WO2022247641A1 - Wee1抑制剂及其用途 - Google Patents

Wee1抑制剂及其用途 Download PDF

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Publication number
WO2022247641A1
WO2022247641A1 PCT/CN2022/092348 CN2022092348W WO2022247641A1 WO 2022247641 A1 WO2022247641 A1 WO 2022247641A1 CN 2022092348 W CN2022092348 W CN 2022092348W WO 2022247641 A1 WO2022247641 A1 WO 2022247641A1
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Prior art keywords
alkyl
alkylene
halogen
substituted
hydrogen
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English (en)
French (fr)
Inventor
宋利
唐海
马晓慧
周水平
蔡金勇
董利明
宋壮
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Jiangsu Tasly Diyi Pharmaceutical Co Ltd
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Jiangsu Tasly Diyi Pharmaceutical Co Ltd
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Priority to US18/282,872 priority Critical patent/US20240199619A1/en
Priority to JP2023547153A priority patent/JP2024520969A/ja
Priority to AU2022280213A priority patent/AU2022280213A1/en
Priority to EP22810368.5A priority patent/EP4349838A4/en
Priority to CA3211181A priority patent/CA3211181A1/en
Publication of WO2022247641A1 publication Critical patent/WO2022247641A1/zh
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • 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
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • 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
    • 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
    • C07D487/04—Ortho-condensed 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 a class of novel compound with Weel inhibitory effect and its application in preparing medicine.
  • the cell cycle is a highly regulated and controlled process designed to allow cells to proliferate only in response to specific stimuli and appropriate conditions.
  • the normal cell cycle will go through G1 phase, S phase (DNA synthesis phase), G2 phase and M phase (cell division phase) in sequence.
  • G1 phase S phase
  • G2 phase DNA synthesis phase
  • M phase cell division phase
  • the Wee1 protein is a tyrosine kinase that is a key component of the G2-M cell cycle checkpoint that prevents cells from DNA damage from entering mitosis.
  • CDK1 Cyclin-dependent kinase 1
  • MYT1 myelin transcription factor
  • Wee1 is therefore a negative regulator of mitosis entry during the G2-M transition and plays an important monitoring role.
  • Wee1 is overexpressed in many malignancies, such as liver cancer, breast cancer, malignant glioma, melanoma, adult and childhood brain tumors.
  • Wee1 inhibitors play a key role in anticancer therapy and have become a hot spot in the research and development of anticancer drugs.
  • Wee1 inhibitors have been reported (WO2007126128, WO2004007499, etc.), but no Wee1 inhibitor has been marketed yet.
  • the compound with the fastest development progress is AZD-1775, which has entered phase II clinical trials, but the incidence of adverse reactions in clinical trials is high, and new Wee1 inhibitor drugs with better activity and higher safety need to be developed.
  • the present invention provides a compound represented by formula I, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt:
  • R 1 is selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted - C 2 ⁇ 6 alkenyl, halogen-substituted -C 2 ⁇ 6 alkynyl, -C 0 ⁇ 4 alkylene-OR 11 , -C 0 ⁇ 4 alkylene-NR 12 R 12 ;
  • R 11 is selected from -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl substituted by halogen;
  • Each R 12 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl substituted by halogen;
  • X 1 , X 2 , and X 4 are independently selected from N or CR 4 ;
  • X 3 is selected from N or CR 3 ;
  • X 5 is selected from O, S or NR 4 ;
  • X 6 is selected from CR 4 or N;
  • X 8 is selected from CR 4 R 4 , O;
  • X 7 is selected from S, NR 4 ; R 2 is selected from
  • R 21 and R 22 are independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl , Halogen substituted -C 2 ⁇ 6 alkenyl, Halogen substituted -C 2 ⁇ 6 alkynyl, -C 0 ⁇ 4 alkylene -OR 24 , -C 0 ⁇ 4 alkylene -NR 24 R 24 ;
  • Each R 24 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl substituted by halogen;
  • R 21 and R 22 together with the connected atoms form a 3-8 membered carbocyclic group, a 4-8 membered heterocycloalkyl group,
  • R 23 is selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted - C 2 ⁇ 6 alkenyl, halogen-substituted -C 2 ⁇ 6 alkynyl, -C 0 ⁇ 4 alkylene-C(O)R 25 , -C 0 ⁇ 4 alkylene-C(O)NR 25 R 25 , -C 0 ⁇ 4 alkylene-C(O)OR 25 , -C 0 ⁇ 4 alkylene-S(O) 2 R 25 , -C 0 ⁇ 4 alkylene-S(O)R 25 , -C 0 ⁇ 4 alkylene-S(O)(NH)R 25 , -C 0 ⁇ 4 alkylene-S(NH) 2 R 25 , -C 0 ⁇ 4 alkylene-S(O
  • Each R 25 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl substituted by halogen;
  • R 23 , R 3 together with the connected atoms form a 4-8 membered carbocyclyl, 4-8 membered heterocycloalkyl;
  • R 3 is selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, hydroxyl substituted -C 1 ⁇ 6 alkyl, halogen substituted- C 1 ⁇ 6 alkyl, halogen substituted -C 2 ⁇ 6 alkenyl, halogen substituted -C 2 ⁇ 6 alkynyl, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 alkylene-O (C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-N (C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl);
  • Each R4 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, Halogen substituted -C 2 ⁇ 6 alkenyl, halogen substituted -C 2 ⁇ 6 alkynyl, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 alkylene-O(C 1 ⁇ 6 alkyl ), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-N(C 1 ⁇ 6 alkyl )(C 1 ⁇ 6 alkyl);
  • R 5 is selected from hydrogen, -C 1 ⁇ 6 alkyl
  • Y 1 , Y 2 , Y 3 , Y 4 are independently selected from N or CRY ;
  • Each R Y is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, Halogen substituted -C 2 ⁇ 6 alkenyl, halogen substituted -C 2 ⁇ 6 alkynyl, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 alkylene-O(C 1 ⁇ 6 alkyl ), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-N(C 1 ⁇ 6 alkyl )(C 1 ⁇ 6 alkyl);
  • Ring B is selected from 3-12 membered carbocyclyl, 4-12 membered heterocycloalkyl; said carbocyclyl and heterocycloalkyl can be further substituted by one, two, three, four or five R B ;
  • Each R B is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, Halogen-substituted -C 2-6 alkenyl, halogen-substituted-C 2-6 alkynyl, -C 0-4 alkylene-OR B1 , -C 0-4 alkylene-OC(O)R B1 , -C 0 ⁇ 4 alkylene-SR B1 , -C 0 ⁇ 4 alkylene-S(O) 2 R B1 , -C 0 ⁇ 4 alkylene-S(O)R B1 , -C 0 ⁇ 4 Alkylene-S(O) 2 NR B1 R B1 , -C 0 ⁇ 4 Alkylene-S(O)NR B1 R B1 , -C 0 ⁇ 4 Alkylene-S(
  • Each R B1 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl substituted by halogen;
  • R 6 , R 7 , R 8 , and R 9 are independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted- C 1 ⁇ 6 alkyl, halogen substituted -C 2 ⁇ 6 alkenyl, halogen substituted -C 2 ⁇ 6 alkynyl, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 alkylene-O (C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-N (C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl);
  • R 6 , R 7 together with the connected atoms form a 3-8 membered carbocyclyl, 4-8 membered heterocycloalkyl; or, R 8 , R 9 together with the connected atoms form a 3-8 membered carbocyclyl, 4 ⁇ 8 membered heterocycloalkyl;
  • Y 5 and Y 6 are independently selected from chemical bonds, -C 0 ⁇ 4 alkylene-O-, -C 0 ⁇ 4 alkylene-S-, -C 0 ⁇ 4 alkylene-NR Y51 -, CRY51 R Y51 ;
  • Each R Y51 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted -C 2-6 alkenyl, -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-OH, -C 0-4 alkylene-O(C 1-6 alkyl), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-N(C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl) 6 alkyl);
  • Y7 is selected from O, S or NR Y71 ;
  • R Y71 is selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted -C 2 ⁇ 6 alkenyl Group, halogen substituted -C 2 ⁇ 6 alkynyl, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 alkylene-O(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene -NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-N(C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl) ;
  • R 10 is selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl, halogen substituted - C 2 ⁇ 6 alkenyl, halogen-substituted -C 2 ⁇ 6 alkynyl, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 alkylene-O(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-N(C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl groups).
  • R 1 is selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -OR 11 , -NR 12 R 12 ;
  • R 11 is selected from -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen substituted -C 1 ⁇ 6 alkyl;
  • Each R 12 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl;
  • R 10 is selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -OH, -O(C 1 ⁇ 6 alkyl), -NH 2 , -NH (C 1-6 alkyl), -N(C 1-6 alkyl)(C 1-6 alkyl).
  • R 1 is selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, trifluoromethyl, -O(C 1 ⁇ 6 alkyl), -O(C 2 ⁇ 6 alkenyl), -O(tri Fluoromethyl), -NH 2 , -NH(C 1 ⁇ 6 alkyl), -N(C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl);
  • R 10 is selected from hydrogen, halogen, -C 1-6 alkyl, -O(C 1-6 alkyl).
  • R2 is selected from
  • R 21 and R 22 are independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl, -OR 24 ;
  • Each R 24 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl
  • R 21 , R 22 together with the connected atoms form carbonyl, 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkane Base, 6-membered heterocycloalkyl; the heteroatom in the heterocycloalkyl is selected from N, O, S;
  • R 23 is selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -S(O) 2 R 25 , -S(O)R 25 , -S( O)(NH)R 25 , -S(NH) 2 R 25 ;
  • Each R 25 is independently selected from hydrogen, -C 1-6 alkyl.
  • R2 is selected from
  • C ring selected from R2 is selected from
  • R 21 and R 22 are independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl, -OR 24 ;
  • Each R 24 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl
  • R 23 and R 3 together with the connected atoms form a 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 7-membered carbocyclyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl.
  • R2 is selected from
  • R 21 and R 22 are independently selected from hydrogen and -C 1-6 alkyl.
  • Y 1 , Y 2 , Y 3 , Y 4 are independently selected from N or CRY ;
  • Each R Y is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 Alkylene-O(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 Alkylene-N(C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl);
  • Ring B is selected from 3-8 membered monocarbocyclyl, 4-8 membered monoheterocycloalkyl, 5-10 membered bridged carbocyclyl, 5-10 membered bridged heterocycloalkyl, 5-10 membered spirocarbocyclyl , 5-10 membered spiroheterocycloalkyl, 8-12 membered condensed carbocyclyl, 8-12 membered condensed heterocycloalkyl; Cycloalkyl, spirocarbocyclyl, spiroheterocycloalkyl, fused carbocyclyl, fused heterocycloalkyl can be further substituted by one, two, three, four or five RB ;
  • Each R B is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -OR B1 , -SR B1 , -S(O) 2 R B1 , -S(O)R B1 , -C(O)R B1 , -C(O)OR B1 , -NR B1 R B1 , 3-12 membered carbocyclyl, 4-12 membered heterocycloalkyl; Carbocyclyl, heterocycloalkyl can be further substituted by one, two, three, four or five R B1 ; alternatively, two independent R B together with connected atoms form
  • Each R B1 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl;
  • Y 5 is selected from O, S, NR Y51 , CR Y51 RY51 ;
  • Each R Y51 is independently selected from hydrogen, -C 1-6 alkyl.
  • Y 1 , Y 2 , Y 3 , Y 4 are independently selected from N or CRY ;
  • Each R Y is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 Alkylene-O(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 Alkylene-N(C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl);
  • R 6 , R 7 , R 8 , and R 9 are each independently selected from hydrogen, -C 1-6 alkyl;
  • R 6 and R 7 form 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl; or, R 8 , R 9 together with the connected atoms form 3-membered carbocyclyl, 4-membered carbocyclyl, 5-membered carbocyclyl, 6-membered carbocyclyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl;
  • R B is selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -S(O) 2 R B1 , -S(O)R B1 , -C(O)R B1 , -C(O)OR B1 ;
  • Each R B1 is independently selected from hydrogen, -C 1-6 alkyl, halogen-substituted -C 1-6 alkyl.
  • Y 1 , Y 2 , and Y 4 are independently selected from N or CRY ;
  • Each R Y is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 Alkylene-O(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 Alkylene-N(C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl);
  • R B is selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -S(O) 2 R B1 , -S(O)R B1 , -C(O)R B1 , -C(O)OR B1 ;
  • Each R B1 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl;
  • Y 5 is selected from chemical bond, O, S, NR Y51 , CR Y51 RY51 ;
  • Each R Y51 is independently selected from hydrogen, -C 1-6 alkyl.
  • a ring is selected from,
  • Y 1 , Y 2 , and Y 4 are independently selected from N or CRY ;
  • Each R Y is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 Alkylene-O(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 Alkylene-N(C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl);
  • R B is selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -S(O) 2 R B1 , -S(O)R B1 , -C(O)R B1 , -C(O)OR B1 ;
  • Each R B1 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl;
  • Y 5 and Y 6 are independently selected from chemical bonds, -C 0 ⁇ 1 alkylene-O-, -C 0 ⁇ 1 alkylene-S-, -C 0 ⁇ 1 alkylene-NR Y51 -, CRY51 R Y51 ;
  • Each R Y51 is independently selected from hydrogen, -C 1-6 alkyl.
  • Y 1 is selected from N or CRY ;
  • R Y is selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -C 0 ⁇ 4 alkylene-OH, -C 0 ⁇ 4 alkylene- O(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene-NH 2 , -C 0 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 0 ⁇ 4 alkylene- N(C 1 ⁇ 6 alkyl)(C 1 ⁇ 6 alkyl);
  • Ring B is selected from 3 to 8 membered monocarbocyclic groups and 4 to 8 membered monoheterocycloalkyl groups; R B replaced;
  • Each R B is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -OR B1 , -SR B1 , -S(O) 2 R B1 , -S(O)R B1 , -C(O)R B1 , -C(O)OR B1 , -NR B1 R B1 ; or, two independent R B1 together with connected atoms form
  • Each R B1 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl;
  • Y7 is selected from O, S or NR Y71 ;
  • R Y71 is selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -C 1 ⁇ 4 alkylene-OH, -C 1 ⁇ 4 alkylene-O(C 1 ⁇ 4 6 alkyl), -C 1 ⁇ 4 alkylene-NH 2 , -C 1 ⁇ 4 alkylene-NH(C 1 ⁇ 6 alkyl), -C 1 ⁇ 4 alkylene-N(C 1 ⁇ 4 6 alkyl) (C 1 ⁇ 6 alkyl).
  • the compound shown in formula I is specifically:
  • the present invention also provides the use of any one of the compounds described above, or its deuterated compound, or its stereoisomer, or a pharmaceutically acceptable salt thereof in the preparation of a Weel inhibitor drug.
  • the present invention also provides the use of any one of the above-mentioned compounds, or their deuterated compounds, or their stereoisomers, or their pharmaceutically acceptable salts in the prevention and/or treatment of cancer.
  • the present invention also provides a pharmaceutical composition, which comprises any one of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof.
  • the above-mentioned pharmaceutical composition further includes a pharmaceutically acceptable carrier, adjuvant, and vehicle.
  • the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
  • substitution means that the hydrogen atom in the molecule is replaced by other different atoms or groups; or the lone pair of electrons of atoms in the molecule is replaced by other atoms or groups, for example, the lone pair of electrons on the S atom can be replaced by O atomic substitution formation
  • C a-b alkyl indicates any alkyl group containing "a" to "b" carbon atoms.
  • C 1-6 alkyl refers to an alkyl group containing 1-6 carbon atoms.
  • Alkyl means a saturated hydrocarbon chain having the indicated number of member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl base) and hexyl. Alkyl groups may also be part of other groups such as -O(C 1-6 alkyl).
  • Alkylene means a divalent saturated aliphatic hydrocarbon group having the indicated number of member atoms.
  • C a ⁇ b alkylene refers to an alkylene group having a to b carbon atoms.
  • Alkylene groups include branched and straight chain hydrocarbyl groups.
  • the term "propylene” can be exemplified by the following structures:
  • the term "dimethylbutylene” can be exemplified, for example, by any of the following structures:
  • the -C 0-4 alkylene in the present invention can be C 0 alkylene, C 1 alkylene (such as -CH 2 -), C 2 alkylene (such as -CH 2 CH 2 -, etc.), C 3 Alkylene or C 4 alkylene;
  • C 0 alkylene means that the groups here are connected in the form of chemical bonds, such as AC 0 alkylene-B means AB, that is, A group and B group connected directly by chemical bonds.
  • the "carbocyclyl” mentioned in the present invention refers to a saturated or non-aromatic partially saturated group with a single ring or multiple rings (fused, bridged, spiro) having multiple carbon atoms and no ring heteroatoms. cyclic group.
  • the term "carbocyclyl” includes cycloalkenyl groups such as cyclohexenyl. Examples of monocarbocyclyl groups include, for example, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl.
  • Examples of carbocyclyl groups of condensed carbocyclyl systems include bicyclohexyl, bicyclopentyl, bicyclooctyl, etc., and two such bicycloalkyl polycyclic structures are exemplified and named below: Bicyclohexyl and Bicyclohexyl.
  • Examples of carbocyclyl groups of bridged carbocyclyl systems include Adamantyl, etc.
  • Examples of carbocyclyl groups for spirocarbocyclyl systems include Wait.
  • Carbocyclyl also includes the case of a partially saturated cyclic group formed by the fusion of an aromatic ring and a non-aromatic ring, and the point of attachment may be at a non-aromatic carbon atom or an aromatic carbon atom, examples include 1,2, 3,4-tetrahydronaphthalen-5-yl, 5,6,7,8-tetrahydronaphthalen-5-yl.
  • saturated in the present invention means that the groups or molecules contain carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, and the like.
  • heterocycloalkyl refers to a saturated ring or a non-aromatic partially saturated ring with a single ring or multiple rings (fused, bridged, spiro) containing at least one heteroatom ;
  • heteroatom refers to nitrogen atom, oxygen atom, sulfur atom, etc.
  • heterocycloalkyl groups for monoheterocycloalkyl systems are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro- Thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1- Dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl, etc.
  • heterocycloalkyl groups for fused heterocycloalkyl systems include 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2 .1] Octyl, 9-aza-bicyclo[3.3.1]nonyl, etc.
  • heterocycloalkyl groups for bridged heterocycloalkyl systems include Wait.
  • heterocycloalkyl groups for spiroheterocycloalkyl systems include Wait.
  • partially saturated heterocycloalkyl are dihydrofuranyl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl and the like.
  • heterocycloalkyl also includes the case where an aromatic ring containing at least one heteroatom is fused with a non-aromatic ring to form a partially saturated cyclic group, and the point of attachment may be at a non-aromatic carbon atom, an aromatic carbon atom or heteroatoms, examples include
  • aromatic ring group refers to an aromatic hydrocarbon group having multiple carbon atoms.
  • Aryl groups are typically monocyclic, bicyclic or tricyclic aryl groups having multiple carbon atoms.
  • aryl refers to an aromatic substituent which may be a single aromatic ring or a plurality of aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.
  • aromatic heterocyclic group refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to nitrogen atom, oxygen atom, sulfur atom and the like.
  • Aromatic monocyclic or bicyclic hydrocarbons usually containing multiple ring atoms, wherein one or more ring atoms are selected from O, N, S heteroatoms. There are preferably one to three heteroatoms.
  • Heterocyclic aryl represents for example: pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolyl, benzothienyl, benzofuryl, benzothienyl, benzopyranyl, benzene Thiopyranyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazole benzothiazolyl, benzoxazolyl.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halogen substituted alkyl in the present invention means that one or more hydrogen atoms in the alkyl are replaced by halogen; for example, monofluoromethyl, difluoromethyl, trifluoromethyl.
  • deuterium-substituted alkyl group means that one or more hydrogen atoms in the alkyl group are replaced by deuterium atoms; for example, trideuteromethyl group.
  • the oxygen atom in "-C(O)R", “-S(O) 2 R” and the like described in the present invention is connected with a carbon atom or a sulfur atom with a double bond, and the R group is connected with an oxygen atom or a sulfur atom Connected by a single bond;
  • another example "-S(O)(NH)R” means that the oxygen atom and nitrogen atom are connected to the sulfur atom by a double bond, and the R group is connected to the sulfur atom by a single bond.
  • the "deuterated compound” of the present invention means that one or more hydrogen atoms in a molecule or group are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.
  • pharmaceutically acceptable means that a certain carrier, carrier, diluent, excipient, and/or formed salt are generally chemically or physically compatible with other ingredients that constitute a pharmaceutical dosage form, and are physiologically compatible Compatible with receptors.
  • salts and “pharmaceutically acceptable salt” refer to the above-mentioned compounds or their stereoisomers, acidic and/or basic salts formed with inorganic and/or organic acids and bases, and also include zwitterionic salts (internal salts), also include quaternary ammonium salts, such as alkyl ammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above-mentioned compound, or its stereoisomer, with a certain amount of acid or base as appropriate (for example, equivalent).
  • salts may form precipitates in solution and be collected by filtration, or may be recovered after evaporation of the solvent, or may be obtained by freeze-drying after reaction in an aqueous medium.
  • Said salt in the present invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, dibutyl salt, oxalate, malate, succinate, fumarate, maleate, tartrate, or trifluoroacetate.
  • one or more compounds of the invention may be used in combination with each other.
  • the compound of the present invention may be used in combination with any other active agents for the preparation of drugs or pharmaceutical compositions for regulating cell functions or treating diseases. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • LC-MS Shimadzu LC-MS 2020 (ESI)).
  • HPLC measurement used a Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A).
  • MPLC Medium Pressure Preparative Chromatography
  • Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates, and the specifications of thin-layer chromatography separation and purification products are 0.4mm to 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.
  • the reaction is carried out under a nitrogen atmosphere.
  • the solution refers to an aqueous solution.
  • the temperature of the reaction is room temperature.
  • M is moles per liter.
  • HPLC test conditions are as follows:
  • Embodiment 1 the synthesis of compound 1
  • Substrate 1-1 (247.51mg, 1.29mmol), 1-2 (200mg, 1.29mmol) was added to a dry single-necked flask, dissolved in acetic acid (2mL) and 1,4-dioxane (2mL), heated to Stir overnight at 110°C, monitored by LC-MS. After the reaction was completed, it was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 1-3 (400 mg, 1.29 mmol).
  • Substrate 1-4 (2 g, 8.44 mmol), dimethylsulfinimide (786.42 mg, 8.44 mmol), Pd(dba) 2 (48.55 mg, 84.43 ⁇ mol), BINAP ( 52.57mg, 84.43 ⁇ mol), potassium tert-butoxide (1.89g, 16.89mmol), add toluene (10mL) to dissolve, microwave reaction at 120°C for 30min under the protection of nitrogen, and monitor by LC-MS. After the reaction was completed, it was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 1-5 (800 mg, 3.21 mmol).
  • Embodiment 2 the synthesis of compound 2
  • Substrate 2-1 (15g, 69.43mmol) was added to a dry single-necked flask, dissolved in THF (50mL) and methylmagnesium bromide (20.70g, 173.59mmol) was added under ice-cooling, reacted overnight at room temperature, LC - MS monitoring. After the reaction was completed, it was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 2-2 (15 g, 69.42 mmol).
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 umol) in step 3 was replaced by 2-1 (45.40 mg, 210.11 umol), and the synthesis method was the same to obtain compound 2 (10.2 mg, 22.95 ⁇ mol).
  • Embodiment 3 the synthesis of compound 3
  • Substrate 3-3 (3 g, 10.10 mmol) was added to a dry one-necked flask, hydrochloric acid (368.11 mg, 10.10 mmol) was added, dissolved in methanol (10 mL), reacted at room temperature overnight, and monitored by LC-MS. After the reaction was completed, it was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 3-4 (2.4 g, 9.96 mmol).
  • Substrate 3-4 400mg, 2.03mmol
  • p-toluenesulfonic acid 171.46mg, 995.68 ⁇ mol
  • toluene 10mL
  • the temperature was raised to 115°C to react overnight, monitored by LC-MS.
  • the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 3-5 (400 mg, 2.03 mmol).
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 3-6 (89.05 mg, 399.20 ⁇ mol), and the synthesis method was the same to obtain compound 3 (30 mg, 66.44 ⁇ mol).
  • Embodiment 4 the synthesis of compound 4
  • Substrate 4-3 (10 g, 49.99 mmol) and potassium carbonate (13.71 g, 99.35 mmol) were dissolved in methanol (50 mL) into a dry one-necked flask, stirred overnight at room temperature, and monitored by LC-MS. After the reaction was completed, it was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 4-4 (13 g, 48.14 mmol).
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 4-4 (113.48 mg, 420.21 ⁇ mol), and the synthesis method was the same to obtain compound 4 (60 mg, 120.36 ⁇ mol).
  • Embodiment 5 the synthesis of compound 5
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 5-4 (116.04 mg, 420.21 ⁇ mol), and the synthesis method was the same to obtain compound 5 (20 mg, 39.63 ⁇ mol).
  • Embodiment 6 the synthesis of compound 6
  • Step 1 in Example 1 According to the synthesis method of Step 1 in Example 1, 1-1 (247.51 mg, 1.29 mmol) in Step 1 was replaced by 6-1 (115.32 mg, 647.01 ⁇ mol), and the synthesis method was the same to obtain compound 6-2 (122 mg ,262.62 ⁇ mol).
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced by 6-2 (100 mg, 337.47 ⁇ mol), and the synthesis method was the same to obtain compound 6 (122 mg, 262.62 ⁇ mol) .
  • Embodiment 7 the synthesis of compound 7
  • Step 1 in Example 1 According to the synthesis method of Step 1 in Example 1, 1-1 (247.51 mg, 1.29 mmol) in Step 1 was replaced with 7-1 (224.93 mg, 905.81 ⁇ mol), and the synthesis method was the same to obtain compound 7-2 (331 mg ,0.90mmol).
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced with 7-2 (224.93 mg, 905.81 ⁇ mol), and the synthesis method was the same to obtain compound 7-3 (100 mg, 187.04 ⁇ mol).
  • Substrate 7-3 (350 mg, 93.52 ⁇ mol) was dissolved in 4M HCl/EA (10 mL) in a dry one-necked flask, stirred at room temperature for 2 hours, and monitored by LC-MS. After the reaction was completed, it was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 7 (32 mg, 73.65 ⁇ mol).
