and Oral bioavailability (F%), the oral absorption of the compounds of the present invention is significantly better than that of MART1133.
附图说明Description of the drawings
图1为化合物M13-1的单晶样品的体式偏光显微镜图谱。Figure 1 is a stereoscopic polarizing microscope diagram of a single crystal sample of compound M13-1.
图2为化合物M13-1的单晶结构解析图。Figure 2 is an analytical diagram of the single crystal structure of compound M13-1.
图3为化合物在NCI-H1975荷瘤小鼠肿瘤组织中分布情况。Figure 3 shows the distribution of compounds in tumor tissues of NCI-H1975 tumor-bearing mice.
具体实施方式Detailed ways
为使上述内容更清楚、明确，本发明将用以下实施例来进一步阐述本发明的技术方案。以下实施例仅用于说明本发明的具体实施方式，以使本领域的技术人员能够理解本发明，但不用于限制本发明的保护范围。本发明的具体实施方式中，未作特别说明的技术手段或方法等为本领域的常规技术手段或方法等。In order to make the above content clearer and clearer, the present invention will use the following examples to further illustrate the technical solution of the present invention. The following examples are only used to illustrate specific implementations of the present invention so that those skilled in the art can understand the present invention, but are not used to limit the scope of the present invention. In the specific embodiments of the present invention, technical means or methods that are not specifically described are conventional technical means or methods in the art.
除非另有说明，本发明所有的温度均指摄氏度。室温是指18-25℃。Unless otherwise stated, all temperatures herein refer to degrees Celsius. Room temperature refers to 18-25℃.
实施例中使用了下列缩略语：The following abbreviations are used in the examples:
DMF：N,N-二甲基甲酰胺；DMF: N,N-dimethylformamide;
NIS：N-碘代丁二酰亚胺；NIS: N-iodosuccinimide;
THF：四氢呋喃；THF: tetrahydrofuran;
EA：乙酸乙酯；EA: ethyl acetate;
PE：石油醚；PE: petroleum ether;
DCM：二氯甲烷；DCM: dichloromethane;
MeOH：甲醇；MeOH: methanol;
mCPBA：间氯过氧苯甲酸；mCPBA: m-chloroperoxybenzoic acid;
CsF：氟化铯；CsF: cesium fluoride;
TBDPSCl：叔丁基二苯基氯硅烷；TBDPSCl: tert-butyldiphenylsilyl chloride;
DPPA：叠氮磷酸二苯酯；DPPA: diphenylphosphate azide;
CDI：N,N'-羰基二咪唑；CDI: N,N'-carbonyldiimidazole;
DIEA：N,N-二异丙基乙胺；DIEA: N,N-diisopropylethylamine;
CataCXium A Pd G3：甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)；CataCXium A Pd G3: methanesulfonate [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II);
SphosPdG2：氯(2-二环己基膦基-2',6'-二甲氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)； SphosPdG2: Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) Palladium(II);
DBU：1,8-二氮杂双环[5.4.0]十一碳-7-烯；DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene;
PyBOP：1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐；PyBOP: 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate;
mCPBA：间氯过氧苯甲酸；mCPBA: m-chloroperoxybenzoic acid;
LAH：四氢铝锂；LAH: lithium aluminum tetrahydride;
TFA：三氟乙酸；TFA: trifluoroacetic acid;
t-BuOK：叔丁醇钾；t-BuOK: potassium tert-butoxide;
t-BuOH：叔丁醇；t-BuOH: tert-butanol;
Tol:甲苯；Tol: toluene;
DMAP：4-二甲氨基吡啶；DMAP: 4-dimethylaminopyridine;
BINAP：1,1'-联萘-2,2'-双二苯膦；BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine;
(S)-DPLT：(S)-二对甲基苯甲酰酒石酸。(S)-DPLT: (S)-Di-p-methylbenzoyltartaric acid.
中间体M1的合成：
Synthesis of intermediate M1:
步骤1：化合物M1-1的合成Step 1: Synthesis of Compound M1-1
室温下，将化合物M1-0(208g)溶解在无水MeOH(2L)中，在0℃滴加氯化亚砜(286mL)，控制温度在5℃反应1小时，反应结束后，浓缩反应液，加入无水DCM(1L)稀释，0℃下，将稀释液体滴加到饱和碳酸氢钠溶液中，分液，有机层用饱和食盐水(500mL)洗涤，无水硫酸钠干燥，浓缩。浓缩物经柱色谱纯化(EA:DCM＝0-50％)得到产物M1-1(240g，95％产率)。ESI-MS m/z＝258.1[M+H]+。Dissolve compound M1-0 (208g) in anhydrous MeOH (2L) at room temperature, add thionyl chloride (286mL) dropwise at 0°C, control the temperature to 5°C and react for 1 hour. After the reaction is completed, the reaction solution is concentrated. , add anhydrous DCM (1L) to dilute, add the diluted liquid dropwise to a saturated sodium bicarbonate solution at 0°C, separate the layers, wash the organic layer with saturated brine (500mL), dry over anhydrous sodium sulfate, and concentrate. The concentrate was purified by column chromatography (EA:DCM=0-50%) to obtain product M1-1 (240 g, 95% yield). ESI-MS m/z=258.1[M+H] + .
步骤2：化合物M1-2的合成Step 2: Synthesis of Compound M1-2
在室温下，将化合物M1-1(235g)溶于无水THF(2.4L)，在0℃分批次加入四氢铝锂(69.4g)，加完后60℃搅拌30min。反应结束后，冷却反应液，冰浴下滴加水(69.4mL)，再滴加15％的氢氧化钠水溶液(69.4mL)，最后滴加水(208.2mL)，加入无水硫酸钠干燥，过滤得到滤液浓缩即得到产物M1-2(165g，90％产率)直接用于下一步。ESI-MS m/z＝202.1[M+H]+。 Dissolve compound M1-1 (235g) in anhydrous THF (2.4L) at room temperature, add lithium aluminum tetrahydride (69.4g) in batches at 0°C, and stir at 60°C for 30 minutes after the addition is completed. After the reaction is completed, cool the reaction solution, add water (69.4mL) dropwise in an ice bath, then add 15% sodium hydroxide aqueous solution (69.4mL) dropwise, and finally add water (208.2mL) dropwise, add anhydrous sodium sulfate, dry, and filter to obtain The filtrate was concentrated to obtain product M1-2 (165 g, 90% yield), which was used directly in the next step. ESI-MS m/z=202.1[M+H] + .
步骤3：化合物M1-3的合成Step 3: Synthesis of compound M1-3
室温下，将化合物M1-2(160g)溶于三氟乙酸(500mL)，加入水(67mL)，60℃下反应过夜，浓缩反应液体得到粗品M1-3(320g，259％)直接用于下一步。ESI-MS m/z＝156.1[M+H]+。Compound M1-2 (160g) was dissolved in trifluoroacetic acid (500mL) at room temperature, water (67mL) was added, and the reaction was carried out at 60°C overnight. The reaction liquid was concentrated to obtain crude product M1-3 (320g, 259%), which was directly used in the next step. step. ESI-MS m/z=156.1[M+H] + .
步骤4：化合物M1-4的合成Step 4: Synthesis of compound M1-4
在室温下，将化合物M1-3(308g)溶于DMF(350mL)中，0℃加入咪唑(540g)后滴加TBDPSCl(170mL)，加完后室温搅拌1小时。反应结束后，加入水和EA稀释，用EA萃取水相3遍。合并有机相，有机相用饱和食盐水洗三遍，用无水硫酸钠干燥，浓缩。浓缩物经柱色谱纯化(EA:PE＝0-15％)得到产物M1-4(192g，25％产率)。ESI-MS m/z＝394.1[M+H]+。Compound M1-3 (308g) was dissolved in DMF (350mL) at room temperature, imidazole (540g) was added at 0°C, and TBDPSCl (170mL) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 1 hour. After the reaction is completed, add water and EA to dilute, and extract the aqueous phase three times with EA. The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (EA:PE=0-15%) to obtain product M1-4 (192 g, 25% yield). ESI-MS m/z=394.1[M+H] + .
步骤5：化合物M1的合成Step 5: Synthesis of Compound M1
室温下，将化合物M1-4(187g)和二氟甲基(2-吡啶基)砜(184g)溶解在无水DMF(1.4L)中，在-50℃滴加叔丁醇钾(107g)的DMF(460mL)溶液，滴加完毕后控制温度在-40℃反应2小时，反应结束后，在-50℃下滴加饱和氯化铵溶液直至溶液成弱酸性，自然升温至室温反应18小时，过滤得到滤液，加入EA(1.4L)稀释，再过滤得到滤液，浓缩。浓缩物经柱色谱纯化(MeOH:DCM＝0-10％)得到产物M1(60g，67％产率)。1H NMR(500MHz,DMSO-d6)δ3.95-3.92(m,1H),3.70-3.67(m,1H),3.32-3.27(m,2H),2.94-2.89(m,1H),2.69-2.66(m,1H),2.50-3.45(m,1H),1.99-1.92(m,2H),1.88-1.75(m,2H)。ESI-MS m/z＝190.1[M+H]+。At room temperature, compound M1-4 (187g) and difluoromethyl (2-pyridyl) sulfone (184g) were dissolved in anhydrous DMF (1.4L), and potassium tert-butoxide (107g) was added dropwise at -50°C. DMF (460mL) solution, after the dropwise addition is completed, control the temperature to react at -40°C for 2 hours. After the reaction is completed, add saturated ammonium chloride solution dropwise at -50°C until the solution becomes weakly acidic, and naturally warm to room temperature for 18 hours. , filter to obtain the filtrate, add EA (1.4L) to dilute, filter again to obtain the filtrate, and concentrate. The concentrate was purified by column chromatography (MeOH:DCM=0-10%) to give product M1 (60 g, 67% yield). 1 H NMR (500MHz, DMSO-d6) δ3.95-3.92(m,1H),3.70-3.67(m,1H),3.32-3.27(m,2H),2.94-2.89(m,1H),2.69- 2.66(m,1H),2.50-3.45(m,1H),1.99-1.92(m,2H),1.88-1.75(m,2H). ESI-MS m/z=190.1[M+H] + .
中间体M2的合成：
Synthesis of intermediate M2:
步骤1：化合物M2-1的合成Step 1: Synthesis of Compound M2-1
在室温下，依次加入2-氯-3-氟-吡啶-4-羧酸(54.00g)，甲苯(390.00mL)，叔丁醇(390.00mL)，三乙胺(128.27mL)，粉末状分子筛(90.00mL)(预活化)，氮气保护下，保温回流 半小时(内温87℃)。再自然冷却至室温，然后加入DPPA(99.44mL)，升温至回流，保温反应5小时。将反应混合物冷却至40℃以下，然后加入EA 500mL稀释；继续冷却至室温，硅藻土助滤，将加入的分子筛过滤除去；并用EA 1500mL多次漂洗滤渣、抽干；收集滤液，依次用水700mL，饱和食盐水700mL洗涤、分液；无水硫酸钠干燥有机相；过滤，除干燥剂，浓缩，浓缩物经柱层析分离纯化(PE/EA＝30:1～20:1)，浓缩洗脱液，最终得到产物M2-1(68.2g，产率89.88％)。ESI-MS m/z:247.1[M+H]+。At room temperature, add 2-chloro-3-fluoro-pyridine-4-carboxylic acid (54.00g), toluene (390.00mL), tert-butanol (390.00mL), triethylamine (128.27mL), powdered Molecular sieve (90.00mL) (pre-activated), under nitrogen protection, insulated and refluxed Half an hour (internal temperature 87°C). Then naturally cool to room temperature, then add DPPA (99.44 mL), raise the temperature to reflux, and keep the reaction for 5 hours. Cool the reaction mixture to below 40°C, then add 500mL of EA to dilute it; continue to cool to room temperature, use diatomaceous earth as a filter, and filter out the added molecular sieve; rinse the filter residue with 1500mL of EA several times and drain it; collect the filtrate and use 700mL of water in turn , wash and separate with 700 mL of saturated brine; dry the organic phase with anhydrous sodium sulfate; filter, remove the desiccant, and concentrate. The concentrate is separated and purified by column chromatography (PE/EA=30:1~20:1), concentrated and washed After deliquification, product M2-1 (68.2g, yield 89.88%) was finally obtained. ESI-MS m/z:247.1[M+H] + .
步骤2：化合物M2-2的合成Step 2: Synthesis of compound M2-2
在室温下，将化合物M2-1(65.00g)溶于CH3CN(82.00mL)中，水浴冷却，慢慢加入盐酸(4M/二氧六环)(38.43g)，室温搅拌反应约16小时，白色固体析出，呈悬浮态。将反应混合物过滤，并用乙腈少量漂洗滤饼，抽干，丢弃滤液。收集滤饼，加入到700mL饱和碳酸氢钠水溶液和700mL乙酸乙酯的混合物中，碱化，萃取、分液；水相再用乙酸乙酯350mL萃取，分液；合并乙酸乙酯相，加入饱和氯化钠水溶液300mL洗涤、分液；无水硫酸钠干燥有机相，过滤，除干燥剂，浓缩得到产物M2-2(36.3g，产率94.0％)。ESI-MS m/z:147.1[M+H]+。Dissolve compound M2-1 (65.00g) in CH 3 CN (82.00 mL) at room temperature, cool in a water bath, slowly add hydrochloric acid (4M/dioxane) (38.43g), stir and react at room temperature for about 16 hours , a white solid precipitated in a suspended state. The reaction mixture was filtered, and the filter cake was rinsed with a small amount of acetonitrile, drained, and the filtrate was discarded. Collect the filter cake, add it to a mixture of 700mL saturated sodium bicarbonate aqueous solution and 700mL ethyl acetate, alkalize, extract, and separate the liquids; extract the water phase with 350mL of ethyl acetate, and separate the liquids; combine the ethyl acetate phases, and add saturated Wash and separate with 300 mL of sodium chloride aqueous solution; dry the organic phase with anhydrous sodium sulfate, filter, remove the desiccant, and concentrate to obtain product M2-2 (36.3 g, yield 94.0%). ESI-MS m/z:147.1[M+H] + .
步骤3：化合物M2-3的合成Step 3: Synthesis of compound M2-3
在室温下，将化合物M2-2(36.00g)溶于乙腈(180.00mL)中，NIS(66.32g)和对甲苯磺酸(2.12g)加入其中，氮气保护下，加热保温70℃反应。反应液冷却至50℃，加入水900mL，有粉白色固体粉末析出，打浆半小时；过滤，并用水漂洗滤饼，抽干。收集滤饼，加入乙酸乙酯1200mL溶解完全，然后依次用饱和亚硫酸钠水溶液350mL，洗涤两次，再用饱和食盐水350mL洗涤、分液，无水硫酸钠干燥有机相，过滤，浓缩，得到产物M2-3(63.2g，产率94.43％)。ESI-MS m/z:272.9[M+H]+。At room temperature, compound M2-2 (36.00g) was dissolved in acetonitrile (180.00mL), NIS (66.32g) and p-toluenesulfonic acid (2.12g) were added, and the reaction was heated and kept at 70°C under nitrogen protection. Cool the reaction solution to 50°C, add 900 mL of water, and a pinkish-white solid powder will precipitate. Beat for half an hour; filter, rinse the filter cake with water, and drain it. Collect the filter cake, add 1200 mL of ethyl acetate to dissolve it completely, then wash twice with 350 mL of saturated sodium sulfite aqueous solution, then wash with 350 mL of saturated brine, separate the layers, dry the organic phase over anhydrous sodium sulfate, filter and concentrate to obtain product M2 -3 (63.2g, yield 94.43%). ESI-MS m/z:272.9[M+H] + .
步骤4：化合物M2-4的合成Step 4: Synthesis of Compound M2-4
在室温下，将化合物M2-3(57.50g)溶于DMF(22.00mL)中，氰化锌(32.22g)、四三苯基膦钯(12.19g)和粉末状分子筛(20.00mL)加入其中，在氮气氛围中，加热保温100℃反应约7小时。撤去油浴，自然冷却至室温，等待后处理。硅藻土助滤，将反应混合物过滤，抽干；收集滤液，60～70℃浓缩，得到淡黄色固体粗品。滤渣用乙酸乙酯500mL漂洗抽干；收集漂洗液，合并到粗品中，再次浓缩至无液体被蒸馏出；加入乙酸乙酯700mL溶解浓缩所得到固体粗品，然后用每次用饱和氯化钠250mL，洗涤3次，分液。无水硫酸钠干燥有机相，过滤，浓缩得到淡黄色固体，加入PE/EA＝3/1混合物160mL，打浆半小时，过滤、抽干。收集滤饼，45℃水浴，浓缩，再高真空油泵抽拉至恒重；最终得到产物M2- 4(36.1g，产率99.7％)。ESI-MS m/z:172.0[M+H]+。At room temperature, compound M2-3 (57.50g) was dissolved in DMF (22.00mL), zinc cyanide (32.22g), tetrakis triphenylphosphine palladium (12.19g) and powdered Molecular sieve (20.00 mL) was added, and the reaction was heated and kept at 100°C for about 7 hours in a nitrogen atmosphere. Remove the oil bath, cool to room temperature naturally, and wait for post-processing. Use diatomaceous earth to assist filtration, filter the reaction mixture, and drain it; collect the filtrate and concentrate at 60-70°C to obtain a pale yellow solid crude product. Rinse the filter residue with 500 mL of ethyl acetate and drain it; collect the rinse liquid, combine it with the crude product, and concentrate again until no liquid is distilled; add 700 mL of ethyl acetate to dissolve and concentrate the solid crude product obtained, and then use 250 mL of saturated sodium chloride each time , washed 3 times and separated. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate to obtain a light yellow solid. Add 160 mL of PE/EA=3/1 mixture, beat for half an hour, filter, and drain. Collect the filter cake, put it in a 45°C water bath, concentrate it, and then pull it to constant weight with a high vacuum oil pump; finally, the product M2- 4 (36.1g, yield 99.7%). ESI-MS m/z:172.0[M+H] + .
步骤5：化合物M2-5的合成Step 5: Synthesis of Compound M2-5
在室温下，500mL的单口烧瓶中，加入浓硫酸(61.37mL)，冰水浴冷却至10℃以下，分批加入化合物M2-4(39.30g)，加毕，搅拌10分钟，在氮气氛围中，用油浴保温60℃，反应约1小时。反应液冷却至室温，然后小心地加入到1100mL的冰水混合物中，稀释淬灭，有少量黄色固体析出。搅拌10分钟后，过滤；收集滤饼，用50mL饱和碳酸氢钠水溶液，打浆20分钟，再次过滤，收集两次滤液，合并；然后慢慢加入碳酸钠固体，调pH约等于7，有类白色固体粉末析出。搅拌半小时，过滤、抽干；每次用水100mL漂洗滤饼、抽干，共漂洗2次。收集滤饼，放入真空烘箱中，55℃烘干至恒重得到产物M2-5(33.6g，产率77.37％)。ESI-MS m/z:190.0[M+H]+。At room temperature, add concentrated sulfuric acid (61.37mL) to a 500mL single-necked flask, cool it to below 10°C in an ice-water bath, add compound M2-4 (39.30g) in batches, complete the addition, and stir for 10 minutes, in a nitrogen atmosphere. Use an oil bath to keep the temperature at 60°C and react for about 1 hour. The reaction solution was cooled to room temperature, then carefully added to 1100 mL of ice-water mixture, diluted and quenched, and a small amount of yellow solid precipitated. After stirring for 10 minutes, filter; collect the filter cake, beat with 50 mL of saturated sodium bicarbonate aqueous solution for 20 minutes, filter again, collect the two filtrates, and combine; then slowly add sodium carbonate solid, adjust the pH to approximately 7, and have an off-white color. Solid powder precipitates. Stir for half an hour, filter, and drain; rinse the filter cake with 100 mL of water each time, drain it, and rinse twice in total. Collect the filter cake, place it in a vacuum oven, and dry it at 55°C to constant weight to obtain product M2-5 (33.6 g, yield 77.37%). ESI-MS m/z:190.0[M+H] + .
步骤6：化合物M2-6的合成Step 6: Synthesis of Compound M2-6
在室温下，加入四氢呋喃(470.00mL)，氮气置换后，微氮气流保护下，加入氢化钠(10.00g)，用油浴加热，保温40～45℃，搅拌15分钟；然后分批加入化合物M2-5(18.95g)，加毕，保温机械搅拌20分钟后，然后小心地分批加入CDI(24.31g)，加毕，搅拌15分钟后，油浴加热升温，保温回流反应。反应液用冰水浴，冷却至10℃以下，然后加入饱和氯化铵水溶液500mL，有浅黄色固体析出，加入水1000mL；然后转移至5L烧杯中，补加水3000mL；搅拌1小时，过滤，抽干；收集滤饼，放入真空烘箱中，50～55℃干燥至恒重得到产物M2-6(18.3g，产率84.93％)。ESI-MS m/z:216.0[M+H]+。At room temperature, add tetrahydrofuran (470.00mL). After nitrogen replacement, add sodium hydride (10.00g) under the protection of a slight nitrogen flow, heat in an oil bath, keep at 40-45°C, and stir for 15 minutes; then add compound M2 in batches -5 (18.95g), complete the addition, keep warm and mechanically stir for 20 minutes, then carefully add CDI (24.31g) in batches, complete the addition, stir for 15 minutes, heat the oil bath to raise the temperature, keep warm and reflux for reaction. Use an ice water bath to cool the reaction solution to below 10°C, then add 500mL of saturated ammonium chloride aqueous solution. If a light yellow solid precipitates, add 1000mL of water; then transfer to a 5L beaker, add 3000mL of water; stir for 1 hour, filter and drain ; Collect the filter cake, put it into a vacuum oven, and dry it at 50-55°C to constant weight to obtain product M2-6 (18.3g, yield 84.93%). ESI-MS m/z:216.0[M+H] + .
步骤7：化合物M2-7的合成Step 7: Synthesis of Compound M2-7
在室温下，将化合物M2-6(18.00g)和DIEA(36.00mL)溶于POCl3(180.00mL)中，氮气氛围下，加热保温100℃反应约2.5小时。减压浓缩除去三氯氧磷，并用DCM 100mL带2次；用400mL二氯甲烷溶解浓缩残留物，然后滴加入到500mL的饱和碳酸氢钠水溶液中，用冰水冷却；搅拌15分钟后，分液；水相，再用二氯甲烷300mL萃取、分液；合并二氯甲烷相，用饱和氯化钠水溶液300mL洗涤、分液；无水硫酸钠干燥，过滤、浓缩，浓缩物经硅胶柱纯化(PE/EA＝90/10～75/25)得到产物M2-7(10.95g，产率51.94％)。ESI-MS m/z:251.9[M+H]+。At room temperature, compound M2-6 (18.00g) and DIEA (36.00mL) were dissolved in POCl 3 (180.00mL). Under a nitrogen atmosphere, the reaction was heated and kept at 100°C for about 2.5 hours. Concentrate under reduced pressure to remove phosphorus oxychloride, and add 100 mL of DCM twice; dissolve the concentrated residue in 400 mL of methylene chloride, and then add it dropwise to 500 mL of saturated aqueous sodium bicarbonate solution, and cool with ice water; stir for 15 minutes, and then separate. liquid; aqueous phase, then extract and separate the liquids with 300 mL of dichloromethane; combine the dichloromethane phases, wash with 300 mL of saturated sodium chloride aqueous solution, and separate the liquids; dry over anhydrous sodium sulfate, filter, and concentrate, and the concentrate will be purified by a silica gel column (PE/EA=90/10～75/25) The product M2-7 (10.95g, yield 51.94%) was obtained. ESI-MS m/z:251.9[M+H] + .
步骤8：化合物M2的合成Step 8: Synthesis of Compound M2
在室温下，将化合物M2-7(10.50g)和DIEA(17.18mL)溶于DCM(120.00mL)中，水浴冷却，分批加入叔丁基3,8-二氮杂二环[3.2.1]辛烷-8-羧酸盐(9.27g)，然后室温搅拌反应约10分钟。补加二氯甲烷120mL，依次用100mL水，100mL饱和氯化钠水溶液洗涤、 分液，无水硫酸钠干燥有机相，过滤，浓缩，浓缩物经硅胶柱(PE/EA＝90/10～75/25)及打浆纯化(40mL EA+160mL PE)得到化合物M2(15.9g，产率89.26％)。Dissolve compound M2-7 (10.50g) and DIEA (17.18mL) in DCM (120.00mL) at room temperature, cool in a water bath, and add tert-butyl 3,8-diazabicyclo [3.2.1 ] Octane-8-carboxylate (9.27g), and then stirred at room temperature for about 10 minutes. Add 120 mL of methylene chloride, and wash with 100 mL of water and 100 mL of saturated sodium chloride aqueous solution. Separate the liquids, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate. The concentrate is purified through silica gel column (PE/EA=90/10~75/25) and beating (40mL EA+160mL PE) to obtain compound M2 (15.9g, Yield 89.26%).
中间体M3的合成：
Synthesis of intermediate M3:
步骤1：化合物M3-1的合成Step 1: Synthesis of Compound M3-1
在室温下，将化合物M3-0(500mg)、苯乙烯(373mg)和Grubbs 2代催化剂(405.72mg)溶于无水DCM(20mL)中，50℃反应过夜。反应完毕后，将反应液减压浓缩，浓缩物经柱色谱分离纯化得目标化合物M3-1(400mg)。Compound M3-0 (500 mg), styrene (373 mg) and Grubbs 2nd generation catalyst (405.72 mg) were dissolved in anhydrous DCM (20 mL) at room temperature and reacted at 50°C overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was separated and purified by column chromatography to obtain the target compound M3-1 (400 mg).
步骤2：化合物M3的合成Step 2: Synthesis of Compound M3
在室温下，将化合物M3-1(400mg)溶于无水THF(10mL)中，0℃下，将LAH(160mg)加入，再升温至70℃反应30min。反应完毕后，降至0℃，先慢慢加入170uL水，再将170uL 15％氢氧化钠水溶液加入，最后加入510uL水，室温反应15min，加入无水硫酸钠干燥，硅藻土过滤，滤液浓缩，即可得到目标化合物M3(277mg)。Compound M3-1 (400 mg) was dissolved in anhydrous THF (10 mL) at room temperature, LAH (160 mg) was added at 0°C, and the temperature was raised to 70°C for 30 min. After the reaction is completed, lower to 0°C, first slowly add 170uL water, then add 170uL 15% sodium hydroxide aqueous solution, and finally add 510uL water, react at room temperature for 15 minutes, add anhydrous sodium sulfate to dry, filter with diatomaceous earth, and concentrate the filtrate , the target compound M3 (277mg) can be obtained.
中间体M4的合成：
Synthesis of intermediate M4:
步骤1：化合物M4-1的合成Step 1: Synthesis of Compound M4-1
在室温下，将化合物M3-0(800mg)、对氯苯乙烯(795mg)和Grubbs 2代催化剂(325mg)溶于无水DCM(20mL)中，50℃反应过夜。反应完毕后，将反应液减压浓缩，浓缩物经柱色谱分离纯化得目标化合物M4-1(729mg)。ESI-MS m/z＝320.1[M+H]+。Compound M3-0 (800 mg), p-chlorostyrene (795 mg) and Grubbs 2nd generation catalyst (325 mg) were dissolved in anhydrous DCM (20 mL) at room temperature, and the reaction was carried out at 50°C overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was separated and purified by column chromatography to obtain the target compound M4-1 (729 mg). ESI-MS m/z=320.1[M+H] + .
步骤2：化合物M4的合成Step 2: Synthesis of Compound M4
在室温下，将化合物M4-1(729mg)溶于无水THF(10mL)中，0℃下将LAH(260mg)加入，再升温至70℃反应30min。反应完毕后，降至0℃，先慢慢加入280uL水，再将280uL15％氢氧化钠水溶液加入，最后加入840uL水，室温反应15min，加入无水硫酸钠干燥，硅藻土过滤，滤液浓缩，即可得到目标化合物M4(563mg)。ESI-MS m/z＝ 264.1[M+H]+。Compound M4-1 (729 mg) was dissolved in anhydrous THF (10 mL) at room temperature, LAH (260 mg) was added at 0°C, and the temperature was raised to 70°C for 30 min. After the reaction is completed, lower to 0°C, first slowly add 280uL water, then add 280uL 15% sodium hydroxide aqueous solution, and finally add 840uL water, react at room temperature for 15 minutes, add anhydrous sodium sulfate to dry, filter with diatomaceous earth, and concentrate the filtrate. The target compound M4 (563 mg) was obtained. ESI-MS m/z= 264.1[M+H] + .
中间体M5的合成：
Synthesis of intermediate M5:
步骤1：化合物M5-1的合成Step 1: Synthesis of Compound M5-1
在室温下，将化合物M3-0(400mg)、亚甲基环戊烷(236mg)和Grubbs 2代催化剂(325mg)溶于无水DCM(20mL)中，50℃反应过夜。反应完毕后，将反应液减压浓缩至少量，直接湿法上样进行柱色谱纯化得目标化合物M5-1(410mg)。Compound M3-0 (400 mg), methylenecyclopentane (236 mg) and Grubbs 2nd generation catalyst (325 mg) were dissolved in anhydrous DCM (20 mL) at room temperature and reacted at 50°C overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure to a small amount, and directly loaded with wet method for column chromatography purification to obtain the target compound M5-1 (410 mg).
步骤2：化合物M5的合成Step 2: Synthesis of Compound M5
将化合物M5-1(410mg)溶于无水THF(10mL)中，0℃下将LAH(204mg)加入，再升温至70℃反应30min。反应完毕后，降至0℃，先慢慢加入210uL水，再将210uL15％氢氧化钠水溶液加入，再加入630uL水，室温反应15min，加入无水硫酸钠干燥，硅藻土过滤，滤液浓缩，即可得到目标化合物M5(370mg)。Compound M5-1 (410 mg) was dissolved in anhydrous THF (10 mL), LAH (204 mg) was added at 0°C, and the temperature was raised to 70°C for 30 min. After the reaction is completed, lower to 0°C, first slowly add 210uL water, then add 210uL 15% sodium hydroxide aqueous solution, then add 630uL water, react at room temperature for 15 minutes, add anhydrous sodium sulfate to dry, filter with diatomaceous earth, and concentrate the filtrate. The target compound M5 (370 mg) was obtained.
中间体M6的合成：
Synthesis of intermediate M6:
步骤1：化合物M6-1的合成Step 1: Synthesis of Compound M6-1
在室温下，将M3-0(1.00g)，2,3-二甲基-2-烯(2.01g)加入DCM(20.00mL)中，再加入Grubbs 2代催化剂(0.41g)。N2置换三次，N2保护下，反应升至50℃搅拌20小时。反应冷却，减压浓缩，浓缩物经柱层析纯化得到目标化合物M6-1(0.2g，收率9.04％)。At room temperature, M3-0 (1.00g) and 2,3-dimethyl-2-ene (2.01g) were added to DCM (20.00mL), and then Grubbs 2nd generation catalyst (0.41g) was added. N2 was replaced three times. Under N2 protection, the reaction was raised to 50°C and stirred for 20 hours. The reaction was cooled and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain the target compound M6-1 (0.2g, yield 9.04%).
步骤2：化合物M6的合成Step 2: Synthesis of Compound M6
在室温下，将M6-1(0.20g)加入THF(4.00mL)，冰浴下，分批加入LAH(0.10g)。反应升至70℃搅拌1小时。反应冷却，在冰浴下滴加入H2O(100uL)，接着滴加入15％NaOH(100uL)溶液，最后滴加入H2O(300uL)，室温搅拌10分钟，再加入无水硫酸钠干燥并搅拌5分钟。过滤，滤饼用EA冲洗，滤液减压浓缩得到目标化合物M6(0.18g)。At room temperature, M6-1 (0.20g) was added to THF (4.00mL), and LAH (0.10g) was added in batches under ice bath. The reaction was warmed to 70°C and stirred for 1 hour. The reaction was cooled, H 2 O (100uL) was added dropwise in an ice bath, then 15% NaOH (100uL) solution was added dropwise, and finally H 2 O (300uL) was added dropwise, stirred at room temperature for 10 minutes, and then added anhydrous sodium sulfate to dry and dry. Stir for 5 minutes. Filter, rinse the filter cake with EA, and concentrate the filtrate under reduced pressure to obtain the target compound M6 (0.18g).
中间体M7的合成：
Synthesis of intermediate M7:
步骤1：化合物M7-1的合成Step 1: Synthesis of Compound M7-1
在室温下，将化合物M3-0(0.5g)，Togni's reagent II(1.51g)和四丁基碘化铵(0.44g)溶解于1,4-二氧六环(10mL)中抽换氮气，80℃反应10小时，将反应液直接浓缩，浓缩物经层析柱(DCM/EA＝2/1)分离纯化得到产物M7-1(0.45g,68％收率)。At room temperature, compound M3-0 (0.5g), Togni's reagent II (1.51g) and tetrabutylammonium iodide (0.44g) were dissolved in 1,4-dioxane (10mL) to replace nitrogen. The reaction was carried out at 80°C for 10 hours. The reaction solution was directly concentrated, and the concentrate was separated and purified by a chromatography column (DCM/EA=2/1) to obtain product M7-1 (0.45g, 68% yield).
步骤2：化合物M7的合成Step 2: Synthesis of Compound M7
在室温下，将化合物M7-1(0.3g)溶解于四氢呋喃中，在冰浴下加入四氢铝锂(123mg)，然后加入硼烷的四氢呋喃溶液(3.2mL)，反应1分钟后立刻用水淬灭反应至不再冒出气泡，加入15％氢氧化钠(0.3mL)，再加入水(0.9mL)，搅拌淬灭完全后，加入硫酸钠干燥，过滤得滤液，浓缩得到产物M7(80mg,33％收率)。Dissolve compound M7-1 (0.3g) in tetrahydrofuran at room temperature, add lithium tetrahydrofuran (123mg) in an ice bath, then add borane in tetrahydrofuran (3.2mL), react for 1 minute and immediately quench with water Kill the reaction until bubbles no longer appear, add 15% sodium hydroxide (0.3 mL), and then add water (0.9 mL). After stirring and quenching is complete, add sodium sulfate to dry, filter the filtrate, and concentrate to obtain product M7 (80 mg, 33% yield).
中间体M8的合成：
Synthesis of intermediate M8:
将化合物((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼-2-基)萘-1-基)乙炔基)三异丙基硅烷(10g)加入到100mL单口瓶中，加入30mL盐酸(4M/Dioxane)。室温下反应半小时后，冰浴下加入饱和碳酸氢钠溶液中和反应液，过滤，滤饼用水洗两次，EA溶解后，无水硫酸钠干燥，浓缩，浓缩物经柱层析纯化(PE:EA＝82:18)得目标中间体M8(9.1g)。The compound ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxabor-2-yl)naphthalene -1-yl)ethynyl)triisopropylsilane (10g) was added to a 100mL single-neck bottle, and 30mL hydrochloric acid (4M/Dioxane) was added. After reacting at room temperature for half an hour, add saturated sodium bicarbonate solution in an ice bath to neutralize the reaction solution, filter, and wash the filter cake with water twice. After EA is dissolved, it is dried over anhydrous sodium sulfate, concentrated, and the concentrate is purified by column chromatography ( PE:EA=82:18) to obtain the target intermediate M8 (9.1g).
中间体M9的合成：
Synthesis of intermediate M9:
