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WO2023232069A1 - 一种氮杂喹啉酮类衍生物、其制备方法及用途 - Google Patents

一种氮杂喹啉酮类衍生物、其制备方法及用途 Download PDF

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Publication number
WO2023232069A1
WO2023232069A1 PCT/CN2023/097403 CN2023097403W WO2023232069A1 WO 2023232069 A1 WO2023232069 A1 WO 2023232069A1 CN 2023097403 W CN2023097403 W CN 2023097403W WO 2023232069 A1 WO2023232069 A1 WO 2023232069A1
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alkyl
methyl
compound
cyano
ethyl
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English (en)
French (fr)
Inventor
宋立强
王琼
满懿
孙玲
张伊
向永哲
李莉
陈洪
王颖
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Chengdu Easton Biopharmaceuticals Co Ltd
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Chengdu Easton Biopharmaceuticals Co Ltd
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Priority to US18/870,833 priority Critical patent/US20250346573A1/en
Priority to EP23815246.6A priority patent/EP4534533A1/en
Priority to JP2024570886A priority patent/JP2025519219A/ja
Priority to CN202380013861.0A priority patent/CN118076597A/zh
Publication of WO2023232069A1 publication Critical patent/WO2023232069A1/zh
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    • C—CHEMISTRY; METALLURGY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present application relates to an azaquinolinone compound as an enzyme inhibitor of the poly(ADP-ribose) polymerase (PARP) family and its pharmaceutically acceptable salts, stereoisomers and pharmaceutical compositions thereof, as well as Preparation methods and uses.
  • PARP poly(ADP-ribose) polymerase
  • PARP1 and PARP2 bind to DNA damage sites and catalyze the synthesis of poly-ADP ribose chains on protein substrates, recruit other DNA repair proteins to the damage site to jointly repair DNA damage, and trigger PARP1/2 at the same time Released from DNA.
  • PARP inhibitors "trap" PARP1/2 on DNA by binding to the catalytic site, causing PARP1/2 to be unable to detach from the DNA damage site, thereby inducing DNA replication fork stalling and DNA replication failing to proceed smoothly. At this point, cells usually repair this error through homologous repeat repair (HRR). Proteins such as BRCA1/2 play an important role in the HRR process. In cells with BRCA mutations, HRR function is dysfunctional, and the presence of PARP inhibitors will prevent DNA damage repair and lead to cell death.
  • HRR homologous repeat repair
  • Olaparib is the world's first approved PARP inhibitor developed by AstraZeneca and has been approved by the FDA for the treatment of multiple cancers. Since then, rucaparib, niraparib and talazoparib have also been approved for marketing; at the same time, there are several inhibitors in the clinical stage. Although PARP inhibitors have shown excellent clinical efficacy in BRCA-deficient patients, these compounds, whether used as single agents or in combination therapy, exhibit significant hematological toxicities, including anemia, neutropenia, and thrombocytopenia. Disease, etc. Hematological toxicity limits the use of first-generation PARP inhibitors, requiring clinical dose reduction, suspension of administration, or discontinuation of medication.
  • the purpose of this application is to provide an azaquinolinone compound and its pharmaceutically acceptable salts and stereoisomers to screen out the effectiveness, safety and selectivity.
  • Compounds used as PARP1 inhibitors with excellent properties.
  • the application provides a compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof, wherein the compound has the structure of Formula (I):
  • X is selected from N, CH or CR a , where R a is selected from halogen, C 1-4 alkyl, C 3-6 cycloalkyl, -O-(C 1-4 alkyl) or halogenated C 1-4 alkyl;
  • Y is selected from N, CH or CR b , wherein R b is selected from halogen, cyano, C 1-4 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl or -ORz , wherein the C 1-4 alkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl is unsubstituted or each is independently substituted by one or more selected from fluorine, cyano, hydroxyl , C 1-4 alkyl or -O-(C 1-4 alkyl) substituent substitution;
  • the conditions are: when X is selected from N or CH, Y is selected from CR b ;
  • Y is selected from N, CH or CR b ;
  • R 1 is selected from hydrogen, halogen, cyano, C 1-4 alkyl, -O-(C 1-4 alkyl), -O-(halo C 1-4 alkyl) or halo C 1-4 alkyl;
  • R 2 is selected from hydrogen, F, Cl, Br, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, -O-(C 1-4 alkyl) or halo C 1-4 alkyl ;
  • R 3 is selected from cyano, C 1-4 alkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl, wherein said C 1-4 alkyl, C 3-6 cycloalkyl or 4-
  • the 6-membered heterocyclyl group is unsubstituted or each is independently substituted by one or more members selected from F, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl, -O -(C 1-4 alkyl) or halogenated C 1-4 alkyl substituent substitution;
  • Q is selected from N or CR c , wherein R c is selected from F, hydroxyl, cyano, C 1-4 alkyl, -O-(C 1-4 alkyl) or halo C 1-4 alkyl;
  • R 4 and R 5 are each independently selected from hydrogen or C 1-4 alkyl at each occurrence, or R 4 and R 5 are connected to each other to form a ring;
  • n 1, 2 or 3.
  • Each occurrence of Rz is independently selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl, wherein said C 1-4 alkyl, C 3-
  • the 6- cycloalkyl or 4-6-membered heterocyclyl is unsubstituted or each is independently substituted by one or more selected from F, cyano, hydroxyl, C 1-4 alkyl, -O-(C 1-4 alkyl group) or fluorinated C 1-4 alkyl substituent.
  • _ -4 alkyl In certain embodiments , _ -4 alkyl
  • R a is selected from F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, -OMe, -CF 3 , -CHF 2 or -CH 2 F; more Preferably, R a is selected from F, Cl, Br, methyl, cyclopropyl, -OMe, -CHF 2 or -CH 2 F;
  • Y is selected from N, CH or CR b , wherein R b is selected from F, Cl, Br, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, oxa Cyclohexyl or -ORz , wherein the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, oxetanyl is unsubstituted or each is independently substituted by one or more Substituted with a substituent selected from fluorine, cyano, hydroxyl, methyl or -OMe;
  • R b is selected from F, Cl, Br, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, or -OR z , wherein The methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl groups are unsubstituted or each is independently substituted by one or two substituents selected from fluorine, cyano, hydroxyl, or methyl;
  • the conditions are: when X is selected from N or CH, Y is selected from CR b ;
  • Y is selected from N, CH or CR b .
  • R is selected from hydrogen, F, Cl, Br, cyano, methyl, ethyl, isopropyl, -OMe, -O-(fluoroC 1-4 alkyl), or fluoro Generation C 1-4 alkyl;
  • R1 is selected from hydrogen, F, Cl, methyl, -OMe, -CHF2 , or -CH2F .
  • R is selected from hydrogen, F, Cl, Br, cyano, methyl, ethyl, cyclopropyl, -OMe, or fluoroC 1-4 alkyl;
  • R2 is selected from hydrogen, F, Cl, Br, methyl, cyclopropyl, -OMe, -CHF2, or -CH2F .
  • R is selected from cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, or oxetanyl, wherein said methyl, ethyl, isopropyl , cyclopropyl, cyclobutyl or oxetanyl is unsubstituted or each is independently substituted by one or more selected from F, cyano, methyl, cyclopropyl, -OMe or fluoro C 1-4 Alkyl substituent substitution;
  • R3 is selected from cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl, wherein said methyl, ethyl, isopropyl group, cyclopropyl, cyclobutyl or oxetanyl is unsubstituted or each independently substituted by one or two substituents selected from F, cyano, -OMe, -CHF 2 or -CH 2 F .
  • Q is selected from N or CR c , wherein R c is selected from F, hydroxy, cyano, methyl, ethyl, -OMe or fluoroC 1-4 alkyl;
  • Q is selected from N or CR c , wherein R c is selected from F, hydroxy, cyano, methyl, -OMe, -CHF 2 or -CH 2 F;
  • Q is selected from N or CRc , wherein Rc is selected from F, hydroxyl, -OMe or methyl.
  • R 4 and R 5 are each independently selected from hydrogen or methyl or ethyl at each occurrence, or R 4 and R 5 are connected to each other to form a ring;
  • R 4 and R 5 are each independently selected from hydrogen or methyl at each occurrence, or R 4 and R 5 are interconnected to form ring, form
  • each occurrence of R 4 and R 5 is independently selected from hydrogen or methyl, or R 4 and R 5 are connected to each other to form a ring, forming
  • the base or oxetanyl group is unsubstituted or each is independently substituted by one or two substituents selected from F, hydroxyl or -OMe;
  • each occurrence of Rz is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, or oxanyl , wherein the methyl, ethyl, cyclopropyl, cyclobutyl or oxanyl group is unsubstituted or each is independently substituted by one or more selected from the group consisting of fluorine, cyano, hydroxyl, -OMe, oxa cyclobutyl or methyl substituent substitution;
  • each occurrence of Rz is independently selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, oxetanyl, oxetanyl, methylene- Oxetanyl, -CF 3 , -CF 2 H or -CH 2 F.
  • n 1 or 2.
  • the application provides a compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof, wherein the compound has the structure of Formula (II):
  • R 1 is selected from hydrogen, F, Cl, Br, cyano, methyl, ethyl, isopropyl or -OMe;
  • R 2 is selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, -O-(C 1-4 alkyl) or fluorinated C 1-4 alkyl;
  • R 3 is selected from cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl, wherein said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl
  • the base or oxetanyl group is unsubstituted or each independently substituted by one or more substituents selected from F, cyano, methyl, cyclopropyl or -OMe;
  • R b is selected from F, Cl, Br, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl or -OR z , wherein the C 1-4 alkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl is unsubstituted or each is independently substituted by one or more selected from fluorine, cyano, hydroxyl, C 1-4 alkyl or -O-(C 1 -4 alkyl) substituent substitution;
  • R 4 and R 5 are each independently selected from hydrogen, C 1-4 alkyl, or R 4 and R 5 are connected to each other to form a ring.
  • n 1, 2 or 3;
  • Each occurrence of Rz is independently selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl, wherein said C 1-4 alkyl, C 3-
  • the 6- cycloalkyl or 4-6-membered heterocyclyl is unsubstituted or each is independently substituted by one or more selected from F, cyano, hydroxyl, C 1-4 alkyl, -O-(C 1-4 alkyl group), 4-6 membered heterocyclic group or fluorinated C 1-4 alkyl substituent.
  • the application provides a compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof, wherein the compound has the structure of Formula (III):
  • R 1 is selected from hydrogen, F, Cl, methyl, -OMe, -CHF 2 or -CH 2 F;
  • R 2 is selected from hydrogen, halogen, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, -O-(C 1-4 alkyl) or halogenated C 1-4 alkyl;
  • R 3 is selected from cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl, wherein said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl
  • the base or oxetanyl group is unsubstituted or each is independently substituted by one or two substituents selected from F, cyano, methyl, cyclopropyl or -OMe;
  • R b is selected from F, Cl, Br, cyano, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl or -OR z , wherein said methyl, ethyl, Isopropyl, cyclopropyl, and cyclobutyl are unsubstituted or each is independently substituted by one or two substituents selected from fluorine, cyano, hydroxyl, or methyl;
  • R 4 and R 5 are each independently selected from hydrogen, C 1-4 alkyl, or R 4 and R 5 are connected to each other to form a ring.
  • R 7 is selected from hydrogen, F, Cl, Br, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclyl or -OR z , wherein the C 1-4 alkyl group, C 3-6 cycloalkyl or 4-6 membered heterocyclyl is unsubstituted or each is independently selected from one or more F, cyano, hydroxyl, C 1-4 alkyl, -O-( C 1-4 alkyl) or halogenated C 1-4 alkyl substituent substitution;
  • n 1 or 2;
  • Each occurrence of Rz is independently selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl, wherein said C 1-4 alkyl, C 3-
  • the 6- cycloalkyl or 4-6-membered heterocyclyl is unsubstituted or each is independently substituted by one or more selected from F, cyano, hydroxyl, C 1-4 alkyl, -O-(C 1-4 alkyl group), 4-6 membered heterocyclic group or fluorinated C 1-4 alkyl substituent.
  • the application provides a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof, wherein the compound has the structure of Formula (IV):
  • R 2 is selected from hydrogen, F, Cl, Br, cyano, C 1-4 alkyl, C 3-6 cycloalkyl, -O-(C 1-4 alkyl) or fluorinated C 1-4 alkyl ;
  • R 3 is selected from cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl or 4-6 membered heterocyclyl, wherein said methyl, ethyl, n-propyl, Isopropyl, cyclopropyl, cyclobutyl or 4-6 membered heterocyclyl is unsubstituted or each is independently substituted by one or more substituents of F, cyano, methyl or -OMe;
  • R b is selected from F, Cl, Br, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl or -OR z , wherein said methyl , ethyl, isopropyl, cyclopropyl, and cyclobutyl are unsubstituted or each is independently substituted by one or two substituents selected from fluorine, cyano, hydroxyl, or methyl;
  • R 4 and R 5 are each independently selected from hydrogen, methyl or ethyl at each occurrence, or R 4 and R 5 are connected to each other to form a ring, forming
  • R 7 is selected from hydrogen, halogen, cyano, -OR z , C 1-4 alkyl, C 3-6 cycloalkyl or 4-6 membered heterocyclyl, wherein the C 1-4 alkyl, C 3 -6 cycloalkyl or 4-6 membered heterocyclyl is unsubstituted or each is independently substituted by one or more substituents selected from F, hydroxyl, methyl, ethyl, methoxy or ethoxy;
  • n 1 or 2;
  • Each occurrence of Rz is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, or oxolanyl, where The methyl, ethyl, n-propyl, isopropyl, cyclopropyl or cyclobutyl groups are unsubstituted or each is independently substituted by one or more selected from F, cyano group, hydroxyl, methyl, ethyl, Substitution with methoxy, ethoxy, oxetanyl or fluoromethyl substituents.
  • the application provides a compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof, wherein the compound is selected from:
  • the present application also relates to a pharmaceutical composition, which composition includes: an effective dose of any compound of the present application or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide, and pharmaceutically acceptable carriers and/or excipients; or further include one or more other therapeutic agents.
  • the present application provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, N-oxide or pharmaceutical composition of the compound of the present application in the preparation of a PARP1 preparation. uses in.
  • the application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer or N-oxide thereof in the preparation of a medicament for the treatment of cancer,
  • the cancer is a BRCA gene-deficient tumor mediated by PARP1.
  • the present application provides compounds of formula (I) or pharmaceutically acceptable salts, stereoisomers, tautomers or N-oxides thereof in the preparation of compounds for the treatment of cancer or other PARP1-related diseases.
  • the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, colorectal cancer, bladder cancer, gastrointestinal cancer, lung cancer or hematological cancer.
  • alkylene refers to a saturated divalent hydrocarbon radical, preferably a saturated divalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
  • an alkyl group has 1 to 12, such as 1 to 6 carbon atoms.
  • C 1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl base, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, new pentyl or n-hexyl), optionally substituted by 1 or more (such as 1 to 3) suitable substituents such as halogen (in which case the group is referred to as "haloalkyl”) (e.g.
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
  • alkenyl means a linear or branched monovalent hydrocarbon radical containing one double bond and having 2 to 5 carbon atoms (C 2-5 alkenyl”).
  • alkenyl For example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-alkenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • the compounds may exist in pure E (enthafen) form, pure Z (zusammen) form, or any mixture thereof.
  • alkynyl means a linear or branched monovalent hydrocarbon group containing one triple bond and having 2-5 carbon atoms (C 2-5 alkynyl).
  • the alkynyl group is, for example, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl , 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2-methyl-2-propynyl and 4-methyl-3-pentynyl.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, cyclononyl, or bicyclo, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, etc.), which is optionally substituted by one or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, cyclononyl, or bicyclo
  • the cycloalkyl group has 3 to 15 carbon atoms.
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) of 3 to 6 ring carbon atoms, It is optionally substituted by 1 or more (such as to 3) suitable substituents, for example methyl-substituted cyclopropyl.
  • cycloalkylene and cycloalkyl refer to saturated (i.e. , “cycloalkylene” and “cycloalkyl”) or unsaturated (i.e., having one or more double bonds and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings, which include but are not limited to ( (ylidene)cyclopropyl, (ylidene)cyclobutyl, (ylidene)cyclopentyl, (ylidene)cyclohexyl, (ylidene)cycloheptyl, (ylidene)cyclooctyl, (ylidene)cyclononyl, (ylidene) Cyclohexenyl etc.
  • heterocyclyl and “heterocyclylene” refer to having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring atoms, wherein at least One ring atom is a heteroatom selected from N, O, and S and the remaining ring atoms are saturated with C (i.e., heterocycloalkyl) or partially unsaturated (i.e., with one or more double bonds within the ring and/or triple bond) cyclic group.
  • C i.e., heterocycloalkyl
  • partially unsaturated i.e., with one or more double bonds within the ring and/or triple bond
  • a “3-10 membered (heterocyclylene) group” has 2-9 (such as 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and is independently selected from N, O and one or more (eg 1, 2, 3 or 4) heteroatoms of S and S. Saturated or partially unsaturated ()heterocyclyl groups.
  • heterocyclylene and heterocyclylene include, but are not limited to: ()oxirylidene, ()aziridinyl, (azetidinyl), ()oxetinyl Butyl (oxetanyl), (ylidene) tetrahydrofuranyl, (ylidene) dioxolinyl (dioxolinyl), (ylidene) pyrrolidinyl, (ylidene) pyrrolidonyl, (ylidene) imidazolidinyl, (ylidene) pyrrolidinyl Azolidinyl, (ylidene) pyrrolelinyl, (ylidene) tetrahydropyranyl, (ylidene) piperidyl, (ylidene) morpholinyl, (ylidene) dithianyl (dithianyl), (ylidene) morpholinyl Linyl, (ylidene)
  • halo or halogen group is defined to include F, Cl, Br or I.
  • substituted means that one or more (e.g., one, two, three or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is present in the case of normal valence and the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • each substituent is selected independently of the other.
  • each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.
  • the point of attachment of a substituent may be from any suitable position on the substituent.
  • the present application also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of the present application except that one or more atoms are substituted with the same atomic number but an atomic mass or mass number different from the atomic mass that predominates in nature. or atomic substitution of mass number.
