WO2022268025A1 - Atr抑制剂及其用途 - Google Patents

Atr抑制剂及其用途 Download PDF

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WO2022268025A1
WO2022268025A1 PCT/CN2022/099809 CN2022099809W WO2022268025A1 WO 2022268025 A1 WO2022268025 A1 WO 2022268025A1 CN 2022099809 W CN2022099809 W CN 2022099809W WO 2022268025 A1 WO2022268025 A1 WO 2022268025A1
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alkylene
alkyl
halogen
substituted
hydrogen
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PCT/CN2022/099809
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English (en)
French (fr)
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向永哲
李莉
戴华胄
刘华
吴先强
孙文博
陈洪
王颖
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成都苑东生物制药股份有限公司
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Priority to CN202280003514.5A priority Critical patent/CN115916775A/zh
Publication of WO2022268025A1 publication Critical patent/WO2022268025A1/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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This application relates to a class of novel compounds with ATR inhibitory effect and their use in the preparation of medicines.
  • Ataxia telangiectasia mutated and Rad3 - related kinase ATR is a member of the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family, which also includes ataxia Telangiectasia mutant kinase (ATM), DNA-dependent protein kinase (DNA-PK), suppressor of genitalia formation-1 (SMG-1), mammalian target of rapamycin (mTOR), and transformation/transcription-associated protein ( TRAPP).
  • ATR and ATM are key regulators of the cellular DNA damage response (DDR) pathway and are involved in maintaining genome integrity in response to DNA damage.
  • DDR DNA damage response
  • ATR is a key member of the DDR that responds to impaired DNA replication, and it is essential for maintaining genome stability and integrity and promoting cell survival.
  • ATR is recruited to the site of DNA damage, and a variety of proteins then participate in the regulation of ATR activation, which regulates some important cellular processes after activation.
  • Many cancer cells lack key tumor suppressor genes, which can make cancer cells more dependent on the ATR pathway than normal cells to regulate cellular DNA damage repair and promote cell survival, making ATR a promising target for cancer therapy. Inhibition of ATR may enhance the potency of replication inhibitors.
  • ATR inhibition may have a lethal effect on cells with high RS levels, such as cells expressing proto-oncogenes or lacking tumor suppressors. Inhibition of ATR activity in these cells produces lethal amounts of RS, resulting in cell death.
  • B ring selected from Wherein B ring can be further optionally replaced by one, two, three or four R B1 ;
  • Each R B1 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 B2 , -C 0 ⁇ 4 alkylene-OC(O)R B2 , -C 0 ⁇ 4 alkylene-C(O)R B2 , -C 0 ⁇ 4 alkylene-C(O)OR B2 , -C 0 ⁇ 4 alkylene-C(O)NR B2 R B3 , -C 0 ⁇ 4 alkylene-NR B2 R B3 , -C 0 ⁇ 4 alkylene-NR B2 C(O)R B3 ;
  • R B2 and R B3 are 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, halogen substituted -C 2 ⁇ 6 alkynyl;
  • X 1 , X 2 , X 3 , and X 4 are independently selected from N or CRC1 ;
  • Y is selected from O, S or NR C1 ;
  • Each R C1 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 C2 , -C 0-4 alkylene-OC(O)R C2 , -C 0 ⁇ 4 alkylene-SR C2 , -C 0 ⁇ 4 alkylene-S(O) 2 R C2 , -C 0 ⁇ 4 alkylene-S(O)R C2 , -C 0 ⁇ 4 Alkylene-S(O) 2 NR C2 R C3 , -C 0 ⁇ 4 Alkylene-S(O)NR C2 R C3 , -C 0 ⁇ 4 Alkylene-S
  • two independent R C1 and connected atoms together form a 5-8 membered carbocyclic group, a 5-8 membered heterocycloalkyl group, a benzene ring, and a 5-6 membered aromatic heterocyclic ring; among them, carbocyclyl, heterocyclic Alkyl, aromatic ring, aromatic heterocyclic ring can be further optionally substituted by one, two, three or four independent R C4 ;
  • R C2 and R C3 are 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-(3 ⁇ 10 membered carbocyclyl), -C 0 ⁇ 4 alkylene-(4 ⁇ 10 membered heterocycloalkyl), -C 0 ⁇ 4 alkylene-(6 ⁇ 10 membered aromatic ring), -C 0 ⁇ 4 alkylene-(5 ⁇ 10 membered aromatic heterocyclic ring);
  • Each R C4 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 C5 , -C 0 ⁇ 4 alkylene-OC(O)R C5 , -C 0 ⁇ 4 alkylene-SR C5 , -C 0 ⁇ 4 alkylene-S(O) 2 R C5 , -C 0 ⁇ 4 alkylene-S(O)R C5 , -C 0 ⁇ 4 Alkylene-S(O) 2 NR C5 R C6 , -C 0 ⁇ 4 Alkylene-S(O)NR C5 R C6 , -C 0 ⁇ 4 Alkylene-S(O)NR
  • R C5 and R C6 are 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-(3 ⁇ 10 membered carbocyclyl), -C 0 ⁇ 4 alkylene-(4 ⁇ 10 membered heterocycloalkyl), -C 0-4 alkylene-(6-10 membered aromatic ring), -C 0-4 alkylene-(5-10 membered aromatic heterocyclic ring).
  • the application provides a compound represented by formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • B ring selected from Wherein B ring can be further optionally replaced by one, two, three or four R B1 ;
  • Each R B1 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 B2 , -C 0 ⁇ 4 alkylene-OC(O)R B2 , -C 0 ⁇ 4 alkylene-C(O)R B2 , -C 0 ⁇ 4 alkylene-C(O)OR B2 , -C 0 ⁇ 4 alkylene-C(O)NR B2 R B3 , -C 0 ⁇ 4 alkylene-NR B2 R B3 , -C 0 ⁇ 4 alkylene-NR B2 C(O)R B3 ;
  • R B2 and R B3 are 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, halogen substituted -C 2 ⁇ 6 alkynyl;
  • X 1 , X 2 , X 3 , and X 4 are independently selected from N or CRC1 ;
  • Y is selected from O, S or NR C1 ;
  • Each R C1 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 C2 , -C 0-4 alkylene-OC(O)R C2 , -C 0 ⁇ 4 alkylene-SR C2 , -C 0 ⁇ 4 alkylene-S(O) 2 R C2 , -C 0 ⁇ 4 alkylene-S(O)R C2 , -C 0 ⁇ 4 Alkylene-S(O) 2 NR C2 R C3 , -C 0 ⁇ 4 Alkylene-S(O)NR C2 R C3 , -C 0 ⁇ 4 Alkylene-S
  • two independent R C1 and connected atoms together form a 5-8 membered carbocyclic group, a 5-8 membered heterocycloalkyl group, a benzene ring, and a 5-6 membered aromatic heterocyclic ring; among them, carbocyclyl, heterocyclic Alkyl, aromatic ring, aromatic heterocyclic ring can be further optionally substituted by one, two, three or four independent R C4 ;
  • R C2 and R C3 are 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-(3 ⁇ 10 membered carbocyclyl), -C 0 ⁇ 4 alkylene-(4 ⁇ 10 membered heterocycloalkyl), -C 0 ⁇ 4 alkylene-(6 ⁇ 10 membered aromatic ring), -C 0 ⁇ 4 alkylene-(5 ⁇ 10 membered aromatic heterocyclic ring);
  • Each R C4 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 C5 , -C 0 ⁇ 4 alkylene-OC(O)R C5 , -C 0 ⁇ 4 alkylene-SR C5 , -C 0 ⁇ 4 alkylene-S(O) 2 R C5 , -C 0 ⁇ 4 alkylene-S(O)R C5 , -C 0 ⁇ 4 Alkylene-S(O) 2 NR C5 R C6 , -C 0 ⁇ 4 Alkylene-S(O)NR C5 R C6 , -C 0 ⁇ 4 Alkylene-S(O)NR
  • R C5 and R C6 are 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-(3 ⁇ 10 membered carbocyclyl), -C 0 ⁇ 4 alkylene-(4 ⁇ 10 membered heterocycloalkyl), -C 0-4 alkylene-(6-10 membered aromatic ring), -C 0-4 alkylene-(5-10 membered aromatic heterocyclic ring).
  • the A ring is selected from preferably selected from more preferably
  • B ring is selected from Wherein B ring can be further optionally replaced by one, two, three or four R B1 ;
  • Each R B1 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -OR B2 , -C(O)R B2 , -C(O )NR B2 R B3 , -NR B2 R B3 , -NR B2 C(O)R B3 ;
  • R B2 and R B3 are independently selected from hydrogen, -C 1-6 alkyl, respectively.
  • each R B1 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl; preferably selected from hydrogen, halogen, cyano, -C 1 ⁇ 4 alkyl, halogen substituted -C 1 ⁇ 6 alkyl; more preferably selected from hydrogen, halogen, cyano, -C 1 ⁇ 3 alkyl, halogen substituted -C 1 ⁇ 6 alkyl;
  • each R B1 is independently selected from hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, halomethyl , haloethyl, halopropyl; preferably selected from hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monochloromethane base, dichloromethyl, trichloromethyl; more preferably selected from hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, further preferably selected from hydrogen, fluorine, chlorine, bromine, methyl, for example Fluorine or methyl.
  • the B ring is selected from
  • the B ring is selected from preferably selected from Wherein B ring can be further optionally substituted by one, two, three or four R B1 , R B1 as defined above.
  • the B ring is selected from
  • the B ring is selected from
  • the B ring is selected from
  • ring B is selected from
  • R and R together with the attached atoms form
  • X 1 , X 2 , X 3 , and X 4 are independently selected from N or CRC1 ;
  • Y is selected from O, S or NR C1 , preferably S or NR C1 ;
  • Each R C1 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 C2 , -C 0 ⁇ 4 alkylene-SR C2 , -C 0 ⁇ 4 Alkylene-S(O) 2 R C2 , -C 0 ⁇ 4 Alkylene-S(O)R C2 , -C 0 ⁇ 4 Alkylene-S(O) 2 NR C2 R C3 , -C 0-4 alkylene-S(O)NR C2 R C3 , -C 0-4 alkylene-NR C2 R C3 ; preferably selected from hydrogen, halogen, cyano, -C 1-6
  • R C2 and R C3 are 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; preferably selected from hydrogen, -C 1 ⁇ 6 alkyl; more preferably selected from hydrogen, -C 1 ⁇ 4 alkyl; further preferably selected from hydrogen , methyl, ethyl, n-propyl, isopropyl; more preferably selected from hydrogen, methyl;
  • Each R C4 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; preferably selected from hydrogen, -C 1 ⁇ 6 alkyl; more preferably selected from hydrogen, -C 1 ⁇ 4 alkyl; further preferably selected from hydrogen, methyl, ethyl, N-propyl, isopropyl; more preferably selected from hydrogen, methyl.
  • CR C1 is selected from CH, C (C 1-6 alkyl), C (C 2-6 alkenyl), C (C 2-6 alkynyl), C (halogen substituted -C 1 ⁇ 6 alkyl), C(C 0 ⁇ 4 alkylene-OR C2 ), wherein the alkylene group can be optionally substituted by one, two, three or four independent R C4 ;
  • R C2 is selected from hydrogen, -C 1 ⁇ 6 alkyl; each R C4 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl.
  • CR C1 is selected from CH, C (C 1-4 alkyl), C (C 1-4 alkylene-OR C2 ), wherein, the alkylene can be optionally replaced by one or two independent R C4 is substituted;
  • CR C1 is selected from CH, C (C 1 ⁇ 3 alkyl), C (C 1 ⁇ 3 alkylene-OR C2 ), wherein, the alkylene can be optionally replaced by one or two Independent R C4 is substituted;
  • R C2 is selected from hydrogen; each R C4 is independently selected from hydrogen, -C 1 ⁇ 3 alkyl.
  • CR C1 is selected from CH , CCH3 , C(C( CH3 )2OH).
  • NR C1 is selected from NH, N(C 1-6 alkyl), N(C 2-6 alkenyl), N(C 2-6 alkynyl), N(C 0-6 4 alkylene-SR C2 ), N(C 0 ⁇ 4 alkylene-S(O) 2 R C2 ), N(C 0 ⁇ 4 alkylene-S(O)R C2 ), wherein, the The alkylene group can be optionally substituted by one, two, three or four independent R C4 ; R C2 is selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 Alkynyl; each R C4 is independently selected from hydrogen, -C 1 ⁇ 6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl.
  • NR C1 is selected from NH, N(C 1 ⁇ 4 alkyl), N(C 1 ⁇ 4 alkylene-S(O) 2 R C2 ), wherein the alkylene group can be optionally One or two independent R C4 substitutions; R C2 is selected from hydrogen, -C 1 ⁇ 4 alkyl; each R C4 is independently selected from hydrogen, -C 1 ⁇ 4 alkyl.
  • NR C1 is selected from NH, N(C 1 ⁇ 3 alkyl), N(C 1 ⁇ 3 alkylene-S(O) 2 R C2 ), wherein, the alkylene can be optionally Substituted by one or two independent R C4 ; R C2 is selected from -C 1 ⁇ 3 alkyl; each R C4 is independently selected from hydrogen, -C 1 ⁇ 3 alkyl.
  • NR C1 is selected from N(CH 3 ), N(CH 2 S(O) 2 CH 3 ), N(CH(CH 3 )S(O) 2 CH 3 ), N(CH(CH 2 CH 3 ) S(O) 2 CH 3 ), N(CH(CHCH 3 CH 3 )S(O) 2 CH 3 ), or N(C(CH 3 ) 2 S(O) 2 CH 3 ).
  • R1 and R2 together with the connected atoms form Each of the foregoing rings wherein R and R are formed together with the atoms to which they are attached may be further optionally substituted by one, two , three or four R C 1 .
  • each R C1 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl, Preferably, each R C1 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl, Or preferably, each R C1 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl, More preferably, each R C1 is independently selected from hydrogen, halogen, cyano, -C 1-4 alkyl, Further preferably, each R C1 is independently selected from hydrogen, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, Even more preferably, each R C1 is independently selected from hydrogen, methyl,
  • R1 and R2 together with the connected atoms form The ring wherein R and R together with the atoms to which they are attached may be further optionally substituted by one, two , three or four R C1 , R C1 being as defined above.
  • R1 and R2 together with the attached atoms form They may optionally be substituted by one, two, three or four R C1 .
  • R 1 and R 2 together with the attached atoms form
  • the A ring is selected from preferably
  • B ring selected from preferably selected from
  • X 1 , X 2 , X 3 , and X 4 are independently selected from N or CRC1 ;
  • Y is selected from S or NR C1 ;
  • CR C1 is selected from CH, C (C 1 ⁇ 4 alkyl), C (C 1 ⁇ 4 alkylene-OR C2 ), wherein the alkylene can be optionally substituted by one or two independent R C4 ;
  • R C2 is selected from hydrogen; each R C4 is independently selected from from hydrogen, -C 1 ⁇ 3 alkyl; for example, CR C1 is selected from CH, CCH 3 , C(C(CH 3 ) 2 OH);
  • NR C1 is selected from NH, N(C 1 ⁇ 4 alkyl), N(C 1 ⁇ 4 alkylene-S(O) 2 R C2 ), wherein, the alkylene can be optionally replaced by one or two Independent R C4 is substituted;
  • R C2 is selected from hydrogen, -C 1 ⁇ 4 alkyl; each R C4 is independently selected from hydrogen, -C 1 ⁇ 4 alkyl; preferably, NR C1 is selected from NH, N(C 1 ⁇ 3 alkyl), N(C 1 ⁇ 3 alkylene-S(O) 2 R C2 ), wherein, the alkylene can be optionally substituted by one or two independent R C4 ;
  • R C2 can be selected from from -C 1 ⁇ 3 alkyl; each R C4 is independently selected from hydrogen, -C 1 ⁇ 3 alkyl; for example, NR C1 is selected from N(CH 3 ), N(CH 2 S(O) 2 CH 3 ), N(CH(CH 3 )S(O) 2 CH 3
  • R1 and R2 together with the attached atoms form
  • each group is as defined above.
  • ring A is selected from
  • B ring selected from Wherein B ring can be further optionally replaced by one, two, three or four R B1 ;
  • Each R B1 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -OR B2 , -C(O)R B2 , -C(O )NR B2 R B3 , -NR B2 R B3 , -NR B2 C(O)R B3 ;
  • R B2 and R B3 are 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, halogen substituted -C 2 ⁇ 6 alkynyl;
  • X 1 and X 2 are independently selected from N or CR C1 ;
  • Y is selected from O, S or NR C1 ;
  • Each R C1 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 C2 , -C 0-4 alkylene-OC(O)R C2 , -C 0 ⁇ 4 alkylene-SR C2 , -C 0 ⁇ 4 alkylene-S(O) 2 R C2 , -C 0 ⁇ 4 alkylene-S(O)R C2 , -C 0 ⁇ 4 Alkylene-S(O) 2 NR C2 R C3 , -C 0 ⁇ 4 Alkylene-S(O)NR C2 R C3 , -C 0 ⁇ 4 Alkylene-S
  • two independent R C1 and connected atoms together form a 5-8 membered carbocyclic group, a 5-8 membered heterocycloalkyl group, a benzene ring, and a 5-6 membered aromatic heterocyclic ring; among them, carbocyclyl, heterocyclic Alkyl, aromatic ring, aromatic heterocyclic ring can be further optionally substituted by one, two, three or four independent R C4 ;
  • R C2 and R C3 are 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-(3 ⁇ 10 membered carbocyclyl), -C 0 ⁇ 4 alkylene-(4 ⁇ 10 membered heterocycloalkyl), -C 0 ⁇ 4 alkylene-(6 ⁇ 10 membered aromatic ring), -C 0 ⁇ 4 alkylene-(5 ⁇ 10 membered aromatic heterocyclic ring);
  • Each R C4 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 C5 , -C 0 ⁇ 4 alkylene-OC(O)R C5 , -C 0 ⁇ 4 alkylene-SR C5 , -C 0 ⁇ 4 alkylene-S(O) 2 R C5 , -C 0 ⁇ 4 alkylene-S(O)R C5 , -C 0 ⁇ 4 Alkylene-S(O) 2 NR C5 R C6 , -C 0 ⁇ 4 Alkylene-S(O)NR C5 R C6 , -C 0 ⁇ 4 Alkylene-S(O)NR
  • R C5 and R C6 are 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-(3 ⁇ 10 membered carbocyclyl), -C 0 ⁇ 4 alkylene-(4 ⁇ 10 membered heterocycloalkyl), -C 0-4 alkylene-(6-10 membered aromatic ring), -C 0-4 alkylene-(5-10 membered aromatic heterocyclic ring).