在室温下，在反应瓶中将2-亚甲基-5-氧代-1,3,6,7-四氢吡咯利嗪-8-羧酸乙酯(10.00g)溶于THF(150.00mL)，缓慢加入LAH(3.63g)，控制温度在60℃以下，加完搅拌0.2h。降温至0℃，加3.6ml水淬灭反应，再加15％的氢氧化钠水溶液3.6ml，最后加10.8ml 水，搅拌10min后加入无水硫酸镁干燥，搅拌10min后过滤，滤饼用EA洗三次，母液浓缩即可得到目标中间体M9(6.5g，89.34％产率)。Dissolve 2-methylene-5-oxo-1,3,6,7-tetrahydropyrrolizine-8-carboxylic acid ethyl ester (10.00g) in THF (150.00mL) in a reaction bottle at room temperature. ), slowly add LAH (3.63g), control the temperature below 60°C, and stir for 0.2h after adding. Cool to 0°C, add 3.6ml of water to quench the reaction, add 3.6ml of 15% sodium hydroxide aqueous solution, and finally add 10.8ml water, stir for 10 minutes, add anhydrous magnesium sulfate to dry, stir for 10 minutes and filter, wash the filter cake three times with EA, and concentrate the mother liquor to obtain the target intermediate M9 (6.5g, 89.34% yield).
中间体M10的合成：
Synthesis of intermediate M10:
步骤1：化合物M10-1的合成Step 1: Synthesis of Compound M10-1
4-氨基-2,6-二氯吡啶(63g)加入到1L三口瓶中，加入440mL ACN和180mL水。升温至45℃下加入selectfluor(164g)，反应放热，使其在空气中自然冷却。反应10min后，冰浴下加入饱和亚硫酸钠溶液淬灭反应，EA萃取3次，收集并合并有机相，无水硫酸钠干燥，浓缩，浓缩物经柱层析纯化(PE:EA＝10:1)得目标化合物M10-1(42.6g)。ESI-MS m/z:163.9[M+H]+。4-Amino-2,6-dichloropyridine (63g) was added to a 1L three-neck bottle, and 440mL ACN and 180mL water were added. When the temperature is raised to 45°C, selectfluor (164g) is added. The reaction is exothermic and allowed to cool naturally in the air. After reacting for 10 minutes, add saturated sodium sulfite solution under ice bath to quench the reaction, extract with EA three times, collect and combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and the concentrate is purified by column chromatography (PE:EA=10:1) The target compound M10-1 (42.6g) was obtained. ESI-MS m/z:163.9[M+H] + .
步骤2：化合物M10-2的合成Step 2: Synthesis of Compound M10-2
M10-1(54g)加入到1L三口瓶中，加入500mL ACN，加入NIS(80g)和TsOH(5.1g)。升温至70℃反应1h后，滴加2.5L水，过滤，滤饼用EA溶解。分液后，浓缩有机相得目标化合物M10-2(94g)。ESI-MS m/z:307.2[M+H]+。M10-1 (54g) was added to a 1L three-necked flask, 500mL ACN was added, NIS (80g) and TsOH (5.1g) were added. After raising the temperature to 70°C and reacting for 1 hour, add 2.5L of water dropwise, filter, and dissolve the filter cake with EA. After liquid separation, the organic phase was concentrated to obtain the target compound M10-2 (94g). ESI-MS m/z:307.2[M+H] + .
步骤3：化合物M10-3的合成Step 3: Synthesis of Compound M10-3
M10-2(88g)加入到1L三口瓶中，加入500mL DMF，加入CuCN(31g)。升温至125℃反应16h后，滴加2L水后，加入到2L水中，过滤，滤饼用水洗，EA溶解。水相用EA萃2次，收集并合并有机相，浓缩得到目标产物M10-3(55.4g)。ESI-MS m/z:207.0[M]-。M10-2 (88g) was added to a 1L three-necked flask, 500mL DMF was added, and CuCN (31g) was added. After raising the temperature to 125°C and reacting for 16 hours, add 2L of water dropwise, then add it to 2L of water, filter, wash the filter cake with water, and dissolve EA. The aqueous phase was extracted twice with EA, the organic phases were collected and combined, and concentrated to obtain the target product M10-3 (55.4g). ESI-MS m/z:207.0[M] - .
步骤4：化合物M10-4的合成Step 4: Synthesis of Compound M10-4
M10-3(88g)加入到250mL三口瓶中，加入83mL浓硫酸和9mL水。60℃反应16h后，补充70mL浓硫酸和5mL水，继续反应24h。降温至0℃，将反应液缓慢倾倒至2L冰水中，过滤，滤饼水洗后，EA溶解。滤液用EA萃取两次，收集并合并有机相，浓缩后，PE：EA＝1：1打浆。过滤，得到目标产物M10-4(59g)。ESI-MS m/z:224.1[M+H]+。 M10-3 (88g) was added to a 250mL three-necked flask, and 83mL concentrated sulfuric acid and 9mL water were added. After reacting at 60°C for 16 hours, add 70 mL of concentrated sulfuric acid and 5 mL of water, and continue the reaction for 24 hours. Cool the temperature to 0°C, slowly pour the reaction solution into 2L ice water, filter, and wash the filter cake with water to dissolve EA. The filtrate was extracted twice with EA, and the organic phases were collected and combined. After concentration, the mixture was pulped into PE:EA=1:1. After filtration, the target product M10-4 (59g) was obtained. ESI-MS m/z:224.1[M+H] + .
步骤5：化合物M10-5的合成Step 5: Synthesis of Compound M10-5
M10-4(58g)加入到1L三口瓶中，加入650mL THF，升温至40℃后，缓慢分批次加入NaH(16g)。搅拌10min后，升温至60℃，缓慢加入N,N'-硫羰基二咪唑(69g)。反应1h后，加入饱和氯化铵溶液淬灭反应，滴加稀盐酸调整pH＝4-5，旋去THF。过滤，滤饼用水洗，甲醇溶解后，浓缩有机相，得到粗品M10-5(85g)。ESI-MS m/z:267.0[M+H]+。M10-4 (58g) was added to a 1L three-necked flask, 650mL THF was added, and after the temperature was raised to 40°C, NaH (16g) was slowly added in batches. After stirring for 10 minutes, the temperature was raised to 60°C, and N,N'-thiocarbonyldiimidazole (69g) was slowly added. After reacting for 1 hour, add saturated ammonium chloride solution to quench the reaction, add dilute hydrochloric acid dropwise to adjust pH=4-5, and spin off THF. Filter, wash the filter cake with water, dissolve the methanol, and concentrate the organic phase to obtain crude product M10-5 (85g). ESI-MS m/z:267.0[M+H] + .
步骤6：化合物M10的合成Step 6: Synthesis of Compound M10
M10-5(74g)加入到1L三口瓶中，加入750mL ACN，加入碘甲烷(22mL)，加入甲醇钠(23g)的水溶液(100mL)。室温下反应15min后，将反应液加入到3.5L的水中，加入稀盐酸调整pH＝4-5,过滤，滤饼用PE：EA＝2：1的混合溶剂打浆。过滤，滤饼即为目标产物M10(42.2g)。ESI-MS m/z:281.2[M+H]+。M10-5 (74g) was added to a 1L three-necked flask, 750mL ACN was added, methyl iodide (22mL) was added, and an aqueous solution (100mL) of sodium methoxide (23g) was added. After reacting at room temperature for 15 minutes, add the reaction solution to 3.5L of water, add dilute hydrochloric acid to adjust pH=4-5, filter, and beat the filter cake with a mixed solvent of PE:EA=2:1. Filter, and the filter cake is the target product M10 (42.2g). ESI-MS m/z:281.2[M+H] + .
中间体M11的合成：
Synthesis of intermediate M11:
步骤1：化合物M11-1的合成Step 1: Synthesis of Compound M11-1
将叔丁醇钾(5.2g)和甲基三苯基溴化磷(14.1g)溶于乙醚(100mL)，氮气保护，降温至0℃以下，搅拌30min，缓慢加入化合物1-(叔丁基)2-甲基-4-氧代吡咯烷-1,2-二羧酸盐(8.0g)的乙醚溶液加毕，35℃反应3h。饱和氯化铵淬灭，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，抽滤，浓缩，浓缩物经柱层析(PE:EA 0％-15％)分离纯化得到化合物M11-1(3.8g)。Dissolve potassium tert-butoxide (5.2g) and methyl triphenylphosphonium bromide (14.1g) in diethyl ether (100 mL), protect with nitrogen, cool to below 0°C, stir for 30 minutes, slowly add compound 1-(tert-butyl ) The diethyl ether solution of 2-methyl-4-oxopyrrolidine-1,2-dicarboxylate (8.0g) was added, and the reaction was carried out at 35°C for 3 hours. Quench with saturated ammonium chloride, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, suction filtrate, concentrate, and the concentrate is separated and purified by column chromatography (PE:EA 0%-15%) to obtain compound M11-1 (3.8g).
步骤2：化合物M11-2的合成Step 2: Synthesis of Compound M11-2
将化合物M11-1(3.8g)溶于四氢呋喃(40mL)，降温至-78℃，缓慢加入双三甲基硅基胺基(35mL)，-78℃搅拌1h，缓慢加入3-氯-2-氯甲基丙烯，移至室温反应16h。反应液加入水中，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，浓缩。浓缩物经柱层析分离纯化(PE:EA 0％-20％)得到化合物M11-2(3.3g)。Dissolve compound M11-1 (3.8g) in tetrahydrofuran (40mL), cool to -78°C, slowly add bistrimethylsilylamine (35mL), stir at -78°C for 1 hour, and slowly add 3-chloro-2- Chloromethylpropylene, moved to room temperature and reacted for 16 hours. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by column chromatography (PE:EA 0%-20%) to obtain compound M11-2 (3.3g).
步骤3：化合物M11-3的合成Step 3: Synthesis of Compound M11-3
将化合物M11-2(3.3g)溶于二氯甲烷(35mL)，加入三氟乙酸(12mL)，室温反应16h。反应液浓缩，用氨甲醇调至pH＝8，液体浓缩。浓缩物经柱层析(DCM:MeOH 0％-10％)分离纯化得到化合物M11-3(2.0g)。 Compound M11-2 (3.3g) was dissolved in dichloromethane (35mL), trifluoroacetic acid (12mL) was added, and the reaction was carried out at room temperature for 16h. The reaction solution was concentrated, adjusted to pH=8 with ammonia methanol, and the liquid was concentrated. The concentrate was separated and purified by column chromatography (DCM: MeOH 0%-10%) to obtain compound M11-3 (2.0 g).
步骤4：化合物M11的合成Step 4: Synthesis of Compound M11
将化合物M11-3(2.0g)溶于四氢呋喃(20mL)，分批加入氢化铝锂(0.4g)，室温反应1Dissolve compound M11-3 (2.0g) in tetrahydrofuran (20mL), add lithium aluminum hydride (0.4g) in batches, and react at room temperature 1
h。反应液淬灭，无水硫酸钠干燥，浓缩。浓缩物经柱层析(DCM:MeOH 0％-10％)分离纯化得到中间体M11(1.6g)。ESI-MS m/z:166[M+H]+。h. The reaction solution was quenched, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by column chromatography (DCM: MeOH 0%-10%) to obtain intermediate M11 (1.6g). ESI-MS m/z:166[M+H] + .
中间体M12的合成：
Synthesis of intermediate M12:
在室温下，将化合物M7-1(0.3g)溶解于四氢呋喃中，在冰浴下加入四氢铝锂(123Dissolve compound M7-1 (0.3g) in tetrahydrofuran at room temperature, and add lithium aluminum tetrahydrogen (123
mg)，然后加入硼烷的四氢呋喃溶液(3.2mL)，撤去冰浴反应5分钟，LC-MS监测反应完全，用水淬灭反应至不再冒出气泡，加入15％氢氧化钠(0.3mL)，再加入水(0.9mL)，搅拌淬灭完全后，加入硫酸钠干燥，过滤得滤液，旋干得到产物M12(164mg，73％收率)。mg), then add borane solution in tetrahydrofuran (3.2mL), remove the ice bath and react for 5 minutes, monitor the reaction is complete by LC-MS, quench the reaction with water until bubbles no longer appear, add 15% sodium hydroxide (0.3mL) , then add water (0.9 mL), stir and quench completely, add sodium sulfate to dry, filter to obtain the filtrate, spin dry to obtain product M12 (164 mg, 73% yield).
中间体M13的制备：
Preparation of intermediate M13:
1)M13化合物的L-(-)-二对甲基苯甲酰酒石酸盐的制备1) Preparation of L-(-)-di-p-methylbenzoyl tartrate of M13 compound
称取11g M9于反应釜中，加入330ml的乙腈/水(30/1,体积比)的混合溶剂，在50℃下搅拌溶解，得M9溶液；称取26.5gL-(-)-二对甲基苯甲酰酒石酸于圆底烧瓶中，加入330ml的乙酸乙酯溶剂，配置成酸液。在50℃体系温度下，将酸液缓慢滴加至M9溶液中，酸液滴加完成后，向反应液中滴加330ml的乙酸乙酯，滴加完成后缓慢降温至10℃，并在10℃下熟化半小时。样品抽滤，滤饼于40℃下真空干燥过夜，得到13.9g(S)-DPLT盐粗品(固体异构体比例为9.2％:90.8％)。(S)-DPLT盐粗品在乙醇/乙腈(1/1,体积比1:1)中重结晶后得到11.6g(S)-DPLT盐M13-1(异构体比例为0.8％:99.2％)。 Weigh 11g of M9 into the reaction kettle, add 330ml of acetonitrile/water (30/1, volume ratio) mixed solvent, stir and dissolve at 50°C to obtain an M9 solution; weigh 26.5gL-(-)-di-p-methyl Place benzoyl tartaric acid in a round-bottomed flask, add 330 ml of ethyl acetate solvent, and prepare an acid solution. At the system temperature of 50°C, slowly drop the acid solution into the M9 solution. After the dropwise addition of the acid solution is completed, add 330 ml of ethyl acetate dropwise to the reaction solution. After the dropwise addition is completed, slowly cool down to 10°C, and incubate at 10 Aging for half an hour at ℃. The sample was suction-filtered, and the filter cake was vacuum-dried at 40° C. overnight to obtain 13.9 g of (S)-DPLT salt crude product (solid isomer ratio: 9.2%:90.8%). The crude (S)-DPLT salt was recrystallized in ethanol/acetonitrile (1/1, volume ratio 1:1) to obtain 11.6g (S)-DPLT salt M13-1 (isomer ratio 0.8%:99.2%) .
单晶培养及鉴定：称取化合物M13-1，用1ml丁酮/水(19/1,v/v)混合溶剂溶解，澄清样品转移至丁酮气氛中气液扩散过夜后得到单晶样品，单晶样品的体式偏光显微镜图见图1，单晶结构解析见图2，单晶结构信息表如下表。
Single crystal culture and identification: Weigh compound M13-1, dissolve it with 1 ml of butanone/water (19/1, v/v) mixed solvent, transfer the clarified sample to a butanone atmosphere for gas-liquid diffusion overnight, and obtain a single crystal sample. The stereoscopic polarizing microscope picture of the single crystal sample is shown in Figure 1, the single crystal structure analysis is shown in Figure 2, and the single crystal structure information table is as follows.
2)M13的制备2) Preparation of M13
称取20.0g M13-1(R/S异构体比例为0.8％:99.2％)于反应釜中，加入200ml二氯甲烷/甲醇(10/1，体积比)，搅拌溶清；向反应液中加入纯化水160ml，搅拌状态下向反应液中加入1M的氢氧化钠，调节水相pH至11～12，搅拌半小时后分液；水相用二氯甲烷/甲醇(10/1，体积比)溶剂200ml搅拌20分钟后分液萃取，重复2次；合并有机相，有机相用纯水200ml洗涤后，再用饱和食盐水200ml洗涤，最后有机相用无水硫酸钠干燥，干燥后的有机相过滤，滤液进行浓缩，浓缩后用ACN套蒸2次，得到5.17g(S)-(2-甲基四氢-1H-吡咯嗪-7a(5H)-基)甲醇M13，R/S异构体比例为0.8％:99.2％。 Weigh 20.0g M13-1 (R/S isomer ratio is 0.8%:99.2%) into the reaction kettle, add 200ml methylene chloride/methanol (10/1, volume ratio), stir to dissolve; add to the reaction solution Add 160 ml of purified water to the reaction solution, add 1M sodium hydroxide to the reaction solution under stirring, adjust the pH of the water phase to 11~12, stir for half an hour and separate the liquids; use dichloromethane/methanol (10/1, volume) for the water phase. (ratio) solvent 200ml, stir for 20 minutes, separate and extract, repeat twice; combine the organic phases, wash the organic phase with 200ml of pure water, and then wash with 200ml of saturated brine, and finally dry the organic phase with anhydrous sodium sulfate. The organic phase was filtered, and the filtrate was concentrated. After concentration, it was evaporated twice with an ACN jacket to obtain 5.17g (S)-(2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol M13, R/S The isomer ratio is 0.8%:99.2%.
实施例1：化合物4-(4-(1R，5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-2-(2-(二氟亚甲基)四氢-1H-吡咯啉-7a(5H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的合成
Example 1: Compound 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2-(difluoromethylene) Tetrahydro-1H-pyrrolin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2- Synthesis of alcohol
步骤1：化合物1-1的合成Step 1: Synthesis of Compound 1-1
室温下，将化合物M2(0.6g)和氢化钠(0.11g)溶解在无水THF(2mL)中,在室温下，滴加化合物M1(0.53g)的THF溶液，室温反应0.5小时。反应结束后，0℃下将液体滴加到饱和氯化铵溶液中，加入EA分液得到有机层，饱和食盐水(500mL)洗一遍，无水硫酸钠干燥，浓缩。浓缩物经柱色谱纯化(EA:DCM＝0-40％)得到产物1-1(0.54g，66％产率)。ESI-MS m/z＝581.1[M+H]+。Dissolve compound M2 (0.6g) and sodium hydride (0.11g) in anhydrous THF (2 mL) at room temperature, add dropwise the THF solution of compound M1 (0.53g) at room temperature, and react at room temperature for 0.5 hours. After the reaction, the liquid was added dropwise to the saturated ammonium chloride solution at 0°C, EA was added to separate the layers to obtain an organic layer, washed once with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (EA:DCM=0-40%) to obtain product 1-1 (0.54 g, 66% yield). ESI-MS m/z=581.1[M+H] + .
步骤2：化合物1-2的合成Step 2: Synthesis of Compound 1-2
室温下，在氮气保护下，将化合物1-1(0.3g)，cataCXium A Pd G3(40mg)，((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)萘-1-基)乙炔基)三异丙基硅烷(0.53g)和磷酸钾(0.33g)溶解在THF(6mL)和水(1mL)中,升温至70℃反应3小时，反应结束后，加入EA分液得到有机层，饱和食盐水洗一遍，无水硫酸钠干燥，浓缩。浓缩物经柱色谱纯化(EA:DCM＝0-30％)得到产物1-2(0.31g，63％产率)。ESI-MS m/z＝931.1[M+H]+。At room temperature, under nitrogen protection, compound 1-1 (0.3g), cataCXium A Pd G3 (40mg), ((2-fluoro-6-(methoxymethoxy)-8-(4,4, 5,5-Tetramethyl-1,3,2-dioxobenzaldehyde-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (0.53g) and potassium phosphate (0.33g) were dissolved in THF (6 mL) and water (1 mL) were heated to 70°C and reacted for 3 hours. After the reaction was completed, EA was added to separate the layers to obtain an organic layer, which was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (EA:DCM=0-30%) to obtain product 1-2 (0.31 g, 63% yield). ESI-MS m/z=931.1[M+H] + .
步骤3：化合物1-3的合成Step 3: Synthesis of Compounds 1-3
将化合物1-2(0.31g)溶解在DMF(3mL)中,室温下分批次加入氟化铯(0.5g)，反应结束后，滴加15mL水到反应液体中，析出大量固体，过滤得到固体经过烘干得到产品 1-3(0.31g，76％产率)。ESI-MS m/z＝775.1[M+H]+。Dissolve compound 1-2 (0.31g) in DMF (3mL), add cesium fluoride (0.5g) in batches at room temperature, after the reaction is completed, drop 15mL of water into the reaction liquid, a large amount of solid precipitates, and filter to obtain The solid is dried to obtain the product 1-3 (0.31 g, 76% yield). ESI-MS m/z=775.1[M+H] + .
步骤4：化合物1的合成Step 4: Synthesis of Compound 1
在室温下，将化合物1-3(0.31g)溶解在DCM(3mL)中，向其中加入三氟乙酸(1mL)，反应结束后，0℃，将反应液滴加到保护碳酸氢钠溶液中，加入DCM分液得到有机层，饱和食盐水洗一遍，无水硫酸钠干燥，浓缩。浓缩物经Pre-HPLC制备纯化得到产物1(31mg，13％产率)。1H NMR(500MHz,DMSO-d6)δ10.15(s,1H),9.04(s,1H),7.97(dd,J＝9.2,5.9Hz,1H),7.46(t,J＝9.0Hz,1H),7.39(d,J＝2.6Hz,1H),7.17(t,J＝2.3Hz,1H),4.47(d,J＝12.4Hz,1H),4.30(d,J＝12.2Hz,1H),4.14(dd,J＝10.6,4.2Hz,1H),4.08(dd,J＝10.6,2.3Hz,1H),3.93(dd,J＝4.0,1.0Hz,1H),3.68–3.60(m,2H),3.55(s,3H),3.30(s,1H),3.00(dq,J＝10.0,4.7,4.1Hz,1H),2.63(d,J＝14.7Hz,1H),2.56(q,J＝8.2Hz,1H),2.41(d,J＝15.8Hz,1H),1.97(td,J＝10.9,10.1,6.9Hz,1H),1.91–1.82(m,1H),1.78(q,J＝7.5Hz,2H),1.65(s,4H)。19F NMR(471MHz,DMSO-d6)δ-90.97(dd,J＝64.9,20.6Hz,1F),-91.46(dd,J＝64.9,38.2Hz,1F),-110.76(d,J＝3.8Hz,1F),-140.20(d,J＝3.1Hz,1F).Dissolve compound 1-3 (0.31g) in DCM (3mL) at room temperature, add trifluoroacetic acid (1mL) thereto, after the reaction is completed, add the reaction solution dropwise to the protective sodium bicarbonate solution at 0°C. , add DCM to separate the layers to obtain the organic layer, wash with saturated brine once, dry over anhydrous sodium sulfate, and concentrate. The concentrate was preparatively purified by Pre-HPLC to give product 1 (31 mg, 13% yield). 1 H NMR (500MHz, DMSO-d 6 ) δ10.15 (s, 1H), 9.04 (s, 1H), 7.97 (dd, J = 9.2, 5.9Hz, 1H), 7.46 (t, J = 9.0Hz, 1H),7.39(d,J＝2.6Hz,1H),7.17(t,J＝2.3Hz,1H),4.47(d,J＝12.4Hz,1H),4.30(d,J＝12.2Hz,1H) ,4.14(dd,J＝10.6,4.2Hz,1H),4.08(dd,J＝10.6,2.3Hz,1H),3.93(dd,J＝4.0,1.0Hz,1H),3.68–3.60(m,2H ),3.55(s,3H),3.30(s,1H),3.00(dq,J＝10.0,4.7,4.1Hz,1H),2.63(d,J＝14.7Hz,1H),2.56(q,J＝ 8.2Hz,1H),2.41(d,J＝15.8Hz,1H),1.97(td,J＝10.9,10.1,6.9Hz,1H),1.91–1.82(m,1H),1.78(q,J＝7.5 Hz,2H),1.65(s,4H). 19 F NMR (471MHz, DMSO-d 6 ) δ-90.97 (dd, J＝64.9, 20.6Hz, 1F), -91.46 (dd, J＝64.9, 38.2Hz, 1F), -110.76 (d, J＝3.8 Hz,1F),-140.20(d,J＝3.1Hz,1F).
实施例2：化合物4-(4-(1R，5S)-3,8-二氮杂二环[3.2.1]辛烷-3-基)-2-(2-(二氟亚甲基)四氢-1H-吡咯啉-7a(5H)-基)甲氧基)-8-氟-5-异丙氧基吡啶[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的合成
Example 2: Compound 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(2-(difluoromethylene) Tetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)-8-fluoro-5-isopropoxypyridine[4,3-d]pyrimidin-7-yl)-5-ethynyl- Synthesis of 6-fluoronaphthalene-2-ol
步骤1：化合物2-1的合成Step 1: Synthesis of compound 2-1
将异丙醇(1.23ml)溶于四氢呋喃(30ml)，加入NaH(0.64g)，在室温下反应10分钟，将温度降至0℃，加入5,7-二氯-8-氟-2-(甲硫基)吡啶[4,3-d]嘧啶-4-醇，移至室温反应1h。反应完全后，使用饱和氯化铵淬灭反应，使用EA萃取两遍，饱和食盐水洗一遍，无水硫酸钠干燥，真空浓缩，得到2-1(2.06g)。ESI-MS m/z:304.26[M+H]+。 Dissolve isopropyl alcohol (1.23ml) in tetrahydrofuran (30ml), add NaH (0.64g), react at room temperature for 10 minutes, lower the temperature to 0°C, and add 5,7-dichloro-8-fluoro-2- (Methylthio)pyridin[4,3-d]pyrimidin-4-ol, move to room temperature and react for 1 hour. After the reaction was completed, the reaction was quenched with saturated ammonium chloride, extracted twice with EA, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain 2-1 (2.06g). ESI-MS m/z:304.26[M+H] + .
步骤2：化合物2-2的合成Step 2: Synthesis of compound 2-2
将2-1(2.06g)和叔丁基(1R，5S)-3,8-二氮杂环[3.2.1]辛烷-8-羧酸酯(1.73g)，溶于DMF(20ml)中，向其中加入DBU(4.13g)，最后加入PyBOP(5.29g)，在室温下反应10分钟。待反应完全，向反应液中缓慢滴加水(100ml)，有大量固体析出，过滤得到的固体，使用EA溶解，无水硫酸钠干燥，浓缩，浓缩物经柱层析纯化，得到2-2(1.35g产率40.0％)。ESI-MS m/z:498.11[M+H]+。Dissolve 2-1 (2.06g) and tert-butyl (1R, 5S)-3,8-diazacyclo[3.2.1]octane-8-carboxylate (1.73g) in DMF (20ml) , add DBU (4.13g), and finally add PyBOP (5.29g), and react at room temperature for 10 minutes. When the reaction is complete, water (100 ml) is slowly added dropwise to the reaction solution, and a large amount of solid is precipitated. The solid obtained is filtered, dissolved with EA, dried over anhydrous sodium sulfate, and concentrated. The concentrate is purified by column chromatography to obtain 2-2( 1.35g yield 40.0%). ESI-MS m/z:498.11[M+H] + .
步骤3：化合物2-3的合成Step 3: Synthesis of Compound 2-3
将2-2(500mg)，((2-氟-6-(甲氧基甲氧基)-8-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)萘-1-基)乙炔基)三异丙基硅烷(705.54mg)，碳酸钾(416.29mg)，[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(81.99mg)溶于1，4-二氧六环(8.00ml)和水(2.00ml)，在氮气保护的氛围下，130℃封罐下反应1h。待反应完全，用EA和水稀释反应液，再用EA萃取一遍，饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，浓缩物经柱层析进行纯化，得到2-3(713mg，产率88.32％)。ESI-MS m/z:805.49[M+H]+。2-2 (500mg), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxobenzaldehyde) -2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (705.54mg), potassium carbonate (416.29mg), [1,1'-bis(diphenylphosphine)ferrocene]dichloro Palladium dichloromethane complex (81.99 mg) was dissolved in 1,4-dioxane (8.00 ml) and water (2.00 ml), and the reaction was carried out in a sealed jar at 130°C for 1 hour in a nitrogen-protected atmosphere. When the reaction is complete, dilute the reaction solution with EA and water, extract it once with EA, wash it once with saturated brine, dry it over anhydrous sodium sulfate, and concentrate it. The concentrate is purified by column chromatography to obtain 2-3 (713 mg, yield 88.32 %). ESI-MS m/z:805.49[M+H] + .
步骤4：化合物2-4的合成Step 4: Synthesis of Compound 2-4
将2-3(713mg)溶于二氯甲烷(10.00ml)加入叔丁基二甲基氯硅烷(668.22mg)和咪唑(422.57mg)中，在室温下反应0.5h。待反应完全，用DCM和水稀释反应液，再用DCM萃取一遍，饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，浓缩物经柱层析进行纯化得到2-4(770mg收率94.56％)。Dissolve 2-3 (713 mg) in dichloromethane (10.00 ml), add tert-butyldimethylsilyl chloride (668.22 mg) and imidazole (422.57 mg), and react at room temperature for 0.5 h. When the reaction is complete, dilute the reaction solution with DCM and water, extract it once with DCM, wash it once with saturated brine, dry it over anhydrous sodium sulfate, and concentrate it. The concentrate is purified by column chromatography to obtain 2-4 (770 mg, yield 94.56%). .
步骤5：化合物2-5的合成Step 5: Synthesis of Compounds 2-5
将2-4(770mg)溶于DCM(10.00mL)，加入mCPBA(578.80mg)，在室温下反应0.5h。用DCM稀释反应液，加入饱和碳酸氢钠淬灭反应，再用DCM萃取一遍，饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，浓缩物经柱层析进行纯化，得到2-5(290mg)。Dissolve 2-4 (770 mg) in DCM (10.00 mL), add mCPBA (578.80 mg), and react at room temperature for 0.5 h. The reaction solution was diluted with DCM, saturated sodium bicarbonate was added to quench the reaction, extracted once with DCM, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by column chromatography to obtain 2-5 (290 mg) .
步骤6：化合物2-6的合成Step 6: Synthesis of Compounds 2-6
将M1溶于THF(3.00mL)，加入NaH(17.17mg)，再将2-5(170.00mg)加入其中，在室温下反应0.5h。用饱和氯化铵淬灭反应，用EA萃取两遍，饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC分离纯化得到2-6(163mg)。ESI-MS m/z:530.53[M/2+H]+。Dissolve M1 in THF (3.00 mL), add NaH (17.17 mg), then add 2-5 (170.00 mg), and react at room temperature for 0.5 h. The reaction was quenched with saturated ammonium chloride, extracted twice with EA, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by Pre-TLC to obtain 2-6 (163 mg). ESI-MS m/z:530.53[M/2+H] + .
步骤7：化合物2-7的合成Step 7: Synthesis of Compounds 2-7
将2-6(163.00mg)溶于DMF(3.00mL)，加入CsF(701.32mg)，在室温下反应6h。用EA和水稀释反应液，用EA萃取一遍，饱和食盐水洗两遍，无水硫酸钠干燥，浓缩， 浓缩物经Pre-TLC分离纯化得到2-7(73mg)。ESI-MS m/z:789.11[M+H]+。Dissolve 2-6 (163.00 mg) in DMF (3.00 mL), add CsF (701.32 mg), and react at room temperature for 6 h. Dilute the reaction solution with EA and water, extract once with EA, wash twice with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The concentrate was separated and purified by Pre-TLC to obtain 2-7 (73 mg). ESI-MS m/z:789.11[M+H] + .
步骤8：化合物2的合成Step 8: Synthesis of Compound 2
将2-7(73.00mg)溶于DCM(2.00mL)，加入三氟化硼乙醚(0.23mL)，在室温下反应0.5h。将反应液加入到冷的饱和碳酸钠溶液中，使用DCM：MeOH＝10:1萃取两遍，饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC分离纯化得到化合物2(37.9mg)。ESI-MS m/z:689.25[M+H]+。1H NMR(500MHz,DMSO)δ10.14(s,1H),10.14(s,1H),7.97(dd,J＝9.2,5.9Hz,1H),7.97(dd,J＝9.2,5.9Hz,1H),7.46(t,J＝9.0Hz,1H),7.46(t,J＝9.0Hz,1H),7.37(d,J＝2.5Hz,1H),7.37(d,J＝2.5Hz,1H),7.20(s,1H),7.20(s,1H),5.37-5.21(m,1H),4.16-4.02(m,3H),3.87(d,J＝2.3Hz,1H),3.64(d,J＝14.4Hz,1H),3.45(dd,J＝45.7,19.5Hz,4H),3.05-2.91(m,1H),2.67-2.53(m,2H),2.40(d,J＝15.9Hz,2H),2.04-1.72(m,4H),1.45-1.65(m,3H),1.30(dd,J＝6.2,2.0Hz,4H)。Dissolve 2-7 (73.00 mg) in DCM (2.00 mL), add boron trifluoride ether (0.23 mL), and react at room temperature for 0.5 h. The reaction solution was added to cold saturated sodium carbonate solution, extracted twice with DCM: MeOH=10:1, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the concentrate was separated and purified by Pre-TLC to obtain compound 2 ( 37.9mg). ESI-MS m/z:689.25[M+H] + . 1 H NMR (500MHz, DMSO) δ10.14(s,1H),10.14(s,1H),7.97(dd,J＝9.2,5.9Hz,1H),7.97(dd,J＝9.2,5.9Hz,1H ),7.46(t,J＝9.0Hz,1H),7.46(t,J＝9.0Hz,1H),7.37(d,J＝2.5Hz,1H),7.37(d,J＝2.5Hz,1H), 7.20(s,1H),7.20(s,1H),5.37-5.21(m,1H),4.16-4.02(m,3H),3.87(d,J＝2.3Hz,1H),3.64(d,J＝ 14.4Hz,1H),3.45(dd,J＝45.7,19.5Hz,4H),3.05-2.91(m,1H),2.67-2.53(m,2H),2.40(d,J＝15.9Hz,2H), 2.04-1.72(m,4H),1.45-1.65(m,3H),1.30(dd,J=6.2,2.0Hz,4H).
实施例3：化合物4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-5-异丙氧基-2-((2-甲基四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的合成
Example 3: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-isopropoxy-2- ((2-Methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene -Synthesis of 2-alcohol
步骤1：化合物3-1的合成Step 1: Synthesis of compound 3-1
M9(13.0mg)，加入1mL THF后，加入NaH(6.7mg)。室温下搅拌5min后，加入2-5(40.0mg)。室温下反应30min后，将反应液加入到饱和氯化铵溶液中淬灭反应。EA萃取两次，收集并合并有机相，无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC分离纯化得到目标产物3-1(44.0mg)。ESI-MS m/z:512.1[M+H]+/2。M9 (13.0 mg), after adding 1 mL of THF, NaH (6.7 mg) was added. After stirring at room temperature for 5 min, 2-5 (40.0 mg) was added. After reacting at room temperature for 30 minutes, the reaction solution was added to saturated ammonium chloride solution to quench the reaction. Extract twice with EA, collect and combine the organic phases, dry over anhydrous sodium sulfate, and concentrate. The concentrate is separated and purified by Pre-TLC to obtain the target product 3-1 (44.0 mg). ESI-MS m/z:512.1[M+H] + /2.
步骤2：化合物3-2的合成Step 2: Synthesis of compound 3-2
将3-1(44.0mg)加入到10mL单口瓶中，加入1mL DMF，加入CsF(129.7mg)，在室温下反应4h。用EA和水稀释反应液，EA萃取两次，收集并合并有机相，无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC分离纯化得到目标产物3-2(16.6mg)。ESI-MS m/z:759.8[M+H]+。Add 3-1 (44.0 mg) into a 10 mL single-neck bottle, add 1 mL DMF, add CsF (129.7 mg), and react at room temperature for 4 hours. The reaction solution was diluted with EA and water, and extracted twice with EA. The organic phases were collected and combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by Pre-TLC to obtain the target product 3-2 (16.6 mg). ESI-MS m/z:759.8[M+H] + .
步骤3：化合物3的合成Step 3: Synthesis of Compound 3
将3-2(100mg)溶于DCM(2.00mL)，加入三氟化硼乙醚(0.4mL)，在室温下反应 0.5h。将反应液加入到冷的饱和碳酸钠溶液中，DCM萃取两次，收集并合并有机相，无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC分离纯化得到化合物3(19.8mg)。ESI-MS m/z:653.3[M+H]+。1H NMR(500MHz,DMSO)δ10.15(s,1H),7.97(dd,J＝9.1,5.9Hz,1H),7.46(t,J＝9.0Hz,1H),7.37(d,J＝2.4Hz,1H),7.19(d,J＝2.4Hz,1H),5.31(dd,J＝11.9,6.0Hz,1H),4.90(s,2H),4.05–3.88(m,4H),3.55(d,J＝13.9Hz,2H),3.20(d,J＝14.5Hz,2H),3.00(s,1H),2.67–2.54(m,2H),2.36(d,J＝15.1Hz,2H),2.00–1.61(m,9H),1.31(d,J＝6.0Hz,6H),1.23(s,1H),1.16(t,J＝7.2Hz,1H).Dissolve 3-2 (100mg) in DCM (2.00mL), add boron trifluoride ether (0.4mL), and react at room temperature 0.5h. The reaction solution was added to cold saturated sodium carbonate solution, and extracted twice with DCM. The organic phases were collected and combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by Pre-TLC to obtain compound 3 (19.8 mg). ESI-MS m/z:653.3[M+H] + . 1 H NMR (500MHz, DMSO) δ10.15 (s, 1H), 7.97 (dd, J = 9.1, 5.9Hz, 1H), 7.46 (t, J = 9.0Hz, 1H), 7.37 (d, J = 2.4 Hz,1H),7.19(d,J＝2.4Hz,1H),5.31(dd,J＝11.9,6.0Hz,1H),4.90(s,2H),4.05–3.88(m,4H),3.55(d ,J＝13.9Hz,2H),3.20(d,J＝14.5Hz,2H),3.00(s,1H),2.67–2.54(m,2H),2.36(d,J＝15.1Hz,2H),2.00 –1.61(m,9H),1.31(d,J＝6.0Hz,6H),1.23(s,1H),1.16(t,J＝7.2Hz,1H).