  • isotopes suitable for inclusion in the compounds of the present application include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g. , 11C , 13C , and 14C ) ; Isotopes of chlorine (e.g. 36 CI); Isotopes of fluorine (e.g.
  • Isotopes of iodine e.g. 123 I and 125 I
  • Isotopes of nitrogen e.g. 13 N and 15 N
  • Isotopes of oxygen e.g. 15 O, 17 O and 18 O
  • isotopes of phosphorus such as 32 P
  • isotopes of sulfur such as 35 S.
  • stereoisomer means an isomer formed due to at least one asymmetric center.
  • compounds with one or more (e.g., one, two, three, or four) asymmetric centers they can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Enantiomers. Certain individual molecules may also exist as geometric isomers (cis/trans). Similarly, compounds of the present application may exist as mixtures of two or more structurally distinct forms in rapid equilibrium (commonly referred to as tautomers).
  • tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. wait. It is to be understood that the scope of this application encompasses all such products in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99 %) isomers or mixtures thereof.
  • Solid lines may be used in this article solid wedge or virtual wedge Depict the carbon-carbon bonds of the compounds of this application.
  • the use of a solid line to depict a bond to an asymmetric carbon atom indicates that all possible stereoisomers at that carbon atom are included (eg, a specific enantiomer, a racemic mixture, etc.).
  • the compounds of the present application are intended to exist as stereoisomers (which includes cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, exist in the form of geometric isomers, rotamers, atropisomers and mixtures thereof).
  • the compounds of the present application may exhibit more than one type of isomerism and consist of mixtures thereof (eg, racemic mixtures and pairs of diastereoisomers).
  • This application encompasses all possible crystalline forms or polymorphs of the compounds of this application, which may be a single polymorph or a mixture of more than one polymorph in any proportion.
  • compositions of the present application may exist in free form for use in therapy, or as pharmaceutically acceptable derivatives thereof, as appropriate.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs that are administered to a patient in need thereof. After administration, the compound of the present application or its metabolites or residues can be provided directly or indirectly. Therefore, when reference is made herein to "a compound of the present application", it is also intended to encompass the various derivative forms of the compound described above.
  • Pharmaceutically acceptable salts of the compounds of the present application include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include hydrochloride, acetate, aspartate, benzoate, bicarbonate/carbonate, glucoheptonate, gluconate, nitrate, orotate, palmitic acid Salt and other similar salts.
  • Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, magnesium salts and other similar salts.
  • esters means esters derived from compounds of each general formula herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the present invention). compound).
  • the compounds of the present application may themselves be esters.
  • the compounds of the present application may exist in the form of solvates (preferably hydrates), in which the compounds of the present application comprise a polar solvent as a structural element of the crystal lattice of said compound, in particular such as water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of said compound, in particular such as water, methanol or ethanol.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • nitrogen-containing heterocycles are capable of forming N-oxides; those skilled in the art will recognize that nitrogen-containing heterocycles are capable of forming N-oxides. Nitrogen-containing heterocycle. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for the preparation of N-oxides of heterocyclic and tertiary amines are well known to those skilled in the art.
  • peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA)
  • hydrogen peroxide alkyl hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxirane such as Dimethyldiethylene oxide is used to oxidize heterocyclic rings and tertiary gums.
  • metabolites of the compounds of this application ie, substances formed in the body upon administration of the compounds of this application. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound.
  • the present application includes metabolites of the compounds of the present application, including compounds prepared by contacting a compound of the present application with a mammal for a time sufficient to produce a metabolite thereof.
  • the present application further includes within its scope prodrugs of the compounds of the present application, which are certain derivatives of the compounds of the present application which may themselves have little or no pharmacological activity when administered into or onto the body. can be converted into compounds of the present application having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compound that are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems, Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). Prodrugs of the present application may be known to those skilled in the art, for example Certain moieties are prepared as "pro-moiety" (e.g. described in “Design of Prorugs", H. Bundgaard (Elsevier, 1985)) in place of appropriate functional groups present in the compounds of the present application.
  • This application also encompasses compounds of this application that contain protecting groups.
  • protecting groups In any process for preparing the compounds of the present application, it may be necessary and/or desirable to protect sensitive or reactive groups on any relevant molecules, thereby forming a chemically protected form of the compounds of the present application. This can be accomplished by conventional protecting groups, for example, those described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. The protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
  • the structure of the compound is determined by mass spectrometry (MS) or nuclear magnetic resonance ( 1 HNMR).
  • Mass spectrometry was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX).
  • the thin layer of silica gel uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel sheet.
  • N2 protection or "nitrogen atmosphere” refers to, for example, connecting the reaction flask to a 1 L nitrogen balloon.
  • the solution mentioned in the reaction in this application is an aqueous solution.
  • room temperature in this application refers to a temperature between 10°C and 25°C.
  • Step 1 Preparation of compound 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (Int-1b)
  • Step 2 Preparation of compound 4-(6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (Int-1c)
  • Step 1 Compound 3-(6-(methoxycarbonyl)-2-methylpyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl Preparation of ester (Int-A2b)
  • a crude product of compound Int-A2b was synthesized using a method similar to that described in the first step of Example A1, except that compound Int-A2a was used instead of compound Int-1a in the first step of Example A1.
  • the obtained crude product was purified by column chromatography to obtain the title compound Int-A2b (1.90 g, yield: 79%).
  • Step 2 Compound 3-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert. Preparation of butyl ester (Int-A2c)
  • Step 3 Preparation of compound 5-(3,6-diazabicyclo[3.1.1]hept-3-yl)-N,6-dimethylpyridinamide (Int-A2)
  • a crude product of compound Int-A2 was synthesized using a method similar to that described in Example A1, except that compound Int-A2c was used instead of compound Int-1c in the third step of Example A1. Add diethyl ether to the crude product to dilute it. If a solid precipitates out of the system, filter and wash with diethyl ether. The solid was collected and dried under vacuum to obtain the hydrochloride salt of the title compound Int-A2 (1.24 g, two-step yield: 92%).
  • Step 1 Compound (1R,4R)-5-(2-methyl-6-(methylcarbamoyl)pyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane -Preparation of 2-carboxylic acid tert-butyl ester (Int-A3b)
  • the aqueous phase is extracted three times with ethyl acetate.
  • the organic phases are combined, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate is concentrated to obtain a crude compound.
  • the obtained crude compound was purified by column chromatography to obtain the title compound Int-A3b (3.8 g, yield 84%).
  • Step 2 Preparation of compound 5-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)-N,6-dimethylpyridinamide (Int-A3)
  • Example A1 Referring to the synthesis method in Example A1, A2 or A3, replace the raw materials and amino compounds in the first step reaction with appropriate aryl halides and amine compounds, and use similar reaction conditions to synthesize the following intermediate compounds: Hydrochloride.
  • Step 1 Preparation of compound 3-(5-bromo-6-methylpyridin-2-yl)oxetane-3-ol (Int-A9c)
  • Step 2 Preparation of compound 3-(6-methyl-5-(piperazin-1-yl)pyridin-2-yl)oxetan-3-ol (Int-A9)
  • Step 2 Preparation of compound 4-(2-(methylcarbamoyl)thiazol-5-yl)piperazine-1-carboxylate tert-butyl ester (Int-A13c)
  • Steps 1 to 3 Preparation of intermediate N-methyl-2-(piperazin-1-yl)thiazole-5-amide hydrochloride (Int-A14)
  • Steps 1 to 3 Preparation of intermediate N-cyclopropyl-5-(piperazin-1-yl)pyridinecarboxamide hydrochloride (Int-A15)
  • a crude product of compound Int-A15 was synthesized using a method similar to that described in the first to third steps in Example A1, except that the compound cyclopropylamine was used instead of the 40% aqueous methylamine solution in the second step of Example A1.
  • the crude product obtained was used directly in the next reaction without further purification.
  • Step 1 Preparation of compound 3-bromo-6-(difluoromethyl)-2-methylpyridine (Int-A17b)
  • Step 2 to Step 3 Preparation of intermediate 1-(6-(difluoromethyl)-2-methylpyridin-3-yl)piperazine (Int-A17) hydrochloride
  • Step 1 Preparation of compound 4-(4-cyano-3-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester
  • Step 1 Preparation of compound 4-(5-cyanothiazol-2-yl)piperazine-1-carboxylic acid tert-butyl ester (Int-A21b)
  • a crude hydrochloride salt of the title compound Int-A21 was synthesized using a method similar to that described in the second step of Example A10, except that compound Int-A21b was used instead of Int-A20b in the second step of Example A10. The crude product obtained was used directly in the next reaction without further purification.
  • Step 1 Preparation of compound 5-bromo-N-(2-methoxyethyl)-6-methylpyridinecarboxamide (Int-A22b)
  • Step 2 to Step 3 Preparation of intermediate N-(2-methoxyethyl)-6-methyl-5-(piperazin-1-yl)pyridinecarboxamide (Int-A22)
  • Step 1 Preparation of compound (4-bromo-2-fluoro-6-nitrophenyl)alanine methyl ester (Int-2b)
  • Step 5 Preparation of compound 8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carbaldehyde (Int-2f)
  • Step 7 Preparation of compound 7-(bromomethyl)-5-fluoro-3-methylquinoxalin-2(1H)-one (Int-2)
  • Step 1 Preparation of compound (4-bromo-2-fluoro-6-nitrophenyl)alanine methyl ester (Int-2b)
  • Step 2 Preparation of compound 3-bromo-4-(1-methoxy-1-oxopropan-2-yl)amino-5-nitrobenzoic acid methyl ester (Int-3c)
  • Steps 3 to 4 Preparation of compound 8-bromo-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid methyl ester (Int-3e)
  • Dissolve compound (Int-3e) 400mg, 1.34mmol) in DCM (10mL). After the reaction solution drops to 0°C, add DIBAL-H (1M in hexane, 4.04mL, 4.04mmol) to the reaction system and complete the addition. , react overnight at room temperature. When the reaction is complete, add saturated potassium sodium tartrate aqueous solution (40 mL) to the reaction system at 0°C to quench the reaction, add methylene chloride, separate the liquids, extract the aqueous phase three times with methylene chloride, combine the organic phases, and add anhydrous sodium sulfate. Dry, filter, and concentrate the filtrate to obtain a crude compound. The obtained crude product is purified by a silica gel column to obtain the title compound (Int-3f) (220 mg, yield 61%).
  • the crude product of compound Int-3 was synthesized using a method similar to that described in the seventh step of Example B, except that compound Int-3f was used instead of compound Int-2g in the seventh step of Example B.
  • the obtained crude product was purified on silica gel plate to obtain the title compound Int-3 (120 mg, yield 31%).
  • Step 1 Preparation of compound 2,3-difluoro-4-((1-methoxy-1-oxoprop-2-yl)amino)-5-nitrobenzoic acid methyl ester (Int-4b)
  • Step 2 Preparation of compound 7,8-difluoro-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid methyl ester (Int-4c)
  • Step 3 Preparation of compound 7,8-difluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid methyl ester (Int-4d)
  • Dissolve compound (Int-4d) (1.17g, 4.60mmol) in DCM (30mL). After cooling to 0°C in an ice-water bath, add DIBAL-H (1M in toluene, 13.8mL, 13.8mmol) to the reaction system. After that, keep stirring at 0°C.
  • Step 5 Preparation of compound 7-(bromomethyl)-5,6-difluoro-3-methylquinoxalin-2(1H)-one (Int-4)
  • Step 1 Preparation of compound (4-bromo-2-methyl-6-nitrophenyl)-L-alanine methyl ester (Int-5b)
  • Steps 1 to 3 Preparation of compound 2,7-dimethyl-3-oxo-3,4-dihydroquinoxaline-6-carboxylic acid methyl ester (Int-6d)
  • Step 4 to Step 5 Preparation of compound 7-(bromomethyl)-3,6-dimethylquinoxalin-2(1H)-one (Int-6)
  • a crude product of compound Int-6 was synthesized using a method similar to that described in the fourth to fifth steps of Embodiment D, except that compound Int-6d was used instead of compound Int-4d in the fourth step of Embodiment D.
  • the obtained crude product was purified by column chromatography to obtain the title compound Int-6 (101 mg, two-step yield: 41%).
  • Step one to step two Preparation of compound (S)-7-bromo-5-chloro-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (Int-9c)
  • a crude product of compound Int-9d was synthesized using a method similar to that described in the fourth step of Example B, Route 2, except that Compound Int-9c was used instead of Compound Int-2d in the fourth step of Example B, Route 2.
  • the obtained crude product was purified by column chromatography to obtain the title compound Int-9d (157 mg, three-step yield: 35%).
  • a crude product of compound Int-9e was synthesized using a method similar to that described in the third step of Example B, Route 2, except that Compound Int-9d was used instead of Compound Int-2c in the third step of Example B, Route 2.
  • the obtained crude product was purified by column chromatography to obtain the title compound Int-9e (53 mg, yield: 34%).
  • a crude product of compound Int-9 was synthesized using a method similar to that described in the fifth step of Example B, Route 2, except that Compound Int-9e was used instead of Compound Int-2g in the fifth step of Example B, Route 2.
  • the obtained crude product was purified by column chromatography to obtain the title compound Int-9 (64 mg, yield: 93%).
  • Step 1 5-(4-(8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)-N -Preparation of methylpyridinamide (1)
  • the crude product of Compound 2 was synthesized using a method similar to that described in Example 1, except that Compound Int-3 was used instead of Compound Int-2 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 2 (9.33 mg).
  • Example 3 Compound 5-(6-(8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-3,6-diaza Preparation of bicyclo[3.1.1]heptan-3-yl)-N,6-dimethylpyridinamide (3)
  • the crude product of compound 3 was synthesized using a method similar to that described in Example 1, except that compound Int-A2 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 3 (8.04 mg).
  • Example 4 Compound 5-((1S,4S)-5-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)- Preparation of 2,5-diazabicyclo[2.2.1]heptan-2-yl)-N,6-dimethylpyridinamide (4)
  • the crude product of compound 4 was synthesized using a method similar to that described in Example 1, except that compound Int-A4 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 4 (11.5 mg).
  • Example 5 Compound 5-(6-(8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-3,6-diaza Preparation of bicyclo[3.1.1]heptan-3-yl)-N-methylpyridinamide (5)
  • the crude product of compound 5 was synthesized using a method similar to that described in Example 1, except that compound Int-A6 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 5 (3.21 mg).
  • the crude product of compound 6 was synthesized using a method similar to that described in Example 1, except that compound Int-A7 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 6 (6.48 mg).
  • Example 7 Compound 6-chloro-5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazine- Preparation of 1-yl)-N-methylpyridinamide (7)
  • the crude product of compound 7 was synthesized using a method similar to that described in Example 1, except that compound Int-A8 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 7 (2.05 mg).
  • Example 8 Compound 5-(4-((7,8-difluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazine-1 Preparation of -yl)-N-methylpyridinamide (8)
  • the crude product of compound 8 was synthesized using a method similar to that described in Example 1, except that compound Int-4 was used instead of compound Int-2 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 8 (8.11 mg).
  • Compound Int-4 was used to replace compound Int-2 in Example 1, and compound Int-A7 was used to replace compound Int-1 in Example 1.
  • a method similar to that described in Example 1 was used to synthesize the crude product of compound 9. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 9 (26.62 mg).
  • Example 11 Compound 3-ethyl-5-fluoro-7-((4-(6-(3-hydroxyoxetan-3-yl)-2-methylpyridin-3-yl)piperazine Preparation of -1-yl)methyl)quinoxaline-2(1H)-one (11)
  • the crude product of Compound 11 was synthesized using a method similar to that described in Example 1, except that Compound Int-A9 was used instead of Compound Int-1 in Example 1, and Compound Int-7 was used instead of Compound Int-2 in Example 1. .
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 11 (6.30 mg).
  • Example 12 Compound 5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) Preparation of -6-methylpyridinenitrile (12)
  • the crude product of compound 12 was synthesized using a method similar to that described in Example 1, except that compound Int-A18 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 12 (45.17 mg).
  • Example 13 Compound 5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) Preparation of pyridine nitrile (13)
  • the crude product of compound 13 was synthesized using a method similar to that described in Example 1, except that compound Int-A19 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 13 (5.46 mg).
  • Example 14 Compound 5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) Preparation of -6-methoxy-N-methylpyridinamide (14)
  • the crude product of compound 14 was synthesized using a method similar to that described in Example 1, except that compound Int-A10 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 14 (66.65 mg).
  • Example 15 Compound 4-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) -Preparation of N-methylthiazole-2-carboxamide (15)
  • the crude product of compound 15 was synthesized using a method similar to that described in Example 1, except that compound Int-A12 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 15 (12.8 mg).
  • Example 16 Compound 5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) -Preparation of N-methylthiazole-2-carboxamide (16)
  • the crude product of compound 16 was synthesized using a method similar to that described in Example 1, except that compound Int-A13 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 16 (15.78 mg).
  • Example 17 Compound 2-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) -Preparation of N-methylthiazole-5-carboxamide (17)
  • the crude product of compound 17 was synthesized using a method similar to that described in Example 1, except that compound Int-A14 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 17 (15.78 mg).
  • the crude product of compound 18 was synthesized using a method similar to that described in Example 1, except that compound Int-A20 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 18 (5.92 mg).
  • the crude product of compound 19 was synthesized using a method similar to that described in Example 18, except that compound Int-5 was used instead of compound Int-2 in Example 18.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 19 (4.63 mg).
  • Example 20 Compound N-cyclopropyl-5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piper Preparation of oxazin-1-yl)pyridinecarboxamide (20)
  • the crude product of compound 20 was synthesized using a method similar to that described in Example 1, except that compound Int-A15 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 20 (1.29 mg).
  • Example 21 Compound 5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) Preparation of -N-(2-methoxyethyl)-6-methylpyridinecarboxamide (21)
  • the crude product of compound 21 was synthesized using a method similar to that described in Example 1, except that compound Int-A22 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 21 (4.0 mg).
  • Example 22 Compound 5-(4-((2,8-dimethyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)- Preparation of N-(2-methoxyethyl)-6-methylpyridinecarboxamide (22)
  • the crude product of compound 22 was synthesized using a method similar to that described in Example 21, except that compound Int-5 was used instead of compound Int-2 in Example 21.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 22 (10.0 mg).