  • each R C1 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -C 0 ⁇ 4 alkylene-OR C2 , -C 0 ⁇ 4 alkylene-S(O) 2 R C2 , -C 0 ⁇ 4 alkylene-NR C2 R C3 , -C 0 ⁇ 4 alkylene-(3 ⁇ 6 membered carbocyclyl), -C 0 ⁇ 4 alkylene-(4 ⁇ 6 membered heterocycloalkyl), -C 0 ⁇ 4 alkylene-(6 membered aromatic ring), -C 0 ⁇ 4 alkylene-(5 ⁇ 6 membered Aromatic heterocycle); Wherein, alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle can be further optionally replaced by one, two, three or four independent R C4 ; preferably selected from Hydrogen, halogen, cyano
  • R C2 and R C3 are independently selected from hydrogen, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl; preferably selected from hydrogen, -C 1 ⁇ 6 alkyl; more preferably selected from hydrogen, - C 1 ⁇ 4 alkyl; More preferably selected from hydrogen, methyl, ethyl, n-propyl, isopropyl; More preferably selected from hydrogen, methyl;
  • Each R C4 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -C 0 ⁇ 4 alkylene-OR C5 , -C 0 ⁇ 4 alkylene-S(O) 2 R C5 , -C 0 ⁇ 4 alkylene-NR C5 R C6 ; preferably selected from hydrogen, -C 1 ⁇ 6 alkyl; more preferably selected from hydrogen, -C 1 ⁇ 4 Alkyl; further preferably selected from hydrogen, methyl, ethyl, n-propyl, isopropyl; further preferably selected from hydrogen, methyl; or, two independent R C4 form together with connected atoms
  • R C5 and R C6 are independently selected from hydrogen, -C 1-6 alkyl, and -C 1-6 alkyl substituted by halogen.
  • ring B is selected from
  • the B ring is selected from Or preferably, ring B is selected from More preferably, the B ring is selected from
  • Each R C1 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl, Preferably, each R C1 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl, Or preferably, each R C1 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl, More preferably, each R C1 is independently selected from hydrogen, halogen, cyano, -C 1-4 alkyl, Further preferably, each R C1 is independently selected from hydrogen, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, Even more preferably, each R C1 is independently selected from hydrogen, methyl,
  • each group is as defined above.
  • ring A is selected from
  • Y is selected from O, S or NR C1 ;
  • X 11 is selected from O, S, NR C4 or
  • R C1 is selected from hydrogen, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl;
  • R C4 is selected from hydrogen, -C 1 ⁇ 6 alkyl, and -C 1 ⁇ 6 alkyl substituted by halogen.
  • the compound shown in formula I is shown in formula IIc:
  • each group is as defined above.
  • ring A is selected from
  • B ring selected from Wherein B ring can be further optionally replaced by one, two, three or four R B1 ;
  • Each R B1 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -OR B2 , -C(O)R B2 , -C(O )NR B2 R B3 , -NR B2 R B3 , -NR B2 C(O)R B3 ;
  • X 1 , X 2 , X 3 , and X 4 are independently selected from N or CRC1 ;
  • Each R C1 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 C2 , -C 0-4 alkylene-OC(O)R C2 , -C 0 ⁇ 4 alkylene-SR C2 , -C 0 ⁇ 4 alkylene-S(O) 2 R C2 , -C 0 ⁇ 4 alkylene-S(O)R C2 , -C 0 ⁇ 4 Alkylene-S(O) 2 NR C2 R C3 , -C 0 ⁇ 4 Alkylene-S(O)NR C2 R C3 , -C 0 ⁇ 4 Alkylene-S
  • two independent R C1 and connected atoms together form a 5-8 membered carbocyclic group, a 5-8 membered heterocycloalkyl group, a benzene ring, and a 5-6 membered aromatic heterocyclic ring; among them, carbocyclyl, heterocyclic Alkyl, aromatic ring, aromatic heterocyclic ring can be further optionally substituted by one, two, three or four independent R C4 ;
  • R C2 and R C3 are 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-(3 ⁇ 10 membered carbocyclyl), -C 0 ⁇ 4 alkylene-(4 ⁇ 10 membered heterocycloalkyl), -C 0 ⁇ 4 alkylene-(6 ⁇ 10 membered aromatic ring), -C 0 ⁇ 4 alkylene-(5 ⁇ 10 membered aromatic heterocyclic ring);
  • Each R C4 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 C5 , -C 0 ⁇ 4 alkylene-OC(O)R C5 , -C 0 ⁇ 4 alkylene-SR C5 , -C 0 ⁇ 4 alkylene-S(O) 2 R C5 , -C 0 ⁇ 4 alkylene-S(O)R C5 , -C 0 ⁇ 4 Alkylene-S(O) 2 NR C5 R C6 , -C 0 ⁇ 4 Alkylene-S(O)NR C5 R C6 , -C 0 ⁇ 4 Alkylene-S(O)NR
  • R C5 and R C6 are 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-(3 ⁇ 10 membered carbocyclyl), -C 0 ⁇ 4 alkylene-(4 ⁇ 10 membered heterocycloalkyl), -C 0-4 alkylene-(6-10 membered aromatic ring), -C 0-4 alkylene-(5-10 membered aromatic heterocyclic ring).
  • R B2 and R B3 are 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, halogen substituted -C 2 ⁇ 6 alkynyl.
  • each R C1 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -C 0 ⁇ 4 alkylene-OR C2 , -C 0 ⁇ 4 alkylene-S(O) 2 R C2 , -C 0 ⁇ 4 alkylene-NR C2 R C3 , -C 0 ⁇ 4 alkylene-(3 ⁇ 6 membered carbocyclyl), -C 0 ⁇ 4 alkylene-(4 ⁇ 6 membered heterocycloalkyl), -C 0 ⁇ 4 alkylene-(6 membered aromatic ring), -C 0 ⁇ 4 alkylene-(5 ⁇ 6 membered Aromatic heterocycle); preferably selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -C 0 ⁇ 4 alkylene-OR C2 , -C
  • R C2 and R C3 are independently selected from hydrogen, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl; preferably selected from hydrogen, -C 1 ⁇ 6 alkyl; more preferably selected from hydrogen, - C 1 ⁇ 4 alkyl; More preferably selected from hydrogen, methyl, ethyl, n-propyl, isopropyl; More preferably selected from hydrogen, methyl;
  • Each R C4 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, -C 1 ⁇ 6 alkyl substituted by halogen, -C 0 ⁇ 4 alkylene-OR C5 , -C 0 ⁇ 4 alkylene-S(O) 2 R C5 , -C 0 ⁇ 4 alkylene-NR C5 R C6 ; preferably selected from hydrogen, -C 1 ⁇ 6 alkyl; more preferably selected from hydrogen, -C 1 ⁇ 4 Alkyl; further preferably selected from hydrogen, methyl, ethyl, n-propyl, isopropyl; further preferably selected from hydrogen, methyl; or, two independent R C4 form together with connected atoms
  • R C5 and R C6 are independently selected from hydrogen, -C 1-6 alkyl, and -C 1-6 alkyl substituted by halogen.
  • ring B is selected from Preferably, the B ring is selected from Or preferably, ring B is selected from More preferably, the B ring is selected from
  • Each R C1 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl, Preferably, each R C1 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl, Or preferably, each R C1 is independently selected from hydrogen, halogen, cyano, -C 1 ⁇ 6 alkyl, halogen substituted -C 1 ⁇ 6 alkyl, More preferably, each R C1 is independently selected from hydrogen, halogen, cyano, -C 1-4 alkyl, Further preferably, each R C1 is independently selected from hydrogen, halogen, cyano, methyl, ethyl, n-propyl, isopropyl, Even more preferably, each R C1 is independently selected from hydrogen, methyl,
  • the present application also relates to any combination of the above-mentioned embodiments and preferred embodiments.
  • compounds shown in formula I include but are not limited to:
  • the present application also provides a pharmaceutical composition, comprising any of the above-mentioned compounds, or their deuterated compounds, or their stereoisomers, or their pharmaceutically acceptable salts.
  • the above pharmaceutical composition further includes pharmaceutically acceptable carriers, adjuvants, and vehicles.
  • the present application also provides the use of any of the above-mentioned compounds, or their deuterated compounds, or their stereoisomers, or their pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions in the preparation of ATR inhibitors.
  • the present application also provides any of the above-mentioned compounds, or their deuterated compounds, or their stereoisomers, or their pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions, which are used as ATR inhibitors.
  • the present application provides any of the above-mentioned compounds, or their deuterated compounds, or their stereoisomers, or their pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions for inhibiting ATR.
  • the present application also provides a method for inhibiting ATR activity in a subject, comprising administering to a subject in need any of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition.
  • the present application also provides the use of any of the above-mentioned compounds, or their deuterated compounds, or their stereoisomers, or their pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions in the preparation of treating or improving cancer.
  • the present application also provides a method for treating or improving cancer, comprising administering any of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof to subjects in need , or the above-mentioned pharmaceutical composition.
  • the present application also provides any of the above-mentioned compounds, or their deuterated compounds, or their stereoisomers, or their pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions for treating or improving cancer.
  • the present application provides the use of any of the above compounds, or their deuterated compounds, or their stereoisomers, or their pharmaceutically acceptable salts, or the above pharmaceutical compositions for treating or improving cancer.
  • the cancer is selected from the group consisting of colon cancer, rectal cancer, gastric cancer, esophageal cancer, primary peritoneal cancer, adrenocortical carcinoma, clear cell renal cell carcinoma, prostate cancer, bladder urothelial carcinoma, ovarian cancer, Breast cancer, endometrial cancer, fallopian tube cancer, non-small cell lung cancer, or small cell lung cancer.
  • 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, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) 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 this application 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 group here does not exist, and is connected in the form of a chemical bond, such as AC 0 alkylene-B means AB, that is, the A group and The B groups are connected directly by chemical bonds.
  • Carbocyclyl refers to a saturated or non-aromatic partially saturated group having 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.
  • the "unsaturated” mentioned in this application means that the group or molecule contains carbon-carbon double bond, carbon-carbon triple bond, carbon-oxygen double bond, carbon-sulfur double bond, carbon-nitrogen triple bond and the like.
  • Alkenyl means a compound having at least one site of ethylenic unsaturation straight-chain or branched-chain hydrocarbon groups.
  • C a-b alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.
  • Alkynyl means a linear or branched monovalent hydrocarbon radical containing at least one triple bond.
  • alkynyl is also intended to include those hydrocarbyl groups having one triple bond and one double bond.
  • C alkynyl is intended to include ethynyl, propynyl, 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; wherein A hetero atom refers to a nitrogen atom, an oxygen atom, a sulfur atom, and the like.
  • a hetero atom refers to a nitrogen atom, an oxygen atom, a sulfur atom, and the like.
  • 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 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 multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.
  • heteromatic ring 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. Preferably one to three heteroatoms are included.
  • 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, etc.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • halogen - substituted alkyl means that one or more hydrogen atoms in the alkyl group are replaced by halogen; Alkyl groups containing 1 to 4 carbon atoms; also such as monohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, etc., such as monochloromethyl, dichloromethyl, trichloromethyl, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, perfluoroethyl group, 2,2,2-trifluoro-1,1-dichloroethyl group, etc.
  • halogen-substituted alkenyl means that one or more hydrogen atoms in the alkenyl are replaced by halogen;
  • halogen-substituted alkynyl refers to the One or more of the hydrogen atoms in is replaced by a halogen.
  • the oxygen atom in "-C(O)R", “-S(O) 2 R” etc. described in this application 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 with a A single bond;
  • another example "-S(O)(NH)R” means that the oxygen atom and the nitrogen atom are connected with the sulfur atom by a double bond, and the R group is connected with the sulfur atom by a single bond.
  • deuterated compound in this application 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.
  • subject is equivalent to "patient” and “individual” and means a human or non-human animal (mammal, eg, primate, rodent, etc.).
  • “Mammal” includes humans and domestic animals (such as laboratory mammals and household pets, such as cats, dogs, pigs, sheep, cattle, sheep, goats, horses, rabbits), and non-domesticated mammals, such as wild mammals, etc. .
  • treating means administering the compound or preparation described in the present application to improve or eliminate a disease or one or more symptoms associated with the disease, and includes inhibiting the progression of the disease or disorder, and alleviating the disease or disorder.
  • 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 physiologically Compatible with the recipient without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • the carrier, adjuvant, and/or vehicle described herein can be any pharmaceutically acceptable carrier, adjuvant, and/or vehicle, such as, but not limited to, solvents (such as water, saline, glycerol, and ethanol), propellants, propellants, Solvents, solubilizers, emulsifiers, colorants, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, antioxidants Agents, penetration enhancers, pH regulators, surfactants, diluents, etc.
  • solvents such as water, saline, glycerol, and ethanol
  • propellants such as water, saline, glycerol, and ethanol
  • Solvents solubilizers, emulsifiers, colorants, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators,
  • salt refers to the acidic and/or basic salts of the above compounds or their stereoisomers with inorganic and/or organic acids and bases , also includes zwitterionic salts (inner salts), and also includes quaternary ammonium salts, such as alkylammonium 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). These 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.
  • one or more compounds of the present application may be used in combination with each other.
  • the compound of the present application can also be used in combination with any other active agent for the preparation of drugs or pharmaceutical compositions for regulating cell function or treating diseases. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.
  • stereoisomers may exist in stereoisomeric forms. Unless otherwise stated, references to stereoisomers herein include geometric isomers and enantiomers. All such isomers, as well as mixtures thereof, are included within the scope of this application.
  • compositions and compounds of the present application can be prepared into any suitable preparations, for example, solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, etc. Agents, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • the preparations can be produced by methods well known in the art, such as conventional mixing, dissolving, tableting, granulating, dragee-making, pulverizing, emulsifying, freeze-drying and the like.
  • Typical routes of administration of the pharmaceutical compositions and compounds of the present application include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration medicine.
  • the structures of the compounds were determined by nuclear magnetic resonance spectroscopy (NMR) and mass spectroscopy (MS). NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm).
  • the determination of NMR uses a nuclear magnetic instrument (Bruker AvanceIII 400 and Bruker Avance 300), and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ) or deuterated methanol (CD 3 OD), The internal standard was tetramethylsilane (TMS).
  • 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 in this application can be synthesized by or 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.
  • the term "room temperature" in the present application means that the temperature is between 10°C and 25°C.
  • M is moles per liter.
  • the unpurified compound 5a (0.29 mmol) in the previous step was dissolved in a mixed solution of 1,4-dioxane (3.0 mL) and water (1.0 mL). Then 4-indoleboronic acid pinacol ester (81.0 mg, 0.33 mmol), anhydrous sodium carbonate (59.0 mg, 0.56 mmol) and bis(triphenylphosphine)palladium(II) dichloride (27.8.0 mg , 0.028mmol). After nitrogen replacement, the reaction was heated to 85° C. for 2 hours. After the reaction was completed, water (3.0 mL) was added to quench, and then the organic phase was extracted with ethyl acetate (3*5.0 mL).
  • Compound 13 was separated into diastereoisomers by SFC to obtain single compound 13-isomer 1 (10.0 mg, fast fraction), purity: 98.6%; 13-isomer 2 (7.0 mg, slow fraction), purity 99.0%.
  • HT-29 Choengdu Zhongyuan Gongchuang Technology Co., Ltd.
  • LOVO Najing Kebai Biotechnology Co., Ltd.
  • HT-29 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum and 100 ⁇ g/mL Normocin, and Dulbecco's Modified Eagle Medium (DMEM) containing 10% fetal bovine serum and 100 ⁇ g/mL Normocin was added to LOVO cells. ) culture medium. Incubate overnight at 37°C and 5% CO 2 to allow cells to adhere to the wall.
  • DMEM Dulbecco's Modified Eagle Medium
  • Test example 2 detection of pCHK1 cell level
  • HT-29 cells were inoculated into 96-well transparent bottom black plates (Greiner Bio-one, product number 655090) at a density of 10,000 cells per well, and cultured overnight in a 37°C, 5% CO 2 incubator. The next day, remove the medium in the cells, first add 150 ⁇ L of fresh medium, then add 50 ⁇ L of medium containing 4 times the final concentration of the compound (the final concentration ranges from 1 nM to 10 ⁇ M), put it in an incubator, and incubate at 37 °C and The cultivation was continued for 60 min under the condition of 5% CO 2 . Then 1 ⁇ L of 600 ⁇ M 4NQO was added to each well for treatment (final concentration was 3 ⁇ M), and culture was continued for 60 min.
  • pCHK1 antibody (CST, product number: 2348, dilution ratio: 1:250) diluted with 1% (w/v) blocking reagent to each well, and incubate overnight at 2-8°C. The next day, remove the antibody in the well, wash the cells with 0.05% (v/v) PBST, 200 ⁇ L per well, and repeat 3 times.
  • a high-content imaging analysis system (GE, In Cell Analyzer, model: 2200) was used to obtain the fluorescence value of pCHK1 in the nucleus, the relative level of pCHK1 was analyzed using GraphPad Prism software, and the inhibition curve of compounds against pCHK1 was fitted to calculate the IC50 value.
  • the compound to be tested (final concentration 1.5 ⁇ M) was co-incubated with human/mouse liver microsomes under the condition of adding NADPH, and the concentration of the compound in the incubation supernatant within 60 minutes was detected.
  • the results for representative compounds are as follows:
  • the compound of the present application has good metabolic stability in human/mouse liver microsomes.
  • Test Example 4 Compound pharmacokinetics experiment in vivo:
  • the purpose of this experiment is to determine the pharmacokinetic parameters of the compound and calculate its oral bioavailability in male CD-1 mice and male SD rats.
  • a total of 36 male CD-1 mice were selected and divided into 4 groups, and AZD6738 and 5-isomer2 were administered intravenously and orally orally, respectively, with 9 animals in each group.
  • mice carry out intravenous administration, and intravenous injection dose is 1mg/kg, collects the plasma sample (5,15,30 minutes and 1,2,4,8,24 hours) after administration; Rats were administered orally by gavage at a dose of 10 mg/kg, plasma samples were collected after administration (15, 30 minutes and 1, 2, 4, 8, 24 hours), and LC/MS was performed to analyze the drugs in the plasma Concentration, using Winnolin 5.2 software to calculate relevant pharmacokinetic parameters.
  • Twelve male SD rats were divided into 4 groups, and AZD6738 and 5-isomer2 were administered intravenously or orally, respectively, with 3 animals in each group.
  • two groups of rats were administered intravenously, and the dose of intravenous administration was 1 mg/kg.
  • the other two groups of rats were administered orally by intragastric administration, and the oral administration dose was 10 mg/kg.
  • the time point of blood collection was the same as that of mice. Plasma was collected to analyze the drug concentration, and relevant pharmacokinetic parameters were obtained.
  • C 0 is the drug concentration in the body at 0 minutes; Cl (mL/min/kg) is the clearance rate of the drug in the body; T 1/2 (h) is the half-life; AUC is the drug exposure in the body; C max is the highest concentration of the drug in the body ; F (%) is the oral bioavailability of the drug.