  • Embodiment 8 the synthesis of compound 8
  • Substrate 8-1 (200 mg, 805.41 ⁇ mol) was dissolved in dry THF (10 mL) in a dry single-necked flask, and lithium aluminum hydride (152.84 mg, 4.03 mmol) was added in an ice bath and stirred at room temperature for 30 min, LC- MS monitoring. After the reaction was completed, it was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 8-2 (130 mg, 801.33 ⁇ mol).
  • Step 1-1 (247.51 mg, 1.29 mmol) in Step 1 was replaced by 8-2 (130 mg, 801.33 ⁇ mol), and the synthesis method was the same to obtain compound 8-3 (224 mg, 799.07 ⁇ mol).
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.4 ⁇ mol) in step 3 was replaced with 8-3 (100 mg, 356.73 ⁇ mol), and the synthesis method was the same to obtain compound 8 (16 mg, 35.67 ⁇ mol) .
  • Embodiment 9 the synthesis of compound 9
  • Substrate 9-3 (3.52g, 14.12mmol) was added to a dry single-necked flask, methanol (10mL) was added and stirred to dissolve, then Pd/C (170.51mg, 1.40mmol) was added, and H 2 was replaced 3 times, at room temperature The reaction was carried out for 3 hours and monitored by LC-MS. After the reaction was completed, Pd/C was removed by filtration with celite, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain product 9-4 (2.1 g, 9.57 mmol).
  • Step 1-1 (247.51 mg, 1.29 mmol) in Step 1 was replaced with 9-4 (123 mg, 560.81 ⁇ mol), and the synthesis method was the same to obtain compound 9-6 (189 mg, 560.13 ⁇ mol).
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced by 9-6 (189 mg, 560.13 ⁇ mol), and the synthesis method was the same to obtain compound 9 (20 mg, 39.55 ⁇ mol) .
  • Embodiment 10 the synthesis of compound 10
  • Substrate 10-1 (3g, 18.62mmol) and iodomethane (8.7g, 61.43mmol) were dissolved in DMF (20mL) into a dry one-necked flask, heated to 70°C, stirred for 15 hours, and monitored by LC-MS. After the reaction was completed, it was quenched with water, extracted 3 times by adding ethyl acetate, the organic phases were combined, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 10-2( 3.4 g, 16.73 mmol).
  • Substrate 10-2 (3.3g, 16.24mmol) was added in a dry single-necked flask and dissolved in H 2 SO 4 (10mL), and HNO 3 (1.02g, 16.24mmol) was slowly added dropwise under ice-cooling, and stirred at 0°C for 6 hours, TLC monitoring. After the reaction was completed, it was quenched with water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 10-3( 3.9 g, 15.71 mmol).
  • Substrate 10-3 (270mg, 1.09mmol) was dissolved in THF (10mL) in a dry single-necked flask, and BMS (334.82mg, 4.35mmol) was slowly added dropwise under ice-cooling, heated to 70°C and stirred for 24 hours, LC - MS monitoring. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 10 -4 (200 mg, 907.99 ⁇ mol).
  • Substrate 10-4 (200mg, 907.99 ⁇ mol) was added to a dry single-necked flask, dissolved in ethanol (10mL), and Pd/C (110.28mg, 907.99 ⁇ mol) was added to replace H 2 for 3 times, then stirred under hydrogen for 3 hours, and LC - MS monitoring. After the reaction was completed, it was filtered with diatomaceous earth, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain product 10-5 (170 mg, 893.40 ⁇ mol).
  • Step 1-1 (247.51 mg, 1.29 mmol) in Step 1 was replaced with 10-5 (132 mg, 693.70 ⁇ mol), and the synthesis method was the same to obtain compound 10-6 (213 mg, 690.71 ⁇ mol).
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced with 10-6 (100 mg, 324.28 ⁇ mol), and the synthesis method was the same to obtain compound 10 (27 mg, 54.95 ⁇ mol) .
  • Embodiment 11 the synthesis of compound 11
  • Embodiment 12 the synthesis of compound 12
  • Embodiment 13 the synthesis of compound 13
  • step 3 in the synthesis of Example 1 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 13-2 (80 mg, 250.0 ⁇ mol), and the synthesis method was the same to obtain compound 13 (25 mg, 39.91 ⁇ mol), prepared by acid method, the product is trifluoroacetate.
  • Embodiment 14 the synthesis of compound 14
  • Substrate 14-1 (182mg, 1.42mmol), 14-2 (200mg, 1.29mmol) and K 2 CO 3 (534mg, 3.87mmol) were added to a dry three-necked flask, dissolved in DMF (10mL), and Under the protection of 2 , the temperature was raised to 90° C. for 3 h, monitored by LC-MS. After the reaction was completed, it was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure without purification. The crude product was directly used in the next reaction to obtain 14-3 (100 mg, crude). LCMS (ESI + ) m/z: 264.3 [M+H] + .
  • Substrate 14-3 (100 mg, 43.0 ⁇ mol) was dissolved in MeOH (5 mL) in a dry one-necked flask, and Pd/C (30 mg) was added, replaced with H 2 three times, stirred at room temperature for 30 min, and monitored by LC-MS. After the reaction was completed, it was filtered with celite, and the filtrate was concentrated under reduced pressure to obtain the crude product 14-4 (109 mg, crude), LCMS (ESI + ) m/z: 234.2[M+H] + .
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced by 14-4 (53 mg, 151.0 ⁇ mol), and the synthesis method was the same to obtain compound 14 (11.9 mg, 22.93 ⁇ mol) ).
  • Embodiment 15 the synthesis of compound 15
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced by 15-2 (35 mg, 101.0 ⁇ mol), and the synthesis method was the same to obtain compound 15 (11.9 mg, 22.93 ⁇ mol ).
  • Embodiment 16 the synthesis of compound 16
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced by 16-2 (98 mg, 303.0 ⁇ mol), and the synthesis method was the same to obtain compound 16 (22.4 mg, 45.53 ⁇ mol) ).
  • Embodiment 17 the synthesis of compound 17
  • step 1 in Example 14 According to the synthesis method of step 1 in Example 14, 14-1 (182 mg, 1.42 mmol) in step 1 was replaced by 17-1 (200 mg, 0.952 mmol), and 14-2 (200 mg, 1.29 mmol) was replaced by 17- 2 (105mg, 1.05mmol) was synthesized by the same method to obtain the product 17-3 (400mg, crude).
  • Substrate 17-3 (100mg, 0.346mmol) was dissolved in EtOH (5mL) in a dry one-necked flask, Fe powder (97mg, 1.73mmol) and AcOH (0.1mL) were added, heated to 80°C and stirred for 1h, LC- MS monitoring. After the reaction was completed, it was filtered with celite, and the filtrate was concentrated under reduced pressure to obtain the product 17-4 (66 mg, crude), LCMS (ESI + ) m/z: 260.1[M+H] + .
  • Embodiment 18 the synthesis of compound 18
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced with HGC041-02 (60 mg, 194.57 ⁇ mol), and the synthesis method was the same to obtain compound 18 (23 mg, 47.78 ⁇ mol) .
  • Embodiment 19 the synthesis of compound 19
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced with 19-2 (80 mg, 245.0 ⁇ mol), and the synthesis method was the same to obtain compound 19 (14 mg, 28.27 ⁇ mol) .
  • Embodiment 20 the synthesis of compound 20
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced by 20-2 (80 mg, 204.0 ⁇ mol), and the synthesis method was the same to obtain compound 20 (20.6 mg, 36.79 ⁇ mol ).
  • Embodiment 21 the synthesis of compound 21
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced by 16-2 (74 mg, 229.0 ⁇ mol), and 1-5 (109.92 mg, 441.22 ⁇ mol) was replaced by 2 -1 (41 mg, 191.0 ⁇ mol) was synthesized in the same way to obtain compound 21 (20.6 mg, 15.72 ⁇ mol).
  • Embodiment 22 the synthesis of compound 22
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced with 22-2 (50 mg, 147.32 ⁇ mol), and the synthesis method was the same to obtain compound 22 (40 mg, 78.8 ⁇ mol) .
  • Embodiment 23 the synthesis of compound 23
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced with 23-2 (100 mg, 294.64 ⁇ mol), and the synthesis method was the same to obtain compound 23 (70 mg, 137.9 ⁇ mol) .
  • Embodiment 24 the synthesis of compound 24
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced by 24-2 (65 mg, 0.172 mmol), and the synthesis method was the same to obtain compound 24 (31.8 mg, 58.35 ⁇ mol) ).
  • Embodiment 25 the synthesis of compound 25
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced with 25-4 (60 mg, 158.95 ⁇ mol), and the synthesis method was the same to obtain compound 25 (35 mg, 51.31 ⁇ mol) .
  • Embodiment 26 the synthesis of compound 26
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-3 (105 mg, 339.40 ⁇ mol) in step 3 was replaced with 26-2 (60 mg, 176.79 ⁇ mol), and the synthesis method was the same to obtain compound 26 (31 mg, 59.85 ⁇ mol) .
  • Embodiment 27 the synthesis of compound 27
  • Substrate 27-A1 (18 mg, 49.39 ⁇ mol) and tetrahydrofuran (2 mL) were added to a dry single-necked flask, stirred and dissolved, then m-CPBA (10.23 mg, 59.27 ⁇ mol) was added, reacted at room temperature for 1 h, and monitored by LC-MS. After the reaction, DIPEA (33.39 mg, 258.36 ⁇ mol) was added, and after stirring for 10 min, 1-1 (20.11 mg, 105.14 ⁇ mol) was added and reacted at room temperature, monitored by LC-MS.
  • Substrate 27-B1 (26 mg, 71.34 ⁇ mol) and tetrahydrofuran (2 mL) were added to a dry single-necked flask, stirred and dissolved, then m-CPBA (14.77 mg, 85.61 ⁇ mol) was added, reacted at room temperature for 1 h, and monitored by LC-MS. After the reaction, DIPEA (40.81 mg, 315.77 ⁇ mol) was added, and after stirring for 10 min, 1-1 (30.17 mg, 157.71 ⁇ mol) was added and reacted at room temperature, monitored by LC-MS.
  • Embodiment 28 the synthesis of compound 28
  • Substrate 28-1 (500mg, 2.60mmol), dimethylsulfinimide (169.41mg, 1.82mmol), Xantphos (75.17mg, 129.91 ⁇ mol), Pd2(dba)3( 47.58mg, 51.96 ⁇ mol) and Cs 2 CO 3 (880.41mg, 2.70mmol), add 1,4-dioxane (30mL) to dissolve, stir in microwave at 110°C for 12 hours under the protection of nitrogen, monitor by LC-MS. After the reaction was completed, it was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain product 28-2 (113.4 mg, 217.97 ⁇ mol). LCMS (ESI + ) m/z: 205.1 [M+H] + .
  • Embodiment 29 Synthesis of compound 29
  • Substrate 29-1 (500mg, 2.91mmol) was added into a dry three-necked flask and dissolved in THF (10ml) for N2 replacement three times, and methylmagnesium bromide (764mg, 6.41mmol) was added dropwise at 0°C, and stirred at room temperature 1h, LC-MS monitoring. After the reaction was completed, it was quenched with saturated ammonium chloride solution, extracted three times with water and ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain product 29-2 (165mg, 0.965 mmol). LCMS (ESI + ) m/z: 172.2 [M+H] + .
  • step 2 in Example 28 According to the synthesis method of step 2 in Example 28, 28-2 (55.13 mg, 269.37 ⁇ mol) in step 2 was replaced with 29-2 (38 mg, 0.22 mmol), and the synthesis method was the same to obtain compound 29 (18 mg, 4.054 ⁇ mol) ).
  • Embodiment 30 the synthesis of compound 30
  • step 1 in Example 28 According to the synthesis method of step 1 in Example 28, 28-1 (500 mg, 2.60 mmol) in step 1 was replaced with 30-1 (500 mg, 2.12 mmol), and the synthesis method was the same to obtain the product 30-2 (340 mg, 1.37 mmol).
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 30-2 (67 mg, 0.27 mmol), and the synthesis method was the same to obtain compound 30 (22.8 mg, 44.17 ⁇ mol).
  • Embodiment 31 the synthesis of compound 31
  • step 1 in Example 28 According to the synthesis method of step 1 in Example 28, 28-1 (500 mg, 2.60 mmol) in step 1 was replaced with 31-1 (300 mg, 1.27 mmol), and the synthesis method was the same to obtain the product 31-2 (310 mg, 1.24 mmol).
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 31-2 (40 mg, 0.16 mmol), and the synthesis method was the same to obtain compound 31 (25.3 mg, 52.50 ⁇ mol).
  • Embodiment 32 the synthesis of compound 32
  • step 1 in Example 29-1 500 mg, 2.91 mmol
  • step 1 32-1 (300 mg, 1.39 mmol)
  • the synthesis method was the same to obtain the product 32-2 (374 mg, crude ).
  • step 3 in Example 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 32-2 (52 mg, 0.24 mmol), and the synthesis method was the same to obtain compound 32 (9.8 mg, 21.65 ⁇ mol).
  • Embodiment 33 the synthesis of compound 33
  • step 1 in Example 28 According to the synthesis method of step 1 in Example 28, 28-1 (500mg, 2.60mmol) in step 1 was replaced by 33-1 (300mg, 1.18mmol), and the synthesis method was the same to obtain the product 33-2 (230mg, 0.864 mmol).
  • step 3 in Example 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 33-2 (60 mg, 0.23 mmol), and the synthesis method was the same to obtain compound 33 (5.4 mg, 10.59 ⁇ mol).
  • Embodiment 34 the synthesis of compound 34
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 34-2 (59 mg, 0.272 mmol), and the synthesis method was the same to obtain compound 34 (30.7 mg, 66.91 ⁇ mol).
  • Embodiment 35 the synthesis of compound 35
  • step 1 in Example 29-1 500 mg, 2.91 mmol
  • step 1 35-1 (400 mg, 1.86 mmol)
  • the synthesis method was the same to obtain the product 35-2 (360 mg, crude ).
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 35-2 (52 mg, 0.242 mmol), and 1-3 (105 mg, 339.40 ⁇ mol) was replaced by 24 -2 (97mg, 0.259mmol) was synthesized in the same way to obtain compound 35 (4.6mg, 7.81 ⁇ mol).
  • Embodiment 36 the synthesis of compound 36
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 36-1 (37 mg, 0.162 mmol), and the synthesis method was the same to obtain compound 36 (32.5 mg, 64.85 ⁇ mol).
  • Embodiment 37 the synthesis of compound 37
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 37-1 (55 mg, 0.259 mmol), and the synthesis method was the same to obtain compound 37 (5.9 mg, 13.11 ⁇ mol).
  • Embodiment 38 the synthesis of compound 38
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 38-1 (37 mg, 0.162 mmol), and the synthesis method was the same to obtain compound 38 (28.7 mg, 53.80 ⁇ mol).
  • Embodiment 39 the synthesis of compound 39
  • Substrate 39-2 (7.00g, 23.90mmol), K 2 CO 3 (3.96g, 28.68mmol), dissolved in ACN (50ml) was added to a dry one-necked flask, stirred at room temperature for 1h, monitored by LC-MS. After the reaction was completed, it was extracted with water and ethyl acetate three times, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain product 39-3 (1.41g, 6.59mmol), LCMS (ESI + ) m/z: 215.1[M+H]+.
  • Substrate 39-3 (427.9mg, 2.00mmol) was added to a dry single-necked flask, dissolved in ACN (4ml), and NaBH 4 (151.8mg, 4.00mmol) was added slowly under ice bath, reacted in ice-water bath for 1h, TLC monitor. After the reaction was completed, it was extracted three times with water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain product 39-4 (210.00 mg, 0.98 mmol).
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 39-4 (42.79 mg, 0.20 mmol), and the synthesis method was the same to obtain compound 39 (10.0 mg, 22.56 ⁇ mol).
  • Embodiment 40 the synthesis of compound 40
  • step 1 in Example 29-1 500 mg, 2.91 mmol
  • step 1 in step 1 was replaced with 40-1 (423.90 mg, 2.00 mmol), and the synthesis method was the same to obtain compound 40-2 (210.00 mg , 0.98 mmol), LCMS (ESI + ) m/z: 211.2 [M+HH 2 O] + .
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 40-2 (45.59 mg, 0.20 mmol), and the synthesis method was the same to obtain compound 40 (20.00 mg, 43.74 ⁇ mol).
  • Embodiment 41 the synthesis of compound 41:
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 41-1 (38 mg, 0.194 mmol), and the synthesis method was the same to obtain compound 41 (2.0 mg, 4.50 ⁇ mol).
  • Embodiment 42 the synthesis of compound 42:
  • step 1 in Example 29-1 500 mg, 2.91 mmol
  • step 1 in step 1 was replaced with 42-1 (1 g, 4.29 mmol), and the synthesis method was the same to obtain compound 42-2 (850 mg, crude ).
  • step 3 in Example 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 42-2 (63 mg, 0.269 mmol), and the synthesis method was the same to obtain compound 42 (12 mg, 23.56 ⁇ mol) ).
  • Embodiment 43 the synthesis of compound 43
  • step 1 in Example 29-1 500 mg, 2.91 mmol
  • step 1 in step 1 was replaced with 43-1 (452.00 mg, 2.00 mmol), and the synthesis method was the same to obtain compound 43-2 (200 mg, 0.88 mmol), LCMS (ESI + ) m/z: 209.2 [M+HH 2 O] + .
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 43-2 (45.20 mg, 0.20 mmol), and the synthesis method was the same to obtain compound 43 (10.00 mg, 21.96 ⁇ mol).
  • Embodiment 44 the synthesis of compound 44
  • step 1 in Example 29-1 (500mg, 2.91mmol) in step 1 was replaced by 44-1 (452.00mg, 2.00mmol) and the synthesis method was the same to obtain compound 44-2 (200.00mg , 0.88 mmol), LCMS (ESI + ) m/z: 209.2 [M+HH 2 O] + .
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 44-2 (45.20 mg, 0.20 mmol), and the synthesis method was the same to obtain compound 44 (10.0 mg, 21.96 ⁇ mol).
  • Embodiment 45 the synthesis of compound 45
  • Substrate 45-2 (214.0 mg, 1.0 mmol) and CH(OMe) 3 (3 mL) were added into a dry one-necked flask, stirred at room temperature for 1 h, and monitored by LC-MS. After the reaction, it was concentrated under reduced pressure to obtain the product 45-3 (210.00 mg, 0.95 mmol), LCMS (ESI + ) m/z: 225.2[M+H] + .
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 45-3 (44.79 mg, 0.20 mmol), and the synthesis method was the same to obtain compound 45 (10.00 mg, 22.06 ⁇ mol).
  • Embodiment 46 the synthesis of compound 46
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 46-1 (57 mg, 0.269 mmol), and the synthesis method was the same to obtain compound 46 (8.8 mg, 19.26 ⁇ mol).
  • Embodiment 47 the synthesis of compound 47
  • Embodiment 48 the synthesis of compound 48
  • reaction solution was filtered with diatomaceous earth, the mother liquor was extracted with water and ethyl acetate three times, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 48-3 (250.00mg , 1.03 mmol), LCMS (ESI + ) m/z: 250.1 [M+H] + .
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 48-3 (49.79 mg, 0.20 mmol), and the synthesis method was the same to obtain compound 48 (12.00 mg, 25.09 ⁇ mol).
  • Embodiment 49 the synthesis of compound 49
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 49-3 (40.69 mg, 0.18 mmol), and the synthesis method was the same to obtain compound 49 (1.50 mg, 2.84 ⁇ mol).
  • Embodiment 50 the synthesis of compound 50
  • step 1 in Example 29-1 500 mg, 2.91 mmol
  • step 1 50-1 (434.04 mg, 2 mmol)
  • the synthesis method was the same to obtain compound 50-2 (200 mg, 878.09 ⁇ mol) as a white solid.
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 50-2 (37.89 mg, 174.55 ⁇ mol), and the synthesis method was the same to obtain compound 50 (17 mg, 38.16 ⁇ mol).
  • Embodiment 51 the synthesis of compound 51
  • Substrate 51-1 600 mg, 3.19 mmol
  • triethyl orthoacetate 1.5 mL
  • the reaction was monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, extracted three times with water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the crude product 51-2 (650 mg, crude), which was directly used in the next reaction.
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 51-2 (65.80 mg, 310.31 ⁇ mol), and 1,4-dioxane (3 mL ) was replaced by DMF (2 mL), and the synthesis method was the same to obtain compound 51 (18.1 mg, 36.78 ⁇ mol).
  • Embodiment 52 the synthesis of compound 52
  • step 1 in Example 29-1 500 mg, 2.91 mmol
  • step 1 52-1 (500.00 mg, 2.15 mmol)
  • the synthesis method was the same to obtain compound 52-2 (300 mg, 1.29 mmol).
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 52-2 (67.81 mg, 290.92 ⁇ mol), and the synthesis method was the same to obtain compound 52 (4.5 mg, 9.23 ⁇ mol).
  • Embodiment 53 the synthesis of compound 53
  • step 1 in Example 29-1 500 mg, 2.91 mmol
  • step 1 was replaced with 53-1 (1.11 g, 5 mmol), and the synthesis method was the same to obtain compound 53-2 (1.0 g, 4.49 mmol).
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 53-2 (39.80 mg, 180.00 ⁇ mol), and the synthesis method was the same to obtain compound 53 (7.1 mg, 12.10 ⁇ mol).
  • Embodiment 54 the synthesis of compound 54
  • reaction solution was filtered with diatomaceous earth, the mother liquor was extracted with water and ethyl acetate three times, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 54-2 (100 mg, 398.28 ⁇ mol).
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 54-2 (49.51 mg, 197.18 ⁇ mol), and the synthesis method was the same to obtain compound 54 (20 mg, 38.12 ⁇ mol).
  • Embodiment 55 the synthesis of compound 55
  • step 1 in Example 29-1 500 mg, 2.91 mmol
  • step 1 was replaced with 55-1, and the synthesis method was the same to obtain compound 55-2.
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 55-2 (50 mg, 195.99 ⁇ mol), and the synthesis method was the same to obtain compound 55 (17 mg, 35.16 ⁇ mol ).
  • Embodiment 56 the synthesis of compound 56
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 30-2 (332.41 mg, 2 mmol), and 1-3 (105 mg, 339.40 ⁇ mol) was replaced by 56 -2 (330.85mg, 1.33mmol) was synthesized in the same way to obtain compound 56-3 (252mg, 755.78 ⁇ mol).
  • Substrate 56-3 (66.69mg, 0.2mmol), m-CPBA (26.45mg, 300.00 ⁇ mol) and THF (0.8mL) were added to a dry single-necked flask, and after stirring at room temperature for 10min, DIPEA (129.24mg, 1.00mmol ), after stirring at room temperature for 5 min, the substrate 56-4 (57.68 mg, 300.00 ⁇ mol) was added, reacted at 100° C. for 6 h, and monitored by LCMS.
  • DIPEA 129.24mg, 1.00mmol
  • Embodiment 57 the synthesis of compound 57
  • Step 1 Synthesis of Compound 57-3:
  • Substrate 57-4 (22.3g, 103.58mmol) was added in a dry three-necked flask dissolved in DMF (75.46mL), POCl 3 (39.71g, 258.95mmol) and MgSO 4 were added dropwise at -10°C under nitrogen protection (22.40g, 186.08mmol), after stirring at room temperature for 1h, the temperature was raised to 105°C for 16h, monitored by LC-MS. After the reaction was completed, it was quenched with ice water, and the pH was adjusted to 9-10 with 30% aqueous sodium hydroxide solution.
  • Substrate 57-7 (3.74g, 17.67mmol), K 2 CO 3 (7.32g, 53.01mmol) and MeOH solution (40mL) were added to a dry one-necked flask, stirred at 15°C for 2h, monitored by LCMS. After the reaction was completed, it was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the product 57-8 (1.94 g, 11.44 mmol) as a bright yellow oil, LCMS (ESI + ) m/z: 170.1 [M+H] + .
  • Substrate 57-8 (3.74g, 17.67mmol) was added to a dry one-necked flask, dissolved in DCM (40mL), added Dess-martin Periodinane (7.36g, 17.36mmol), stirred at 15°C for 2h, monitored by LCMS. After the reaction, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, extracted three times with DCM, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the product 57-9 (2 g, crude) as a white solid, LCMS (ESI+ ) m/z: 168.0[M+H]+.
  • Embodiment 58 the synthesis of compound 58
  • Step 1 Synthesis of Compound 58-2:
  • Substrate 58-1 (87mg, 395.46 ⁇ mol) and methylamine (120.00mg, 3.86mmol, 1M tetrahydrofuran solution) were added to a dry one-necked flask, reacted at room temperature for 2h, and monitored by LC-MS. After the reaction, the reaction solution was concentrated under reduced pressure to obtain the crude product 58-2, which was directly used in the next reaction.
  • Substrate 58-3 (25 mg, crude) and triethyl orthoacetate (1 mL) were added into a dry one-necked bottle, reacted at room temperature for 2 h, and monitored by LC-MS. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain product 58-4 (7 mg, 31.10 ⁇ mol).
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 58-4 (34.7 mg, 154.16 ⁇ mol), and the synthesis method was the same to obtain compound 58 (2.0 mg, 4.41 ⁇ mol).
  • Embodiment 59 the synthesis of compound 59
  • Step 1 Synthesis of Compound 59-2:
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced by 59-3 (34.60 mg, 135.11 ⁇ mol), and the synthesis method was the same to obtain compound 59 (3.49 mg, 7.07 ⁇ mol).
  • Embodiment 60 the synthesis of compound 60
  • step 2 in Example 28 According to the synthesis method of step 2 in Example 28, 28-2 (55.13 mg, 269.37 ⁇ mol) in step 2 was replaced with 60-2 (35.22 mg, 193.94 ⁇ mol), and the synthesis method was the same to obtain compound 60 (4.13 mg, 8.20 ⁇ mol).
  • Embodiment 61 the synthesis of compound 61
  • Substrate 61-2 (700mg, 2.94mmol), ethyl iodide (458.57mg, 2.94mmol), Cs 2 CO 3 (1.05g, 3.23mmol) were added to a single-necked flask, DMF (3mL) was added and stirred to dissolve. The reaction was carried out at °C for 8h, monitored by LCMS.