  • Example 23 Compound 2-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) Preparation of thiazole-5-nitrile (23)
  • the crude product of compound 23 was synthesized using a method similar to that described in Example 1, except that compound Int-A21 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 23 (4.0 mg).
  • Example 24 Compound (S)-5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-2- Preparation of methylpiperazin-1-yl)-N-methylpyridinamide (24)
  • the crude product of compound 24 was synthesized using a method similar to that described in Example 1, except that compound Int-A11 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 24 (7.00 mg).
  • Example 25 Compound (R)-5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)-2- Preparation of methylpiperazin-1-yl)-N-methylpyridinamide (25)
  • the crude product of compound 25 was synthesized using a method similar to that described in Example 1, except that compound Int-A5 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 25 (3.66 mg).
  • the crude product of compound 26 was synthesized using a method similar to that described in Example 1, except that compound Int-A17 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 26 (12.62 mg).
  • Example 27 Compound 7-((4-(6-(difluoromethyl)pyridin-3-yl)piperazin-1-yl)methyl)-5-fluoro-3-methylquinoxaline-2 Preparation of (1H)-ketone (27)
  • the crude product of compound 27 was synthesized using a method similar to that described in Example 1, except that compound Int-A16 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 27 (50.20 mg).
  • Example 28 Compound N-(2,2-difluoroethyl)-5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxaline-6 Preparation of -methyl)piperazin-1-yl)-6-methylpyridinecarboxamide (28)
  • the crude product of compound 28 was synthesized using a method similar to that described in Example 1, except that compound Int-A23 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 28 (3.30 mg).
  • Example 29 Compound 5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) Preparation of -N-(2-fluoroethyl)-6-methylpyridinecarboxamide (29)
  • the crude product of compound 29 was synthesized using a method similar to that described in Example 1, except that compound Int-A24 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 29 (8.93 mg).
  • Example 30 Compound 5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) Preparation of -N-(2-fluoroethyl)-6-methylpyridinecarboxamide (30)
  • the crude product of compound 30 was synthesized using a method similar to that described in Example 29, except that compound Int-7 was used instead of compound Int-2 in Example 29.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 30 (9.83 mg).
  • Example 31 Compound 5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) Preparation of -N-(2-hydroxyethyl)-6-methylpyridinecarboxamide (31)
  • the crude product of compound 31 was synthesized using a method similar to that described in Example 30, except that compound Int-A26 was used instead of compound Int-A24 in Example 30.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 31 (5.80 mg).
  • Example 32 Compound 5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) Preparation of -N,6-dimethylpyridinecarboxamide (32)
  • the crude product of compound 32 was synthesized using a method similar to that described in Example 30, except that compound Int-A7 was used instead of compound Int-A24 in Example 30.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 32 (9.00 mg).
  • Example 33 Compound 5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) Preparation of -6-methyl-N-(oxetan-3-ylmethyl)pyridinecarboxamide (33)
  • the crude product of compound 33 was synthesized using a method similar to that described in Example 30, except that compound Int-A25 was used instead of compound Int-A24 in Example 30.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 33 (6.6 mg).
  • Example 34 Compound 5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) Preparation of -N-(2-methoxyethyl)-6-methylpyridinecarboxamide (34)
  • the crude product of compound 34 was synthesized using a method similar to that described in Example 30, except that compound Int-A22 was used instead of compound Int-A24 in Example 30.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 34 (13.70 mg).
  • Example 35 Compound 4-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) Preparation of -2-fluorobenzonitrile (35)
  • Example 30 A method similar to that described in Example 30 was used except that Compound Int-A20 was used instead of Compound Int-A24 in Example 30. Methods The crude product of compound 35 was synthesized. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 35 (5.60 mg).
  • Example 36 Compound 5-(4-((7,8-difluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazine-1 Preparation of -N-(2-methoxyethyl)-6-methylpyridinecarboxamide (36)
  • the crude product of compound 36 was synthesized using a method similar to that described in Example 8, except that compound Int-A22 was used instead of compound Int-1 in Example 8.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 36 (13.58 mg).
  • Example 37 Compound 6-chloro-5-(4-((7-methoxy-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piper Preparation of oxazin-1-yl)-N-methylpyridinecarboxamide (37)
  • the crude product of compound 37 was synthesized using a method similar to that described in Example 7, except that compound Int-8 was used instead of compound Int-2 in Example 7.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 37 (1.06 mg).
  • Example 38 Compound 5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) Preparation of -N,3-dimethylpyridinecarboxamide (38)
  • the crude product of compound 38 was synthesized using a method similar to that described in Example 1, except that compound Int-A36 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 38 (9.72 mg).
  • Example 39 Compound 3-fluoro-5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazine- Preparation of 1-yl)-N-methylpyridinecarboxamide (39)
  • the crude product of compound 39 was synthesized using a method similar to that described in Example 1, except that compound Int-A37 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 39 (2.81 mg).
  • Example 40 Compound 5-(4-((2,7-dimethyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)- Preparation of N,6-dimethylpyridinecarboxamide (40)
  • the crude product of compound 40 was synthesized using a method similar to that described in Example 6, except that compound Int-6 was used instead of compound Int-2 in Example 6.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 40 (1.35 mg).
  • Example 41 Compound 5-(4-((7-methoxy-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazine-1- Preparation of -N,6-dimethylpyridinecarboxamide (41)
  • the crude product of compound 41 was synthesized using a method similar to that described in Example 40, except that compound Int-8 was used instead of compound Int-6 in Example 40.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 41 (7.19 mg).
  • Example 42 Compound 5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) Preparation of -6-methyl-N-(oxetan-3-yl)pyridinecarboxamide (42)
  • Example 30 A method similar to that described in Example 30 was used except that compound Int-A30 was used instead of compound Int-A24 in Example 30. Methods The crude product of compound 42 was synthesized. The obtained crude product was purified by preparative silica gel plate to obtain the title compound 42 (8.23 mg).
  • Example 43 Compound N-cyclopropyl-5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piper Preparation of oxazin-1-yl)-6-methylpyridinecarboxamide (43)
  • the crude product of compound 43 was synthesized using a method similar to that described in Example 30, except that compound Int-A29 was used instead of compound Int-A24 in Example 30.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 43 (5.86 mg).
  • Example 44 Compound 5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) Preparation of -N-((1s,3s)-3-hydroxycyclobutyl)-6-methylpyridinecarboxamide (44)
  • the crude product of compound 44 was synthesized using a method similar to that described in Example 30, except that compound Int-A32 was used instead of compound Int-A24 in Example 30.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 44 (7.83 mg).
  • Example 45 Compound 5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) Preparation of -N-((1r,3r)-3-hydroxycyclobutyl)-6-methylpyridinecarboxamide (45)
  • the crude product of compound 45 was synthesized using a method similar to that described in Example 30, except that compound Int-A31 was used instead of compound Int-A24 in Example 30.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 45 (4.56 mg).
  • Example 46 Compound (R)-5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazine- Preparation of 1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)pyridinecarboxamide (46)
  • the crude product of compound 46 was synthesized using a method similar to that described in Example 1, except that compound Int-A33 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 46 (2.38 mg).
  • Example 47 Compound (R)-5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazine- Preparation of 1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)pyridinecarboxamide (47)
  • the crude product of compound 47 was synthesized using a method similar to that described in Example 1, except that compound Int-A34 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 47 (6.98 mg).
  • Example 48 Compound (R)-5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazine- Preparation of 1-yl)-N-(2-hydroxypropyl)-6-methylpyridinecarboxamide (48)
  • the crude product of compound 48 was synthesized using a method similar to that described in Example 30, except that compound Int-A28 was used instead of compound Int-A24 in Example 30.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 48 (4.62 mg).
  • Example 49 Compound (S)-5-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazine- Preparation of 1-yl)-N-(2-hydroxypropyl)-6-methylpyridinecarboxamide (49)
  • the crude product of compound 49 was synthesized using a method similar to that described in Example 30, except that compound Int-A27 was used instead of compound Int-A24 in Example 30.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 49 (3.54 mg).
  • Example 50 Compound N-(2-hydroxyethyl)-5-(4-((7-methoxy-2-methyl-3-oxo-3,4-dihydroquinoxaline-6- Preparation of methyl)piperazin-1-yl)-6-methylpyridinecarboxamide (50)
  • the crude product of compound 50 was synthesized using a method similar to that described in Example 31, except that compound Int-8 was used instead of compound Int-7 in Example 31.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 50 (2.56 mg).
  • Example 51 Compound 5-(4-((8-chloro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl) Preparation of -N,6-dimethylpyridinecarboxamide (51)
  • the crude product of compound 51 was synthesized using a method similar to that described in Example 40, except that compound Int-9 was used instead of compound Int-6 in Example 40.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 51 (3.19 mg).
  • Example 52 Compound (R)-5-(4-((7,8-difluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl) Preparation of piperazin-1-yl)-6-methyl-N-(tetrahydrofuran-3-yl)pyridinecarboxamide (52)
  • the crude product of compound 52 was synthesized using a method similar to that described in Example 46, except that compound Int-4 was used instead of compound Int-2 in Example 46.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 52 (6.85 mg).
  • Example 53 Compound 5-(4-((7,8-difluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazine-1 Preparation of -yl)-6-methyl-N-(oxetan-3-ylmethyl)pyridinecarboxamide (53)
  • the crude product of compound 53 was synthesized using a method similar to that described in Example 52, except that compound Int-A25 was used instead of compound Int-A33 in Example 52.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 53 (3.99 mg).
  • Example 54 Compound 5-(4-((7,8-difluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazine-1 Preparation of -(yl)-N-(2-fluoroethyl)-6-methylpyridinecarboxamide (54)
  • the crude product of compound 54 was synthesized using a method similar to that described in Example 52, except that compound Int-A24 was used instead of compound Int-A33 in Example 52.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 54 (8.88 mg).
  • Example 55 Compound N-cyclopropyl-5-(4-((8-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piper Preparation of oxazin-1-yl)-6-methylpyridinecarboxamide (55)
  • the crude product of compound 55 was synthesized using a method similar to that described in Example 1, except that compound Int-A29 was used instead of compound Int-1 in Example 1.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 55 (6.01 mg).
  • Example 56 Compound 5-(4-((2-cyclopropyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl )-N, 6- Preparation of lutidine carboxamide (56)
  • the crude product of compound 55 was synthesized using a method similar to that described in Example 6, except that compound Int-10 was used instead of compound Int-2 in Example 6.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 55 (40.2 mg).
  • Example 57 Compound 6-chloro-5-(4-((2-cyclopropyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazine Preparation of -1-yl)-N-methylpyridinecarboxamide (57)
  • the crude product of compound 57 was synthesized using a method similar to that described in Example 56, except that compound Int-A8 was used instead of compound Int-A7 in Example 56.
  • the obtained crude product was purified by preparative silica gel plate to obtain the title compound 57 (13.4 mg).
  • Test Example 1 BRCA1 mutated MDA-MB-436 cell proliferation inhibition test
  • CCK-8 was used to measure the dehydrogenase content in mitochondria under different drug concentrations, and the luminescence intensity was used to reflect cell activity.
  • the IC 50 values of different compounds against BRCA1-mutated MDA-MB-436 cells were calculated using survival rates, and the proliferation inhibitory effect of the compounds of the present invention on BRCA1-mutated MDA-MB-436 cells was studied to evaluate the anti-bacterial activity of the test compounds at the cellular level. Tumor efficacy.
  • MDA-MB-436 cell-specific medium DMEM
  • Prenox MDA-MB-436 cell-specific medium
  • Fetal bovine serum Fetal Bovine Serum (FBS), Hyclone;
  • PBS Phosphate Buffered Saline
  • Multifunctional microplate reader (Omega), BMG.
  • MDA-MB-436 cells were purchased from Prenox.
  • Test drugs Compounds AZD5305 and AZD9574 were purchased from Chengdu Dingdang Times Pharmaceutical Technology Co., Ltd.;
  • Test drug Compounds 1-57 were prepared by the synthesis methods of Examples 1-57 respectively;
  • Test Example 2 BRCA1 mutated HCC1395 cell proliferation inhibition test
  • CCK-8 was used to measure the dehydrogenase content in mitochondria under different drug concentrations, and the luminescence intensity was used to reflect cell activity.
  • the survival rates were used to calculate the IC 50 values of different compounds against BRCA1-mutated HCC1395 cells, and to study the inhibitory effect of the compounds of the present invention on the proliferation of BRCA1-mutated HCC1395 cells, and to evaluate the anti-tumor efficacy of the test compounds at the cellular level.
  • Fetal bovine serum Fetal Bovine Serum (FBS), Gibco;
  • PBS Phosphate Buffered Saline
  • Najing Vicente Biotechnology
  • Multifunctional microplate reader (Omega), BMG.
  • HCC1395 cells were purchased from ATCC.
  • PBS In house, 20210819;
  • Compound 10mM stock solution preparation Dissolve the compound powder in 100% DMSO and prepare a 10mM compound stock solution.
  • SD rats were used as test animals, and the LC-MS/MS method was used to determine the plasma drug concentration in the plasma of the rats at different times after oral administration of the compound of the present invention. Obtain the pharmacokinetic parameters of the compound of the present application in rats and study its pharmacokinetic characteristics.
  • each compound was prepared into a clear solution with solvent, and the corresponding test drug was administered to each group by gavage before administration and at 15min, 30min, 1h, 2h, 4h, 6h, 8h, and 24h after administration.
  • a fixed volume of blood was collected from the venous sinus, placed in an EDTA-K2 anticoagulant tube, centrifuged at 4000 rpm for 10 min, and the plasma was separated into a centrifuge tube and frozen in a -80°C refrigerator.