  • the compound of this application has better absorption and exposure when taken orally, and is suitable for oral administration.
  • the compound of the present application has obvious advantages in pharmacokinetics compared with the clinical phase II ATR inhibitor AZD6738, wherein the mouse Cmax is 1.6 times, and the AUC is 5.7 times (p ⁇ 0.05); the rat Cmax is 1.4 times, and the AUC 1.9 times (p ⁇ 0.05).
  • LOVO is colorectal cancer tumor cells with MRE11A mutation (MRE11A is a key component of DNA double-strand exercise repair ATM signaling pathway), which is sensitive to ATR inhibitors.
  • MRE11A is a key component of DNA double-strand exercise repair ATM signaling pathway
  • the LOVO CDX model of colorectal cancer will be used to verify the inhibitory effect of ATR inhibitor single drug on tumors with ATM signaling pathway defects.
  • Weeks of age 8 weeks (arrival), 9 weeks (grouping)
  • LOVO cells were purchased from Nanjing Kebai Biotechnology Co., Ltd., and the medium used was DMEM plus 10% FBS serum, cultured at 37°C and 5% CO 2 .
  • Test drug compound 5-isomer2, AZD6738
  • LOVO cells were cultured in vitro (adhesive growth), and the cells in the logarithmic growth phase were collected, and the cells were gently rinsed twice with PBS, and the cell pellet was gently blown with PBS to resuspend the cells to prepare a single cell suspension, and the final concentration of the cells was adjusted after counting Mix well for 5 x 10 6 cells/100 ⁇ l. Inoculate 5 ⁇ 10 6 cells/mouse in the right armpit, and the inoculation volume is 100 ⁇ L/mouse. The tumor growth was observed regularly, and when the tumor grew to an average of 94 mm 3 , the mice were randomly divided into 5 groups, 8 mice in each group, according to the tumor size and body weight. The day the mice were grouped was defined as day 0. Dosing according to the table below.
  • p.o. is oral administration
  • QD is once a day administration.
  • the main observation indicators of this experiment are:
  • T/C (%) Relative tumor proliferation rate (%), at a certain time point, the percentage value of the relative tumor volume or tumor weight between the treatment group and the control group.
  • T/C% T TW /C TW ⁇ 100% (T TW : the average tumor weight at the end of the experiment in the treatment group; C TW : the average tumor weight at the end of the experiment in the control group).
  • Relative tumor inhibition rate TGI (%) (1-(mean T-mean T 0 )/(mean C-mean C 0 )) ⁇ 100%.
  • Mean T and mean C are the average tumor volumes of the treatment group and the control group at a specific time, respectively, and mean T 0 and mean C 0 are the average tumor volumes of the treatment group and the control group when grouped, respectively.
  • This experiment evaluated the efficacy of the compound 5-isomer2 in the CDX model of human colorectal cancer. After 22 days of administration, the tumor volume of the control group reached 1739mm 3 . Compared with the control group, the AZD6738 group, the 5-isomer2 low-dose The TGI of isomer2 medium dose group and 5-isomer2 high dose group were 58.3%, 60.4%, 90%, and 93.3%, respectively. The reduction of tumor volume in each dose group of compound 5-isomer2 was statistically significant (p ⁇ 0.01).
  • Compound 5-isomer2 can significantly inhibit tumor growth in LOVO tumor-bearing mice in a dose-effect relationship.
  • the compound of the present application has better drug efficacy, respectively, at the same dose, the tumor growth inhibition rate is better (AZD6738: 58.3%; 5-isomer2: 90%); Under the efficacy of inhibition rate, the dosage of the compound of this application is lower (AZD6738: 50mg/kg; 5-isomer2: 25mg/kg), which provides strong support for better efficacy and better safety in clinical transformation .
  • Test Example 6 Study on the maximum tolerated dose (MTD) in rats:
  • the general condition of the rats in each group was observed every day; the body weight was measured twice a week. On the 14th day, the experiment was terminated and the rats were sacrificed.
  • the maximum tolerated dose (MTD) of the tested rats to AZD6738 was less than the dose level of 500mg/kg, and all the rats in the high dose group died, all the female rats in the middle dose group died, and 3 male rats died.
  • One female rat in the dose group died; the maximum tolerated dose (MTD) of the tested rats to compound 5-isomer2 was greater than 2000 mg/kg, and the rats in each dose group had no abnormalities.
  • AZD6738 was highly toxic. All the rats in the high-dose group died, all the female rats in the middle-dose group died, and 2 males died; only one female rat in the high-dose group of compound 5-isomer2 died, and the rest showed no abnormalities.

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Abstract

一类式I所示的具有ATR抑制作用的新化合物及其在制备药物中的用途。

Description

ATR抑制剂及其用途 技术领域
本申请涉及一类具有ATR抑制作用的新化合物及其在制备药物中的用途。
背景技术
共济失调毛细血管扩张突变基因和Rad 3相关激酶ATR(ataxia telangiectasia mutated and Rad3-related，ATR)是磷脂酰肌醇3-激酶相关蛋白激酶(PIKK)家族的成员，该家族还包括共济失调毛细血管扩张突变激酶(ATM)、DNA依赖性蛋白激酶(DNA-PK)、生殖器形成抑制基因-1(SMG-1)、哺乳动物雷帕霉素靶蛋白(mTOR)和转化/转录相关蛋白(TRAPP)。ATR和ATM是细胞DNA损伤应答(DDR)通路的关键调节因子，并参与响应于DNA损伤而维持基因组的完整性。ATR是对受损DNA复制应答的DDR的关键成员，它对于维持基因组的稳定性和完整性，促使细胞存活至关重要。当细胞内DNA损伤产生时，ATR被募集至DNA损伤部位，多种蛋白继而参与调控ATR的激活，ATR激活后调控一些重要的细胞过程。许多癌细胞缺乏关键肿瘤抑制基因，这可以使得癌细胞比正常细胞更加依赖ATR通路来调控细胞DNA损伤修复促进细胞存活，使ATR成为有希望的癌症治疗靶点。抑制ATR可能增强复制抑制剂的效力。此外，ATR抑制对于具有高RS水平的细胞(如表达原癌基因或缺乏肿瘤抑制因子的细胞)可能有杀伤作用。在这些细胞中抑制ATR活性将产生致死量的RS，从而导致细胞死亡。
已有部分关于ATR抑制剂的报道(WO2015/084384、WO2017/180723、WO2016/061097、WO2014/140644等)，但目前已有的ATR抑制剂均还在临床试验过程中，未有对应的药物上市。因此，可能需要开发更多效果更好、副作用更小的ATR抑制剂药物。
发明内容
本申请提供了一种式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 PCTCN2022099809-appb-000001
其中，
A环选自
Figure PCTCN2022099809-appb-000002
Figure PCTCN2022099809-appb-000003
B环选自
Figure PCTCN2022099809-appb-000004
Figure PCTCN2022099809-appb-000005
其中B环可进一步任选被一个、两个、三个或四个R B1取代；
每个R B1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 B2、-C 0～4亚烷基-OC(O)R B2、-C 0～4亚烷基-C(O)R B2、-C 0～4亚烷基-C(O)OR B2、-C 0～4亚烷基-C(O)NR B2R B3、-C 0～4亚烷基-NR B2R B3、-C 0～4亚烷基-NR B2C(O)R B3；
R B2、R B3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 1和R 2与相连的原子一起形成
Figure PCTCN2022099809-appb-000006
X 1、X 2、X 3、X 4分别独立选自N或CR C1；
Y选自O、S或NR C1；
每个R C1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 C2、-C 0～4亚烷基-OC(O)R C2、-C 0～4亚烷基-SR C2、-C 0～4亚烷基-S(O) 2R C2、-C 0～4亚烷基-S(O)R C2、-C 0～4亚烷基-S(O) 2NR C2R C3、-C 0～4亚烷基-S(O)NR C2R C3、-C 0～4亚烷基-S(O)(NH)R C2、-C 0～4亚烷基-S(O)(NH)NR C2R C3、-C 0～4亚烷基-C(O)R C2、-C 0～4亚烷基-C(O)OR C2、-C 0～4亚烷基-C(O)NR C2R C3、-C 0～4亚烷基-NR C2R C3、-C 0～4亚烷基-NR C2C(O)R C3、-C 0～4亚烷基-NR C2S(O) 2R C3、-C 0～4亚烷基-NR C2S(O)R C3、-C 0～4亚烷基-P(O)R C2R C3、-C 0～4亚烷基-P(O)(OR C2)R C3、-C 0～4亚烷基-P(O)(OR C2)(OR C3)、-C 0～4亚烷基-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；其中，亚烷基、碳环基、杂环烷基、芳环、芳杂环可进一步任选被一个、两个、三个或四个独立的R C4取代；
或者，两个独立的R C1与相连的原子一起形成5～8元碳环基、5～8元杂环烷基、苯环、5～6元芳杂环；其中，碳环基、杂环烷基、芳环、芳杂环可进一步任选被一个、两个、三个或四个独立的R C4取代；
R C2、R C3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-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；
每个R C4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 C5、-C 0～4亚烷基-OC(O)R C5、-C 0～4亚烷基-SR C5、-C 0～4亚烷基-S(O) 2R C5、-C 0～4亚烷基-S(O)R C5、-C 0～4亚烷基-S(O) 2NR C5R C6、-C 0～4亚烷基-S(O)NR C5R C6、-C 0～4亚烷基-S(O)(NH)R C5、-C 0～4亚烷基-S(O)(NH)NR C5R C6、-C 0～4亚烷基-C(O)R C5、-C 0～4亚烷基-C(O)OR C5、-C 0～4亚烷基-C(O)NR C5R C6、-C 0～4亚烷基-NR C5R C6、-C 0～4亚烷基-NR C5C(O)R C6、-C 0～4亚烷基-NR C5S(O) 2R C6、-C 0～4亚烷基-NR C5S(O)R C6、-C 0～4亚烷基-P(O)R C5R C6、-C 0～4亚烷基-P(O)(OR C5)R C6、-C 0～4亚烷基-P(O)(OR C5)(OR C6)；或者，两个独立的R C4与相连的原子一起形成
Figure PCTCN2022099809-appb-000007
R C5、R C6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-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)。
或者，本申请提供了一种式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 PCTCN2022099809-appb-000008
其中，
A环选自
Figure PCTCN2022099809-appb-000009
Figure PCTCN2022099809-appb-000010
B环选自
Figure PCTCN2022099809-appb-000011
其中B环可进一步任选被一个、两个、三个或四个R B1取代；
每个R B1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 B2、-C 0～4亚烷基-OC(O)R B2、-C 0～4亚烷基-C(O)R B2、-C 0～4亚烷基-C(O)OR B2、-C 0～4亚烷基-C(O)NR B2R B3、-C 0～4亚烷基-NR B2R B3、-C 0～4亚烷基-NR B2C(O)R B3；
R B2、R B3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 1和R 2与相连的原子一起形成
Figure PCTCN2022099809-appb-000012
X 1、X 2、X 3、X 4分别独立选自N或CR C1；
Y选自O、S或NR C1；
每个R C1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 C2、-C 0～4亚烷基-OC(O)R C2、-C 0～4亚烷基-SR C2、-C 0～4亚烷基-S(O) 2R C2、-C 0～4亚烷基-S(O)R C2、-C 0～4亚烷基-S(O) 2NR C2R C3、-C 0～4亚烷基-S(O)NR C2R C3、-C 0～4亚烷基-S(O)(NH)R C2、-C 0～4亚烷基-S(O)(NH)NR C2R C3、-C 0～4亚烷基-C(O)R C2、-C 0～4亚烷基-C(O)OR C2、-C 0～4亚烷基-C(O)NR C2R C3、-C 0～4亚烷基-NR C2R C3、-C 0～4亚烷基-NR C2C(O)R C3、-C 0～4亚烷基-NR C2S(O) 2R C3、-C 0～4亚烷基-NR C2S(O)R C3、-C 0～4亚烷基-P(O)R C2R C3、-C 0～4亚烷基-P(O)(OR C2)R C3、-C 0～4亚烷基-P(O)(OR C2)(OR C3)、-C 0～4亚烷基-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；其中，亚烷基、碳环基、杂环烷基、芳环、芳杂环可进一步任选被一个、两个、三个或四个独立的R C4取代；
或者，两个独立的R C1与相连的原子一起形成5～8元碳环基、5～8元杂环烷基、苯环、5～6元芳杂环；其中，碳环基、杂环烷基、芳环、芳杂环可进一步任选被一个、两个、三个或四个独立的R C4取代；
R C2、R C3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-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；
每个R C4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 C5、-C 0～4亚烷基-OC(O)R C5、-C 0～4亚烷基-SR C5、-C 0～4亚烷基-S(O) 2R C5、-C 0～4亚烷基-S(O)R C5、-C 0～4亚烷基-S(O) 2NR C5R C6、-C 0～4亚烷基-S(O)NR C5R C6、-C 0～4亚烷基-S(O)(NH)R C5、-C 0～4亚烷基-S(O)(NH)NR C5R C6、-C 0～4亚烷基-C(O)R C5、-C 0～4亚烷基-C(O)OR C5、-C 0～4亚烷基-C(O)NR C5R C6、-C 0～4亚烷基-NR C5R C6、-C 0～4亚烷基-NR C5C(O)R C6、-C 0～4亚烷基-NR C5S(O) 2R C6、-C 0～4亚烷基-NR C5S(O)R C6、-C 0～4亚烷基-P(O)R C5R C6、-C 0～4亚烷基-P(O)(OR C5)R C6、-C 0～4亚烷基-P(O)(OR C5)(OR C6)；或者，两个独立的R C4与相连的原子一起形成
Figure PCTCN2022099809-appb-000013
R C5、R C6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-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)。
在某些优选的实施方案中，A环选自
Figure PCTCN2022099809-appb-000014
Figure PCTCN2022099809-appb-000015
优选选自
Figure PCTCN2022099809-appb-000016
更优选为
Figure PCTCN2022099809-appb-000017
进一步地，B环选自
Figure PCTCN2022099809-appb-000018
Figure PCTCN2022099809-appb-000019
其中B环可进一步任选被一个、两个、三个或四个R B1取代；
每个R B1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 B2、-C(O)R B2、-C(O)NR B2R B3、-NR B2R B3、-NR B2C(O)R B3；R B2、R B3分别独立选自氢、-C 1～6烷基。
优选地，每个R B1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；优选选自氢、卤素、氰基、-C 1～4烷基、卤素取代的-C 1～6烷基；更优选选自氢、卤素、氰基、-C 1～3烷基、卤素取代的-C 1～6烷基；
更优选地，每个R B1分别独立选自氢、卤素、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基、卤代甲基、卤代乙基、卤代丙基；优选选自氢、卤素、甲基、乙基、正丙基、异丙基、一氟甲基、二氟甲基、三氟甲基、一氯甲基、二氯甲基、三氯甲基；更优选选自氢、卤素、甲基、乙基、正丙基、异丙基，进一步优选选自氢、氟、氯、溴、甲基，例如氟或甲基。
更进一步地，B环选自
Figure PCTCN2022099809-appb-000020
Figure PCTCN2022099809-appb-000021
在某些优选的实施方案中，B环选自
Figure PCTCN2022099809-appb-000022
优选选自
Figure PCTCN2022099809-appb-000023
其中B环可进一步任选被一个、两个、三个或四个R B1取代，R B1如上文所定义。
在某些优选的实施方案中，B环选自
Figure PCTCN2022099809-appb-000024
Figure PCTCN2022099809-appb-000025
Figure PCTCN2022099809-appb-000026
优选地，B环选自
Figure PCTCN2022099809-appb-000027
Figure PCTCN2022099809-appb-000028
更优选地，B环选自
Figure PCTCN2022099809-appb-000029
Figure PCTCN2022099809-appb-000030
进一步优选地，B环选自
Figure PCTCN2022099809-appb-000031
Figure PCTCN2022099809-appb-000032
在某些优选的实施方案中，R 1和R 2与相连的原子一起形成
Figure PCTCN2022099809-appb-000033
X 1、X 2、X 3、X 4分别独立选自N或CR C1；
Y选自O、S或NR C1，优选S或NR C1；