  • step 3 in Example 1 According to the synthesis method of step 3 in Example 1, 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 was replaced with 61-3 (30 mg, 112.73 ⁇ mol), and the synthesis method was the same to obtain compound 61 (8.85 mg, 17.89 ⁇ mol).
  • Embodiment 62 the synthesis of compound 62
  • Substrates 62-2 (142 mg, 755.2 ⁇ mol), 62-3 (77.1 mg, 755.2 ⁇ mol) and methanol (2 mL) were added into a dry microwave tube, and reacted in an oil bath at 60°C under nitrogen protection for 1 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure, then 1,4-dioxane (2 mL) and iodobenzene acetate (267.2 mg, 830.7 ⁇ mol) were added, and reacted overnight under nitrogen protection at room temperature, monitored by LC-MS.
  • reaction solution was concentrated under reduced pressure, extracted three times with ethyl acetate and water, the organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 62-4 (116 mg, 429.5 ⁇ mol) as an orange solid.
  • step 3 in Example 1 replace 1-5 (109.92 mg, 441.22 ⁇ mol) in step 3 with 62-4 (134 mg, 496.14 ⁇ mol), the synthesis method is the same, and during the reaction, a decarboxylation reaction occurs , thus obtaining compound 62 (10 mg, 19.06 ⁇ mol).
  • AZD-1775 used in some biological evaluation experiments in this part of the examples is used as a control, and the structural information of AZD-1775 (CAS number: 955365-80-7) is as follows:
  • Test Example 1 Evaluation of compound binding to Tracer 178 on Wee1 protein by TR-FRET method.
  • Tracer 178 and MAb Anti-GST-Eu crypate are configured in buffer (50mM HEPES pH 7.5, 10mM MgCl2, 1mM EGTA, 0.01% Brij-35), and the final reaction concentration of Tracer178 is 50 nM, MAb Anti-GST-Eu crypate The final concentration was 2nM, and the negative control (minimum signal control) used an equal amount of buffer instead of protein solution.
  • Compound number IC50 measured value Compound number IC50 measured value Compound number IC50 measured value Compound number IC50 measured value 1 ++++ twenty three ++++ 43B +++ 2 +++ twenty four +++ 44 ++ 3 +++ 25 ++++ 45 +++ 4 +++ 26 ++++ 46 +++ 5 +++ 27A ++++ 47 ++ 6 +++ 27B +++ 48 +++ 7 ++++ 28 ++ 49 ++ 8 ++++ 29 ++ 50 ++ 9 ++++ 30 +++ 51 +++ 10 ++++ 31 +++ 52 ++ 11 +++ 32 ++ 53 +++
  • Test Example 2 The anti-proliferation effect of the compound on H1299 and MIA Paca-2 cells was evaluated by the Cell Titer-Glo method.
  • DMSO was dissolved to a concentration of 10 mM test compound and 10 mM reference compound AZD1775, and the compounds were serially diluted in the medium, with a total of 9 dose points, and 2 parallel replicates were set for each concentration.
  • the cell growth group without compound was used as a positive control (maximum signal control), and the culture medium was used as a negative control (minimum signal control), while ensuring that the final DMSO content in each reaction well was 0.2%.
  • IC50 of the compound on cell activity inhibition was calculated by GraphPad Prism 6 with log(inhibitor)vs.response–Variable slope model fitting.
  • the compound of the present invention has strong cell proliferation inhibitory activity on H1299 and MIA Paca-2
  • Test Example 3 Evaluation of metabolic stability of liver microsomes (mouse and human) in vitro
  • the microsomes were taken out from the -80°C refrigerator, quickly thawed in a 37°C water bath, and placed on ice for use.
  • the test article was diluted with DMSO to make a 10 mM stock solution, and then diluted with acetonitrile to make a 0.5 mM secondary stock solution.
  • Use Buffer C to dilute NADPH to 6mM working solution, which is the starting solution.
  • the internal standard is Verapamil-HCl with a concentration of 4 ng/ml.
  • the reaction was carried out on an incubator and shaking device, and 15 ⁇ L/sample of the starting solution was sucked up with a discharge gun, and added to the reaction plate. Shake slightly to start the reaction, use a timer to accurately time and record;
  • the compounds of the present invention have good metabolic stability in liver microsomes (mouse and human) in vitro.
  • Sample preparation Dissolve the compound in DMSO into a 10mM stock solution, then dilute the compound into a 0.02mM secondary stock solution with PBS, and then use blank plasma to dilute the above 0.02mM to 1 ⁇ M, which is the sample to be incubated.
  • Dialysis device preparation first add 400 ⁇ L of blank PBS to the white well of the equilibrium dialysis plate, add 200 ⁇ L of the prepared plasma sample to the red well, and seal the dialysis plate with a sealing film.
  • acetonitrile Verapamil-HCl, 4 ng/mL
  • the dialysis device and the T5 plate were placed in a microplate constant temperature shaker and incubated together for 5 hours (37° C., using 300 rpm or the minimum rotation speed). After incubation, 300 ⁇ L of acetonitrile (Verapamil-HCl, 4 ng/mL) was added, followed by 50 ⁇ L of PBS solution. After the dialysis incubation, take a new 96-well deep-well plate.
  • ⁇ Plasma protein binding rate [(Rpe-Rb)/Rpe] ⁇ 100%
  • R pe ratio of the peak area of the test product on the plasma side to the internal standard
  • R b ratio of the peak area of the test product on the buffer side to the internal standard
  • ⁇ R 5 Incubator stability sample peak area to internal standard ratio
  • ⁇ R 0 The ratio of the peak area of the refrigerator stability sample to the internal standard
  • the compound of the present invention has a good ratio of plasma protein binding to free drug. Compared with AZD-1775, the plasma protein binding of the compound of the present invention is similar, and the fluctuation difference among species is smaller.
  • Caco-2 cells were purchased from the American Type Tissue Cell Collection (Rockville, MD).
  • the cell culture medium is modified Eagle's medium (MEM) containing 10% inactivated fetal bovine serum and 1% non-essential amino acids.
  • MEM modified Eagle's medium
  • Cells were inoculated on polycarbonate filter membrane (product number: 3396) and cultured in a 37°C, 5% CO 2 incubator.
  • Cells cultured for 21-28 days after inoculation can be used for transport experiments, and the compactness of the cell monolayer can be characterized and verified by the apparent permeability coefficient (P app ) of Lucifer yellow.
  • P app apparent permeability coefficient
  • the compound was dissolved in DMSO to prepare a 10 mM stock solution, and was diluted with Hanks' balanced salt solution (HBSS, Invitrogen, Cat#14025-092) containing 25 mM HEPES (pH 7.4) to obtain a working solution. Add 10 ⁇ M working solution of the compound to be tested to the apical side and basolateral side of Caco-2 and incubate at 37°C for 90 minutes.
  • HBSS Hanks' balanced salt solution
  • HEPES pH 7.4
  • the compounds of the present invention have good membrane-permeability properties.
  • the compound was given to 6 male ICR mice at corresponding doses by oral gavage (10 mg/kg).
  • Anticoagulant whole blood was collected at 5min, 30min, 2h, and 8h after the administration of the mice in group B, and the anticoagulant whole blood was collected at 15min, 1h, 4h, and 24h after the administration of the mice in group B, and the plasma was separated;
  • Plasma concentrations of compounds were determined by standard curve calibration using LC-MS. The plasma concentration-time data were fitted to pharmacokinetic parameters using Winnolin 5.2 software.
  • PK parameters AZD-1775 Compound 1 Compound 28 Compound 40 T1/2, hr 0.77 1.71 1.78 0.70 C max (ng/mL) 445 169 337 377 AUC inf_Pred (hr*ng/mL) 500 260 743 493 Cl_pred (L/hr/kg) 20.8 39.5 13.8 24.3
  • the compound of the present invention has good in vivo pharmacokinetic properties, can significantly increase the half-life of the compound and reduce the clearance rate.
  • Test Example 8 Evaluation of compound's inhibition of cytochrome P450
  • Enzyme experiments use the fluorescence generated by the oxidation of substrates by cytochrome P450 to quantitatively detect the inhibition of small molecule inhibitors on the enzymatic activity of each subtype of CYP450.
  • the experiment was carried out in a 384-well plate (Corning, Cat#3575), and the reaction buffer used was: 142.86mM Potassium Phosphate, pH 7.4.
  • the components of Solution A used in the experiment are: 26.13mM NADP+ (Sigma-aldrich, Cat#N0505), 65.77mM G6P (J&K, Cat#968161) and 65.42mM MgCl2 (Sigma-aldrich, Cat#M2670).
  • the composition of Solution B used in the experiment is: 40U/mL G6PDH (Sigma-aldrich, Cat#G6378).
  • the composition of the substrate mixed solution is: 0.05X Solution A, 0.01X Solution B, 50mM Potassium Phosphate, 0.01mM BOMCC/0.01mM EOMCC/0.001mM DBOMF.
  • the reaction system is 50 ⁇ L or 20 ⁇ L, respectively, including 3 nM CYP3A4 or 120 nM CYP2C9, BOMCC substrate mixed solution and different concentrations of test compounds.
  • the reaction system is 20 ⁇ L, including 12.5nM CYP2C19, 80nM CYP2D6 or 1nM CYP1A2, EOMCC substrate mixed solution and different concentrations of test compounds.
  • the reaction system is 50 ⁇ L, including 1.5 nM CYP2C8, DBOMF substrate mixed solution and different concentrations of the test compound.
  • the cell line used in the patch clamp experiment was the 10th passage CHO cells overexpressing the hERG potassium ion channel cDNA.
  • CHO hERG cells were cultured in culture dishes or flasks in a 37°C, 5% CO2 incubator. 24-48 hours before the electrophysiological experiment, the cells were dropped on a circular glass slide and cultured in the cell culture medium, and used for the experiment after the cells adhered to the wall.
  • the final concentration of the compound used for electrophysiological detection was 5, 20 ⁇ M, and the final concentration of DMSO was 0.1%.
  • Cisapride (C4740-10 mg, Sigma) was used as a positive control in the experiment to ensure that the cells used had a normal response.
  • test data in the report needs to meet the following criteria:
  • the hERG inhibitory activity of the compound of the present invention is significantly lower than that of AZD-1775.

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Abstract

提供了一类式I所示的具有Wee1抑制作用的新化合物及其在制备药物中的用途。

Description

Wee1抑制剂及其用途 技术领域
本发明涉及一类具有Wee1抑制作用的新化合物及其在制备药物中的用途。
背景技术
细胞周期是一个高度调节和控制的过程，目的在于使细胞仅按照特定的刺激和适当的条件进行增殖。正常的细胞周期会依次经历G1期、S期(DNA合成期)、G2期和M期(细胞分裂期)。在G1-S转换、S期、G2-M转换等期间具有数个周期阻滞检查点，用于维持基因组的完整性，并在进入有丝分裂前为修复损伤性DNA提供时间。
Wee1蛋白是一种酪氨酸激酶，它是G2-M细胞周期检查点的一个关键组成部分，可以阻止细胞DNA损伤进入有丝分裂。CDK1(Cyclin-dependent kinase 1)通过Wee1磷酸化其酪氨酸15而维持在无活性状态，然后CDK1在苏氨酸14被髓磷脂转录因子(MYT1)磷酸化。因此Wee1是G2-M转变中进入有丝分裂的负调节器，起着重要的监测作用。Wee1在很多恶性肿瘤中过表达，比如肝癌、乳腺癌、恶性胶质瘤、黑色素瘤、成人和儿童脑瘤。其中部分肿瘤细胞G1检查点异常，如果抑制Wee1活性会导致G2期检查点故障，导致没有修复的损伤DNA的细胞最终分裂致死。因此Wee1抑制剂在抗癌治疗中有关键作用，目前已成为抗癌药物的研发热点。
目前已有小分子Wee1抑制剂报道(WO2007126128、WO2004007499等)，但尚未有Wee1抑制剂上市。目前研发进度最快的化合物是AZD-1775，已经进入临床Ⅱ期实验，但临床实验中不良反应发生率较高，还需要开发新的活性更好、安全性更高的Wee1抑制剂药物。
发明内容
本发明提供了一种式I所示的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐：
Figure PCTCN2022092348-appb-000001
其中，
R 1选自氢、卤素、氰基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素 取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR 11、-C 0～4亚烷基-NR 12R 12；
R 11选自-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基；
每个R 12分别独立选自氢、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基；
C环选自
Figure PCTCN2022092348-appb-000002
Figure PCTCN2022092348-appb-000003
X 1、X 2、X 4分别独立选自N或CR 4；
X 3选自N或CR 3；
X 5选自O、S或NR 4；
X 6选自CR 4或N；
X 8选自CR 4R 4、O；
X 7选自S、NR 4；R 2选自
Figure PCTCN2022092348-appb-000004
R 21、R 22分别独立选自氢、卤素、氰基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR 24、-C 0～4亚烷基-NR 24R 24；
每个R 24分别独立选自氢、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基；
或者，R 21、R 22与相连原子一起形成3～8元碳环基、4～8元杂环烷基、
Figure PCTCN2022092348-appb-000005
R 23选自氢、卤素、氰基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-C(O)R 25、-C 0～4亚烷基-C(O)NR 25R 25、-C 0～4亚烷基-C(O)OR 25、-C 0～4亚烷基-S(O) 2R 25、-C 0～4亚烷基-S(O)R 25、-C 0～4亚烷基-S(O)(NH)R 25、-C 0～4亚烷基-S(NH) 2R 25、-C 0～4亚烷基-S(O) 2NR 25R 25、-C 0～4亚烷基-S(O)NR 25R 25、-C 0～4亚烷基-S(O)(NH)NR 25R 25、-C 0～4亚烷基-S(NH) 2NR 25R 25、-C 0～4亚烷基-OR 25、-C 0～4亚烷基-OC(O)R 25、 -C 0～4亚烷基-OS(O) 2R 25、-C 0～4亚烷基-OS(O)R 25、-C 0～4亚烷基-NR 25R 25、-C 0～4亚烷基-NR 25C(O)R 25、-C 0～4亚烷基-NR 25S(O) 2R 25、-C 0～4亚烷基-NR 25S(O)R 25、-C 0～4亚烷基-NR 25S(O)(NH)R 25、-C 0～4亚烷基-NR 25S(NH) 2R 25；
每个R 25分别独立选自氢、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基；
或者，R 23、R 3与相连原子一起形成4～8元碳环基、4～8元杂环烷基；
R 3选自氢、卤素、氰基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、羟基取代的-C 1～6烷基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
每个R 4分别独立选自氢、卤素、氰基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
R 5选自氢、-C 1～6烷基；
A环选自
Figure PCTCN2022092348-appb-000006
Figure PCTCN2022092348-appb-000007
Figure PCTCN2022092348-appb-000008
表示单键或双键；
Y 1、Y 2、Y 3、Y 4分别独立选自N或CR Y；
每个R Y分别独立选自氢、卤素、氰基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6 烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
B环选自3～12元碳环基、4～12元杂环烷基；所述碳环基、杂环烷基可进一步被一个、两个、三个、四个或五个R B取代；
每个R B分别独立选自氢、卤素、氰基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR B1、-C 0～4亚烷基-OC(O)R B1、-C 0～4亚烷基-SR B1、-C 0～4亚烷基-S(O) 2R B1、-C 0～4亚烷基-S(O)R B1、-C 0～4亚烷基-S(O) 2NR B1R B1、-C 0～4亚烷基-S(O)NR B1R B1、-C 0～4亚烷基-C(O)R B1、-C 0～4亚烷基-C(O)OR B1、-C 0～4亚烷基-C(O)NR B1R B1、-C 0～4亚烷基-NR B1R B1、-C 0～4亚烷基-NR B1C(O)R B1、3～12元碳环基、4～12元杂环烷基；所述碳环基、杂环烷基可进一步被一个、两个、三个、四个或五个R B1取代；
或者，两个独立的R B与相连原子一起形成
Figure PCTCN2022092348-appb-000009
每个R B1分别独立选自氢、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基；
R 6、R 7、R 8、R 9分别独立选自氢、卤素、氰基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
或者，R 6、R 7与相连原子一起形成3～8元碳环基、4～8元杂环烷基；或者，R 8、R 9与相连原子一起形成3～8元碳环基、4～8元杂环烷基；
Y 5、Y 6分别独立选自化学键、-C 0～4亚烷基-O-、-C 0～4亚烷基-S-、-C 0～4亚烷基-NR Y51-、CR Y51R Y51；
每个R Y51分别独立选自氢、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
Y 7选自O、S或NR Y71；
R Y71选自氢、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
R 10选自氢、卤素、氰基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素 取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)。
进一步地，
R 1选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OR 11、-NR 12R 12；
R 11选自-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基；
每个R 12分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；
R 10选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OH、-O(C 1～6烷基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)。
更进一步地，
R 1选自氢、卤素、氰基、-C 1～6烷基、三氟甲基、-O(C 1～6烷基)、-O(C 2～6烯基)、-O(三氟甲基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)；
R 10选自氢、卤素、-C 1～6烷基、-O(C 1～6烷基)。
进一步地，
C环选自
Figure PCTCN2022092348-appb-000010
Figure PCTCN2022092348-appb-000011
更进一步地，
R 2选自
Figure PCTCN2022092348-appb-000012
R 21、R 22分别独立选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OR 24；
每个R 24分别独立选自氢、-C 1～6烷基；
或者，R 21、R 22与相连原子一起形成羰基、3元碳环基、4元碳环基、5元碳环基、6元碳环基、4元杂环烷基、5元杂环烷基、6元杂环烷基；所述杂环烷基中的杂原子选自N、O、S；
R 23选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-S(O) 2R 25、-S(O)R 25、-S(O)(NH)R 25、-S(NH) 2R 25；
每个R 25分别独立选自氢、-C 1～6烷基。
更进一步具体地，
R 2选自
Figure PCTCN2022092348-appb-000013
进一步地，
C环选自
Figure PCTCN2022092348-appb-000014
R 2选自
Figure PCTCN2022092348-appb-000015
R 21、R 22分别独立选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OR 24；
每个R 24分别独立选自氢、-C 1～6烷基；
R 23、R 3与相连原子一起形成4元碳环基、5元碳环基、6元碳环基、7元碳环基、5元杂环烷基、6元杂环烷基。
更进一步地，
C环选自
Figure PCTCN2022092348-appb-000016
其中，m选自0、1、2、3。
更进一步地，
R 2选自
Figure PCTCN2022092348-appb-000017
R 21、R 22分别独立选自氢、-C 1～6烷基。
进一步地，
A环选自
Figure PCTCN2022092348-appb-000018
Y 1、Y 2、Y 3、Y 4分别独立选自N或CR Y；
每个R Y分别独立选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
B环选自3～8元单碳环基、4～8元单杂环烷基、5～10元桥碳环基、5～10元桥杂环烷基、5～10元螺碳环基、5～10元螺杂环烷基、8～12元稠碳环基、8～12元稠杂环烷基；所述单碳环基、单杂环烷基、桥碳环基、桥杂环烷基、螺碳环基、螺杂环烷基、稠碳环基、稠杂环烷基可进一步被一个、两个、三个、四个或五个R B取代；
每个R B分别独立选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OR B1、-SR B1、-S(O) 2R B1、-S(O)R B1、-C(O)R B1、-C(O)OR B1、-NR B1R B1、3～12元碳环基、4～12元杂环烷基；所述碳环基、杂环烷基可进一步被一个、两个、三个、四个或五个R B1取代；或者，两个独立的R B与相连原子一起形成
Figure PCTCN2022092348-appb-000019
每个R B1分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；
Y 5选自O、S、NR Y51、CR Y51R Y51；
每个R Y51分别独立选自氢、-C 1～6烷基。
更进一步地，
B环选自
Figure PCTCN2022092348-appb-000020
Figure PCTCN2022092348-appb-000021
更进一步具体地，
B环选自
Figure PCTCN2022092348-appb-000022
Figure PCTCN2022092348-appb-000023
进一步地，
A环选自
Figure PCTCN2022092348-appb-000024
Y 1、Y 2、Y 3、Y 4分别独立选自N或CR Y；
每个R Y分别独立选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
R 6、R 7、R 8、R 9分别独立选自氢、-C 1～6烷基；
或者，R 6、R 7与相连原子一起形成3元碳环基、4元碳环基、5元碳环基、6元碳环基、4元杂环烷基、5元杂环烷基、6元杂环烷基；或者，R 8、R 9与相连原子一起形成3元碳环基、4元碳环基、5元碳环基、6元碳环基、4元杂环烷基、5元杂环烷基、6元杂环烷基；
R B选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、-S(O) 2R B1、-S(O)R B1、-C(O)R B1、-C(O)OR B1；
每个R B1分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基。
更进一步地，
A环选自
Figure PCTCN2022092348-appb-000025
Figure PCTCN2022092348-appb-000026
进一步地，
A环选自
Figure PCTCN2022092348-appb-000027
Y 1、Y 2、Y 4分别独立选自N或CR Y；
每个R Y分别独立选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
R B选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、-S(O) 2R B1、-S(O)R B1、-C(O)R B1、-C(O)OR B1；
每个R B1分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；
Y 5选自化学键、O、S、NR Y51、CR Y51R Y51；
每个R Y51分别独立选自氢、-C 1～6烷基。
更进一步地，
A环选自
Figure PCTCN2022092348-appb-000028
进一步地，
A环选自、
Figure PCTCN2022092348-appb-000029
Figure PCTCN2022092348-appb-000030
Figure PCTCN2022092348-appb-000031
表示单键或双键；
Y 1、Y 2、Y 4分别独立选自N或CR Y；
每个R Y分别独立选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