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Abstract

一种作为聚(ADP-核糖)聚合酶(PARP)家族的酶抑制剂的具备下式(I)结构的氮杂喹啉酮类化合物，及其药学上可接受的盐、立体异构体、互变异构或N-氧化物药物以及其制备方法和用途。

Description

一种氮杂喹啉酮类衍生物、其制备方法及用途 技术领域
本申请涉及作为聚(ADP﹣核糖)聚合酶(PARP)家族的酶抑制剂的一种氮杂喹啉酮类化合物及其药学上可接受的盐、立体异构体及其药物组合物以及其制备方法和用途。
背景技术
PARP1和PARP2(PARP1/2)通过与DNA损伤位点相结合并且催化多聚ADP核糖链在蛋白底物上的合成，募集其它DNA修复蛋白到损伤位点共同修复DNA损伤，同时触发PARP1/2从DNA中释放。PARP抑制剂通过与PARP1/2催化位点的结合，将其“捕获”至DNA上，导致PARP1/2无法从DNA损伤位点上脱落，从而诱导DNA复制叉停滞和DNA复制无法顺利进行。此时，细胞通常会通过同源重复修复(HRR)的方法来修复这个错误。在HRR过程中BRCA1/2等蛋白发挥着重要作用，而在BRCA突变的细胞中，HRR功能失常，PARP抑制剂的存在会阻止DNA的损伤修复作用从而导致细胞死亡。
Olaparib是由阿斯利康开发的全球第一个获批上市的PARP抑制剂，已被FDA批准用于多种癌症的治疗。此后，rucaparib、niraparib和talazoparib等也相继获批上市；同时，还有多个抑制剂处于临床阶段。尽管PARP抑制剂在BRCA缺陷患者中已经表现出优异的临床疗效，然而，无论是单药使用还是联合疗法，这些化合物均表现出明显的血液毒性，包括贫血、中性粒细胞减少症和血小板减少症等。血液毒性限制了一代PARP抑制剂的使用，临床上需要降低剂量、暂停给药或终止用药。
近期研究表明，PARP2的抑制与血液毒性密切相关，PARP2而不是PARP1在小鼠造血干/祖细胞(HSPC)存活中至关重要，用于维持造血稳态，且BRCA突变的合成致死仅由PARP1驱动，并不需要将PARP2“捕获”至DNA。由于PARP1与PARP2高度同源，目前多数PARP抑制剂缺乏对PARP1的选择性，因而，开发具有高选择性的PARP1抑制剂有利于降低血液毒性并改善治疗指数。
与其他PARP1/2抑制剂相比，高选择性的PARP1抑制剂有望提高功效和降低毒性。因此，对于有效且安全的PARP抑制剂存在未满足的医学需求。目前无高选择性的PARP1抑制剂上市，选择性PARP1抑制剂AZD5305进入临床I/II期，相比AZD5305更高选择性的PARP1抑制剂AZD9574也进入临床I/II期。
现有技术中公开的化合物以及试验药物在有效性、安全性等方面依然存在不确定性，因此仍有必要筛选出在有效性、安全性和选择性等性能方面均具有优异性能的用作PARP1抑制剂的化合物。
发明内容
为了解决现有技术的上述问题，本申请的目的在于提供一种氮杂喹啉酮类化合物及其药学上可接受的盐、立体异构体，以筛选出在有效性、安全性和选择性等性能方面均具有优异性能的用作PARP1抑制剂的化合物。
为达到此申请目的，本申请采用以下技术方案：
在一些实施方案中，本申请提供化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，其中所述化合物具有式(I)的结构：
其中：
X选自N、CH或CRa，其中Ra选自卤素、C1-4烷基、C3-6环烷基、-O-(C1-4烷基)或卤代C1-4烷基；
Y选自N、CH或CRb，其中Rb选自卤素、氰基、C1-4烷基、C2-6烯基、C3-6环烷基、4-6元杂环基或-ORz，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自氟、氰基、羟基、C1-4烷基或-O-(C1-4烷基)的取代基取代；
条件是：当X选自N或CH时，Y选自CRb；
当X选自CRa时，Y选自N、CH或CRb；
R1选自氢、卤素、氰基、C1-4烷基、-O-(C1-4烷基)、-O-(卤代C1-4烷基)或卤代C1-4烷基；
R2选自氢、F、Cl、Br、氰基、C1-4烷基、C3-6环烷基、-O-(C1-4烷基)或卤代C1-4烷基；
R3选自氰基、C1-4烷基、C3-6环烷基或4-6元杂环基，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自F、氰基、C1-4烷基、C3-6环烷基、4-6元杂环基、-O-(C1-4烷基)或卤代C1-4烷基的取代基取代；
Q选自N或CRc，其中Rc选自F、羟基、氰基、C1-4烷基、-O-(C1-4烷基)或卤代C1-4烷基；
R4和R5在每次出现时各自独立地选自氢或C1-4烷基，或R4和R5相互连接成环；
选自苯基，或含有1至2个选自N、O或S原子的五元或六元杂芳基；
R6在每次出现时各自独立地选自氢、卤素、氰基、-ORz、-C(＝O)-Rz、-C(＝O)-NH-Rz、C1-4烷基、C3-6环烷基或4-6元杂环基，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自F、氰基、羟基、C1-4烷基、-O-(C1-4烷基)或卤代C1-4烷基的取代基取代；
n为1、2或3。
Rz在每次出现时各自独立地选自氢、C1-4烷基、C3-6环烷基或4-6元杂环基，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自F、氰基、羟基、C1-4烷基、-O-(C1-4烷基)或氟代C1-4烷基的取代基取代。
在某些实施方案中，X选自N、CH或CRa，其中Ra选自F、Cl、Br、C1-4烷基、C3-6环烷基、-OMe或氟代C1-4烷基；
在某些优选实施方案中，Ra选自F、Cl、Br、甲基、乙基、异丙基、环丙基、-OMe、-CF3、-CHF2或-CH2F；更为优选地，Ra选自F、Cl、Br、甲基、环丙基、-OMe、-CHF2或-CH2F；
Y选自N、CH或CRb，其中Rb选自F、Cl、Br、氰基、甲基、乙基、异丙基、环丙基、环丁基、氧杂环丁基、氧杂环己基或-ORz，其中所述甲基、乙基、异丙基、环丙基、环丁基、氧杂环丁基、氧杂环己基是未取代的或各自独立地被一个或多个选自氟、氰基、羟基、甲基或-OMe的取代基取代；
在某些优选实施方案中，Rb选自F、Cl、Br、氰基、甲基、乙基、异丙基、环丙基、环丁基、氧杂环丁基或-ORz，其中所述甲基、乙基、异丙基、环丙基、环丁基是未取代的或各自独立地被一个或两个选自氟、氰基、羟基或甲基的取代基取代；
条件是：当X选自N或CH时，Y选自CRb；
当X选自CRa时，Y选自N、CH或CRb。
在某些实施方案中，R1选自氢、F、Cl、Br、氰基、甲基、乙基、异丙基、-OMe、-O-(氟代C1-4烷基)或氟代C1-4烷基；
在某些优选实施方案中，R1选自氢、F、Cl、甲基、-OMe、-CHF2或-CH2F。
在某些实施方案中，R2选自氢、F、Cl、Br、氰基、甲基、乙基、环丙基、-OMe或氟代C1-4烷基；
在某些优选实施方案中，R2选自氢、F、Cl、Br、甲基、环丙基、-OMe、-CHF2或-CH2F。
在某些实施方案中，R3选自氰基、甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基，其中所述甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基是未取代的或各自独立地被一个或多个选自F、氰基、甲基、环丙基、-OMe或氟代C1-4烷基的取代基取代；
在某些优选实施方案中，R3选自氰基、甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基，其中所述甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基是未取代的或各自独立地被一个或两个选自F、氰基、-OMe、-CHF2或-CH2F的取代基取代。
在某些实施方案中，Q选自N或CRc，其中Rc选自F、羟基、氰基、甲基、乙基、-OMe或氟代C1-4烷基；
在某些优选实施方案中，Q选自N或CRc，其中Rc选自F、羟基、氰基、甲基、-OMe、-CHF2或-CH2F；
在某些更为优选的实施方案中，Q选自N或CRc，其中Rc选自F、羟基、-OMe或甲基。
在某些实验方案中，R4和R5在每次出现时各自独立地选自氢或甲基、乙基，或R4和R5相互连接成环；
在某些优选实施方案中，R4和R5在每次出现时各自独立地选自氢或甲基，或R4和R5相互连接成 环，形成
在某些更为优选的实施方案中，所述R4和R5在每次出现时各自独立地选自氢或甲基，或R4和R5相互连接成环，形成
在某些实施方案中，选自苯基、吡啶、嘧啶、吡嗪、哒嗪、吡唑、噁唑、异噁唑、噻吩或噻唑；
在某些优选实施方案中，选自苯基、吡啶、吡唑、噁唑、噻吩或噻唑；
在某些更为优选的实施方案中，选自
在某些实施方案中，R6在每次出现时各自独立地选自氢、F、Cl、Br、氰基、-ORz、-C(＝O)-Rz、-C(＝O)-NH-Rz、甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基，其中所述甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基是未取代的或各自独立地被一个或多个选自F、氰基、羟基、甲基、-OMe、-CF3或-CHF2的取代基取代；
在某些优选实施方案中，R6在每次出现时各自独立地选自氢、F、Cl、Br、氰基、-ORz、-C(＝O)-Rz、-C(＝O)-NH-Rz、甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基，其中所述甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基是未取代的或各自独立地被一个或两个选自F、羟基或-OMe的取代基取代；
在某些实施方案中，Rz在每次出现时各自独立地选自氢、甲基、乙基、异丙基、环丙基、环丁基、氧杂环丁基或氧杂环戊基，其中所述甲基、乙基、环丙基、环丁基或氧杂环戊基是未取代的或各自独立地被一个或多个选自氟、氰基、羟基、-OMe、氧杂环丁基或甲基的取代基取代；
在某些优选实施方案中，所述Rz在每次出现时各自独立地选自氢、甲基、乙基、环丙基、氧杂环丁基、氧杂环戊基、亚甲基-氧杂环丁基、-CF3、-CF2H或-CH2F。
在某些实施方案中，n为1或2。
在某些实施方案中，本申请提供化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，其中所述化合物具有式(II)的结构：
其中：
R1选自氢、F、Cl、Br、氰基、甲基、乙基、异丙基或-OMe；
R2选自氢、卤素、氰基、C1-4烷基、C3-6环烷基、-O-(C1-4烷基)或氟代C1-4烷基；
R3选自氰基、甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基，其中所述甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基是未取代的或各自独立地被一个或多个选自F、氰基、甲基、环丙基或-OMe的取代基取代；
Rb选自F、Cl、Br、氰基、C1-4烷基、C3-6环烷基、4-6元杂环基或-ORz，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自氟、氰基、羟基、C1-4烷基或-O-(C1-4烷基)的取代基取代；
R4和R5在每次出现时各自独立地选自氢、C1-4烷基，或R4和R5相互连接成环，形成
选自苯基、吡啶、嘧啶、吡嗪、哒嗪、吡唑、噁唑、异噁唑、噻吩或噻唑；
R6在每次出现时各自独立地选自氢、卤素、氰基、-ORz、-C(＝O)-Rz、-C(＝O)-NH-Rz、C1-4烷基、C3-6环烷基或4-6元杂环基，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自F、氰基、羟基、C1-4烷基、-O-(C1-4烷基)或卤代C1-4烷基的取代基取代；
n为1、2或3；
Rz在每次出现时各自独立地选自氢、C1-4烷基、C3-6环烷基或4-6元杂环基，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自F、氰基、羟基、C1-4烷基、-O-(C1-4烷基)、4-6元杂环基或氟代C1-4烷基的取代基取代。
在某些实施方案中，本申请提供化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，其中所述化合物具有式(III)的结构：
其中：
R1选自氢、F、Cl、甲基、-OMe、-CHF2或-CH2F；
R2选自氢、卤素、氰基、C1-4烷基、C3-6环烷基、-O-(C1-4烷基)或卤代C1-4烷基；
R3选自氰基、甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基，其中所述甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基是未取代的或各自独立地被一个或两个选自F、氰基、甲基、环丙基或-OMe的取代基取代；
Rb选自F、Cl、Br、氰基、甲基、乙基、异丙基、环丙基、环丁基、氧杂环丁基或-ORz，其中所述甲基、乙基、异丙基、环丙基、环丁基是未取代的或各自独立地被一个或两个选自氟、氰基、羟基或甲基的取代基取代；
R4和R5在每次出现时各自独立地选自氢、C1-4烷基，或R4和R5相互连接成环，形成
选自
R7选自氢、F、Cl、Br、氰基、C1-4烷基、C3-6环烷基、4-6元杂环基或-ORz，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自F、氰基、羟基、C1-4烷基、-O-(C1-4烷基)或卤代C1-4烷基的取代基取代；
n为1或2；
Rz在每次出现时各自独立地选自氢、C1-4烷基、C3-6环烷基或4-6元杂环基，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自F、氰基、羟基、C1-4烷基、-O-(C1-4烷基)、4-6元杂环基或氟代C1-4烷基的取代基取代。
在某些实验方案中，本申请提供化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，其中所述化合物具有式(IV)的结构：
其中，
R2选自氢、F、Cl、Br、氰基、C1-4烷基、C3-6环烷基、-O-(C1-4烷基)或氟代C1-4烷基；
R3选自氰基、甲基、乙基、正丙基、异丙基、环丙基、环丁基或4-6元杂环基，其中所述甲基、乙基、正丙基、异丙基、环丙基、环丁基或4-6元杂环基是未取代的或各自独立地被一个或多个F、氰基、甲基或-OMe的取代基取代；
Rb选自F、Cl、Br、氰基、甲基、乙基、正丙基、异丙基、环丙基、环丁基、氧杂环丁基或-ORz，其中所述甲基、乙基、异丙基、环丙基、环丁基是未取代的或各自独立地被一个或两个选自氟、氰基、羟基或甲基的取代基取代；
R4和R5在每次出现时各自独立地选自氢、甲基或乙基，或R4和R5相互连接成环，形成
R7选自氢、卤素、氰基、-ORz、C1-4烷基、C3-6环烷基或4-6元杂环基，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自F、羟基、甲基、乙基、甲氧基或乙氧基的取代基取代；
n为1或2；
Rz在每次出现时各自独立地选自氢、甲基、乙基、正丙基、异丙基、环丙基、环丁基、氧杂环丁基或氧杂环戊基，其中所述甲基、乙基、正丙基、异丙基、环丙基或环丁基是未取代的或各自独立地被一个或多个选自F、氰基、羟基、甲基、乙基、甲氧基、乙氧基、氧杂环丁基或氟甲基的取代基取代。
在某些具体实施方案中，本申请提供化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，其中所述化合物选自：





在另一方面，本申请还涉及一种药物组合物，所述组合物包括：有效剂量的任一本申请的化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，以及药学上可接受的载体和/或赋形剂；或进一步包括一种或多种其他治疗剂。
在另一方面，本申请提供式(I)的化合物或其药学上可接受的盐、立体异构体、互变异构体、N-氧化物或本申请化合物的药物组合物在制备PARP1制剂中的用途。
在另一方面，本申请提供式(I)的化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物在制备用于治疗癌症的药物中的用途，其中所述癌症为由PARP1介导的BRCA基因缺陷型肿瘤。
更为详细地，本申请提供式(I)的化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物在制备用于治疗癌症或PARP1相关其他疾病的药物中的用途，其中所述癌症选自乳腺癌、卵巢癌、胰腺癌、前列腺癌、结直肠癌、膀胱癌、胃肠道癌、肺癌或血液瘤。
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及文中使用的技术意图是指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员理解，但仍然阐述以下定义以更好地解释本申请。
本申请所表述的化合物，是依据化学结构式命名的。如果表示同一化合物时，化合物的命名与化学结构式不符，则以化学结构式为准。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
如本文中所使用，术语“亚烷基”表示饱和二价烃基，优选表示具有1、2、3、4、5或6个碳原子的饱和二价烃基，例如亚甲基、亚乙基、亚丙基或亚丁基。
如本文中所使用，术语“烷基”定义为线性或支化饱和脂肪族烃。在一些实施方案中，烷基具有1至12个，例如1至6个碳原子。例如，如本文中所使用，术语“C1-6烷基”指1至6个碳原子的线性或支化的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新 戊基或正己基)，其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CH2F、CHF2、CF3、CCl3、CH2CF3、CH2Cl或﹣CH2CH2CF3等)。术语“C1-4烷基”指1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。
如本文中所使用，术语“烯基”意指线性的或支化的单价烃基，其包含一个双键，且具有2-5个碳原子(C2-5烯基”)。所述烯基为例如乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-烯基、3-戊烯基、4-戊烯基、2-己烯基、3-已烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本申请的化合物含有亚烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。
如本文中所使用，术语“炔基”意指线性的或支化的单价烃基，其包含一个三键，且具碳原子2-5个碳原子(C2-5炔基)。所述炔基为例如乙炔基、1-丙炔基、2-丙炔基、2-丁炔基、3-丁炔基、2-戊炔基、3-戊炔基、4-戊炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、2-甲基-2-丙炔基和4-甲基-3-戊炔基。
如本文中所使用，术语“环烷基”指饱和的单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基等)，其任选地被一个或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子。例如，术语“C3-6环烷基”指3至6个成环碳原子的饱和的单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)，其任选地被1或多个(诸如至3个)适合的取代基取代，例如甲基取代的环丙基。
如本文中所使用，术语“亚环烃基”和“环烃基”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环碳原子的饱和(即，“亚环烷基”和“环烷基”)或不饱和的(即在环内具有一个或多个双键和/或三键)单环或多环烃环，其包括但不限于(亚)环丙基、(亚)环丁基、(亚)环戊基、(亚)环己基、(亚)环庚基、(亚)环辛基、(亚)环壬基、(亚)环己烯基等。
如本文中所使用，术语“杂环基”和“亚杂环基”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环原子、其中至少一个环原子是选自N、O和S的杂原子且其余环原子是C的饱和(即，杂环烷基)或部分不饱和的(即在环内具有一个或多个双键和/或三键)环状基团。例如，“3-10元(亚)杂环基”是具有2-9个(如2、3、4、5、6、7、8或9个)环碳原子和独立地选自N、O和S的一个或多个(例如1个、2个、3个或4个)杂原子的饱和或部分不饱和(亚)杂环基。亚杂环基和杂环基的实例包括但不限于：(亚)环氧乙烷基、(亚)氮丙啶基、(亚)氮杂环丁基(azetidinyl)、(亚)氧杂环丁基(oxetanyl)、(亚)四氢呋喃基、(亚)二氧杂环戊烯基(dioxolinyl)、(亚)吡咯烷基、(亚)吡咯烷酮基、(亚)咪唑烷基、(亚)吡唑烷基、(亚)吡咯琳基、(亚)四氢吡喃基、(亚)哌啶基、(亚)吗琳基、(亚)二噻烷基(dithianyl)、(亚)硫吗琳基、(亚)哌嗪基或(亚)三噻烷基(trithianyl)。亚杂环基和杂环基可任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。
如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、C1、Br或I。
如本文中所使用，术语“含氮杂环”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8、9、10、11、12或13个碳原子和至少一个氮原子，其还可任选地包含一个或多个(例如一个、两个、三个或四个)选自N、O、C＝O、S、S＝O和S(＝O)2的环成员，其通过所述含氮杂环中的氮原子以及任一其余环原子与分子的其余部分连接，所述含氮杂环任选地为苯并稠合的，选通过所述含氮杂环中的氮原子以及所稠合的苯环中的任一碳原了与分了的其余部分连接。
术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
如果取代基被描述为“各自独立地选自”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。
如本文中所使用，术语“一个或多个“意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环的任一成环原子。
本申请还包括所有药学上可接受的同位素标记的化合物，其与本申请的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本申请的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘(2H)、氚(3H))；碳的同位素(例如11C、13C及14C)；氯的同位素(例如36CI)；氟的同位素(例如18F)；碘的同素(例如123I及125I)；氮的同位素(例如13N及15N)；氧的同位素(例如15O、17O及18O)；磷的同位素(例如32P)；及硫的同位素(例如35S)。
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如一两个、三个或四个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本申请的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮﹣烯醇互变异构体、苯酚﹣酮互变异构体、亚硝基﹣肟互变异构体、亚胺﹣烯胺互变异构体等。要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。
本文中可使用实线实楔形或虚楔形描绘本申请的化合物的碳-碳键。使用实线以描绘键连至不对称碳原子的键表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本申请的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、阻转异构体及其混合物)的形式存在。本申请的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。
本申请涵盖本申请的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
还应当理解，本申请的某些化合物可以游离形式存在用于治疗，或适当时以其药学上可接受的衍生物形式存在。在本申请中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、N-氧化物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本申请的化合物或其代谢物或残余物。因此，当在本文中提及“本申请的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本申请的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。
适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括盐酸盐、乙酸盐、天冬氨酸盐、苯甲酸盐、碳酸氢盐/碳酸盐、葡庚糖酸盐、葡糖酸盐、硝酸盐、乳清酸盐、棕榈酸盐及其他类似的盐。
适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、胆碱盐、镁盐及其它类似的盐。
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection and Use”(Wiley-VCH,2002)。用于制备本申请的化合物的药学上可接受的盐的本领域技术人员已知的。
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本申请的化合物)。本申请的化合物本身也可以是酯。
本申请的化合物可以溶剂合物(优选水合物)的形式存在，共中本申请的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物；本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的。包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胶。这些用于制备N-氧化物的方 法已在文献中得到广泛描述和综述，参见例如：T.L.Gilehrist,Comprehensive Organic Synthesis,vol.7,pp 748-750；A.R.Katritzky和A.J.Boulton,Eds.,Academic Press；以及G.W.H.Cheeseman和E.S.G.Werstiuk,Advances in Heterocyclic Chemistry,vol.22,pp 390-392.A.R.Katritzky和A.J.Boulton,Eds.,Academic Press.