每个R C1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 C2、-C 0～4亚烷基-SR C2、-C 0～4亚烷基-S(O) 2R C2、-C 0～4亚烷基-S(O)R C2、-C 0～4亚烷基-S(O) 2NR C2R C3、-C 0～4亚烷基-S(O)NR C2R C3、-C 0～4亚烷基-NR C2R C3；优选选自氢、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-OR C2、-C 0～4亚烷基-S(O) 2R C2、-C 0～4亚烷基-NR C2R C3；更优选选自氢、卤素、氰基、-C 1～3烷基、-C 1～3亚烷基-OR C2、-C 1～3亚烷基-S(O) 2R C2；进一步优选选自氢、卤素、氰基、甲基、乙基、正丙基、异丙基、-C 1～2亚烷基-OR C2、-C 1～2亚烷基-S(O) 2R C2； 更进一步优选选自氢、甲基、-C 1亚烷基-OR C2、-C 1亚烷基-S(O) 2R C2；其中，亚烷基、碳环基、杂环烷基、芳环、芳杂环可进一步任选被一个、两个、三个或四个独立的R C4取代；
R C2、R C3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；优选选自氢、-C 1～6烷基；更优选选自氢、-C 1～4烷基；进一步优选选自氢、甲基、乙基、正丙基、异丙基；更进一步优选选自氢、甲基；
每个R C4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；优选选自氢、-C 1～6烷基；更优选选自氢、-C 1～4烷基；进一步优选选自氢、甲基、乙基、正丙基、异丙基；更进一步优选选自氢、甲基。在某些优选的实施方案中，CR C1选自CH、C(C 1～6烷基)、C(C 2～6烯基)、C(C 2～6炔基)、C(卤素取代的-C 1～6烷基)、C(C 0～4亚烷基-OR C2)，其中，所述亚烷基可任选被一个、两个、三个或四个独立的R C4取代；R C2选自氢、-C 1～6烷基；每个R C4分别独立选自氢、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基。
进一步优选地，CR C1选自CH、C(C 1～4烷基)、C(C 1～4亚烷基-OR C2)，其中，所述亚烷基可任选被一个或两个独立的R C4取代；R C2选自氢、-C 1～4烷基；每个R C4分别独立选自氢、-C 1～4烷基。更进一步优选地，CR C1选自CH、C(C 1～3烷基)、C(C 1～3亚烷基-OR C2)，其中，所述亚烷基可任选被一个或两个独立的R C4取代；R C2选自氢；每个R C4分别独立选自氢、-C 1～3烷基。例如，CR C1选自CH、CCH 3、C(C(CH 3) 2OH)。
在某些优选的实施方案中，NR C1选自NH、N(C 1～6烷基)、N(C 2～6烯基)、N(C 2～6炔基)、N(C 0～4亚烷基-SR C2)、N(C 0～4亚烷基-S(O) 2R C2)、N(C 0～4亚烷基-S(O)R C2)，其中，所述亚烷基可任选被一个、两个、三个或四个独立的R C4取代；R C2选自氢、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基；每个R C4分别独立选自氢、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基。
进一步优选地，NR C1选自NH、N(C 1～4烷基)、N(C 1～4亚烷基-S(O) 2R C2)，其中，所述亚烷基可任选被一个或两个独立的R C4取代；R C2选自氢、-C 1～4烷基；每个R C4分别独立选自氢、-C 1～4烷基。更进一步优选地，NR C1选自NH、N(C 1～3烷基)、N(C 1～3亚烷基-S(O) 2R C2)，其中，所述亚烷基可任选被一个或两个独立的R C4取代；R C2选自-C 1～3烷基；每个R C4分别独立选自氢、-C 1～3烷基。例如，NR C1选自N(CH 3)、N(CH 2S(O) 2CH 3)、N(CH(CH 3)S(O) 2CH 3)、N(CH(CH 2CH 3)S(O) 2CH 3)、N(CH(CHCH 3CH 3)S(O) 2CH 3)或N(C(CH 3) 2S(O) 2CH 3)。
进一步地，R 1和R 2与相连的原子一起形成
Figure PCTCN2022099809-appb-000034
Figure PCTCN2022099809-appb-000035
其中R 1和R 2与相连的原子一起形成的前述各环可进一步任选被一个、两个、三个或四个R C1取代。
更进一步地，每个R C1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、
Figure PCTCN2022099809-appb-000036
Figure PCTCN2022099809-appb-000037
Figure PCTCN2022099809-appb-000038
优选地，每个R C1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、
Figure PCTCN2022099809-appb-000039
Figure PCTCN2022099809-appb-000040
Figure PCTCN2022099809-appb-000041
或者优选地，每个R C1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、
Figure PCTCN2022099809-appb-000042
更优选地，每个R C1分别独立选自氢、卤素、氰基、-C 1～4烷基、
Figure PCTCN2022099809-appb-000043
进一步优选地，每个R C1分别独立选自氢、卤素、氰基、甲基、乙基、正丙基、异丙基、
Figure PCTCN2022099809-appb-000044
Figure PCTCN2022099809-appb-000045
更进一步优选地，每个R C1分别独立选自氢、甲基、
Figure PCTCN2022099809-appb-000046
Figure PCTCN2022099809-appb-000047
进一步地，R 1和R 2与相连的原子一起形成
Figure PCTCN2022099809-appb-000048
Figure PCTCN2022099809-appb-000049
其中R 1和R 2与相连的原子一起形成的环可进一步任选被一个、两个、三个或四个R C1取代，R C1如上文所定义。优选地，R 1和R 2与相连的原子一起形成
Figure PCTCN2022099809-appb-000050
它们可任选被一个、两个、三个或四个R C1取代。
进一步地，R 1和R 2与相连的原子一起形成
Figure PCTCN2022099809-appb-000051
在一些实施方案中，R 1和R 2与相连的原子一起形成
Figure PCTCN2022099809-appb-000052
Figure PCTCN2022099809-appb-000053
在一些实施方案中，A环选自
Figure PCTCN2022099809-appb-000054
优选为
Figure PCTCN2022099809-appb-000055
Figure PCTCN2022099809-appb-000056
B环选自
Figure PCTCN2022099809-appb-000057
Figure PCTCN2022099809-appb-000058
Figure PCTCN2022099809-appb-000059
优选选自
Figure PCTCN2022099809-appb-000060
Figure PCTCN2022099809-appb-000061
R 1和R 2与相连的原子一起形成
Figure PCTCN2022099809-appb-000062
X 1、X 2、X 3、X 4分别独立选自N或CR C1；
Y选自S或NR C1；
CR C1选自CH、C(C 1～4烷基)、C(C 1～4亚烷基-OR C2)，其中，所述亚烷基可任选被一个或两个独立的R C4取代；R C2选自氢、-C 1～4烷基；每个R C4分别独立选自氢、-C 1～4烷基；优选地，CR C1选自CH、C(C 1～3烷基)、C(C 1～3亚烷基-OR C2)，其中，所述亚烷基可任选被一个或两个独立的R C4取代；R C2选自氢；每个R C4分别独立选自氢、-C 1～3烷基；例如，CR C1选自CH、CCH 3、C(C(CH 3) 2OH)；
NR C1选自NH、N(C 1～4烷基)、N(C 1～4亚烷基-S(O) 2R C2)，其中，所述亚烷基可任选被一个或两个独立的R C4取代；R C2选自氢、-C 1～4烷基；每个R C4分别独立选自氢、-C 1～4烷基；优选地，NR C1选自NH、N(C 1～3烷基)、N(C 1～3亚烷基-S(O) 2R C2)，其中，所述亚烷基可任选被一个或两个独立的R C4取代；R C2选自-C 1～3烷基；每个R C4分别独立选自氢、-C 1～3烷基；例如，NR C1选自N(CH 3)、N(CH 2S(O) 2CH 3)、N(CH(CH 3)S(O) 2CH 3)、N(CH(CH 2CH 3)S(O) 2CH 3)、N(CH(CHCH 3CH 3)S(O) 2CH 3)或N(C(CH 3) 2S(O) 2CH 3)；
优选R 1和R 2与相连的原子一起形成
Figure PCTCN2022099809-appb-000063
Figure PCTCN2022099809-appb-000064
进一步地，式I所示的化合物如式IIa或式IIb所示：
Figure PCTCN2022099809-appb-000065
其中，各基团如上文所定义。
进一步地，在式IIa或式IIb中，A环选自
Figure PCTCN2022099809-appb-000066
Figure PCTCN2022099809-appb-000067
B环选自
Figure PCTCN2022099809-appb-000068
Figure PCTCN2022099809-appb-000069
其中B环可进一步任选被一个、两个、三个或四个R B1取代；
每个R B1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 B2、-C(O)R B2、-C(O)NR B2R B3、-NR B2R B3、-NR B2C(O)R B3；
R B2、R B3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；
X 1、X 2分别独立选自N或CR C1；
Y选自O、S或NR C1；
每个R C1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 C2、-C 0～4亚烷基-OC(O)R C2、-C 0～4亚烷基-SR C2、-C 0～4亚烷基-S(O) 2R C2、-C 0～4亚烷基-S(O)R C2、-C 0～4亚烷基-S(O) 2NR C2R C3、-C 0～4亚烷基-S(O)NR C2R C3、-C 0～4亚烷基-S(O)(NH)R C2、-C 0～4亚烷基-S(O)(NH)NR C2R C3、-C 0～4亚烷基-C(O)R C2、-C 0～4亚烷基-C(O)OR C2、-C 0～4亚烷基-C(O)NR C2R C3、-C 0～4亚烷基-NR C2R C3、-C 0～4亚烷基-NR C2C(O)R C3、-C 0～4亚烷基-NR C2S(O) 2R C3、-C 0～4亚烷基-NR C2S(O)R C3、-C 0～4亚烷基-P(O)R C2R C3、-C 0～4亚烷基-P(O)(OR C2)R C3、-C 0～4亚烷基-P(O)(OR C2)(OR C3)、 -C 0～4亚烷基-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；其中，亚烷基、碳环基、杂环烷基、芳环、芳杂环可进一步任选被一个、两个、三个或四个独立的R C4取代；
或者，两个独立的R C1与相连的原子一起形成5～8元碳环基、5～8元杂环烷基、苯环、5～6元芳杂环；其中，碳环基、杂环烷基、芳环、芳杂环可进一步任选被一个、两个、三个或四个独立的R C4取代；
R C2、R C3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-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；
每个R C4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 C5、-C 0～4亚烷基-OC(O)R C5、-C 0～4亚烷基-SR C5、-C 0～4亚烷基-S(O) 2R C5、-C 0～4亚烷基-S(O)R C5、-C 0～4亚烷基-S(O) 2NR C5R C6、-C 0～4亚烷基-S(O)NR C5R C6、-C 0～4亚烷基-S(O)(NH)R C5、-C 0～4亚烷基-S(O)(NH)NR C5R C6、-C 0～4亚烷基-C(O)R C5、-C 0～4亚烷基-C(O)OR C5、-C 0～4亚烷基-C(O)NR C5R C6、-C 0～4亚烷基-NR C5R C6、-C 0～4亚烷基-NR C5C(O)R C6、-C 0～4亚烷基-NR C5S(O) 2R C6、-C 0～4亚烷基-NR C5S(O)R C6、-C 0～4亚烷基-P(O)R C5R C6、-C 0～4亚烷基-P(O)(OR C5)R C6、-C 0～4亚烷基-P(O)(OR C5)(OR C6)；或者，两个独立的R C4与相连的原子一起形成
Figure PCTCN2022099809-appb-000070
R C5、R C6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-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)。
更进一步地，每个R C1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-OR C2、-C 0～4亚烷基-S(O) 2R C2、-C 0～4亚烷基-NR C2R C3、-C 0～4亚烷基-(3～6元碳环基)、-C 0～4亚烷基-(4～6元杂环烷基)、-C 0～4亚烷基-(6元芳环)、-C 0～4亚烷基-(5～6元芳杂环)；其中，亚烷基、碳环基、杂环烷基、芳环、芳杂环可进一步任选被一个、两个、三个或四个独立的R C4取代；优选选自氢、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-OR C2、-C 0～4亚烷基-S(O) 2R C2、-C 0～4亚烷基-NR C2R C3；更优选选自氢、卤素、氰基、-C 1～3烷基、-C 1～3亚烷基-OR C2、-C 1～3亚烷基-S(O) 2R C2；进一步优选选自氢、卤素、氰基、甲基、乙基、正丙基、异丙基、-C 1～2亚烷基-OR C2、-C 1～2亚烷基-S(O) 2R C2；更进一步优选选自氢、甲基、-C 1亚烷基-OR C2、-C 1亚烷基-S(O) 2R C2；其中，亚烷基、碳环基、杂环烷基、芳环、芳杂环可进一步任选被一个、两个、三个或四个独立的R C4取代；
R C2、R C3分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；优选选自氢、-C 1～6烷基；更优选选自氢、-C 1～4烷基；进一步优选选自氢、甲基、乙基、正丙基、异丙基；更进一步优选选自氢、甲基；
每个R C4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-OR C5、-C 0～4亚烷基-S(O) 2R C5、-C 0～4亚烷基-NR C5R C6；优选选自氢、-C 1～6烷基；更优选选自氢、-C 1～4烷基；进一步优选选自氢、甲基、乙基、正丙基、异丙基；更进一步优选选自氢、甲基；或者，两个独立的R C4与相连的原子一起形成
Figure PCTCN2022099809-appb-000071
R C5、R C6分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基。
进一步具体地，B环选自
Figure PCTCN2022099809-appb-000072
Figure PCTCN2022099809-appb-000073
优选地，B环选自
Figure PCTCN2022099809-appb-000074
Figure PCTCN2022099809-appb-000075
或者优选地，B环选自
Figure PCTCN2022099809-appb-000076
Figure PCTCN2022099809-appb-000077
更优选地，B环选自
Figure PCTCN2022099809-appb-000078
Figure PCTCN2022099809-appb-000079
每个R C1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、
Figure PCTCN2022099809-appb-000080
Figure PCTCN2022099809-appb-000081
Figure PCTCN2022099809-appb-000082
优选地，每个R C1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、
Figure PCTCN2022099809-appb-000083
Figure PCTCN2022099809-appb-000084
Figure PCTCN2022099809-appb-000085
或者优选地，每个R C1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、
Figure PCTCN2022099809-appb-000086
更优选地，每个R C1分别独立选自 氢、卤素、氰基、-C 1～4烷基、
Figure PCTCN2022099809-appb-000087
进一步优选地，每个R C1分别独立选自氢、卤素、氰基、甲基、乙基、正丙基、异丙基、
Figure PCTCN2022099809-appb-000088
Figure PCTCN2022099809-appb-000089
更进一步优选地，每个R C1分别独立选自氢、甲基、
Figure PCTCN2022099809-appb-000090
Figure PCTCN2022099809-appb-000091
更进一步地，式IIb所示的化合物如式III所示：
Figure PCTCN2022099809-appb-000092
其中，各基团如上文所定义。
进一步地，在式III中，A环选自
Figure PCTCN2022099809-appb-000093
Figure PCTCN2022099809-appb-000094
B环选自
Figure PCTCN2022099809-appb-000095
Figure PCTCN2022099809-appb-000096
Figure PCTCN2022099809-appb-000097
Y选自O、S或NR C1；
X 11选自O、S、NR C4或
Figure PCTCN2022099809-appb-000098
R C1选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；
R C4选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基。
在某些优选的实施方案中，式I所示的化合物如式IIc所示：
Figure PCTCN2022099809-appb-000099
其中，各基团如上文所定义。
进一步地，在式IIc中，A环选自
Figure PCTCN2022099809-appb-000100
Figure PCTCN2022099809-appb-000101
B环选自
Figure PCTCN2022099809-appb-000102
Figure PCTCN2022099809-appb-000103
其中B环可进一步任选被一个、两个、三个或四个R B1取代；
每个R B1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 B2、-C(O)R B2、-C(O)NR B2R B3、-NR B2R B3、-NR B2C(O)R B3；
X 1、X 2、X 3、X 4分别独立选自N或CR C1；
每个R C1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 C2、-C 0～4亚烷基-OC(O)R C2、-C 0～4亚烷基-SR C2、-C 0～4亚烷基-S(O) 2R C2、-C 0～4亚烷基-S(O)R C2、-C 0～4亚烷基-S(O) 2NR C2R C3、-C 0～4亚烷基-S(O)NR C2R C3、-C 0～4亚烷基-S(O)(NH)R C2、-C 0～4亚烷基-S(O)(NH)NR C2R C3、-C 0～4亚烷基-C(O)R C2、-C 0～4亚烷基-C(O)OR C2、-C 0～4亚烷基-C(O)NR C2R C3、-C 0～4亚烷基-NR C2R C3、-C 0～4亚烷基-NR C2C(O)R C3、-C 0～4亚烷基-NR C2S(O) 2R C3、-C 0～4亚烷基-NR C2S(O)R C3、-C 0～4亚烷基-P(O)R C2R C3、-C 0～4亚烷基-P(O)(OR C2)R C3、-C 0～4亚烷基-P(O)(OR C2)(OR C3)、-C 0～4亚烷基-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；其中，亚烷基、碳环基、杂环烷基、芳环、芳杂环可进一步任选被一个、两个、三个或四个独立的R C4取代；
或者，两个独立的R C1与相连的原子一起形成5～8元碳环基、5～8元杂环烷基、苯环、5～6元芳杂环；其中，碳环基、杂环烷基、芳环、芳杂环可进一步任选被一个、两个、三个或四个独立的R C4取代；
R C2、R C3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-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；
每个R C4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 C5、-C 0～4亚烷基-OC(O)R C5、-C 0～4亚烷基-SR C5、-C 0～4亚烷基-S(O) 2R C5、-C 0～4亚烷基-S(O)R C5、-C 0～4亚烷基-S(O) 2NR C5R C6、-C 0～4亚烷基-S(O)NR C5R C6、-C 0～4亚烷基-S(O)(NH)R C5、-C 0～4亚烷基-S(O)(NH)NR C5R C6、-C 0～4亚烷基-C(O)R C5、-C 0～4亚烷基-C(O)OR C5、-C 0～4亚烷基-C(O)NR C5R C6、-C 0～4亚烷基-NR C5R C6、-C 0～4亚烷基-NR C5C(O)R C6、-C 0～4亚烷基-NR C5S(O) 2R C6、-C 0～4亚烷基-NR C5S(O)R C6、-C 0～4亚烷基-P(O)R C5R C6、-C 0～4亚烷基-P(O)(OR C5)R C6、-C 0～4亚烷基-P(O)(OR C5)(OR C6)；或者，两个独立的R C4与相连的原子一起形成
Figure PCTCN2022099809-appb-000104
R C5、R C6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-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)。
优选地，R B2、R B3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。
更进一步地，每个R C1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-OR C2、-C 0～4亚烷基-S(O) 2R C2、-C 0～4亚烷基-NR C2R C3、-C 0～4亚烷基-(3～6元碳环基)、-C 0～4亚烷基-(4～6元杂环烷基)、-C 0～4亚烷基-(6元芳环)、-C 0～4亚烷基-(5～6元芳杂环)；优选选自氢、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-OR C2、-C 0～4亚烷基-S(O) 2R C2、-C 0～4亚烷基-NR C2R C3；更优选选自氢、卤素、氰基、-C 1～3烷基、-C 1～3亚烷基-OR C2、-C 1～3亚烷基-S(O) 2R C2；进一步优选选自氢、卤素、氰基、甲基、乙基、正丙基、异丙基、-C 1～2亚烷基-OR C2、-C 1～2亚烷基-S(O) 2R C2；更进一步优选选自氢、甲基、-C 1亚烷基-OR C2、-C 1亚烷基-S(O) 2R C2；最优选氢或甲基；其中，亚烷基、碳环基、杂环烷基、芳环、芳杂环可进一步任选被一个、两个、三个或四个独立的R C4取代；