实施例5：4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-5-乙氧基-8-氟-2-((2-甲基四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的合成
Example 5: 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-5-ethoxy-8-fluoro-2-(( 2-Methyltetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene-2 -Synthesis of alcohol
步骤1：化合物5-1的合成Step 1: Synthesis of compound 5-1
在EtOH(0.31mL)的无水THF(10mL)溶液中分批加入NaH(357mg,60％纯度)，搅拌5min后将反应体系冷却到0℃，然后分批加入粉末固体M10(500mg)，自然升至室温22℃搅拌反应30分钟。再次将反应体系冷却到0℃，滴入饱和氯化铵溶液(20mL)淬灭反应，加入20mL乙酸乙酯进行萃取分液，水相用乙酸乙酯洗2遍，合并有机相并用无水硫酸钠干燥，有机相浓缩后得目标化合物5-1(600mg)直接用于下一步反应。ESI-MS m/z:290.1[M+H]+。 NaH (357 mg, 60% purity) was added in batches to a solution of EtOH (0.31 mL) in anhydrous THF (10 mL). After stirring for 5 min, the reaction system was cooled to 0°C, and then powdered solid M10 (500 mg) was added in batches. Naturally The mixture was heated to room temperature 22°C and stirred for 30 minutes. The reaction system was cooled to 0°C again, saturated ammonium chloride solution (20 mL) was added dropwise to quench the reaction, 20 mL of ethyl acetate was added for extraction and liquid separation, the aqueous phase was washed twice with ethyl acetate, the organic phases were combined and washed with anhydrous sulfuric acid. After drying over sodium, the organic phase was concentrated to obtain target compound 5-1 (600 mg), which was directly used in the next reaction. ESI-MS m/z:290.1[M+H] + .
步骤2：化合物5-2的合成Step 2: Synthesis of compound 5-2
室温下，向5-1(600mg)和(1R，5S)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(528mg)的DMF(6mL)溶液中依次加入DBU(1.24mL)和PyBOP(1.6g)，室温搅拌反应30分钟后LCMS显示反应完全。向反应中加入30mL饱和食盐水和30mL EA萃取分液，有机相用饱和食盐水洗涤3次后经无水硫酸钠干燥，有机相进一步浓缩后经柱层析纯化(EA/PE＝0％-15％)得目标化合物5-2(420mg)。ESI-MS m/z:484.3[M+H]+。To a solution of 5-1 (600 mg) and (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (528 mg) in DMF (6 mL) at room temperature DBU (1.24 mL) and PyBOP (1.6 g) were added in sequence, and the reaction was stirred at room temperature for 30 minutes. LCMS showed that the reaction was complete. Add 30 mL saturated brine and 30 mL EA to the reaction for extraction and separation. The organic phase was washed 3 times with saturated brine and dried over anhydrous sodium sulfate. The organic phase was further concentrated and purified by column chromatography (EA/PE=0%- 15%) to obtain target compound 5-2 (420 mg). ESI-MS m/z:484.3[M+H] + .
步骤3：化合物5-3的合成Step 3: Synthesis of compound 5-3
微波管中分别加入5-2(420mg)，M8(569mg)，K2CO3(360mg)，Pd(dppf)Cl2(106mg)和6mL Dioxane/1.5mL H2O后，N2置换10min后，微波130℃反应70分钟。向反应液中加入EA和H2O各20mL，萃取分液，水相再用EA萃取两遍，有机相经无水硫酸钠干燥后减压浓缩，浓缩物经柱层析纯化(EA/PE＝0％-30％)得目标化合物5-3(400mg)。ESI-MS m/z:790.2[M+H]+。After adding 5-2 (420mg), M8 (569mg), K 2 CO 3 (360mg), Pd(dppf)Cl 2 (106mg) and 6mL Dioxane/1.5mL H 2 O respectively, N 2 was replaced for 10 minutes. , microwave at 130°C for 70 minutes. Add 20 mL each of EA and H 2 O to the reaction solution, extract and separate the liquids. The aqueous phase is extracted twice with EA. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is purified by column chromatography (EA/PE =0%-30%) to obtain target compound 5-3 (400 mg). ESI-MS m/z:790.2[M+H] + .
步骤4：化合物5-4的合成Step 4: Synthesis of compound 5-4
向5-3(400mg)的DCM(15mL)溶液中加入咪唑(241mg)和TBSCl(382mg)，让反应体系在室温搅拌20min。向反应中加入15mL水，萃取分液，水相用10mL DCM洗两遍，有机相合并后用20mL饱和食盐水洗涤一次，然后经无水硫酸钠干燥后减压浓缩，浓缩物经柱层析纯化(EA/PE＝0％-10％)得目标化合物5-4(270mg)。To a solution of 5-3 (400 mg) in DCM (15 mL), imidazole (241 mg) and TBSCl (382 mg) were added, and the reaction system was allowed to stir at room temperature for 20 min. Add 15 mL of water to the reaction, extract and separate the liquids. Wash the aqueous phase twice with 10 mL of DCM. The organic phase is combined and washed once with 20 mL of saturated saline. Then it is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is subjected to column chromatography. Purification (EA/PE=0%-10%) gave target compound 5-4 (270 mg).
步骤5：化合物5-5的合成Step 5: Synthesis of compound 5-5
向5-4(260mg)的DCM(5mL)溶液中加入mCPBA(198mg)，室温搅拌30分钟。向反应中加入20mL DCM和20mL饱和NaHCO3溶液，萃取分液，水相再用10mL DCM萃取两遍，有机相合并后经无水硫酸钠干燥，浓缩，浓缩物经柱层析纯化(EA/PE＝0％-30％)得目标化合物5-5(148mg)。ESI-MS m/z:936.5.[M+H]+。mCPBA (198 mg) was added to a solution of 5-4 (260 mg) in DCM (5 mL), and the mixture was stirred at room temperature for 30 minutes. Add 20 mL DCM and 20 mL saturated NaHCO solution to the reaction, extract and separate the liquids, extract the aqueous phase twice with 10 mL DCM, combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and the concentrate is purified by column chromatography (EA/ PE=0%-30%) to obtain target compound 5-5 (148 mg). ESI-MS m/z:936.5.[M+H] + .
步骤6：化合物5-6的合成Step 6: Synthesis of Compounds 5-6
向M9(48mg)的无水THF(3mL)溶液中加入NaH(25mg)，搅拌10分钟后，再加入5-5(148mg)，体系在室温下搅拌15min。反应结束后将体系冷却到0℃，滴入饱和氯化铵水溶液(20mL)淬灭反应，加入乙酸乙酯(20mL)，萃取分液，水相用乙酸乙酯洗2遍，有机相合并后经无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC(DCM/NH3：MeOH(7M)＝100:6)分离纯化得目标化合物5-6(96mg)。ESI-MS m/z:895.6[M+H]+。NaH (25 mg) was added to a solution of M9 (48 mg) in anhydrous THF (3 mL), and after stirring for 10 minutes, 5-5 (148 mg) was added, and the system was stirred at room temperature for 15 min. After the reaction, the system was cooled to 0°C, saturated aqueous ammonium chloride solution (20 mL) was added dropwise to quench the reaction, ethyl acetate (20 mL) was added, extraction was performed, and the aqueous phase was washed twice with ethyl acetate, and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, concentrated, and the concentrate was separated and purified by Pre-TLC (DCM/NH 3 :MeOH (7M) = 100:6) to obtain target compound 5-6 (96 mg). ESI-MS m/z:895.6[M+H] + .
步骤7：化合物5-7的合成Step 7: Synthesis of Compounds 5-7
向5-6(75mg,1.0eq.)的DMF(1mL)溶液中加入CsF(255mg,20.0eq.)，然后让 反应体系在35℃搅拌2小时。反应结束后向反应中加入20mL饱和食盐水和20mL EA，萃取分液，有机相用20mL饱和食盐水再洗涤两遍后经无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC(DCM/NH3in MeOH(7M)＝100:7)分离纯化得目标化合物5-7(42mg)。ESI-MS m/z:739.5[M+H]+。Add CsF (255mg, 20.0eq.) to a solution of 5-6 (75mg, 1.0eq.) in DMF (1mL) and let The reaction system was stirred at 35°C for 2 hours. After the reaction, 20 mL of saturated saline and 20 mL of EA were added to the reaction, and the liquid was extracted and separated. The organic phase was washed twice with 20 mL of saturated saline, dried over anhydrous sodium sulfate, concentrated, and the concentrate was subjected to Pre-TLC (DCM/NH) 3 in MeOH (7M) = 100:7) was isolated and purified to obtain the target compound 5-7 (42 mg). ESI-MS m/z:739.5[M+H] + .
步骤8：化合物5的合成Step 8: Synthesis of Compound 5
向5-7(40mg,1.0eq.)的无水DCM(1mL)溶液中加入BF3.Et2O(0.14mL,20.0eq.)，所得体系在室温下搅拌10分钟。反应结束后，将反应体系冷却到0℃，然后加入饱和Na2CO3(10mL)淬灭，加入DCM/MeOH(10:1，20mL)萃取，水相用相同混合溶剂继续萃取两遍。有机相合并后经无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC(DCM/NH3：MeOH(7M)＝9:1)分离纯化得目标化合物5(29mg)。1H NMR(500MHz,CDCl3)δ7.68(dd,J＝8.8,5.9Hz,1H),7.36(d,J＝2.3Hz,1H),7.26(d,J＝2.3Hz,1H),7.17(t,J＝8.8Hz,1H),4.97–4.85(m,2H),4.46–4.38(m,1H),4.36–4.27(m,1H),4.24–4.16(m,2H),3.56(d,J＝17.8Hz,3H),3.44(d,J＝12.5Hz,1H),3.31–3.20(m,2H),2.86–2.76(m,2H),2.71–2.64(m,1H),2.44–2.33(m,2H),2.24–2.12(m,2H),1.95–1.87(m,2H),1.81–1.57(m,5H),1.32(t,J＝7.1Hz,2H),1.29–1.23(m,3H).ESI-MS m/z:639.5[M+H]+。To a solution of 5-7 (40 mg, 1.0 eq.) in anhydrous DCM (1 mL) was added BF 3 .Et 2 O (0.14 mL, 20.0 eq.), and the resulting system was stirred at room temperature for 10 minutes. After the reaction, the reaction system was cooled to 0°C, then saturated Na 2 CO 3 (10 mL) was added to quench, DCM/MeOH (10:1, 20 mL) was added for extraction, and the aqueous phase was extracted twice with the same mixed solvent. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the concentrate was separated and purified by Pre-TLC (DCM/NH 3 :MeOH (7M) = 9:1) to obtain target compound 5 (29 mg). 1 H NMR (500MHz, CDCl 3 ) δ7.68 (dd, J＝8.8, 5.9Hz, 1H), 7.36 (d, J＝2.3Hz, 1H), 7.26 (d, J＝2.3Hz, 1H), 7.17 (t,J＝8.8Hz,1H),4.97–4.85(m,2H),4.46–4.38(m,1H),4.36–4.27(m,1H),4.24–4.16(m,2H),3.56(d ,J＝17.8Hz,3H),3.44(d,J＝12.5Hz,1H),3.31–3.20(m,2H),2.86–2.76(m,2H),2.71–2.64(m,1H),2.44– 2.33(m,2H),2.24–2.12(m,2H),1.95–1.87(m,2H),1.81–1.57(m,5H),1.32(t,J＝7.1Hz,2H),1.29–1.23( m,3H).ESI-MS m/z:639.5[M+H] + .
实施例6：化合物4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-((2-(二氟亚甲基)四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-乙氧基-8-氟吡啶并[4,3d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的合成
Example 6: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2-(difluoromethylene)) Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-ethoxy-8-fluoropyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-6- Synthesis of fluoronaphthalene-2-ol
步骤1：化合物6-1合成Step 1: Synthesis of compound 6-1
向M1(113mg)的无水THF(6mL)溶液中加入NaH(25mg)，搅拌10min后，再加入5-5(148mg)，体系在室温下搅拌30分钟。反应结束后将体系冷却到0℃，滴入饱和氯化铵水溶液(20mL)淬灭反应，加入乙酸乙酯(20mL)，萃取分液，水相用乙酸 乙酯洗2遍，有机相合并后经无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC纯化(DCM/NH3：MeOH(7M)＝100:5)得目标化合物6-1(240mg)。ESI-MS m/z:985.5[M+H]+。NaH (25 mg) was added to a solution of M1 (113 mg) in anhydrous THF (6 mL), and after stirring for 10 min, 5-5 (148 mg) was added, and the system was stirred at room temperature for 30 min. After the reaction, the system was cooled to 0°C, saturated aqueous ammonium chloride solution (20 mL) was added dropwise to quench the reaction, ethyl acetate (20 mL) was added, extraction was performed, and the aqueous phase was separated with acetic acid. Wash 2 times with ethyl ester, combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify the concentrate by Pre-TLC (DCM/NH 3 : MeOH (7M) = 100:5) to obtain target compound 6-1 (240 mg) . ESI-MS m/z:985.5[M+H] + .
步骤2：化合物6-2的合成Step 2: Synthesis of compound 6-2
向6-1(240mg)的DMF(2.0mL)溶液中加入CsF(353mg)，然后让反应体系在35℃搅拌3小时。反应结束后向反应中加入20mL饱和食盐水和20mL EA，萃取分液，有机相用20mL饱和食盐水再洗涤两遍后经无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC纯化(DCM/NH3：MeOH(7M)＝100:6)得目标化合物6-2(144mg)。ESI-MS m/z:775.4[M+H]+。To a solution of 6-1 (240 mg) in DMF (2.0 mL) was added CsF (353 mg), and the reaction system was allowed to stir at 35°C for 3 hours. After the reaction, 20 mL of saturated brine and 20 mL of EA were added to the reaction, and the liquid was extracted and separated. The organic phase was washed twice with 20 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by Pre-TLC (DCM/ NH 3 : MeOH (7M) = 100:6) to obtain target compound 6-2 (144 mg). ESI-MS m/z:775.4[M+H] + .
步骤3：化合物6的合成Step 3: Synthesis of Compound 6
向6-2(140mg)的无水DCM(3mL)溶液中加入BF3.Et2O(0.46mL)，所得体系在室温下搅拌10分钟。反应结束后，将反应体系冷却到0℃，然后加入饱和Na2CO3(10mL)淬灭，加入DCM/MeOH(10:1，20mL)萃取，水相用相同混合溶剂继续萃取两遍。有机相合并后经无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC纯化(DCM/NH3：MeOH(7M)＝7:1)得目标化合物6(90mg)。1H NMR(500MHz,DMSO)δ10.15(s,1H),7.97(dd,J＝9.0,6.0Hz,1H),7.46(t,J＝9.0Hz,1H),7.38(d,J＝2.4Hz,1H),7.20(s,1H),4.42–4.27(m,2H),4.10(dd,J＝26.8,10.6Hz,2H),3.96(s,1H),3.87(s,1H),3.64(d,J＝14.1Hz,1H),3.51(s,2H),3.47–3.34(m,3H),3.02–2.95(m,1H),2.65–2.53(m,2H),2.43–2.35(m,1H),1.99–1.92(m,1H),1.89–1.82(m,1H),1.80–1.73(m,2H),1.66–1.51(m,5H),1.40(s,1H),1.32(t,J＝7.0Hz,3H).ESI-MS m/z:675.5[M+H]+。To a solution of 6-2 (140 mg) in anhydrous DCM (3 mL) was added BF 3 .Et 2 O (0.46 mL), and the resulting system was stirred at room temperature for 10 minutes. After the reaction, the reaction system was cooled to 0°C, then saturated Na 2 CO 3 (10 mL) was added to quench, DCM/MeOH (10:1, 20 mL) was added for extraction, and the aqueous phase was extracted twice with the same mixed solvent. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by Pre-TLC (DCM/NH 3 :MeOH (7M) = 7:1) to obtain target compound 6 (90 mg). 1 H NMR (500MHz, DMSO) δ10.15 (s, 1H), 7.97 (dd, J = 9.0, 6.0Hz, 1H), 7.46 (t, J = 9.0Hz, 1H), 7.38 (d, J = 2.4 Hz,1H),7.20(s,1H),4.42–4.27(m,2H),4.10(dd,J＝26.8,10.6Hz,2H),3.96(s,1H),3.87(s,1H),3.64 (d,J＝14.1Hz,1H),3.51(s,2H),3.47–3.34(m,3H),3.02–2.95(m,1H),2.65–2.53(m,2H),2.43–2.35(m ,1H),1.99–1.92(m,1H),1.89–1.82(m,1H),1.80–1.73(m,2H),1.66–1.51(m,5H),1.40(s,1H),1.32(t ,J＝7.0Hz,3H).ESI-MS m/z:675.5[M+H] + .
实施例7：化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-8-氟-5-甲氧基-2-((2-亚甲基四氢-1H-吡咯烷-7a(5H)-基)甲氧基)吡啶[4,3-d]嘧啶-7-基)-5-乙炔-6-氟萘-2-醇的合成
Example 7: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-5-methoxy-2- ((2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidin-7-yl)-5-ethyne-6-fluoronaphthalene- Synthesis of 2-alcohols
步骤1：化合物7-1的合成Step 1: Synthesis of compound 7-1
反应瓶中分别加入MeOH(1.80mL)和无水THF后，于冰水浴降温5min，缓慢分批加入NaH(2.86g),搅拌5min后，分批加入粉末固体M10(4.00g)，自然升至室温22℃搅拌反应10min；反应于冰水浴降温5min，滴入饱和NH4Cl 100mL淬灭，加入200mL乙酸乙酯，萃取，水相用乙酸乙酯洗2遍，合并有机相减压蒸干，得目标化合物7-1(4.23g)。ESI-MS m/z:276.0[M+H]+。After adding MeOH (1.80mL) and anhydrous THF respectively to the reaction flask, cool down in an ice water bath for 5 minutes, slowly add NaH (2.86g) in batches, stir for 5 minutes, add powdered solid M10 (4.00g) in batches, and naturally rise to Stir the reaction at room temperature 22°C for 10 minutes; cool down the reaction in an ice water bath for 5 minutes, add 100 mL of saturated NH 4 Cl dropwise to quench, add 200 mL of ethyl acetate, extract, wash the aqueous phase twice with ethyl acetate, combine the organic phases and evaporate to dryness under reduced pressure. The target compound 7-1 (4.23g) was obtained. ESI-MS m/z:276.0[M+H] + .
步骤2：化合物7-2的合成Step 2: Synthesis of compound 7-2
在室温下，向反应瓶中依次加入7-1(4.23g)，(1R，5S)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(3.91g),DBU(11.47mL)和无水DMF(10.0mL)后，室温搅拌溶清，最后加入PyBOP(12.00g)，室温搅拌反应0.5h。向反应中加入200mL饱和NaCl自来水，200mL EA洗两遍，萃取分液，有机相于减压蒸干，浓缩物经柱层析纯化(PE/EA＝3:1)得目标化合物7-2(2.57g)。ESI-MS m/z:470.3[M+H]+。At room temperature, add 7-1 (4.23g), (1R, 5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (3.91g) to the reaction bottle in sequence. ), DBU (11.47mL) and anhydrous DMF (10.0mL), stir and dissolve at room temperature, finally add PyBOP (12.00g), stir and react at room temperature for 0.5h. 200 mL saturated NaCl tap water was added to the reaction, washed twice with 200 mL EA, extracted and separated, the organic phase was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (PE/EA=3:1) to obtain target compound 7-2 ( 2.57g). ESI-MS m/z:470.3[M+H] + .
步骤3：化合物7-3的合成Step 3: Synthesis of compound 7-3
微波管中分别加入7-2(0.70g)，M8(1.40g)，K2CO3(0.63g)，Pd(dppf)Cl2(0.20g)和7mL Dioxane/1mL H2O后，N2置换2min后，微波140℃反应0.5h。向反应液中加入DCM和H2O各20mL，萃取，水相用DCM洗两遍，有机相减压浓缩，浓缩物经柱层析纯化(PE/EA＝4:1)得目标化合物7-3(1.23g)。ESI-MS m/z:776.4[M+H]+。 After adding 7-2 (0.70g), M8 (1.40g), K 2 CO 3 (0.63g), Pd(dppf)Cl 2 (0.20g) and 7mL Dioxane/1mL H 2 O respectively into the microwave tube, N 2 After replacement for 2 minutes, microwave reaction was carried out at 140°C for 0.5 hours. Add 20 mL each of DCM and H 2 O to the reaction solution, extract, wash the aqueous phase twice with DCM, concentrate the organic phase under reduced pressure, and purify the concentrate by column chromatography (PE/EA=4:1) to obtain the target compound 7- 3(1.23g). ESI-MS m/z:776.4[M+H] + .
步骤4：化合物7-4的合成Step 4: Synthesis of compound 7-4
向反应瓶中分别加入7-3(1.13g)，TBSCl(1.10g)，咪唑(0.69g)和无水DCM(15mL)后，室温搅拌反应20min。向反应中加入15mL饱和NaCl自来水，萃取分液，水相用10mL DCM洗两遍，有机相减压蒸干，浓缩物经柱层析纯化(PE/EA＝10:1)得目标化合物7-4(1.06g)。ESI-MS m/z:890.3[M+H]+。7-3 (1.13g), TBSCl (1.10g), imidazole (0.69g) and anhydrous DCM (15mL) were added to the reaction flask respectively, and the reaction was stirred at room temperature for 20 minutes. Add 15 mL saturated NaCl tap water to the reaction, extract and separate the liquids, wash the aqueous phase twice with 10 mL DCM, evaporate the organic phase to dryness under reduced pressure, and purify the concentrate by column chromatography (PE/EA=10:1) to obtain the target compound 7- 4(1.06g). ESI-MS m/z:890.3[M+H] + .
步骤5：化合物7-5的合成Step 5: Synthesis of compound 7-5
向反应瓶中分别加入7-4(1.00g)，mCPBA(0.47g)和无水DCM(15mL)后，室温搅拌反应15min。向反应中加入20mL饱和NaHCO3，萃取分液，水相用10mL DCM洗两遍，有机相减压蒸干，浓缩物经柱层析纯化(PE/EA＝3:1)得目标化合物7-5(0.40g)。ESI-MS m/z:923.0[M+H]+。After adding 7-4 (1.00g), mCPBA (0.47g) and anhydrous DCM (15mL) respectively to the reaction bottle, stir the reaction at room temperature for 15min. Add 20 mL saturated NaHCO 3 to the reaction, extract and separate the liquids, wash the aqueous phase twice with 10 mL DCM, evaporate the organic phase to dryness under reduced pressure, and purify the concentrate by column chromatography (PE/EA=3:1) to obtain the target compound 7- 5(0.40g). ESI-MS m/z:923.0[M+H] + .
步骤6：化合物7-6的合成Step 6: Synthesis of Compound 7-6
向反应瓶中分别加入M4(0.11g)和溶剂无水THF(1mL)，分批缓慢加入NaH(0.25g)，搅拌10min后，再加入7-5(0.33g)，于室温搅拌反应15min。反应液用冰水浴降温5min，滴入饱和NH4Cl 20mL淬灭，加入20mL乙酸乙酯，萃取，水相用乙酸乙酯洗2遍，合并有机相，减压蒸干，浓缩物经柱层析纯化(DCM/NH3：MeOH＝20:1)得目标化合物7-6(0.32g)。ESI-MS m/z:881.6[M+H]+。Add M4 (0.11g) and solvent anhydrous THF (1mL) to the reaction flask, add NaH (0.25g) slowly in batches, stir for 10 min, then add 7-5 (0.33g), and stir at room temperature for 15 min. The reaction solution was cooled in an ice water bath for 5 minutes, 20 mL of saturated NH 4 Cl was added dropwise to quench, and 20 mL of ethyl acetate was added to extract. The aqueous phase was washed twice with ethyl acetate, the organic phases were combined, and evaporated to dryness under reduced pressure. The concentrate was passed through column layer. Analytical purification (DCM/NH 3 :MeOH=20:1) gave the target compound 7-6 (0.32g). ESI-MS m/z:881.6[M+H] + .
步骤7：化合物7-7的合成Step 7: Synthesis of Compound 7-7
向反应瓶中分别加入7-6(0.32g),CsF(0.55g)和无水DMF(3mL)后，室温搅拌反应5.0h。向反应中加入20mL饱和NaCl，萃取分液，水相用20mL EA洗两遍，有机相减压蒸干，浓缩物经柱层析纯化(DCM/NH3in MeOH＝20:1)得目标化合物7-7(0.18g)。ESI-MS m/z:725.5[M+H]+。After adding 7-6 (0.32g), CsF (0.55g) and anhydrous DMF (3mL) respectively to the reaction bottle, the reaction was stirred at room temperature for 5.0h. Add 20 mL saturated NaCl to the reaction, extract and separate the liquids, wash the aqueous phase twice with 20 mL EA, evaporate the organic phase to dryness under reduced pressure, and purify the concentrate by column chromatography (DCM/NH 3 in MeOH = 20:1) to obtain the target compound. 7-7(0.18g). ESI-MS m/z:725.5[M+H] + .
步骤8：化合物7的合成Step 8: Synthesis of Compound 7
向反应瓶中分别加入7-7(0.18g)和无水DCM(3mL)后，加入BF3.Et2O(0.30mL)，于室温反应0.5h。反应结束后，于冰水浴降温5min，滴入饱和Na2CO3(10mL)淬灭，加入DCM/MeOH(10:1，20mL)萃取，有机相减压蒸干，浓缩物经柱层析纯化(DCM/NH3in MeOH＝8:1)得到目标化合物7(126.0mg，82.60％产率)。1H NMR(500MHz,MeOD)δ7.81(dd,J＝9.1,5.7Hz,1H),7.31–7.22(m,3H),5.48(s,1H),4.96(d,J＝1.5Hz,2H),4.22(dt,J＝10.5,6.8Hz,2H),3.99(s,3H),3.70(d,J＝14.2Hz,1H),3.55(s,3H),3.45(d,J＝13.0Hz,1H),3.34–3.25(m,3H),3.12(dt,J＝10.6,5.5Hz,1H),2.79–2.64(m,2H),2.44(dd,J＝15.8,1.8Hz,1H),2.17–2.07(m,1H),2.01–1.85(m,2H),1.84–1.72(m,4H),1.65(s,1H). ESI-MS m/z:625.3[M+H]+。After adding 7-7 (0.18g) and anhydrous DCM (3mL) to the reaction bottle respectively, add BF 3 .Et 2 O (0.30mL) and react at room temperature for 0.5h. After the reaction, the temperature was cooled in an ice-water bath for 5 min, saturated Na 2 CO 3 (10 mL) was added dropwise to quench, DCM/MeOH (10:1, 20 mL) was added for extraction, the organic phase was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography. (DCM/NH 3 in MeOH=8:1) obtained target compound 7 (126.0 mg, 82.60% yield). 1 H NMR (500MHz, MeOD) δ7.81 (dd, J＝9.1, 5.7Hz, 1H), 7.31–7.22 (m, 3H), 5.48 (s, 1H), 4.96 (d, J＝1.5Hz, 2H ),4.22(dt,J＝10.5,6.8Hz,2H),3.99(s,3H),3.70(d,J＝14.2Hz,1H),3.55(s,3H),3.45(d,J＝13.0Hz ,1H),3.34–3.25(m,3H),3.12(dt,J＝10.6,5.5Hz,1H),2.79–2.64(m,2H),2.44(dd,J＝15.8,1.8Hz,1H), 2.17–2.07(m,1H),2.01–1.85(m,2H),1.84–1.72(m,4H),1.65(s,1H). ESI-MS m/z:625.3[M+H] + .
实施例8：化合物4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-((2-(二氟亚甲基)四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-8-氟-5-甲氧基吡啶并[4,3d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的合成
Example 8: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2-(difluoromethylene)) Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-5-methoxypyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-6- Synthesis of fluoronaphthalene-2-ol
步骤1：化合物8-1的合成Step 1: Synthesis of compound 8-1
在反应瓶中加入化合物M1(274.91mg)，THF(4.00mL)，NaH(69.74mg)，然后再加7-5(670.00mg)，室温反应0.4h。反应液用冰水浴降温5min，滴入饱和NH4Cl 20mL淬灭，加入20mL乙酸乙酯，萃取，水相用乙酸乙酯洗2遍，合并有机相，减压蒸干，浓缩物经柱层析纯化(DCM/NH3：MeOH＝20:1)得目标化合物8-1(470mg，产率70.45％)。ESI-MS m/z:917.44[M+H]+。Add compound M1 (274.91mg), THF (4.00mL), NaH (69.74mg) to the reaction bottle, then add 7-5 (670.00mg), and react at room temperature for 0.4h. The reaction solution was cooled in an ice water bath for 5 minutes, 20 mL of saturated NH 4 Cl was added dropwise to quench, and 20 mL of ethyl acetate was added to extract. The aqueous phase was washed twice with ethyl acetate, the organic phases were combined, and evaporated to dryness under reduced pressure. The concentrate was passed through column layer. Analytical purification (DCM/NH 3 :MeOH=20:1) gave the target compound 8-1 (470 mg, yield 70.45%). ESI-MS m/z:917.44[M+H] + .
步骤2：化合物8-2的合成Step 2: Synthesis of compound 8-2
在反应瓶中加入化合物8-1(300.00mg)，DMF(3.00mL)，CsF(441.88mg)，室温反应3h。向反应中加入20mL水和20mL EA，萃取分液，水相再用20mL EA洗一遍，有机相减压蒸干，浓缩物经Pre-TLC纯化(DCM:MeOH:氨水＝15:1：0.15)，得目标化合物8-2(200.00mg,90.37％)。ESI-MS m/z:761.30[M+H]+。Add compound 8-1 (300.00 mg), DMF (3.00 mL), and CsF (441.88 mg) to the reaction bottle, and react at room temperature for 3 hours. Add 20 mL water and 20 mL EA to the reaction, extract and separate the liquids, wash the water phase with 20 mL EA again, evaporate the organic phase to dryness under reduced pressure, and purify the concentrate by Pre-TLC (DCM: MeOH: ammonia water = 15: 1: 0.15) , the target compound 8-2 (200.00 mg, 90.37%) was obtained. ESI-MS m/z:761.30[M+H] + .
步骤3：化合物8的合成Step 3: Synthesis of Compound 8
在反应瓶中加入化合物8-2(190.00mg)，DCM(3.00mL)，三氟化硼乙醚(0.63mL)，室温反应2h。反应结束后，于冰水浴降温5min，然后将反应液滴入到饱和Na2CO3(10mL)中淬灭，加入DCM/MeOH(10:1，20mL)萃取，有机相减压蒸干，浓缩物经Pre-TLC纯化(DCM:MeOH:氨水＝8.5:1：0.15)，得到目标化合物8(122.00mg,73.95％)。ESI-MS m/z: 661.30[M+H]+。1H NMR(500MHz,MeOD)δ7.88–7.77(m,1H),7.34–7.21(m,3H),4.40–4.21(m,3H),4.12(s,1H),4.01(s,3H),3.80(d,J＝14.3Hz,1H),3.64–3.53(m,3H),3.46(dd,J＝31.7,13.6Hz,2H),3.33(m,1H),3.14(d,J＝5.3Hz,1H),2.75(dd,J＝52.0,11.6Hz,2H),2.50(d,J＝15.7Hz,1H),2.13(s,1H),2.04–1.87(m,3H),1.81(m,3H),1.69(s,1H).Add compound 8-2 (190.00 mg), DCM (3.00 mL), and boron trifluoride ether (0.63 mL) into the reaction bottle, and react at room temperature for 2 h. After the reaction is completed, cool down in an ice-water bath for 5 minutes, then drop the reaction solution into saturated Na 2 CO 3 (10 mL) to quench, add DCM/MeOH (10:1, 20 mL) for extraction, and evaporate the organic phase to dryness under reduced pressure and concentrate. The material was purified by Pre-TLC (DCM:MeOH:ammonia=8.5:1:0.15) to obtain target compound 8 (122.00 mg, 73.95%). ESI-MS m/z: 661.30[M+H]+. 1 H NMR(500MHz,MeOD)δ7.88–7.77(m,1H),7.34–7.21(m,3H),4.40–4.21(m,3H),4.12(s,1H),4.01(s,3H) ,3.80(d,J＝14.3Hz,1H),3.64–3.53(m,3H),3.46(dd,J＝31.7,13.6Hz,2H),3.33(m,1H),3.14(d,J＝5.3 Hz,1H),2.75(dd,J＝52.0,11.6Hz,2H),2.50(d,J＝15.7Hz,1H),2.13(s,1H),2.04–1.87(m,3H),1.81(m ,3H),1.69(s,1H).
实施例9：化合物4-(4-(1R，5S)-3，8-二氮杂双环[3.2.1]辛烷-3-基)-5-环丙氧基-8-氟-2-(2-亚甲基四氢-1H-吡咯烷-7a(5H)-基)甲氧基)吡啶并[4，3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的合成
Example 9: Compound 4-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-5-cyclopropoxy-8-fluoro-2- (2-methylenetetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene -Synthesis of 2-alcohol
步骤1：化合物9-1的合成Step 1: Synthesis of compound 9-1
反应瓶中分别加入环丙醇(0.41g)和无水THF后，室温缓慢分批加入NaH(0.29g),搅拌5min后，分批加入粉末固体M10(4.00g)，搅拌反应10min；反应，滴入饱和NH4Cl100mL淬灭，加入200mL乙酸乙酯，萃取，水相用乙酸乙酯洗2遍，合并有机相减压浓缩得目标化合物9-1(0.82g)。ESI-MS m/z:301.7[M+H]+。After adding cyclopropanol (0.41g) and anhydrous THF respectively to the reaction bottle, NaH (0.29g) was slowly added in batches at room temperature. After stirring for 5 minutes, powdered solid M10 (4.00g) was added in batches and stirred for 10 minutes; the reaction was 100 mL of saturated NH 4 Cl was added dropwise to quench, and 200 mL of ethyl acetate was added for extraction. The aqueous phase was washed twice with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to obtain the target compound 9-1 (0.82g). ESI-MS m/z:301.7[M+H] + .
步骤2：化合物9-2的合成Step 2: Synthesis of compound 9-2
在室温下，向反应瓶中依次加入9-1(0.86g),(1R，5S)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.21g),DIPEA(0.99mL)和无水DMF(5.0mL)后，室温搅拌溶清，最后加入PyBOP(2.97g)，室温搅拌反应0.5h。向反应中加入50mL自来水，50mL EA洗两遍，萃取分液，有机相于减压蒸干，浓缩物经柱层析纯化(PE/EA＝3:1)得目标化合物9-2(0.97g)。ESI-MS m/z:496.0[M+H]+。 At room temperature, add 9-1 (0.86g), (1R, 5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.21g) into the reaction bottle. ), DIPEA (0.99mL) and anhydrous DMF (5.0mL), stir and dissolve at room temperature, finally add PyBOP (2.97g), stir and react at room temperature for 0.5h. Add 50mL tap water to the reaction, wash twice with 50mL EA, extract and separate the liquids, evaporate the organic phase to dryness under reduced pressure, and purify the concentrate by column chromatography (PE/EA=3:1) to obtain target compound 9-2 (0.97g ). ESI-MS m/z:496.0[M+H] + .
步骤3：化合物9-3的合成Step 3: Synthesis of compound 9-3
将化合物9-2(377mg)，中间体M8(200mg)，磷酸钾(172mg)，cataCXium A Pd G3(29.30mg)溶于1，4-二氧六环(5.00ml)和水(2.00ml)，在氮气保护的氛围下，70℃封管下反应过夜。待反应完全，用EA和水稀释反应液，再用EA萃取一遍，饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，浓缩物经柱层析进行纯化，得到9-3(300mg)。ESI-MS m/z:802.1[M+H]+。Compound 9-2 (377mg), intermediate M8 (200mg), potassium phosphate (172mg), cataCXium A Pd G3 (29.30mg) were dissolved in 1,4-dioxane (5.00ml) and water (2.00ml) , in a nitrogen-protected atmosphere, react overnight at 70°C with the tube sealed. When the reaction is complete, dilute the reaction solution with EA and water, extract once with EA, wash once with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The concentrate is purified by column chromatography to obtain 9-3 (300 mg). ESI-MS m/z:802.1[M+H] + .
步骤4：化合物9-4的合成Step 4: Synthesis of compound 9-4