在本申请的范国内还包括本申请的化合物的代谢物，即在给药本申请的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本申请包括本申请的化合物的代谢物，包括通过使本申请的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本申请在其范围内进一步包括本申请的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本申请的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本申请的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)。本申请的前药可例如通过本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prorugs”,H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本申请的化合物中存在的适当官能团来制备。
本申请还涵盖含有保护基的本申请的化合物。在制备本申请的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本申请的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在T.W.Greene & P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley & Sons,1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。
术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。
具体实施方式
实施例
以下结合实施例对本申请作进一步的详细描述，但并非对本申请的限制，凡依照本申请公开内容所作的任何本领域的等同替换，均属于本申请的保护范围。
化合物的结构是通过质谱(MS)或核磁共振(1HNMR)来确定的。
核磁共振(1HNMR)的测定是用BrukerAVANCE-400核磁仪，测定溶剂为氘代氯仿(CDCl3)，内标为四甲基硅烷(TMS)，化学位移是以10-6(ppm)作为单位给出。
质谱(MS)的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Therm，型号：Finnigan LCQ advantage MAX)进行。
薄层硅胶使用烟台黄海HSGF254或青岛GF254硅胶板。
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
在本申请未给出特殊说明的情况下，本申请中所提及的反应均在N2保护下或氮气氛下进行。
在本申请的术语，“N2保护”或“氮气氛”是指例如将反应瓶连接一个1L容积的氮气气球。
在本申请未给出特殊说明的情况下，本申请反应中提及的溶液是水溶液。
在本申请的术语“室温”是指温度处于10℃-25℃之间。
如本文中所使用的缩写具有以下含义：

实施例A1:中间体N-甲基-5-(哌嗪-1-基)吡啶酰胺(Int-1)二盐酸盐的制备
第一步：化合物4-(6-(甲氧基羰基)吡啶-3-基)哌嗪-1-甲酸叔丁酯(Int-1b)的制备
将化合物Int-1a(10.0g,46.3mmol)、叔丁基哌嗪-1-甲酸酯(9.07g，48.6mmol)和Cs2CO3(30.0g，92.6mmol)称入圆底烧瓶，加入1,4-二氧六环(180mL)，N2保护下加入Ruphos Pd G3(1.36g,1.62mmol)，加毕后升温至80℃反应。待反应完后，在反应体系中加入水和乙酸乙酯稀释，分液，水相用乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，抽滤，滤液浓缩得到粗品化合物。所得粗品化合物经柱层析纯化得到标题化合物Int-1b(8.18g，收率55％)。
MS m/z(ES):322.2[M+H]+
第二步：化合物4-(6-(甲基氨基甲酰基)吡啶-3-基)哌嗪-1-甲酸叔丁酯(Int-1c)的制备
将化合物Int-1b(12.1g,37.3mmol)溶于甲醇(50mL),然后加入40％甲胺水溶液(33mL,0.38mol)中，室温搅拌。待反应完全，将反应体系浓缩，将残余物用饱和氯化铵溶液和DCM稀释分层，水相用DCM萃取三次，合并有机相，无水硫酸钠干燥，抽滤，滤液浓缩得到粗品化合物。所得粗品经柱层析纯化得标题化合物Int-1c(12.0g，收率：100％)。
MS m/z(ES):321.2[M+H]+
第三步：化合物N-甲基-5-(哌嗪-1-基)吡啶酰胺(Int-1)的制备
将化合物Int-1c(12.0g,37.3mmol)溶于MeOH(100mL)，在0℃下向其中加入HCl的1,4-二氧六环溶液(4M,50mL,200mmol)，随后缓慢升至室温搅拌。待反应完全，向反应体系中加入乙醚稀释，体系中有固体析出，过滤并用乙醚洗涤。收集固体并真空干燥得标题化合物Int-1的二盐酸盐(11.1g，收率：99％)。
MS m/z(ES):221.1[M+H]+
实施例A2:中间体5-(3,6-二氮杂双环[3.1.1]庚-3-基)-N,6-二甲基吡啶酰胺(Int-A2)盐酸盐的制备
第一步：化合物3-(6-(甲氧基羰基)-2-甲基吡啶-3-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯(Int-A2b)的制备
除使用化合物Int-A2a代替实施例A1第一步中的化合物Int-1a之外，采用与实施例A1中第一步所描述的类似方法合成化合物Int-A2b的粗品。所得粗品经柱层析纯化得标题化合物Int-A2b(1.90g，收率：79％)。
MS m/z(ES):348.2[M+H]+
第二步：化合物3-(2-甲基-6-(甲基氨基甲酰基)吡啶-3-基)-3,6-二氮杂双环[3.1.1]庚烷-6-羧酸叔丁酯(Int-A2c)的制备
将化合物Int-A2b(1.90g,5.48mmol)溶于甲醇(10mL)，然后加入33％甲胺乙醇溶液(5mL,54.8mol)，室温搅拌。待反应完全，将反应体系浓缩得到标题化合物Int-A2c的粗品(1.83g)，所得粗品直接用作下一步，未进一步纯化。
MS m/z(ES):347.1[M+H]+
第三步：化合物5-(3,6-二氮杂双环[3.1.1]庚-3-基)-N,6-二甲基吡啶酰胺(Int-A2)的制备
除使用化合物Int-A2c代替实施例A1中第三步的化合物Int-1c之外，采用与实施例A1中所描述的类似方法合成化合物Int-A2的粗品。向粗品中加入乙醚稀释，体系中有固体析出，过滤并用乙醚洗涤。收集固体并真空干燥得标题化合物Int-A2的盐酸盐(1.24g，两步收率：92％)。
MS m/z(ES):247.2[M+H]+
实施例A3:中间体5-((1R,4R)-2,5-二氮杂双环[2.2.1]庚-2-基)-N,6-二甲基吡啶酰胺(Int-A3)的制备
第一步：化合物(1R,4R)-5-(2-甲基-6-(甲基氨基甲酰基)吡啶-3-基)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯(Int-A3b)的制备
将化合物Int-A3a(3.0g,13.1mmol)、叔丁基(1R，4R)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸酯(2.8g,14.4mmol)和Cs2CO3(12.1g,39.3mmol)称入圆底烧瓶，加入1,4-二氧六环(20mL)，N2保护下加入Ruphos Pd G3(0.5g,0.65mmol)，加毕后升温至90℃反应。待反应完后，在反应体系中加入水和乙酸乙酯稀释，分液，水相用乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，抽滤，滤液浓缩得到粗品化合物。所得粗品化合物经柱层析纯化得到标题化合物Int-A3b(3.8g，收率84％)。
MS m/z(ES):347.1[M+H]+
第二步：化合物5-((1R,4R)-2,5-二氮杂双环[2.2.1]庚-2-基)-N,6-二甲基吡啶酰胺(Int-A3)的制备
将化合物Int-A3b(200mg,0.57mmol)溶于1,4-二氧六环溶液(2mL)，在0℃下向其中加入HCl的1,4-二氧六环溶液(4M,1.5mL,5.7mmol)，随后缓慢升至室温搅拌。待反应完全，向反应体系中加入石油醚稀释，体系中有固体析出，过滤并用石油醚洗涤。收集固体并真空干燥得标题化合物Int-A3的盐酸盐(123mg，收率：86％)
MS m/z(ES):247.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),9.26(s,1H),8.66(s,1H),7.87(d,J＝8.4Hz,1H),7.44(d,J＝8.4Hz,1H),4.56(s,1H),4.39(s,1H),3.75(d,J＝10.0Hz,1H),3.60(d,J＝10.4Hz,1H),3.40–3.30(m,1H),3.30–3.18(m,1H),2.81(d,J＝4.4Hz,3H),2.55(s,3H),2.11(d,J＝10.8Hz,1H),1.98(d,J＝10.8Hz,1H).
参考实施例A1、A2或A3中的合成方法，用适当的芳基卤代物和胺基化合物替换其中第一步反应中的原料和胺基化合物，采用类似的反应条件，合成下列中间体化合物的盐酸盐。

实施例A4：中间体6-氯-N-甲基-5-(哌嗪-1-基)吡啶酰胺(Int-A8)的制备
第一步：化合物6-氯-5-氟吡啶甲酸甲酯(Int-A8b)的制备
将化合物Int-A8a(5.0g,22.7mmol)称入圆底烧瓶，加入甲醇(25mL)溶解，冰浴下加入SOCl2(8ml,113.6mmol)，加毕后室温反应。待反应完后，将反应液浓缩至干，缓慢加入冰水淬灭反应，水相用二氯甲烷萃取三次，合并有机相，无水硫酸钠干燥，抽滤，滤液浓缩得到粗品化合物Int-A8b(4.2g，收率97％)。
MS m/z(ES)：190.0[M+H]+
第二步：化合物6-氯-5-(哌嗪-1-基)吡啶甲酸甲酯(Int-A8c)的制备
将化合物Int-A8b(1.45g,7.57mmol)溶于乙腈(50mL)，然后加入无水哌嗪(1.8g,21.0mmol)，加毕80℃反应。待反应完全，将反应体系浓缩，得到粗品化合物Int-A8c，所得粗品未进一步纯化，直接用作下一步。
MS m/z(ES):256.1[M+H]+
第三步：化合物6-氯-N-甲基-5-(哌嗪-1-基)吡啶酰胺(Int-A8)的制备
将上一步化合物Int-A8c的粗品溶于EtOH(10mL)，然后加入33％甲胺乙醇溶液(9.8mL,78mmol)室温搅拌反应。待反应完全，浓缩得标题化合物Int-A8(1.9g，两步收率98％)
MS m/z(ES):255.1[M+H]+
实施例A5：中间体3-(6-甲基-5-(哌嗪-1-基)吡啶-2-基)氧杂环丁烷-3-醇(Int-A9)的制备
第一步：化合物3-(5-溴-6-甲基吡啶-2-基)氧杂环丁烷-3-醇(Int-A9c)的制备
化合物Int-A9a(2.0g,8.0mmol)溶于甲苯(25mL)中，降温至-78℃，在氮气氛围下缓慢滴加正丁基锂(1.6M in hexane,5mL,8.0mmol)，加毕后于-78℃下继续搅拌20分钟后，加入Int-A9b(577mg,8.0mmol)的甲苯(3mL)溶液。反应体系继续在此温度下反应1小时。待LCMS监测反应完全，向反应体系中加入饱和NH4Cl溶液(15mL)淬灭反应，然后用乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，过滤，将滤液浓缩得粗品化合物。所得粗品经柱层析纯化得标题化合物(Int-A9c)(1.76g,收率90％)。
MS m/z(ES):244.0[M+H]+
第二步：化合物3-(6-甲基-5-(哌嗪-1-基)吡啶-2-基)氧杂环丁烷-3-醇(Int-A9)的制备
将化合物Int-A9c(500mg,2.1mmol)、哌嗪(361mg,4.2mmol)、RuPhosPdG3(176mg,0.21mmol)和Cs2CO3(2.05g,6.3mmol)溶于1，4-二氧六环(20mL)中，氮气氛围下将反应体系置于120℃下反应4小时。LCMS监测反应完全后，加水淬灭反应，然后用乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，过滤，将滤液浓缩得粗品化合物。所得粗品经柱层析纯化得标题化合物(Int-A9)(60mg,收率11％)。
MS m/z(ES):250.1[M+H]+
实施例A6：中间体N-甲基-5-(哌嗪-1-基)噻唑-2-酰胺盐酸盐(Int-A13)的盐酸盐制备
第一步：化合物5-溴-N-甲基噻唑-2-甲酰胺(Int-A13b)的制备
化合物Int-A13a(3.0g,14.4mmol)，甲胺盐酸盐(1.46g,21.6mmol)溶于N，N-二甲基甲酰胺(30mL)中，0℃下加入DIPEA(4.64g,36.0mmol)和HATU(13.69g,36.0mmol)，将反应体系升温至室温反应。待LCMS监测反应完全，向其中加入水(50mL)淬灭反应，然后用乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，过滤，将滤液浓缩得粗品化合物。所得粗品经柱层析纯化得标题化合物(Int-A13b)(2.5g，收率79％)。
MS m/z(ES):220.9[M+H]+
第二步：化合物4-(2-(甲基氨基甲酰基)噻唑-5-基)哌嗪-1-羧酸酯叔丁酯(Int-A13c)的制备
化合物Int-A13b(300mg，1.36mmol)，哌嗪-1-羧酸叔丁酯(454mg,2.04mmol)和碳酸铯(1.33g，4.08mmol)溶于N，N-二甲基甲酰胺(5mL)中，将反应体系升温至120℃搅拌。待反应完全，向其中加入水(10mL)淬灭反应，然后用乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，过滤，将滤液浓缩得粗品化合物。所得粗品经柱层析纯化得标题化合物Int-A13c(70mg，收率：16％)。
MS m/z(ES):327.0[M+H]+
第三步：化合物N-甲基-5-(哌嗪-1-基)噻唑-2-酰胺盐酸盐(Int-A13)的制备
化合物Int-A13c(70mg,0.21mmol)溶于MeOH(5mL)中，加入HCl的1,4-二氧六环溶液(4M,0.53mL,2.1mmol)，在室温条件下搅拌。待LCMS监测反应完全，浓缩反应液，得标题化合物Int-A13的粗品化合物(60mg)，所得粗品直接用做下一步反应，未进一步纯化。
MS m/z(ES):227.0[M+H]+。
实施例A7：中间体N-甲基-2-(哌嗪-1-基)噻唑-5-酰胺盐酸盐(Int-A14)盐酸盐的制备
第一步至第三步：中间体N-甲基-2-(哌嗪-1-基)噻唑-5-酰胺盐酸盐(Int-A14)的制备
除使用化合物Int-A14a代替实施例A6第一步中的化合物Int-A13a之外，采用与实施例A6中第一步至第三步所描述的类似方法合成化合物Int-A14的粗品。所得粗品直接用做下一步反应，未进一步纯化。
MS m/z(ES):227.0[M+H]+
实施例A8：中间体N-环丙基-5-(哌嗪-1-基)吡啶甲酰胺盐酸盐(Int-A15)的制备
第一步至第三步：中间体N-环丙基-5-(哌嗪-1-基)吡啶甲酰胺盐酸盐(Int-A15)的制备
除使用化合物环丙胺代替实施例A1第二步中的40％甲胺水溶液之外，采用与实施例A1中第一步至第三步所描述的类似方法合成化合物Int-A15的粗品。所得粗品直接用做下一步反应，未进一步纯化。
MS m/z(ES):247.1[M+H]+
实施例A9：中间体1-(6-(二氟甲基)-2-甲基吡啶-3-基)哌嗪(Int-A17)盐酸盐的制备
第一步：化合物3-溴-6-(二氟甲基)-2-甲基吡啶(Int-A17b)的制备
将化合物Int-A17a(300mg,1.50mmol)溶于DCM(20mL)，然后滴加BAST(0.69mL,3.75mmol)。然后将反应体系升温至40℃搅拌。待LCMS监测反应完全，向其中加入饱和碳酸氢钠水溶液(50mL)淬灭反应，分层，水相用二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，过滤，将滤液浓缩得标题化合物Int-A17b的粗品。所得粗品直接用做下一步反应，未进一步纯化。
MS m/z(ES):221.9[M+H]+
第二步至第三步：中间体1-(6-(二氟甲基)-2-甲基吡啶-3-基)哌嗪(Int-A17)盐酸盐的制备
使用化合物Int-A17b代替实施例A3第一步中的化合物Int-A3a，使用哌嗪-1-甲酸叔丁酯代替实施例A3第一步中的化合物(1R，4R)-2,5-二氮杂双环[2.2.1]庚烷-2-羧酸叔丁酯，采用与实施例A3中第一步至第二步所描述的类似方法合成标题化合物Int-A17盐酸盐的粗品。所得粗品直接用做下一步反应，未进一步纯化。
MS m/z(ES):228.1[M+H]+
实施例A10：中间体2-氟-4-(哌嗪-1-基)苯甲腈(Int-A20)盐酸盐的制备
第一步：化合物4-(4-氰基-3-氟苯基)哌嗪-1-甲酸叔丁酯的制备
将化合物Int-A20a(1.1g,7.9mmol)、哌嗪-1-甲酸叔丁酯(1.0g,5.3mmol)和K2CO3(1.1g,7.9mmol)称入圆底烧瓶，加入DMSO(20mL)，加毕后升温至100℃反应过夜。待反应完后，向反应体系中加入水和乙酸乙酯稀释，分液，水相用乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，抽滤，滤液浓缩得到粗品化合物Int-A20b(2.2g，收率50％)。所得粗品直接用作下一步，未进一步纯化。
MS m/z(ES):306.1[M+H]+
第二步：化合物2-氟-4-(哌嗪-1-基)苯甲腈(Int-A20)的制备
将化合物Int-A20b(2.2g,7.2mmol)溶于1,4-二氧六环溶液(10mL)，在0℃下向其中加入HCl的1,4-二氧六环溶液(4M,15mL,60mmol)，随后缓慢升至室温搅拌。待反应完全，向反应体系中加入石油醚稀释，体系中有固体析出，过滤并用石油醚洗涤。收集固体并真空干燥得标题化合物Int-A20的盐酸盐(1.5g，收率：86％)。
MS m/z(ES):206.1[M+H]+
实施例A11：中间体2-(哌嗪-1-基)噻唑-5-腈(Int-A21)盐酸盐的制备
第一步：化合物4-(5-氰基噻唑-2-基)哌嗪-1-甲酸叔丁酯(Int-A21b)的制备
化合物Int-A21a(2.1g,11.0mmol)，哌嗪-1-甲酸叔丁酯(2.5g,13.1mmol)和碳酸铯(10.7g,32.9mmol)称入圆底烧瓶，加入1,4-二氧六环(30mL)，将反应体系升温至110℃反应过夜。待反应完全，向反应体系中加入水和乙酸乙酯稀释，分液，水相用乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，抽滤，滤液浓缩得到粗品化合物，所得粗品经硅胶柱纯化得标题化合物Int-A21b(2.6g,收率80％)。
MS m/z(ES):295.1[M+H]+
第二步：中间体2-(哌嗪-1-基)噻唑-5-腈(Int-A21)的制备
除使用化合物Int-A21b代替实施例A10第二步中的Int-A20b之外，采用与实施例A10中第二步所描述的类似方法合成标题化合物Int-A21的盐酸盐粗品。所得粗品直接用做下一步反应，未进一步纯化。
MS m/z(ES):195.1[M+H]+
实施例A12：中间体N-(2-甲氧基乙基)-6-甲基-5-(哌嗪-1-基)吡啶甲酰胺(Int-A22)盐酸盐的制备
第一步：化合物5-溴-N-(2-甲氧基乙基)-6-甲基吡啶甲酰胺(Int-A22b)的制备