R C2、R C3分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；优选选自氢、-C 1～6烷基；更优选选自氢、-C 1～4烷基；进一步优选选自氢、甲基、乙基、正丙基、异丙基；更进一步优选选自氢、甲基；
每个R C4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-OR C5、-C 0～4亚烷基-S(O) 2R C5、-C 0～4亚烷基-NR C5R C6；优选选自氢、-C 1～6烷基；更优选选自氢、-C 1～4烷基；进一步优选选自氢、甲基、乙基、正丙基、异丙基；更进一步优选选自氢、甲基；或者，两个独立的R C4与相连的原子一起形成
Figure PCTCN2022099809-appb-000105
R C5、R C6分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基。
进一步具体地，B环选自
Figure PCTCN2022099809-appb-000106
Figure PCTCN2022099809-appb-000107
优选地，B环选自
Figure PCTCN2022099809-appb-000108
Figure PCTCN2022099809-appb-000109
或者优选 地，B环选自
Figure PCTCN2022099809-appb-000110
Figure PCTCN2022099809-appb-000111
更优选地，B环选自
Figure PCTCN2022099809-appb-000112
Figure PCTCN2022099809-appb-000113
每个R C1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、
Figure PCTCN2022099809-appb-000114
Figure PCTCN2022099809-appb-000115
Figure PCTCN2022099809-appb-000116
优选地，每个R C1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、
Figure PCTCN2022099809-appb-000117
Figure PCTCN2022099809-appb-000118
Figure PCTCN2022099809-appb-000119
或者优选地，每个R C1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、
Figure PCTCN2022099809-appb-000120
更优选地，每个R C1分别独立选自氢、卤素、氰基、-C 1～4烷基、
Figure PCTCN2022099809-appb-000121
进一 步优选地，每个R C1分别独立选自氢、卤素、氰基、甲基、乙基、正丙基、异丙基、
Figure PCTCN2022099809-appb-000122
Figure PCTCN2022099809-appb-000123
更进一步优选地，每个R C1分别独立选自氢、甲基、
Figure PCTCN2022099809-appb-000124
Figure PCTCN2022099809-appb-000125
本申请还涉及上述各实施方案和优选的实施方案的任意组合。
在本申请的一些具体实施方案中，式I所示的化合物包括但不限于：
Figure PCTCN2022099809-appb-000126
Figure PCTCN2022099809-appb-000127
Figure PCTCN2022099809-appb-000128
Figure PCTCN2022099809-appb-000129
Figure PCTCN2022099809-appb-000130
Figure PCTCN2022099809-appb-000131
本申请还提供了一种药物组合物，包括任一上述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐。
在某些实施方案中，上述药物组合物进一步包括药学上可接受的载体、辅料、媒介物。
本申请还提供了任一上述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐、或上述药物组合物在制备ATR抑制剂中的用途。
本申请还提供了用作ATR抑制剂的任一上述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐、或上述药物组合物。或者，本申请提供了用于抑制ATR的任一上述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐、或上述药物组合物。
本申请还提供了一种抑制受试者体内的ATR活性的方法，包括向有需要的受试者给予任一上述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐、或上述药物组合物。
本申请还提供了任一上述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐、或上述药物组合物在制备治疗或改善癌症中的用途。
本申请还提供了用于治疗或改善癌症的方法，包括向有需要的受试者给予任一上述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐、或上述药物组合物。
本申请还提供了用于治疗或改善癌症的任一上述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐、或上述药物组合物。或者，本申请提供了任一上述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐、或上述药物组合物用于治疗或改善癌症的用途。
在某些实施方案中，所述癌症选自结肠癌、直肠癌、胃癌、食道癌、原发性腹膜癌、肾上腺皮质癌、肾透明细胞癌、前列腺癌、膀胱尿路上皮癌、卵巢癌、乳腺癌、子宫内膜癌、输卵管癌、非小细胞肺癌或小细胞肺癌。
定义和说明
除非另有说明，本申请中所用的术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
本申请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。
关于本申请的使用术语的定义：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 PCTCN2022099809-appb-000132
“可进一步任选被取代”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，即，取代或未被取代的。
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。烷基包括但不限于甲基、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 PCTCN2022099809-appb-000133
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 PCTCN2022099809-appb-000134
Figure PCTCN2022099809-appb-000135
本申请的-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不存在，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。
本申请中所述的“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 PCTCN2022099809-appb-000136
双环己基和
Figure PCTCN2022099809-appb-000137
双环己基。桥碳环基体系的碳环基基团的实例包括
Figure PCTCN2022099809-appb-000138
金刚烷基等。螺碳环基体系的碳环基基团的实例包括
Figure PCTCN2022099809-appb-000139
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。
本申请中所述的“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。
“烯基”是指具有至少1个乙烯基不饱和位点
Figure PCTCN2022099809-appb-000140
的直链或支链烃基基团。例如，C a～b烯基是指具有a至b个碳原子的烯基基团并且意在包括例如乙烯基、丙烯基、异丙烯基、1,3-丁二烯基等。
“炔基”是指含有至少一个三键的直链一价烃基或支链一价烃基。术语“炔基”还意在包括具有一个三键和一个双键的那些烃基基团。例如，C 2-6炔基意在包括乙炔基、丙炔基等。
本申请中所述的“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 PCTCN2022099809-appb-000141
Figure PCTCN2022099809-appb-000142
等。螺杂环烷基体系的杂环烷基基团实例包含
Figure PCTCN2022099809-appb-000143
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 PCTCN2022099809-appb-000144
本申请中所述的“芳环”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。
本申请中所述的“芳杂环”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。优选地包含一至三个杂原子。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 基等。
本申请中所述的“卤素”是指氟、氯、溴或碘。
本申请中所述的“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；例如卤素取代的C 1～4烷基指氢原子被一个或多个卤素原子取代的包含1～4个碳原子的烷基；还例如单卤代烷基、二卤代烷基、三卤代烷基、全卤代烷基等，如单氯甲基、二氯甲基、三氯甲基、单氟甲基、双氟甲基、三氟甲基、2,2,2-三氟乙基、全氟乙基、2,2,2-三氟-1,1-二氯乙基等。类似地，本申请中所述的“卤素取代的烯基”是指烯基中的一个或多个氢原子被卤素取代；本申请中所述的“卤素取代的炔基”是指炔基中的一个或多个氢原子被卤素取代。
本申请中所述的“-OR”、“-NRR”等是指R基团与氧原子或氮原子以单键相连。
本申请中所述的“-C(O)R”、“-S(O) 2R”等中的氧原子与碳原子或硫原子以双键相连。
本申请中所述的“-C(O)R”、“-S(O) 2R”等中的氧原子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。
本申请中所述的
Figure PCTCN2022099809-appb-000145
是指氧原子、硫原子通过双键连接到取代位置。
本申请基团描述中的“---”
Figure PCTCN2022099809-appb-000146
是用来描述基团取代的位置。例如
Figure PCTCN2022099809-appb-000147
是指四氢吡咯环通过“---”的位置与结构中的其它环进行稠合。
本申请的“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“受试者”与“患者”和“个体”等同，并且表示人或非人动物(哺乳动物，例如灵长类动物、啮齿动物等)。“哺乳动物”包括人和家畜(如实验室哺乳动物与家庭宠物，例如猫、狗、猪、羊、牛、绵羊、山羊、马、家兔)，及非驯养哺乳动物，如野生哺乳动物等。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括抑制疾病或病症的进展、缓解疾病或病症。
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，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
本文所述的载体、辅料、和/或媒介物可为药学上可接受的任何载体、辅料、和/或媒介物，例如但不限于溶剂(如水、盐水、甘油和乙醇)、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、抗氧剂、渗透促进剂、pH值调节剂、表面活性剂、稀释剂等。关于其它可用的药学上可接受的药用辅料，可参见例如《药用辅料手册》(第4版)，R.C.罗等著，郑泽民主译，2005年，化学工业出版社。
术语“盐”、“可药用的盐”和“药学上可接受的盐”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。
在某些实施方式中，本申请的一种或多种化合物可以彼此联合使用。也可选择将本申请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。
词语“包括”、“包含”和“含有”及其等同物应理解为开放的、非排他性的意义，即“包括但不限于”，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
本申请的化合物可以存在立体异构体形式。除非另有说明，本文提到的立体异构体包括几何异构体和对映异构体。所有这些异构体以及它们的混合物，均包括在本申请的范围之内。
本申请的药物组合物和化合物可被制备成任何适宜的制剂，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。所述制剂可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、压片法、制 粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
本申请的药物组合物和化合物的典型给予途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
在本文中，除非上下文另有明确规定，否则单数术语涵盖复数指代物，反之亦然。类似地，除非上下文另有明确指示，词语“或”意在包括“和”，反之亦然。
除非另有说明，在本文中，代表成分的量或理化性质或者反应条件等的参数值应当被理解为在所有情况下均由术语“约”修饰。当用术语“约”描述本申请时，术语“约”表示存在的误差值，例如表示在某一特定值的±5％、例如±1％或±0.1％的范围内变化。
显然，根据本申请的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本申请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。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本文中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
以下通过实施例形式的具体实施方式，对本申请的上述内容再作进一步的详细说明。但不应将此理解为本申请上述主题的范围仅限于以下的实例。凡基于本申请上述内容所实现的技术均属于本申请的范围。
具体实施方式
化合物的结构是通过核磁共振波谱(NMR)和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定使用核磁仪(Bruker AvanceIII 400和Bruker Avance 300)，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)或氘代甲醇(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。
本申请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。本申请的术语“室温”是指温度处于10℃-25℃之间。实施例中无特殊说明，M是摩尔每升。
实施例1
Figure PCTCN2022099809-appb-000148
第一步
将化合物1a(200.0mg，0.9mmol)溶于乙腈(3.0mL)中，再加入(R)-3-甲基吗啉(100.0mg，0.9mmol)和N-乙基二异丙胺(254.0mg，2.0mmol)。将上述反应液加热到60℃反应1小时。反应结束后，减压蒸馏去除溶剂得粗品。粗品经柱层析纯化得到化合物1b(180.0mg，0.7mmol,收率：68.4％)。
MS-ESI计算值[M+H] +268.1，实测值268.1。
第二步
将化合物1b(180.0mg，0.6mmol)溶于1,4-二氧六环(6.0mL)与水(3.0mL)的混合溶液，然后依次加入4-吲哚硼酸频那醇酯(246.0mg，1.0mmol)、无水碳酸钠(127.2mg，1.2mmol)和双(三苯基膦)二氯化钯(II)(47.0mg，0.07mmol)，氮气置换后将混合物加热到125℃反应1小时。反应结束后，加乙酸乙酯(3*10mL)萃取出有机相，合并有机相并使用无水硫酸钠干燥，过滤干燥剂后减压浓缩，柱层析 制备后得到化合物1(14.8mg，0.04mmol，收率：6.3％)，HPLC纯度：97.2％。
MS-ESI计算值[M+H] +349.2，实测值349.1。
1H NMR(400MHz,DMSO-d 6)δ11.25(s,1H),8.25(s,1H),8.20(d,J＝7.5Hz,1H),7.55–7.463(m,3H),7.20(t,J＝7.7Hz,1H),4.05-4.01(m,4H),3.85–3.72(m,4H),3.61(dd,J＝12.5,9.4Hz,2H),1.36(d,J＝6.8Hz,3H).
实施例2
Figure PCTCN2022099809-appb-000149
第一步
将化合物2a(1.5g，8.0mmol)溶解到乙腈(36.0ml)中，在20℃下依次加入N,N-二异丙基乙胺(2.1g，16.1mmol)、(R)-3-甲基吗啉(976.1mg，9.7mmol)。所得反应液在20℃搅拌反应2小时。反应结束后，加水(50.0mL)稀释，乙酸乙酯(50.0mL*3)萃取，所得有机相用无水硫酸钠干燥，过滤，所得滤液减压蒸馏去除溶剂得粗品，粗品经柱层析纯化得化合物2b(940.0mg，3.7mmol，收率：45.6％)。
MS-ESI计算值[M+H] +254.1，实测值254.1。
第二步
将化合物2b(940.0mg，3.7mmol)、叔丁醇钾(831.6mg，7.4mmol)溶解到乙二醇二甲醚(40.0mL)中。上述反应液升温至65℃，并缓慢滴加氯甲基甲硫醚(536.8mg，5.6mmol)的乙二醇二甲醚(5.0ml)溶液，反应在65℃搅拌反应3小时。反应结束后，加水(50.0mL)稀释，乙酸乙酯(50.0mL*3)萃取，所得有机相用无水硫酸钠干燥，过滤，所得滤液减压蒸馏去除溶剂得粗品，所得粗品经柱层析纯化得化合物2c(216.0mg，0.7mmol，收率：17.1％)。
MS-ESI计算值[M+H] +314.1，实测值314.2。
第三步
将化合物2c(165.0mg，0.5mmol)溶解到甲醇(5.0ml)中，于0℃缓慢加入过氧单硫酸钾盐(678.0mg，1.1mmol)的水(2.5mL)溶液。所得反应液在20℃搅拌反应3小时。反应结束后，减压浓缩除去甲醇，加水(50.0mL)稀释，乙酸乙酯(50.0mL*3)萃取，所得有机相用无水硫酸钠干燥，过滤，所得滤液减压蒸馏去除溶剂得粗品，所得粗品经柱层析纯化得化合物2d(172.5mg，0.5mmol，收率：100％)。
MS-ESI计算值[M+H] +346.1，实测值346.2。
第四步
将化合物2d(172.5mg，0.5mmol)、4-吲哚硼酸频那醇酯(129.0mg，0.5mmol)、双(三苯基膦)二氯化钯(II)(37.2mg，0.05mmol)、碳酸钠(112.5mg，1.1mmol)加入到二氧六环(4.0mL)与水(2.0mL)的混合溶液中，氮气保护下100℃反应2小时。反应结束后，加水(50.0mL)稀释，乙酸乙酯(50.0mL*3)萃取，合并有机相，用无水硫酸钠干燥，过滤得到的滤液经减压蒸馏去除溶剂得粗品，所得粗品经柱层析和高效液相色谱分离制备得化合物2(43.0mg，0.1mmol，收率：18.1％)，HPLC纯度：95.1％。
MS-ESI计算值[M+H] +427.2，实测值427.2。
1H NMR(400MHz,DMSO-d 6)δ:11.27(s,1H),8.47(s,1H),8.19(dd,J＝7.6,1.0Hz,1H),7.56(dd,J＝8.0,1.0Hz,1H),7.49-7.45(m,2H),7.21(t,J＝7.8Hz,1H),5.91(s,2H),4.40-4.15(m,2H),4.06(d,J＝8.9Hz,1H),3.87–3.73(m,2H),3.67-3.45(m,2H),3.17(s,3H),1.39(d,J＝6.7Hz,3H).
实施例3
Figure PCTCN2022099809-appb-000150
第一步
将化合物3a(266.0mg，1.3mmol)溶于乙腈(10.0mL)，然后加入(R)-3-甲基吗啉(144.0mg，1.4mmol)和N-乙基二异丙胺(362.0mg，2.8mmol)。将上述反应液加热到60℃反应1小时。反应结束后减压浓缩得粗品，所得粗品经柱层析得到化合物3b(332.0mg，1.2mmol，收率：92.0％)。
MS-ESI计算值[M+H] +279.1，实测值279.2。
第二步
将化合物3b(332.0mg，1.2mmol)溶于1,4-二氧六环(8mL)和水(4mL)的混合溶剂。然后依次加入4-吲哚硼酸频那醇酯(435.0mg，1.8mmol)、无水碳酸钠(253.0mg，2.4mmol)和双(三苯基膦)二氯化钯(II)(84.0mg,0.1mmol)，氮气置换后将混合物加热到125℃搅拌1小时。反应结束后，加乙酸乙酯(3*20mL)萃取出有机相，合并有机相并使用无水硫酸钠干燥，过滤干燥剂后减压浓缩，柱层析制备得到化合物3(106.2mg，0.3mmol，收率：24.8％)，HPLC纯度：99.6％。
MS-ESI计算值[M+H] +360.2，实测值360.2。
1H NMR(400MHz,DMSO-d 6)δ11.52(s,1H),8.56(d,J＝8.6Hz,1H),8.07(d,J＝7.5Hz,1H),7.71(d,J＝8.0Hz,1H),7.65–7.50(m,2H),7.35–7.24(m,2H),5.10-4.90(m,1H),4.45-4.25(m,1H),4.07–3.91(m,2H),3.85-3.79(m,2H),3.72–3.67(m,1H),2.76(s,3H),1.56(d,J＝6.8Hz,3H).
实施例4
Figure PCTCN2022099809-appb-000151
第一步
将化合物4a(2.0g，9.7mmol)溶于乙腈(30.0mL)，然后加入(R)-3-甲基吗啉(1.0g，9.8mmol)和N-乙基二异丙胺(2.5g，19.0mmol)。将上述反应液加热到60℃反应1小时。反应结束后减压浓缩得到粗品，所得粗品经柱层析纯化得到化合物4b(2.1g，7.8mmol，收率：81.3％)。
MS-ESI计算值[M+H] +270.1，实测值270.1。
第二步
将化合物4b(800.0mg，2.9mmol)溶于无水四氢呋喃(20.0mL)中，氮气置换后，于-78℃缓慢滴加正丁基锂(3.5mL正己烷溶液，2.5M，8.9mmol)，保持该温度反应搅拌两小时后加入无水丙酮(517.0mg，8.9mmol)，再于-78℃反应1小时。反应结束后，加水(30.0mL)淬灭反应，加乙酸乙酯(3*50.0mL)萃取出有机相，合并有机相并使用无水硫酸钠干燥，过滤干燥剂后减压浓缩得到粗品。所得粗品经柱层析纯化得到化合物4c(360.0mg，1.1mmol，收率：36.9％)。
MS-ESI计算值[M+H] +328.1，实测值328.0。
第三步
将化合物4c(330.0mg，1.0mmol)溶于1,4-二氧六环(20mL)和水(10.0mL)的混合溶液中。然后依次加入4-吲哚硼酸频那醇酯(367.0mg，1.5mmol)、无水碳酸钠(212.0mg，2.0mmol)和双(三苯基膦)二氯化钯(II)(70.0mg，0.1mmol)。氮气置换后将反应加热到125℃反应1小时。反应完成后加乙酸乙酯(3*20mL)萃取出有机相，合并有机相并使用无水硫酸钠干燥，过滤干燥剂后减压浓缩得到粗品。所得粗品经柱层析纯化得到化合物4(335.3mg，0.8mmol，收率：81.7％)，HPLC纯度：95.9％。
MS-ESI计算值[M+H] +409.2，实测值409.3。
1H NMR(600MHz,DMSO-d 6)δ11.21(s,1H),8.12(d,J＝7.5Hz,1H),7.51(d,J＝8.0Hz,1H),7.48-7.40(m,2H),7.35(s,1H),7.20(t,J＝7.7Hz,1H),5.87(s,1H),4.90-4.80(m,1H),4.55-4.47(m,1H),4.10-4.02(m,1H),3.90-3.82(m,1H),3.80-3.72(m,1H),3.60(t,J＝12.0Hz,1H),3.53(t,J＝12.0Hz,1H),1.62(d,J＝9.8Hz,6H),1.38(d,J＝6.9Hz,3H).