将9-3(300mg)溶于二氯甲烷(5.00ml)加入叔丁基二甲基氯硅烷(281.85mg)和咪唑(127.31mg)中，在室温下反应0.5h。待反应完全，用DCM和水稀释反应液，再用DCM萃取一遍，饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，浓缩物经柱层析进行纯化得到9-4(1.0g)。ESI-MS m/z:916.3[M+H]+。Dissolve 9-3 (300 mg) in dichloromethane (5.00 ml), add tert-butyldimethylsilyl chloride (281.85 mg) and imidazole (127.31 mg), and react at room temperature for 0.5 h. When the reaction is complete, dilute the reaction solution with DCM and water, extract once with DCM, wash once with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The concentrate is purified by column chromatography to obtain 9-4 (1.0g). ESI-MS m/z:916.3[M+H] + .
步骤5：化合物9-5的合成Step 5: Synthesis of Compound 9-5
将9-4(1.0g)溶于DCM(5.00mL)，加入mCPBA(376.70mg)，在室温下反应0.5h。用DCM稀释反应液，加入饱和碳酸氢钠淬灭反应，再用DCM萃取一遍，饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，浓缩物经柱层析进行纯化，得到9-5(200mg)。ESI-MS m/z:948.3[M+H]+。Dissolve 9-4 (1.0g) in DCM (5.00mL), add mCPBA (376.70mg), and react at room temperature for 0.5h. The reaction solution was diluted with DCM, saturated sodium bicarbonate was added to quench the reaction, extracted once with DCM, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by column chromatography to obtain 9-5 (200 mg) . ESI-MS m/z:948.3[M+H] + .
步骤6：化合物9-6的合成Step 6: Synthesis of Compound 9-6
将M9溶于THF(3.00mL)，加入NaH(15.17mg)，再将9-5(200.00mg)加入其中，在室温下反应0.5h。用饱和氯化铵淬灭反应，用EA萃取两遍，饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC分离纯化得到9-6(200mg)。ESI-MS m/z:907.5[M+H]+。Dissolve M9 in THF (3.00 mL), add NaH (15.17 mg), and then add 9-5 (200.00 mg), and react at room temperature for 0.5 h. The reaction was quenched with saturated ammonium chloride, extracted twice with EA, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by Pre-TLC to obtain 9-6 (200 mg). ESI-MS m/z:907.5[M+H] + .
步骤7：化合物9-7的合成Step 7: Synthesis of Compound 9-7
将9-6(200.00mg)溶于DMF(3.00mL)，加入CsF(3000mg)，在室温下反应1h。用EA和水稀释反应液，用EA萃取一遍，饱和食盐水洗两遍，无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC分离纯化得到9-7(70mg)。ESI-MS m/z:751.1[M+H]+。Dissolve 9-6 (200.00 mg) in DMF (3.00 mL), add CsF (3000 mg), and react at room temperature for 1 h. The reaction solution was diluted with EA and water, extracted once with EA, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by Pre-TLC to obtain 9-7 (70 mg). ESI-MS m/z:751.1[M+H] + .
步骤8：化合物9的合成Step 8: Synthesis of Compound 9
将9-7(70.00mg)溶于DCM(2.00mL)，加入三氟化硼乙醚(27mg)，在室温下反应0.5h。将反应液加入到冷的饱和碳酸氢钠溶液中，使用DCM：MeOH＝10:1萃取两遍，饱和食盐水洗一遍，无水硫酸钠干燥，浓缩，浓缩物经制备液相进一步纯化得到目标化合物9(7.9mg)。ESI-MS m/z:651.3[M+H]+。1H NMR(500MHz,DMSO)δ10.15(s,1H),7.45 (dd,J＝9.1,5.7Hz,1H),7.38-7.36(m,1H),7.23-7.22(m,1H),4.90(s,5H),4.27-4.24(m,1H),4.04-4.90(m,5H),3.70(d,J＝14.2Hz,1H),3.55(s,3H),3.45(d,J＝13.0Hz,1H),3.12(dt,J＝10.6,5.5Hz,1H),2.79–2.64(m,2H),2.44(dd,J＝15.8,1.8Hz,1H),2.17–2.07(m,1H),2.01–1.85(m,2H),1.84–1.72(m,4H),1.65(s,1H).0.73–0.68(m,4H).Dissolve 9-7 (70.00 mg) in DCM (2.00 mL), add boron trifluoride ether (27 mg), and react at room temperature for 0.5 h. The reaction solution was added to cold saturated sodium bicarbonate solution, extracted twice with DCM: MeOH = 10:1, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the concentrate was further purified through the preparative liquid phase to obtain the target compound. 9(7.9mg). ESI-MS m/z:651.3[M+H] + . 1H NMR(500MHz,DMSO)δ10.15(s,1H),7.45 (dd,J＝9.1,5.7Hz,1H),7.38-7.36(m,1H),7.23-7.22(m,1H),4.90(s,5H),4.27-4.24(m,1H),4.04-4.90 (m,5H),3.70(d,J＝14.2Hz,1H),3.55(s,3H),3.45(d,J＝13.0Hz,1H),3.12(dt,J＝10.6,5.5Hz,1H) ,2.79–2.64(m,2H),2.44(dd,J＝15.8,1.8Hz,1H),2.17–2.07(m,1H),2.01–1.85(m,2H),1.84–1.72(m,4H) ,1.65(s,1H).0.73–0.68(m,4H).
实施例39：化合物4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-5-甲氧基-2-((2-甲基四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟萘-2-醇的合成
Example 39: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-methoxy-2-( (2-Methyltetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene- Synthesis of 2-alcohols
步骤1：化合物39-1的合成：Step 1: Synthesis of compound 39-1:
将中间体M8(500mg)溶于3mL的DMF中，然后将CsF(1.94g)加入，室温反应1.5h，EA和水萃取反应液，保留有机相，无水硫酸钠干燥，过滤，减压浓缩，得粗产物39-1(550mg)，直接用于下一步反应。Dissolve intermediate M8 (500mg) in 3mL of DMF, then add CsF (1.94g), react at room temperature for 1.5h, extract the reaction solution with EA and water, retain the organic phase, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure , to obtain crude product 39-1 (550 mg), which was directly used in the next reaction.
步骤2：化合物39-2的合成：Step 2: Synthesis of compound 39-2:
将上一步化合物39-1(300mg)溶于5mL的甲醇中，然后将Pd/C(50mg)加入，氢气置换5次，室温反应20min，硅藻土过滤，滤液减压浓缩，浓缩物经柱色谱纯化得目标化合物39-2(208mg)。Dissolve compound 39-1 (300 mg) in the previous step in 5 mL of methanol, then add Pd/C (50 mg), replace with hydrogen 5 times, react at room temperature for 20 min, filter through diatomaceous earth, and concentrate the filtrate under reduced pressure. The concentrate is passed through a column Purification by chromatography gave the target compound 39-2 (208 mg).
步骤3：化合物39-3的合成：Step 3: Synthesis of compound 39-3:
将化合物39-2(403mg)、中间体7-2(300mg)、CataCXium A Pd G3(93mg)和K3PO4(300mg)溶于THF(4mL)和H2O(1mL)中，氮气保护下，80℃反应3h，降温至室温，用EA和水萃取反应液，保留有机相，无水硫酸钠干燥，过滤，减压浓缩，浓缩物经柱色谱纯化得目标化合物39-3(330mg)。Compound 39-2 (403 mg), intermediate 7-2 (300 mg), CataCXium A Pd G3 (93 mg) and K 3 PO 4 (300 mg) were dissolved in THF (4 mL) and H 2 O (1 mL) under nitrogen protection. , react at 80°C for 3 hours, cool to room temperature, extract the reaction solution with EA and water, retain the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The concentrate is purified by column chromatography to obtain target compound 39-3 (330 mg) .
步骤4：化合物39-4的合成： Step 4: Synthesis of compound 39-4:
将化合物39-3(330mg)溶于DCM(5mL)中，然后将TBSCl(800mg)和咪唑(550mg)依次加入，室温反应0.5h，DCM和水萃取反应液，保留有机相，无水硫酸钠干燥，过滤，减压浓缩，浓缩物经柱色谱纯化得目标化合物39-4(270mg)。Dissolve compound 39-3 (330mg) in DCM (5mL), then add TBSCl (800mg) and imidazole (550mg) in sequence, react at room temperature for 0.5h, extract the reaction solution with DCM and water, retain the organic phase, and add anhydrous sodium sulfate Dry, filter, and concentrate under reduced pressure. The concentrate is purified by column chromatography to obtain target compound 39-4 (270 mg).
步骤5：化合物39-5的合成：Step 5: Synthesis of compound 39-5:
将化合物39-4(270mg)溶于DCM(5mL)中，然后将m-CPBA(270mg)加入，室温反应0.5h，加适量饱和亚硫酸钠溶液搅拌20min淬灭，用DCM和水萃取反应液，保留有机相，无水硫酸钠干燥，过滤，减压浓缩，浓缩物经柱色谱纯化得目标化合物39-5(150mg)。Dissolve compound 39-4 (270mg) in DCM (5mL), then add m-CPBA (270mg), react at room temperature for 0.5h, add an appropriate amount of saturated sodium sulfite solution and stir for 20min to quench, extract the reaction solution with DCM and water, and retain The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain target compound 39-5 (150 mg).
步骤6：化合物39-6的合成：Step 6: Synthesis of compound 39-6:
将中间体M9(90mg)溶于无水THF(2mL)中，然后将NaH(30mg)加入，室温反应20min,然后将化合物39-5(150mg)加入，室温反应30min。加适量饱和氯化铵溶液淬灭，用EA和水萃取反应液，保留有机相，无水硫酸钠干燥，过滤，减压浓缩，浓缩物经柱色谱纯化得目标化合物39-6(59mg)。Intermediate M9 (90 mg) was dissolved in anhydrous THF (2 mL), then NaH (30 mg) was added, and the reaction was carried out at room temperature for 20 min. Then compound 39-5 (150 mg) was added and the reaction was carried out at room temperature for 30 min. Add an appropriate amount of saturated ammonium chloride solution to quench, extract the reaction solution with EA and water, retain the organic phase, dry it over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The concentrate is purified by column chromatography to obtain target compound 39-6 (59 mg).
步骤7：化合物39的合成：Step 7: Synthesis of compound 39:
将化合物39-6(59mg)溶于2mL的DCM中，然后将TFA(1mL)加入，室温反应20min。减压浓缩，浓缩物经柱色谱纯化得目标化合物39(23mg)。Compound 39-6 (59 mg) was dissolved in 2 mL of DCM, then TFA (1 mL) was added, and the reaction was carried out at room temperature for 20 min. The mixture was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain target compound 39 (23 mg).
实施例55：化合物4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-5-甲氧基-2-((2-甲基四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5,6-二氟萘-2-醇的合成
Example 55: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-methoxy-2-( (2-Methyltetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5,6-difluoronaphthalene-2- Synthesis of alcohol
步骤1：化合物55-1的合成 Step 1: Synthesis of Compound 55-1
微波管中分别加入化合物7-2(0.29g)，5,6-二氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)萘-2-醇(0.31g)，K2CO3(0.18g)，Pd(dppf)Cl2(0.05g)和7mL Dioxane/1mL H2O后，N2置换2min后，微波140℃反应0.5h。向反应液中加入DCM和H2O各20mL，萃取，水相用DCM洗两遍，有机相减压浓缩，浓缩物经柱层析纯化(PE/EA＝4:1)得目标化合物55-1(0.31g)。ESI-MS m/z:614.2[M+H]+。Add compound 7-2 (0.29g) and 5,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-) into the microwave tube respectively. After adding base) naphthalene-2-ol (0.31g), K 2 CO 3 (0.18g), Pd(dppf)Cl 2 (0.05g) and 7mL Dioxane/1mL H 2 O, replace with N 2 for 2 min, microwave at 140°C Reaction 0.5h. Add 20 mL each of DCM and H 2 O to the reaction solution, extract, wash the aqueous phase twice with DCM, concentrate the organic phase under reduced pressure, and purify the concentrate by column chromatography (PE/EA=4:1) to obtain the target compound 55- 1(0.31g). ESI-MS m/z:614.2[M+H] + .
步骤2：化合物55-2的合成Step 2: Synthesis of Compound 55-2
向反应瓶中分别加入55-1(0.22g),TBSCl(0.11g),咪唑(0.05g)和无水DCM(5mL)后，室温搅拌反应20min。向反应中加入15mL饱和NaCl自来水，萃取分液，水相用10mL DCM洗两遍，有机相减压蒸干，浓缩物经柱层析纯化(PE/EA＝10:1)得目标化合物55-2(0.21g)。ESI-MS m/z:728.3[M+H]+。55-1 (0.22g), TBSCl (0.11g), imidazole (0.05g) and anhydrous DCM (5mL) were added to the reaction flask respectively, and the reaction was stirred at room temperature for 20 minutes. Add 15 mL saturated NaCl tap water to the reaction, extract and separate the liquids, wash the aqueous phase twice with 10 mL DCM, evaporate the organic phase to dryness under reduced pressure, and purify the concentrate by column chromatography (PE/EA=10:1) to obtain the target compound 55- 2(0.21g). ESI-MS m/z:728.3[M+H] + .
步骤3：化合物55-3的合成Step 3: Synthesis of Compound 55-3
向反应瓶中分别加入55-2(0.2g)，mCPBA(0.17g)和无水DCM(5mL)后，室温搅拌反应15min。向反应中加入10mL饱和NaHCO3，萃取分液，水相用5mL DCM洗两遍，有机相减压蒸干，浓缩物经柱层析纯化(PE/EA＝3:1)得目标化合物55-3(0.13g)。ESI-MS m/z:760.1[M+H]+。After adding 55-2 (0.2g), mCPBA (0.17g) and anhydrous DCM (5mL) respectively to the reaction bottle, the reaction was stirred at room temperature for 15 minutes. Add 10 mL saturated NaHCO 3 to the reaction, extract and separate the liquids, wash the aqueous phase twice with 5 mL DCM, evaporate the organic phase to dryness under reduced pressure, and purify the concentrate by column chromatography (PE/EA=3:1) to obtain the target compound 55- 3(0.13g). ESI-MS m/z:760.1[M+H] + .
步骤4：化合物55-4的合成Step 4: Synthesis of Compound 55-4
向反应瓶中分别加入中间体M9(0.04g)和无水THF(1mL)，分批缓慢加入NaH(0.02g)，搅拌10min后，再加入55-3(0.11g)，室温搅拌反应15min。反应液用冰水浴降温5min，滴入饱和NH4Cl 2mL淬灭，加入5mL乙酸乙酯，萃取，水相用乙酸乙酯洗2遍，合并有机相，减压蒸干，浓缩物经柱层析纯化(DCM/NH3：MeOH＝20:1)得目标化合物55-4(0.08g)。ESI-MS m/z:719.3[M+H]+。Add intermediate M9 (0.04g) and anhydrous THF (1mL) to the reaction flask respectively, add NaH (0.02g) slowly in batches, stir for 10 minutes, then add 55-3 (0.11g), and stir at room temperature for 15 minutes. The reaction solution was cooled down in an ice-water bath for 5 minutes, 2 mL of saturated NH 4 Cl was added dropwise to quench, and 5 mL of ethyl acetate was added to extract. The aqueous phase was washed twice with ethyl acetate, the organic phases were combined, and evaporated to dryness under reduced pressure. The concentrate was passed through column layer. Analytical purification (DCM/NH 3 :MeOH=20:1) gave the target compound 55-4 (0.08g). ESI-MS m/z:719.3[M+H] + .
步骤5：化合物55的合成Step 5: Synthesis of Compound 55
向反应瓶中分别加入55-4(0.08g)，三氟乙酸(0.1mL)和无水DCM(2mL)后，室温搅拌反应0.5h。反应液体减压蒸干，浓缩物经柱层析纯化(DCM/NH3：MeOH＝8:1)得到目标化合物55(20mg，41.0％产率)。1H NMR(500MHz,DMSO)δ10.25(s,1H),7.75–7.72(m,1H),7.60–7.54(m,1H),7.38–7.29(m,2H),4.89(d,J＝1.5Hz,2H),4.42(s,1H),4.00–3.97(m,2H),3.94(s,3H),3.56–3.37(m,4H),3.20–3.17(m,2H),3.01–2.97(m,1H),2.59–2.51(m,4H),2.36–2.33(m,1H),1.97–1.64(m,4H),1.70–1.48(m,4H).ESI-MS m/z:619.2[M+H]+。After adding 55-4 (0.08g), trifluoroacetic acid (0.1mL) and anhydrous DCM (2mL) to the reaction flask, the reaction was stirred at room temperature for 0.5h. The reaction liquid was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM/NH 3 :MeOH=8:1) to obtain target compound 55 (20 mg, 41.0% yield). 1 H NMR (500MHz, DMSO) δ10.25(s,1H),7.75–7.72(m,1H),7.60–7.54(m,1H),7.38–7.29(m,2H),4.89(d,J＝ 1.5Hz,2H),4.42(s,1H),4.00–3.97(m,2H),3.94(s,3H),3.56–3.37(m,4H),3.20–3.17(m,2H),3.01–2.97 (m,1H),2.59–2.51(m,4H),2.36–2.33(m,1H),1.97–1.64(m,4H),1.70–1.48(m,4H).ESI-MS m/z:619.2 [M+H] + .
实施例109：化合物4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-((2-(二氟 亚甲基)四氢-1H-吡咯烷-7a(5H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-胺的合成
Example 109: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((2-(difluoro methylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6- Synthesis of fluoronaphthyl-2-amine
步骤1：化合物109-1的合成Step 1: Synthesis of Compound 109-1
将中间体化合物1-1(500mg)和6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧苯并呋喃-2-基)-5-((三异丙基甲硅烷基)乙炔基)萘-2-醇(882mg)溶于1，4-二氧六环(10mL)和水(2mL)的混合溶剂中，加入磷酸钾(548mg)，氮气保护下加入cataCXium A Pd G3(63mg)，升温至70℃反应3h。停止加热，冷却至室温，加水稀释(20mL)，二氯甲烷萃取两遍，每次20ml，合并有机相，有机相水洗两遍后无水硫酸钠干燥，拌样，柱层析分离产物(DCM:MeOH＝20:1)分离得到770mg目标化合物109-1。Intermediate compound 1-1 (500 mg) and 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxobenzofuran-2-yl)-5-( (Triisopropylsilyl)ethynyl)naphthalene-2-ol (882mg) was dissolved in a mixed solvent of 1,4-dioxane (10mL) and water (2mL), and potassium phosphate (548mg) was added. Add cataCXium A Pd G3 (63 mg) under nitrogen protection, raise the temperature to 70°C and react for 3 hours. Stop heating, cool to room temperature, add water to dilute (20 mL), extract with dichloromethane twice, 20 ml each time, combine the organic phases, wash the organic phases twice with water and dry over anhydrous sodium sulfate, mix the sample, and separate the product by column chromatography (DCM :MeOH=20:1), 770 mg of target compound 109-1 was isolated.
步骤2：化合物109-2的合成Step 2: Synthesis of Compound 109-2
将109-1(720mg)溶于THF(20mL),加入三乙胺(0.34mL)和DMAP(10mg)，氮气保护下，降温至0℃，将N-苯基双(三氟甲烷磺酰)亚胺(580mg)溶于THF(4mL)，滴入上述反应液中，滴毕后保温反应10min，后升至室温搅拌2h。LCMS监测原料转化完全后，将反应液淬灭于饱和碳酸氢钠溶液中(50mL)，DCM萃取两遍，每次50ml，合并有机相，水洗两遍，有机相无水硫酸钠干燥，柱层析分离产物(DCM:MeOH)＝25:1，分离得到686mg目标化合物109-2。Dissolve 109-1 (720mg) in THF (20mL), add triethylamine (0.34mL) and DMAP (10mg), cool to 0°C under nitrogen protection, and add N-phenylbis(trifluoromethanesulfonyl) Imine (580 mg) was dissolved in THF (4 mL) and dropped into the above reaction solution. After the drop was completed, the reaction was maintained at room temperature for 10 min, then raised to room temperature and stirred for 2 h. After LCMS monitors the complete conversion of the raw materials, the reaction solution is quenched in saturated sodium bicarbonate solution (50 mL), extracted with DCM twice, 50 ml each time, the organic phases are combined, washed twice with water, the organic phase is dried over anhydrous sodium sulfate, and column layered The product was analyzed and separated (DCM:MeOH) = 25:1, and 686 mg of the target compound 109-2 was isolated.
步骤3：化合物109-3的合成Step 3: Synthesis of Compound 109-3
将化合物109-2(200mg)、二苯甲酮亚胺(71mg)以及碳酸铯(192mg)溶于1，4-二氧六环(3mL)，氮气保护下加入BINAP(12mg)和醋酸钯(4.4mg)，升至100℃反应2h。反应完成后，加入水(10mL)稀释,DCM萃取两遍，每次15ml，合并有机相，水洗两遍，有机相无水硫酸钠干燥，柱层析分离产物(DCM:MeOH)＝50:1,分离得到230mg目标化合物109-3。 Compound 109-2 (200 mg), benzophenone imine (71 mg) and cesium carbonate (192 mg) were dissolved in 1,4-dioxane (3 mL), and BINAP (12 mg) and palladium acetate ( 4.4 mg), raised to 100°C and reacted for 2 hours. After the reaction is completed, add water (10 mL) to dilute, extract with DCM twice, 15 ml each time, combine the organic phases, wash with water twice, dry the organic phase over anhydrous sodium sulfate, and separate the product by column chromatography (DCM:MeOH) = 50:1 , 230 mg of target compound 109-3 was isolated.
步骤4：化合物109-4的合成Step 4: Synthesis of Compound 109-4
将109-3(200mg)溶于盐酸溶液(5ml,2mol/L)和THF(10mL)的混合溶液中，室温搅拌15min。将反应液淬灭于饱和碳酸溶液中，DCM萃取两遍，每次15ml，合并有机相，水洗两遍，有机相无水硫酸钠干燥，旋干所得粗品不经纯化直接投下一步反应。Dissolve 109-3 (200 mg) in a mixed solution of hydrochloric acid solution (5 ml, 2 mol/L) and THF (10 mL), and stir at room temperature for 15 min. The reaction solution was quenched in saturated carbonic acid solution, extracted with DCM twice, 15 ml each time, the organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product that was directly used in the next reaction without purification.
步骤5：化合物109-5的合成Step 5: Synthesis of Compound 109-5
将上述粗品溶于DMF(3mL)中，加入氟化铯(48mg)，室温搅拌15min。加水(10mL)，DCM萃取两遍，每次15ml，合并有机相，水洗两遍，有机相无水硫酸钠干燥，旋干所得粗品不经纯化直接投下一步反应。Dissolve the above crude product in DMF (3 mL), add cesium fluoride (48 mg), and stir at room temperature for 15 min. Add water (10 mL), extract with DCM twice, 15 ml each time, combine the organic phases, wash with water twice, dry the organic phase over anhydrous sodium sulfate, spin dry, and the crude product obtained is directly used in the next reaction without purification.
步骤6：化合物109的合成Step 6: Synthesis of Compound 109
将上述粗品溶于DCM(3mL),氮气保护，室温下滴加三氟化硼乙醚(0.12ml)，加毕，室温搅拌30min。将反应液淬灭于饱和碳酸溶液中，DCM萃取两遍，每次15ml，合并有机相，水洗两遍，有机相无水硫酸钠干燥，浓缩。浓缩物经Pre-TLC(DCM:MeOH＝100:12)分离得到化合物109(22.3mg，纯度为99.09％)。ESI-MS m/z:630.5[M+H]+。1H NMR(500MHz,DMSO)δ9.06(s,1H),7.77(dd,J＝9.2,5.9Hz,1H),7.33(t,J＝9.0Hz,1H),7.07-7.01(m,2H),5.65(s,2H),4.58(d,J＝13.3Hz,1H),4.40(d,J＝12.9Hz,1H),4.20-4.06(m,2H),3.86-3.84(m,1H),3.82-3.62(m,3H),3.04-2.96(m,1H),2.70-2.54(m,2H),2.46-2.32(m,2H),2.04-1.94(m,2H),1.91-1.70(m,4H),1.49-1.18(m,4H)。Dissolve the above crude product in DCM (3 mL), under nitrogen protection, add boron trifluoride ether (0.12 ml) dropwise at room temperature, complete the addition, and stir at room temperature for 30 min. The reaction solution was quenched in saturated carbonic acid solution, extracted with DCM twice, 15 ml each time, the organic phases were combined, washed twice with water, the organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrate was separated by Pre-TLC (DCM:MeOH=100:12) to obtain compound 109 (22.3 mg, purity: 99.09%). ESI-MS m/z:630.5[M+H] + . 1 H NMR (500MHz, DMSO) δ9.06 (s, 1H), 7.77 (dd, J = 9.2, 5.9Hz, 1H), 7.33 (t, J = 9.0Hz, 1H), 7.07-7.01 (m, 2H ),5.65(s,2H),4.58(d,J＝13.3Hz,1H),4.40(d,J＝12.9Hz,1H),4.20-4.06(m,2H),3.86-3.84(m,1H) ,3.82-3.62(m,3H),3.04-2.96(m,1H),2.70-2.54(m,2H),2.46-2.32(m,2H),2.04-1.94(m,2H),1.91-1.70( m,4H),1.49-1.18(m,4H).
实施例110：化合物4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((2-甲基四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-胺的合成
Example 110: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((2-methyltetrakis) Synthesis of hydrogen-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine
步骤1：化合物110-1的合成Step 1: Synthesis of Compound 110-1
将中间体M9(430mg)溶于无水THF(20mL)，氮气保护，加入氢化钠(220mg)，后加入中间体M2(1g，2.33mmol)，室温搅拌4h。将反应液淬灭于无水氯化铵(40mL)中,乙酸乙酯萃取两遍，每次40ml，合并有机相，有机相水洗两遍后无水硫酸钠干燥，浓缩。浓缩物经柱层析分离纯化(DCM:MeOH＝40:1)得到760mg化合物110-1。Intermediate M9 (430 mg) was dissolved in anhydrous THF (20 mL), protected by nitrogen, sodium hydride (220 mg) was added, and then intermediate M2 (1 g, 2.33 mmol) was added, and the mixture was stirred at room temperature for 4 h. The reaction solution was quenched in anhydrous ammonium chloride (40 mL), extracted twice with ethyl acetate, 40 ml each time, and the organic phases were combined. The organic phases were washed twice with water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by column chromatography (DCM:MeOH=40:1) to obtain 760 mg of compound 110-1.
步骤2：化合物110-2的合成Step 2: Synthesis of Compound 110-2
将110-1(760mg)和中间体M8(980mg)溶于1，4-二氧六环(15mL)和水(3mL)的混合溶剂中，加入磷酸钾(888mg)，氮气保护下加入cataCXium A Pd G3(101mg)，升温至100℃反应3h。停止加热，冷却至室温，加水稀释(40mL)，二氯甲烷萃取两遍，每次40ml，合并有机相，有机相水洗两遍后无水硫酸钠干燥，浓缩。浓缩物经柱层析分离纯化(DCM:MeOH＝20:1)得到760mg化合物110-2。Dissolve 110-1 (760mg) and intermediate M8 (980mg) in a mixed solvent of 1,4-dioxane (15mL) and water (3mL), add potassium phosphate (888mg), and add cataCXium A under nitrogen protection Pd G3 (101 mg), heat to 100°C and react for 3 hours. Stop heating, cool to room temperature, add water to dilute (40 mL), extract twice with dichloromethane, 40 ml each time, combine the organic phases, wash the organic phases twice with water, dry over anhydrous sodium sulfate, and concentrate. The concentrate was separated and purified by column chromatography (DCM:MeOH=20:1) to obtain 760 mg of compound 110-2.
步骤3：化合物110-3的合成Step 3: Synthesis of Compound 110-3
将化合物110-2(760mg)溶于THF(20mL)，加入三乙胺(0.37mL)和DMAP(11mg)，氮气保护，降温至0℃，将N-苯基双(三氟甲烷磺酰)亚胺(638mg)溶于THF(4mL)，滴入上述反应液中，滴毕后保温反应10min，后升至室温搅拌1h。将反应液淬灭于饱和碳酸氢钠溶液中(50mL)，DCM萃取两遍，每次50ml，合并有机相，水洗两遍，有机相无水硫酸钠干燥，浓缩。浓缩物经柱层析分离纯化(DCM:MeOH＝25:1)得到635mg化合物110-3。 Dissolve compound 110-2 (760 mg) in THF (20 mL), add triethylamine (0.37 mL) and DMAP (11 mg), protect with nitrogen, cool to 0°C, and add N-phenylbis(trifluoromethanesulfonyl) Imine (638 mg) was dissolved in THF (4 mL) and dropped into the above reaction solution. After the drop was completed, the reaction was maintained at room temperature for 10 min, then raised to room temperature and stirred for 1 h. The reaction solution was quenched in saturated sodium bicarbonate solution (50 mL), extracted with DCM twice, 50 ml each time, the organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by column chromatography (DCM:MeOH=25:1) to obtain 635 mg of compound 110-3.
步骤4：化合物110-4的合成Step 4: Synthesis of Compound 110-4
将110-3(635mg)、二苯甲酮亚胺(234mg)以及碳酸铯(631mg)溶于1，4-二氧六环(15mL)，氮气保护下加入BINAP(40mg)和醋酸钯(15mg)，升至100℃反应1h。用水(40mL)稀释，DCM萃取两遍，每次50ml，合并有机相，水洗两遍，有机相无水硫酸钠干燥，浓缩。浓缩物经柱层析分离(DCM:MeOH＝50:1)纯化得到560mg黄色油状物110-4。Dissolve 110-3 (635mg), benzophenone imine (234mg) and cesium carbonate (631mg) in 1,4-dioxane (15mL), add BINAP (40mg) and palladium acetate (15mg) under nitrogen protection ), rise to 100°C and react for 1 hour. Dilute with water (40 mL), extract with DCM twice, 50 ml each time, combine the organic phases, wash with water twice, dry the organic phase over anhydrous sodium sulfate, and concentrate. The concentrate was separated and purified by column chromatography (DCM:MeOH=50:1) to obtain 560 mg of yellow oil 110-4.
步骤5：化合物110-5的合成Step 5: Synthesis of Compound 110-5
将110-4(450mg)溶于盐酸溶液(5mL，2mol/L)和THF(10mL)的混合溶液中，室温搅拌15min。将反应液淬灭于饱和碳酸钠溶液中，DCM萃取两遍，每次30ml，合并有机相，水洗两遍，有机相无水硫酸钠干燥，浓缩即可得到粗品110-5，不经纯化直接投下一步反应。Dissolve 110-4 (450 mg) in a mixed solution of hydrochloric acid solution (5 mL, 2 mol/L) and THF (10 mL), and stir at room temperature for 15 min. Quench the reaction solution in saturated sodium carbonate solution, extract with DCM twice, 30 ml each time, combine the organic phases, wash with water twice, dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain crude product 110-5, which can be directly used without purification. Cast the next reaction.
步骤6：化合物110-6的合成Step 6: Synthesis of Compound 110-6
将上述粗品溶于DMF(7mL)中，加入氟化铯(1.3g)，35℃搅拌30min。加水稀释(30mL),DCM萃取两遍，每次3ml，合并有机相，水洗两遍，有机相无水硫酸钠干燥，浓缩。浓缩即可得到粗品，不经纯化直接投下一步反应。Dissolve the above crude product in DMF (7 mL), add cesium fluoride (1.3 g), and stir at 35°C for 30 min. Add water to dilute (30 mL), extract with DCM twice, 3 ml each time, combine the organic phases, wash twice with water, dry the organic phase over anhydrous sodium sulfate, and concentrate. The crude product can be obtained by concentration, which can be directly put into the next reaction without purification.
步骤7：化合物110的合成Step 7: Synthesis of Compound 110
将上述粗品溶于DCM(6mL),氮气保护，室温下滴加三氟化硼乙醚(0.34mL)，加毕，室温搅拌10min，将反应液淬灭于饱和碳酸溶液中，DCM萃取两遍，每次30ml，合并有机相，水洗两遍，有机相无水硫酸钠干燥，浓缩。浓缩物经Pre-TLC(DCM:MeOH＝100:12)分离纯化得到110(23.0mg，纯度为98.24％)。[M+H]+＝594.45。1H NMR(500MHz,CDCl3)δ8.96(s,1H),7.66(dd,J＝9.1,5.7Hz,1H),7.20(t,J＝8.9Hz,1H),7.09(dd,J＝15.6,2.4Hz,2H),4.93(s,2H),4.72–4.60(m,1H),4.55–4.43(m,1H),4.24–4.12(m,2H),3.92(s,2H),3.76–3.64(m,4H),3.58(dd,J＝12.3,4.8Hz,1H),3.28(d,J＝14.1Hz,1H),3.22–3.15(m,1H),2.86–2.75(m,2H),2.71–2.61(m,1H),2.40(d,J＝14.4Hz,1H),2.19(ddd,J＝17.4,11.9,7.2Hz,1H),1.97–1.87(m,2H),1.85-1.75(m,2H),1.72-1.54(m,4H)。Dissolve the above crude product in DCM (6mL), under nitrogen protection, add boron trifluoride ether (0.34mL) dropwise at room temperature, complete the addition, stir at room temperature for 10 minutes, quench the reaction solution in saturated carbonic acid solution, and extract twice with DCM. 30ml each time, combine the organic phases, wash twice with water, dry the organic phase over anhydrous sodium sulfate, and concentrate. The concentrate was separated and purified by Pre-TLC (DCM:MeOH=100:12) to obtain 110 (23.0 mg, purity: 98.24%). [M+H] + =594.45. 1 H NMR (500MHz, CDCl 3 ) δ8.96 (s, 1H), 7.66 (dd, J＝9.1, 5.7Hz, 1H), 7.20 (t, J＝8.9Hz, 1H), 7.09 (dd, J＝ 15.6,2.4Hz,2H),4.93(s,2H),4.72–4.60(m,1H),4.55–4.43(m,1H),4.24–4.12(m,2H),3.92(s,2H),3.76 –3.64(m,4H),3.58(dd,J＝12.3,4.8Hz,1H),3.28(d,J＝14.1Hz,1H),3.22–3.15(m,1H),2.86–2.75(m,2H ),2.71–2.61(m,1H),2.40(d,J＝14.4Hz,1H),2.19(ddd,J＝17.4,11.9,7.2Hz,1H),1.97–1.87(m,2H),1.85- 1.75(m,2H),1.72-1.54(m,4H).
实施例112：化合物4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((2-甲基四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3d]嘧啶-7-基)-5-乙炔基-1,6-二氟萘-2-胺的合成
Example 112: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((2-methyltetrakis) Synthesis of Hydrogen-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-1,6-difluoronaphthalene-2-amine
步骤1：化合物112-1的合成Step 1: Synthesis of Compound 112-1
将110-5(50mg)溶于乙腈(2mL)，加入氟试剂(8mg)，室温搅拌30min。将反应液淬灭于饱和亚硫酸钠溶液中(10mL)，DCM(10mL)萃取两遍，每次10ml，合并有机相，水洗两遍，有机相无水硫酸钠干燥，浓缩后得到粗品112-1，直接投下一步反应。Dissolve 110-5 (50 mg) in acetonitrile (2 mL), add fluorine reagent (8 mg), and stir at room temperature for 30 min. The reaction solution was quenched in saturated sodium sulfite solution (10 mL), extracted twice with DCM (10 mL), 10 ml each time, the organic phases were combined, washed twice with water, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain crude product 112-1. Directly vote for the next reaction.
步骤2：化合物112-2的合成Step 2: Synthesis of Compound 112-2