R B选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、-S(O) 2R B1、-S(O)R B1、-C(O)R B1、-C(O)OR B1；
每个R B1分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；
Y 5、Y 6分别独立选自化学键、-C 0～1亚烷基-O-、-C 0～1亚烷基-S-、-C 0～1亚烷基-NR Y51-、CR Y51R Y51；
每个R Y51分别独立选自氢、-C 1～6烷基。
更进一步地，
A环选自
Figure PCTCN2022092348-appb-000032
Figure PCTCN2022092348-appb-000033
进一步地，
A环选自
Figure PCTCN2022092348-appb-000034
Figure PCTCN2022092348-appb-000035
Y 1选自N或CR Y；
R Y选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
B环选自3～8元单碳环基、4～8元单杂环烷基；所述单碳环基、单杂环烷基可进一步被一个、两个、三个、四个或五个R B取代；
每个R B分别独立选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OR B1、-SR B1、-S(O) 2R B1、-S(O)R B1、-C(O)R B1、-C(O)OR B1、-NR B1R B1；或者，两个独立的R B与相连原子一起形成
Figure PCTCN2022092348-appb-000036
每个R B1分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；
Y 7选自O、S或NR Y71；
R Y71选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 1～4亚烷基-OH、-C 1～4亚烷基-O(C 1～6烷基)、-C 1～4亚烷基-NH 2、-C 1～4亚烷基-NH(C 1～6烷基)、-C 1～4亚烷基-N(C 1～6烷基)(C 1～6烷基)。
更进一步地，
A环选自
Figure PCTCN2022092348-appb-000037
Figure PCTCN2022092348-appb-000038
更进一步地，
C环选自
Figure PCTCN2022092348-appb-000039
Figure PCTCN2022092348-appb-000040
Figure PCTCN2022092348-appb-000041
更进一步地，
A环选自
Figure PCTCN2022092348-appb-000042
Figure PCTCN2022092348-appb-000043
Figure PCTCN2022092348-appb-000044
在本发明的一些具体实施方案中，式I所示的化合物具体为：
Figure PCTCN2022092348-appb-000045
Figure PCTCN2022092348-appb-000046
Figure PCTCN2022092348-appb-000047
Figure PCTCN2022092348-appb-000048
Figure PCTCN2022092348-appb-000049
Figure PCTCN2022092348-appb-000050
Figure PCTCN2022092348-appb-000051
Figure PCTCN2022092348-appb-000052
Figure PCTCN2022092348-appb-000053
Figure PCTCN2022092348-appb-000054
Figure PCTCN2022092348-appb-000055
Figure PCTCN2022092348-appb-000056
Figure PCTCN2022092348-appb-000057
本发明还提供了上述任一所述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐在制备Wee1抑制剂药物中的用途。
本发明还提供了任一所述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐在制备预防和/或治疗癌症中的用途。
本发明还提供了一种药物组合物，包括上述任一所述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐制备而成的制剂。
上述的药物组合物，其进一步包括药学上可接受的载体、辅料、媒介物。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或基团所替换；或者是分子中原子的孤对电 子被其它的原子或基团替换，例如S原子上的孤对电子可被O原子取代形成
Figure PCTCN2022092348-appb-000058
“可进一步被取代”是指“取代”可以但不必须发生，该说明包括发生或不发生的情形。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀C a～b烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，C 1～6烷基是指包含1～6个碳原子的烷基。
“烷基”是指具有指定数目的成员原子的饱和烃链。烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷基基团可任选地被一个或多个如本文所定义的取代基取代。烷基包括甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)、戊基(正戊基、异戊基和新戊基)和己基。烷基基团也可以是其他基团的一部分，所述其他基团为例如-O(C 1～6烷基)。
“亚烷基”是指具有指定数目的成员原子的二价饱和脂族烃基。C a～ b亚烷基是指具有a至b个碳原子的亚烷基基团。亚烷基基团包括支链和直链烃基基团。例如，术语“亚丙基”可以通过下列结构例举：
Figure PCTCN2022092348-appb-000059
同样地，术语“二甲基亚丁基”可以例如通过下列结构的任一种例举：
Figure PCTCN2022092348-appb-000060
本发明的-C 0-4亚烷基可以为C 0亚烷基、C 1亚烷基(例如-CH 2-)、C 2亚烷基(例如-CH 2CH 2-等)、C 3亚烷基或C 4亚烷基；C 0亚烷基指的是此处的基团以化学键的形式连接，如A-C 0亚烷基-B指的是A-B，即A基团与B基团直接通过化学键连接。
本发明中所述的“碳环基”是指具有多个碳原子且没有环杂原子的具有单个环或多个环(稠合、桥连、螺合)的饱和或非芳香性的部分饱和的环状基团。术语“碳环基”包括环烯基基团，诸如环己烯基。单碳环基基团的实例包括例如环丙基、环丁基、环己基、环戊基、环辛基、环戊烯基和环己烯基。稠碳环基体系的碳环基基团实例包含双环己基、双环戊基、双环辛基等，下面例举并命名两种此类双环烷基多环结构：
Figure PCTCN2022092348-appb-000061
双环己基和
Figure PCTCN2022092348-appb-000062
双环己基。桥碳环基体系的碳环基基团的实例包括
Figure PCTCN2022092348-appb-000063
金刚烷基等。螺碳环基体系的碳环基基团的实 例包括
Figure PCTCN2022092348-appb-000064
等。术语“碳环基”还包括芳香环与非芳香环稠合形成的部分饱和环状基团的情形，其连接位点可以位于非芳族碳原子或芳族碳原子，实例包括1,2,3,4-四氢化萘-5-基、5,6,7,8-四氢化萘-5-基。
本发明中所述的不饱和是指基团或者分子中含有碳碳双键、碳碳三键、碳氧双键、碳硫双键、碳氮三键等。
进一步的本发明中所述的“杂环烷基”是指包含至少一个杂原子的具有单个环或多个环(稠合、桥连、螺合)的饱和环或非芳香性的部分饱和环；其中杂原子指氮原子、氧原子、硫原子等。通常表示多个环原子的一价饱和或部分不饱和单环或多环环系，其包含1、2或3个选自N、O和S的环杂原子，其余的环原子是碳。单杂环烷基体系的杂环烷基基团的实例是氧杂环丁基、氮杂环丁基、吡咯烷基、2-氧代-吡咯烷-3-基、四氢呋喃基、四氢-噻吩基、吡唑烷基、咪唑烷基、噻唑烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、硫代吗啉基、1，1-二氧代-硫代吗啉-4-基、氮杂环庚基、二氮杂环庚基、高哌嗪基或氧杂氮杂环庚基等。稠杂环烷基体系的杂环烷基基团的实例包括8-氮杂-二环[3.2.1]辛基、奎宁环基、8-氧杂-3-氮杂-二环[3.2.1]辛基、9-氮杂-二环[3.3.1]壬基等。桥杂环烷基体系的杂环烷基基团实例包含
Figure PCTCN2022092348-appb-000065
等。螺杂环烷基体系的杂环烷基基团实例包含
Figure PCTCN2022092348-appb-000066
Figure PCTCN2022092348-appb-000067
等。部分饱和杂环烷基的实例是二氢呋喃基、咪唑啉基、四氢-吡啶基或二氢吡喃基等。术语“杂环烷基”还包括包含至少一个杂原子的芳香环与非芳香环稠合形成的部分饱和环状基团的情形，其连接位点可以位于非芳族碳原子、芳族碳原子或杂原子，实例包括
Figure PCTCN2022092348-appb-000068
Figure PCTCN2022092348-appb-000069
本发明中所述的“芳环基”是指具有多个碳原子的芳烃基团。芳基通常是具有多个碳原子的单环、二环或三环芳基。此外，本文所用的术语“芳基”是指可以是单个芳环或稠合在一起的多 个芳环的芳族取代基。非限制性实例包括苯基、萘基或四氢萘基。
本发明中所述的“芳杂环基”是指包含至少一个杂原子的芳香性不饱和环；其中杂原子指氮原子、氧原子、硫原子等。通常包含多个环原子的、其中一个或多个环原子选自O、N、S的杂原子的芳族单环或双环烃。优选地有一到三个杂原子。杂环芳基例如代表：吡啶基、吲哚基、喹噁啉基、喹啉基、异喹啉基、苯并噻吩基、苯并呋喃基、苯并噻吩基、苯并吡喃基、苯并噻吡喃基、呋喃基、吡咯基、噻唑基、噁唑基、异噁唑基、三唑基、四唑基、吡唑基、咪唑基、噻吩基、噁二唑基、苯并咪唑基、苯并噻唑基、苯并噁唑基。
本发明中所述的“卤素”是指氟、氯、溴或碘。
本发明中所述的“卤素取代的烷基”是指烷基中的一个或多个氢原子被卤素取代；例如单氟甲基、二氟甲基、三氟甲基。
本发明中所述的“氘取代的烷基”是指烷基中的一个或多个氢原子被氘原子取代；例如三氘甲基。
本发明中所述的“-OR”、“-NRR”等是指R基团与氧原子或氮原子以单键相连。
本发明中所述的“-C(O)R”、“-S(O) 2R”等中的氧原子是与碳原子或硫原子以双键相连，R基团与氧原子或硫原子以单键相连；又例如“-S(O)(NH)R”是指氧原子和氮原子以双键与硫原子相连，R基团与硫原子以单键相连。
本发明中所述的
Figure PCTCN2022092348-appb-000070
是指氧原子、硫原子通过双键连接到取代位置。
本发明基团描述中的
Figure PCTCN2022092348-appb-000071
是用来描述基团取代的位置。
本发明的“氘代化合物”是指分子或基团中的1个或多个氢原子被氘原子取代，其中氘原子的占比大于氘在自然界中的丰度。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述 盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
在某些实施方式中，本发明的一种或多种化合物可以彼此联合使用。也可选择将本发明的化合物与任何其它的活性试剂结合使用，用于制备调控细胞功能或治疗疾病的药物或药物组合物。如果使用的是一组化合物，则可将这些化合物同时、分别或有序地对受试对象进行给药。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
化合物的结构是通过核磁共振(NMR)和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker AvanceIII 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3),氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
LC-MS的测定使用岛津液质联用仪(Shimadzu LC-MS 2020(ESI))。HPLC的测定使用岛津高压液相色谱仪(Shimadzu LC-20A)。MPLC(中压制备色谱)使用Gilson GX-281反相制备色谱仪。薄层层析硅胶板用烟台黄海HSGF254或青岛GF254硅胶板，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于安耐吉化学、成都科龙化工、韶远化学科技、百灵威科技等公司。
实施例中无特殊说明，反应在氮气氛围下进行。实施例中无特殊说明，溶液是指水溶液。实施例中无特殊说明，反应的温度为室温。实施例中无特殊说明，M是摩尔每升。
实施例中无特殊说明时，HPLC测试条件如下：
方法A(method A)：
柱子:Boston Green C18 150mm*4.6mm 5μm；流动相A:0.05％三氟乙酸水溶液,流动相B:0.05％三氟乙酸的乙腈溶液；梯度:10分钟时间流动相B从5％升到95％，然后保持95％持续5分钟；流速:1.5毫升/分钟；柱温:40℃。
方法B(method B)：
柱子:Boston Green ODS 150mm*4.6mm 5μm；流动相A:0.01M碳酸氢钠水溶液，流动相B:乙腈；梯度:10分钟时间流动相B从5％升到95％，然后保持95％持续5分钟；流速:1.5毫升/分钟；柱温:40℃。
实施例1：化合物1的合成
Figure PCTCN2022092348-appb-000072
步骤1：化合物1-3的合成：
在干燥的单口瓶中加入底物1-1(247.51mg,1.29mmol)，1-2(200mg,1.29mmol)用乙酸(2mL)和1,4-二氧六环(2mL)溶解，加热至110℃搅拌过夜，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物1-3(400mg,1.29mmol)。
步骤2：化合物1-5的合成：
在干燥的微波管中加入底物1-4(2g,8.44mmol)，二甲基亚磺酰亚胺(786.42mg,8.44mmol)，Pd(dba) 2(48.55mg,84.43μmol)，BINAP(52.57mg,84.43μmol)，叔丁醇钾(1.89g,16.89mmol)，加入甲苯(10mL)溶解，在氮气保护下微波120℃反应30min，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物1-5(800mg,3.21mmol)。
步骤3：化合物1的合成：
在干燥的微波管中加入底物1-5(109.92mg,441.22μmol)，1-3(105mg,339.40μmol)，N,N'-二乙基乙二胺(78.88mg,678.80μmol)，CuI(64.64mg,339.40μmol)，K 2CO 3(65.57mg,475.16μmol)，加入1,4-二氧六环(3mL)溶解，在氮气保护下，110℃微波反应，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物1(23mg,48.16μmol)。 1H NMR(400MHz,Methanol-d 4)δ8.94(s,1H),8.20(s,1H),7.82(t,J＝8.0Hz,1H),7.71(d,J＝7.6Hz,1H),7.64(d,J＝8.6Hz,2H),7.03(d,J＝8.5Hz,2H), 6.81(d,J＝7.7Hz,1H),3.80(d,J＝12.7Hz,2H),3.61(d,J＝12.2Hz,2H),3.47(d,J＝8.6Hz,6H),3.29–3.23(m,2H),3.03(s,2H),2.98(s,3H).LCMS(ESI +)m/z:478.3[M+H] +,HPLC method A:R T＝4.44min,purity:99.9％。
实施例2：化合物2的合成
Figure PCTCN2022092348-appb-000073
步骤1：化合物2-2的合成：
在干燥的单口瓶中加入底物2-1(15g,69.43mmol)，溶于THF(50mL)中在冰浴下加入甲基溴化镁(20.70g,173.59mmol)，室温下反应过夜，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物2-2(15g,69.42mmol)。
步骤2：化合物2的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22umol)替换为2-1(45.40mg,210.11umol)，合成方法相同，得到化合物2(10.2mg,22.95μmol)。 1H NMR(400MHz,Methanol-d 4)δ8.99(s,1H),8.30(s,2H),8.01(d,J＝7.4Hz,1H),7.71(d,J＝8.8Hz,2H),7.56(d,J＝7.6Hz,1H),7.05(d,J＝8.7Hz,2H),3.88–3.73(m,2H),3.69–3.56(m,2H),3.29–3.24(m,2H),3.07(d,J＝12.2Hz,2H),2.99(s,3H),1.62(s,6H).LCMS(ESI +)m/z:445.4[M+H] +,HPLC method A:R T＝4.83min,purity:99.9％。
实施例3：化合物3的合成
Figure PCTCN2022092348-appb-000074
步骤1：化合物3-3的合成：
在干燥的单口瓶中加入底物3-1(3g,12.66mmol)，3-2(1.97g,13.93mmol)和碳酸钾(3.50g,25.33mmol)，溶于DMF(10mL)，升温至80℃反应过夜，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物3-3(3g,10.10mmol)。
步骤2：化合物3-4的合成：
在干燥的单口瓶中加入底物3-3(3g,10.10mmol)，加入盐酸(368.11mg,10.10mmol)，溶于甲醇(10mL)，室温反应过夜，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物3-4(2.4g,9.96mmol)。
步骤3：化合物3-5的合成：
在干燥的单口瓶中加入底物3-4(400mg,2.03mmol)，对甲苯磺酸(171.46mg,995.68μmol),加入甲苯(10mL)溶解，升温至115℃反应过夜，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物3-5(400mg,2.03mmol)。
步骤4：化合物3-6的合成：
在干燥的单口瓶中加入底物3-5(350mg,1.78mmol)，1,2-二溴乙烷(500.56mg,2.66mmol)，四丁基硫酸铵(TBAHS,120.44mg,355.27μmol)，NaOH(71.05mg,1.78mmol)，加入甲苯(5mL)溶解，在氮气保护和室温条件下反应过夜，LC-MS监测。反应结束后，反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物3-6(366mg,1.64mmol)。
步骤5：化合物3的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为3-6(89.05mg,399.20μmol)，合成方法相同，得到化合物3(30mg,66.44μmol)。 1H NMR(400MHz,DMSO-d 6)δ9.90(s,1H),9.79(s,1H),9.05(d,J＝0.9Hz,1H),8.34(d,J＝0.9Hz,1H),8.11(t,J＝7.9Hz,1H),8.02(d,J＝8.0Hz,1H),7.71(d,J＝8.7Hz,1H),7.63(d,J＝7.6Hz,1H),7.01(d,J＝8.6Hz,2H),3.78(d,J＝12.7Hz,4H),3.27–3.11(m,2H),3.00–2.91(m,2H),2.88(s,3H),1.81(d,J＝4.2Hz,4H).LCMS(ESI +)m/z:452.4[M+H] +,HPLC method A:R T＝5.54min,purity:99.9％。
实施例4：化合物4的合成
Figure PCTCN2022092348-appb-000075
步骤1：化合物4-3的合成：
在干燥的单口瓶中加入底物4-1(10g,49.99mmol)，4-2(15.64g,109.98mmol)和醋酸钾(4.90g,49.99mmol)溶于DMSO(80mL)，室温搅拌过夜，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物4-3(17g,49.67mmol)。
步骤2：化合物4-4的合成：
在干燥的单口瓶中加入底物4-3(10g,49.99mmol)和碳酸钾(13.71g,99.35mmol)溶于甲醇(50mL)，室温搅拌过夜，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物4-4(13g,48.14mmol)。
步骤3：化合物4的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为4-4(113.48mg,420.21μmol)，合成方法相同，得到化合物4(60mg,120.36μmol)。 1H NMR(400MHz,Methanol-d 4)δ9.00–8.96(m,1H),8.21(s,1H),7.91–7.76(m,2H),7.75–7.67(m,1H),7.60–7.54(m,1H),7.26–7.18(m,1H),6.85–6.76(m,1H),4.58–4.42(m,1H),4.40–4.26(m,1H),3.76(s,2H),3.50(s,6H),3.20(s,1H),3.16–3.12(m,1H),3.07(s,3H).LCMS(ESI +)m/z:499.5[M+H] +,HPLC method A:R T＝5.85min,purity:99.7％。
实施例5：化合物5的合成
Figure PCTCN2022092348-appb-000076
步骤1：化合物5-3的合成：
在干燥的单口瓶中加入底物5-1(5g,28.41mmol)溶于THF(50mL)在-17℃和氮气保护下加入NaHMDS(26.05g,142.06mmol)和5-2(5.35g,56.82mmol)，在-17℃反应1小时，LC-MS监测。反应结束后用乙醚稀释，加入水萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物5-3(6.18g,24.71mmol)。
步骤2：化合物5-4的合成：
在干燥的单口瓶中加入底物5-3(3g,11.99mmol)溶于甲苯(20mL)，加入1,2-二溴乙烷(3.38g,17.99mmol)和四丁基硫酸氢铵(TBAHS,813.23mg,2.40mmol)，室温下搅拌过夜，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物5-4(2.4g,8.69mmol)。
步骤3：化合物5的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为5-4(116.04mg,420.21μmol)，合成方法相同，得到化合物5(20mg,39.63μmol)。 1H NMR(400MHz,DMSO-d 6)δ9.91(s,1H),9.73(s,1H),9.07(s,1H),8.37(s,1H),8.20(d,J＝8.1Hz,1H),8.16–8.07(m,1H),7.71(d,J＝9.0Hz,1H),7.62(dd,J＝7.5,0.9Hz,1H),7.02(d,J＝9.1Hz,1H),3.78(d,J＝13.1Hz,2H),3.54(d,J＝12.1Hz,2H),3.20(s,3H),3.24–3.12(m,2H),2.96(m,2H),2.87(d,J＝3.3Hz,3H),1.75–1.67(m,2H),1.63–1.54(m,2H).LCMS(ESI +)m/z:499.5[M+H] +,HPLC method A:R T＝5.85min,purity:99.7％
实施例6：化合物6的合成
Figure PCTCN2022092348-appb-000077
步骤1：化合物6-2的合成：
按照实施例1中步骤1的合成方法，将步骤1中的1-1(247.51mg,1.29mmol)替换为6-1(115.32mg,647.01μmol)，合成方法相同，得到化合物6-2(122mg,262.62μmol)。
步骤2：化合物6的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-3(105mg,339.40μmol)替换为6-2(100mg,337.47μmol)，合成方法相同，得到化合物6(122mg,262.62μmol)。 1H NMR(400MHz,Methanol-d4)δ7.87(s,2H),7.53(t,J＝7.6Hz,2H),7.19(d,J＝50.6Hz,3H),6.84(s,1H),6.68(s,1H),3.89(d,J＝30.8Hz,4H),3.50–3.34(m,10H).LCMS(ESI +)m/z:465.4[M+H] +,HPLC method A:R T＝5.07min,purity:96.2％。
实施例7：化合物7的合成
Figure PCTCN2022092348-appb-000078
步骤1：化合物7-2的合成：
按照实施例1中步骤1的合成方法，将步骤1中的1-1(247.51mg,1.29mmol)替换为7-1(224.93mg,905.81μmol)，合成方法相同，得到化合物7-2(331mg,0.90mmol)。
步骤2：化合物7-3的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-3(105mg,339.40μmol)替换为7-2(224.93mg,905.81μmol)，合成方法相同，得到化合物7-3(100mg,187.04μmol)。
步骤3：化合物7的合成：
在干燥的单口瓶中加入底物7-3(350mg,93.52μmol)溶于4M HCl/EA(10mL)，室温下搅拌2小时，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物7(32mg,73.65μmol)。 1H NMR(400MHz,DMSO-d 6)δ10.09(s,1H),9.11(s,1H),9.09(s,1H),8.38(s,1H),7.91(s,1H),7.88–7.81(m,1H),7.67(d,J＝7.6Hz,1H),7.55(dd,J＝8.4,2.0Hz,1H),7.19(d,J＝8.4Hz,1H),6.69(d,J＝7.8Hz,1H),4.29(s,2H),3.49(s,6H),3.41(d,J＝5.3Hz,2H),2.96(t,J＝6.1Hz,2H).LCMS(ESI +)m/z:435.4[M+H] +,HPLC method A:R T＝4.41min,purity:99.6％。
实施例8：化合物8的合成
Figure PCTCN2022092348-appb-000079
步骤1：化合物8-2的合成：
在干燥的单口瓶中加入底物8-1(200mg,805.41μmol)溶于干燥的THF(10mL)，在冰浴下加入四氢铝锂(152.84mg,4.03mmol)室温下搅拌30min，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物8-2(130mg,801.33μmol)。
步骤2：化合物8-4的合成：
按照实施例1中步骤1的合成方法，将步骤1中的1-1(247.51mg,1.29mmol)替换为8-2(130mg,801.33μmol)，合成方法相同，得到化合物8-3(224mg,799.07μmol)。
步骤3：化合物8的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-3(105mg,339.4μmol)替换为8-3(100mg,356.73μmol)，合成方法相同，得到化合物8(16mg,35.67μmol)。 1H NMR(400MHz,Methanol-d4)δ9.00–8.96(m,1H),8.21(s,1H),7.91–7.76(m,2H),7.75–7.67(m,1H),7.60–7.54(m,1H),7.26–7.18(m,1H),6.85–6.76(m,1H),4.58–4.42(m,1H),4.40–4.26(m,1H),3.76(s,2H),3.50(s,6H),3.20(s,1H),3.16–3.12(m,1H),3.07(s,3H).LCMS(ESI +)m/z:449.4[M+H] +,HPLC method A:R T＝4.52min,purity:99.5％。
实施例9：化合物9的合成
Figure PCTCN2022092348-appb-000080
步骤1：化合物9-3的合成：
在干燥的单口瓶中加入底物对氟硝基苯(2g,14.17mmol)，9-1(1.82g,14.17mmol)和DIPEA(2.20g,17.01mmol,2.96mL)溶于的ACN(30mL)，升温至85℃，搅拌15小时，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物9-3(3.52g,14.12mmol)。
步骤2：化合物9-4的合成：
在干燥的单口瓶中加入底物9-3(3.52g,14.12mmol)，加入甲醇(10mL)搅拌溶解，随后加入Pd/C(170.51mg,1.40mmol)，H 2置换3次后，室温条件下反应3小时，LC-MS监测。反应结束后用硅藻土过滤除去Pd/C，有机相减压浓缩，残余物用柱层析纯化得到产物9-4(2.1g,9.57mmol)。
步骤3：化合物9-6的合成：
按照实施例1中步骤1的合成方法，将步骤1中的1-1(247.51mg,1.29mmol)替换为9-4(123mg,560.81μmol)，合成方法相同，得到化合物9-6(189mg,560.13μmol)。
步骤4：化合物9的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-3(105mg,339.40μmol)替换为9-6(189mg,560.13μmol)，合成方法相同，得到化合物9(20mg,39.55μmol)。 1H NMR(400MHz,Chloroform-d)δ8.94(s,1H),8.20(s,1H),7.80(t,J＝7.9Hz,1H),7.68(d,J＝7.7Hz,1H),7.62(s,2H),7.05(s,2H),6.78(d,J＝8.1Hz,1H),3.89-3.73(m,2H),3.46-3.43(m,7H),3.43-3.34(m,2H),2.92(s,6H),2.19(s,2H),1.91(s,2H).LCMS(ESI +)m/z:506.5[M+H] +,HPLC method A:R T＝4.31min,purity:95.7％.
实施例10：化合物10的合成
Figure PCTCN2022092348-appb-000081
步骤1：化合物10-2的合成：
在干燥的单口瓶中加入底物10-1(3g,18.62mmol)和碘甲烷(8.7g,61.43mmol)溶于DMF(20mL)，升温至70℃，搅拌15小时，LC-MS监测。反应结束后用水淬灭，加入乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物10-2(3.4g,16.73mmol)。
步骤2：化合物10-3的合成：
在干燥的单口瓶中加入底物10-2(3.3g,16.24mmol)溶于H 2SO 4(10mL)，冰浴下缓慢滴加HNO 3(1.02g,16.24mmol)，0℃下搅拌6小时，TLC监测。反应结束后用水淬灭，加入乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗，有机相用无水硫酸钠干燥后减压浓缩，残余物 用柱层析纯化得到产物10-3(3.9g,15.71mmol)。
步骤3：化合物10-4的合成：
在干燥的单口瓶中加入底物10-3(270mg,1.09mmol)溶于THF(10mL)，冰浴下缓慢滴加BMS(334.82mg,4.35mmol)，升温至70℃下搅拌24小时，LC-MS监测。反应结束后用饱和的亚硫酸钠淬灭，加入乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物10-4(200mg,907.99μmol)。
步骤4：化合物10-5的合成：
在干燥的单口瓶中加入底物10-4(200mg,907.99μmol)溶于乙醇(10mL)加入Pd/C(110.28mg,907.99μmol)H 2置换3次后，在氢气下搅拌3小时，LC-MS监测。反应结束后用硅藻土过滤，有机相减压浓缩，残余物用柱层析纯化得到产物10-5(170mg,893.40μmol)。
步骤5：化合物10-6的合成：
按照实施例1中步骤1的合成方法，将步骤1中的1-1(247.51mg,1.29mmol)替换为10-5(132mg,693.70μmol)，合成方法相同，得到化合物10-6(213mg,690.71μmol)。
步骤6：化合物10的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-3(105mg,339.40μmol)替换为10-6(100mg,324.28μmol)，合成方法相同，得到化合物10(27mg,54.95μmol)。 1H NMR(400MHz,Chloroform-d)δ8.98(s,1H),8.21(s,1H),7.87-7.78(m,2H),7.68(d,J＝7.3Hz,1H),7.62(dd,J＝8.6,2.3Hz,1H),7.46(d,J＝8.7Hz,1H),6.83-6.76(m,1H),4.41(d,J＝6.0Hz,2H),3.55-3.45(m,7H),3.40(s,1H),3.11(s,3H),1.46(s,6H).LCMS(ESI +)m/z:477.4[M+H] +,HPLC method A:R T＝5.02min,purity:96.9％.
实施例11：化合物11的合成
Figure PCTCN2022092348-appb-000082
步骤1：化合物11的合成：
在干燥的三口瓶中加入化合物7(23mg,crude)，(CH 3CO) 2O(6mg,59.0μmol)和Et 3N(12 mg,118.0μmol)并溶于DCM(1mL)中室温搅拌过夜，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到化合物11(4mg,8.40μmol)。 1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),9.09(s,1H),8.36(s,1H),7.92-7.83(m,2H),7.73-7.65(m,1H),7.47-7.42(m,1H),7.12(d,J＝8.4Hz,1H),6.69-6.66(m,1H),4.61(s,2H),3.68(s,2H),3.49(s,6H),2.83(s,2H),2.11(d,J＝4Hz,3H).LCMS(ESI +)m/z:477.2[M+H] +,HPLC method B:R T＝5.77min,purity:92.1％.
实施例12：化合物12的合成
Figure PCTCN2022092348-appb-000083
步骤1：化合物12-2的合成：
在干燥的三口瓶中加入底物甲基溴化镁(1.0M in dry THF,4.4mL)，将底物12-1(8.7g,61.43mmol)溶于THF(5mL)，在0℃和氮气保护下缓慢滴加到三口瓶中，缓慢恢复至室温反应16h，TLC监测。反应结束后用水淬灭，用饱和碳酸氢钠溶液将体系调节至pH＝6-7，加入乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物12-2(210mg，0.99mmol)。 1H NMR(400MHz,Chloroform-d)δ7.58(t,J＝1.9Hz,1H),7.32(t,J＝7.9Hz,2H),7.14(t,J＝7.9Hz,1H),2.17(s,1H),1.50(s,6H).
步骤2：化合物12的合成：
按照化合物1的合成中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为12-2(100mg,470.0μmol)，合成方法相同，得到化合物12(11mg,25.0μmol)。 1H NMR(400MHz,Chloroform-d)δ8.77(s,1H),8.30(t,J＝1.8Hz,1H),8.20(s,1H),7.93(dt,J＝7.2,2.2Hz,1H),7.67(d,J＝8.9Hz,2H),7.53–7.46(m,2H),6.98–6.91(m,2H),3.61(d,J＝39.5Hz,4H),3.35(s,2H),3.04(s,2H),2.88(s,3H),1.62(s,6H).LCMS(ESI +)m/z:444.3[M+H] +,HPLC method A:R T＝5.32min,purity:82.7％.
实施例13：化合物13的合成
Figure PCTCN2022092348-appb-000084
步骤1：化合物13-2的合成：
按照实施例1的合成中步骤1的合成方法，将步骤1中的1-1(247.51mg,1.29mmol)替换为13-1(120mg,0.59mmol)，合成方法相同，得到化合物13-2(80mg,0.25mmol)。
步骤2：化合物13的合成：
按照实施例1的合成中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为13-2(80mg,250.0μmol)，合成方法相同，得到化合物13(25mg,39.91μmol)，酸法制备，产品为为三氟乙酸盐。 1H NMR(400MHz,DMSO-d 6)δ9.66(s,1H),9.02(s,1H),8.31(s,1H),7.80(dd,J＝8.8,7.0Hz,1H),7.72–7.57(m,3H),6.76–6.62(m,3H),4.62(s,1H),4.34(d,J＝2.3Hz,1H),3.69–3.61(m,2H),3.48(d,J＝1.7Hz,6H),3.28(d,J＝10.9Hz,1H),3.09(dt,J＝11.2,2.9Hz,1H),2.88(d,J＝5.0Hz,3H),2.44–2.31(m,1H),2.15(d,J＝11.3Hz,1H).LCMS(ESI +)m/z:490.5[M+H] +,HPLC method A:R T＝4.56min,purity:96.4％.