实施例5
Figure PCTCN2022099809-appb-000152
第一步
将化合物2d(100.0mg，0.29mmol)溶于DMF(1.5mL)和THF(1.5mL)的混合溶剂中，然后将反应置于冰浴中，2分钟后加入NaH(14mg，0.58mmol)，反应在氮气球保护下于冰浴中搅拌20分钟后加入MeI(61.60mg，0.43mmol)，加完后将反应逐步升温至室温下搅拌5小时后，TLC显示原料2d消失完全，然后缓慢加入水(5.0mL)淬灭反应，所得溶液用乙酸乙酯萃取(3*5.0mL)，合并有机相并使用无水硫酸钠干燥，减压蒸干溶剂后残余物不经分离纯化，直接用于下一步反应。
MS-ESI计算值[M+H]+360.1，实测值360.2。
第二步
将上步未经纯化的化合物5a(0.29mmol)溶于1,4-二氧六环(3.0mL)和水(1.0mL)的混合溶液中。然后依次加入4-吲哚硼酸频那醇酯(81.0mg，0.33mmol)、无水碳酸钠(59.0mg，0.56mmol)和双(三苯基膦)二氯化钯(II)(27.8.0mg，0.028mmol)。氮气置换后将反应加热到85℃反应2小时。反应完成后加水(3.0mL)淬灭，然后用乙酸乙酯(3*5.0mL)萃取出有机相，合并有机相并用无水硫酸钠干燥后减压浓缩得到粗品。所得粗品经柱层析纯化后再由SFC拆分非对映异构体，得到单一化合物5-isomer 1(17.4mg，两步收率13.7％，fast fraction)，纯度：98.4％；5-isomer 2(18.1mg，两步收率14.2％，slow fraction)，纯度98.6％。SFC条件：Column:CHIRALPAK AS-3 150*3mm l.D.,3μm,Mobile phase:A:CO 2,B:ethanol,Gradient:A/B＝78/22,Flow rate:1mL/min,Column temp.:35℃,ABPR:14MPa.[P1,4.14min；P2,6.05min]。
5-isomer 1:MS-ESI计算值[M+H] +441.2，实测值441.2。
5-isomer 2:MS-ESI计算值[M+H] +441.2，实测值441.2。
5-isomer 1: 1H NMR(400MHz,DMSO-d 6)δ11.28(s,1H),8.46(s,1H),8.20(d,J＝7.3Hz,1H),7.56(d,J＝8.0Hz,1H),7.49(t,J＝2.7Hz,1H),7.45(s,1H),7.21(t,J＝7.7Hz,1H),6.18(q,J＝7.0Hz,1H),5.46-4.28(brs,2H),4.07(d,J＝8.4Hz,1H),3.84(d,J＝11.6Hz,1H),3.76(dd,J＝11.7,3.2Hz,1H),3.66-3.40(m,2H),3.00(s,3H),2.03(d,J＝7.1Hz,3H),1.39(d,J＝6.7Hz,3H).
5-isomer 2: 1H NMR(400MHz,DMSO-d 6)δ11.28(s,1H),8.46(s,1H),8.20(d,J＝7.4Hz,1H),7.56(d,J＝7.9Hz,1H),7.49(t,J＝2.8Hz,1H),7.46(s,1H),7.21(t,J＝7.7Hz,1H),6.19(q,J＝7.0Hz,1H),5.46-4.39(brs,2H),4.07(d,J＝8.4Hz,1H),3.84(d,J＝11.6Hz,1H),3.76(dd,J＝11.6,3.2Hz,1H),3.65-3.43(m,2H),3.00(s,3H),2.04(d,J＝7.1Hz,3H),1.39(d,J＝6.8Hz,3H).
实施例6
Figure PCTCN2022099809-appb-000153
第一步
将化合物2d(200.0mg，0.58mmol)溶于DMF(2.0mL)和THF(2.0mL)的混合溶剂中，然后将反应置于冰浴中，2分钟后加入NaH(93.0mg，2.32mmol)，反应在氮气球保护下于冰浴中搅拌20分钟后加入MeI(329.4mg，2.32mmol)，加完后将反应逐步升温至室温下搅拌5小时后，TLC显示原料2d消 失完全，然后缓慢加入水(5.0mL)淬灭反应，所得溶液用乙酸乙酯萃取(3*5.0mL)，合并有机相并使用无水硫酸钠干燥，减压蒸干溶剂后残余物经柱层析分离纯化，得化合物6a(123.2mg，收率：56％)。
6a:MS-ESI计算值[M+H] +374.1，实测值374.2。
第二步
将化合物6a(100mg，0.28mmol)溶于1,4-二氧六环(4.0mL)和水(1.0mL)的混合溶液中。然后依次加入4-吲哚硼酸频那醇酯(78.1mg，0.32mmol)、无水碳酸钠(56.7mg，0.53mmol)和双(三苯基膦)二氯化钯(II)(18.8mg，0.027mmol)。氮气置换后将反应加热到60℃反应1小时。反应完成后加水(3.0mL)淬灭，然后用乙酸乙酯(3*5.0mL)萃取出有机相，合并有机相并用无水硫酸钠干燥后减压浓缩得到粗品。所得粗品经柱层析纯化后再由碱法反相制备纯化得到化合物6(21.5mg，收率18.2％)，纯度：93.1％。
6:MS-ESI计算值[M+H] +455.2，实测值455.2。
1H NMR(600MHz,DMSO-d 6)δ11.25(s,1H),8.43(s,1H),8.05(d,J＝7.5Hz,1H),7.57(d,J＝8.0Hz,1H),7.48(s,1H),7.36(s,1H),7.23(t,J＝7.9Hz,1H),5.25-4.37(brs,2H),4.07(d,J＝10.1Hz,1H),3.85(d,J＝11.5Hz,1H),3.79-3.75(m,1H),3.65-3.43(m,2H),2.92(s,3H),2.36(m,6H),1.39(d,J＝6.8Hz,3H).
实施例7
Figure PCTCN2022099809-appb-000154
第一步
参照实施例5的方法，使用化合物5a(83.0mg，0.23mmol)、6-氮-4-吲哚硼酸频那醇酯(67.3mg，0.28mmol)、无水碳酸钠(48.7mg，0.53mmol)和双(三苯基膦)二氯化钯(II)(18.8mg，0.027mmol)得到7-isomer 1和7-isomer 2。7-isomer 1(3.24mg，两步收率：3.4％，fast fraction)，纯度：94.2％(220nm)，化合物7-isomer 2(3.16mg，两步收率3.1％，slow fraction)，纯度：97.8％。SFC拆分条件：Column:CHIRALCEL OJ-3 150*3mm l.D.,3μm,Mobile phase:A:CO 2,B:ethanol(0.2％DEA),Gradient:A/B＝75/25,Flow rate:1mL/min,Column temp.:35℃,ABPR:14MPa.[P1,2.69min；P2,4.06min]
7-isomer 1:MS-ESI计算值[M+H]+442.2，实测值442.3。
7-isomer 2:MS-ESI计算值[M+H]+442.2，实测值442.3。
7-isomer 1: 1H NMR(600MHz,DMSO-d 6)δ11.80(s,1H),9.22(s,1H),8.85(s,1H),8.48(s,1H),7.76(t,J＝2.8Hz,1H),7.44(t,J＝2.3Hz,1H),6.24(q,J＝7.0Hz,1H),5.39-4.47(brs,2H),4.07(d,J＝10.4Hz,1H),3.84(d,J＝11.4Hz,1H),3.77(dd,J＝11.5,3.2Hz,1H),3.67-3.50(m,2H),3.01(s,3H),2.04(d,J＝7.1Hz,3H),1.40(d,J＝6.7Hz,3H).
7-isomer 2: 1H NMR(600MHz,DMSO-d 6)δ11.81(s,1H),9.21(s,1H),8.85(s,1H),8.48(s,1H),7.76(d,J＝2.8Hz,1H),7.43(s,1H),6.23(q,J＝7.0Hz,1H),5.42-4.42(brs,2H),4.07(d,J＝9.6Hz,1H),3.88-3.82(m,1H),3.76(d,J＝11.7Hz,1H),3.62(m,2H),3.00(s,3H),2.03(d,J＝7.1Hz,3H),1.40(d,J＝6.8Hz,3H).
实施例8
Figure PCTCN2022099809-appb-000155
第一步
参照实施例5的方法，使用化合物5a(150.0mg，0.42mmol)、7-氮-4-吲哚硼酸频那醇酯(123.0mg，0.51mmol)、无水碳酸钠(88.5mg，0.84mmol)双(三苯基膦)二氯化钯(II)(29.4mg，0.042mmol)，得 到8-isomer 1和8-isomer 2。8-isomer 1(42.85mg，两步收率：23.1％，fast fraction)，纯度：99.0％，8-isomer2(62.2mg，两步收率：34.0％，slow fraction)，纯度：99.4％。SFC条件：Column:CHIRALPAK AD-3 150*3mm l.D.,3μm Mobile phase:A:CO 2,B:ethanol,Gradient:A/B＝77/23,Flow rate:1mL/min Column temp.:35℃,ABPR:14MPa.[P1,4.11min；P2,5.16min]。
8-isomer 1:MS-ESI计算值[M+H] +442.2，实测值442.1。
8-isomer 2:MS-ESI计算值[M+H] +442.2，实测值442.1。
8-isomer 1: 1H NMR(600MHz,DMSO-d 6)δ11.81(s,1H),8.51(s,1H),8.36(d,J＝5.0Hz,1H),8.10(d,J＝4.9Hz,1H),7.63(t,J＝2.9Hz,1H),7.45–7.35(m,1H),6.24(q,J＝7.0Hz,1H),5.54-4.40(brs,2H),4.08(d,J＝10.3Hz,1H),3.85(d,J＝11.7Hz,1H),3.77(d,J＝11.7Hz,1H),3.70-3.56(m,2H),3.02(s,3H),2.05(d,J＝7.1Hz,3H),1.40(d,J＝6.8Hz,3H).
8-isomer 2: 1H NMR(600MHz,DMSO-d 6)δ11.81(s,1H),8.51(s,1H),8.36(d,J＝5.0Hz,1H),8.09(d,J＝4.9Hz,1H),7.63(t,J＝2.9Hz,1H),7.46-7.23(m,1H),6.23(q,J＝7.1Hz,1H),5.41-4.48(brs,2H),4.07(d,J＝10.0Hz,1H),3.85(d,J＝11.6Hz,1H),3.76(d,J＝11.6Hz,1H),3.67-3.61(m,2H),3.01(s,3H),2.04(d,J＝7.1Hz,3H),1.40(d,J＝6.7Hz,3H).
实施例9
Figure PCTCN2022099809-appb-000156
第一步
参照实施例5的方法，使用化合物5a(150.0mg，0.42mmol)、6-甲基-4-吲哚硼酸频那醇酯(123.0mg，0.51mmol)、无水碳酸钠(88.5mg，0.84mmol)和双(三苯基膦)二氯化钯(II)(29.4mg，0.042mmol)，得到9-isomer 1和9-isomer 2。9-isomer 1(27.7mg，两步收率：15.4％，fast fraction)，纯度：99.6％，9-isomer2(23.3mg，12.9％，slow fraction)，纯度：99.7％。SFC拆分条件：Column:CHIRALPAK AD-3 150*3mm l.D.,3μm,Mobile phase:A:CO 2,B:ethanol,Gradient:A/B＝75/25,Flow rate:1mL/min,Column temp.:35℃,ABPR:14MPa.[P1,3.89min；P2,5.28min]。
9-isomer 1:MS-ESI计算值[M+H] +455.2，实测值455.1。
9-isomer 2:MS-ESI计算值[M+H] +455.2，实测值455.1。
9-isomer 1: 1H NMR(600MHz,DMSO-d 6)δ11.10(s,1H),8.45(s,1H),8.02(s,1H),7.39(s,1H),7.36(s,2H),6.18(q,J＝7.1Hz,1H),5.33-4.37(brs,2H),4.78(d,J＝8.4Hz,1H),3.84(d,J＝11.6Hz,1H),3.76(d,J＝11.5Hz,1H),3.66-3.51(m,2H),3.00(s,3H),2.49(s,3H),2.03(d,J＝7.1Hz,3H),1.39(d,J＝6.7Hz,3H).
9-isomer 2: 1H NMR(600MHz,DMSO-d 6)δ11.10(s,1H),8.45(s,1H),8.02(s,1H),7.38(s,1H),7.36(s,1H),7.35(s,1H),6.18(q,J＝7.1Hz,1H),5.32-4.45(brs,2H),4.07(d,J＝15.6Hz,1H),3.84(d,J＝11.6Hz,1H),3.76(d,J＝11.8,1H),3.68-3.55(m,J＝11.8,2H),3.00(s,3H),2.49(s,3H),2.03(d,J＝7.0Hz,3H),1.39(d,J＝6.7Hz,3H).
实施例10
Figure PCTCN2022099809-appb-000157
第一步
参照实施例5的方法，使用化合物5a(150.0mg，0.42mmol)、6-氟-4-吲哚硼酸频那醇酯(123.0mg，0.51mmol)、无水碳酸钠(88.5mg，0.84mmol)和双(三苯基膦)二氯化钯(II)(29.4mg，0.042mmol)，得到10-isomer 1和10-isomer 2。10-isomer 1(61.14mg，两步收率：32.1％，fast fraction)，纯度：98.8％。10-isomer 2(50.3mg，两步收率：26.3％，slow fraction)，纯度：98.9％。SFC拆分条件：Column:CHIRALPAK AS-3 150*3mm l.D.,3μm,Mobile phase:A:CO 2,B:ethanol,Gradient:A/B＝78/22,Flow rate:1mL/min,Column temp.:35℃,ABPR:14MPa.[P1,3.22min；P2,4.53min]。
10-isomer 1:MS-ESI计算值[M+H] +459.2，实测值459.2。
10-isomer 2:MS-ESI计算值[M+H] +459.2，实测值459.2。
10-isomer 1: 1H NMR(600MHz,DMSO-d 6)δ11.35(s,1H),8.48(s,1H),7.99(d,J＝11.4,1H),7.50(s,1H),7.46(s,1H),7.36(d,J＝9.1Hz,1H),6.22(q,J＝7.1Hz,1H),5.46-4.45(brs,2H),4.07(d,J＝10.0Hz,1H),3.85(d,J＝11.6Hz,1H),3.76(d,J＝11.7,1H),3.72-3.52(m,2H),3.00(s,3H),2.03(d,J＝7.0Hz,3H),1.40(d,J＝6.7Hz,3H).
10-isomer 2: 1H NMR(600MHz,DMSO-d 6)δ11.36(s,1H),8.48(s,1H),7.99(d,J＝11.4Hz,1H),7.50(d,J＝3.1Hz,1H),7.46(d,J＝2.9Hz,1H),7.35(d,J＝9.1Hz,1H),6.23(q,J＝7.1Hz,1H),5.36-4.45(brs,2H),4.07(d,J＝8.4Hz,1H),3.84(d,J＝11.6Hz,1H),3.76(d,J＝11.7Hz,1H),3.67-3.46(m,2H),3.01(s,3H),2.03(d,J＝7.1Hz,3H),1.40(d,J＝6.8Hz,3H).
实施例11
Figure PCTCN2022099809-appb-000158
第一步
将化合物2d(150.0mg，0.43mmol)加入到N,N-二甲基甲酰胺(8.0mL)和四氢呋喃(8.0mL)的混合溶液中，降温至0℃，0℃氮气保护下加入NaH(69.4mg，1.74mmol)，0℃搅拌反应30分钟。0℃氮气保护下加入碘乙烷(81.2mg，0.50mmol)，0℃搅拌反应30分钟后缓慢升温至25℃并继续搅拌反应2.0小时。反应结束后，加水(50.0mL)淬灭反应，乙酸乙酯(50.0mL*3)萃取，合并有机相，用无水硫酸钠干燥，过滤后的滤液经减压蒸馏去除溶剂得粗品，所得粗品经柱层析得化合物11a(71.0mg，收率：35.0％)。
MS-ESI计算值[M+H] +374.1，实测值374.3。
第二步
将化合物11a(65.0mg，0.17mmol)、4-吲哚硼酸频那醇酯(66.4mg，0.26mmol)、双(三苯基膦)二氯化钯(II)(24.4mg，0.03mmol)、碳酸钠(18.4mg，0.17mmol)加入到二氧六环(15.0mL)与水(5.0mL)的混合溶液中，氮气保护下100℃反应2.0小时。反应结束后，加水(50.0mL)稀释，乙酸乙酯(50.0mL*3)萃取，合并有机相，用无水硫酸钠干燥，过滤后的滤液经减压蒸馏去除溶剂得粗品，所得粗品经柱层析、高效液相色谱及超临界液相色谱分离制备得到11-isomer 1和11-isomer 2。11-isomer 1(11.0mg，收率：13.9％，fast fraction)，纯度：95.0％。11-isomer 2(13.0mg，收率：16.5％，slow fraction)，纯度：98.9％。SFC拆分条件：Column:CHIRALPAK AD-3 150*3mm l.D.,3μm,Mobile phase:A:CO 2,B:ethanol+0.1％TEA,Gradient:A/B＝75/25,Flow rate:1mL/min,Column temp.:35℃,ABPR:14MPa.[P1,3.29min；P2,4.37min]。
11-isomer 1:MS-ESI计算值[M+H] +455.2，实测值455.1。
11-isomer 2:MS-ESI计算值[M+H] +455.2，实测值455.1。
11-isomer 1: 1H NMR(600MHz,DMSO-d 6)δ:11.34(s,1H),8.54(s,1H),8.23(d,J＝7.4Hz,1H),7.64(d,J＝7.9Hz,1H),7.57-7.51(m,1H),7.50-7.44(m,1H),7.29(t,J＝7.7Hz,1H),5.97(dd,J＝11.7,3.6Hz,1H),5.50-4.51(m,2H),4.13(d,J＝10.1Hz,1H),3.90(d,J＝11.5Hz,1H),3.82(d,J＝12.1Hz,2H),3.65-3.60(m,1H),3.09(s,3H),2.69(dq,J＝13.1,6.9Hz,1H),2.55–2.50(m,1H),1.50-1.41(m,3H),0.92(t,J＝7.2Hz,3H).
11-isomer 2: 1H NMR(600MHz,DMSO-d 6)δ:11.34(s,1H),8.54(s,1H),8.23(d,J＝7.4Hz,1H),7.64(d,J＝7.9Hz,1H),7.57-7.51(m,1H),7.50-7.44(m,1H),7.29(t,J＝7.7Hz,1H),5.97(dd,J＝11.7,3.6Hz,1H),5.50-4.51(m,2H),4.13(d,J＝10.1Hz,1H),3.90(d,J＝11.5Hz,1H),3.82(d,J＝12.1Hz,2H),3.65-3.60(m,1H),3.09(s,3H),2.69(dq,J＝13.1,6.9Hz,1H),2.55–2.50(m,1H),1.50-1.41(m,3H),0.92(t,J＝7.2Hz,3H).