将上一步112-1粗品溶于DMF(4mL)，加入氟化铯(357mg)室温反应1h。用水(20mL)稀释，DCM萃取两遍，每次20ml，水洗两遍，饱和盐水洗，有机相无水硫酸钠干燥，浓缩后得到粗品112-2，直接投下一步反应。Dissolve the crude product 112-1 in the previous step in DMF (4 mL), add cesium fluoride (357 mg) and react at room temperature for 1 hour. Dilute with water (20 mL), extract twice with DCM, 20 ml each time, wash twice with water and saturated brine, dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain crude product 112-2, which is directly used in the next step of the reaction.
步骤3：化合物112的合成Step 3: Synthesis of Compound 112
将上一步112-2粗品溶于DCM(5mL),氮气保护，室温下滴加三氟化硼乙醚(0.09mL),加毕，室温搅拌1h，将反应液淬灭于饱和碳酸溶液中，DCM萃取两遍，每次20ml，合并有机相，水洗两遍，有机相无水硫酸钠干燥，有机相浓缩，浓缩物经Pre-TLC分离纯化(DCM:MeOH＝100:12)得到目标化合物112(9.2mg，纯度为98.29％)。ESI-MS m/z:612.5[M+H]+。1H NMR(500MHz,DMSO)δ10.86(s,1H),9.63(d,J＝8.8Hz,1H),9.38(s,1H),9.15(s,1H),8.00(dd,J＝9.0,5.8Hz,1H),7.51(t,J＝9.1Hz,1H),7.24(d,J＝8.6Hz,1H),5.22(d,J＝11.9Hz,2H),4.63(ddd,J＝37.1,25.8,13.7Hz,1H),4.30-4.10(m,4H),4.03-3.80(m,4H),3.70-3.55(m,1H),3.25-3.10(m,1H),2.99–2.87(m,1H),2.77(d,J＝15.9Hz,1H),2.30-2.21(m,1H),2.19-2.11(s,1H)，2.09-1.87(m,8H).Dissolve the crude product 112-2 in the previous step in DCM (5mL), under nitrogen protection, add boron trifluoride ether (0.09mL) dropwise at room temperature, complete the addition, stir at room temperature for 1 hour, quench the reaction solution in saturated carbonic acid solution, DCM Extract twice, 20 ml each time, combine the organic phases, wash with water twice, dry the organic phase over anhydrous sodium sulfate, concentrate the organic phase, and the concentrate is separated and purified by Pre-TLC (DCM:MeOH=100:12) to obtain the target compound 112 ( 9.2 mg, purity 98.29%). ESI-MS m/z:612.5[M+H] + . 1 H NMR (500MHz, DMSO) δ10.86 (s, 1H), 9.63 (d, J = 8.8Hz, 1H), 9.38 (s, 1H), 9.15 (s, 1H), 8.00 (dd, J = 9.0 ,5.8Hz,1H),7.51(t,J＝9.1Hz,1H),7.24(d,J＝8.6Hz,1H),5.22(d,J＝11.9Hz,2H),4.63(ddd,J＝37.1 ,25.8,13.7Hz,1H),4.30-4.10(m,4H),4.03-3.80(m,4H),3.70-3.55(m,1H),3.25-3.10(m,1H),2.99–2.87(m ,1H),2.77(d,J＝15.9Hz,1H),2.30-2.21(m,1H),2.19-2.11(s,1H),2.09-1.87(m,8H).
实施例120：化合物4-(4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-5-氯-2-((2-(二氟亚甲基)四氢-1H-吡咯烷-7a(5H)-基)甲氧基)-8-氟吡啶[4,3-d]嘧啶-7-基)-5-乙炔基6-氟萘-2-醇的合成
Example 120: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-chloro-2-((2-(di Fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-8-fluoropyridine[4,3-d]pyrimidin-7-yl)-5-ethynyl6-fluoro Synthesis of naphthalene-2-ol
步骤1：化合物120-1的合成Step 1: Synthesis of Compound 120-1
室温下，反应瓶中分别称入化合物M10(0.7g)，DIEA(1.65mL)，POCl3(0.7mL)和无水ACN(20mL),在80℃反应0.5小时，取样监测反应完。将反应液降至0℃，向反应液中加入DIEA(1.24mL)和(1R，5S)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(1.59g)，升至室温反应0.5小时；反应结束，向反应液中加入饱和氯化钠水溶液，加入EA分液得到有机层，无水硫酸钠干燥，浓缩。浓缩物经柱色谱纯化(PE:EA＝0-25％)得到产物120-1(0.73g，56％产率)。ESI-MS m/z＝474.3[M+H]+。At room temperature, compound M10 (0.7g), DIEA (1.65mL), POCl 3 (0.7mL) and anhydrous ACN (20mL) were respectively weighed into the reaction bottle, and the reaction was carried out at 80°C for 0.5 hours. Samples were taken to monitor the completion of the reaction. The reaction solution was lowered to 0°C, and DIEA (1.24 mL) and (1R, 5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.59 g), rise to room temperature and react for 0.5 hours; when the reaction is completed, add saturated sodium chloride aqueous solution to the reaction solution, add EA to separate the layers to obtain an organic layer, dry over anhydrous sodium sulfate, and concentrate. The concentrate was purified by column chromatography (PE:EA=0-25%) to give product 120-1 (0.73 g, 56% yield). ESI-MS m/z=474.3[M+H] + .
步骤2：化合物120-2的合成Step 2: Synthesis of Compound 120-2
室温下，在氮气保护下，将化合物120-1(0.25g)，Pd(PPh3)4(140mg)，M8(0.49g)和碳酸钠(0.23g)溶解在1,4-dioxane(3mL)和水(0.3mL)中,于105℃微波反应2小时，反应结束后，加入EA分液得到有机层，饱和食盐水洗一遍，无水硫酸钠干燥，浓缩。浓缩物经柱色谱纯化(PE:EA＝0-20％)得到产物120-2(0.22g，50％产率)。ESI-MS m/z＝780.4[M+H]+。At room temperature, under nitrogen protection, compound 120-1 (0.25g), Pd(PPh 3 ) 4 (140mg), M8 (0.49g) and sodium carbonate (0.23g) were dissolved in 1,4-dioxane (3mL) and water (0.3 mL), react in microwave at 105°C for 2 hours. After the reaction is completed, add EA to separate the layers to obtain an organic layer, wash it once with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The concentrate was purified by column chromatography (PE:EA=0-20%) to obtain product 120-2 (0.22 g, 50% yield). ESI-MS m/z=780.4[M+H] + .
步骤3：化合物120-3的合成Step 3: Synthesis of Compound 120-3
室温下，反应瓶中分别称入化合物120-2(0.22g)，TBSCl(65mg)，imidazole(58mg)和DCM(5mL)，室温反应0.5h。反应结束后，加入饱和食盐水(15mL)洗，有 机相用无水硫酸钠干燥，浓缩。浓缩物经柱色谱纯化(PE:EA＝0-10％)得到产物120-3(0.30g)。ESI-MS m/z＝894.5[M+H]+。At room temperature, compound 120-2 (0.22g), TBSCl (65mg), imidazole (58mg) and DCM (5mL) were respectively weighed into the reaction bottle, and the reaction was carried out at room temperature for 0.5h. After the reaction is completed, add saturated brine (15 mL) to wash. The organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography (PE:EA=0-10%) to obtain product 120-3 (0.30 g). ESI-MS m/z=894.5[M+H] + .
步骤4：化合物120-4的合成Step 4: Synthesis of Compound 120-4
室温下，反应瓶中分别称入化合物120-3(0.30g)，mCPBA(70mg)和DCM(10mL)，室温反应1.0h。反应结束后，加入饱和食盐水(15mL)洗，有机相用无水硫酸钠干燥，浓缩。浓缩物经柱色谱纯化(PE:EA＝0-50％)得到产物120-4(0.11g)。ESI-MS m/z＝910.7[M+H]+。At room temperature, compound 120-3 (0.30g), mCPBA (70mg) and DCM (10mL) were weighed into the reaction bottle respectively, and the reaction was carried out at room temperature for 1.0h. After the reaction was completed, saturated brine (15 mL) was added to wash, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography (PE:EA=0-50%) to obtain product 120-4 (0.11 g). ESI-MS m/z=910.7[M+H] + .
步骤5：化合物120-5的合成Step 5: Synthesis of Compound 120-5
室温下，反应瓶中分别称入M1(35mg)和溶剂无水THF(0.5mL)，加入NaH(36mg)，室温反应10min后，向反应中加入120-4(83mg),于室温反应15min；；反应液降至0℃，滴入饱和NH4Cl(20mL)淬灭，加入乙酸乙酯(20mL)，萃取，水相用乙酸乙酯洗2遍，合并有机相无水硫酸钠干燥，减压蒸干，浓缩物经柱层析纯化(DCM/NH3in MeOH＝15:1)，得目标化合物120-5(74mg)。ESI-MS m/z:921.6[M+H]+。At room temperature, weigh M1 (35 mg) and solvent anhydrous THF (0.5 mL) into the reaction bottle, add NaH (36 mg), react at room temperature for 10 minutes, add 120-4 (83 mg) to the reaction, and react at room temperature for 15 minutes; ; The reaction solution was lowered to 0°C, saturated NH 4 Cl (20 mL) was added dropwise to quench, ethyl acetate (20 mL) was added, extracted, the aqueous phase was washed twice with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and reduced to The mixture was evaporated to dryness, and the concentrated product was purified by column chromatography (DCM/NH 3 in MeOH=15:1) to obtain the target compound 120-5 (74 mg). ESI-MS m/z:921.6[M+H] + .
步骤6：化合物120-6的合成Step 6: Synthesis of Compound 120-6
室温下，反应瓶中分别加入120-5(74),CsF(129mg)和无水DMF(1mL)后，室温反应2.0h；向反应中加入aq.NaCl水溶液(20mL)和EA(20mL)，萃取分液，有机相用无水硫酸钠干燥，减压蒸干，浓缩物经Pre-TLC纯化(DCM/NH3in MeOH＝12:1)，得目标化合物120-6(49mg)。ESI-MS m/z:765.4[M+H]+。At room temperature, add 120-5 (74), CsF (129mg) and anhydrous DMF (1mL) to the reaction bottle, and react at room temperature for 2.0h; add aq.NaCl aqueous solution (20mL) and EA (20mL) to the reaction. After extraction and liquid separation, the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The concentrate was purified by Pre-TLC (DCM/NH 3 in MeOH=12:1) to obtain the target compound 120-6 (49 mg). ESI-MS m/z:765.4[M+H] + .
步骤7：化合物120的合成Step 7: Synthesis of Compound 120
室温下，将化合物120-6(49mg)溶解在DCM(1mL)中，加入三氟化硼乙醚(0.2mL)，室温反应10min；反应结束后，将反应液滴加到预冷却至0℃的饱和碳酸钠水溶液(10mL)中，加入DCM分液得到有机层，饱和食盐水洗一遍，无水硫酸钠干燥，浓缩。浓缩物经Pre-TLC(DCM/NH3：MeOH＝8:1)纯化得目标化合物120(10.7mg，25％产率)。1H NMR(500MHz,MeOD)δ7.88(ddd,J＝16.4,9.1,5.7Hz,2H),7.39–7.30(m,4H),7.24(d,J＝2.2Hz,1H),7.08(d,J＝10.3Hz,1H),4.56–4.24(m,6H),4.17–3.91(m,2H),3.80(dd,J＝29.2,22.0Hz,7H),3.50–3.40(m,3H),3.35(d,J＝8.2Hz,1H),3.24–3.12(m,3H),2.76(ddd,J＝23.1,19.3,8.2Hz,4H),2.53(dd,J＝15.9,3.4Hz,2H),2.22–2.08(m,2H),2.07–1.97(m,2H),1.97–1.88(m,2H),1.84(s,2H),1.61(d,J＝4.4Hz,3H),1.41–1.25(m,3H).ESI-MS m/z:665.2[M+H]+。Dissolve compound 120-6 (49 mg) in DCM (1 mL) at room temperature, add boron trifluoride ether (0.2 mL), and react at room temperature for 10 min; after the reaction is completed, add the reaction solution dropwise to a solution precooled to 0°C. To a saturated aqueous sodium carbonate solution (10 mL), DCM was added to separate the layers to obtain an organic layer, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by Pre-TLC (DCM/NH 3 :MeOH=8:1) to obtain the target compound 120 (10.7 mg, 25% yield). 1 H NMR (500MHz, MeOD) δ7.88 (ddd, J＝16.4, 9.1, 5.7Hz, 2H), 7.39–7.30 (m, 4H), 7.24 (d, J＝2.2Hz, 1H), 7.08 (d ,J＝10.3Hz,1H),4.56–4.24(m,6H),4.17–3.91(m,2H),3.80(dd,J＝29.2,22.0Hz,7H),3.50–3.40(m,3H), 3.35(d,J＝8.2Hz,1H),3.24–3.12(m,3H),2.76(ddd,J＝23.1,19.3,8.2Hz,4H),2.53(dd,J＝15.9,3.4Hz,2H) ,2.22–2.08(m,2H),2.07–1.97(m,2H),1.97–1.88(m,2H),1.84(s,2H),1.61(d,J＝4.4Hz,3H),1.41–1.25 (m,3H).ESI-MS m/z:665.2[M+H] + .
实施例121：化合物4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-((2-(二氟亚 甲基)四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-8-氟吡啶[4,3d]嘧啶-7-基)-5-乙炔基-1,6-二氟萘-2-醇的合成
Example 121: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2-(difluoroalkyl) Methyl)tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoropyridin[4,3d]pyrimidin-7-yl)-5-ethynyl-1,6-difluoro Synthesis of naphthalene-2-ol
步骤1：化合物121-1的合成Step 1: Synthesis of Compound 121-1
将中间体M8(500.00mg)加入到25mL单口瓶中，加入乙腈(10.00mL)，然后加氟试剂(453.74mg)，室温搅拌反应4h。LCMS监测反应完成。向反应液中加入EA和水，萃取，收集有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，经柱层析纯化(PE/EA,15％EA)得到化合物121-1(253.0mg收率48.7％)。Add intermediate M8 (500.00 mg) to a 25 mL single-neck bottle, add acetonitrile (10.00 mL), then add fluorine reagent (453.74 mg), and stir the reaction at room temperature for 4 hours. LCMS monitored reaction completion. EA and water were added to the reaction solution, extracted, and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE/EA, 15% EA) to obtain compound 121-1 (253.0 mg yield 48.7%).
步骤2：化合物121-2的合成Step 2: Synthesis of Compound 121-2
将中间体1-1(150.00mg)加入到25mL单口瓶中，依次加入121-1(251.22mg)，1,4-二氧六环(4.00mL)，水(0.80mL)，PdCl2(dppf)(28.32mg)和碳酸钾(107.06mg)。N2置换三次，N2保护下升至130℃搅拌3小时。LCMS监测反应完成。减压浓缩，经柱层析纯化(DCM/MeOH,5％MeOH)得到化合物121-2(68.0mg收率29.1％)。Add intermediate 1-1 (150.00mg) into a 25mL single-neck bottle, then add 121-1 (251.22mg), 1,4-dioxane (4.00mL), water (0.80mL), PdCl 2 (dppf ) (28.32mg) and potassium carbonate (107.06mg). Replace N2 three times, raise to 130°C and stir for 3 hours under N2 protection. LCMS monitored reaction completion. Concentrate under reduced pressure and purify through column chromatography (DCM/MeOH, 5% MeOH) to obtain compound 121-2 (68.0 mg, yield 29.1%).
步骤3：化合物121-3的合成Step 3: Synthesis of Compound 121-3
化合物121-2(58.00mg)加入到25mL单口瓶中，加入N,N-二甲基甲酰胺(1.50mL)，加入氟化铯(77.89mg)。室温搅拌反应2小时。向反应液中加入EA和水，萃取，收集有机相，有机相用饱和食盐水洗涤3次，无水硫酸钠干燥。经Pre-TLC分离纯化(DCM/MeOH＝15/1)得到化合物121-3(28.0mg收率58.3％)。Compound 121-2 (58.00 mg) was added to a 25 mL single-neck bottle, N, N-dimethylformamide (1.50 mL) was added, and cesium fluoride (77.89 mg) was added. The reaction was stirred at room temperature for 2 hours. EA and water were added to the reaction solution, extracted, and the organic phase was collected. The organic phase was washed three times with saturated brine and dried over anhydrous sodium sulfate. Compound 121-3 was obtained through Pre-TLC separation and purification (DCM/MeOH=15/1) (28.0 mg, yield 58.3%).
步骤4：化合物121的合成Step 4: Synthesis of Compound 121
化合物121-3(28.00mg)加入到25mL单口瓶中，加入DCM(1.50mL)，再加入三氟化硼乙醚(0.30mL)。室温搅拌反应5分钟。将反应液加入0℃的饱和Na2CO3溶液。加入 DCM/MeOH＝5/1和水，萃取3次，收集有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥。粗品经Pre-HPLC制备得化合物121(9.8mg收率39.8％)。1H NMR(500MHz,DMSO-d6)δ9.04(s,1H),8.13(dd,J＝9.3,5.7Hz,1H),7.60(t,J＝9.0Hz,1H),7.36(dd,J＝8.6,2.1Hz,1H),4.46(d,J＝12.5Hz,1H),4.30(d,J＝12.3Hz,1H),4.17–4.02(m,3H),3.64(t,J＝11.9Hz,3H),3.56(d,J＝13.5Hz,4H),3.03–2.95(m,2H),2.61(s,2H),2.56(d,J＝7.7Hz,1H),2.41(dt,J＝16.0,3.9Hz,2H),1.98(ddt,J＝13.2,9.7,6.8Hz,3H),1.86(tt,J＝10.2,5.2Hz,1H),1.77(ddd,J＝12.5,8.8,6.6Hz,2H).ESI-MS m/z:694.41[M+H]+。Compound 121-3 (28.00 mg) was added to a 25 mL single-neck bottle, DCM (1.50 mL) was added, and then boron trifluoride ether (0.30 mL) was added. Stir the reaction at room temperature for 5 minutes. Add the reaction solution to a saturated Na 2 CO 3 solution at 0°C. join in DCM/MeOH = 5/1 and water, extracted three times, collected the organic phase, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was prepared by Pre-HPLC to obtain compound 121 (9.8 mg, yield 39.8%). 1 H NMR (500MHz, DMSO-d 6 ) δ9.04 (s, 1H), 8.13 (dd, J = 9.3, 5.7Hz, 1H), 7.60 (t, J = 9.0Hz, 1H), 7.36 (dd, J＝8.6,2.1Hz,1H),4.46(d,J＝12.5Hz,1H),4.30(d,J＝12.3Hz,1H),4.17–4.02(m,3H),3.64(t,J＝11.9 Hz,3H),3.56(d,J＝13.5Hz,4H),3.03–2.95(m,2H),2.61(s,2H),2.56(d,J＝7.7Hz,1H),2.41(dt,J ＝16.0,3.9Hz,2H),1.98(ddt,J＝13.2,9.7,6.8Hz,3H),1.86(tt,J＝10.2,5.2Hz,1H),1.77(ddd,J＝12.5,8.8,6.6 Hz,2H).ESI-MS m/z:694.41[M+H] + .
实施例122：化合物4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-((2-(二氟亚甲基)四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-8-氟-5-(2,2,2-三氟乙氧基)吡啶并[4,3d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的合成
Example 122: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2-(difluoromethylene)) Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-5-(2,2,2-trifluoroethoxy)pyrido[4,3d]pyrimidine-7- Synthesis of 5-ethynyl-6-fluoronaphthalene-2-ol
步骤1：化合物122-1的合成Step 1: Synthesis of Compound 122-1
在EtOH(0.39mL)的无水THF(10mL)溶液中分批加入NaH(357mg,60％纯度)，搅拌5min后将反应体系冷却到0℃，然后分批加入粉末固体M10(500mg,1.0eq.)，自然升至室温22℃搅拌反应30分钟。再次将反应体系冷却到0℃，滴入饱和氯化铵溶液(20mL)淬灭反应，加入20mL乙酸乙酯进行萃取分液，水相用乙酸乙酯洗2遍，合并有机相并用无水硫酸钠干燥，有机相浓缩后得目标化合物粗产品122-1(660mg)直接用于下一步反应。ESI-MS m/z:344.1[M+H]+。 NaH (357 mg, 60% purity) was added in batches to a solution of EtOH (0.39 mL) in anhydrous THF (10 mL). After stirring for 5 min, the reaction system was cooled to 0°C, and then powdered solid M10 (500 mg, 1.0 eq. .), naturally raised to room temperature 22°C and stirred for 30 minutes. The reaction system was cooled to 0°C again, saturated ammonium chloride solution (20 mL) was added dropwise to quench the reaction, 20 mL of ethyl acetate was added for extraction and liquid separation, the aqueous phase was washed twice with ethyl acetate, the organic phases were combined and washed with anhydrous sulfuric acid. After drying over sodium, the organic phase was concentrated to obtain the target compound crude product 122-1 (660 mg), which was directly used in the next reaction. ESI-MS m/z:344.1[M+H] + .
步骤2：化合物122-2的合成Step 2: Synthesis of Compound 122-2
室温下，向122-1(660mg)和(1R，5S)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(490mg)的DMF(6mL)溶液中依次加入DBU(1.14mL)和PyBOP(1.5g)，室温搅拌反应30分钟后LCMS显示反应完全。向反应中加入30mL饱和食盐水和30mL EA萃取分液，有机相用饱和食盐水洗涤3次后经无水硫酸钠干燥，有机相进一步浓缩后经柱层析纯化(EA/PE＝0％-15％)得目标化合物122-2(360mg)。ESI-MS m/z:538.2[M+H]+。To a solution of 122-1 (660 mg) and (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (490 mg) in DMF (6 mL) at room temperature. DBU (1.14 mL) and PyBOP (1.5 g) were added in sequence, and the reaction was stirred at room temperature for 30 minutes. LCMS showed that the reaction was complete. Add 30 mL saturated brine and 30 mL EA to the reaction for extraction and separation. The organic phase was washed 3 times with saturated brine and dried over anhydrous sodium sulfate. The organic phase was further concentrated and purified by column chromatography (EA/PE=0%- 15%) to obtain the target compound 122-2 (360 mg). ESI-MS m/z:538.2[M+H] + .
步骤3：化合物122-3的合成Step 3: Synthesis of Compound 122-3
微波管中分别加入122-2(360mg)，M8(470mg)，K2CO3(277mg)，Pd(dppf)Cl2(82mg)和6mL Dioxane/1.5mL H2O后，N2置换10min后，微波135℃反应70分钟。向反应液中加入EA和H2O各20mL，萃取分液，水相再用EA萃取两遍，有机相经无水硫酸钠干燥后减压浓缩，浓缩物经柱层析纯化(EA/PE＝0％-30％)得目标化合物122-3(390mg)。ESI-MS m/z:844.3[M+H]+。After adding 122-2 (360mg), M8 (470mg), K 2 CO 3 (277mg), Pd(dppf)Cl 2 (82mg) and 6mL Dioxane/1.5mL H 2 O respectively into the microwave tube, N 2 was replaced for 10 minutes. , microwave at 135°C for 70 minutes. Add 20 mL each of EA and H 2 O to the reaction solution, extract and separate the liquids. The aqueous phase is extracted twice with EA. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is purified by column chromatography (EA/PE =0%-30%) to obtain target compound 122-3 (390 mg). ESI-MS m/z:844.3[M+H] + .
步骤4：化合物122-4的合成Step 4: Synthesis of Compound 122-4
向122-3(390mg)的DCM(15mL)溶液中加入咪唑(220mg)和TBSCl(348mg)，让反应体系在室温搅拌30min。向反应中加入15mL水，萃取分液，水相用10mL DCM洗两遍，有机相合并后用20mL饱和食盐水洗涤一次，然后经无水硫酸钠干燥后减压浓缩，浓缩物经柱层析纯化(EA/PE＝0％-10％)得目标化合物122-4(320mg)。To a solution of 122-3 (390 mg) in DCM (15 mL), imidazole (220 mg) and TBSCl (348 mg) were added, and the reaction system was allowed to stir at room temperature for 30 min. Add 15 mL of water to the reaction, extract and separate the liquids. Wash the aqueous phase twice with 10 mL of DCM. The organic phase is combined and washed once with 20 mL of saturated saline. Then it is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is subjected to column chromatography. Purification (EA/PE=0%-10%) gave target compound 122-4 (320 mg).
步骤5：化合物122-5的合成Step 5: Synthesis of Compound 122-5
向122-4(320mg)的DCM(6mL)溶液中加入mCPBA(230mg)，室温搅拌70分钟。向反应中加入20mL DCM和20mL饱和NaHCO3溶液，萃取分液，水相再用10mL DCM萃取两遍，有机相合并后经无水硫酸钠干燥，浓缩，浓缩物经柱层析纯化(EA/PE＝0％-20％)得目标化合物122-5(160mg)。ESI-MS m/z:990.3.[M+H]+。mCPBA (230 mg) was added to a solution of 122-4 (320 mg) in DCM (6 mL), and the mixture was stirred at room temperature for 70 minutes. Add 20 mL DCM and 20 mL saturated NaHCO solution to the reaction, extract and separate the liquids, extract the aqueous phase twice with 10 mL DCM, combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and the concentrate is purified by column chromatography (EA/ PE=0%-20%) to obtain the target compound 122-5 (160 mg). ESI-MS m/z:990.3.[M+H] + .
步骤6：化合物122-6的合成Step 6: Synthesis of Compound 122-6
向M1(54mg)的无水THF(3mL)溶液中加入NaH(23mg)，搅拌10min后，再加入122-5(140mg)，体系在室温下搅拌15min。反应结束后将体系冷却到0℃，滴入饱和氯化铵水溶液(20mL)淬灭反应，加入乙酸乙酯(20mL)，萃取分液，水相用乙酸乙酯洗2遍，有机相合并后经无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC纯化(DCM/NH3：MeOH(7M)＝100:5)得目标化合物122-6(130mg)。ESI-MS m/z:493.6[M+2H]+/2。NaH (23 mg) was added to a solution of M1 (54 mg) in anhydrous THF (3 mL), and after stirring for 10 min, 122-5 (140 mg) was added, and the system was stirred at room temperature for 15 min. After the reaction, the system was cooled to 0°C, saturated aqueous ammonium chloride solution (20 mL) was added dropwise to quench the reaction, ethyl acetate (20 mL) was added, extraction was performed, and the aqueous phase was washed twice with ethyl acetate, and the organic phases were combined. Dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by Pre-TLC (DCM/NH 3 :MeOH (7M) = 100:5) to obtain target compound 122-6 (130 mg). ESI-MS m/z:493.6[M+2H] + /2.
步骤7：化合物122-7的合成Step 7: Synthesis of Compound 122-7
向122-6(130mg)的DMF(1mL)溶液中加入CsF(401mg)，然后让反应体系在 35℃搅拌1小时。反应结束后向反应中加入20mL饱和食盐水和20mL EA，萃取分液，有机相用20mL饱和食盐水再洗涤两遍后经无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC纯化(DCM/NH3：MeOH(7M)＝100:7)得目标化合物122-7(94mg)。ESI-MS m/z:829.5[M+H]+。CsF (401 mg) was added to a solution of 122-6 (130 mg) in DMF (1 mL), and then the reaction system was allowed to Stir at 35°C for 1 hour. After the reaction, 20 mL of saturated brine and 20 mL of EA were added to the reaction, and the liquid was extracted and separated. The organic phase was washed twice with 20 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by Pre-TLC (DCM/ NH 3 : MeOH (7M) = 100:7) to obtain the target compound 122-7 (94 mg). ESI-MS m/z:829.5[M+H] + .
步骤8：化合物122的合成Step 8: Synthesis of Compound 122
向122-7(90mg)的无水DCM(2mL)溶液中加入BF3.Et2O(0.27mL)，所得体系在室温下搅拌10分钟。反应结束后，将反应体系冷却到0℃，然后加入饱和Na2CO3(10mL)淬灭，加入DCM/MeOH(10:1，20mL)萃取，水相用相同混合溶剂继续萃取两遍。有机相合并后经无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC纯化(DCM/NH3in MeOH(7M)＝9:1)得目标化合物122(54mg)。1H NMR(500MHz,DMSO)δ10.19(s,1H),7.98(dd,J＝9.1,5.9Hz,1H),7.47(t,J＝9.0Hz,1H),7.40(d,J＝2.5Hz,1H),7.24(t,J＝2.2Hz,1H),5.08–4.92(m,2H),4.14(dd,J＝10.6,2.2Hz,1H),4.09(dd,J＝10.6,3.0Hz,1H),3.92(d,J＝2.2Hz,1H),3.64(d,J＝14.0Hz,1H),3.53–3.39(m,4H),2.99(dd,J＝9.4,3.8Hz,1H),2.65–2.55(m,2H),2.44–2.34(m,2H),2.00–1.92(m,1H),1.89–1.83(m,1H),1.81–1.73(m,2H),1.62–1.45(m,5H),1.23(s,2H).ESI-MS m/z:729.4[M+H]+。To a solution of 122-7 (90 mg) in anhydrous DCM (2 mL) was added BF 3 .Et 2 O (0.27 mL), and the resulting system was stirred at room temperature for 10 minutes. After the reaction, the reaction system was cooled to 0°C, then saturated Na 2 CO 3 (10 mL) was added to quench, DCM/MeOH (10:1, 20 mL) was added for extraction, and the aqueous phase was extracted twice with the same mixed solvent. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by Pre-TLC (DCM/NH 3 in MeOH (7M) = 9:1) to obtain target compound 122 (54 mg). 1 H NMR (500MHz, DMSO) δ10.19 (s, 1H), 7.98 (dd, J = 9.1, 5.9Hz, 1H), 7.47 (t, J = 9.0Hz, 1H), 7.40 (d, J = 2.5 Hz,1H),7.24(t,J＝2.2Hz,1H),5.08–4.92(m,2H),4.14(dd,J＝10.6,2.2Hz,1H),4.09(dd,J＝10.6,3.0Hz ,1H),3.92(d,J＝2.2Hz,1H),3.64(d,J＝14.0Hz,1H),3.53–3.39(m,4H),2.99(dd,J＝9.4,3.8Hz,1H) ,2.65–2.55(m,2H),2.44–2.34(m,2H),2.00–1.92(m,1H),1.89–1.83(m,1H),1.81–1.73(m,2H),1.62–1.45( m,5H),1.23(s,2H).ESI-MS m/z:729.4[M+H] + .
实施例123：化合物4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-2-((2-甲基四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5-(2,2,2-三氟乙氧基)吡啶[4,3d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的合成
Example 123: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-((2-methyltetrakis) Hydrogen-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(2,2,2-trifluoroethoxy)pyridine[4,3d]pyrimidin-7-yl)-5-ethyne Synthesis of 6-fluoronaphthalene-2-ol
步骤1：化合物123-1的合成Step 1: Synthesis of Compound 123-1
向M9(62mg)的无水THF(3mL)溶液中加入NaH(32mg)，搅拌10min后，再加入122-5(190mg,1.0eq.)，体系在室温下搅拌反应30min。反应结束后将体系冷却到0℃，滴入饱和氯化铵水溶液(20mL)淬灭反应，加入乙酸乙酯(20mL)，萃取分液，水 相用乙酸乙酯洗2遍，有机相合并后经无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC纯化(DCM/NH3：MeOH(7M)＝100:7)得目标化合物123-1(84mg)。ESI-MS m/z:949.5[M+H]+。NaH (32 mg) was added to a solution of M9 (62 mg) in anhydrous THF (3 mL), and after stirring for 10 min, 122-5 (190 mg, 1.0 eq.) was added, and the system was stirred and reacted at room temperature for 30 min. After the reaction, the system was cooled to 0°C, saturated aqueous ammonium chloride solution (20 mL) was added dropwise to quench the reaction, ethyl acetate (20 mL) was added, extraction was performed, and water was separated. The phase was washed twice with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by Pre-TLC (DCM/NH 3 :MeOH (7M) = 100:7) to obtain target compound 123-1. (84mg). ESI-MS m/z:949.5[M+H] + .
步骤2：化合物123-2的合成Step 2: Synthesis of Compound 123-2
向123-1(84mg)的DMF(1mL)溶液中加入CsF(269mg)，然后让反应体系在室温下搅拌2小时。反应结束后向反应中加入20mL饱和食盐水和20mL EA，萃取分液，有机相用20mL饱和食盐水再洗涤两遍后经无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC纯化(DCM/NH3：MeOH(7M)＝100:8)得目标化合物123-2(53mg)。ESI-MS m/z:793.2[M+H]+。To a solution of 123-1 (84 mg) in DMF (1 mL) was added CsF (269 mg), and the reaction was allowed to stir at room temperature for 2 hours. After the reaction, 20 mL of saturated brine and 20 mL of EA were added to the reaction, and the liquid was extracted and separated. The organic phase was washed twice with 20 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by Pre-TLC (DCM/ NH 3 : MeOH (7M) = 100:8) to obtain the target compound 123-2 (53 mg). ESI-MS m/z:793.2[M+H] + .
步骤3：化合物123的合成Step 3: Synthesis of Compound 123
向123-2(53mg)的无水DCM(1mL)溶液中加入BF3.Et2O(0.17mL)，所得体系在室温下搅拌10分钟。反应结束后，将反应体系冷却到0℃，然后加入饱和Na2CO3(10mL)淬灭，加入DCM/MeOH(10:1，20mL)萃取，水相用相同混合溶剂继续萃取两遍。有机相合并后经无水硫酸钠干燥，浓缩，浓缩物经Pre-TLC纯化(DCM/NH3in MeOH(7M)＝8:1)得目标化合物123(39mg)。1H NMR(500MHz,CDCl3)δ7.73–7.65(m,1H),7.32(d,J＝5.7Hz,1H),7.28–7.26(m,1H),7.21–7.14(m,1H),4.98–4.92(m,4H),4.26(d,J＝10.3Hz,1H),4.20(d,J＝10.0Hz,1H),3.93–3.79(m,1H),3.63–3.38(m,5H),3.34–3.20(m,3H),2.85–2.62(m,5H),2.41(d,J＝15.7Hz,1H),2.33(d,J＝15.5Hz,1H),2.19–2.09(m,1H),1.98–1.86(m,2H),1.83–1.71(m,2H),1.65–1.46(m,2H).ESI-MS m/z:693.5[M+H]+。To a solution of 123-2 (53 mg) in anhydrous DCM (1 mL) was added BF 3 .Et 2 O (0.17 mL) and the resulting system was stirred at room temperature for 10 min. After the reaction, the reaction system was cooled to 0°C, then saturated Na 2 CO 3 (10 mL) was added to quench, DCM/MeOH (10:1, 20 mL) was added for extraction, and the aqueous phase was extracted twice with the same mixed solvent. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by Pre-TLC (DCM/NH 3 in MeOH (7M) = 8:1) to obtain target compound 123 (39 mg). 1 H NMR (500MHz, CDCl 3 ) δ7.73–7.65 (m, 1H), 7.32 (d, J = 5.7Hz, 1H), 7.28–7.26 (m, 1H), 7.21–7.14 (m, 1H), 4.98–4.92(m,4H),4.26(d,J＝10.3Hz,1H),4.20(d,J＝10.0Hz,1H),3.93–3.79(m,1H),3.63–3.38(m,5H) ,3.34–3.20(m,3H),2.85–2.62(m,5H),2.41(d,J＝15.7Hz,1H),2.33(d,J＝15.5Hz,1H),2.19–2.09(m,1H ),1.98–1.86(m,2H),1.83–1.71(m,2H),1.65–1.46(m,2H).ESI-MS m/z:693.5[M+H] + .
实施例125：化合物3-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-5-甲氧基-2-((2-甲基四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-氯-4-环丙基苯酚的合成
Example 125: Compound 3-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-methoxy-2-( (2-Methyltetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-chloro-4-cyclopropylphenol Synthesis
步骤1：化合物125-1的合成 Step 1: Synthesis of Compound 125-1
化合物(3-溴-5-氯-4-环丙基苯氧基)(叔丁基)二甲基硅烷(2.00g)加入到100mL单口瓶中，加入THF(30.00mL)，N2保护下-70℃滴加入n-BuLi(2.5M/正己烷)(4.42mL,2.50mol/L)。-70℃搅拌1小时。再滴加入2-甲氧基-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(2.73mL)，升至室温搅拌反应1小时。反应液倒入饱和NH4Cl溶液，EA萃取两次，收集有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥，经柱层析纯化(PE/EA，5％EA)得到化合物125-1(1.8g收率79.6％)。Compound (3-bromo-5-chloro-4-cyclopropylphenoxy) (tert-butyl)dimethylsilane (2.00g) was added to a 100mL single-mouth bottle, and THF (30.00mL) was added under N2 protection. Add n-BuLi (2.5M/n-hexane) (4.42mL, 2.50mol/L) dropwise at -70°C. Stir at -70°C for 1 hour. Then 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2.73 mL) was added dropwise, and the mixture was raised to room temperature and stirred for 1 hour. The reaction solution was poured into saturated NH 4 Cl solution, and extracted twice with EA. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE/EA, 5% EA) to obtain compound 125. -1 (1.8g yield 79.6%).
步骤2：化合物125-2的合成Step 2: Synthesis of Compound 125-2