实施例14：化合物14的合成
Figure PCTCN2022092348-appb-000085
步骤1：化合物14-3的合成：
在干燥的三口瓶中加入底物14-1(182mg,1.42mmol)，14-2(200mg,1.29mmol)和K 2CO 3(534mg,3.87mmol)，溶于DMF(10mL)中，在N 2保护下，升温至90℃反应3h，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，无需纯化，粗产物可直接用于下一步反应，得到14-3(100mg,crude)。LCMS(ESI +)m/z:264.3[M+H] +。
步骤2：化合物14-4的合成：
在干燥的单口瓶中加入底物14-3(100mg,43.0μmol)溶于MeOH(5mL)中，加入Pd/C(30mg)，用H 2置换三次后，室温搅拌30min，LC-MS监测。反应结束后硅藻土过滤，滤液减压浓缩，得到粗产物14-4(109mg,crude)，LCMS(ESI +)m/z:234.2[M+H] +。
步骤3：化合物14-5的合成：
按照实施例1中步骤1的合成方法，将步骤1中的1-1(247.51mg,1.29mmol)替换为14-4(109mg,0.468mmol)，合成方法相同，得到产物14-5(53mg,0.151mmol)。LCMS(ESI +)m/z:352.4[M+H] +。
步骤4：化合物14的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-3(105mg,339.40μmol)替换为14-4(53mg,151.0μmol)，合成方法相同，得到化合物14(11.9mg,22.93μmol)。 1H NMR(400MHz,DMSO-d 6)δ9.79(s,1H),9.03(d,J＝3.6Hz,1H),8.32(s,1H),7.81(d,J＝8Hz,1H),7.77(d,J＝10.4Hz,1H),7.68(d,J＝7.6Hz,1H),7.46-7.44(m,1H),6.98(d,J＝8.4Hz,1H),6.6(d,J＝12.8Hz,1H),3.48(s,1H),3.47(s,6H),3.05(d,J＝10.8Hz,4H),2.24(d,J＝3.6Hz,9H),1.85(d,J＝10.8Hz,2H),1.57-1.53(m,2H).LCMS(ESI +)m/z:520.3[M+H] +,HPLC method B:R T＝4.75min,purity:76.0％.
实施例15：化合物15的合成
Figure PCTCN2022092348-appb-000086
步骤1：化合物15-2的合成：
按照实施例1中步骤1的合成方法，将步骤1中的1-1(247.51mg,1.29mmol)替换为15-1(50mg,0.217mmol)，合成方法相同，得到产物15-2(35mg,0.101mmol)。LCMS(ESI +)m/z: 349.2[M+H] +。
步骤2：化合物15的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-3(105mg,339.40μmol)替换为15-2(35mg,101.0μmol)，合成方法相同，得到化合物15(11.9mg,22.93μmol)。 1H NMR(400MHz,DMSO-d 6)δ9.86(s,1H),9.07(s,1H),8.34(s,1H),7.79(t,J＝7.6Hz,1H),7.65(d,J＝8.4Hz,2H),7.61(d,J＝7.6Hz,1H),7.19(d,J＝8.4Hz,2H),6.66(d,J＝8.0Hz,1H),3.44(s,6H),3.11(s,1H),3.01-2.87(m,2H),2.77-2.66(m,4H),2.30-2.28(m,1H),1.98-1.88(m,4H).LCMS(ESI +)m/z:517.2[M+H] +,HPLC method B:R T＝4.84min,purity:85.7％.
实施例16：化合物16的合成
Figure PCTCN2022092348-appb-000087
步骤1：化合物16-2的合成：
按照实施例1中步骤1的合成方法，将步骤1中的1-1(247.51mg,1.29mmol)替换为16-1(50mg,0.217mmol)，合成方法相同，得到产物16-2(98mg,0.302mmol)。LCMS(ESI +)m/z:324.4[M+H] +。
步骤2：化合物16的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-3(105mg,339.40μmol)替换为16-2(98mg,303.0μmol)，合成方法相同，得到化合物16(22.4mg,45.53μmol)。 1H NMR(400MHz,DMSO-d 6)δ9.82(s,1H),9.05(d,J＝3.6Hz,1H),8.33(s,1H),7.82-7.77(m,2H),7.68(d,J＝7.6Hz,1H),7.47(dd,J＝8.4Hz,1H),7.00(d,J＝8.4Hz,1H),6.66(d,J＝7.6Hz,1H),3.47(s,6H),2.84(s,4H),2.59(s,3H),2.29(s,4H),2.26(s,3H).LCMS(ESI +)m/z:492.2[M+H] +,HPLC method B:R T＝6.50min,purity:92.9％.
实施例17：化合物17的合成
Figure PCTCN2022092348-appb-000088
步骤1：化合物17-3的合成：
按照实施例14中步骤1的合成方法，将步骤1中的14-1(182mg,1.42mmol)替换为17-1(200mg,0.952mmol)，14-2(200mg,1.29mmol)替换为17-2(105mg,1.05mmol)，合成方法相同，得到产物17-3(400mg,crude)。LCMS(ESI +)m/z:290.0[M+H] +。
步骤2：化合物17-4的合成：
在干燥的单口瓶中加入底物17-3(100mg,0.346mmol)溶于EtOH(5mL)，加入Fe粉(97mg,1.73mmol)和AcOH(0.1mL)，升温至80℃搅拌1h，LC-MS监测。反应结束后用硅藻土过滤，滤液减压浓缩，得到产物17-4(66mg,crude)，LCMS(ESI +)m/z:260.1[M+H] +。
步骤3：化合物17-5的合成：
按照实施例1中步骤1的合成方法，将步骤1中的1-1(247.51mg,1.29mmol)替换为17-4(66mg,0.255mmol)，合成方法相同，得到产物17-5(57mg,0.151mmol)。LCMS(ESI +)m/z:378.1[M+H] +。
步骤4：化合物17的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-3(105mg,339.40μmol)替换为17-5(57mg,151.0μmol)，合成方法相同，得到化合物17(7.5mg,13.74μmol)。 1H NMR(400MHz,DMSO-d 6)δ10.34(s,1H),9.16(d,J＝3.6Hz,1H),8.43(s,1H),8.02(s,2H),7.83-7.79(m,2H),7.64(d,J＝8.0Hz,1H),6.70(d,J＝8.0Hz,1H),3.49(s,8H),3.03(s,5H),2.53(s,4H).LCMS(ESI +)m/z:546.1[M+H] +,HPLC method B:R T＝7.80min,purity:65.4％.
实施例18：化合物18的合成
Figure PCTCN2022092348-appb-000089
步骤1：化合物18-2的合成：
按照实施例1中步骤1的合成方法，将步骤1中的1-1(247.51mg,1.29mmol)替换为18-1(27mg,141.89μmol)，合成方法相同，得到产物18-2(40mg,116.74μmol)。LCMS(ESI +)m/z:309.3[M+H] +。
步骤2：化合物18的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-3(105mg,339.40μmol)替换为HGC041-02(60mg,194.57μmol)，合成方法相同，得到化合物18(23mg,47.78μmol)。 1H NMR(400MHz,DMSO-d 6)δ9.88(s,1H),9.08(s,1H),8.34(s,1H),7.91–7.77(m,1H),7.71(d,J＝8.6Hz,2H),7.62(d,J＝7.5Hz,1H),7.20(dd,J＝8.9,2.4Hz,2H),6.70–6.61(m,1H),3.46(s,6H),2.90–2.82(m,2H),2.47–2.35(m,2H),2.19(s,3H),2.00–1.90(m,2H),1.75–1.59(m,3H).LCMS(ESI +)m/z:477.3[M+H] +,HPLC method B:R T＝5.74min,purity:99.0％.
实施例19：化合物19的合成
Figure PCTCN2022092348-appb-000090
步骤1：化合物19-2的合成：
按照实施例1中步骤1的合成方法，将步骤1中的1-1(247.51mg,1.29mmol)替换为19-1(100mg,0.478mmol)，合成方法相同，得到产物19-2(156mg,0.477mmol)。LCMS(ESI +)m/z:328.4[M+H] +。
步骤2：化合物19的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-3(105mg,339.40μmol)替换为19-2(80mg,245.0μmol)，合成方法相同，得到化合物19(14mg,28.27μmol)。 1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),9.03(s,1H),8.36(s,1H),7.79(t,J＝8.0Hz,2H),7.61(d,J＝8.0Hz,1H),7.44(t,J＝6.4Hz,1H),7.02(d,J＝9.6Hz,1H),6.68(d,J＝8.0Hz,1H),3.48(s,6H),3.38(s,4H),2.97(s,4H),2.23(s,3H).LCMS(ESI +)m/z:496.1[M+H] +,HPLC method B:R T＝6.15min,purity:88.7％.
实施例20：化合物20的合成
Figure PCTCN2022092348-appb-000091
步骤1：化合物20-2的合成：
按照实施例1中步骤1的合成方法，将步骤1中的1-1(247.51mg,1.29mmol)替换为20-1(100mg,0.365mmol)，合成方法相同，得到产物20-2(168mg,0.429mmol)。LCMS(ESI +)m/z:393.5[M+H] +。
步骤2：化合物20的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-3(105mg,339.40μmol)替换为20-2(80mg,204.0μmol)，合成方法相同，得到化合物20(20.6mg,36.79μmol)。 1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),9.02(s,1H),8.31(s,1H),7.81(t,J＝8.0Hz,1H),7.64-7.59(m,3H),6.92(d,J＝8.8Hz,2H),6.65(d,J＝8.0Hz,1H),3.65(d,J＝8.0Hz,2H),3.46(s,6H),2.61(t,J＝11.6Hz,2H),2.51(d,J＝2.0Hz,5H),2.29-2.25(m,4H),2.14(s,3H),1.83(d,J＝12.0Hz,2H),1.54-1.47(m,2H).LCMS(ESI +)m/z:561.3[M+H] +,HPLC method B:R T＝5.57min,purity:87.8％.
实施例21：化合物21的合成
Figure PCTCN2022092348-appb-000092
步骤1：化合物21的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-3(105mg,339.40μmol)替换为16-2(74mg,229.0μmol)，1-5(109.92mg,441.22μmol)替换为2-1(41mg,191.0μmol)，合成方法相同，得到化合物21(20.6mg,15.72μmol)。 1H NMR(400MHz,DMSO-d 6)δ9.91(s,1H),9.07(s,1H),8.34(s,1H),8.05(t,J＝7.6Hz,1H),7.98(d,J＝8.8Hz,1H),7.75-7.70(m,2H),7.62(d,J＝2.4Hz,1H),6.99(d,J＝8.8Hz,1H),5.34(s,1H),2.95(s,7H),2.61(s,4H),2.56(s,3H),1.51(s,6H).LCMS(ESI +)m/z:459.2[M+H] +,HPLC method B:R T＝7.24min,purity:85.1％.
实施例22：化合物22的合成
Figure PCTCN2022092348-appb-000093
步骤1：化合物22-2的合成：
按照实施例1中步骤1的合成方法，将步骤1中的1-1(247.51mg,1.29mmol)替换为22-1，合成方法相同，得到产物22-2(50mg,147.32μmol)。LCMS(ESI +)m/z:340.4[M+H] +。
步骤2：化合物22的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-3(105mg,339.40μmol)替换为22-2(50mg,147.32μmol)，合成方法相同，得到化合物22(40mg,78.8μmol)。 1H NMR(400MHz,Chloroform-d)δ8.88(s,1H),8.32(d,J＝9.7Hz,1H),8.07(s,1H),7.76–7.67(m,2H),6.81(d,J＝7.7Hz,1H),6.60–6.55(m,2H),3.91(s,3H),3.50(s,6H),3.30–3.18(m,4H),2.77–2.67(m,4H),2.45(s,3H).
实施例23：化合物23的合成
Figure PCTCN2022092348-appb-000094
步骤1：化合物23-2的合成：
按照实施例1中步骤1的合成方法，将步骤1中的1-1(247.51mg,1.29mmol)替换为23-1，合成方法相同，得到产物23-2(100mg,294.64μmol)。LCMS(ESI +)m/z:340.4[M+H] +。
步骤2：化合物23的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-3(105mg,339.40μmol)替换为23-2(100mg,294.64μmol)，合成方法相同，得到化合物23(70mg,137.9μmol)。 1H NMR(400MHz, DMSO-d 6)δ9.87(s,1H),9.05(s,1H),8.33(s,1H),7.99(s,1H),7.87–7.72(m,2H),7.55(d,J＝8.7Hz,1H),7.04(d,J＝8.7Hz,1H),6.65(d,J＝8.5Hz,1H),5.76(s,1H),5.14–5.01(m,1H),4.58(d,J＝5.1Hz,2H),3.48(s,6H),2.87–2.81(m,4H),2.53–2.50(m,4H),2.25(s,3H)； 1H NMR(400MHz,DMSO-d 6+D 2O)δ9.05(s,1H),8.33(s,1H),7.95(s,1H),7.83(t,J＝7.9Hz,1H),7.74(d,J＝7.7Hz,1H),7.54(dd,J＝8.6,2.7Hz,1H),7.07(d,J＝8.7Hz,1H),6.68(d,J＝7.9Hz,1H),5.69(s,1H),4.59(s,2H),3.47(s,6H),2.87–2.81(m,4H),2.53–2.50(m,4H),2.25(s,3H).
实施例24：化合物24的合成
Figure PCTCN2022092348-appb-000095
步骤1：化合物24-2的合成：
按照实施例1中步骤1的合成方法，将步骤1中的1-2(200mg,1.29mmol)替换为24-1(65mg,2.57mmol)，合成方法相同，得到产物24-2(65mg,0.172mmol)。LCMS(ESI +)m/z:378.2[M+H] +。
步骤2：化合物24的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-3(105mg,339.40μmol)替换为24-2(65mg,0.172mmol)，合成方法相同，得到化合物24(31.8mg,58.35μmol)。 1H NMR(400MHz,DMSO-d 6)δ10.14(s,1H),9.15(s,1H),7.87(s,1H),7.61(d,J＝5.4Hz,3H),6.94(d,J＝7.2Hz,2H),6.74(d,J＝7.8Hz,1H),3.45(s,6H),3.09(s,4H),2.46(s,4H),2.22(s,3H).LCMS(ESI +)m/z:546.2[M+H] +,HPLC method B:R T＝7.51min,purity:95.3％.
实施例25：化合物25的合成
Figure PCTCN2022092348-appb-000096
步骤1：化合物25-2的合成：
在干燥的单口瓶中加入底物25-1(261mg,947.90μmol)，甲醛(85.38mg,2.84mmol)溶于的甲醇(10mL)和乙酸(0.1mL)，室温搅拌1小时后加入NaCNBH 3(148.92mg,2.37mmol)，升温至50℃，搅拌5小时，LC-MS监测。反应结束后，有机相减压浓缩，用水和乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗，有机相用无水硫酸钠干燥后，得到粗产物25-2(260mg,898.50μmol)。LCMS(ESI +)m/z:290.3[M+H] +。
步骤2：化合物25-3的合成：
在干燥的单口瓶中加入底物25-2(260mg,898.50μmol)溶于的甲醇(10mL)加入Pd/C(35.25mg,290.28μmol)，H 2置换3次后，室温条件下反应3h，LC-MS监测。反应结束后用硅藻土过滤，有机相减压浓缩，残余物用柱层析纯化得到产物25-3(231mg,801.50μmol)。LCMS(ESI +)m/z:260.4[M+H] +。
步骤3：化合物25-4的合成：
按照实施例1中步骤1的合成方法，将步骤1中的1-1(247.51mg,1.29mmol)替换为25-3(231mg,801.50μmol)，合成方法相同，得到产物25-4(60mg,158.95μmol)。LCMS(ESI +)m/z:378.5[M+H] +。
步骤4：化合物25的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-3(105mg,339.40μmol)替换为25-4(60mg,158.95μmol)，合成方法相同，得到化合物25(35mg,51.31μmol)。 1H NMR(400MHz,DMSO-d 6)δ9.70(s,1H),9.02(s,1H),8.30(s,1H),7.81(t,J＝7.9Hz,1H),7.62(dd,J＝14.0,8.3Hz,3H),6.92(d,J＝9.0Hz,2H),6.65(d,J＝8.0Hz,1H),3.46(s,6H),3.16–2.92(m,4H),2.33– 2.23(m,4H),2.15(s,3H),1.61–1.51(m,4H),1.51–1.40(m,4H)LCMS(ESI +)m/z:545.7[M+H] +,HPLC method B:R T＝6.09min,purity:81.9％.
实施例26：化合物26的合成
Figure PCTCN2022092348-appb-000097
步骤1：化合物26-2的合成：
按照实施例1中步骤1的合成方法，将步骤1中的1-1(247.51mg,1.29mmol)替换为26-1，合成方法相同，得到产物26-2(100mg,451.88μmol)。LCMS(ESI +)m/z:340.4[M+H] +。
步骤2：化合物26的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-3(105mg,339.40μmol)替换为26-2(60mg,176.79μmol)，合成方法相同，得到化合物26(31mg,59.85μmol)。 1H NMR(600MHz,DMSO-d 6)δ9.83(s,1H),9.06(s,1H),8.33(s,1H),7.77(t,J＝7.7Hz,1H),7.62–7.56(m,2H),7.22(d,J＝8.4Hz,1H),6.85(d,J＝8.5Hz,1H),6.67(d,J＝8.0Hz,1H),3.70(s,3H),3.45(s,6H),2.94–2.91(m,4H),2.46–2.43(m,4H),2.21(s,3H).LCMS(ESI +)m/z:508.2[M+H] +,HPLC method B:R T＝5.64min,purity:98.0％.
实施例27：化合物27的合成
Figure PCTCN2022092348-appb-000098
步骤1：化合物27-A1、27-B1的合成：
在干燥的单口瓶中加入底物27-1(35mg,99.88μmol)，Cs 2CO 3(97mg,299.64μmol)和DMF(5mL)，搅拌5min后加入碘甲烷(40.10mg,282.52μmol)，升温至90℃反应，LC-MS监测。反应完成后，减压浓缩，残余物用中压液相色谱(碱法)纯化得到27-A1(18mg,19.23％yield)或27-B1(26mg,27.78％yield)，LCMS(E+)m/z:365.3[M+H] +。
步骤2：化合物27-A的合成：
在干燥的单口瓶中加入底物27-A1(18mg,49.39μmol)，四氢呋喃(2mL)，搅拌溶解后，加入m-CPBA(10.23mg,59.27μmol)，室温反应1h，LC-MS监测。反应结束后，加入DIPEA(33.39mg,258.36μmol)，搅拌10min后，加入1-1(20.11mg,105.14μmol)，室温条件下反应，LC-MS监测。反应完成后，减压浓缩，得到残余物用中压液相色谱(碱法)纯化得到27-A(3mg,5.91μmol)。 1H NMR(400MHz,DMSO-d 6)δ8.79(s,1H),7.85(d,J＝6.8Hz,1H),7.58(s,2H),7.33(d,J＝8.0Hz,1H),6.92(d,J＝9.2Hz,2H),6.61(d,J＝8.4Hz,1H),3.43(s,3H),3.36(s,6H),3.10(s,4H),2.53(s,4H),2.24(s,3H). 1H NMR(400MHz,DMSO-d 6，D 2O)δ8.79(s,1H),7.85(s,1H),7.57(s,2H),7.33(d,J＝7.8Hz,1H),6.94(d,J＝8.5Hz,2H),6.66(d,J＝7.9Hz,1H),3.44(s,3H),3.35(s,6H),3.11(s,4H),2.49(s,4H),2.24(s,3H).LCMS(ESI +)m/z:508.2[M+H] +,HPLC method B:R T＝5.36min,purity:84.4％.
步骤3：化合物27-B的合成：
在干燥的单口瓶中加入底物27-B1(26mg,71.34μmol)加人四氢呋喃(2mL)，搅拌溶解后，加入m-CPBA(14.77mg,85.61μmol)，室温反应1h，LC-MS监测。反应结束后，加入DIPEA(40.81mg,315.77μmol)，搅拌10min后，加入1-1(30.17mg,157.71μmol)，室温条件下反应，LC-MS监测。反应完成后，减压浓缩，得到残余物用中压液相色谱(碱法)纯化得到27-B(4mg,7.89μmol)。 1H NMR(600MHz,DMSO-d 6)δ9.76(s,1H),8.88(s,1H),7.75(s,1H),7.68(s,1H),7.62–7.61(m,2H),6.95(d,J＝6.0Hz,2H),6.55(d,J＝6.0Hz,1H),4.06(s,3H),3.50(s,6H),3.12(s,4H),2.56(s,4H),2.32(s,3H). 1H NMR(600MHz,DMSO-d 6,D2O)δ8.86(s,1H),7.77(t,J＝7.0Hz,1H),7.68(d,J＝7.2Hz,1H),7.60(d,J＝6.6Hz,2H),6.97(d,J＝7.2Hz,2H),6.59(d,J＝7.2Hz,1H),4.07(s,3H),3.50(s,6H),3.14(s,4H),2.65(s,4H),2.31(s,3H).LCMS(ESI +)m/z:508.2[M+H] +,HPLC method B:R T＝6.54min,purity:96.5％.
实施例28：化合物28的合成
Figure PCTCN2022092348-appb-000099
步骤1：化合物28-2的合成：
在干燥的微波管中加入底物28-1(500mg,2.60mmol)，二甲基亚磺酰亚胺(169.41mg,1.82mmol),Xantphos(75.17mg,129.91μmol),Pd2(dba)3(47.58mg,51.96μmol)和Cs 2CO 3(880.41mg,2.70mmol)，加入1,4-二氧六环(30mL)溶解，在氮气保护下微波110℃搅拌12小时，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物28-2(113.4mg,217.97μmol)。LCMS(ESI +)m/z:205.1[M+H] +。
步骤2：化合物28的合成：
在干燥的微波管中加入底物1-3(100mg,323.24μmol)，28-2(55.13mg,269.37μmol)，t-BuOK(30.23mg,269.37μmol),Pd 2(dba) 3(8.63mg,9.43μmol)和Xantphos(15.59mg,26.94μmol)，加入1,4-二氧六环(3mL)溶解，在氮气保护下微波130℃搅拌10小时，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物重结晶纯化得到产物28(113.4mg,217.97μmol)。 1H NMR(400MHz,DMSO-d 6)δ10.84(s,1H),10.03(s,1H),9.05(s,1H),8.36(s,1H),8.23(d,J＝5.4Hz,1H),7.73(d,J＝6.6Hz,3H),7.05(d,J＝9.0Hz,2H),3.77(s,2H),3.44(s,6H),3.17(s,2H),3.09(s,2H),2.81(s,3H),2.53(s,2H).LCMS(ESI +)m/z:478.2[M+H] +,HPLC method B:R T＝5.86min,purity:91.8％.
实施例29：化合物29的合成
Figure PCTCN2022092348-appb-000100
步骤1：化合物29-2的合成：
在干燥的三口瓶中加入底物29-1(500mg,2.91mmol)溶于THF(10ml)中N 2置换三次，0℃下滴加甲基溴化镁(764mg,6.41mmol)后，室温搅拌1h，LC-MS监测。反应结束后用饱和氯化铵溶液淬灭，用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物29-2(165mg,0.965mmol)。LCMS(ESI +)m/z:172.2[M+H] +。
步骤2：化合物29的合成：
按照实施例28中步骤2的合成方法，将步骤2中的28-2(55.13mg,269.37μmol)替换为29-2(38mg,0.22mmol)，合成方法相同，得到化合物29(18mg,4.054μmol)。 1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),9.10(s,1H),8.68(d,J＝5.4Hz,1H),8.61(s,1H),8.44(s,1H),8.20(S,1H),7.76(d,J＝6.6Hz,2H),7.06(d,J＝8.4Hz,2H),5.44(s,1H),3.17(s,4H),2.54(s,4H),2.29(s,3H),1.57(s,6H).LCMS(ESI +)m/z:445.2[M+H] +,HPLC method B:R T＝6.65min,purity:92.9％.
实施例30：化合物30的合成
Figure PCTCN2022092348-appb-000101
步骤1：化合物30-2的合成：
按照实施例28中步骤1的合成方法，将步骤1中的28-1(500mg,2.60mmol)替换为30-1(500mg,2.12mmol)，合成方法相同，得到产物30-2(340mg,1.37mmol)。LCMS(ESI +)m/z:249.0[M+H] +。
步骤2：化合物30的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为30-2(67mg,0.27mmol)，合成方法相同，得到化合物30(22.8mg,44.17μmol)。 1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),9.02(s,1H),8.27(s,1H),7.82-7.80(m,1H),7.75(s,1H),7.69(d,J＝5.6Hz,2H),7.38(t,J＝5.6Hz,1H),6.95-6.92(m,3H),3.26(s,6H),3.09(t,J＝2.8Hz,4H),2.47(t,J＝2.8Hz,4H),2.23(s,3H).LCMS(ESI +)m/z:477.1[M+H] +,HPLC method B:R T＝6.11min,purity:95.9％.
实施例31：化合物31的合成
Figure PCTCN2022092348-appb-000102
步骤1：化合物31-2的合成：
按照实施例28中步骤1的合成方法，将步骤1中的28-1(500mg,2.60mmol)替换为31-1(300mg,1.27mmol)，合成方法相同，得到产物31-2(310mg,1.24mmol)。LCMS(ESI +)m/z: 249.0[M+H] +。
步骤2：化合物31的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为31-2(40mg,0.16mmol)，合成方法相同，得到化合物31(25.3mg,52.50μmol)。 1H NMR(400MHz,DMSO-d 6)δ9.88(s,1H),9.06(s,1H),9.04(s,1H),8.34(s,1H),8.17(s,1H),8.06(s,1H),7.65(d,J＝6.0Hz,2H),6.93(d,J＝6.0Hz,2H),3.33(s,6H),3.11(s,4H),2.52(s,4H),2.26(s,3H).LCMS(ESI +)m/z:478.1[M+H] +,HPLC method B:R T＝5.46min,purity:98.9％.