化合物Int-A22a(5.0g,23.1mmol)，2-甲氧基乙胺(3.48g,46.3mmol)，HATU(17.6g,46.3mmol)和DIPEA(5.97g,46.3mmol)溶于DMF(40mL)中，反应体系维持室温搅拌。待LCMS监测反应完全，向其中加入水(50mL)淬灭反应，然后用乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，过滤，将滤液浓缩得粗品化合物。所得粗品经柱层析纯化得标题化合物Int-A22b(5.3g，收率73％)。
MS m/z(ES):273.0[M+H]+
第二步至第三步：中间体N-(2-甲氧基乙基)-6-甲基-5-(哌嗪-1-基)吡啶甲酰胺(Int-A22)的制备
除使用化合物Int-A22b代替实施例A3第一步中的Int-A3a之外，采用与实施例A3中第一步至第二步所描述的类似方法合成标题化合物Int-A22盐酸盐的粗品。所得粗品直接用做下一步反应，未进一步纯化。
MS m/z(ES):279.1[M+H]+
参考上述实施例A12中的合成方法，采用类似的反应条件，合成下列中间体化合物。

实施例B：7-(溴甲基)-5-氟-3-甲基喹喔啉-2(1H)-酮(Int-2)的制备
路线1：
第一步：化合物(4-溴-2-氟-6-硝基苯基)丙氨酸甲酯(Int-2b)的制备
化合物Int-2a(5.0g，21.0mmol)，丙氨酸甲酯盐酸盐(4.39g,31.5mmol)和DIPEA(14.6mL,84.0mmol)溶于1,4-二氧六环(70mL)中，将反应体系升温至110℃反应24小时。待反应完全，将反应液浓缩，所得粗品经硅胶柱纯化得标题化合物(Int-2b)(3.97g，收率73％)。
MS m/z(ES):321.0[M+H]+
第二步：化合物7-溴-5-氟-3-甲基-3,4-二氢喹喔啉-2(1H)-酮(Int-2c)的制备
化合物Int-2b(3.50g，10.9mmol)和连二亚硫酸钠(5.70g,32.7mmol)溶于DMSO(80mL)中，将反应体系升温至120℃反应4小时。待反应完全，将上述反应液降至0℃，缓慢向其中加入水(200mL)猝灭反应，然后用乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，过滤，将滤液浓缩得粗品化合物。所得粗品经柱层析纯化得标题化合物Int-2c(734mg，收率：26％)。
MS m/z(ES):259.0[M+H]+
第三步：化合物7-溴-5-氟-3-甲基喹啉-2(1H)-酮(Int-2d)的制备
化合物Int-2c(700mg，2.70mmol)和DDQ(683mg,3.01mmol)溶于1,4-二氧六环(20mL)中，在室温条件下反应4小时。待反应完全，浓缩反应液，向所得固体粗产品加入饱和碳酸氢钠水溶液(20mL)。搅拌2小时后，过滤，用水和饱和碳酸氢钠溶液洗涤，得标题化合物Int-2d(624mg，收率：90％)。
MS m/z(ES):257.0[M+H]+
第四步：化合物5-氟-3-甲基-7-乙烯基喹啉-2(1H)-酮(Int-2e)的制备
将化合物Int-2d(300g,1.17mmol)和三丁基乙烯基锡(740mg,2.33mmol)溶于甲苯(10mL)中，N2保护下加入Pd(PPh3)4(136mg,0.12mmol)，升温至100℃，反应过夜。将反应液浓缩得粗品化合物。所得粗品经柱层析纯化得标题化合物Int-2e(228mg，收率：95％)。
MS m/z(ES):205.1[M+H]+
第五步：化合物8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-甲醛(Int-2f)的制备
化合物Int-2e(800mg，3.86mmol)，二水合锇酸钾(60mg,0.193mmol)，2,6-二甲基吡啶(0.9mL,7.72mmol)和NaIO4(4.13g,19.3mmol)溶于THF(30mL)和水(20mL)中，室温反应过夜。待反应完全，向其中加入饱和氯化铵水溶液(50mL)淬灭反应，然后用二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，过滤，将滤液浓缩得粗品化合物。所得粗品经柱层析纯化得标题化合物Int-2f(711mg，收率：89％)。
MS m/z(ES)：207.1[M+H]+
第六步：化合物5-氟-7-羟甲基-3-甲基喹喔啉-2(1H)-酮(Int-2g)的制备
在0℃下，将化合物Int-2f(700mg，3.35mmol)溶于甲醇(20mL)中，加入NaBH4(253mg,6.70mmol)。 加毕后在0℃下反应1小时。待反应完全，在0℃下缓慢向其中加入水(2mL)淬灭反应，将反应液浓缩得粗品化合物。所得粗品经柱层析纯化得标题化合物Int-2g(504mg，收率：72％)。
MS m/z(ES)：209.1[M+H]+
第七步：化合物7-(溴甲基)-5-氟-3-甲基喹喔啉-2(1H)-酮(Int-2)的制备
在0℃下，化合物Int-2g(600mg，2.87mmol)，四溴化碳(1.90g,5.74mmol)和PPh3(1.51g,5.74mmol)溶于DCM(30mL)，0℃搅拌。待反应完全，将反应液浓缩得粗品化合物。所得粗品经柱层析纯化得标题化合物Int-2(163mg，收率：21％)。
MS m/z(ES)：271.0[M+H]+
路线2：
第一步：化合物(4-溴-2-氟-6-硝基苯基)丙氨酸甲酯(Int-2b)的制备
采用路线1中的第一步类似的操作，得到标题化合物(Int-2b)(6.20g，收率90％)。
MS m/z(ES):321.0[M+H]+
第二步：化合物7-溴-5-氟-3-甲基-3,4-二氢喹喔啉-2(1H)-酮(Int-2c)的制备
化合物Int-2b(6.20g,19.4mmol)和NH4Cl(20.7g,388mmol)溶于MeOH/H2O(70mL/7mL)中，将反应体系冷却至0℃，加入锌粉，加毕将反应体系升至25℃反应6小时。待反应完全，将反应体系过滤，甲醇洗涤滤饼，浓缩滤液得粗品化合物。所得粗品化合物Int-2-3(4.7g)直接用于下一步反应。
MS m/z(ES):259.0[M+H]+
第三步：化合物7-溴-5-氟-3-甲基喹啉-2(1H)-酮(Int-2d)的制备
采用路线1中的第三步类似的操作，得到粗品化合物。所得粗品化合物经柱层析纯化得Int-2d(2.5g，两步收率：50％)。
MS m/z(ES):257.0[M+H]+
第四步：化合物5-氟-7-羟甲基-3-甲基喹喔啉-2(1H)-酮(Int-2g)的制备
将化合物Int-2d(300mg,1.17mmol)和(三丁基锡)甲醇(450mg,1.41mmol)溶于二氧六环(10mL)中，N2保护下加入Xphos Pd G2(92mg,0.12mmol)，升温至80℃搅拌，反应过夜。将反应液浓缩得粗品化合物。所得粗品经柱层析纯化得标题化合物Int-2g(190mg，收率：78％)。
MS m/z(ES)：209.1[M+H]+
第五步：化合物7-(溴甲基)-5-氟-3-甲基喹喔啉-2(1H)-酮(Int-2)的制备
采用路线1中的第七步类似的操作，得到粗品化合物。所得粗品化合物经柱层析纯化得Int-2(148mg，收率：60％)。
MS m/z(ES)：271.0[M+H]+
实施例C:5-溴-7-(溴甲基)-3-3-甲基喹喔啉-2(1H)-酮(Int-3)的制备
第一步：化合物3-溴-4-氟-5-硝基苯甲酸甲酯(Int-3b)的制备
在0℃下，化合物Int-3a(5.0g，18.9mmol)溶于MeOH(100mL)中，然后向其中滴加SOCl2(4.1mL,56.7mmol)。将反应体系升至室温反应过夜。待反应完全，在0℃加入饱和碳酸氢钠(200mL)稀释，乙酸乙酯萃取三次，无水硫酸钠干燥，过滤，将滤液浓缩得粗品化合物。所得粗品经柱层析纯化得标题化合物Int-3b(4.47g，收率：86％)。
MS m/z(ES):278.0[M+H]+
第二步：化合物3-溴-4-(1-甲氧基-1-氧代丙烷-2-基)氨基-5-硝基苯甲酸甲酯(Int-3c)的制备
化合物Int-3b(4.4g，15.8mmol)，丙氨酸甲酯盐酸盐(4.41g,31.6mmol)和NaHCO3(4.0g,47.4mmol)溶于THF(70mL)。反应体系在室温条件下反应过夜。待反应完全，加入水(150mL)稀释，乙酸乙酯萃取三次，饱和食盐水洗涤有机相，无水硫酸钠干燥，过滤，将滤液浓缩得粗品化合物。所得粗品经柱层析纯化得标题化合物Int-3c(5.1g，收率：89％)。
MS m/z(ES):361.0[M+H]+
第三步至第四步：化合物8-溴-2-甲基-3-氧代-3,4-二氢喹喔啉-6-羧酸甲酯(Int-3e)的制备
除使用化合物Int-3c代替实施例B第二步中的化合物Int-2b之外，采用与实施例B中第二步至第三步所描述的类似方法合成化合物Int-3e的粗品。所得粗品经柱层析纯化得标题化合物Int-3e(1.4g，收率：25％)。
MS m/z(ES):297.0[M+H]+
第五步：化合物5-溴-7-羟甲基-3-甲基喹喔啉-2(1H)-酮(Int-3f)的制备
将化合物(Int-3e)(400mg,1.34mmol)溶于DCM(10mL)，反应液降至0℃后，向反应体系中加入DIBAL-H(1M in hexane,4.04mL,4.04mmol)，加毕，室温下反应过夜。待反应完全，0℃下向反应体系中加入饱和酒石酸钾钠水溶液(40mL)淬灭反应，加入二氯甲烷，分液，水相用二氯甲烷萃取三遍，合并有机相，无水硫酸钠干燥，抽滤，将滤液浓缩，得到粗品化合物，所得粗品经硅胶柱纯化得到标题化合物(Int-3f)(220mg，收率61％)。
MS m/z(ES):269.0[M+H]+
第六步：化合物5-溴-7-(溴甲基)-3-甲基喹喔啉-2(1H)-酮(Int-3)的制备
除使用化合物Int-3f代替实施例B第七步中的化合物Int-2g之外，采用与实施例B中第七步所描述的类似方法合成化合物Int-3的粗品。所得粗品经制备硅胶板纯化得标题化合物Int-3(120mg，收率31％)。
MS m/z(ES):471.1[M+H]+
实施例D:化合物7-(溴甲基)-5,6-二氟-3-甲基喹喔啉-2(1H)-酮(Int-4)的制备
第一步：化合物2,3-二氟-4-((1-甲氧基-1-氧代丙-2-基)氨基)-5-硝基苯甲酸甲酯(Int-4b)的制备
化合物Int-4a(4.0g,17.0mmol)，丙氨酸甲酯盐酸盐(3.31g,23.8mmol)和DIPEA(4.39g,34.0mmol)溶于THF(70mL)中，反应体系维持室温反应。待反应完全，缓慢向其中加入水(200mL)淬灭反应，然后用乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，过滤，将滤液浓缩得标题化合物Int-4b的粗品化合物(5.41g)。所得粗品未进一步纯化，直接用作下一步反应。
MS m/z(ES):319.0[M+H]+
第二步：化合物7,8-二氟-2-甲基-3-氧代-1,2,3,4-四氢喹喔啉-6-甲酸甲酯(Int-4c)的制备
将上述粗品化合物Int-4b(5.41g,17.0mmol)和连二亚硫酸钠(8.87g,51.0mmol)溶于DMSO(80mL)中，将反应体系升温至120℃搅拌。待反应完全，将上述反应液降至0℃，缓慢向其中加入水(200mL)淬灭反应，然后用乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，过滤，将滤液浓缩得粗品化合物。所得粗品经柱层析纯化得标题化合物Int-4c(1.63g，两步收率：37％)。
MS m/z(ES):257.0[M+H]+
第三步：化合物7,8-二氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-甲酸甲酯(Int-4d)的制备
将化合物(Int-4c)(1.63g,6.36mmol)和DDQ(1.6g,7.00mmol)溶于1,4-二氧六环(40mL)中，在室温条件下搅拌。待反应完全，浓缩反应液，向所得固体粗产品加入饱和碳酸氢钠水溶液(20mL)。搅拌2小时后，过滤，滤饼用水和饱和碳酸氢钠溶液洗涤，收集固体，干燥得标题化合物Int-4d(1.17g，收率：72％)
MS m/z(ES):255.0[M+H]+
第四步：化合物5,6-二氟-7-(羟甲基)-3-甲基喹喔啉-2(1H)-酮(Int-4e)的制备
将化合物(Int-4d)(1.17g,4.60mmol)溶于DCM(30mL)，冰水浴冷至0℃后，向反应体系中加入DIBAL-H(1M in toluene,13.8mL,13.8mmol)，加毕，维持0℃搅拌。待反应完全，0℃下向反应体系中加入饱和酒石酸钾钠水溶液(40mL)淬灭反应，加入二氯甲烷稀释，搅拌30分钟后，分液，水相用二氯甲烷萃取三遍，合并有机相，无水硫酸钠干燥，抽滤，将滤液浓缩，得到粗品化合物，所得粗品经硅胶柱纯化得到标题化合物(Int-4e)(800mg，收率77％)。
MS m/z(ES):227.0[M+H]+
第五步：化合物7-(溴甲基)-5,6-二氟-3-甲基喹喔啉-2(1H)-酮(Int-4)的制备
在0℃下，向化合物Int-4e(115mg,0.51mmol)和四溴化碳(505mg,1.53mmol)的DCM(10mL)溶液中，加入PPh3(401mg,1.53mmol)，反应体系维持0℃搅拌。待反应完全，将反应液浓缩得粗品化合物。所得粗品经柱层析纯化得标题化合物Int-4(110mg，收率：75％)。
MS m/z(ES)：289.0[M+H]+
实施例E:7-(溴甲基)-3,5-二甲基喹喔啉-2(1H)-酮(Int-5)的制备
第一步：化合物(4-溴-2-甲基-6-硝基苯基)-L-丙氨酸甲酯(Int-5b)的制备
化合物Int-5a(5.0g，21.4mmol)、L-丙氨酸甲酯盐酸盐(4.47g,32.1mmol)和DIPEA(14.6mL,84.0mmol)溶于1,4-二氧六环(70mL)中，将反应体系升温至110℃反应搅拌。待反应完全，将反应体系冷至室温，加水和乙酸乙酯稀释体系，分层，水相用乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，抽滤，将滤液浓缩，得标题化合物(Int-5b)的粗品(6.6g)。所得粗品未进一步纯化，直接用做下一步反应。
MS m/z(ES):317.0[M+H]+
第二步：化合物(S)-7-溴-3,5-二甲基-3,4-二氢喹喔啉-2(1H)-酮(Int-5c)的制备
将上述粗品化合物Int-5b(6.6g,20.8mmol)溶于THF/EtOH(100mL/100mL)中，降温至0℃，在氮气氛围下加入二氯化锡(11.8g,62.2mmol)，然后升至室温搅拌。待反应完全，将反应液浓缩，残余物用水和二氯甲烷稀释，再用饱和碳酸氢钠溶液调节水相pH至9～10，垫硅藻土过滤，滤去不溶物，用二氯甲烷洗涤滤饼。滤液分层，水相用二氯甲烷萃取三次，合并有机相，用无水硫酸钠干燥，过滤，将滤液浓缩得标题化合物Int-5c的粗品(4.2g)。所得粗品直接用做下一步反应，未进一步纯化。
MS m/z(ES):255.0[M+H]+
第三步：化合物7-溴-3,5-二甲基喹喔啉-2(1H)-酮(Int-5d)的制备
将上述粗品化合物Int-5c(4.2g,16.5mmol)溶于二氯甲烷(100mL)中，加入二氧化锰(7.2g,82.8mmol),于室温下反应过夜。待反应完全，垫硅藻土过滤，滤饼用甲醇洗涤三次，滤液浓缩至干，得标题化合物Int-5d的粗品(4.0g)。所得粗品直接用做下一步反应，未进一步纯化。
MS m/z(ES):253.0[M+H]+
第四步至第五步：化合物7-(溴甲基)-3,5-二甲基喹喔啉-2(1H)-酮(Int-5)的制备
除使用化合物Int-5d代替实施例B路线2第四步中的化合物Int-2d之外，采用与实施施例B路线2第四步至第五步所描述的类似方法合成化合物Int-5的粗品。所得粗品经柱层析纯化得标题化合物Int-5(760mg，五步收率：13％)。
MS m/z(ES)：267.0[M+H]+
实施例F:化合物7-(溴甲基)-3,6-二甲基喹喔啉-2(1H)-酮(Int-6)的制备
第一步至第三步：化合物2,7-二甲基-3-氧代-3,4-二氢喹喔啉-6-甲酸甲酯(Int-6d)的制备
除使用化合物Int-6a代替实施例B路线2第一步中的化合物Int-2a之外，采用与实施例B路线2第一步至第三步所描述的类似方法合成化合物Int-6d的粗品。所得粗品经柱层析纯化得标题化合物Int-6d(7.1g，三步收率：75％)。
MS m/z(ES)：233.0[M+H]+
第四步至第五步：化合物7-(溴甲基)-3,6-二甲基喹喔啉-2(1H)-酮(Int-6)的制备
除使用化合物Int-6d代替实施例D第四步中的化合物Int-4d之外，采用与实施例D第四步至第五步所描述的类似方法合成化合物Int-6的粗品。所得粗品经柱层析纯化得标题化合物Int-6(101mg，两步收率：41％)。
MS m/z(ES)：267.0[M+H]+
实施例G:化合物7-(溴甲基)-5-氯-3-甲基喹喔啉-2(1H)-酮(Int-9)的制备
第一步至第二步：化合物(S)-7-溴-5-氯-3-甲基-3,4-二氢喹喔啉-2(1H)-酮(Int-9c)的制备
除使用化合物Int-9a代替实施例B路线2第一步中的化合物Int-2a之外，采用与实施例B路线2第一步至第二步所描述的类似方法合成化合物Int-9c的粗品(2.41g)。所得粗品未进一步纯化，直接用作下一步。
MS m/z(ES)：274.9[M+H]+
第三步：化合物(S)-5-氯-7-羟甲基-3-甲基-3,4-二氢喹喔啉-2(1H)-酮(Int-9d)的制备
除使用化合物Int-9c代替实施例B路线2第四步中的化合物Int-2d之外，采用与实施例B路线2第四步所描述的类似方法合成化合物Int-9d的粗品。所得粗品经柱层析纯化得标题化合物Int-9d(157mg，三步收率：35％)。
MS m/z(ES)：227.0[M+H]+
第四步：化合物5-氯-7-羟甲基-3-甲基喹喔啉-2(1H)-酮(Int-9e)的制备
除使用化合物Int-9d代替实施例B路线2第三步中的化合物Int-2c之外，采用与实施例B路线2第三步所描述的类似方法合成化合物Int-9e的粗品。所得粗品经柱层析纯化得标题化合物Int-9e(53mg，收率：34％)。
MS m/z(ES)：225.0[M+H]+
第五步：化合物7-(溴甲基)-5-氯-3-甲基喹喔啉-2(1H)-酮(Int-9)的制备
除使用化合物Int-9e代替实施例B路线2第五步中的化合物Int-2g之外，采用与实施例B路线2第五步所描述的类似方法合成化合物Int-9的粗品。所得粗品经柱层析纯化得标题化合物Int-9(64mg，收率：93％)。
MS m/z(ES)：286.9[M+H]+
参考实施例B至实施例G中的合成方法，采用类似的反应条件，合成下列中间体化合物。
实施例1：5-(4-(8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(1)的制备
第一步：5-(4-(8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(1)的制备
化合物Int-2(50mg，0.185mmol)，化合物Int-1(41mg,0.185mmol)和DIPEA(0.10mL,0.57mmol)溶于乙腈(4mL)。将反应体系升温至70℃反应2小时。待反应完全，将反应液浓缩得粗品化合物。所得粗品经制备硅胶板纯化得标题化合物1(21.04mg，收率：28％)。
MS m/z(ES)：411.2[M+H]+。
1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),8.40(q,J＝4.4Hz,1H),8.27(d,J＝2.8Hz,1H),7.84(d,J＝8.4Hz,1H),7.39(dd,J＝8.8,2.8Hz,1H),7.13–7.06(m,2H),3.60(s,2H),3.39–3.31(m,4H),2.78(d,J＝4.8Hz,3H),2.59–2.53(m,4H),2.41(s,3H).