将中间体7-2(400.00mg)加入到25mL单口瓶中，依次加入125-1(695.93mg)，1,4-二氧六环(7.00mL)，水(1.00mL)，SphosPdG2(61.24mg)和磷酸钾(541.98mg)。N2置换三次，N2保护下升至80℃搅拌2小时。减压浓缩，经柱层析纯化(PE/EA,10-15％EA)得到化合物125-2(528.0mg，收率86.6％)。Add intermediate 7-2 (400.00mg) into a 25mL single-neck bottle, then add 125-1 (695.93mg), 1,4-dioxane (7.00mL), water (1.00mL), SphosPdG2 (61.24mg) ) and potassium phosphate (541.98mg). N2 was replaced three times, and the mixture was raised to 80°C under N2 protection and stirred for 2 hours. Concentrate under reduced pressure and purify through column chromatography (PE/EA, 10-15% EA) to obtain compound 125-2 (528.0 mg, yield 86.6%).
步骤3：化合物125-3的合成Step 3: Synthesis of Compound 125-3
将化合物125-2(434.00mg)加入到25mL单口瓶中，加入二氯甲烷(7.00mL)，加入mCPBA(418.17mg)。室温搅拌反应1小时。向反应液中加入饱和亚硫酸钠溶液淬灭，再加入DCM和水，萃取2次，收集有机相，有机相用饱和NaHCO3溶液洗涤两次，再用饱和食盐水洗涤，无水硫酸钠干燥。经柱层析纯化(PE/EA,25％EA)得到化合物125-3(284.0mg，收率51.5％)。Compound 125-2 (434.00 mg) was added to a 25 mL single-neck bottle, dichloromethane (7.00 mL) was added, and mCPBA (418.17 mg) was added. The reaction was stirred at room temperature for 1 hour. Add saturated sodium sulfite solution to the reaction solution to quench, then add DCM and water, extract twice, collect the organic phase, wash the organic phase twice with saturated NaHCO 3 solution, then wash with saturated brine, and dry over anhydrous sodium sulfate. Purification by column chromatography (PE/EA, 25% EA) gave compound 125-3 (284.0 mg, yield 51.5%).
步骤4：化合物125-4的合成Step 4: Synthesis of Compound 125-4
化合物125-3(264.00mg)加入到25mL单口瓶中，加入THF(4.00mL)，再加入中间体M9(108.11mg)。冰浴下，分批加入氢化钠(56.45mg,60％)。室温搅拌反应3.5小时。向反应液中加入饱和NH4Cl溶液淬灭，减压浓缩。再加入DCM和水，萃取两次，收集有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥。经柱层析纯化(DCM/MeOH，5-10％MeOH)得到化合物125-4(119.0mg，收率41％)。Compound 125-3 (264.00 mg) was added to a 25 mL single-neck bottle, THF (4.00 mL) was added, and then intermediate M9 (108.11 mg) was added. Under ice bath, add sodium hydride (56.45 mg, 60%) in batches. The reaction was stirred at room temperature for 3.5 hours. Saturated NH 4 Cl solution was added to the reaction solution to quench, and the mixture was concentrated under reduced pressure. Then add DCM and water, extract twice, collect the organic phase, wash the organic phase with saturated brine, and dry over anhydrous sodium sulfate. Purification by column chromatography (DCM/MeOH, 5-10% MeOH) gave compound 125-4 (119.0 mg, yield 41%).
步骤5：化合物125的合成Step 5: Synthesis of Compound 125
化合物125-4(109.00mg)加入到25mL单口瓶中，加入DCM(3.00mL)，再加入TFA(1.50mL)。室温搅拌反应15分钟。减压浓缩。粗品经Pre-HPLC制备得到化合物125(70.6mg，收率75.3％)。1H NMR(500MHz,DMSO-d6)δ10.78(s,1H),10.17(s,1H),9.37(d,J＝95.1Hz,2H),6.96(d,J＝2.6Hz,1H),6.83(d,J＝2.5Hz,1H),5.21(dt,J＝13.4,2.1Hz,2H),4.65–4.54(m,2H),4.32–4.09(m,6H),3.98(s,5H),3.65(d,J＝14.3Hz,2H),3.17(dd,J＝12.5,5.8Hz,1H),2.93(d,J＝16.1Hz,1H),2.75(d,J＝16.2Hz,1H),2.25(qd,J＝9.6,5.3Hz, 1H),2.19–2.10(m,1H),2.03(dt,J＝9.2,6.6Hz,2H),1.95–1.89(m,2H),1.84(q,J＝5.9,5.2Hz,2H),0.63(s,2H),0.05(s,2H).ESI-MS m/z:607.49[M+H]+。Compound 125-4 (109.00 mg) was added to a 25 mL single-neck bottle, DCM (3.00 mL) was added, and then TFA (1.50 mL) was added. The reaction was stirred at room temperature for 15 minutes. Concentrate under reduced pressure. The crude product was prepared by Pre-HPLC to obtain compound 125 (70.6 mg, yield 75.3%). 1 H NMR (500MHz, DMSO-d 6 ) δ10.78 (s, 1H), 10.17 (s, 1H), 9.37 (d, J = 95.1Hz, 2H), 6.96 (d, J = 2.6Hz, 1H) ,6.83(d,J＝2.5Hz,1H),5.21(dt,J＝13.4,2.1Hz,2H),4.65–4.54(m,2H),4.32–4.09(m,6H),3.98(s,5H ),3.65(d,J＝14.3Hz,2H),3.17(dd,J＝12.5,5.8Hz,1H),2.93(d,J＝16.1Hz,1H),2.75(d,J＝16.2Hz,1H ),2.25(qd,J＝9.6,5.3Hz, 1H),2.19–2.10(m,1H),2.03(dt,J＝9.2,6.6Hz,2H),1.95–1.89(m,2H),1.84(q,J＝5.9,5.2Hz,2H),0.63 (s,2H),0.05(s,2H).ESI-MS m/z:607.49[M+H] + .
实施例141：化合物4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-5-甲氧基-2-((2-甲基四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-胺的合成
Example 141: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-methoxy-2-( (2-Methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalene- Synthesis of 2-amines
步骤1：化合物141-1的合成Step 1: Synthesis of Compound 141-1
将化合物7-3(1.43g)溶于二氯甲烷(20mL)，加入间氯过氧苯甲酸(1.59g)，在室温下反应1h。反应完全后，使用饱和碳酸氢钠淬灭反应，使用DCM萃取两遍，通过柱层析进行纯化得到化合物141-1(0.48g，收率32.24％)。ESI-MS m/z:808.51[M+H]+。Compound 7-3 (1.43g) was dissolved in dichloromethane (20 mL), m-chloroperoxybenzoic acid (1.59g) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate, extracted twice with DCM, and purified by column chromatography to obtain compound 141-1 (0.48 g, yield 32.24%). ESI-MS m/z:808.51[M+H]+.
步骤2：化合物141-2的合成Step 2: Synthesis of Compound 141-2
将中间体M9(182.02mg)溶于四氢呋喃(5mL)，加入氢化钠(118.8mg)，然后加入化合物141-1(480mg)，在室温下反应10分钟。反应完全后，使用饱和氯化铵淬灭反应液，使用EA萃取两遍，通过柱层析进行纯化得到化合物141-2(389mg，收率74.38％)。ESI-MS m/z:881.65[M+H]+。Intermediate M9 (182.02 mg) was dissolved in tetrahydrofuran (5 mL), sodium hydride (118.8 mg) was added, and then compound 141-1 (480 mg) was added, and the reaction was carried out at room temperature for 10 minutes. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride, extracted twice with EA, and purified by column chromatography to obtain compound 141-2 (389 mg, yield 74.38%). ESI-MS m/z:881.65[M+H]+.
步骤3：化合物141-3的合成Step 3: Synthesis of Compound 141-3
将化合物141-2(389mg)，DMAP(5.29mg)，三乙胺(0.181mL)溶于四氢呋喃(5mL)，最后加入1,1,1-三氟-N-苯基-N-(三氟甲基磺酰基)甲磺酰胺(309.81mg)，在室温下反应1h。反应完全后，使用EA和水稀释反应液，使用EA萃取两遍，通过柱层析进行纯化得到化合物141-3(480mg)。ESI-MS m/z:507.4[M+H]+。Compound 141-2 (389 mg), DMAP (5.29 mg), and triethylamine (0.181 mL) were dissolved in tetrahydrofuran (5 mL), and finally 1,1,1-trifluoro-N-phenyl-N-(trifluoro Methylsulfonyl)methanesulfonamide (309.81 mg), reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with EA and water, extracted twice with EA, and purified by column chromatography to obtain compound 141-3 (480 mg). ESI-MS m/z:507.4[M+H]+.
步骤4：化合物141-4的合成Step 4: Synthesis of Compound 141-4
将化合物141-3(480mg)，二苯甲酮亚胺(171.70mg)，碳酸铯(463.02mg)，Pd(OAc)2(10.62mg)，BINAP(29.45mg)溶于1,4-二氧六环(6mL)，氮气置换，在100℃反应1h。 反应完全后，使用EA和水稀释反应液，使用EA萃取两遍，通过柱层析进行纯化得到化合物141-4(383mg收率77.42％)。ESI-MS m/z:522.91[M+H]+。Compound 141-3 (480mg), benzophenone imine (171.70mg), cesium carbonate (463.02mg), Pd(OAc) 2 (10.62mg), BINAP (29.45mg) were dissolved in 1,4-dioxy Six rings (6 mL), replaced with nitrogen, reacted at 100°C for 1 hour. After the reaction was completed, the reaction solution was diluted with EA and water, extracted twice with EA, and purified by column chromatography to obtain compound 141-4 (383 mg, yield 77.42%). ESI-MS m/z:522.91[M+H]+.
步骤5：化合物141-5的合成Step 5: Synthesis of Compound 141-5
将化合物141-4(383mg)溶于四氢呋喃(8mL)中，加入2N的稀盐酸(4ml)在室温反应10分钟。反应完全后，将温度降至0℃，使用饱和碳酸钠游离化合物，使用EA萃取两遍，饱和食盐水洗一遍，干燥过滤旋干，粗品直接用于下一步得到化合物141-5(380mg)。ESI-MS m/z:880.67[M+H]+。Compound 141-4 (383 mg) was dissolved in tetrahydrofuran (8 mL), 2N dilute hydrochloric acid (4 ml) was added, and the mixture was reacted at room temperature for 10 minutes. After the reaction was completed, the temperature was lowered to 0°C, the free compound was extracted with saturated sodium carbonate, extracted twice with EA, washed once with saturated brine, dried, filtered and spin-dried, and the crude product was directly used in the next step to obtain compound 141-5 (380 mg). ESI-MS m/z:880.67[M+H] + .
步骤6：化合物141-6的合成Step 6: Synthesis of Compound 141-6
将化合物141-5(380mg)溶于N,N-二甲基甲酰胺(5mL)，加入氟化铯(1311.50mg)，在室温反应3h。反应完全后，使用EA和水稀释反应液，使用EA萃取两遍，饱和食盐水洗三遍，通过柱层析进行纯化得到化合物141-6(215mg收率68.81％)。ESI-MS m/z:724.53[M+H]+。Compound 141-5 (380 mg) was dissolved in N,N-dimethylformamide (5 mL), cesium fluoride (1311.50 mg) was added, and the reaction was carried out at room temperature for 3 h. After the reaction was completed, the reaction solution was diluted with EA and water, extracted twice with EA, washed three times with saturated brine, and purified by column chromatography to obtain compound 141-6 (215 mg, yield 68.81%). ESI-MS m/z:724.53[M+H]+.
步骤7：化合物141的合成Step 7: Synthesis of Compound 141
将化合物141-6(215mg)溶于二氯甲烷(5mL)，加入三氟化硼乙醚(0.94mL)，在室温下反应0.5h。反应完全后，将反应液加入到冷的饱和碳酸钠溶液中，使用DCM萃取两遍，干燥过滤旋干，通过Pre-TLC进行纯化得到化合物141(120.70mg收率65.06％)。ESI-MS m/z:624.48[M+H]+。1H NMR(500MHz,DMSO)δ7.77(dd,J＝9.2,5.9Hz,1H),7.33(t,J＝9.0Hz,1H),7.07(d,J＝2.1Hz,1H),7.04(d,J＝2.2Hz,1H),5.63(s,2H),4.90(s,2H),4.11–3.92(m,3H),3.88(s,4H),3.81(s,1H),3.55(d,J＝14.0Hz,1H),3.47(s,2H),3.41–3.33(m,2H),3.18(d,J＝13.8Hz,1H),3.03–2.94(m,1H),2.62–2.53(m,2H),2.35(d,J＝15.5Hz,1H),2.05–1.64(m,4H),1.63-1.52(m,4H),1.23(s,1H).Compound 141-6 (215 mg) was dissolved in dichloromethane (5 mL), boron trifluoride ether (0.94 mL) was added, and the reaction was carried out at room temperature for 0.5 h. After the reaction was completed, the reaction solution was added to cold saturated sodium carbonate solution, extracted twice with DCM, dried, filtered and spin-dried, and purified by Pre-TLC to obtain compound 141 (120.70 mg, yield 65.06%). ESI-MS m/z:624.48[M+H]+. 1 H NMR (500MHz, DMSO) δ7.77(dd,J＝9.2,5.9Hz,1H),7.33(t,J＝9.0Hz,1H),7.07(d,J＝2.1Hz,1H),7.04( d,J＝2.2Hz,1H),5.63(s,2H),4.90(s,2H),4.11–3.92(m,3H),3.88(s,4H),3.81(s,1H),3.55(d ,J＝14.0Hz,1H),3.47(s,2H),3.41–3.33(m,2H),3.18(d,J＝13.8Hz,1H),3.03–2.94(m,1H),2.62–2.53( m,2H),2.35(d,J=15.5Hz,1H),2.05–1.64(m,4H),1.63-1.52(m,4H),1.23(s,1H).
实施例143：化合物4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-((2-(二氟亚甲基)四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-8-氟-5-甲氧基吡啶并[4,3d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-胺的合成
Example 143: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2-(difluoromethylene)) Tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-5-methoxypyrido[4,3d]pyrimidin-7-yl)-5-ethynyl-6- Synthesis of fluoronaphthyl-2-amine
步骤1：化合物143-1的合成Step 1: Synthesis of Compound 143-1
将化合物141-1(88.96mg)溶于四氢呋喃(2mL)，加入氢化钠(47.02mg)，然后加入化合物M1(190mg)，在室温下反应10分钟。反应完全后，使用饱和氯化铵淬灭反应液，使用EA萃取两遍，饱和食盐水洗一遍，干燥过滤浓缩，粗品直接用于下一步得到化合物143-1(277mg)。ESI-MS m/z:917.63[M+H]+。Compound 141-1 (88.96 mg) was dissolved in tetrahydrofuran (2 mL), sodium hydride (47.02 mg) was added, and then compound M1 (190 mg) was added, and the reaction was carried out at room temperature for 10 minutes. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride, extracted twice with EA, washed once with saturated brine, dried, filtered and concentrated, and the crude product was directly used in the next step to obtain compound 143-1 (277 mg). ESI-MS m/z:917.63[M+H]+.
步骤2：化合物143-2的合成Step 2: Synthesis of Compound 143-2
将化合物143-1(277mg)，DMAP(3.76mg)，三乙胺(0.129mL)溶于四氢呋喃(5mL)，最后加入1,1,1-三氟-N-苯基-N-(三氟甲基磺酰基)甲磺酰胺(220.57mg)，在室温下反应1h。反应完全后，使用EA和水稀释反应液，使用EA萃取两遍，通过柱层析进行纯化得到化合物143-2(168mg)。ESI-MS m/z:525.39[M+H]+。Compound 143-1 (277mg), DMAP (3.76mg), triethylamine (0.129mL) were dissolved in tetrahydrofuran (5mL), and finally 1,1,1-trifluoro-N-phenyl-N-(trifluoro Methylsulfonyl) methanesulfonamide (220.57 mg), reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with EA and water, extracted twice with EA, and purified by column chromatography to obtain compound 143-2 (168 mg). ESI-MS m/z:525.39[M+H]+.
步骤3：化合物143-3的合成Step 3: Synthesis of Compound 143-3
将143-2(168mg)，二苯甲酮亚胺(57.16mg)，碳酸铯(154.15mg)，Pd(OAc)2(3.55mg)，BINAP(9.84mg)溶于1,4-二氧六环(4mL)，氮气置换，在100℃反应1h。反应完全后，使用EA和水稀释反应液，使用EA萃取两遍，通过柱层析进行纯化得到化合物143-3(161mg，收率93.12％)。ESI-MS m/z:540.96[M+H]+。Dissolve 143-2 (168mg), benzophenone imine (57.16mg), cesium carbonate (154.15mg), Pd(OAc) 2 (3.55mg), BINAP (9.84mg) in 1,4-dioxane (4 mL), replaced with nitrogen, and reacted at 100°C for 1 h. After the reaction was completed, the reaction solution was diluted with EA and water, extracted twice with EA, and purified by column chromatography to obtain compound 143-3 (161 mg, yield 93.12%). ESI-MS m/z:540.96[M+H]+.
步骤4：化合物143-4的合成Step 4: Synthesis of Compound 143-4
将化合物143-3(161mg)溶于四氢呋喃(4mL)中，加入2N的稀盐酸(2ml)在室温反应10分钟。反应完全后，将温度降至0℃，使用饱和碳酸钠游离化合物，使用EA萃取两遍，饱和食盐水洗一遍，干燥过滤旋干，粗品直接用于下一步得到化合物143-4(160mg)。ESI-MS m/z:916.65[M+H]+。Compound 143-3 (161 mg) was dissolved in tetrahydrofuran (4 mL), 2N dilute hydrochloric acid (2 ml) was added, and the reaction was carried out at room temperature for 10 minutes. After the reaction is complete, lower the temperature to 0°C, use saturated sodium carbonate to free the compound, extract twice with EA, wash once with saturated brine, dry, filter and spin dry. The crude product is directly used in the next step to obtain compound 143-4 (160 mg). ESI-MS m/z:916.65[M+H]+.
步骤5：化合物143-5的合成Step 5: Synthesis of Compound 143-5
将化合物143-4(160mg)溶于N,N-二甲基甲酰胺(3mL)，加入氟化铯(521.35mg)， 在室温反应3h。反应完全后，使用EA和水稀释反应液，使用EA萃取两遍，饱和食盐水洗三遍，通过柱层析进行纯化得到化合物143-5(102mg收率76.62％)。ESI-MS m/z:760.52[M+H]+。Compound 143-4 (160 mg) was dissolved in N,N-dimethylformamide (3 mL), and cesium fluoride (521.35 mg) was added. React at room temperature for 3 hours. After the reaction was completed, the reaction solution was diluted with EA and water, extracted twice with EA, washed three times with saturated brine, and purified by column chromatography to obtain compound 143-5 (102 mg, yield 76.62%). ESI-MS m/z:760.52[M+H]+.
步骤6：化合物143的合成Step 6: Synthesis of Compound 143
将化合物143-5(102mg)溶于二氯甲烷(2mL)，加入三氟化硼乙醚(0.17mL)，在室温下反应0.5h。反应完全后，将反应液加入到冷的饱和碳酸钠溶液中，使用DCM萃取两遍，干燥过滤旋干，通过Pre-TCL进行纯化，得到化合物143(39.9mg收率44.94％)。ESI-MS m/z:660.46[M+H]+。1H NMR(500MHz,DMSO)δ7.77(dd,J＝9.2,5.9Hz,1H),7.33(t,J＝9.0Hz,1H),7.07(s,1H),7.04(d,J＝2.2Hz,1H),5.63(s,2H),4.15-4.02(m,3H),3.88(s,4H),3.80(s,1H),3.64(d,J＝14.1Hz,1H),3.48(s,2H),3.43–3.33(m,3H),3.03–2.94(m,1H),2.70–2.52(m,2H),2.40(d,J＝15.8Hz,1H),2.09–1.72(m,4H),1.67-1.49(m,4H),1.24(s,1H).Compound 143-5 (102 mg) was dissolved in dichloromethane (2 mL), boron trifluoride ether (0.17 mL) was added, and the reaction was carried out at room temperature for 0.5 h. After the reaction was completed, the reaction solution was added to cold saturated sodium carbonate solution, extracted twice with DCM, dried, filtered and spin-dried, and purified by Pre-TCL to obtain compound 143 (39.9 mg, yield 44.94%). ESI-MS m/z:660.46[M+H]+. 1 H NMR (500MHz, DMSO) δ7.77 (dd, J＝9.2, 5.9Hz, 1H), 7.33 (t, J＝9.0Hz, 1H), 7.07 (s, 1H), 7.04 (d, J＝2.2 Hz,1H),5.63(s,2H),4.15-4.02(m,3H),3.88(s,4H),3.80(s,1H),3.64(d,J＝14.1Hz,1H),3.48(s ,2H),3.43–3.33(m,3H),3.03–2.94(m,1H),2.70–2.52(m,2H),2.40(d,J＝15.8Hz,1H),2.09–1.72(m,4H ),1.67-1.49(m,4H),1.24(s,1H).
实施例180：化合物4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-2-((2,6-二亚甲基四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-8-氟-5-甲氧基吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的合成
Example 180: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((2,6-dimethylenetetrakis) Hydrogen-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-5-methoxypyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Synthesis of fluoronaphthalen-2-ol
步骤1：化合物180-1的合成Step 1: Synthesis of Compound 180-1
将化合物7-3(1.43g)溶于二氯甲烷(20mL)，加入间氯过氧苯甲酸(0.80g)，在室温下反应1h。反应完全后，使用饱和碳酸氢钠淬灭反应，使用DCM萃取两遍，合并有机相，浓缩，浓缩物经柱层析进行纯化得到化合物180-1(0.48g，收率30.24％)。ESI-MS m/z:792[M+H]+。Compound 7-3 (1.43g) was dissolved in dichloromethane (20 mL), m-chloroperoxybenzoic acid (0.80g) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate, extracted twice with DCM, the organic phases were combined, concentrated, and the concentrate was purified by column chromatography to obtain compound 180-1 (0.48 g, yield 30.24%). ESI-MS m/z:792[M+H] + .
步骤2：化合物180-2的合成 Step 2: Synthesis of Compound 180-2
将中间体M11(87.1mg)溶于四氢呋喃(1mL)，加入氢化钠(15.2mg)，然后加入化合物180-1(167mg)的四氢呋喃(1mL)溶液，在室温下反应10分钟。反应完全后，使用饱和氯化铵淬灭反应液，使用EA萃取两遍，合并有机相，浓缩，浓缩物经柱层析分离纯化得到化合物180-2(100mg，收率52.6％)。ESI-MS m/z:893[M+H]+。Intermediate M11 (87.1 mg) was dissolved in tetrahydrofuran (1 mL), sodium hydride (15.2 mg) was added, and then a solution of compound 180-1 (167 mg) in tetrahydrofuran (1 mL) was added, and the reaction was carried out at room temperature for 10 minutes. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride, extracted twice with EA, the organic phases were combined, concentrated, and the concentrate was separated and purified by column chromatography to obtain compound 180-2 (100 mg, yield 52.6%). ESI-MS m/z:893[M+H] + .
步骤2：化合物180-3的合成Step 2: Synthesis of Compound 180-3
将化合物180-2(30mg)溶于N,N-二甲基甲酰胺(2mL)，加入氟化铯(78mg)，在室温反应3h。反应完全后，使用EA和水稀释反应液，使用EA萃取两遍，饱和食盐水洗，合并有机相，浓缩，浓缩物经柱层析进行纯化得到化合物180-3(40mg)。ESI-MS m/z:637[M+H]+。Compound 180-2 (30 mg) was dissolved in N,N-dimethylformamide (2 mL), cesium fluoride (78 mg) was added, and the reaction was carried out at room temperature for 3 h. After the reaction was completed, the reaction solution was diluted with EA and water, extracted twice with EA, washed with saturated brine, the organic phases were combined, concentrated, and the concentrate was purified by column chromatography to obtain compound 180-3 (40 mg). ESI-MS m/z:637[M+H] + .
步骤3：化合物180的合成Step 3: Synthesis of Compound 180
将化合物180-3(40mg)溶于二氯甲烷(2mL)，加入三氟化硼乙醚(0.03mL)，在室温下反应0.5h。反应完全后，将反应液加入到冷的饱和碳酸钠溶液中，使用DCM萃取两遍，合并有机相，浓缩，浓缩物经Pre-TLC分离纯化得到化合物180(5.4mg收率15.62％)。ESI-MS m/z:637.3[M+H]+。1H NMR(500MHz,DMSO)δ10.15(s,1H),7.98–7.95(m,1H),7.48–7.44(m,1H),7.38(s,2H),7.22(s,1H),4.94(d,J＝10.0Hz,5H),4.05(s,2H),3.89(d,J＝5.0Hz,5H),3.62(d,J＝15.0Hz,2H),3.47(s,2H),3.2(d,J＝15.0Hz,4H),2.62(d,J＝15.0Hz,3H),2.02–1.99(m,1H),1.61(s,4H).Compound 180-3 (40 mg) was dissolved in dichloromethane (2 mL), boron trifluoride ether (0.03 mL) was added, and the reaction was carried out at room temperature for 0.5 h. After the reaction was complete, the reaction solution was added to cold saturated sodium carbonate solution, extracted twice with DCM, the organic phases were combined, concentrated, and the concentrate was separated and purified by Pre-TLC to obtain compound 180 (5.4 mg, yield 15.62%). ESI-MS m/z:637.3[M+H] + . 1 H NMR(500MHz,DMSO)δ10.15(s,1H),7.98–7.95(m,1H),7.48–7.44(m,1H),7.38(s,2H),7.22(s,1H),4.94 (d,J＝10.0Hz,5H),4.05(s,2H),3.89(d,J＝5.0Hz,5H),3.62(d,J＝15.0Hz,2H),3.47(s,2H),3.2 (d,J＝15.0Hz,4H),2.62(d,J＝15.0Hz,3H),2.02–1.99(m,1H),1.61(s,4H).
实施例181：化合物4-(4-((1R，5S)-3,8-二氮杂双环[3.2.1]辛-3-基)-8-氟-5-甲氧基-2-((2-甲基四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-6-氟-5-乙烯基萘-2-醇的合成
Example 181: Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-methoxy-2-( (2-Methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-6-fluoro-5-vinylnaphthalene- Synthesis of 2-alcohols
步骤1：化合物181-1的合成Step 1: Synthesis of Compound 181-1
将化合物5-乙炔基-6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)萘-2-醇(200mg)溶于3mL的甲醇中，然后将Pd/C(20mg)加入，氢气置换5次，室温反应5min，硅藻土过滤，滤液减压浓缩，浓缩物经柱色谱分离纯化得目标化合物181-1(120mg)。Compound 5-ethynyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)naphthalene-2-ol (200 mg) Dissolve in 3 mL of methanol, then add Pd/C (20 mg), replace with hydrogen 5 times, react at room temperature for 5 min, filter through diatomaceous earth, and concentrate the filtrate under reduced pressure. The concentrate is separated and purified by column chromatography to obtain the target compound 181-1 ( 120mg).
步骤2：化合物181-2的合成Step 2: Synthesis of Compound 181-2
将化合物181-1(120mg)、7-2(80mg)、CataCXium A Pd G3(30mg)和K3PO4(100mg)溶于THF(2mL)和H2O(0.5mL)中，氮气保护下，80℃反应3h，降温至室温，用EA和水萃取反应液，保留有机相，无水硫酸钠干燥，过滤，减压浓缩，浓缩物经柱色谱纯化得目标化合物181-2(95mg)。Compounds 181-1 (120 mg), 7-2 (80 mg), CataCXium A Pd G3 (30 mg) and K 3 PO 4 (100 mg) were dissolved in THF (2 mL) and H 2 O (0.5 mL) under nitrogen protection. , reacted at 80°C for 3 hours, cooled to room temperature, extracted the reaction solution with EA and water, retained the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain the target compound 181-2 (95 mg).
步骤3：化合物181-3的合成Step 3: Synthesis of Compound 181-3
将化合物181-2(95mg)溶于DCM(2mL)中，然后将TBSCl(220mg)和咪唑(150mg)依次加入，室温反应0.5h，DCM和水萃取反应液，保留有机相，无水硫酸钠干燥，过滤，减压浓缩，浓缩物经柱色谱纯化得目标化合物181-3(90mg)。Dissolve compound 181-2 (95 mg) in DCM (2 mL), then add TBSCl (220 mg) and imidazole (150 mg) in sequence, react at room temperature for 0.5 h, extract the reaction solution with DCM and water, retain the organic phase, and add anhydrous sodium sulfate Dry, filter, and concentrate under reduced pressure, and the concentrate is purified by column chromatography to obtain target compound 181-3 (90 mg).
步骤4：化合物181-4的合成Step 4: Synthesis of Compound 181-4
将化合物181-3(90mg)溶于DCM(2mL)中，然后将m-CPBA(90mg)加入，室温反应0.5h，加适量饱和亚硫酸钠溶液搅拌20min淬灭，用DCM和水萃取反应液，保留有机相，无水硫酸钠干燥，过滤，减压浓缩，浓缩物经柱色谱纯化得目标化合物181-4(60mg)。Dissolve compound 181-3 (90 mg) in DCM (2 mL), then add m-CPBA (90 mg), react at room temperature for 0.5 h, add an appropriate amount of saturated sodium sulfite solution and stir for 20 min to quench, extract the reaction solution with DCM and water, and retain The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain target compound 181-4 (60 mg).
步骤5：化合物181-5的合成Step 5: Synthesis of Compound 181-5
将化合物M9(40mg)溶于无水THF(1mL)中，然后将NaH(18mg)加入，室温反应20min,然后将化合物181-4(60mg)加入，室温反应30min，。加适量饱和氯化铵溶液淬灭，用EA和水萃取反应液，保留有机相，无水硫酸钠干燥，过滤，减压浓缩，浓缩物经柱色谱纯化得目标化合物181-5(35mg)。Compound M9 (40 mg) was dissolved in anhydrous THF (1 mL), then NaH (18 mg) was added, reacted at room temperature for 20 min, then compound 181-4 (60 mg) was added, and reacted at room temperature for 30 min. Add an appropriate amount of saturated ammonium chloride solution to quench, extract the reaction solution with EA and water, retain the organic phase, dry it over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The concentrate is purified by column chromatography to obtain target compound 181-5 (35 mg).
步骤6：化合物181的合成Step 6: Synthesis of Compound 181
将化合物181-5(35mg)溶于1mL的DCM中，然后将TFA(0.5mL)加入，室温反应20min。减压浓缩，浓缩物经柱色谱纯化得目标化合物181(7.7mg)。Compound 181-5 (35 mg) was dissolved in 1 mL of DCM, then TFA (0.5 mL) was added, and the reaction was carried out at room temperature for 20 min. The mixture was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain target compound 181 (7.7 mg).
实施例214化合物4-(4-((1R，5S)-3,8-二氮杂二环[3.2.1]辛-3-基)-8-氟-5-甲氧基-2-(((S)-2-甲基四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟萘-2-醇的合成
Example 214 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-5-methoxy-2-( ((S)-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6 -Synthesis of fluoronaphthalen-2-ol
步骤1：化合物214-1的合成Step 1: Synthesis of Compound 214-1
将M13(4.84g，1.86mmol)溶于无水四氢呋喃中(85ml)，加入NaH(2.52g，3.71mmol)，将温度降至5℃，将化合物7-5(17g 1.24mmol)溶于无水四氢呋喃(170ml)，缓慢将化合物7-5滴加到反应液中，控制温度5-10℃，滴毕，继续保温5-10℃搅拌反应，直至原料反应完全。反应完全后使用饱和氯化铵淬灭反应，加入EA(200ml)和水(200ml)稀释反应液，搅拌分液，得到有机相，继续使用EA(100ml)萃取一遍，合并有机相，使用饱和食盐水(200ml)洗一遍，无水硫酸钠干燥、过滤、旋干、浓缩，得到得到化合物214-1(19.75g)。Dissolve M13 (4.84g, 1.86mmol) in anhydrous tetrahydrofuran (85ml), add NaH (2.52g, 3.71mmol), lower the temperature to 5°C, and dissolve compound 7-5 (17g 1.24mmol) in anhydrous Tetrahydrofuran (170 ml), slowly add compound 7-5 dropwise into the reaction solution, control the temperature to 5-10°C, complete the dropping, continue to keep the temperature at 5-10°C and stir the reaction until the raw material reaction is complete. After the reaction is complete, use saturated ammonium chloride to quench the reaction, add EA (200ml) and water (200ml) to dilute the reaction solution, stir and separate the liquids to obtain an organic phase, continue to use EA (100ml) to extract once, combine the organic phases, and use saturated salt Wash once with water (200 ml), dry over anhydrous sodium sulfate, filter, spin dry, and concentrate to obtain compound 214-1 (19.75 g).
ESI-MS m/z:881.65[M+H]+。ESI-MS m/z:881.65[M+H] + .
步骤2：化合物214-2的合成Step 2: Synthesis of Compound 214-2
将化合物214-1(19.75g 22.41mmol)溶于DMF，加入CsF(34.05g 224.14mmol)，在35℃油浴锅中反应4h。反应完全后，使用冰浴降温，将温度降至10℃，缓慢滴加水(800ml)，产生大量固体，过滤得到滤饼。使用EA(200ml)将其溶解，使用饱和食盐水(100ml)洗一遍，分液得到有机相，通过柱层析进行纯化(DCM:MeOH＝20：1)，得到化合物214-2(14.82g)。Dissolve compound 214-1 (19.75g 22.41mmol) in DMF, add CsF (34.05g 224.14mmol), and react in a 35°C oil bath for 4 hours. After the reaction is complete, use an ice bath to cool down the temperature to 10°C. Water (800 ml) is slowly added dropwise to produce a large amount of solid, which is filtered to obtain a filter cake. Dissolve it in EA (200 ml), wash it once with saturated brine (100 ml), separate the liquids to obtain the organic phase, and purify it by column chromatography (DCM:MeOH=20:1) to obtain compound 214-2 (14.82g) .
ESI-MS m/z:725.51[M+H]+。ESI-MS m/z:725.51[M+H] + .
步骤3：化合物214的合成Step 3: Synthesis of Compound 214
将化合物214-2(14.82g 20.45mmol)溶于DCM(140ml)，加入三氟化硼乙醚(56ml)，在35℃油浴锅反应0.5h。反应完全后，直接过滤得到滤饼。使用DCM:MeOH＝10:1的混合液将其溶解，使用饱和碳酸钠游离化合物，使用DCM:MeOH＝10:1的混合液萃取三遍，饱和食盐水洗一遍，无水硫酸钠干燥过滤旋干，得到粗品使用甲醇溶解，在50℃解离化合物 与三氟化硼的络合物，解离完拌硅胶通过柱层析(DCM:MeOH＝10:1)进行纯化，得到化合物214(10.61g)。Compound 214-2 (14.82g 20.45mmol) was dissolved in DCM (140ml), boron trifluoride ether (56ml) was added, and the reaction was carried out in an oil bath at 35°C for 0.5h. After the reaction is complete, filter directly to obtain a filter cake. Use a mixture of DCM:MeOH=10:1 to dissolve it, use saturated sodium carbonate to free the compound, use a mixture of DCM:MeOH=10:1 to extract three times, wash once with saturated brine, dry with anhydrous sodium sulfate, filter and spin dry , the crude product was obtained and dissolved in methanol, and the compound was dissociated at 50°C. The complex with boron trifluoride was dissociated and purified through column chromatography (DCM:MeOH=10:1) on silica gel to obtain compound 214 (10.61g).
ESI-MS m/z:625.47[M+H]+ ESI-MS m/z:625.47[M+H] +
1H NMR(500MHz,DMSO)δ10.16(s,1H),7.97(dd,J＝9.2,5.9Hz,1H),7.47(t,J＝9.0Hz,1H),7.38(d,J＝2.5Hz,1H),7.22(d,J＝2.4Hz,1H),4.90(s,2H),4.08(s,1H),4.02(dd,J＝10.4,4.0Hz,1H),3.98–3.93(m,1H),3.90(s,1H),3.88(s,3H),3.54(d,J＝14.1Hz,1H),3.47(s,2H),3.38(d,J＝12.5Hz,1H),3.32(s,1H),3.18(d,J＝13.9Hz,1H),3.03–2.95(m,1H),2.61–2.52(m,2H),2.35(d,J＝16.2Hz,1H),2.03–1.73(m,4H),1.71-1.64(m,1H),1.63–1.44(m,4H),1.23(s,1H). 1 H NMR (500MHz, DMSO) δ10.16 (s, 1H), 7.97 (dd, J = 9.2, 5.9Hz, 1H), 7.47 (t, J = 9.0Hz, 1H), 7.38 (d, J = 2.5 Hz,1H),7.22(d,J＝2.4Hz,1H),4.90(s,2H),4.08(s,1H),4.02(dd,J＝10.4,4.0Hz,1H),3.98–3.93(m ,1H),3.90(s,1H),3.88(s,3H),3.54(d,J＝14.1Hz,1H),3.47(s,2H),3.38(d,J＝12.5Hz,1H),3.32 (s,1H),3.18(d,J＝13.9Hz,1H),3.03–2.95(m,1H),2.61–2.52(m,2H),2.35(d,J＝16.2Hz,1H),2.03– 1.73(m,4H),1.71-1.64(m,1H),1.63–1.44(m,4H),1.23(s,1H).
下述的实施例采用上述方法合成，或使用相应中间体的类似方法合成。