实施例32：化合物32的合成
Figure PCTCN2022092348-appb-000103
步骤1：化合物32-2的合成：
按照实施例29中步骤1的合成方法，将步骤1中的29-1(500mg,2.91mmol)替换为32-1(300mg,1.39mmol)，合成方法相同，得到产物32-2(374mg,crude)。LCMS(ESI +)m/z:217.0[M+H] +。
步骤2：化合物32的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为32-2(52mg,0.24mmol)，合成方法相同，得到化合物32(9.8mg,21.65μmol)。 1H NMR(400MHz,DMSO-d 6)δ9.89(s,1H),9.24(s,1H),9.05(s,1H),8.66(d,J＝1.2Hz,1H),8.62(s,1H),8.36(s,1H),7.66(d,J＝6.0Hz,2H),6.93(d,J＝6.0Hz,2H),5.41(s,1H),3.10(d,J＝2.8Hz,4H),2.52(s,4H),2.25(s,3H),1.54(s,6H).LCMS(ESI +)m/z:445.2[M+H] +,HPLC method B:R T＝5.98min,purity:98.2％.
实施例33：化合物33的合成
Figure PCTCN2022092348-appb-000104
步骤1：化合物33-2的合成：
按照实施例28中步骤1的合成方法，将步骤1中的28-1(500mg,2.60mmol)替换为33-1 (300mg,1.18mmol)，合成方法相同，得到产物33-2(230mg,0.864mmol)。LCMS(ESI +)m/z:266.1[M+H] +。
步骤2：化合物33的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为33-2(60mg,0.23mmol)，合成方法相同，得到化合物33(5.4mg,10.59μmol)。 1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),9.02(s,1H),8.29(s,1H),7.59(d,J＝8.4Hz,2H),7.32-7.29(m,1H),7.20(t,J＝7.8Hz,1H),7.16(t,J＝6.0Hz,1H),6.83(d,J＝9.0Hz,2H),3.32(s,6H),3.05(t,J＝4.2Hz,4H),2.46(s,4H),2.23(s,3H).LCMS(ESI +)m/z:495.2[M+H] +,HPLC method B:RT＝5.62min,purity:96.1％.
实施例34：化合物34的合成
Figure PCTCN2022092348-appb-000105
步骤1：化合物:34-2的合成：
按照实施例29中步骤1的合成方法，将步骤1中的29-1(500mg,2.91mmol)替换为34-1(300mg,1.39mmol)，合成方法相同，得到产物34-2(330mg,crude)。LCMS(ESI +)m/z:216.1[M+H] +。
步骤2：化合物34的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为34-2(59mg,0.272mmol)，合成方法相同，得到化合物34(30.7mg,66.91μmol)。 1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),9.03(s,1H),8.57(s,1H),8.31(s,1H),8.15(s,1H),7.78(d,J＝7.2Hz,2H),7.51(s,1H),6.91(d,J＝9.0Hz,2H),5.43(s,1H),3.07(t,J＝4.2Hz,4H),2.46(t,J＝4.2Hz,4H),2.22(s,3H),1.49(s,6H).LCMS(ESI +)m/z:445.3[M+H] +,HPLC method B:R T＝5.60min,purity:96.7％.
实施例35：化合物35的合成
Figure PCTCN2022092348-appb-000106
步骤1：化合物35-2的合成：
按照实施例29中步骤1的合成方法，将步骤1中的29-1(500mg,2.91mmol)替换为35-1(400mg,1.86mmol)，合成方法相同，得到产物35-2(360mg,crude)。TLC(PE/EA＝3/1)显示原料反应完毕，有新点生成。
步骤2：化合物35的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为35-2(52mg,0.242mmol)，1-3(105mg,339.40umol)替换成24-2(97mg,0.259mmol)，合成方法相同，得到化合物35(4.6mg,7.81μmol)。 1H NMR(400MHz,DMSO-d 6)δ10.19(s,1H),9.16(s,1H),8.57(s,1H),8.21(s,1H),7.91(s,1H),7.68(d,J＝3.6Hz,2H),7.57-7.53(m,2H),6.94(d,J＝9.0Hz,2H),5.25(s,1H),3.09(t,J＝4.2Hz,4H),2.46(t,J＝4.8Hz,4H),2.23(s,3H),1.50(s,6H).LCMS(ESI +)m/z:512.2[M+H] +,HPLC method B:R T＝8.86min,purity:87.4％.
实施例36：化合物36的合成
Figure PCTCN2022092348-appb-000107
步骤1：化合物36的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为36-1(37mg,0.162mmol)，合成方法相同，得到化合物36(32.5mg,64.85μmol)。 1H NMR(600MHz,DMSO-d 6)δ9.92(s,1H),9.36(s,1H),9.08(s,1H),9.02(s,1H),8.69(d,J＝8.4Hz,1H),8.54(d,J＝5.4Hz,1H),8.39(s,1H),8.20(d,J＝9.0Hz,1H),7.91(d,J＝6.0Hz,1H),7.70(d,J＝7.8Hz,2H),7.01(d,J＝9.0Hz,2H),3.14(d,J＝4.8Hz,4H),2.52(s,4H),2.24(s,3H).LCMS(ESI +)m/z:437.2[M+H] +,HPLC method B:R T＝7.63min,purity:87.1％.
实施例37：化合物37的合成
Figure PCTCN2022092348-appb-000108
步骤1：化合物37的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为37-1 (55mg,0.259mmol)，合成方法相同，得到化合物37(5.9mg,13.11μmol)。 1H NMR(600MHz,DMSO-d 6)δ9.93(s,1H),9.52(s,1H),9.07(s,1H),8.96(s,1H),8.41(dd,J＝9.0Hz,1H),8.38(d,J＝7.2Hz,2H),7.73(d,J＝7.8Hz,2H),6.98(d,J＝9.0Hz,2H),3.19(s,4H),2.79(s,3H),2.52(s,4H).LCMS(ESI +)m/z:443.1[M+H] +,HPLC method B:R T＝7.47min,purity:98.3％.
实施例38：化合物38的合成
Figure PCTCN2022092348-appb-000109
步骤1：化合物38的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为38-1(37mg,0.162mmol)，合成方法相同，得到化合物38(28.7mg,53.80μmol)。 1H NMR(600MHz,DMSO-d 6)δ9.88(s,1H),9.04(s,1H),8.72(s,1H),8.31(d,J＝9.0Hz,2H),8.10(s,1H),7.75(d,J＝7.8Hz,2H),7.53(d,J＝8.4Hz,1H),7.00(d,J＝8.6Hz,2H),3.45-3.43(m,2H),3.10(s,4H),2.99(t,J＝6.0Hz,2H),2.52(s,4H),2.27(s,3H).LCMS(ESI +)m/z:455.2[M+H] +,HPLC method B:R T＝6.25min,purity:85.2％.
实施例39：化合物39的合成
Figure PCTCN2022092348-appb-000110
步骤1：化合物39-2的合成：
在干燥的单口瓶中加入CuBr 2(16.70g,72.00mmol)的乙酸乙酯溶液(30mL)中，在室温下向反应液中缓慢滴加底物39-1(5.20g,24.00mmol)的三氯甲烷溶液(30mL)，搅拌30分钟后转入80℃的油浴继续反应，TLC监测。反应结束后将反应液过滤，取母液用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩得到产物39-2(7.00g,23.90mmol)。
步骤2：化合物39-3的合成：
在干燥的单口瓶中加入底物39-2(7.00g,23.90mmol)，K 2CO 3(3.96g,28.68mmol)，溶于ACN(50ml)中，在室温搅拌1h，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物39-3(1.41g,6.59mmol)，LCMS(ESI +)m/z:215.1[M+H]+。
步骤3：化合物39-4的合成：
在干燥的单口瓶中加入底物39-3(427.9mg,2.00mmol)，溶于ACN(4ml)中，在冰浴下缓慢加入NaBH 4(151.8mg,4.00mmol)，冰水浴反应1h，TLC监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩得到产物39-4(210.00mg,0.98mmol)。
步骤4：化合物39的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为39-4(42.79mg,0.20mmol)，合成方法相同，得到化合物39(10.0mg,22.56μmol)。 1H NMR(600MHz,Methanol-d6)δ9.82(s,1H),9.02(s,1H),8.25(s,1H),8.17(s,1H),7.95(d,J＝8.4Hz,1H),7.72(d,J＝8.4Hz,2H),7.05(d,J＝8.4Hz,1H),6.95(d,J＝9.0Hz,2H),5.80(d,J＝6.0Hz,1H),5.39(q,J＝3.2Hz,1H),4.66-4.63(m,1H),4.35-4.33(m,1H),3.08(s,4H),2.46(s,4H),2.23(s,3H).LCMS(ESI +)m/z:444.2[M+H] +,HPLC method B:R T＝6.24min,purity:88.2％。
实施例40：化合物40的合成
Figure PCTCN2022092348-appb-000111
步骤1：化合物40-2的合成：
按照实施例29中步骤1的合成方法，将步骤1中的29-1(500mg,2.91mmol)替换为40-1(423.90mg,2.00mmol)，合成方法相同，得到化合物40-2(210.00mg,0.98mmol)，LCMS(ESI +)m/z:211.2[M+H-H 2O] +。
步骤2：化合物40的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为40-2(45.59mg,0.20mmol)，合成方法相同，得到化合物40(20.00mg,43.74μmol)。 1H NMR(600MHz,Methanol-d 4)δ9.83(s,1H),9.02(s,1H),8.25(s,1H),8.15(s,1H),7.93(d,J＝9.6Hz,1H),7.72(d,J＝8.4Hz,2H),7.03(d,J＝9.0Hz,1H),6.95(d,J＝8.4Hz,2H),5.68(s,1H),4.42(d,J＝9.6Hz,1H),4.38(d,J＝9.6Hz,1H),3.08(s,4H),2.46(s,4H),2.22(s,3H),1.61(s,3H).LCMS(ESI +)m/z:458.1[M+H] +,HPLC method B:R T＝6.53min,purity:87.3％。将化合物40进行手性拆分，得到化合物40-A和化合物40-B。
40-A: 1H NMR(600MHz,DMSO-d 6)δ9.83(s,1H),9.02(s,1H),8.25(s,1H),8.16(s,1H),7.93(d,J＝8.4Hz,1H),7.72(d,J＝8.4Hz,2H),7.03(d,J＝8.4Hz,1H),6.95(d,J＝9.6Hz,2H),5.69(s,1H),4.42(d,J＝9.6Hz,1H),4.38(d,J＝9.6Hz,1H),3.07(s,4H),2.46(s,4H),2.22(s,3H),1.62(s,3H).LCMS(ESI +)m/z:458.1[M+H] +.HPLC:method B:R T:6.40min,purity:95.5％.
40-B: 1H NMR(600MHz,DMSO-d 6)δ9.83(s,1H),9.02(s,1H),8.25(s,1H),8.15(s,1H),7.93 (d,J＝8.4Hz,1H),7.72(d,J＝8.4Hz,2H),7.03(d,J＝8.4Hz,1H),6.95(d,J＝9.6Hz,2H),5.69(s,1H),4.43(d,J＝9.6Hz,1H),4.38(d,J＝9.6Hz,1H),3.08(s,4H),2.50–2.46(m,4H),2.22(s,3H),1.61(s,3H).LCMS(ESI +)m/z:458.1[M+H] +.HPLC:method B,R T:6.53min,purity:100％.
实施例41：化合物41的合成:
Figure PCTCN2022092348-appb-000112
步骤1：化合物41-1的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为41-1(38mg,0.194mmol)，合成方法相同，得到化合物41(2.0mg,4.50μmol)。 1H NMR(600MHz,DMSO-d 6)δ11.34(s,1H),9.79(s,1H),9.03(s,1H),8.28(d,J＝4.8Hz,1H),8.08(s,1H),7.85(dd,J＝8.4Hz,1H),7.75-7.71(m,3H),7.46(t,J＝2.4Hz,1H),6.95(d,J＝9.0Hz,2H),6.52(s,1H),3.09(s,4H),2.48(s,4H),2.24(s,3H).LCMS(ESI +)m/z:425.1[M+H] +,HPLC method B:R T＝7.54min,purity:95.5％.
实施例42：化合物42的合成:
Figure PCTCN2022092348-appb-000113
步骤1：化合物42-2的合成：
按照实施例29中步骤1的合成方法，将步骤1中的29-1(500mg,2.91mmol)替换为42-1(1g,4.29mmol)，合成方法相同，得到化合物42-2(850mg,crude)。TLC(PE/EA＝3/1)显示原料反应完毕，有新点生成。
步骤2：化合物42的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为42-2(63mg,0.269mmol)，合成方法相同，得到化合物42(12mg,23.56μmol)。 1H NMR(600 MHz,DMSO-d 6)δ9.85(s,1H),9.03(s,1H),8.40(d,J＝4.8Hz,1H),8.29(s,1H),8.06(s,1H),7.73(d,J＝7.8Hz,2H),7.37(q,J＝11.4Hz,1H),6.96(d,J＝9.0Hz,2H),5.47(s,1H),3.09(s,4H),2.47(s,3H),2.23(s,4H),1.58(s,6H).LCMS(ESI +)m/z:462.1[M+H] +,HPLC method B:R T＝7.56min,purity:93.9％.
实施例43：化合物43的合成
Figure PCTCN2022092348-appb-000114
步骤1：化合物43-2的合成：
按照实施例29中步骤1的合成方法，将步骤1中的29-1(500mg,2.91mmol)替换为43-1(452.00mg,2.00mmol)，合成方法相同，得到化合物43-2(200mg,0.88mmol)，LCMS(ESI +)m/z:209.2[M+H-H 2O] +。
步骤2：化合物43的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为43-2(45.20mg,0.20mmol)，合成方法相同，得到化合物43(10.00mg,21.96μmol)。 1H NMR(600MHz,Methanol-d 6)δ9.85(s,1H),9.02(s,1H),8.27(s,1H),8.17(s,1H),7.74(d,J＝8.4Hz,2H),7.39(d,J＝8.4Hz,1H),7.16(d,J＝8.4Hz,1H),6.84(d,J＝8.4Hz,2H),5.13(s,1H),3.09(s,4H),2.87–2.79(m,2H),2.49(s,4H),2.26(s,3H),2.04(t,J＝7.2Hz,2H),1.47(s,3H).LCMS(ESI +)m/z:456.1[M+H] +,HPLC method B:R T＝7.17min,purity:93.5％。
实施例44：化合物44的合成
Figure PCTCN2022092348-appb-000115
步骤1：化合物44-2的合成：
在按照实施例29中步骤1的合成方法，将步骤1中的29-1(500mg,2.91mmol)替换为44-1(452.00mg,2.00mmol)合成方法相同，得到化合物44-2(200.00mg,0.88mmol)，LCMS(ESI +) m/z:209.2[M+H-H 2O] +。
步骤2：化合物44的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为44-2(45.20mg,0.20mmol)，合成方法相同，得到化合物44(10.0mg,21.96μmol)。 1H NMR(600MHz,DMSO-d6)δ9.75(s,1H),9.02(s,1H),8.27(s,1H),7.62(d,J＝8.4Hz,2H),7.57(d,J＝8.4Hz,1H),7.45–7.40(m,2H),6.84(d,J＝8.4Hz,2H),5.19(s,1H),3.05(s,4H),2.95–2.84(m,2H),2.47(s,4H),2.23(s,3H),2.06(t,J＝7.2Hz,2H),1.46(s,3H).LCMS(ESI +)m/z:456.1[M+H] +,HPLC method B:R T＝6.50min,purity:94.0％。
实施例45：化合物45的合成
Figure PCTCN2022092348-appb-000116
步骤1：化合物45-2的合成：
在干燥的单口瓶中加入底物45-1(1.23g,5.00mmol)，AcOH(1mL)的THF(4ml)溶液，在室温下缓慢加入Zn粉(3.30g,50.00mmol)，室温搅拌0.5h，TLC监测。反应结束后用硅藻土过滤，取母液用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩得到产物45-2(0.86g,4.0mmol)。
步骤2：化合物45-3的合成
在干燥的单口瓶中加入底物45-2(214.0mg,1.0mmol)与CH(OMe) 3(3mL)，室温搅拌1h，LC-MS监测。反应结束后减压浓缩得到产物45-3(210.00mg,0.95mmol)，LCMS(ESI +)m/z:225.2[M+H] +。
步骤3：化合物45的合成
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为45-3(44.79mg,0.20mmol)，合成方法相同，得到化合物45(10.00mg,22.06μmol)。 1H NMR(600MHz,DMSO-d 6)δ9.82(s,1H),9.04(s,1H),8.40(s,2H),8.31(s,1H),8.05(d,J＝7.8Hz,1H), 7.86(s,1H),7.68(d,J＝8.4Hz,2H),6.94(d,J＝9.0Hz,2H),4.31(q,J＝7.2Hz,2H),3.10(s,4H),2.47(s,4H),2.23(s,3H),1.42(t,J＝7.2Hz,3H).LCMS(ESI +)m/z:454.1[M+H] +,HPLC method B:R T＝6.44min,purity:96.5％。
实施例46：化合物46的合成
Figure PCTCN2022092348-appb-000117
步骤1：化合物46的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为46-1(57mg,0.269mmol)，合成方法相同，得到化合物46(8.8mg,19.26μmol)。 1H NMR(600MHz,DMSO-d6)δ9.83(s,1H),9.05(s,1H),8.78(s,1H),8.68(s,1H),8.42(d,J＝8.4Hz,1H),8.34(s,1H),7.79-7.74(m,3H),7.02(d,J＝8.4Hz,2H),4.46(s,2H),3.10(s,4H),2.47(s,4H),2.23(s,3H).LCMS(ESI +)m/z:441.1[M+H] +,HPLC method B:R T＝7.56min,purity:96.5％.
实施例47：化合物47的合成
Figure PCTCN2022092348-appb-000118
步骤1：化合物47-2的合成：
在干燥的单口瓶中加入47-1(3g,21mmol)，加入DCM(60mL)溶解，再依次加入DIPEA(3.27g,25mmol)和N-甲基哌嗪(2.1g,21mmol),室温下搅拌1小时。向反应液中加入水(50mL)，充分搅拌后分液，有机相用无水硫酸钠干燥后过滤，浓缩滤液，无需纯化粗产物可直接用于下一步反应，得到粗产物47-2(4.2g,crude)为黄色固体。
步骤2：化合物47-3的合成：
在干燥的单口瓶中加入47-2(2.2g,10mmol)，加入甲醇(100mL)溶解，加入氯化铵(2.6g,50mmol)，搅拌条件下慢慢加入锌粉(3.3g,50mmol)，有放热现象产生，室温下搅拌2小时。将反应液过滤，浓缩滤液，剩余物用柱层析硅胶柱纯化(DCM:MeOH＝8:1)得到产物47-3(1.2g)为棕色固体。
步骤3：化合物47-4的合成：
在干燥的单口瓶中加入47-3(400mg,2.1mmol)和1-2(323mg,2.1mmol)，加入1,4-二氧六环/乙酸(20mL/2mL)的混合溶剂溶解，加热到110℃，反应4小时，反应完成后将反应液冷却，浓缩溶剂，剩余杂质用柱层析硅胶柱纯化(DCM:MeOH＝10:1)得到47-4(260mg)为黄色固体。
步骤4：化合物47-6的合成：
在干燥的两口瓶中加入甲基碘化镁(2M in THF,21.5mL)，在冰浴和氮气保护条件下，加入47-5(2g,8.7mmol)的THF(dry,20mL)溶液，慢慢升温到室温搅拌过夜。用饱和氯化铵溶液(50mL)淬灭反应，然后用乙酸乙酯萃取3次，合并有机相，并用无水硫酸钠干燥过滤，滤液减压浓缩，残余物用柱层析硅胶柱纯化(PE/EA＝5/1)得到产物47-6(1.8g)为透明油状物。
步骤5：化合物47-7的合成：
在干燥的三口瓶中加入47-6(430mg,2mmol)，加入无水THF(20mL)溶解，氮气保护后冷却到-78℃，然后缓慢滴加正丁基锂(2.5M,1.2mL)，搅拌0.5小时，然后加入硼酸三异丙酯(560mg,3mmol)，继续搅拌2小时，用水(30mL)淬灭反应，，然后用乙酸乙酯萃取3次，合并有机相并用无水硫酸钠干燥后过滤，滤液减压浓缩，得到粗产物47-7(380mg,crude)为白色固体，粗产物直接用于下一步反应。
步骤6：化合物47的合成：
在干燥的单口瓶中加入47-4(31mg,0.1mmol)、47-7(27mg,0.15mmol)和吡啶(16mg, 0.2mmol)溶于DCM中，加入乙酸铜(36mg,0.2mmol)。室温下搅拌16小时。将反应液过滤，滤液减压浓缩，残余物用Prep-TLC纯化后再用Prep-HPLC纯化得到化合物47(3mg,6.15μmol). 1H NMR(600MHz,Methanol-d 4)δ8.94(s,1H),8.59(d,J＝2.7Hz,1H),8.32(d,J＝1.7Hz,1H),8.17(s,1H),8.04(dd,J＝9.1,2.7Hz,1H),7.95(d,J＝5.6Hz,1H),7.54–7.45(m,2H),6.92(d,J＝9.1Hz,1H),3.61(s,4H),2.87(s,4H),2.57(s,3H),1.58(s,6H).LCMS(ESI +)m/z:445.2[M+H] +,HPLC method B:R T＝5.12min,purity:91.1％。
实施例48：化合物48的合成
Figure PCTCN2022092348-appb-000119
步骤1：化合物48-3的合成：
在干燥的单口瓶中加入底物48-1(399.9mg,2.0mmol)、底物48-2(190.08mg,2.0mmol)、Cu(OAc) 2(39.93mg,0.2mmol)、碳酸铯(325.82mg,1.0mmol)与N,N-二甲基甘氨酸(206.22mg,2.00mmol)的1,4-二氧六环(4mL)溶液，在100℃下搅拌18h，LC-MS监测。反应结束后用硅藻土过滤反应液，取母液用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物48-3(250.00mg,1.03mmol)，LCMS(ESI +)m/z:250.1[M+H] +。
步骤2：化合物48的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为48-3(49.79mg,0.20mmol)，合成方法相同，得到化合物48(12.00mg,25.09μmol)。 1H NMR(600MHz,DMSO-d 6)δ9.93(s,1H),9.05(s,1H),8.53(s,1H),8.35(s,1H),8.19(s,1H),7.81(d,J＝6.6Hz,1H),7.73–7.71(m,1H),7.62(d,J＝8.4Hz,2H),7.60–7.57(m,1H),7.37(d,J＝8.4Hz,1H),6.73(d,J＝8.4Hz,2H),6.57(d,J＝9.3Hz,1H),6.40–6.37(m,1H),3.02(s,4H),2.48(s,4H),2.24(s,3H).LCMS(ESI +)m/z:479.3[M+H] +,HPLC method B:R T＝6.35min,purity:96.9％。
实施例49：化合物49的合成
Figure PCTCN2022092348-appb-000120
步骤1：化合物49-3的合成：
在干燥的单口瓶中加入底物49-2(2.3g,50.0mmol)和K 2CO 3(11.06g,80.0mmol)的乙醇(60mL)溶液，氮气保护下冷却到5℃，然后加入49-1(2.0g,10mmol)，在80℃下搅拌18h，LC-MS监测。反应结束后，冷却至室温，反应液减压浓缩，用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析(PE/EA＝2/3)纯化得到产物49-3(1.8g,7.96mmol)，LCMS(ESI +)m/z:226.1[M+H] +。
步骤2：化合物49的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为49-3(40.69mg,0.18mmol)，合成方法相同，得到化合物49(1.50mg,2.84μmol)。 1H NMR(600MHz,DMSO-d 6)δ9.77(s,1H),9.03(s,1H),8.39–8.33(m,1H),8.27(s,1H),8.02(dd,J＝9.0,2.1Hz,1H),7.73(d,J＝8.1Hz,2H),7.53(d,J＝9.0Hz,1H),6.94(d,J＝8.5Hz,2H),5.55(s,2H),3.80(s,3H),3.07(d,J＝5.0Hz,4H),2.46(s,4H),2.23(s,3H).LCMS(ESI +)m/z:455.2[M+H] +，HPLC Method B:R T＝8.92min,purity＝86.2％。
实施例50：化合物50的合成
Figure PCTCN2022092348-appb-000121
步骤1：化合物50-2的合成：
在按照实施例29中步骤1的合成方法，将步骤1中的29-1(500mg,2.91mmol)替换为50-1 (434.04mg,2mmol)，合成方法相同，得到化合物50-2(200mg,878.09μmol)为白色固体。
步骤2：化合物50的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为50-2(37.89mg,174.55μmol)，合成方法相同，得到化合物50(17mg,38.16μmol)。 1H NMR(600MHz,Chloroform-d)δ9.44(s,1H),8.89(s,1H),8.70(s,1H),8.17(s,1H),7.57(d,J＝8.4Hz,2H),7.43(d,J＝7.9Hz,1H),6.99(d,J＝8.9Hz,2H),3.25(t,J＝4.9Hz,4H),2.69(t,J＝4.8Hz,4H),2.42(s,3H),1.69(s,6H).LCMS(ESI +)m/z:445.2[M+H] +,HPLC Method B:R T＝7.98min,purity>87.1％。
实施例51：化合物51的合成
Figure PCTCN2022092348-appb-000122
步骤1：化合物51-2的合成：
在干燥的单口瓶中加入底物51-1(600mg,3.19mmol)和原乙酸三乙酯(1.5mL)，升温至100℃反应12h，LC-MS监测反应。反应结束后减压浓缩，用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，得到粗产物51-2(650mg,crude)，直接用于下一步反应。
步骤2：化合物51的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为51-2(65.80mg,310.31μmol)，将1,4-二氧六环(3mL)替换为DMF(2mL)，合成方法相同，得到化合物51(18.1mg,36.78μmol)。 1H NMR(600MHz,DMSO-d 6)δ9.86(s,1H),9.07(s,1H),8.39(s,1H),7.87(d,J＝7.8Hz,1H),7.76(d,J＝7.8Hz,1H),7.59(d,J＝8.4Hz,2H),7.76(t,J＝7.8Hz,1H),6.81(d,J＝9.0Hz,2H),3.05(s,4H),2.59(s,3H),2.45(s,4H),2.22(s,3H).LCMS(ESI +)m/z:441.2[M+H] +,HPLC method B:R T＝6.48min,purity:89.5％.