实施例2：5-(4-((8-溴-2-甲基-3-氧代-3,4--二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(2)的制备
除使用化合物Int-3代替实施例1中的化合物Int-2之外，采用与实施例1中所描述的类似方法合成化合物2的粗品。所得粗品经制备硅胶板纯化得标题化合物2(9.33mg)。
MS m/z(ES)：471.1[M+H]+
实施例3：化合物5-(6-(8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-N,6-二甲基吡啶酰胺(3)的制备
除使用化合物Int-A2代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物3的粗品。所得粗品经制备硅胶板纯化得标题化合物3(8.04mg)。
MS m/z(ES)：437.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.38(q,J＝5.2Hz,1H),7.78(d,J＝8.4Hz,1H),7.61(d,J＝8.4Hz,1H),7.08(s,1H),7.04(d,J＝12.4Hz,1H),3.72–3.61(m,6H),3.39(d,J＝10.8Hz,2H),2.81(d,J＝4.8Hz,3H),2.63(s,3H),2.53–2.51(m,1H),2.37(s,3H),1.86(d,J＝8.0Hz,1H).
实施例4：化合物5-((1S,4S)-5-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)-2,5-二氮杂双环[2.2.1]庚烷-2-基)-N,6-二甲基吡啶酰胺(4)的制备
除使用化合物Int-A4代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物4的粗品。所得粗品经制备硅胶板纯化得标题化合物4(11.5mg)。
MS m/z(ES)：437.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.37(s,1H),8.29(q,J＝4.8Hz,1H),7.65(d,J＝8.0Hz,1H),7.10(d,J＝8.8Hz,1H),7.06(s,1H),7.05(d,J＝12.8Hz,1H),4.24(s,1H),3.74(s,2H),3.65–3.57(m,1H),3.53(s,1H),3.36–3.30(m,1H),2.87–2.81(m,1H),2.79(d,J＝4.8Hz,3H),2.77–2.71(m,1H),2.51(s,3H),2.39(s,3H),1.97–1.90(m,1H),1.85–1.78(m,1H).
实施例5：化合物5-(6-(8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)-3,6-二氮杂双环[3.1.1]庚烷-3-基)-N-甲基吡啶酰胺(5)的制备
除使用化合物Int-A6代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物5的粗品。所得粗品经制备硅胶板纯化得标题化合物5(3.21mg)。
MS m/z(ES)：423.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.36(s,1H),8.37(q,J＝4.8Hz,1H),8.11(d,J＝2.8Hz,1H),7.89(d,J＝8.8Hz,1H),7.20(dd,J＝8.8,2.8Hz,1H),7.11(s,1H),7.10(d,J＝9.6Hz,1H),3.74(d,J＝6.0Hz,2H),3.61(s,2H),3.59(d,J＝11.2Hz,2H),3.43(d,J＝11.6Hz,2H),2.80(d,J＝5.2Hz,3H),2.63–2.55(m,1H),2.40(s,3H),1.63(d,J＝8.4Hz,1H).
实施例6：化合物5-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶酰胺(6)的制备
除使用化合物Int-A7代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物6的粗品。所得粗品经制备硅胶板纯化得标题化合物6(6.48mg)。
MS m/z(ES)：425.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.41(q,J＝4.8Hz,1H),7.79(d,J＝8.4Hz,1H),7.48(d,J＝8.4Hz,1H),7.07(s,1H),7.05(d,J＝10.8Hz,1H),3.61(s,2H),3.00–2.91(m,4H),2.80(d,J＝4.8Hz,3H),2.62–2.54(m,4H),2.49(s,3H),2.40(s,3H).
实施例7：化合物6-氯-5-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(7)的制备
除使用化合物Int-A8代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物7的粗品。所得粗品经制备硅胶板纯化得标题化合物7(2.05mg)。
MS m/z(ES)：445.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.45(s,1H),8.43(q,J＝4.8Hz,1H),7.94(d,J＝8.0Hz,1H),7.67(d,J＝8.0Hz,1H),7.11(d,J＝11.2Hz,1H),7.09(s,1H),3.63(s,2H),3.18–3.09(m,4H),2.79(d,J＝4.8Hz,3H),2.66–2.56(m,4H),2.41(s,3H).
实施例8：化合物5-(4-((7,8-二氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-甲基吡啶酰胺(8)的制备
除使用化合物Int-4代替实施例1中的化合物Int-2之外，采用与实施例1中所描述的类似方法合成化合物8的粗品。所得粗品经制备硅胶板纯化得标题化合物8(8.11mg)。
MS m/z(ES)：429.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.40(q,J＝4.8Hz,1H),8.26(d,J＝2.8Hz,1H),7.82(d,J＝8.8Hz,1H),7.39(dd,J＝8.8,2.8Hz,1H),7.08–7.04(m,1H),3.68(s,2H),3.39–3.31(m,4H),2.78(d,J＝4.8Hz,3H),2.61–2.56(m,4H),2.37(s,3H).
实施例9：化合物5-(4-((7,8-二氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶酰胺(9)的制备
用化合物Int-4代替实施例1中的化合物Int-2，化合物Int-A7代替实施例1中的化合物Int-1，采用与实施例1中所描述的类似方法合成化合物9的粗品。所得粗品经制备硅胶板纯化得标题化合物9(26.62mg)。
MS m/z(ES)：443.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.42(q,J＝4.4Hz,1H),7.79(d,J＝8.4Hz,1H),7.47(d,J＝8.0Hz,1H),7.12–7.04(m,1H),3.70(s,2H),2.99–2.92(m,4H),2.80(d,J＝4.8Hz,3H),2.65–2.58(m,4H),2.48(s,3H),2.38(s,3H).
实施例10：化合物5-(4-((2,8-二甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶酰胺(10)的制备
用化合物Int-5代替实施例1中的化合物Int-2，化合物Int-A7代替实施例1中的化合物Int-1，采用与实施例1中所描述的类似方法合成化合物10的粗品。所得粗品经制备硅胶板纯化得标题化合物10(9.66mg)。
MS m/z(ES)：421.2[M+H]+
1H NMR(400MHz,DMSO-d6))δ12.23(s,1H),8.43(q,J＝4.8Hz,1H),7.79(d,J＝8.0Hz,1H),7.47(d,J＝8.4Hz,1H),7.15–7.04(m,2H),3.57(s,2H),2.99–2.91(m,4H),2.79(d,J＝4.8Hz,3H),2.63–2.54(m,4H),2.54(s,3H),2.48(s,3H),2.40(s,3H).
实施例11：化合物3-乙基-5-氟-7-((4-(6-(3-羟基氧杂环丁烷-3-基)-2-甲基吡啶-3-基)哌嗪-1-基)甲基)喹喔啉-2(1H)-酮(11)的制备
除使用化合物Int-A9代替实施例1中的化合物Int-1，化合物Int-7代替实施例1中的化合物Int-2之外，采用与实施例1中所描述的类似方法合成化合物11的粗品。所得粗品经制备硅胶板纯化得标题化合物11(6.30mg)。
MS m/z(ES)：454.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),7.43(d,J＝8.4Hz,1H),7.37(d,J＝8.4Hz,1H),7.09–7.00(m,2H),6.33(s,1H),4.88(d,J＝6.0Hz,2H),4.60(d,J＝6.0Hz,2H),3.61(s,2H),2.95–2.84(m,4H),2.79(q,J＝7.6Hz,2H),2.63–2.53(m,4H),2.47(s,3H),1.21(t,J＝7.6Hz,3H).
实施例12：化合物5-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基吡啶腈(12)的制备
除使用化合物Int-A18代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物12的粗品。所得粗品经制备硅胶板纯化得标题化合物12(45.17mg)。
MS m/z(ES)：393.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),7.80(d,J＝8.4Hz,1H),7.48(d,J＝8.4Hz,1H),7.12–7.07(m,2H),3.62(s,2H),3.05–2.97(m,4H),2.63–2.54(m,4H),2.46(s,3H),2.41(s,3H).
实施例13：化合物5-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)吡啶腈(13)的制备
除使用化合物Int-A19代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物13的粗品。所得粗品经制备硅胶板纯化得标题化合物13(5.46mg)。
MS m/z(ES)：379.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),8.42(d,J＝3.2Hz,1H),7.75(d,J＝8.4Hz,1H),7.36(dd,J＝8.8,2.8Hz,1H),7.12–7.06(m,2H),3.60(s,2H),3.47–3.40(m,4H),2.56–2.50(m,4H),2.41(s,3H).
实施例14：化合物5-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲氧基-N-甲基吡啶酰胺(14)的制备
除使用化合物Int-A10代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物14的粗品。所得粗品经制备硅胶板纯化得标题化合物14(66.65mg)。
MS m/z(ES)：441.2[M+H]+
1H NMR(400MHz,DMSO-d6))δ8.30(q,J＝4.8Hz,1H),7.54(d,J＝8.0Hz,1H),7.25(d,J＝8.0Hz,1H),7.04(s,1H),7.00(d,J＝11.2Hz,1H),3.99(s,3H),3.58(s,2H),3.16–3.05(m,4H),2.81(d,J＝4.8Hz,3H),2.59–2.52(m,4H),2.38(s,3H).
实施例15：化合物4-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-甲基噻唑-2-甲酰胺(15)的制备
除使用化合物Int-A12代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物15的粗品。所得粗品经制备硅胶板纯化得标题化合物15(12.8mg)。
MS m/z(ES)：417.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.54(q,J＝4.4Hz,1H),7.13–7.07(m,2H),6.57(s,1H),3.60(s,2H),3.32–3.26(m,4H),2.77(d,J＝4.8Hz,3H),2.56–2.52(m,4H),2.41(s,3H).
实施例16：化合物5-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-甲基噻唑-2-甲酰胺(16)的制备
除使用化合物Int-A13代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物16的粗品。所得粗品经制备硅胶板纯化得标题化合物16(15.78mg)。
MS m/z(ES)：417.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.38(s,1H),8.38(q,J＝4.4Hz,1H),7.13(s,1H),7.11–7.05(m,2H),3.60(s,2H),3.27–3.18(m,4H),2.74(d,J＝4.8Hz,3H),2.59–2.53(m,4H),2.41(s,3H).
实施例17：化合物2-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-甲基噻唑-5-甲酰胺(17)的制备
除使用化合物Int-A14代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物17的粗品。所得粗品经制备硅胶板纯化得标题化合物17(15.78mg)。
MS m/z(ES)：417.1[M+H]+
实施例18：化合物2-氟-4-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)苯甲腈(18)的制备
除使用化合物Int-A20代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物18的粗品。所得粗品经制备硅胶板纯化得标题化合物18(5.92mg)。
MS m/z(ES)：396.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),7.59(t,J＝8.4Hz,1H),7.12–7.05(m,2H),6.95(dd,J＝14.0,2.4Hz,1H),6.85(dd,J＝9.2,2.4Hz,1H),3.59(s,2H),3.44–3.36(m,4H),2.51–2.47(m,4H),2.41(s,3H).
实施例19：化合物4-(4-((2,8-二甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-2-氟苯甲腈(19)的制备
除使用化合物Int-5代替实施例18中的化合物Int-2之外，采用与实施例18中所描述的类似方法合成化合物19的粗品。所得粗品经制备硅胶板纯化得标题化合物19(4.63mg)。
MS m/z(ES)：392.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.19(s,1H),7.62–7.56(m,1H),7.12–7.07(m,2H),6.94(dd,J＝14.0,2.4Hz,1H),6.85(dd,J＝9.2,2.4Hz,1H),3.54(s,2H),3.43–3.36(m,4H),2.54(s,3H),2.51–2.45(m,4H),2.41(s,3H).
实施例20：化合物N-环丙基-5-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)吡啶甲酰胺(20)的制备
除使用化合物Int-A15代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物20的粗品。所得粗品经制备硅胶板纯化得标题化合物20(1.29mg)。
MS m/z(ES)：437.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.35(d,J＝5.2Hz,1H),8.24(d,J＝2.8Hz,1H),7.83(d,J＝8.8Hz,1H),7.40(dd,J＝8.8,2.8Hz,1H),7.14–7.06(m,2H),3.60(s,2H),3.38–3.31(m,4H),2.89–2.80(m,1H),2.58–2.53(m,4H),2.41(s,3H),0.70–0.64(m,2H),0.64–0.58(m,2H).
实施例21：化合物5-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-(2-甲氧基乙基)-6-甲基吡啶甲酰胺(21)的制备
除使用化合物Int-A22代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物21的粗品。所得粗品经制备硅胶板纯化得标题化合物21(4.0mg)。
MS m/z(ES)：469.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),8.44–8.35(m,1H),7.81(d,J＝8.0Hz,1H),7.50(d,J＝8.4Hz,1H),7.14–7.06(m,2H),3.62(s,2H),3.49–3.42(m,4H),3.27(s,3H),3.04–2.89(m,4H),2.64–2.55(m,4H),2.49(s,3H),2.41(s,3H).
实施例22：化合物5-(4-((2,8-二甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-(2-甲氧基乙基)-6-甲基吡啶甲酰胺(22)的制备
除使用化合物Int-5代替实施例21中的化合物Int-2之外，采用与实施例21中所描述的类似方法合成化合物22的粗品。所得粗品经制备硅胶板纯化得标题化合物22(10.0mg)。
MS m/z(ES)：465.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.21(s,1H),8.43–8.36(m,1H),7.81(d,J＝8.4Hz,1H),7.49(d,J＝8.4Hz,1H),7.12(s,1H),7.11(s,1H),3.58(s,2H),3.49–3.41(m,4H),3.27(s,3H),3.00–2.91(m,4H),2.62–2.53(m,4H),2.55(s,3H),2.41(s,3H).
实施例23：化合物2-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)噻唑-5-腈(23)的制备
除使用化合物Int-A21代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物23的粗品。所得粗品经制备硅胶板纯化得标题化合物23(4.0mg)。
MS m/z(ES)：385.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),8.02(s,1H),7.12–7.05(m,2H),3.61(s,2H),3.59–3.53(m,4H),2.57–2.50(m,4H),2.41(s,3H).
实施例24：化合物(S)-5-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N-甲基吡啶酰胺(24)的制备
除使用化合物Int-A11代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物24的粗品。所得粗品经制备硅胶板纯化得标题化合物24(7.00mg)。
MS m/z(ES)：425.2[M+H]+
1H NMR(600MHz,DMSO-d6)δ12.48(s,1H),8.36(q,J＝4.8Hz,1H),8.21(d,J＝3.0Hz,1H),7.82(d,J＝9.0Hz,1H),7.33(dd,J＝9.0,3.0Hz,1H),7.13(s,1H),7.11(d,J＝11.4Hz,1H),4.25–4.20(m,1H),3.65(d,J＝13.8Hz,1H),3.60(d,J＝12.0Hz,1H),3.52(d,J＝14.4Hz,1H),3.10(td,J＝12.0,3.6Hz,1H),2.92(d,J＝10.2Hz,1H),2.78(d,J＝4.8Hz,3H),2.72(d,J＝10.8Hz,1H),2.41(s,3H),2.33(dd,J＝11.4,3.6Hz,1H),2.22(td,J＝11.4,3.6Hz,1H),1.15(d,J＝6.0Hz,3H).