The following examples were synthesized using the above method, or similar methods using corresponding intermediates.








对比实施例D1：
Comparative Example D1:
D1D1
对比化合物MART1133(D1)的制备方法，参考WO2021041671A1中的实施例252制备得到。For the preparation method of comparative compound MART1133 (D1), refer to Example 252 in WO2021041671A1.
生物学测试biology test
药理实验1:细胞增殖实验(AGS)Pharmacological Experiment 1: Cell Proliferation Test (AGS)
将KRAS G12D突变型肿瘤细胞AGS(CRL-1739TM)按1×103/孔的细胞密度铺于低吸附96孔板中，置于细胞培养箱隔夜培养。待细胞贴壁后，将待测化合物按照终浓 度10000、2000、400、80、16、3.2、0.64、0.128、0.025、0nM(DMSO终浓度均为0.5％)加入96孔板中，37℃培养96h后向各孔加入50μL Cell-titer GLO工作液，震荡混匀后室温孵育10min，在多功能酶标仪读取Luminescence发光值，将发光值数据计算转换为抑制百分数。并根据以下公式，计算细胞增殖抑制百分数：KRAS G12D mutant tumor cells AGS ( CRL-1739 TM ) was plated in a low-adsorption 96-well plate at a cell density of 1×10 3 /well, and placed in a cell culture incubator for overnight culture. After the cells adhere to the wall, add the compound to be tested according to the final concentration Add 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.025, 0nM (the final concentration of DMSO is 0.5%) into the 96-well plate, incubate at 37°C for 96 hours, and then add 50 μL Cell-titer GLO to each well. solution, shake and mix well, incubate at room temperature for 10 minutes, read the Luminescence value on a multifunctional microplate reader, and calculate and convert the luminescence value data into an inhibition percentage. And calculate the percentage of cell proliferation inhibition according to the following formula:
抑制百分数＝(最大值-所测值)/(最大值-Blank)×100Inhibition percentage = (maximum value - measured value) / (maximum value - Blank) × 100
(“最大值”来自0.5％DMSO对照孔，“Blank”来自空白对照孔，“所测值”来自化合物处理孔)。("Maximum value" is from the 0.5% DMSO control well, "Blank" is from the blank control well, and "measured value" is from the compound-treated well).
利用GraphPad Prism软件进行曲线拟合并获取IC50值。Use GraphPad Prism software to perform curve fitting and obtain IC 50 values.
表1
Table 1
药理实验2：细胞p-ERK检测试验Pharmacological experiment 2: Cellular p-ERK detection test
将KRAS G12D突变型肿瘤细胞AGS(CRL-1739TM)按4×104/孔的细胞密度 铺于96孔板中，置于细胞培养箱隔夜培养。待细胞贴壁后，将待测化合物按照终浓度3000nM、600nM、120nM、24nM、4.8nM、0.96nM、0.19nM、0.5％DMSO加入96孔板中，培养3h后，利用pERK HTRF Kit(Cisbio)中的裂解液裂解96孔板中各处理细胞样品(40ul/孔)，充分裂解完成后分别向HTRF检测96孔板中加入16ul/孔的蛋白液以及4ul预混好的pERK-d2抗体和pERK-Eu Cryptate抗体。4℃过夜孵育后在多功能酶标仪读取665nM/620nM的ratio信号值，采集原始数据。并根据以下公式，计算p-ERK抑制百分数：KRAS G12D mutant tumor cells AGS ( CRL-1739 TM ) at a cell density of 4×10 4 /well Spread in a 96-well plate and culture in a cell culture incubator overnight. After the cells are adhered, the compound to be tested is added to the 96-well plate at the final concentration of 3000nM, 600nM, 120nM, 24nM, 4.8nM, 0.96nM, 0.19nM, and 0.5% DMSO. After culturing for 3 hours, use pERK HTRF Kit (Cisbio) Lyse each treated cell sample (40ul/well) in the 96-well plate with the lysis buffer in the 96-well plate. After full lysis, add 16ul/well protein solution and 4ul premixed pERK-d2 antibody and pERK to the HTRF detection 96-well plate. -Eu Cryptate antibody. After overnight incubation at 4°C, read the ratio signal value of 665nM/620nM on a multifunctional microplate reader and collect raw data. And calculate the p-ERK inhibition percentage according to the following formula:
抑制百分数＝(最大值-所测值)/(最大值-Blank)×100Inhibition percentage = (maximum value - measured value) / (maximum value - Blank) × 100
(“最大值”来自0.5％DMSO对照孔，“Blank”来自空白对照孔，“所测值”来自化合物处理孔)。("Maximum value" is from the 0.5% DMSO control well, "Blank" is from the blank control well, and "measured value" is from the compound-treated well).
利用GraphPad Prism软件进行曲线拟合并获取IC50值。Use GraphPad Prism software to perform curve fitting and obtain IC 50 values.
表2
Table 2
药理实验3:不同细胞增殖实验Pharmacological Experiment 3: Different Cell Proliferation Experiments
将KRAS G12D突变型肿瘤细胞HPAC，A427，Aspc-1，LS180，Panc04.03按1×103/孔的细胞密度铺于低吸附96孔板中，置于细胞培养箱隔夜培养。待细胞贴壁后，将待测化合物按照终浓度10000、2000、400、80、16、3.2、0.64、0.128、0.025、0nM(DMSO终浓度均为0.5％)加入96孔板中，37℃培养96h后向各孔加入50μL Cell-titer GLO工作液，震荡混匀后室温孵育10min，在多功能酶标仪读取Luminescence发光值，将发光值数据计算转换为抑制百分数。并根据以下公式，计算细胞增殖抑制百分数：KRAS G12D mutant tumor cells HPAC, A427, Aspc-1, LS180, and Panc04.03 were spread in a low-adsorption 96-well plate at a cell density of 1×10 3 /well and placed in a cell culture incubator for overnight culture. After the cells are adhered, the compound to be tested is added to the 96-well plate according to the final concentration of 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.025, 0nM (the final DMSO concentration is 0.5%), and cultured at 37°C. After 96 hours, add 50 μL of Cell-titer GLO working solution to each well, shake and mix, and incubate at room temperature for 10 minutes. Read the Luminescence value on a multifunctional microplate reader, and calculate and convert the luminescence value data into an inhibition percentage. And calculate the percentage of cell proliferation inhibition according to the following formula:
抑制百分数＝(最大值-所测值)/(最大值-Blank)×100Inhibition percentage = (maximum value - measured value) / (maximum value - Blank) × 100
(“最大值”来自0.5％DMSO对照孔，“Blank”来自空白对照孔，“所测值”来自化合物处理孔)。 ("Maximum value" is from the 0.5% DMSO control well, "Blank" is from the blank control well, and "measured value" is from the compound-treated well).
利用GraphPad Prism软件进行曲线拟合并获取IC50值，结果见表3。Use GraphPad Prism software to perform curve fitting and obtain IC 50 values. The results are shown in Table 3.
表3
table 3
结果表明：化合物214在所测试的另外5种不同癌种的KRAS G12D突变细胞中都具有显著更高的抑制细胞增殖的活性。The results showed that compound 214 had significantly higher activity in inhibiting cell proliferation in KRAS G12D mutant cells of the other five different cancer types tested.
药理实验4：不同细胞p-ERK检测试验Pharmacological experiment 4: p-ERK detection test in different cells
将KRAS G12D突变型肿瘤细胞HPAC，A427，Aspc-1，LS180，Panc04.03按4×104/孔的细胞密度铺于96孔板中，置于细胞培养箱隔夜培养。待细胞贴壁后，将待测化合物按照终浓度3000nM、600nM、120nM、24nM、4.8nM、0.96nM、0.19nM、0.5％DMSO加入96孔板中，培养3h后，利用pERK HTRF Kit(Cisbio)中的裂解液裂解96孔板中各处理细胞样品(40ul/孔)，充分裂解完成后分别向HTRF检测96孔板中加入16ul/孔的蛋白液以及4ul预混好的pERK-d2抗体和pERK-Eu Cryptate抗体。4℃过夜孵育后在多功能酶标仪读取665nM/620nM的ratio信号值，采集原始数据。并根据以下公式，计算p-ERK抑制百分数：KRAS G12D mutant tumor cells HPAC, A427, Aspc-1, LS180, and Panc04.03 were spread in a 96-well plate at a cell density of 4×10 4 /well and placed in a cell culture incubator for overnight culture. After the cells are adhered, the compound to be tested is added to the 96-well plate at the final concentration of 3000nM, 600nM, 120nM, 24nM, 4.8nM, 0.96nM, 0.19nM, and 0.5% DMSO. After culturing for 3 hours, use pERK HTRF Kit (Cisbio) Lyse each treated cell sample (40ul/well) in the 96-well plate with the lysis buffer in the 96-well plate. After full lysis, add 16ul/well protein solution and 4ul premixed pERK-d2 antibody and pERK to the HTRF detection 96-well plate. -Eu Cryptate antibody. After overnight incubation at 4°C, read the ratio signal value of 665nM/620nM on a multifunctional microplate reader and collect raw data. And calculate the p-ERK inhibition percentage according to the following formula:
抑制百分数＝(最大值-所测值)/(最大值-Blank)×100Inhibition percentage = (maximum value - measured value) / (maximum value - Blank) × 100
(“最大值”来自0.5％DMSO对照孔，“Blank”来自空白对照孔，“所测值”来自化合物处理孔)。("Maximum value" is from the 0.5% DMSO control well, "Blank" is from the blank control well, and "measured value" is from the compound-treated well).
利用GraphPad Prism软件进行曲线拟合并获取IC50值，结果见表4。 Use GraphPad Prism software to perform curve fitting and obtain IC 50 values. The results are shown in Table 4.
表4
Table 4
结果表明：化合物214在所测试的另外5种不同癌种的KRAS G12D突变细胞中都具有显著更高抑制下游pERK水平的活性。The results showed that compound 214 had significantly higher activity in inhibiting downstream pERK levels in KRAS G12D mutant cells of the other five different cancer types tested.
药理实验5：化合物在小鼠中的PK考察Pharmacological experiment 5: PK investigation of compounds in mice
静脉给药考察：将化合物与溶媒10％DMSO/5％Solutol/85％生理盐水混合，涡旋并超声，制备得到0.2mg/ml澄清静脉注射溶液。选取6至7周龄的Balbc雌性小鼠，静脉给予化合物7，110,141和D1，收集5min、15min、30min、1h、2h、4h、7h、24h全血样品。以LC-MS/MS方法分析药物浓度，并用Phoenix WinNolin软件(美国Pharsight公司)计算药代参数，给药剂量和实验方案如下表5所示，结果如表6所示。Intravenous administration investigation: Mix the compound with the solvent 10% DMSO/5% Solutol/85% physiological saline, vortex and sonicate to prepare a 0.2 mg/ml clear intravenous injection solution. Balbc female mice aged 6 to 7 weeks were selected and intravenously administered compounds 7, 110, 141 and D1, and whole blood samples were collected at 5min, 15min, 30min, 1h, 2h, 4h, 7h and 24h. The drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNolin software (Pharsight Company, USA). The dosage and experimental protocol are shown in Table 5 below, and the results are shown in Table 6.
表5