实施例12：
Figure PCTCN2022099809-appb-000159
第一步
将化合物2d(400.0mg，1.16mmol)加入到N,N-二甲基甲酰胺(40.0mL)中，降温至-70℃，-70℃氮气保护下加入NaH(115.7mg，2.89mmol)，-70℃搅拌反应30分钟。-70℃氮气保护下加入2-碘代异丙烷(393.3mg，2.31mmol)，-70℃搅拌反应30分钟后缓慢升温至25℃并继续搅拌反应3.0小时。反应结束后，加水(50.0mL)稀释，乙酸乙酯(50.0mL*3)萃取，合并有机相，用无水硫酸钠干燥，过滤得到的滤液经减压蒸馏去除溶剂得粗品，所得粗品经柱层析和高效液相色谱分离制备得化合物12a(83.0mg，收率：16.5％)。
MS-ESI计算值[M+H] +388.1，实测值388.3。
第二步
将化合物12a(72.0mg，0.18mmol)、4-硼酸频那醇酯(67.7mg，0.28mmol)、双(三苯基膦)二氯化钯(II)(26.1mg，37.1umol)、碳酸钠(43.3mg，408.4μmol)加入到二氧六环(10.0mL)与水(3.0mL)的混合溶液中，氮气保护下100℃反应3.0小时。反应结束后，加水(50.0mL)稀释，乙酸乙酯(50.0mL*3)萃取，合并有机相，用无水硫酸钠干燥，过滤的滤液经减压蒸馏去除溶剂得粗品，所得粗品经柱层析、高效液相色谱及超临界液相色谱分离制备得到化合物12-isomer 1和12-isomer 2。
12-isomer 1(8.0mg，收率：8.7％，fast fraction)，纯度：99.0％；12-isomer 2(12.0mg，收率：13.1％，slow fraction)，纯度：99.0％。SFC拆分条件：Column:CHIRALPAK AS-3 150*3mm l.D.,3μm,Mobile phase:A:CO 2,B:ethanol,Gradient:A/B＝75/25,Flow rate:1mL/min,Column temp.:35℃,ABPR:14MPa.[P1,2.61min；P2,5.01min]。
12-isomer 1:MS-ESI计算值[M+H] +469.2，实测值469.1。
12-isomer 2:MS-ESI计算值[M+H] +469.2，实测值469.1。
12-isomer 1: 1H NMR(600MHz,DMSO-d6)δ:11.29(s,1H),8.49(s,1H),8.17(d,J＝7.5Hz,1H),7.58(d,J＝8.0Hz,1H),7.51(t,J＝2.7Hz,1H),7.36(t,J＝2.5Hz,1H),7.23(t,J＝7.7Hz,1H),5.65(d,J＝10.0Hz,1H),4.79(d,J＝167.4Hz,1H),4.10–4.04(m,1H),3.84(d,J＝11.5Hz,1H),3.76(dd,J＝11.5,3.2Hz,1H),3.61(dt,J＝12.0,6.1Hz,2H),3.43–3.41(m,1H),3.03(qd,J＝6.7,3.4Hz,1H),2.93(s,3H),1.41(d,J＝6.7Hz,3H),1.35(d,J＝6.6Hz,3H),0.83(d,J＝6.7Hz,3H).
12-isomer 2: 1H NMR(600MHz,DMSO-d6)δ:11.29(s,1H),8.49(s,1H),8.17(d,J＝7.5Hz,1H),7.57(d,J＝7.9Hz,1H),7.50(d,J＝2.9Hz,1H),7.37(s,1H),7.22(t,J＝7.7Hz,1H),5.65(d,J＝10.0Hz,1H),5.03–4.57(m,1H),4.13–4.02(m,1H),3.84(d,J＝11.6Hz,1H),3.76(dd,J＝11.7,3.2Hz,1H),3.62(t,J＝11.4Hz,1H),3.47–3.45(m,2H),3.07–2.99(m,1H),2.95(s,3H),1.40(d,J＝6.7Hz,3H),1.35(d,J＝6.6Hz,3H),0.83(d,J＝6.6Hz,3H).
实施例13：
Figure PCTCN2022099809-appb-000160
第一步
将化合物5a(80.0mg，0.22mmol)溶于1,4-二氧六环(10.0mL)和水(5.0mL)的混合溶液中。然后依次加入化合物13b(82.2mg，0.24mmol)、无水碳酸钠(70.0mg，0.66mmol)和双(三苯基膦)二氯化钯(II)(15.6mg，0.02mmol)。氮气置换后将反应加热到100℃反应2小时。反应完成后加水(3.0mL)淬灭，然后用乙酸乙酯(3*5.0mL)萃取出有机相，合并有机相并用无水硫酸钠干燥后减压浓缩得到粗品。所得粗品经柱层析和高效液相色谱分离制备得化合物13(25mg，收率：24.7％)，纯度：99％。
13:MS-ESI计算值[M+H] +460.2，实测值460.1。
1H NMR(600MHz,DMSO-d 6)δ11.80(s,1H),8.50(s,1H),8.43(s,1H),7.79(t,J＝2.6Hz,1H),7.00–6.99(m,1H),6.08(q,J＝7.1Hz,1H),5.00-4.45(m,2H),4.03–4.01(m,1H),3.80-3.78(m,1H),3.73-3.72(m,1H),3.58-3.56(m,1H),3.38-3.28(m,1H),3.01(s,3H),2.00(dd,J＝7.1,5.4Hz,3H),1.37(s,3H).
化合物13再由SFC拆分非对映异构体，得到单一化合物13-isomer 1(10.0mg，fast fraction)，纯度：98.6％；13-isomer 2(7.0mg，slow fraction)，纯度99.0％。SFC条件：Column:CHIRALPAK AD-3 150*3mm l.D.,3μm,Mobile phase:A:CO 2,B:ethanol,Gradient:A/B＝80/20,Flow rate:1mL/min,Column temp.:35℃,ABPR:14MPa.[P1,3.88min；P2,5.81min]。
13-isomer 1:MS-ESI计算值[M+H] +460.2，实测值460.1。
13-isomer 2:MS-ESI计算值[M+H] +460.2，实测值460.1。
13-isomer 1: 1H NMR(600MHz,DMSO-d 6)δ11.80(s,1H),8.50(s,1H),8.43(s,1H),7.79(t,J＝2.6Hz,1H),7.00–6.99(m,1H),6.08(q,J＝7.1Hz,1H),5.00-4.45(m,2H),4.03–4.01(m,1H),3.80-3.78(m,1H),3.73-3.72(m,1H),3.58-3.56(m,1H),3.38-3.28(m,1H),3.01(s,3H),2.00(dd,J＝7.1,5.4Hz,3H),1.30-1.41(m,3H).
13-isomer 2: 1H NMR(600MHz,DMSO-d 6)δ11.80(s,1H),8.50(s,1H),8.43(s,1H),7.79(t,J＝2.6Hz,1H),7.00–6.99(m,1H),6.08(q,J＝7.1Hz,1H),5.00-4.45(m,2H),4.03–4.01(m,1H),3.80-3.78(m,1H),3.73-3.72(m,1H),3.58-3.56(m,1H),3.38-3.28(m,1H),3.01(s,3H),2.00(dd,J＝7.1,5.4Hz,3H),1.30-1.41(m,3H).
生物实施例
试验例1：细胞增殖试验
本申请中，运用细胞增殖实验法来评价化合物对肿瘤细胞的生物活性。分别将HT-29(成都中源共创科技有限公司)细胞和LOVO(南京科佰生物科技有限公司)细胞接种于96孔板中，其中HT-29细胞每孔接种5000个细胞，LOVO细胞每孔接种10000个细胞。向HT-29细胞中加入含10％胎牛血清和100μg/mL Normocin的RPMI-1640培养基进行培养，向LOVO细胞中加入含10％胎牛血清和100μg/mL Normocin的Dulbecco's Modified Eagle Medium(DMEM)培养基进行培养。在37℃及5％CO 2条件下培养过夜，使细胞附着贴壁。次日，移除细胞中的培养基，先加入150μL新鲜培养基，再加入50μL含有4倍终浓度化合物(终浓度范围为1nM～10μM)的培养基，放入培养箱中，在37℃及5％CO 2条件下继续培养72h。培养72h后再次移除细胞中的培养基，加入含有10％CCK8试剂的无血清RPMI-1640基础培养基。在37℃条件下孵育1h后使用酶标仪(BMG LABTECH)于450nm波长下读取吸光度(OD)值。使用GraphPad Prism软件对数据进行分析，拟合化合物抑制生长曲线并计算IC 50值。
表1：
化合物编号 IC 50(HT-29,μM) IC 50(LOVO,μM)
AZD6738 2.950 0.538
1 2.215 0.448
2 2.085 0.625
3 >10 6.843
4 1.805 0.596
5-isomer 1 0.676 0.157
5-isomer 2 0.673 0.079
6 3.591 0.764
7-isomer 1 0.859 0.968
7-isomer 2 0.626 0.784
8-isomer 1 1.203 0.715
8-isomer 2 2.182 0.711
9-isomer 1 0.951 0.349
9-isomer 2 1.616 0.610
10-isomer 1 0.655 0.180
10-isomer 2 0.613 0.193
11-isomer 1 0.630 0.225
11-isomer 2 2.00 0.760
12-isomer 1 1.350 0.470
12-isomer 2 0.510 0.162
13 0.710 0.690
13-isomer 1 1.377 0.603
13-isomer 2 9.785 2.175
结论：通过上述实验，可以得知本申请化合物对HT-29和LOVO细胞具有良好的抗增殖活性。
试验例2：pCHK1细胞水平检测
HT-29细胞按照每孔10000个细胞的密度接种到96孔透明底黑板(Greiner Bio-one，货号655090)中，于37℃、5％CO 2培养箱中培养过夜。次日，移除细胞中的培养基，先加入150μL新鲜培养基，再加入50μL含有4倍终浓度化合物(终浓度范围为1nM～10μM)的培养基，放入培养箱中，在37℃及5％CO 2条件下继续培养60min。然后每孔加入600μM的4NQO 1μL进行处理(终浓度为3μM)，并继续培养60min。阴性对照孔中加入等体积DMSO替代4NQO。之后，移除细胞中的培养基，使用4％多聚甲醛固定细胞，每孔150μL，室温孵育15min。细胞固定后使用0.1％(v/v)Triton X-100通透细胞，每孔150μL，室温孵育15min。细胞使用1％封闭试剂(罗氏)封闭，每孔100μL，室温孵育60min。封闭后每孔加入50μL使用1％(w/v)封闭试剂稀释后的pCHK1抗体(CST，货号：2348，稀释比例为1:250)，于2～8℃孵育过夜。次日，移除孔中的抗体，使用0.05％(v/v)PBST洗细胞，每孔200μL，重复3次。然后加入1％(w/v)封闭试剂稀释的羊抗兔荧光二抗(Invitrogen，货号：A32731)和DAPI染液(Thermofisher，货号：62247)(荧光二抗稀释比例为1:1000(v/v)，DAPI的稀释比例为1:2000(v/v))，每孔50μL，室温环境下于振荡器上300rpm避光孵育2h。然后移除孔中的抗体，使用0.05％(v/v)PBST洗细胞，每孔200μL，重复3次(最后一次保留孔内的洗液)。使用高内涵成像分析系统(GE，In Cell Analyzer，型号：2200)获取细胞核内的pCHK1荧光值，使用GraphPad Prism软件对pCHK1相对水平进行分析，拟合化合物对pCHK1抑制曲线并计算IC 50值。
表2：
化合物编号 IC 50(μM)
AZD6738 0.071
1 0.512
2 0.207
3 3.663
4 0.167
5-isomer 1 0.092
5-isomer 2 0.053
6 0.492
7-isomer 1 0.032
7-isomer 2 0.026
8-isomer 1 0.236
8-isomer 2 0.128
9-isomer 1 0.082
9-isomer 2 0.175
10-isomer 1 0.076
10-isomer 2 0.083
11-isomer 1 0.044
11-isomer 2 0.224
12-isomer 1 0.093
12-isomer 2 0.054
13 0.030
13-isomer 1 0.064
13-isomer 2 0.201
结论：通过上述实验，可以得知本申请化合物对HT-29细胞中ATR下游CHK1磷酸化水平具有较好的抑制作用。
试验例3：化合物体外肝微粒体稳定性实验
对本申请化合物进行肝微粒体稳定性实验研究。
实验方法：
将待测化合物(终浓度1.5μM)在加入NADPH情况下与人/小鼠的肝微粒体进行共孵育，检测60分钟内孵育上清中的化合物浓度。代表性化合物的结果如下：
表3
化合物编号 人肝微粒T 1/2(min) 小鼠肝微粒T 1/2(min)
AZD6738 >120 52
5-isomer2 >120 30
13 >120 81
结论：本申请化合物在人/小鼠的肝微粒体中具有很好的代谢稳定性。
试验例4：化合物体内药代动力学实验：
供试样品：在上述研究的基础上，选择其中一些高活性、结构有代表性的化合物进行体内药代动力学研究。
实验方法：
该实验的目的是为了测定该化合物药代动力学参数，并计算其在雄性CD-1小鼠和雄性SD大鼠中的口服生物利用度。选择36只雄性CD-1小鼠，分4组，分别静脉注射和口服灌胃给予AZD6738和5-isomer2，每组9只动物。其中两组小鼠进行静脉注射给药，静脉注射剂量为1mg/kg，收集给药后(5、15、30分钟以及1、2、4、8、24小时)的血浆样品；另外两组小鼠进行口服灌胃给药，给药剂量为10mg/kg，收集给药后(15、30分钟以及1、2、4、8、24小时)的血浆样品，进行LC/MS分析血浆中的药物浓度，用Winnolin 5.2软件计算相关药代动力学参数。
12只雄性SD大鼠分为4组，分别静脉注射和口服灌胃给予AZD6738和5-isomer2，每组3只动物。其中两组大鼠进行静脉注射给药，静脉给药剂量为1mg/kg。另外两组大鼠进行口服灌胃给药，口服给药剂量为10mg/kg。采血时间点与小鼠相同。采集血浆分析药物浓度，获得相关药代动力学参数。
实验结果如下：
表4.1静脉注射给药结果
Figure PCTCN2022099809-appb-000161
表4.2口服给药结果
Figure PCTCN2022099809-appb-000162
注：C 0为0分钟时体内药物浓度；Cl(mL/min/kg)为药物体内清除率；T 1/2(h)为半衰期；AUC为体内药物暴露量；C max为体内药物最高浓度；F(％)为药物口服生物利用度。
实验结论：本申请化合物口服有较好的吸收与暴露量，适合于口服用药。并且本申请化合物与临床二期ATR抑制剂AZD6738相比较在药代动力学上优势十分明显，其中小鼠Cmax为1.6倍，AUC为5.7倍(p<0.05)；大鼠Cmax为1.4倍，AUC为1.9倍(p<0.05)。
试验例5：结直肠癌LOVO CDX体内药效研究：
LOVO是MRE11A突变(MRE11A是关于DNA双链锻炼修复ATM信号通路的关键组成部分)的结直肠癌肿瘤细胞，其对ATR抑制剂敏感。本实验将通过结直肠癌LOVO CDX模型以验证ATR抑制剂单药对ATM信号通路缺陷的肿瘤的抑制作用。
1.实验动物
种属：小鼠
品系：BALB/c Nude
周龄：8周(到达)，9周(分组)
体重：16-20g(到达)，18-22g(分组)
性别：雌性
供应商：北京维通利华实验动物技术有限公司
2.实验细胞
LOVO细胞，购于南京科佰生物科技有限公司，所用培养基为DMEM加10％FBS血清，37℃和5％CO 2条件下培养。
3.药品
受试药：化合物5-isomer2，AZD6738
4.实验方法
LOVO细胞体外培养(贴壁生长)，收集对数生长期的细胞，用PBS轻轻漂洗细胞两次，用PBS轻轻吹打细胞沉淀重悬细胞，制备单细胞悬液，计数后调整细胞终浓度为5×10 6个细胞/100μL混匀。右侧腋下接种5×10 6个/只，接种体积为100μL/只。定期观察肿瘤生长情况，待肿瘤生长至平均94mm 3时根据肿瘤大小和小鼠体重随机分为5组，每组8只。小鼠分组当天定义为0天。按照下表给药。
表5.1药物配置方法
Figure PCTCN2022099809-appb-000163
表5.2动物模型中的给药途径、剂量及方案
Figure PCTCN2022099809-appb-000164
注：p.o.为口服给药；QD为每天给药一次。
本实验的主要观察指标为：
相对肿瘤增值率T/C(％)，在某一时间点，治疗组与对照组的相对肿瘤体积或瘤重的百分比值。计算公式如下：T/C％＝T RTV/C RTV×100％(T RTV：治疗组平均RTV；C RTV：对照组平均RTV；RTV＝V t/V 0，V 0为分组时的肿瘤体积，V t为治疗后的肿瘤体积)。或T/C％＝T TW/C TW×100％(T TW：治疗组实验终结时平均瘤重；C TW：对照组实验终结时平均瘤重)。
相对肿瘤抑制率TGI(％)＝(1-(mean T-mean T 0)/(mean C-mean C 0))×100％。Mean T和mean C分别为治疗组和对照组在某一特定时间的平均肿瘤体积，mean T 0和mean C 0分别为治疗组和对照组分组时的平均肿瘤体积。
5.实验结果
本实验评价了化合物5-isomer2在人结直肠癌CDX模型中的药效，给药22天，对照组肿瘤体达到1739mm 3，与对照组比较，AZD6738组、5-isomer2低剂量组、5-isomer2中剂量组、5-isomer2高剂量组TGI分别为58.3％、60.4％、90％、93.3％。化合物5-isomer2各剂量组小鼠肿瘤体积的减小均有统计学意义(p<0.01)。
结论：化合物5-isomer2能显著抑制LOVO荷瘤小鼠肿瘤生长，且呈量效关系。与临床二期ATR抑制剂AZD6738相比，本申请化合物药效更优，分别表现在同等剂量下，肿瘤生长抑制率更优(AZD6738：58.3％；5-isomer2：90％)；在获得相同肿瘤抑制率的药效下，本申请化合物使用剂量更低(AZD6738：50mg/kg；5-isomer2：25mg/kg)，这为临床转化中更好的药效以及更优的安全性提供了有力支撑。
试验例6：大鼠最大耐受剂量(MTD)研究：
目的：SD大鼠单次经口灌胃AZD6738、5-isomer2后观察14天，观察受试物最大耐受剂量，为多次给药毒性试验提供参考信息。
方法：本实验设7个组，分别为对照组及AZD6738的500、1000、2000mg/kg组和化合物5-isomer2的500、1000、2000mg/kg组，每组10只小鼠，雌雄各半。大鼠按5μL/g的体积经口灌胃给予对照品或相应浓度的AZD6738/5-isomer2，分组当天给药1次后观察2周。给药当天为第0天。
实验期间每天观察各组大鼠一般状况；每周测定2次体重。第14天结束试验，处死大鼠。
结果：受试大鼠对AZD6738的最大耐受剂量(MTD)小于500mg/kg的剂量水平，其中高剂量组大鼠全部死亡，中剂量组雌性大鼠全部死亡，雄性大鼠死亡3只，低剂量组雌性大鼠死亡1只；受试大鼠对化合物5-isomer2的最大耐受剂量(MTD)大于2000mg/kg，其中各剂量组大鼠均无异常。
结论：化合物5-isomer2的大鼠最大耐受剂量水平远高于AZD6738，可知本申请化合物较原研化合物AZD6738在毒性方面有较大优势。
试验例7：大鼠两周毒性研究：
目的：对AZD6738和5-isomer2进行了SD大鼠经口灌胃2周毒性实验，观察供试品是否可能引起毒性反应，判断毒性靶器官或靶组织。
方法：本实验设7个组，分别为对照组及AZD6738的50、150、450mg/kg和化合物5-isomer2的50、150、450mg/kg组，每组10只小鼠，雌雄各半。大鼠按10μL/g的体积经口灌胃给予对照品或相应浓度的AZD6738/5-isomer2，每天给药1次、连续2周。首次给药当天为给药期第1天。
实验期间每天观察各组大鼠一般状况；给药期每周测定2次体重。给药期结束，所有存活大鼠采血进 行血液学、血生化检查，安乐死后进行大体解剖观察、脏器重量及组织病理学检查。
结果：AZD6738毒性较大，其中高剂量组大鼠全部死亡，中剂量组雌性全部死亡、雄性死亡2只；化合物5-isomer2仅高剂量组雌性大鼠死亡1只，其余均未见异常。
结论：在两周毒性研究中，本申请化合物5-isomer2毒性远优于原研化合物AZD6738。
根据上述结果表明本申请实施例化合物显示出在体内药效、药代动力学以及毒理(最大耐受剂量以及2周毒性研究)等方面均优于阳性化合物。
对于本领域的普通技术人员而言明显的是在不偏离本申请的精神或者范围，可对本申请化合物、组合物以及方法进行的多种修饰和变化，因此，本申请包含对本申请的修饰和变化，只要在权利要求和其等同的范围内。

Claims (15)

  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 PCTCN2022099809-appb-100001
    其中，
    A环选自
    Figure PCTCN2022099809-appb-100002
    Figure PCTCN2022099809-appb-100003
    B环选自
    Figure PCTCN2022099809-appb-100004
    Figure PCTCN2022099809-appb-100005
    其中B环任选被一个、两个、三个或四个R B1取代；
    每个R B1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 B2、-C 0～4亚烷基-OC(O)R B2、-C 0～4亚烷基-C(O)R B2、-C 0～4亚烷基-C(O)OR B2、-C 0～4亚烷基-C(O)NR B2R B3、-C 0～4亚烷基-NR B2R B3、-C 0～4亚烷基-NR B2C(O)R B3；
    R B2、R B3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 1和R 2与相连的原子一起形成
    Figure PCTCN2022099809-appb-100006
    X 1、X 2、X 3、X 4分别独立选自N或CR C1；
    Y选自O、S或NR C1；