实施例52：化合物52的合成
Figure PCTCN2022092348-appb-000123
步骤1：化合物52-2的合成：
按照实施例29中步骤1的合成方法，将步骤1中的29-1(500mg,2.91mmol)替换为52-1(500.00mg,2.15mmol)，合成方法相同，得到化合物52-2(300mg,1.29mmol)。
步骤2：化合物52的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为52-2(67.81mg,290.92μmol)，合成方法相同，得到化合物52(4.5mg,9.23μmol)。 1H NMR(600MHz,DMSO-d 6)δ8.79(s,1H),8.04(s,1H),7.73(dd,J＝6.6Hz,1H),7.46(d,J＝8.4Hz,3H),7.27(s,1H),7.21(d,J＝9.0Hz,1H),6.81(d,J＝9.0Hz,2H),3.09(s,4H),2.53(s,4H),2.29(s,3H),1.55(s,6H).LCMS(ESI +)m/z:462.2[M+H] +,HPLC method B:R T＝6.42min,purity:94.7％。
实施例53：化合物53的合成
Figure PCTCN2022092348-appb-000124
步骤1：化合物53-2的合成：
按照实施例29中步骤1的合成方法，将步骤1中的29-1(500mg,2.91mmol)替换为53-1(1.11g,5mmol)，合成方法相同，得到化合物53-2(1.0g,4.49mmol)。
步骤2：化合物53的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为53-2(39.80mg,180.00μmol)，合成方法相同，得到化合物53(7.1mg,12.10μmol)。 1H NMR(600MHz,Chloroform-d)δ8.82(s,1H),8.00(s,1H),7.79(d,J＝1.7Hz,1H),7.75(d,J＝1.6Hz,1H), 7.61–7.56(m,2H),7.31(s,1H),7.01–6.95(m,2H),3.22(t,J＝4.9Hz,4H),2.65(t,J＝4.8Hz,4H),2.40(s,3H),1.73(s,6H).LCMS(ESI +)m/z:450.2[M+H] +,HPLC Method B:R T＝8.55min,purity>76.6％。
实施例54：化合物54的合成
Figure PCTCN2022092348-appb-000125
步骤1：化合物54-2的合成：
在干燥的单口瓶中加入底物54-1(472mg,1.99mmol)，底物48-2(94.74mg,996.23μmol)、CuI(37.95mg,0.2mmol)、碳酸铯(323.78mg,1.0mmol)和N,N-二甲基甘氨酸(102.73mg,1.0mmol)的1,4-二氧六环(4mL)溶液，在100℃下搅拌18h，LC-MS监测。反应结束后用硅藻土过滤反应液，取母液用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物54-2(100mg,398.28μmol)。
步骤2：化合物54的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为54-2(49.51mg,197.18μmol)，合成方法相同，得到化合物54(20mg,38.12μmol)。 1H NMR(600MHz,DMSO-d 6)δ9.91(s,1H),9.05(s,1H),8.37(s,1H),8.26-8.23(m,1H),8.11(d,J＝8.4Hz,1H),8.02-8.01(m,1H),7.79(d,J＝7.8Hz,1H),7.74(d,J＝8.4Hz,2H),7.61-7.58(m,1H),6.68(d,J＝8.4Hz,2H),6.61(d,J＝9.0Hz,1H),6.35(t,J＝6.6Hz,1H),3.01(t,J＝4.8Hz,4H),2.47(d,J＝5.0Hz,4H),2.24(s,3H).LCMS(ESI +)m/z:480.1[M+H] +，HPLC Method B:R T＝8.16min,purity>91.4％。
实施例55：化合物55的合成
Figure PCTCN2022092348-appb-000126
步骤1：化合物55-2的合成：
按照实施例29中步骤1的合成方法，将步骤1中的29-1(500mg,2.91mmol)替换为55-1，合成方法相同，得到化合物55-2。
步骤2：化合物55的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为55-2(50mg,195.99μmol)，合成方法相同，得到化合物55(17mg,35.16μmol)。 1H NMR(600MHz,Methanol-d 4)δ9.56(s,1H),8.93(s,1H),8.27(d,J＝8.7Hz,1H),8.20(s,1H),7.70(d,J＝9.7Hz,1H),7.64–7.39(m,3H),6.97(d,J＝9.0Hz,2H),3.17(t,J＝5.1Hz,4H),2.64(t,J＝5.0Hz,4H),2.36(s,3H),1.73(s,6H).LCMS(ESI +)m/z:484.2[M+H] +，HPLC Method B:R T＝5.21min,purity 90.0％。
实施例56：化合物56的合成
Figure PCTCN2022092348-appb-000127
步骤1：化合物56-2的合成：
在干燥的单口瓶中加入底物56-1(943.17mg,5mmol)和EtOH(10mL)搅拌溶解，随后 加入DIPEA(969.30mg,7.50mmol,1.31mL)，在0℃下加入缓慢滴加水合肼(272.38mg,8.50mmol)，升温至50℃反应1h.反应完成后，反应液减压浓缩，得到粗产物56-2(790mg,4.75mmol)。
步骤2：化合物56-3的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为30-2(332.41mg,2mmol)，1-3(105mg,339.40μmol)替换为56-2(330.85mg,1.33mmol)，合成方法相同，得到化合物56-3(252mg,755.78μmol)。
步骤3：化合物56的合成：
在干燥的单口瓶中加入底物56-3(66.69mg,0.2mmol)，m-CPBA(26.45mg,300.00μmol)和THF(0.8mL)，室温搅拌10min后，加入DIPEA(129.24mg,1.00mmol)，室温搅拌5min后，加入底物56-4(57.68mg,300.00μmol)，100℃反应6h，LCMS监测。反应结束后减压浓缩，用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到化合物56(6.5mg,)。 1H NMR(600MHz,DMSO-d 6)δ9.96(s,1H),9.09(s,1H),8.33(s,1H),8.18(d,J＝9.1Hz,1H),8.05(d,J＝3.1Hz,1H),7.79(dd,J＝8.0,2.1Hz,1H),7.76-7.75(m,1H),7.47(dd,J＝9.1,3.1Hz,1H),7.41-7.39(m,1H),6.94(dd,J＝8.0,2.1Hz,1H),3.27(s,6H),3.17–3.14(m,4H),2.48(t,J＝4.9Hz,4H),2.23(s,3H).LCMS(ESI +)m/z:478.2[M+H] +,HPLC Method B:R T＝5.69min,purity 89.9％。
实施例57：化合物57的合成
Figure PCTCN2022092348-appb-000128
步骤1：化合物57-3的合成：
在干燥的单口瓶中加入底物57-1(20g,186.65mmol)和甲苯(120mL)溶液，加入底物57-2(15.70g,186.65mmol)和MgSO 4(22.40g,186.08mmol),在30℃下搅拌18h，LC-MS监测。反应结束后过滤，用甲苯(40mL)溶液洗，过滤后得到产物57-3(32.34g,crude)。
步骤2：化合物57-4的合成：
在干燥的单口瓶中加入底物57-3(32.34g,186.66mmol)和甲苯(160mL)溶液，在0℃下，加入TEA(19.27g,190.40mmol)，缓慢滴加Ac 2O(19.44g,190.40mmol)，在室温下搅拌18h，LC-MS监测。反应结束后，用水洗两次，用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物57-4(22.3g,103.58mmol)为黄色油状物，LCMS(ESI +)m/z:216.2[M+H] +。
步骤3：化合物57-5的合成：
在干燥的三口瓶中加入底物57-4(22.3g,103.58mmol)溶于DMF(75.46mL)中，在-10℃和氮气保护下滴加POCl 3(39.71g,258.95mmol)和MgSO 4(22.40g,186.08mmol)，在室温下搅拌1h后，升温至105℃下反应16h，LC-MS监测。反应结束后用冰水淬灭，用30％氢氧化钠水溶液调节pH＝9-10。用水和乙酸乙酯萃取3次，无水硫酸钠干燥，过滤后减压浓缩，残余物用柱层析纯化得到产物57-5(10.6g,69.01mmol)为黄色固体，LCMS(ESI +)m/z:154.1 [M+H] +。
步骤4：化合物57-6的合成：
在干燥的单口瓶中加入底物57-5(3g,19.53mmol)和邻苯二甲酸酐(5.79g,39.06mmol)，溶于DCM(13.5mL)中，加入H 2O 2(6.64g,58.59mmol)，40℃下搅拌18h后，LC-MS监测。反应结束后减压浓缩，残余物用柱层析纯化得到产物57-6(3g,17.69mmol)为白色固体，LCMS(ESI +)m/z:170.0[M+H] +。
步骤5：化合物57-7的合成：
在干燥的单口瓶中加入Ac 2O(9.03g,88.44mmol),在85℃下滴加57-6(3g,17.69mmol)的MeCN(20mL)溶液，在85℃下搅拌3h，LCMS监测。反应结束后减压浓缩，残余物用饱和碳酸氢钠溶液调节pH＝8-9，用DCM萃取3次，无水硫酸钠干燥，过滤后减压浓缩得到产物57-7(3.8g,crude)为亮黄色油状，LCMS(ESI +)m/z:212.2[M+H] +。
步骤6：化合物57-8的合成：
在干燥的单口瓶中加入底物57-7(3.74g,17.67mmol)，K 2CO 3(7.32g,53.01mmol)和MeOH溶液(40mL)，在15℃下搅拌2h，LCMS监测。反应结束后过滤并减压浓缩，残余物用柱层析纯化得到产物57-8(1.94g,11.44mmol)为亮黄色油状，LCMS(ESI +)m/z:170.1[M+H] +。
步骤7：化合物57-9的合成：
在干燥的单口瓶中加入底物57-8(3.74g,17.67mmol)，溶于DCM(40mL)，加入Dess-martin Periodinane(7.36g,17.36mmol),在15℃下搅拌2h，LCMS监测。反应结束后用饱和碳酸氢钠溶液调节pH＝8-9，用DCM萃取3次，无水硫酸钠干燥，过滤后减压浓缩得到产物57-9(2g,crude)为白色固体，LCMS(ESI+)m/z:168.0[M+H]+。
步骤8：化合物57-10的合成：
在干燥的三口瓶中加入底物57-9(0.5g,2.98mmol)，溶于无水THF(15mL)，在冰浴和氮 气保护下，缓慢滴加甲基溴化镁(1M in THF,11.93mL)中，慢慢升温到室温搅拌1h。用饱和氯化铵溶液淬灭反应，然后用EA萃取3次，合并有机相，并用无水硫酸钠干燥过滤，浓缩滤液，剩余物用柱层析纯化得到产物57-10(0.29g,1.47mmol)为黄色油状,LCMS(ESI+)m/z:198.0[M+H]+。
步骤9：化合物57的合成：
在干燥的单口瓶中加入底物57-10(16mg,80.95μmol)，1-3(25mg,80.81μmol)，XantPhos(4.67mg,8.09μmol)，Pd 2(dba) 3(2.59mg,2.83μmol)，t-BuOK(9.08mg,80.95μmol)，加入1,4-二氧六环(1mL)溶解，在氮气保护下150℃搅拌1h，LC-MS监测。反应结束后用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物57(8.33mg,17.70μmol)。 1H NMR(600MHz,DMSO-d 6)δ9.79(s,1H),8.05(s,1H),8.01(d,J＝9.6Hz,1H),7.66(d,J＝7.6Hz,1H),7.55(d,J＝8.4Hz,2H),7.34(s,1H),6.89(d,J＝9.0Hz,2H),3.23(s,4H),3.00-2.96(m,1H),2.95-2.78(s,1H),2.71(s,4H),2.42(s,3H),2.36-2.31(m,1H),2.22-2.17(m,1H),2.06-2.02(m,1H),1.83-1.79(m,1H),0.94(t,J＝7.2Hz,3H).LCMS(ESI +)m/z:471.1[M+H] +,HPLC method B:R T＝4.90min,purity 99.9％。
实施例58：化合物58的合成
Figure PCTCN2022092348-appb-000129
步骤1：化合物58-2的合成：
在干燥的单口瓶中加入底物58-1(87mg,395.46μmol)和甲胺(120.00mg,3.86mmol，1M四氢呋喃溶液)，室温下反应2h，LC-MS监测。反应结束后，反应液减压浓缩得到粗产物58-2，直接用于下一步反应。
步骤2：化合物58-3的合成：
在干燥的单口瓶中加入底物58-2和THF(1mL)搅拌溶解，加入CH 3COOH(1mL)和锌粉(500mg)，室温下反应2h，LC-MS监测。反应结束后，硅藻土滤除锌粉和不溶物，滤液减压浓缩，得到粗产物58-3(25mg,crude)。
步骤3：化合物58-4的合成：
在干燥的单口瓶中加入底物58-3(25mg,crude)和原乙酸三乙酯(1mL)，室温反应2h，LC-MS监测。反应结束后，反应液减压浓缩，残余物用柱层析进行纯化得到产物58-4(7mg,31.10μmol)。
步骤4：化合物58的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为58-4(34.7mg,154.16μmol)，合成方法相同，得到化合物58(2.0mg,4.41μmol)。 1H NMR(600MHz,DMSO-d 6)δ9.82(s,1H),9.04(s,1H),8.30(d,J＝4.1Hz,2H),7.96(dd,J＝8.7,2.1Hz,1H),7.72(d,J＝8.4Hz,2H),7.69(d,J＝8.6Hz,1H),6.98–6.92(m,2H),3.78(s,3H),3.10(t,J＝4.9Hz,4H),2.58(s,3H),2.47(t,J＝4.9Hz,4H),2.23(s,3H).LCMS(ESI +)m/z:454.1[M+H] +,HPLC method B:R T＝6.50min,purity 92.2％。
实施例59：化合物59的合成
Figure PCTCN2022092348-appb-000130
步骤1：化合物59-2的合成：
在干燥的双口瓶中加入底物59-1(1g,5.32mmol)和碳酸氢钠(893.62mg,10.64mmol)，加入THF(8mL)溶解，在0℃和氮气保护下，加入氯乙酰氯(600.69mg,5.32mmol)，搅拌30min后加入K 2CO 3(1.47g,10.64mmol)，升温至80℃反应3h。反应结束后，用水和乙酸乙酯萃取3次，有机相无水硫酸钠干燥，减压浓缩得到粗产物59-2(1.4g,crude)。
步骤2：化合物59-3的合成：
在干燥的双口瓶中加入底物59-2(500mg,2.19mmol)和碳酸铯(785.82mg,2.41mmol)，加入DMF(2.5mL)搅拌溶解，在0℃和氮气保护下加入碘乙烷(341.96mg,2.19mmol)，恢复至室温条件反应2h。反应结束后，用水和乙酸乙酯萃取3次，有机相无水硫酸钠干燥，减压浓缩，残余物用中压色谱柱纯化得到产物59-3(190mg,741.91μmol)。
步骤3：化合物59的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为59-3(34.60mg,135.11μmol)，合成方法相同，得到化合物59(3.49mg,7.07μmol)。 1H NMR(600MHz,DMSO-d 6)δ9.78(s,1H),9.03(s,1H),8.29(s,1H),7.88(d,J＝2.4Hz,1H),7.82(dd,J＝8.4Hz,1H),7.60(d,J＝9.0Hz,2H),),7.23(d,J＝3.0Hz,1H),6.93(d,J＝9.0Hz,2H),4.70(s,2H),3.90(d,J＝7.2Hz,2H),3.09(t,J＝4.8Hz,4H),2.47(s,4H),2.23(s,3H),1.08(t,J＝7.2Hz,3H).LCMS(ESI +)m/z:485.2[M+H] +,HPLC method B:R T＝5.67min,purity:95.1％。
实施例60：化合物60的合成
Figure PCTCN2022092348-appb-000131
步骤1：化合物60-2的合成：
在干燥的双口瓶中加入底物60-1(200mg,1.30mmol)和碳酸钾(540mg,3.91mmol)，加入DMF(2.5mL)搅拌溶解，在0℃和氮气保护下加入碘乙烷(406.24mg,2.60mmol)，升温至75℃反应1h。反应结束后，用水和乙酸乙酯萃取3次，有机相无水硫酸钠干燥，减压浓缩，残余物用中压色谱柱纯化得到产物60-2(140mg,770.83μmol)。
步骤2：化合物60的合成：
按照实施例28中步骤2的合成方法，将步骤2中的28-2(55.13mg,269.37μmol)替换为60-2(35.22mg,193.94μmol)，合成方法相同，得到化合物60(4.13mg,8.20μmol)。 1H NMR(400MHz,DMSO-d 6)δ9.91(s,1H),9.05(s,1H),8.55(s,1H),8.44(d,J＝8.8Hz,1H),8.36(s,1H),7.97(s,2H),7.90(d,J＝8.8Hz,1H),6.98(d,J＝8.8Hz,2H),4.54(q,J＝16.8Hz,2H),3.09(t,J＝4.4Hz,4H),2.47(t,J＝4.8Hz,4H),2.23(s,3H),1.59(t,J＝3.2Hz,3H).LCMS(ESI +)m/z:455.1[M+H] +,HPLC method A:R T＝5.86min,purity:90.3％。
实施例61：化合物61的合成
Figure PCTCN2022092348-appb-000132
步骤1：化合物61-2的合成：
在干燥的三口瓶中加入底物61-1(1g,4.72mmol)和THF(10mL)溶液，氮气保护下冷却到-40℃，缓慢滴加n-BuLi(2.5M in THF,4.15mL)，在-40℃下搅拌1h后缓慢滴加1,2-二溴乙烷(2.66g,14.15mmol)，逐渐恢复至室温搅拌12h，LC-MS监测。反应结束后用4N HCl(5mL)淬灭，用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物61-2(1.2g,crude)，LCMS(ESI +)m/z:238.1[M+H] +。
步骤2：化合物61-3的合成：
在单口瓶中加入底物61-2(700mg,2.94mmol)、碘乙烷(458.57mg,2.94mmol)、Cs 2CO 3(1.05g,3.23mmol)，加入DMF(3mL)搅拌溶解，在75℃下反应8h，LCMS监测。反应结束后用4N HCl(5mL)淬灭，用水和乙酸乙酯萃取3次，有机相用无水硫酸钠干燥，减压浓缩，残余物用柱层析纯化得到产物61-3(285mg,1.07mmol)，LCMS(ESI +)m/z:266.1[M+H] +。
步骤3：化合物61的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为61-3(30mg,112.73μmol)，合成方法相同，得到化合物61(8.85mg,17.89μmol)。 1H NMR(400MHz,DMSO-d 6)δ9.82(s,1H),9.03(s,1H),8.30(s,1H),7.89-7.85(m,2H),7.64(d,J＝8.8Hz,2H),7.21(d,J＝8.4Hz,1H),6.93(d,J＝9.2Hz,2H),3.80(q,J＝14.0Hz,2H),3.09(t,J＝4.8Hz,4H),2.46(t,J＝4.8Hz,4H),2.23(s,3H),1.71-1.68(m,2H),1.58-1.57(m,2H),1.13(t,J＝7.2Hz,3H).LCMS(ESI +)m/z:495.3[M+H]+,HPLC method A:R T＝6.17min,purity 99.9％。
实施例62：化合物62的合成
Figure PCTCN2022092348-appb-000133
步骤1：化合物62-2的合成：
在干燥的单口瓶中加入底物62-1(192mg,997.71μmol)和水合肼溶液(160mg,4.99mmol)，加入乙醇(3mL)搅拌溶解，升温至80℃反应16h，LC-MS监测。反应结束后，反应液减压浓缩，残余物用中压色谱柱纯化得到产物62-2(180mg,957.32μmol)。
步骤2：化合物62-4的合成：
在干燥的微波管中加入底物62-2(142mg,755.2μmol)，62-3(77.1mg,755.2μmol)和甲醇(2mL)，在氮气保护下60℃油浴中反应1h。反应完成后反应液减压浓缩，随后加入1,4-二氧六环(2mL)和醋酸碘苯(267.2mg,830.7μmol)，氮气保护和室温条件下反应过夜，LC-MS监测。反应结束后，反应液减压浓缩，用乙酸乙酯与水萃取3次，有机相用饱和食盐水洗涤3次，用无水硫酸钠干燥，减压浓缩得到粗产物62-4(116mg,429.5μmol)为橙色固体。
步骤3：化合物62的合成：
按照实施例1中步骤3的合成方法，将步骤3中的1-5(109.92mg,441.22μmol)替换为62-4(134mg,496.14μmol)，合成方法相同，在反应过程中，发生脱羧反应，因此得到化合物62(10mg,19.06μmol)。 1H NMR(600MHz,DMSO-d 6)δ9.94(s,1H),9.36(d,J＝18.3Hz,2H),9.06(s,1H),8.38(s,1H),8.32(dd,J＝9.8,2.0Hz,1H),8.07(d,J＝9.9Hz,1H),7.66(d,J＝8.6Hz,2H),7.00(d,J＝8.7Hz,2H),3.17(d,J＝5.3Hz,1H),3.12(t,J＝5.0Hz,4H),2.49-2.47(m,4H),2.23(s,3H).LCMS(ESI +)m/z:427.2[M+H]+,HPLC method B:R T＝5.48min,purity:97％。
生物活性评价试验：
无特殊说明时，该部分实施例中部分生物学评价实验用化合物AZD-1775作为对照，AZD-1775(CAS号：955365-80-7)的结构信息如下：
Figure PCTCN2022092348-appb-000134
试验例1：通过TR-FRET方法评价化合物在Wee1蛋白与Tracer 178结合。
首先准备不同浓度梯度的化合物溶液。将化合物溶解于DMSO中，并将化合物进行4倍稀释，共10个剂量点，每个浓度设置2个平行重复，加入DMSO作为阳性对照(最大信号对照)和阴性对照(最小信号对照)，同时确保每个反应孔中的DMSO最终含量为0.25％。
将配置于缓冲液(50mM HEPES pH 7.5,10mM MgCl2,1mM EGTA,0.01％Brij-35)WEE1(Thermo Fisher,Cat#PR7373A)蛋白最终反应浓度为15nM),不同浓度的化合物中，反应底物Tracer 178(Invitrogen,PV5593)和MAb Anti-GST-Eu crypate(Cisbio,61GSTKLA)加入384孔板(Corning,cat#3574)中，1000rpm离心1min，将384孔反应板置于恒温摇床孵育60min,25℃，300rpm。其中Tracer 178和MAb Anti-GST-Eu crypate配置于缓冲液(50mM HEPES pH 7.5,10mM MgCl2,1mM EGTA,0.01％Brij-35)，且Tracer178最终反应浓度为50 nM,MAb Anti-GST-Eu crypate的最终浓度为2nM，其中阴性对照(最小信号对照)使用等量的缓冲液来代替蛋白溶液。
孵育完成后，使用BMG PHERAStar读数(用337nm波长为激发光，在620nm和665nm波长值为发射光读荧光信号值)。计算荧光信号比值：665/620*1000为最终的酶活性信号值，根据阳性对照(最大信号对照)和阴性对照(最小信号对照)获得的读数TR-FRET信号进行标准化，以给出不同浓度化合物的抑制率。再通过GraphPad Prism 6以log(inhibitor)vs.response–Variable slope模式拟合计算得出化合物对酶活性抑制的IC50。拟合方程为：Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))，其中Y代表已知的百分剩余酶活性，X代表Log后的已知化合物的浓度。
按照上述方法对实施例化合物进行Wee1抑制活性检测，试验结果见表1，其中测定各化合物的IC 50按照说明分类如下：
“-”表示IC 50测定值大于10μM；
“+”表示IC 50测定值小于等于10μM大于1μM；
“++”表示IC 50测定值小于等于1μM大于100nM；
“+++”表示IC 50测定值小于等于100nM大于10nM；
“++++”表示IC 50测定值小于等于10nM大于1nM；
“+++++”表示IC 50测定值小于等于1nM。
表1本发明化合物对Wee1激酶的抑制活性
化合物编号 IC 50测定值 化合物编号 IC 50测定值 化合物编号 IC 50测定值
1 ++++ 23 ++++ 43B +++
2 +++ 24 +++ 44 ++
3 +++ 25 ++++ 45 +++
4 +++ 26 ++++ 46 +++
5 +++ 27A ++++ 47 ++
6 +++ 27B +++ 48 +++
7 ++++ 28 ++ 49 ++
8 ++++ 29 ++ 50 ++
9 ++++ 30 +++ 51 +++
10 ++++ 31 +++ 52 ++
11 +++ 32 ++ 53 +++
12 +++ 33 ++ 54 +++
13 ++++ 34 ++ 55 +++
14 ++++ 35 ++ 56 ++
15 +++ 36 +++ 57 ++
16 ++++ 37 +++ 58 +++
17 +++ 38 +++ 59 +++
18 ++++ 39 +++ 60 +++
19 +++ 40 +++ 61 ++
20 ++++ 41 +++ 62 ++
21 +++ 42 +++ AZD-1775 ++++
22 ++ 43A +++    
上述实验表明，本发明公开化合物的对Wee1激酶有明显的抑制活性。
试验例2：通过Cell Titer-Glo方法评价化合物对H1299和MIA Paca-2细胞抗增殖的效果。
配置不同浓度梯度的化合物溶液。取DMSO溶解到浓度为10mM测试化合物和10mM参考化合物AZD1775，将化合物进行系列稀释于培养基中，共9个剂量点，每个浓度设置2个平行重复。不添加化合物的细胞生长组作为阳性对照(最大信号对照)，将培养基作为阴性对照(最小信号对照)，同时确保每个反应孔中的DMSO最终含量为0.2％。移除384孔板中的培养基后，将配置好的25ul的不同浓度化合物转移进孔板中，化合物和细胞在细胞培养箱37℃，5％CO2孵育3天。
将384孔板从细胞培养箱中取出使其平衡1h至室温，再将25ul的Cell Titer-Glo检测试剂加入每个反应孔，摇床裂解2min后，于孵育10min后，用BMG PHERAStar读数(Luminescence)。根据发光信号计算抑制率：先计算出阳性对照(最大信号对照)和阴性对照(最小信号对照)平均值。
以
Figure PCTCN2022092348-appb-000135
来计算出不同浓度化合物对细胞的抑制率。通过GraphPad Prism 6以log(inhibitor)vs.response–Variable slope模式拟合计算得出化合物对细胞活性抑制的IC50。拟合方程为：Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))，其中Y代表抑制率，X代表Log后的已知化合物的浓度。
按照上述方法对实施例化合物进行H1299和MIA Paca-2体外抗细胞增殖试验，试验结果 见表2，其中测定各化合物的IC 50按照说明分类如下：
“-”表示IC 50测定值大于50μM；
“+”表示IC 50测定值小于等于50μM大于20μM；
“++”表示IC 50测定值小于等于20μM大于5μM；
“+++”表示IC 50测定值小于等于5μM大于1μM；
“++++”表示IC 50测定值小于等于1μM大于0.1μM；
“+++++”表示IC 50测定值小于等于0.1μM。
表2本发明化合物对H1299和MIA Paca-2体外细胞增殖抑制活性
Figure PCTCN2022092348-appb-000136
Figure PCTCN2022092348-appb-000137
结论：本发明化合物对H1299和MIA Paca-2具有较强的细胞增殖抑制活性
试验例3：体外肝微粒体(小鼠和人)代谢稳定性评价
1.工作液的配制：
微粒体从-80℃冰箱取出，在37℃水浴锅中迅速融解，置于冰上待用。将供试品用DMSO稀释配制成10mM的储备液，然后用乙腈稀释成0.5mM的次级储备液。使用Buffer C将微粒体稀释为0.75mg/ml；再加入次级储备液至化合物终浓度1.5μM为工作液，依据n＝2，5个时间点计算，每个化合物配制350μL，使用前置于冰上。用Buffer C将NADPH稀释为6mM的工作液，为启动液。配制含内标的乙腈溶液作为沉淀剂，内标选用Verapamil-HCl，浓度为4ng/ml。
2.实验过程：
取一块圆底孔板，记做反应板，将各化合物配置好的工作液按照复样数和时间点分装到孔板中(0h的样品同样加在反应板上)，30μL/孔；反应板于37℃孵育10分钟。另取一块尖底孔板，记做沉淀板，每孔加入135μL沉淀剂；0h的样品在孵育10分钟后转移至沉淀板中，再加入15μL启动液，沉淀板在离心前置于冰上待用。
将稀释好的启动液足量加入至分装板中，方便排枪吸取操作。
反应在温孵震荡装置上进行，使用排枪吸取启动液15μL/样品，加入反应板中。稍震荡混匀以启动反应，使用计时器准确计时并记录；
到反应时间后，使用排枪将反应板中的所有溶液吸出加入到沉淀板中以终止该时间点反应。所有反应终止后，将沉淀板在摇板机上600rpm震荡十分钟沉淀蛋白。离心机最大转数在4℃离心15分钟，取上清80μL，加入320μL纯水，混匀后进行LC-MS分析。
3.测试结果：
Figure PCTCN2022092348-appb-000138
结论：本发明化合物具有良好的体外肝微粒体(小鼠和人)代谢稳定性。