table 5

所测小鼠PK数据如下表6：The tested mouse PK data are as follows in Table 6:
表6
Table 6
结果表明，静脉给药中，化合物7，110，141相比对比化合物D1在小鼠中具有更高的全血暴露量和更低的清除率。The results showed that during intravenous administration, compounds 7, 110, and 141 had higher whole blood exposure and lower clearance in mice than the comparative compound D1.
口服给药考察：将化合物110、109与溶媒10％DMSO/5％Solutol/85％生理盐水混合，涡旋并超声，制备得到1mg/ml澄清溶液；D1与溶媒10％DMSO/10％Solutol/80％生理盐水混合，涡旋并超声，制备得到2mg/ml澄清溶液。选取6至7周龄的Balbc雌性小鼠，不禁食，口服给予化合物，收集一定时间的全血，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNolin软件(美国Pharsight公司)计算药代参数，结果如表7所示。Oral administration investigation: Mix compounds 110 and 109 with the solvent 10% DMSO/5% Solutol/85% normal saline, vortex and sonicate to prepare a 1 mg/ml clear solution; D1 and the solvent 10% DMSO/10% Solutol/ Mix 80% normal saline, vortex and sonicate to prepare a clear 2 mg/ml solution. Balbc female mice aged 6 to 7 weeks were selected, and the compound was administered orally without fasting. Whole blood was collected for a certain period of time, and the drug concentration was analyzed by LC-MS/MS method, and Phoenix WinNolin software (Pharsight Company, USA) was used to calculate the pharmacokinetics. parameters, and the results are shown in Table 7.
表7
Table 7
结果表明，在小鼠中，化合物110的口服暴露量(AUC)以及口服生物利用度(F％)都高于化合物D1；化合物109的口服暴露量(AUC)和口服生物利用度(F％)都高于化 合物D1。The results show that in mice, the oral exposure (AUC) and oral bioavailability (F%) of compound 110 are higher than those of compound D1; the oral exposure (AUC) and oral bioavailability (F%) of compound 109 are higher than Compound D1.
药理实验6：化合物在大鼠中的PK考察Pharmacological experiment 6: PK investigation of compounds in rats
将化合物7，110，141，214和与溶媒10％DMSO/5％Solutol/85％生理盐水混合，对比化合物D1与溶媒10％DMSO/5％Solutol/85％葡萄糖混合，涡旋并超声，制备得到0.5mg/ml澄清溶液。选取6-7周龄的SD雄性大鼠，禁食过夜，静脉注射给予化合物7，110，141，214和对比化合物D1，收集5min、15min、30min、1h、2h、4h、7h、24h全血样品，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNolin软件(美国Pharsight公司)计算药代参数，给药剂量和实验方案如下表8所示，结果如表9所示。Compounds 7, 110, 141, 214 were mixed with the solvent 10% DMSO/5% Solutol/85% normal saline, and the comparative compound D1 was mixed with the solvent 10% DMSO/5% Solutol/85% glucose, vortexed and sonicated to prepare A clear solution of 0.5 mg/ml was obtained. SD male rats aged 6-7 weeks were selected, fasted overnight, and compounds 7, 110, 141, 214 and comparative compound D1 were intravenously administered, and whole blood was collected at 5min, 15min, 30min, 1h, 2h, 4h, 7h, and 24h. For the sample, the drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNolin software (Pharsight Company, USA). The dosage and experimental protocol are shown in Table 8 below, and the results are shown in Table 9.
表8
Table 8
所测大鼠PK数据如表9下： The measured rat PK data are shown in Table 9:
表9
Table 9
结果表明，化合物7相比对比化合物D1在大鼠中具有更高的全血暴露量和更低的清除率。化合物110，141比对比化合物D1在大鼠中具有更高的表观分布容积，化合物110，141比对比化合物D1在大鼠中具有更长的半衰期。化合物214相比对比化合物D1在大鼠中具有更高的全血暴露量，更低的清除率，更长的半衰期。The results showed that compound 7 had higher whole blood exposure and lower clearance in rats than the comparative compound D1. Compounds 110, 141 have a higher apparent volume of distribution in rats than comparative compound D1, and compounds 110, 141 have a longer half-life in rats than comparative compound D1. Compound 214 had higher whole blood exposure, lower clearance, and longer half-life in rats than comparative compound D1.
药理实验7：化合物在比格犬中的PK考察Pharmacological experiment 7: PK investigation of compounds in beagle dogs
静脉给药考察：将化合物7，110，141与溶媒10％DMSO/5％Solutol/85％生理盐水混合，对比化合物D1与溶媒10％DMSO/5％Solutol/85％葡萄糖混合涡旋并超声，制备得到0.5mg/ml澄清静脉注射溶液。选取雌性比格犬，收集5min、15min、30min、1h、2h、4h、6h、8h、10h、12h、24h、48h全血样品。以LC-MS/MS方法分析药物浓度，并用Phoenix WinNolin软件(美国Pharsight公司)计算药代参数，给药剂量和实验方案如下表10所示，结果如表11所示。Investigation of intravenous administration: Compounds 7, 110, and 141 were mixed with the solvent 10% DMSO/5% Solutol/85% normal saline. Comparative compound D1 was mixed with the solvent 10% DMSO/5% Solutol/85% glucose, vortexed and ultrasonicated. Prepare a clear 0.5 mg/ml intravenous solution. Select female beagle dogs and collect whole blood samples at 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 24h, and 48h. The drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNolin software (Pharsight Company, USA). The dosage and experimental protocol are shown in Table 10 below, and the results are shown in Table 11.
表10

Table 10

所测比格犬PK数据如表11下：The tested beagle PK data are shown in Table 11:
表11
Table 11
结果表明，化合物7，110，141比对比化合物D1在比格犬中具有更高的表观分布容积且化合物7，化合物141具有更长的半衰期。The results showed that compounds 7, 110, and 141 had higher apparent distribution volumes in beagle dogs than the comparative compound D1 and that compounds 7 and 141 had longer half-lives.
药理实验8：化合物在NCI-H1975荷瘤小鼠肿瘤组织中的PK考察Pharmacological experiment 8: PK investigation of compounds in tumor tissues of NCI-H1975 tumor-bearing mice
构建人肺腺癌细胞NCI-H1975的皮下异种移植肿瘤Balbc nude裸小鼠模型，肿瘤体积达到200mm3后，挑选21只肿瘤荷瘤小鼠，进行化合物7和D1 1mpk IV Cassette给药，溶媒为10％DMSO/5％Solutol/85％生理盐水。给药后0.5h,4h,7h,24h,48h,72h,96h采集小鼠全血样品和肿瘤组织样品。以LC-MS/MS方法分析药物浓度，并用Phoenix WinNolin软件(美国Pharsight公司)计算药代参数，结果如表12所示。A Balbc nude nude mouse model of subcutaneous xenograft tumor of human lung adenocarcinoma cell NCI-H1975 was constructed. After the tumor volume reached 200 mm, 21 tumor-bearing mice were selected and administered Compound 7 and D1 1mpk IV Cassette. The solvent was 10% DMSO/5% Solutol/85% saline. Mouse whole blood samples and tumor tissue samples were collected at 0.5h, 4h, 7h, 24h, 48h, 72h, and 96h after administration. The drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNolin software (Pharsight Company, USA). The results are shown in Table 12.
表12

Table 12

给药后0.5h,4h,7h,24h,48h,72h,96h，采集肿瘤组织，并检测肿瘤组织中化合物7和D1的浓度，检测结果如下图3。Tumor tissue was collected at 0.5h, 4h, 7h, 24h, 48h, 72h, and 96h after administration, and the concentrations of compound 7 and D1 in the tumor tissue were detected. The detection results are as shown in Figure 3.
结果表明：在小鼠荷瘤模型的肿瘤组织中，化合物7相比对比化合物D1具有显著更高的肿瘤组织暴露量，显著更长的肿瘤组织t1/2，更高的Tumor/Blood Ratio。The results showed that in the tumor tissue of the mouse tumor-bearing model, Compound 7 had significantly higher tumor tissue exposure, significantly longer tumor tissue t 1/2 and higher Tumor/Blood Ratio than the comparative compound D1.
虽然本发明已通过其实施方式进行了全面的描述，但是值得注意的是，各种变化和修改对于本领域技术人员都是显而易见的。这样的变化和修改都应该包括在本发明所附权利要求的范围内。 While the invention has been fully described in terms of embodiments thereof, it is to be noted that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications should be included within the scope of the appended claims of the present invention.

Claims (38)

  1. 一种通式(I)所示的化合物，或其立体异构体、互变异构体、氘代物或药用盐：
    A compound represented by general formula (I), or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt:
    其中，in,
    X选自键、NRa、O或S；X is selected from bond, NR a , O or S;
    选自单键或双键； Selected from single or double bonds;
    L选自键、-C1-3亚烷基-、-C3-14环烷基-C0-3亚烷基-或-3-14元杂环基-C0-3亚烷基-；所述-C1-3亚烷基-、-C3-14环烷基-C0-3亚烷基-或-3-14元杂环基-C0-3亚烷基-任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基或羟基所取代；L is selected from bond, -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene- ;The -C 1-3 alkylene-, -C 3-14 cycloalkyl-C 0-3 alkylene- or -3-14 membered heterocyclyl-C 0-3 alkylene-optional Further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
    所述环A选自C5-14环烷基、5-14元杂环基、C6-18芳基或5-18元杂芳基；所述C5-14环烷基、5-14元杂环基、C6-18芳基或5-18元杂芳基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基、羟基、所取代；The ring A is selected from C 5-14 cycloalkyl, 5-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 5-14 cycloalkyl, 5-14 The one-membered heterocyclyl group, C 6-18 aryl group or 5-18 membered heteroaryl group is optionally further substituted by one or more halogen, C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, cyano group, Amino, nitro, hydroxyl, replaced;
    选自其中，中的两个R6可与其所连接的原子一起形成C3-8的环烷基或3-8元杂环基，所述C3-8环烷基、3-8元杂环基任选地进一步被一个或多个Ra所取代； Selected from in, The two R 6 in can together form a C 3-8 cycloalkyl group or a 3-8 membered heterocyclyl group with the atoms to which they are connected. The C 3-8 cycloalkyl group and 3-8 membered heterocyclyl group are optional ground is further replaced by one or more R a ;
    R2选自C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基；所述C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选地进一步被一个或多个Ra取代；R 2 is selected from C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 3-14 cycloalkyl, 3-14 membered heterocyclyl The ring group, C 6-18 aryl group or 5-18 membered heteroaryl group is optionally further substituted by one or more R a ;
    R3独立地选自C1-6烷氧基、C3-14环烷基-O-或C1-6卤代烷氧基；所述C1-6烷氧基、C3- 14环烷基-O-或C1-6卤代烷氧基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、C1- 6卤代烷基、氰基、氨基、硝基或羟基所取代；R 3 is independently selected from C 1-6 alkoxy, C 3-14 cycloalkyl-O- or C 1-6 haloalkoxy; the C 1-6 alkoxy, C 3-14 cycloalkyl -O- or C 1-6 haloalkoxy is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, cyano, amino, nitro or substituted by hydroxyl;
    R4独立地选自H、卤素、氰基、氨基、-NHRa、-N(Ra)2、硝基、C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、C1-6卤代烷基、C1-6卤代烷氧基或羟基；所述C1-6烷基、C1-6烷氧基、C3- 14环烷基-O-、C1-6卤代烷基或C1-6卤代烷氧基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、氰基、氨基、硝基或羟基所取代；R 4 is independently selected from H, halogen, cyano, amino, -NHR a , -N(R a ) 2 , nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 ring Alkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy or hydroxyl; the C 1-6 alkyl, C 1-6 alkoxy, C 3- 14 cycloalkyl-O-, C 1-6 haloalkyl or C 1-6 haloalkoxy is optionally further substituted by one or more halogens, C 1-6 alkyl, C 1-6 alkoxy, C 1- 6 substituted by haloalkyl, cyano, amino, nitro or hydroxyl;
    R5选自H、卤素、-C0-3亚烷基氰基、C1-6烷基、C1-6烷氧基或C1-6卤代烷基；R 5 is selected from H, halogen, -C 0-3 alkylenecyano, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 haloalkyl;
    R6选自H、卤素、羟基、氰基、C1-6烷基、C1-6卤代烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基；所述C1-6烷基、C1-6卤代烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选进一步被一个或多个卤素、羟基、氰基、氨基、硝基、C1-6烷基或C1-6烷氧基所取代；R 6 is selected from H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 The heteroaryl group is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy;
    Ra各自独立地选自H、羟基、氰基、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、-C0- 3亚烷基-ORb、-OC(＝O)C1-6烷基、-C0-3亚烷基-SRb、-C0-3亚烷基-N(Rb)2、-C0-3亚烷基-S(＝O)Rb、-C0-3亚烷基-S(＝O)2Rb、-C0-3亚烷基-SRb、-C0-3亚烷基-S(Rb)5、-C0-3亚烷基-C(＝O)Rb、-C0-3亚烷基-C(＝O)ORb、-C0-3亚烷基-C(＝O)N(Rb)2、C2-6烯基、C2-6炔基、-C0-3亚烷基-C3-14环烷基、-C0-3亚烷基-(3-14元杂环基)、-C0-3亚烷基-C6-18芳基或-C0-3亚烷基-(5-18元杂芳基)；所述C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-C0-3亚烷基-C3-14环烷基、-C0-3亚烷基-(3-14元杂环基)、-C0-3亚烷基-C6-18芳基或-C0-3亚烷基-(5-18元杂芳基)任选地进一步被一个或多个Rb取代； R a is each independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -C 0-3 alkylene -OR b , -OC(=O)C 1-6 alkyl, -C 0-3 alkylene -SR b , -C 0-3 alkylene -N(R b ) 2 , -C 0-3 alkylene- S(=O)R b , -C 0-3 alkylene -S(=O) 2 R b , -C 0-3 alkylene -SR b , -C 0-3 alkylene -S(R b ) 5 , -C 0-3 alkylene-C(=O)R b , -C 0-3 alkylene-C(=O)OR b , -C 0-3 alkylene-C(= O)N(R b ) 2 , C 2-6 alkenyl, C 2-6 alkynyl, -C 0-3 alkylene -C 3-14 cycloalkyl, -C 0-3 alkylene -( 3-14 membered heterocyclyl), -C 0-3 alkylene-C 6-18 aryl or -C 0-3 alkylene-(5-18 membered heteroaryl); the C 1-6 Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-3 alkylene -C 3-14 cycloalkyl, - C 0-3 alkylene-(3-14 membered heterocyclyl), -C 0-3 alkylene-C 6-18 aryl or -C 0-3 alkylene-(5-18 membered heteroaryl radical) optionally further substituted by one or more R b ;
    每个Rb独立地为H、卤素、羟基、氰基、C1-6烷基、C3-6环烷基、C1-6卤代烷基、-C(＝O)C1-6烷基或-C(＝O)OC1-6烷基；Each R b is independently H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, -C(=O)C 1-6 alkyl Or -C(=O)OC 1-6 alkyl;
    m选自0、1、2、3或4。m is selected from 0, 1, 2, 3 or 4.
  2. 如权利要求1所述一种通式(I)所示的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述每个Rb独立地为H、卤素、羟基、氰基、C1-6烷基、C3-6环烷基或C1-6卤代烷基。A compound represented by general formula (I) as claimed in claim 1, or a stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt thereof, characterized in that each R b is independently is H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl or C 1-6 haloalkyl.
  3. 如权利要求1所述一种通式(I)所示的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于：A compound represented by general formula (I) as claimed in claim 1, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that:
    所述X选自键、NH、O或S；The X is selected from bond, NH, O or S;
    所述环A选自C5-14环烷基、5-14元杂环基、C6-18芳基或5-18元杂芳基，所述C5-14环烷基或5-14元杂环基选自单环、稠环、螺环或桥环，所述C5-14环烷基、5-14元杂环基、C6-18芳基或5-18元杂芳基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基或羟基所取代； The ring A is selected from C 5-14 cycloalkyl, 5-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, and the C 5-14 cycloalkyl or 5-14 The membered heterocyclyl group is selected from a single ring, a condensed ring, a spiro ring or a bridged ring, and the C 5-14 cycloalkyl group, 5-14 membered heterocyclyl group, C 6-18 aryl group or 5-18 membered heteroaryl group Optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
    选自其中，为双键，选自Z构型或E构型； Selected from in, is a double bond, Selected from Z configuration or E configuration;
    R3独立选自C1-6烷氧基、C3-14环烷基-O-或C1-6卤代烷氧基，所述C1-6烷氧基或C3-14环烷基-O-进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基或羟基所取代；R 3 is independently selected from C 1-6 alkoxy, C 3-14 cycloalkyl-O- or C 1-6 haloalkoxy, said C 1-6 alkoxy or C 3-14 cycloalkyl- O- is further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
    R4选自H、卤素、氰基、氨基、硝基、C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、C1-6卤代烷基、C1-6卤代烷氧基、羟基或羟基烷基，所述C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、卤代烷基或羟基烷基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、卤代烷基、氰基、氨基、硝基或羟基所取代；R 4 is selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxyl or hydroxyalkyl, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, haloalkyl or hydroxyalkyl optionally further Substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl;
    每个Rb独立地为H、卤素、羟基、氰基、C1-6烷基、C3-6环烷基或C1-6卤代烷基。Each R b is independently H, halogen, hydroxyl, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, or C 1-6 haloalkyl.
  4. 根据权利要求1-3所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述X为O。The compound according to claims 1-3, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said X is O.
  5. 根据权利要求1-4所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述L选自-C1-3亚烷基-或-C3-14环烷基-C0-3亚烷基-。The compound according to claims 1-4, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said L is selected from -C 1-3 alkylene- or -C 3-14 cycloalkyl-C 0-3 alkylene-.
  6. 根据权利要求1-5中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述环A选自C5-14环烷基或5-14元杂环基。The compound according to any one of claims 1-5, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that the ring A is selected from the group consisting of C 5-14 rings Alkyl or 5-14 membered heterocyclyl.
  7. 根据权利要求6所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述5-14元杂环基为稠环。The compound according to claim 6, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that the 5-14 membered heterocyclic group is a fused ring.
  8. 根据权利要求7所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述稠环选自 The compound according to claim 7, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that the fused ring is selected from
  9. 根据权利要求1-8中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述选自 The compound according to any one of claims 1 to 8, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that, Selected from
  10. 根据权利要求9中所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R6独立选自H、卤素、C1-6烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基；所述C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选地进一步被一个或多个卤素、羟基、氰基、氨基、硝基或C1-6烷基所取代。The compound according to claim 9, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said R 6 is independently selected from H, halogen, C 1-6 alkane base, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl; the C 3-14 cycloalkyl, 3-14 membered heterocyclyl , C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro or C 1-6 alkyl.
  11. 根据权利要求1-10中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述选自所述可任选地进一步被一个或多个卤素、C1-6烷基或所取代。The compound according to any one of claims 1-10, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that, Selected from described may optionally be further substituted by one or more halogens, C 1-6 alkyl or replaced.
  12. 根据权利要求11所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述选自所述任选地进一步被一个或多个所取代。The compound according to claim 11, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that, Selected from described optionally further by one or more replaced.
  13. 根据权利要求12所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述选自 其中，表示Z构型或E构型。The compound according to claim 12, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that, Selected from in, Indicates Z configuration or E configuration.
  14. 根据权利要求13所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述选自 The compound according to claim 13, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that, Selected from
  15. 根据权利要求1-14中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R2选自C6-18芳基或5-18元杂芳基；所述C6-18芳基或5-18元杂芳基任选地进一步被一个或多个Ra取代，Ra独立地选自H、羟基、氰基、氨基、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基或-C0-3亚烷基-C3-14环烷基。 The compound according to any one of claims 1-14, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 2 is selected from C 6-18 aryl or 5-18 membered heteroaryl; the C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R a , R a is independently selected from H, hydroxyl, cyano, Amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene-C 3-14 cycloalkyl.
  16. 根据权利要求1-15中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R2选自 其中，所述 任选地进一步被一个或多个Ra取代，所述Ra独立地选自H、羟基、氰基、氨基、卤素、C1-6烷基、C1- 6烷氧基、C2-6烯基、C2-6炔基或-C0-3亚烷基-C3-14环烷基。The compound according to any one of claims 1-15, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said R 2 is selected from Among them, the Optionally further substituted by one or more Ra independently selected from H, hydroxyl, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl.
  17. 根据权利要求1-16中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R2选自 The compound according to any one of claims 1-16, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that, R 2 is selected from
  18. 根据权利要求1-17中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R3选自C1-6烷氧基或C3-14环烷基-O-。The compound according to any one of claims 1-17, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 3 is selected from C 1-6 alkoxy Or C 3-14 cycloalkyl-O-.
  19. 根据权利要求1-18中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R3选自甲氧基、 The compound according to any one of claims 1-18, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 3 is selected from methoxy,
  20. 根据权利要求1-19中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R4选自H、卤素、C1-6烷氧基或C1-6卤代烷氧基；优选为F。The compound according to any one of claims 1-19, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 4 is selected from H, halogen, C 1- 6 alkoxy or C 1-6 haloalkoxy; preferably F.
  21. 根据权利要求1-220中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R5为H。The compound according to any one of claims 1-220, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 5 is H.
  22. 根据权利要求1-21中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，式(I)化合物选自式(IA)或(IB)：
    The compound according to any one of claims 1-21, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that the compound of formula (I) is selected from the group consisting of formula (IA) or (IB):
    其中，所述环A，X，L，R2，R3，R4及R6的定义如权利要求1-21中的任一项所述。Wherein, the definitions of ring A, X, L, R 2 , R 3 , R 4 and R 6 are as described in any one of claims 1-21.
  23. 根据权利要求1-22中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，式(I)化合物选自式(IA-1)或(IB-1)：
    The compound according to any one of claims 1-22, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that the compound of formula (I) is selected from the group consisting of formula (IA- 1) or (IB-1):
    其中，所述X，L，R2，R3，R4及R6的定义如权利要求1-21中的任一项所述。Wherein, the definitions of X, L, R 2 , R 3 , R 4 and R 6 are as described in any one of claims 1-21.
  24. 根据权利要求1-23中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，式(I)化合物选自式(IA-1’)或(IB-1’)：
    The compound according to any one of claims 1-23, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that the compound of formula (I) is selected from the group consisting of formula (IA- 1') or (IB-1'):
    其中，所述X，L，R2，R3，R4、R6和Ra的定义如权利要求1-21中的任一项所述。Wherein, the definitions of X, L, R 2 , R 3 , R 4 , R 6 and R a are as described in any one of claims 1-21.
  25. 根据权利要求23或24所述的式(IA-1)、(IB-1)、(IA-1’)或(IB-1’)化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R2选自C6-18芳基或5-18元杂芳基；其中，所述C6-18芳基或5-18元杂芳基任选地进一步被一个或多个Ra取代，所述Ra独立地选自H、羟基、氰基、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-C0-3亚烷基-C3-14环烷基、-C0-3亚烷基-(3-14元杂环基)、-C0-3亚烷基-C6-18芳基或-C0-3亚烷基-(5-18元杂芳基)；The compound of formula (IA-1), (IB-1), (IA-1') or (IB-1') according to claim 23 or 24, or its stereoisomer, tautomer, Deuterated product or pharmaceutically acceptable salt, characterized in that the R 2 is selected from C 6-18 aryl or 5-18 membered heteroaryl; wherein, the C 6-18 aryl or 5-18 membered heteroaryl Optionally further substituted by one or more R a independently selected from H, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy Base, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-3 alkylene -C 3-14 cycloalkyl, -C 0-3 alkylene - (3-14 membered heterocyclyl ), -C 0-3 alkylene-C 6-18 aryl or -C 0-3 alkylene-(5-18 membered heteroaryl);
    所述R3选自C1-6烷氧基、C3-14环烷基-O-或C1-6卤代烷氧基；其中，所述C1-6烷氧基、C3-14环烷基-O-或C1-6卤代烷氧基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、氰基、氨基、硝基或羟基所取代；The R 3 is selected from C 1-6 alkoxy, C 3-14 cycloalkyl-O- or C 1-6 haloalkoxy; wherein, the C 1-6 alkoxy, C 3-14 cycloalkyl Alkyl-O- or C 1-6 haloalkoxy is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, cyano, amino, Substituted by nitro or hydroxyl;
    R4选自H、卤素、氰基、氨基、硝基、C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、C1-6卤代烷基、C1-6卤代烷氧基或羟基；其中，所述C1-6烷基、C1-6烷氧基、C3-14环烷基-O-、C1- 6卤代烷基或C1-6卤代烷氧基任选进一步被一个或多个卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、氰基、氨基、硝基或羟基所取代；R 4 is selected from H, halogen, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl, C 1-6 haloalkoxy or hydroxyl; wherein, the C 1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C 1-6 haloalkyl or C 1-6 The haloalkoxy group is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, cyano, amino, nitro or hydroxyl;
    所述X选自键、NH、O或S；The X is selected from bond, NH, O or S;
    所述L选自键或-C1-3亚烷基-； The L is selected from bond or -C 1-3 alkylene-;
    所述R6独立选自H、卤素、C1-6烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基，所述C1-6烷基、C3-14环烷基、3-14元杂环基、C6-18芳基或5-18元杂芳基任选地进一步被一个或多个卤素、羟基、氰基、氨基、硝基或C1-6烷基所取代。The R 6 is independently selected from H, halogen, C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl, so The C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogens, hydroxyl groups , cyano, amino, nitro or C 1-6 alkyl substituted.
  26. 根据权利要求23中所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，式(I)化合物选自式(IA-1-1)或(IB-1-1)：
    The compound according to claim 23, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that the compound of formula (I) is selected from the group consisting of formula (IA-1-1) or (IB-1-1):
    所述R2选自所述任选地进一步被一个或多个Ra取代，所述Ra独立地选自H、羟基、氰基、氨基、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基或-C0-3亚烷基-C3-14环烷基；The R 2 is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl;
    所述R4选自氢或卤素；The R 4 is selected from hydrogen or halogen;
    所述R6选自氢或卤素；The R 6 is selected from hydrogen or halogen;
    所述R7选自C1-6烷基、C1-6卤代烷基或C3-14环烷基；优选为甲基、乙基、异丙基、三氟乙基或环丙基。The R 7 is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-14 cycloalkyl; preferably it is methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.
  27. 根据权利要求24中所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，式(I)选自(IA-1’-1)或(IB-1’-1)：
    The compound according to claim 24, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that formula (I) is selected from (IA-1'-1) or ( IB-1'-1):
    所述R2选自所述任选地进一步被一个或多个Ra取代，所述Ra独立地选自H、羟基、氰基、氨基、卤素、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基或-C0-3亚烷基-C3-14环烷基；The R 2 is selected from described Optionally further substituted by one or more Ra independently selected from H, hydroxy, cyano, amino, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 2- 6 alkenyl, C 2-6 alkynyl or -C 0-3 alkylene -C 3-14 cycloalkyl;
    所述R4选自氢或卤素；The R 4 is selected from hydrogen or halogen;
    所述R6选自氢或卤素；The R 6 is selected from hydrogen or halogen;
    所述R7选自C1-6烷基、C1-6卤代烷基或C3-14环烷基，优选为甲基、乙基、异丙基、三氟乙基或环丙基。The R 7 is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-14 cycloalkyl, preferably methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.
  28. 根据权利要求1-27中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述式(I)化合物选自


    The compound according to any one of claims 1-27, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that the compound of formula (I) is selected from


  29. 中间体化合物，其特征在于，所述中间体化合物选自：

    Intermediate compound, characterized in that the intermediate compound is selected from:

  30. 中间体化合物M13的制备方法，其特征在于，包括以下步骤：将消旋体M9与手性酸反应生成对应的盐，在碱性条件下游离，得到S构型的游离碱M13。Intermediate compound M13 The preparation method is characterized in that it includes the following steps: adding racemate M9 It reacts with a chiral acid to form the corresponding salt, which is dissociated under alkaline conditions to obtain the S-configured free base M13.
  31. 如权利要求30所述的中间体化合物M13的制备方法，其特征在于所述手性酸选自L-(-)-二对甲基苯甲酰酒石酸、L-(-)-二苯甲酰酒石酸或L-(-)-二对甲氧基苯甲酰酒石酸。The preparation method of intermediate compound M13 as claimed in claim 30, characterized in that the chiral acid is selected from the group consisting of L-(-)-di-p-toluoyl tartaric acid and L-(-)-dibenzoyl tartaric acid. Tartaric acid or L-(-)-di-p-methoxybenzoyltartaric acid.
  32. 如权利要求30或31所述的中间体化合物M13的制备方法，其特征在于包括以下步骤：The preparation method of intermediate compound M13 as claimed in claim 30 or 31, characterized in that it includes the following steps:
    1)将消旋体M9与手性酸L-(-)-二对甲基苯甲酰酒石酸(DPLT)反应生成对应化合物M13-1，1) React racemate M9 with chiral acid L-(-)-di-p-methylbenzoyltartaric acid (DPLT) to generate the corresponding compound M13-1,
    2)在碱性条件下游离得到S构型的游离碱M13；
    2) Dissociate under alkaline conditions to obtain S-configuration free base M13;
  33. 一种药物组合物，其特征在于，所述药物组合物含有治疗有效量的权利要求1-28任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐。A pharmaceutical composition, characterized in that the pharmaceutical composition contains a therapeutically effective amount of the compound described in any one of claims 1-28, or its stereoisomer, tautomer, deuterated product or drug. Use salt.
  34. 权利要求1-28任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐或权利要求33所述的药物组合物在制备药物中的应用。The use of the compound according to any one of claims 1 to 28, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt or the pharmaceutical composition according to claim 33 in the preparation of medicines.
  35. 权利要求34所述的应用，其特征在于，所述在制备药物中的应用为在制备治疗和/或预由KRAS G12D介导疾病的药物中的应用。The application of claim 34, characterized in that the application in the preparation of medicines is the application in the preparation of medicines for the treatment and/or pre-treatment of diseases mediated by KRAS G12D.
  36. 根据权利要求35所述的应用，其特征在于，所述疾病选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、宫颈癌、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺 癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、前列腺癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。The application according to claim 35, wherein the disease is selected from the group consisting of breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, and small cell lung cancer. , polymorphic lung Cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocellular carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Xuwang cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
  37. 一种治疗和/或预防疾病的方法，其特征在于，包括向治疗对象施用治疗有效量的权利要求1-28任一项所述的化合物或其立体异构体、互变异构体、氘代物或药用盐或权利要求33所述的药物组合物。A method for treating and/or preventing diseases, characterized by comprising administering to a treatment subject a therapeutically effective amount of the compound of any one of claims 1-28 or its stereoisomer, tautomer, deuterium substitute or pharmaceutically acceptable salt or the pharmaceutical composition of claim 33.
  38. 根据权利要求37所述的方法，其特征在于，所述治疗和/或预防的疾病为由KRAS G12D介导的疾病，所述疾病选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、宫颈癌、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、前列腺癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。 The method of claim 37, wherein the disease to be treated and/or prevented is a disease mediated by KRAS G12D, and the disease is selected from the group consisting of breast cancer, multiple myeloma, bladder cancer, endometrium Cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, polymorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocellular carcinoma , myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or fat sarcoma.
PCT/CN2023/106296 2022-07-08 2023-07-07 Kras g12d inhibitor and application thereof in medicine WO2024008178A1 (en)

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