    每个R C1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 C2、-C 0～4亚烷基-OC(O)R C2、-C 0～4亚烷基-SR C2、-C 0～4亚烷基-S(O) 2R C2、-C 0～4亚烷基-S(O)R C2、-C 0～4亚烷基-S(O) 2NR C2R C3、-C 0～4亚烷基-S(O)NR C2R C3、-C 0～4亚烷基-S(O)(NH)R C2、-C 0～4亚烷基-S(O)(NH)NR C2R C3、-C 0～4亚烷基-C(O)R C2、-C 0～4亚烷基-C(O)OR C2、-C 0～4亚烷基-C(O)NR C2R C3、-C 0～4亚烷基-NR C2R C3、-C 0～4亚烷基-NR C2C(O)R C3、-C 0～4亚烷基-NR C2S(O) 2R C3、-C 0～4亚烷基-NR C2S(O)R C3、-C 0～4亚烷基-P(O)R C2R C3、-C 0～4亚烷基-P(O)(OR C2)R C3、-C 0～4亚烷基-P(O)(OR C2)(OR C3)、-C 0～4亚烷基-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；其中，亚烷基、碳环基、杂环烷基、芳环、芳杂环任选被一个、两个、三个或四个独立的R C4取代；
    或者，两个独立的R C1与相连的原子一起形成5～8元碳环基、5～8元杂环烷基、苯环、5～6元芳杂环；其中，碳环基、杂环烷基、芳环、芳杂环任选被一个、两个、三个或四个独立的R C4取代；
    R C2、R C3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-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基 -(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；
    每个R C4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 C5、-C 0～4亚烷基-OC(O)R C5、-C 0～4亚烷基-SR C5、-C 0～4亚烷基-S(O) 2R C5、-C 0～4亚烷基-S(O)R C5、-C 0～4亚烷基-S(O) 2NR C5R C6、-C 0～4亚烷基-S(O)NR C5R C6、-C 0～4亚烷基-S(O)(NH)R C5、-C 0～4亚烷基-S(O)(NH)NR C5R C6、-C 0～4亚烷基-C(O)R C5、-C 0～4亚烷基-C(O)OR C5、-C 0～4亚烷基-C(O)NR C5R C6、-C 0～4亚烷基-NR C5R C6、-C 0～4亚烷基-NR C5C(O)R C6、-C 0～4亚烷基-NR C5S(O) 2R C6、-C 0～4亚烷基-NR C5S(O)R C6、-C 0～4亚烷基-P(O)R C5R C6、-C 0～4亚烷基-P(O)(OR C5)R C6、-C 0～4亚烷基-P(O)(OR C5)(OR C6)；或者，两个独立的R C4与相连的原子一起形成
    Figure PCTCN2022099809-appb-100007
    R C5、R C6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-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)。
  2. 根据权利要求1所述的式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，其中，
    B环选自
    Figure PCTCN2022099809-appb-100008
    Figure PCTCN2022099809-appb-100009
    其中B环任选被一个、两个、三个或四个R B1取代；
    每个R B1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 B2、-C(O)R B2、-C(O)NR B2R B3、-NR B2R B3、-NR B2C(O)R B3；
    R B2、R B3分别独立选自氢、-C 1～6烷基；
    优选地，
    B环选自
    Figure PCTCN2022099809-appb-100010
    Figure PCTCN2022099809-appb-100011
    更优选地，
    B环选自
    Figure PCTCN2022099809-appb-100012
  3. 根据权利要求1或2所述的式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，其中，
    R 1和R 2与相连的原子一起形成
    Figure PCTCN2022099809-appb-100013
    Figure PCTCN2022099809-appb-100014
    其中R 1和R 2与相连的原子一起形成的前述环任选被一个、两个、三个或四个R C1取代；优选地，每个R C1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、
    Figure PCTCN2022099809-appb-100015
    Figure PCTCN2022099809-appb-100016
  4. 根据权利要求1-3任一项所述的式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，其中，
    R 1和R 2与相连的原子一起形成
    Figure PCTCN2022099809-appb-100017
    Figure PCTCN2022099809-appb-100018
  5. 根据权利要求1-4任一项所述的式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，其中，A环选自
    Figure PCTCN2022099809-appb-100019
    优选选自
    Figure PCTCN2022099809-appb-100020
    更优选为
    Figure PCTCN2022099809-appb-100021
  6. 根据权利要求1所述的式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，其中，式I所示的化合物如式IIa或式IIb所示：
    Figure PCTCN2022099809-appb-100022
    其中，
    A环选自
    Figure PCTCN2022099809-appb-100023
    Figure PCTCN2022099809-appb-100024
    B环选自
    Figure PCTCN2022099809-appb-100025
    Figure PCTCN2022099809-appb-100026
    其中B环任选被一个、两个、三个或四个R B1取代；
    每个R B1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 B2、-C(O)R B2、-C(O)NR B2R B3、-NR B2R B3、-NR B2C(O)R B3；
    X 1、X 2分别独立选自N或CR C1；
    Y选自O、S或NR C1；
    每个R C1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 C2、-C 0～4亚烷基-OC(O)R C2、-C 0～4亚烷基-SR C2、-C 0～4亚烷基-S(O) 2R C2、-C 0～4亚烷基-S(O)R C2、-C 0～4亚烷基-S(O) 2NR C2R C3、-C 0～4亚烷基-S(O)NR C2R C3、-C 0～4亚烷基-S(O)(NH)R C2、-C 0～4亚烷基-S(O)(NH)NR C2R C3、-C 0～4亚烷基-C(O)R C2、-C 0～4亚烷基-C(O)OR C2、-C 0～4亚烷基-C(O)NR C2R C3、-C 0～4亚烷基-NR C2R C3、-C 0～4亚烷基-NR C2C(O)R C3、-C 0～4亚烷基-NR C2S(O) 2R C3、-C 0～4亚烷基-NR C2S(O)R C3、-C 0～4亚烷基-P(O)R C2R C3、-C 0～4亚烷基-P(O)(OR C2)R C3、-C 0～4亚烷基-P(O)(OR C2)(OR C3)、-C 0～4亚烷基-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；其中，亚烷基、碳环基、杂环烷基、芳环、芳杂环任选被一个、两个、三个或四个独立的R C4取代；
    或者，两个独立的R C1与相连的原子一起形成5～8元碳环基、5～8元杂环烷基、苯环、5～6元芳杂环；其中，碳环基、杂环烷基、芳环、芳杂环任选被一个、两个、三个或四个独立的R C4取代；
    R C2、R C3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-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；
    每个R C4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 C5、-C 0～4亚烷基-OC(O)R C5、-C 0～4亚烷基-SR C5、-C 0～4亚烷基-S(O) 2R C5、-C 0～4亚烷基-S(O)R C5、-C 0～4亚烷基-S(O) 2NR C5R C6、-C 0～4亚烷基-S(O)NR C5R C6、-C 0～4亚烷基-S(O)(NH)R C5、-C 0～4亚烷基-S(O)(NH)NR C5R C6、-C 0～4亚烷基-C(O)R C5、-C 0～4亚烷基-C(O)OR C5、-C 0～4亚烷基-C(O)NR C5R C6、-C 0～4亚烷基-NR C5R C6、-C 0～4亚烷基-NR C5C(O)R C6、-C 0～4亚烷基-NR C5S(O) 2R C6、-C 0～4亚烷基-NR C5S(O)R C6、-C 0～4亚烷基-P(O)R C5R C6、-C 0～4亚烷基-P(O)(OR C5)R C6、-C 0～4亚烷基-P(O)(OR C5)(OR C6)；或者，两个独立的R C4与相连的原子一起形成
    Figure PCTCN2022099809-appb-100027
    R C5、R C6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-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；
    优选地，
    每个R C1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-OR C2、-C 0～4亚烷基-S(O) 2R C2、-C 0～4亚烷基-NR C2R C3、-C 0～4亚烷基-(3～6元碳环基)、-C 0～4亚烷基-(4～6元杂环烷基)、-C 0～4亚烷基-(6元芳环)、-C 0～4亚烷基-(5～6元芳杂环)；其中，亚烷基、碳环基、杂环烷基、芳环、芳杂环任选被一个、两个、三个或四个独立的R C4取代；
    R C2、R C3分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；
    每个R C4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-OR C5、-C 0～4亚烷基-S(O) 2R C5、-C 0～4亚烷基-NR C5R C6；或者，两个独立的R C4与相连的原子一起形成
    Figure PCTCN2022099809-appb-100028
    Figure PCTCN2022099809-appb-100029
    R C5、R C6分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基。
  7. 根据权利要求6所述的式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，其中，
    B环选自
    Figure PCTCN2022099809-appb-100030
    Figure PCTCN2022099809-appb-100031
    每个R C1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、
    Figure PCTCN2022099809-appb-100032
    Figure PCTCN2022099809-appb-100033
  8. 根据权利要求1所述的式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，其中，式I所示的化合物如式IIc所示：
    Figure PCTCN2022099809-appb-100034
    其中，
    A环选自
    Figure PCTCN2022099809-appb-100035
    Figure PCTCN2022099809-appb-100036
    B环选自
    Figure PCTCN2022099809-appb-100037
    Figure PCTCN2022099809-appb-100038
    其中B环任选被一个、两个、三个或四个R B1取代；
    每个R B1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 B2、-C(O)R B2、-C(O)NR B2R B3、-NR B2R B3、-NR B2C(O)R B3；
    X 1、X 2、X 3、X 4分别独立选自N或CR C1；
    每个R C1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 C2、-C 0～4亚烷基-OC(O)R C2、-C 0～4亚烷基-SR C2、-C 0～4亚烷基-S(O) 2R C2、-C 0～4亚烷基-S(O)R C2、-C 0～4亚烷基-S(O) 2NR C2R C3、-C 0～4亚烷基-S(O)NR C2R C3、-C 0～4亚烷基-S(O)(NH)R C2、-C 0～4亚烷基-S(O)(NH)NR C2R C3、-C 0～4亚烷基-C(O)R C2、-C 0～4亚烷基-C(O)OR C2、-C 0～4亚烷基-C(O)NR C2R C3、-C 0～4亚烷基-NR C2R C3、-C 0～4亚烷基-NR C2C(O)R C3、-C 0～4亚烷基-NR C2S(O) 2R C3、-C 0～4亚烷基-NR C2S(O)R C3、-C 0～4亚烷基-P(O)R C2R C3、-C 0～4亚烷基-P(O)(OR C2)R C3、-C 0～4亚烷基-P(O)(OR C2)(OR C3)、-C 0～4亚烷基-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；其中，亚烷基、碳环基、杂环烷基、芳环、芳杂环任选被一个、两个、三个或四个独立的R C4取代；
    或者，两个独立的R C1与相连的原子一起形成5～8元碳环基、5～8元杂环烷基、苯环、5～6元芳杂环；其中，碳环基、杂环烷基、芳环、芳杂环任选被一个、两个、三个或四个独立的R C4取代；
    R C2、R C3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-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；
    每个R C4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 C5、-C 0～4亚烷基-OC(O)R C5、-C 0～4亚烷基-SR C5、-C 0～4亚烷基-S(O) 2R C5、-C 0～4亚烷基-S(O)R C5、-C 0～4亚烷基-S(O) 2NR C5R C6、-C 0～4亚烷基-S(O)NR C5R C6、-C 0～4亚烷基-S(O)(NH)R C5、-C 0～4亚烷基-S(O)(NH)NR C5R C6、-C 0～4亚烷基-C(O)R C5、-C 0～4亚烷基-C(O)OR C5、-C 0～4亚烷基-C(O)NR C5R C6、-C 0～4亚烷基-NR C5R C6、-C 0～4亚烷基-NR C5C(O)R C6、-C 0～4亚烷基-NR C5S(O) 2R C6、-C 0～4亚烷基-NR C5S(O)R C6、-C 0～4亚烷基-P(O)R C5R C6、-C 0～4亚烷基-P(O)(OR C5)R C6、-C 0～4亚烷基-P(O)(OR C5)(OR C6)；或者，两个独立的R C4与相连的原子一起形成
    Figure PCTCN2022099809-appb-100039
    R C5、R C6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-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环)、-C 0～4亚烷基-(5～10元芳杂环)；
    优选地，
    每个R C1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-OR C2、-C 0～4亚烷基-S(O) 2R C2、-C 0～4亚烷基-NR C2R C3、-C 0～4亚烷基-(3～6元碳环基)、-C 0～4亚烷基-(4～6元杂环烷基)、-C 0～4亚烷基-(6元芳环)、-C 0～4亚烷基-(5～6元芳杂环)；其中，亚烷基、碳环基、杂环烷基、芳环、芳杂环任选被一个、两个、三个或四个独立的R C4取代；
    R C2、R C3分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基；
    每个R C4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-OR C5、-C 0～4亚烷基-S(O) 2R C5、-C 0～4亚烷基-NR C5R C6；或者，两个独立的R C4与相连的原子一起形成
    Figure PCTCN2022099809-appb-100040
    Figure PCTCN2022099809-appb-100041
    R C5、R C6分别独立选自氢、-C 1～6烷基、卤素取代的-C 1～6烷基。
  9. 根据权利要求8所述的式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，其中，
    B环选自
    Figure PCTCN2022099809-appb-100042
    Figure PCTCN2022099809-appb-100043
    每个R C1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、
    Figure PCTCN2022099809-appb-100044
    Figure PCTCN2022099809-appb-100045
  10. 根据权利要求1-9任一项所述的式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，其中，
    A环选自
    Figure PCTCN2022099809-appb-100046
    B环选自
    Figure PCTCN2022099809-appb-100047
    Figure PCTCN2022099809-appb-100048
    R 1和R 2与相连的原子一起形成
    Figure PCTCN2022099809-appb-100049
    X 1、X 2、X 3、X 4分别独立选自N或CR C1；
    Y选自S或NR C1；
    CR C1选自CH、C(C 1～4烷基)、C(C 1～4亚烷基-OR C2)，其中，所述亚烷基任选被一个或两个独立的R C4取代；R C2选自氢、-C 1～4烷基；每个R C4分别独立选自氢、-C 1～4烷基；
    NR C1选自NH、N(C 1～4烷基)、N(C 1～4亚烷基-S(O) 2R C2)，其中，所述亚烷基任选被一个或两个独立的R C4取代；R C2选自氢、-C 1～4烷基；每个R C4分别独立选自氢、-C 1～4烷基；
    优选地，
    A环为
    Figure PCTCN2022099809-appb-100050
    B环选自
    Figure PCTCN2022099809-appb-100051
    R 1和R 2与相连的原子一起形成
    Figure PCTCN2022099809-appb-100052
    X 1、X 2、X 3、X 4分别独立选自N或CR C1；
    Y选自S或NR C1；
    CR C1选自CH、C(C 1～3烷基)、C(C 1～3亚烷基-OR C2)，其中，所述亚烷基任选被一个或两个独立的R C4取代；R C2选自氢；每个R C4分别独立选自氢、-C 1～3烷基；
    NR C1选自NH、N(C 1～3烷基)、N(C 1～3亚烷基-S(O) 2R C2)，其中，所述亚烷基任选被一个或两个独立的R C4取代；R C2选自-C 1～3烷基；每个R C4分别独立选自氢、-C 1～3烷基；
    更优选地，
    A环为
    Figure PCTCN2022099809-appb-100053
    B环选自
    Figure PCTCN2022099809-appb-100054
    R 1和R 2与相连的原子一起形成
    Figure PCTCN2022099809-appb-100055
    Figure PCTCN2022099809-appb-100056
  11. 根据权利要求1-10任一项所述的式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，其中，式I所示的化合物为：
    Figure PCTCN2022099809-appb-100057
    Figure PCTCN2022099809-appb-100058
    Figure PCTCN2022099809-appb-100059
    Figure PCTCN2022099809-appb-100060
    Figure PCTCN2022099809-appb-100061
    Figure PCTCN2022099809-appb-100062
  12. 用作ATR抑制剂的权利要求1-11任一项所述的式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。
  13. 用于治疗或改善癌症的权利要求1-11任一项所述的式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；优选地，所述癌症选自结肠癌、直肠癌、胃癌、食道癌、原发性腹膜癌、肾上腺皮质癌、肾透明细胞癌、前列腺癌、膀胱尿路上皮癌、卵巢癌、乳腺癌、子宫内膜癌、输卵管癌、非小细胞肺癌或小细胞肺癌。
  14. 一种药物组合物，包括权利要求1-11任一项所述的式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。
  15. 根据权利要求14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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