试验例4：血浆蛋白结合率(PPB)评价
1.实验过程
样品准备：将化合物用DMSO溶解为10mM的储备液，然后用PBS将化合物稀释为0.02mM的次级储备液，再使用空白血浆将上述0.02mM稀释至1μM，即为待孵育样品。
透析装置准备：先在平衡透析板的白色孔中加入400μL空白PBS，红色孔中加入200μL配置好的血浆样品，用封口膜将透析板进行封口。
回收率孔板准备：准备两块96孔深孔板，标记为T0及T5，所有血浆样品以n＝2分别加入两板。T0板直接加入300μL乙腈(Verapamil-HCl，4ng/mL)，再补加50μL空白PBS混匀5min，放入4℃冰箱中静置至孵育实验结束。
实验操作：透析装置和T5板置于微孔板恒温振荡器中共同孵育5h(37℃，使用300rpm或最小转速)。孵育结束后，加入300μL乙腈(Verapamil-HCl，4ng/mL)，再补加50μL PBS溶液。透析孵育结束后，取一块新96孔深孔板。取50μL血浆孔样品加入96孔板对应位置，再加入300μL乙腈，补加50μL空白PBS；取50μL缓冲孔样品加入96孔板对应位置，再加入300μL乙腈，补加50μL空白血浆。T5板含血浆孔中加入300μL乙腈(Verapamil-HCl，4ng/mL)，再补加50μL PBS溶液。振荡5min以充分沉淀蛋白，4℃，20000g离心10分钟。取200μL上清液加入200μL纯水中，混匀后进行LC-MS/MS分析。
2.数据处理和参数计算
●血浆蛋白结合率＝[(Rpe-Rb)/Rpe]×100％
●回收率＝[(Rpe+Rb)/R5h]×100％
●稳定性＝(R5/R0)×100％
其中：
●R pe＝血浆侧供试品峰面积与内标比值
●R b＝缓冲液侧供试品峰面积与内标比值
●R 5＝孵箱稳定性样品峰面积与内标比值
●R 0＝冰箱稳定性样品峰面积与内标比值
3.测试结果：
Figure PCTCN2022092348-appb-000139
结论：本发明化合物具有良好的血浆蛋白结合与游离药物比例。与AZD-1775相比，本发明化合物血浆蛋白结合相近，种属间波动差异更小。
试验例5：透膜性研究(Caco-2)
Caco-2细胞购买自美国模式组织细胞收藏中心(Rockville，MD)。细胞培养液为含10％灭活胎牛血清和1％非必须氨基酸的改良Eagle’s培养基(MEM)。细胞接种于聚碳酸脂滤膜(货号：3396)并置于37℃，5％CO 2培养箱中培养。
细胞接种后培养21～28天可用于转运实验，并通过路西法黄的表观通透系数(P app)来表征和验证细胞单层的致密性。实验中将化合物溶解于DMSO中制备10mM的储备液，并使用含有25mM HEPES(pH 7.4)的汉克斯平衡盐溶液(HBSS，Invitrogen，Cat#14025-092)进行稀释得到工作液。将10μM的待测化合物工作液加入Caco-2顶膜侧(apical side)和基底侧(basolateral side)并于37℃孵育90分钟，孵育结束后，将顶膜侧和基底侧的样品稀释，并通过LC-MS/MS检测顶膜侧和基底侧化合物的浓度，并通过标准曲线定量计算化合物的浓度。
测试结果：
Figure PCTCN2022092348-appb-000140
Figure PCTCN2022092348-appb-000141
结论：本发明化合物具有良好的透膜性质。
试验例6：化合物代谢动力学评价
为考察化合物的小鼠药代属性，化合物通过口服灌胃(10mg/kg)方式，以相应剂量分别给予6只雄性ICR小鼠，每途径给药小鼠分为A/B两组，其中A组小鼠给药后在5min,30min,2h,8h采集抗凝全血，B组小鼠在给药后在15min,1h,4h,24h采集抗凝全血，分离血浆；
使用LC-MS，通过标准曲线校正法测定化合物的血浆浓度。使用Winnolin 5.2软件，将血浆浓度-时间数据拟合为药代参数。
测试结果：
PK参数 AZD-1775 化合物1 化合物28 化合物40
T1/2,hr 0.77 1.71 1.78 0.70
C max(ng/mL) 445 169 337 377
AUC inf_Pred(hr*ng/mL) 500 260 743 493
Cl_pred(L/hr/kg) 20.8 39.5 13.8 24.3
结论：本发明化合物具有良好的体内药物代谢动力学性质，能够显著提高化合物的半衰期，降低清除率。
试验例7：溶解度测试
将化合物置缓冲溶液中，恒温振摇24h，取上清液配制成约100μg/ml供试品溶液，采用反相高效液相色谱法，梯度洗脱，外标法计算溶解度。色谱条件：C18柱，流动相A：0.02M磷酸二氢钾：乙腈＝90:10，流动相B：乙腈；V:1.0ml/min，T:35℃，λ:210nm。
测试结果：
化合物编号 溶解度(mg/mL)
AZD-1775 0.03
化合物1 0.12
化合物3 0.06
化合物16 0.35
结论：本发明化合物的溶解度明显优于AZD-1775。
试验例8：化合物对细胞色素P450抑制评价
酶学实验通过细胞色素P450对底物的氧化产生的荧光，定量检测小分子抑制剂对CYP450各亚型酶活性的抑制情况。实验在384孔板(Corning，Cat#3575)中进行，使用的反应缓冲液为：142.86mM Potassium Phosphate，pH 7.4。实验所用Solution A成分为：26.13mM NADP+(Sigma-aldrich，Cat#N0505)，65.77mM G6P(J&K，Cat#968161)及65.42mM MgCl2(Sigma-aldrich，Cat#M2670)。实验所用的Solution B成分为：40U/mL G6PDH(Sigma-aldrich，Cat#G6378)。底物混合溶液成分为：0.05X Solution A，0.01X Solution B，50mM Potassium Phosphate，0.01mM BOMCC/0.01mM EOMCC/0.001mM DBOMF。对于CYP3A4和CYP2C9，反应体系分别为50μL或20μL，包括3nM CYP3A4或120nM CYP2C9，BOMCC底物混合溶液和不同浓度的待测化合物。对于CYP2C19，CYP2D6及CYP1A2，反应体系为20μL，包括12.5nM CYP2C19，80nM CYP2D6或1nM CYP1A2，EOMCC底物混合溶液和不同浓度的待测化合物。对于CYP2C8，反应体系为50μL，包括1.5nM CYP2C8，DBOMF底物混合溶液和不同浓度的待测化合物。化合物与酶预孵10分钟后，加入底物，并根据不同底物使用BMG PHERAStar读取不同波段的荧光信号(BOMCC/EOMCC Ex430nm/Em480nm，DBOMF Ex490nm/Em520nm)，反应间隔30秒或更多(根据实际实验孔数设置)，反应时长为30分钟。实验数据通过GraphPad Prism 6软件进行分析处理得到IC50值。
测试结果：
Figure PCTCN2022092348-appb-000142
结论：本发明化合物均无明显CYP抑制作用。
试验例9：hERG钾离子通道抑制试验
实验步骤：
(一)实验材料：
A.CHO(中华仓鼠卵巢细胞)稳定转染细胞系培养
膜片钳实验所用细胞株为过表达hERG钾离子通道cDNA的第10代CHO细胞。
CHO hERG细胞在37℃、5％CO2培养箱中用培养皿或培养瓶培养。电生理实验前24-48小时，将细胞滴于圆形玻片上在细胞培养液中培养，待细胞贴壁后用于实验。
细胞培养基(购自Invitrogen)成分：
·Ham’s F12培养基
·10％(v/v)热灭活FBS
·100μg/ml Hygromycin B(潮霉素)
·100μg/ml Geneticin(遗传霉素，G418)
B.化合物准备
化合物粉末溶解在细胞外液中，都经过常规的5到10分钟超声和振荡以保证化合物完 全溶解。
用于电生理检测的化合物终浓度为5、20μM，DMSO的终浓度为0.1％。
(二)实验方案：
A.电生理记录实验过程
细胞膜电流记录使用HEKA EPC-10USB膜片钳放大器(德国HEKA Elektronik)。
1)取表面有大量单个CHO hERG细胞均匀生长的盖玻片，放置于倒置显微镜上的连续记录池中，灌流细胞外液(大约每分钟1毫升)并持续记录，等待电流稳定。
2)使用标准的全细胞记录模式记录单个细胞的HERG通道电流。首先将膜电压钳制在-80mV，给予细胞持续5s，+20mV电压刺激，以激活hERG钾通道，再复极化至-50mV，持续5s，产生外向尾电流，持续灌注待电流稳定，此时尾电流峰值即为对照电流值。
3)接着灌流含待测药物的细胞外液并持续记录直到药物对hERG电流的抑制作用到达稳定状态，此时尾电流峰值即为加药后电流值。
4)再次用细胞外溶液灌注细胞，直到hERG电流回复或接近加药物之前的水平，则可以继续灌流测试其它浓度或药物。可在每个细胞上测试一种或多种化合物或药物浓度。
5)以Cisapride(C4740-10mg，Sigma)作为实验中的阳性对照以保证所使用的细胞反应正常。
(三)质量控制
报告中的试验数据需要满足以下标准：
电生理记录参数
a)封接电阻>500MΩ
b)接触电阻(Ra)<10MΩ
c)初始尾电流幅度>200pA
d)电流rundown(自发性减小)<2％/min
e)漏电流<200pA或者hERG电流峰值的10％(在90％的记录时间之内)
测试结果：
Figure PCTCN2022092348-appb-000143
结论：本发明化合物的hERG抑制活性明显低于AZD-1775。

Claims (27)

  1. 式I所示的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐：
    Figure PCTCN2022092348-appb-100001
    其中，
    R 1选自氢、卤素、氰基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR 11、-C 0～4亚烷基-NR 12R 12；
    R 11选自-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基；
    每个R 12分别独立选自氢、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基；
    C环选自
    Figure PCTCN2022092348-appb-100002
    Figure PCTCN2022092348-appb-100003
    X 1、X 2、X 4分别独立选自N或CR 4；
    X 3选自N或CR 3；
    X 5选自O、S或NR 4；
    X 6选自CR 4或N；
    X 8选自CR 4R 4、O；
    X 7选自S、NR 4；
    X 9选自CR 4R 4；
    R 2选自
    Figure PCTCN2022092348-appb-100004
    R 21、R 22分别独立选自氢、卤素、氰基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR 24、-C 0～4亚烷基-NR 24R 24；
    每个R 24分别独立选自氢、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基；
    或者，R 21、R 22与相连原子一起形成3～8元碳环基、4～8元杂环烷基、
    Figure PCTCN2022092348-appb-100005
    R 23选自氢、卤素、氰基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-C(O)R 25、-C 0～4亚烷基-C(O)NR 25R 25、-C 0～4亚烷基-C(O)OR 25、-C 0～4亚烷基-S(O) 2R 25、-C 0～4亚烷基-S(O)R 25、-C 0～4亚烷基-S(O)(NH)R 25、-C 0～4亚烷基-S(NH) 2R 25、-C 0～4亚烷基-S(O) 2NR 25R 25、-C 0～4亚烷基-S(O)NR 25R 25、-C 0～4亚烷基-S(O)(NH)NR 25R 25、-C 0～4亚烷基-S(NH) 2NR 25R 25、-C 0～4亚烷基-OR 25、-C 0～4亚烷基-OC(O)R 25、-C 0～4亚烷基-OS(O) 2R 25、-C 0～4亚烷基-OS(O)R 25、-C 0～4亚烷基-NR 25R 25、-C 0～4亚烷基-NR 25C(O)R 25、-C 0～4亚烷基-NR 25S(O) 2R 25、-C 0～4亚烷基-NR 25S(O)R 25、-C 0～4亚烷基-NR 25S(O)(NH)R 25、-C 0～4亚烷基-NR 25S(NH) 2R 25；
    每个R 25分别独立选自氢、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基；
    或者，R 23、R 3与相连原子一起形成4～8元碳环基、4～8元杂环烷基；
    R 3选自氢、卤素、氰基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、羟基取代的-C 1～6烷基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
    每个R 4分别独立选自氢、卤素、氰基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
    R 5选自氢、-C 1～6烷基；
    A环选自
    Figure PCTCN2022092348-appb-100006
    Figure PCTCN2022092348-appb-100007
    Figure PCTCN2022092348-appb-100008
    表示单键或双键；
    Y 1、Y 2、Y 3、Y 4分别独立选自N或CR Y；
    每个R Y分别独立选自氢、卤素、氰基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
    B环选自3～12元碳环基、4～12元杂环烷基；所述碳环基、杂环烷基可进一步被一个、两个、三个、四个或五个R B取代；
    每个R B分别独立选自氢、卤素、氰基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR B1、-C 0～4亚烷基-OC(O)R B1、-C 0～4亚烷基-SR B1、-C 0～4亚烷基-S(O) 2R B1、-C 0～4亚烷基-S(O)R B1、-C 0～4亚烷基-S(O) 2NR B1R B1、-C 0～4亚烷基-S(O)NR B1R B1、-C 0～4亚烷基-C(O)R B1、-C 0～4亚烷基-C(O)OR B1、-C 0～4亚烷基-C(O)NR B1R B1、-C 0～4亚烷基-NR B1R B1、-C 0～4亚烷基-NR B1C(O)R B1、3～12元碳环基、4～12元杂环烷基；所述碳环基、杂环烷基可进一步被一个、两个、三个、四个或五个R B1取代；或者，两个独立的R B与相连原子一起形成
    Figure PCTCN2022092348-appb-100009
    每个R B1分别独立选自氢、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基；
    R 6、R 7、R 8、R 9分别独立选自氢、卤素、氰基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6 烷基)；
    或者，R 6、R 7与相连原子一起形成3～8元碳环基、4～8元杂环烷基；或者，R 8、R 9与相连原子一起形成3～8元碳环基、4～8元杂环烷基；
    Y 5、Y 6分别独立选自化学键、-C 0～4亚烷基-O-、-C 0～4亚烷基-S-、-C 0～4亚烷基-NR Y51-、CR Y51R Y51；
    每个R Y51分别独立选自氢、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
    Y 7选自O、S或NR Y71；
    R Y71选自氢、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
    R 10选自氢、卤素、氰基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基、卤素取代的-C 2～6烯基、卤素取代的-C 2～6炔基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)。
  2. 根据权利要求1所述的化合物，其特征在于：
    R 1选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OR 11、-NR 12R 12；
    R 11选自-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、卤素取代的-C 1～6烷基；
    每个R 12分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；
    R 10选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OH、-O(C 1～6烷基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)。
  3. 根据权利要求2所述的化合物，其特征在于：
    R 1选自氢、卤素、氰基、-C 1～6烷基、三氟甲基、-O(C 1～6烷基)、-O(C 2～6烯基)、-O(三氟甲基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)；
    R 10选自氢、卤素、-C 1～6烷基、-O(C 1～6烷基)。
  4. 根据权利要求1所述的化合物，其特征在于：
    C环选自
    Figure PCTCN2022092348-appb-100010
    Figure PCTCN2022092348-appb-100011
  5. 根据权利要求4所述的化合物，其特征在于：
    R 2选自
    Figure PCTCN2022092348-appb-100012
    R 21、R 22分别独立选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OR 24；
    每个R 24分别独立选自氢、-C 1～6烷基；
    或者，R 21、R 22与相连原子一起形成羰基、3元碳环基、4元碳环基、5元碳环基、6元碳环基、4元杂环烷基、5元杂环烷基、6元杂环烷基；所述杂环烷基中的杂原子选自N、O、S；
    R 23选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-S(O) 2R 25、-S(O)R 25、-S(O)(NH)R 25、-S(NH) 2R 25；
    每个R 25分别独立选自氢、-C 1～6烷基。
  6. 根据权利要求5所述的化合物，其特征在于：
    R 2选自
    Figure PCTCN2022092348-appb-100013
  7. 根据权利要求1所述的化合物，其特征在于：
    C环选自
    Figure PCTCN2022092348-appb-100014
    R 2选自
    Figure PCTCN2022092348-appb-100015
    R 21、R 22分别独立选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OR 24；
    每个R 24分别独立选自氢、-C 1～6烷基；
    R 23、R 3与相连原子一起形成4元碳环基、5元碳环基、6元碳环基、7元碳环基、5元杂环烷基、6元杂环烷基。
  8. 根据权利要求7所述的化合物，其特征在于：
    C环选自
    Figure PCTCN2022092348-appb-100016
    其中，m选自0、1、2、3。
  9. 根据权利要求4所述的化合物，其特征在于：
    R 2选自
    Figure PCTCN2022092348-appb-100017
    R 21、R 22分别独立选自氢、-C 1～6烷基。
  10. 根据权利要求1所述的化合物，其特征在于：
    A环选自
    Figure PCTCN2022092348-appb-100018
    Y 1、Y 2、Y 3、Y 4分别独立选自N或CR Y；
    每个R Y分别独立选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
    B环选自3～8元单碳环基、4～8元单杂环烷基、5～10元桥碳环基、5～10元桥杂环烷基、5～10元螺碳环基、5～10元螺杂环烷基、8～12元稠碳环基、8～12元稠杂环烷基；所述单碳环基、单杂环烷基、桥碳环基、桥杂环烷基、螺碳环基、螺杂环烷基、稠碳环基、稠杂环烷基可进一步被一个、两个、三个、四个或五个R B取代；
    每个R B分别独立选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OR B1、-SR B1、-S(O) 2R B1、-S(O)R B1、-C(O)R B1、-C(O)OR B1、-NR B1R B1、3～12元碳环基、4～12元杂环烷基； 所述碳环基、杂环烷基可进一步被一个、两个、三个、四个或五个R B1取代；或者，两个独立的R B与相连原子一起形成
    Figure PCTCN2022092348-appb-100019
    每个R B1分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；
    Y 5选自O、S、NR Y51、CR Y51R Y51；
    每个R Y51分别独立选自氢、-C 1～6烷基。
  11. 根据权利要求10所述的化合物，其特征在于：
    B环选自
    Figure PCTCN2022092348-appb-100020
    Figure PCTCN2022092348-appb-100021
  12. 根据权利要求11所述的化合物，其特征在于：
    B环选自
    Figure PCTCN2022092348-appb-100022
    Figure PCTCN2022092348-appb-100023
  13. 根据权利要求1所述的化合物，其特征在于：
    A环选自
    Figure PCTCN2022092348-appb-100024
    Y 1、Y 2、Y 3、Y 4分别独立选自N或CR Y；
    每个R Y分别独立选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
    R 6、R 7、R 8、R 9分别独立选自氢、-C 1～6烷基；
    或者，R 6、R 7与相连原子一起形成3元碳环基、4元碳环基、5元碳环基、6元碳环基、4元杂环烷基、5元杂环烷基、6元杂环烷基；或者，R 8、R 9与相连原子一起形成3元碳环基、4元碳环基、5元碳环基、6元碳环基、4元杂环烷基、5元杂环烷基、6元杂环烷基；
    R B选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、-S(O) 2R B1、-S(O)R B1、-C(O)R B1、-C(O)OR B1；
    每个R B1分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基。
  14. 根据权利要求13所述的化合物，其特征在于：
    A环选自
    Figure PCTCN2022092348-appb-100025
    Figure PCTCN2022092348-appb-100026
  15. 根据权利要求1所述的化合物，其特征在于：
    A环选自
    Figure PCTCN2022092348-appb-100027
    Y 1、Y 2、Y 4分别独立选自N或CR Y；
    每个R Y分别独立选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
    R B选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、-S(O) 2R B1、-S(O)R B1、-C(O)R B1、-C(O)OR B1；
    每个R B1分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；
    Y 5选自化学键、O、S、NR Y51、CR Y51R Y51；
    每个R Y51分别独立选自氢、-C 1～6烷基。
  16. 根据权利要求15所述的化合物，其特征在于：
    A环选自
    Figure PCTCN2022092348-appb-100028
  17. 根据权利要求1所述的化合物，其特征在于：
    A环选自、
    Figure PCTCN2022092348-appb-100029
    Figure PCTCN2022092348-appb-100030
    Figure PCTCN2022092348-appb-100031
    表示单键或双键；
    Y 1、Y 2、Y 4分别独立选自N或CR Y；
    每个R Y分别独立选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
    R B选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、-S(O) 2R B1、-S(O)R B1、-C(O)R B1、-C(O)OR B1；
    每个R B1分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；
    Y 5、Y 6分别独立选自化学键、-C 0～1亚烷基-O-、-C 0～1亚烷基-S-、-C 0～1亚烷基-NR Y51-、CR Y51R Y51；
    每个R Y51分别独立选自氢、-C 1～6烷基。
  18. 根据权利要求17所述的化合物，其特征在于：
    A环选自
    Figure PCTCN2022092348-appb-100032
    Figure PCTCN2022092348-appb-100033
    Figure PCTCN2022092348-appb-100034
  19. 根据权利要求1所述的化合物，其特征在于：
    A环选自
    Figure PCTCN2022092348-appb-100035
    Figure PCTCN2022092348-appb-100036
    Y 1选自N或CR Y；
    R Y选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 0～4亚烷基-OH、-C 0～4亚烷基-O(C 1～6烷基)、-C 0～4亚烷基-NH 2、-C 0～4亚烷基-NH(C 1～6烷基)、-C 0～4亚烷基-N(C 1～6烷基)(C 1～6烷基)；
    B环选自3～8元单碳环基、4～8元单杂环烷基；所述单碳环基、单杂环烷基可进一步被一个、两个、三个、四个或五个R B取代；
    每个R B分别独立选自氢、卤素、氰基、-C 1～6烷基、卤素取代的-C 1～6烷基、-OR B1、-SR B1、-S(O) 2R B1、-S(O)R B1、-C(O)R B1、-C(O)OR B1、-NR B1R B1；或者，两个独立的R B与相连原子一起形成
    Figure PCTCN2022092348-appb-100037
    每个R B1分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；
    Y 7选自O、S或NR Y71；
    R Y71选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基、-C 1～4亚烷基-OH、-C 1～4亚烷基-O(C 1～6烷基)、-C 1～4亚烷基-NH 2、-C 1～4亚烷基-NH(C 1～6烷基)、-C 1～4亚烷基-N(C 1～6烷基)(C 1～6烷基)。
  20. 根据权利要求19所述的化合物，其特征在于：
    A环选自
    Figure PCTCN2022092348-appb-100038
    Figure PCTCN2022092348-appb-100039
  21. 根据权利要求1所述的化合物，其特征在于：
    C环选自
    Figure PCTCN2022092348-appb-100040
    Figure PCTCN2022092348-appb-100041
    Figure PCTCN2022092348-appb-100042
  22. 根据权利要求10所述的化合物，其特征在于：
    A环选自
    Figure PCTCN2022092348-appb-100043
    Figure PCTCN2022092348-appb-100044
  23. 根据权利要求1所述的化合物，其特征在于：所述式I的化合物具体为：
    Figure PCTCN2022092348-appb-100045
    Figure PCTCN2022092348-appb-100046
    Figure PCTCN2022092348-appb-100047
    Figure PCTCN2022092348-appb-100048
    Figure PCTCN2022092348-appb-100049
    Figure PCTCN2022092348-appb-100050
    Figure PCTCN2022092348-appb-100051
    Figure PCTCN2022092348-appb-100052
    Figure PCTCN2022092348-appb-100053
    Figure PCTCN2022092348-appb-100054
    Figure PCTCN2022092348-appb-100055
    Figure PCTCN2022092348-appb-100056
    Figure PCTCN2022092348-appb-100057
    Figure PCTCN2022092348-appb-100058
  24. 权利要求1～23任一所述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐在制备Wee1抑制剂药物中的用途。
  25. 权利要求1～23任一所述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐在制备预防和/或治疗癌症中的用途。
  26. 一种药物组合物，包括权利要求1～23任一所述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐制备而成的制剂。
  27. 根据权利要求26所述的药物组合物，其进一步包括药学上可接受的载体、辅料、媒介物。
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