实施例25：化合物(R)-5-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)-2-甲基哌嗪-1-基)-N-甲基吡啶酰胺(25)的制备
除使用化合物Int-A5代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物25的粗品。所得粗品经制备硅胶板纯化得标题化合物25(3.66mg)。
MS m/z(ES)：425.2[M+H]+
1H NMR(600MHz,DMSO-d6)δ12.48(s,1H),8.36(q,J＝4.8Hz,1H),8.21(d,J＝3.0Hz,1H),7.82(d,J＝9.0Hz,1H),7.33(dd,J＝9.0,3.0Hz,1H),7.13(s,1H),7.11(d,J＝11.4Hz,1H),4.25–4.20(m,1H),3.65(d,J＝13.8Hz,1H),3.60(d,J＝12.0Hz,1H),3.52(d,J＝14.4Hz,1H),3.10(td,J＝12.0,3.6Hz,1H),2.92(d,J＝10.2Hz,1H),2.78(d,J＝4.8Hz,3H),2.72(d,J＝10.8Hz,1H),2.41(s,3H),2.33(dd,J＝11.4,3.6Hz,1H),2.22(td,J＝11.4,3.6Hz,1H),1.15(d,J＝6.0Hz,3H).
实施例26：化合物7-((4-(6-(二氟甲基)-2-甲基吡啶-3-基)哌嗪-1-基)甲基)-5-氟-3-甲基喹喔啉-2(1H)-酮(26)的制备
除使用化合物Int-A17代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物26的粗品。所得粗品经制备硅胶板纯化得标题化合物26(12.62mg)。
MS m/z(ES)：418.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ7.52(d,J＝8.4Hz,1H),7.46(d,J＝8.0Hz,1H),7.10–7.02(m,2H),6.81(t,J＝55.2Hz,1H),3.61(s,2H),3.00–2.89(m,4H),2.65–2.53(m,4H),2.46(s,3H),2.40(s,3H).
实施例27：化合物7-((4-(6-(二氟甲基)吡啶-3-基)哌嗪-1-基)甲基)-5-氟-3-甲基喹喔啉-2(1H)-酮(27)的制备
除使用化合物Int-A16代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物27的粗品。所得粗品经制备硅胶板纯化得标题化合物27(50.20mg)。
MS m/z(ES)：403.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.35(d,J＝2.8Hz,1H),7.49(d,J＝8.8Hz,1H),7.42(dd,J＝8.8,2.8Hz,1H),7.13–7.06(m,2H),6.81(t,J＝55.2Hz,1H),3.60(s,2H),3.36–3.29(m,4H),2.59–2.52(m,4H),2.41(s,3H).
实施例28：化合物N-(2,2-二氟乙基)-5-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基吡啶甲酰胺(28)的制备
除使用化合物Int-A23代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物28的粗品。所得粗品经制备硅胶板纯化得标题化合物28(3.30mg)。
MS m/z(ES)：475.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.73(t,J＝6.0Hz,1H),7.84(d,J＝8.4Hz,1H),7.51(d,J＝8.4Hz,1H),7.14–7.06(m,2H),6.13(tt,J＝56.4,4.0Hz,,1H),3.76–3.64(m,2H),3.63(s,2H),3.02–2.93(m,4H),2.64–2.56(m,4H),2.51(s,3H),2.41(s,3H).
实施例29：化合物5-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-(2-氟乙基)-6-甲基吡啶甲酰胺(29)的制备
除使用化合物Int-A24代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物29的粗品。所得粗品经制备硅胶板纯化得标题化合物29(8.93mg)。
MS m/z(ES)：457.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),8.66–8.54(m,1H),7.83(d,J＝8.0Hz,1H),7.51(d,J＝8.0Hz,1H),7.17–7.03(m,2H),4.54(dt,J＝47.2,5.2Hz,2H),3.67–3.52(m,4H),3.05–2.88(m,4H),2.65–2.55(m,4H),2.51(s,3H),2.42(s,3H).
实施例30：化合物5-(4-((2-乙基-8-氟-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-(2-氟乙基)-6-甲基吡啶甲酰胺(30)的制备
除使用化合物Int-7代替实施例29中的化合物Int-2之外，采用与实施例29中所描述的类似方法合成化合物30的粗品。所得粗品经制备硅胶板纯化得标题化合物30(9.83mg)。
MS m/z(ES)：471.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.36(s,1H),8.59(t,J＝6.0Hz,1H),7.82(d,J＝8.4Hz,1H),7.50(d,J＝8.4Hz,1H),7.15–7.07(m,2H),4.54(dt,J＝47.6,5.2Hz,2H),3.68–3.50(m,4H),3.02–2.91(m,4H),2.81(q,J＝7.4Hz,2H),2.65–2.55(m,4H),2.51(s,3H),1.22(t,J＝7.2Hz,3H).
实施例31：化合物5-(4-((2-乙基-8-氟-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-(2-羟乙基)-6-甲基吡啶甲酰胺(31)的制备
除使用化合物Int-A26代替实施例30中的化合物Int-A24之外，采用与实施例30中所描述的类似方法合成化合物31的粗品。所得粗品经制备硅胶板纯化得标题化合物31(5.80mg)。
MS m/z(ES)：469.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),8.40(t,J＝5.6Hz,1H),7.81(d,J＝8.0Hz,1H),7.50(d,J＝8.4Hz,1H),7.09–7.00(m,2H),4.79(s,1H),3.62(s,2H),3.54–3.47(m,2H),3.39–3.33(m,2H),3.01–2.91(m,4H),2.79(q,J＝7.2Hz,2H),2.64–2.55(m,4H),2.49(s,3H),1.21(t,J＝7.6Hz,3H).
实施例32：化合物5-(4-((2-乙基-8-氟-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(32)的制备
除使用化合物Int-A7代替实施例30中的化合物Int-A24之外，采用与实施例30中所描述的类似方法合成化合物32的粗品。所得粗品经制备硅胶板纯化得标题化合物32(9.00mg)。
MS m/z(ES)：439.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.41(q,J＝4.8Hz,1H),7.79(d,J＝8.0Hz,1H),7.49(d,J＝8.0Hz,1H),7.00(s,1H),6.92(d,J＝11.2Hz,1H),3.59(s,2H),3.00–2.90(m,4H),2.80(d,J＝4.8Hz,3H),2.76(q,J＝7.6Hz,2H),2.63–2.54(m,4H),2.48(s,3H),1.19(t,J＝7.6Hz,3H).
实施例33：化合物5-(4-((2-乙基-8-氟-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(氧杂环丁烷-3-基甲基)吡啶甲酰胺(33)的制备
除使用化合物Int-A25代替实施例30中的化合物Int-A24之外，采用与实施例30中所描述的类似方法合成化合物33的粗品。所得粗品经制备硅胶板纯化得标题化合物33(6.6mg)。
MS m/z(ES)：495.2[M+H]+
实施例34：化合物5-(4-((2-乙基-8-氟-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-(2-甲氧基乙基)-6-甲基吡啶甲酰胺(34)的制备
除使用化合物Int-A22代替实施例30中的化合物Int-A24之外，采用与实施例30中所描述的类似方法合成化合物34的粗品。所得粗品经制备硅胶板纯化得标题化合物34(13.70mg)。
MS m/z(ES)：483.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.43–8.36(m,1H),7.82(d,J＝8.4Hz,1H),7.50(d,J＝8.0Hz,1H),7.13–7.04(m,2H),3.63(s,2H),3.48–3.43(m,4H),3.27(s,3H),3.00–2.91(m,4H),2.81(q,J＝7.6Hz,2H),2.65–2.55(m,4H),2.50(s,3H),1.22(t,J＝7.2Hz,3H).
实施例35：化合物4-(4-((2-乙基-8-氟-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-2-氟苯甲腈(35)的制备
除使用化合物Int-A20代替实施例30中的化合物Int-A24之外，采用与实施例30中所描述的类似 方法合成化合物35的粗品。所得粗品经制备硅胶板纯化得标题化合物35(5.60mg)。
MS m/z(ES)：410.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),7.59(t,J＝8.4Hz,1H),7.12–7.05(m,2H),6.95(dd,J＝14.4,2.4Hz,1H),6.85(dd,J＝9.2,2.4Hz,1H),3.59(s,2H),3.45–3.37(m,4H),2.80(q,J＝7.2Hz,2H),2.53–2.47(m,4H),1.21(t,J＝7.2Hz,3H).
实施例36：化合物5-(4-((7,8-二氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-(2-甲氧基乙基)-6-甲基吡啶甲酰胺(36)的制备
除使用化合物Int-A22代替实施例8中的化合物Int-1之外，采用与实施例8中所描述的类似方法合成化合物36的粗品。所得粗品经制备硅胶板纯化得标题化合物36(13.58mg)。
MS m/z(ES)：487.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.43–8.36(m,1H),7.81(d,J＝8.4Hz,1H),7.49(d,J＝8.4Hz,1H),7.17(d,J＝4.8Hz,1H),3.73(s,2H),3.48–3.43(m,4H),3.27(s,3H),3.01–2.91(m,4H),2.67–2.56(m,4H),2.49(s,3H),2.43(s,3H).
实施例37：化合物6-氯-5-(4-((7-甲氧基-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺(37)的制备
除使用化合物Int-8代替实施例7中的化合物Int-2之外，采用与实施例7中所描述的类似方法合成化合物37的粗品。所得粗品经制备硅胶板纯化得标题化合物37(1.06mg)。
MS m/z(ES)：457.1[M+H]+
实施例38：化合物5-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N,3-二甲基吡啶甲酰胺(38)的制备
除使用化合物Int-A36代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物38的粗品。所得粗品经制备硅胶板纯化得标题化合物38(9.72mg)。
MS m/z(ES)：425.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),8.31(q,J＝4.8Hz,1H),8.11(d,J＝2.4Hz,1H),7.19–7.05(m,3H),3.60(s,2H),3.35–3.29(m,4H),2.74(d,J＝4.8Hz,3H),2.60–2.51(m,7H),2.41(s,3H).
实施例39：化合物3-氟-5-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺(39)的制备
除使用化合物Int-A37代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物39的粗品。所得粗品经制备硅胶板纯化得标题化合物39(2.81mg)。
MS m/z(ES)：429.1[M+H]+
实施例40：化合物5-(4-((2,7-二甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(40)的制备
除使用化合物Int-6代替实施例6中的化合物Int-2之外，采用与实施例6中所描述的类似方法合成化合物40的粗品。所得粗品经制备硅胶板纯化得标题化合物40(1.35mg)。
MS m/z(ES)：421.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.18(s,1H),8.42(q,J＝4.4Hz,1H),7.80(d,J＝8.4Hz,1H),7.51(s,1H),7.48(d,J＝8.4Hz,1H),7.26(s,1H),3.59(s,2H),3.01–2.91(m,4H),2.80(d,J＝5.2Hz,3H),2.65–2.55(m,4H),2.50(s,3H),2.40(s,3H),2.39(s,3H).
实施例41：化合物5-(4-((7-甲氧基-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(41)的制备
除使用化合物Int-8代替实施例40中的化合物Int-6之外，采用与实施例40中所描述的类似方法合成化合物41的粗品。所得粗品经制备硅胶板纯化得标题化合物41(7.19mg)。
MS m/z(ES)：437.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),8.42(q,J＝4.8Hz,1H),7.81(d,J＝8.0Hz,1H),7.48(d,J＝8.4Hz,1H),7.38(s,1H),7.26(s,1H),3.85(s,3H),3.63(s,2H),3.02–2.91(m,4H),2.80(d,J＝4.8Hz,3H),2.67–2.57(m,4H),2.50(s,3H),2.39(s,3H).
实施例42：化合物5-(4-((2-乙基-8-氟-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(氧杂环丁烷-3-基)吡啶甲酰胺(42)的制备
除使用化合物Int-A30代替实施例30中的化合物Int-A24之外，采用与实施例30中所描述的类似 方法合成化合物42的粗品。所得粗品经制备硅胶板纯化得标题化合物42(8.23mg)。
MS m/z(ES)：481.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),9.08(d,J＝7.2Hz,1H),7.79(d,J＝8.4Hz,1H),7.49(d,J＝8.4Hz,1H),7.15–7.08(m,2H),5.08–4.95(m,1H),4.73(t,J＝6.4Hz,2H),4.66(t,J＝6.8Hz,2H),3.63(s,2H),3.03–2.92(m,4H),2.81(q,J＝7.6Hz,2H),2.66–2.56(m,4H),2.53(s,3H),1.22(t,J＝7.6Hz,3H).
实施例43：化合物N-环丙基-5-(4-((2-乙基-8-氟-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基吡啶甲酰胺(43)的制备
除使用化合物Int-A29代替实施例30中的化合物Int-A24之外，采用与实施例30中所描述的类似方法合成化合物43的粗品。所得粗品经制备硅胶板纯化得标题化合物43(5.86mg)。
MS m/z(ES)：465.2[M+H]+
实施例44：化合物5-(4-((2-乙基-8-氟-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-((1s,3s)-3-羟基环丁基)-6-甲基吡啶甲酰胺(44)的制备
除使用化合物Int-A32代替实施例30中的化合物Int-A24之外，采用与实施例30中所描述的类似方法合成化合物44的粗品。所得粗品经制备硅胶板纯化得标题化合物44(7.83mg)。
MS m/z(ES)：495.2[M+H]+
实施例45：化合物5-(4-((2-乙基-8-氟-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-((1r,3r)-3-羟基环丁基)-6-甲基吡啶甲酰胺(45)的制备
除使用化合物Int-A31代替实施例30中的化合物Int-A24之外，采用与实施例30中所描述的类似方法合成化合物45的粗品。所得粗品经制备硅胶板纯化得标题化合物45(4.56mg)。
MS m/z(ES)：495.2[M+H]+
实施例46：化合物(R)-5-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(四氢呋喃-3-基)吡啶甲酰胺(46)的制备
除使用化合物Int-A33代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物46的粗品。所得粗品经制备硅胶板纯化得标题化合物46(2.38mg)。
MS m/z(ES)：481.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),8.36(d,J＝7.2Hz,1H),7.80(d,J＝8.4Hz,1H),7.49(d,J＝8.4Hz,1H),7.13–7.06(m,2H),4.52–4.38(m,1H),3.91–3.77(m,2H),3.76–3.67(m,1H),3.62(s,2H),3.59(dd,J＝8.8,4.4Hz,1H),3.03–2.91(m,4H),2.64–2.55(m,4H),2.50(s,3H),2.41(s,3H),2.23–2.11(m,1H),1.99–1.88(m,1H).
实施例47：化合物(R)-5-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(四氢呋喃-3-基)吡啶甲酰胺(47)的制备
除使用化合物Int-A34代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物47的粗品。所得粗品经制备硅胶板纯化得标题化合物47(6.98mg)。
MS m/z(ES)：481.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),8.36(d,J＝7.2Hz,1H),7.80(d,J＝8.4Hz,1H),7.49(d,J＝8.4Hz,1H),7.13–7.06(m,2H),4.52–4.38(m,1H),3.91–3.77(m,2H),3.76–3.67(m,1H),3.62(s,2H),3.59(dd,J＝8.8,4.4Hz,1H),3.03–2.91(m,4H),2.64–2.55(m,4H),2.50(s,3H),2.41(s,3H),2.23–2.11(m,1H),1.99–1.88(m,1H).
实施例48：化合物(R)-5-(4-((2-乙基-8-氟-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-(2-羟丙基)-6-甲基吡啶甲酰胺(48)的制备
除使用化合物Int-A28代替实施例30中的化合物Int-A24之外，采用与实施例30中所描述的类似方法合成化合物48的粗品。所得粗品经制备硅胶板纯化得标题化合物48(4.62mg)。
MS m/z(ES)：483.2[M+H]+
实施例49：化合物(S)-5-(4-((2-乙基-8-氟-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-(2-羟丙基)-6-甲基吡啶甲酰胺(49)的制备
除使用化合物Int-A27代替实施例30中的化合物Int-A24之外，采用与实施例30中所描述的类似方法合成化合物49的粗品。所得粗品经制备硅胶板纯化得标题化合物49(3.54mg)。
MS m/z(ES)：483.2[M+H]+
实施例50：化合物N-(2-羟乙基)-5-(4-((7-甲氧基-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基吡啶甲酰胺(50)的制备
除使用化合物Int-8代替实施例31中的化合物Int-7之外，采用与实施例31中所描述的类似方法合成化合物50的粗品。所得粗品经制备硅胶板纯化得标题化合物50(2.56mg)。
MS m/z(ES)：467.2[M+H]+
实施例51：化合物5-(4-((8-氯-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N,6-二甲基吡啶甲酰胺(51)的制备
除使用化合物Int-9代替实施例40中的化合物Int-6之外，采用与实施例40中所描述的类似方法合成化合物51的粗品。所得粗品经制备硅胶板纯化得标题化合物51(3.19mg)。
MS m/z(ES)：441.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.42(q,J＝5.2Hz,1H),7.79(d,J＝8.4Hz,1H),7.48(d,J＝8.4Hz,1H),7.08–6.98(m,2H),3.55(s,2H),3.02–2.87(m,4H),2.80(d,J＝4.8Hz,3H),2.64–2.54(m,4H),2.48(s,3H),2.32(s,3H).
实施例52：化合物(R)-5-(4-((7,8-二氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(四氢呋喃-3-基)吡啶甲酰胺(52)的制备
除使用化合物Int-4代替实施例46中的化合物Int-2之外，采用与实施例46中所描述的类似方法合成化合物52的粗品。所得粗品经制备硅胶板纯化得标题化合物52(6.85mg)。
MS m/z(ES)：499.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.37(d,J＝7.6Hz,1H),7.80(d,J＝8.4Hz,1H),7.48(d,J＝8.4Hz, 1H),7.10(d,J＝4.4Hz,1H),4.51–4.40(m,1H),3.91–3.79(m,2H),3.75–3.67(m,3H),3.59(dd,J＝8.8,4.4Hz,1H),3.01–2.89(m,4H),2.67–2.58(m,4H),2.50(s,3H),2.40(s,3H),2.23–2.11(m,1H),2.00–1.88(m,1H).
实施例53：化合物5-(4-((7,8-二氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基-N-(氧杂环丁烷-3-基甲基)吡啶甲酰胺(53)的制备
除使用化合物Int-A25代替实施例52中的化合物Int-A33之外，采用与实施例52中所描述的类似方法合成化合物53的粗品。所得粗品经制备硅胶板纯化得标题化合物53(3.99mg)。
MS m/z(ES)：499.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.68(t,J＝6.0Hz,1H),7.81(d,J＝8.4Hz,1H),7.48(d,J＝8.4Hz,1H),7.15(d,J＝5.2Hz,1H),4.60(dd,J＝7.6,6.0Hz,2H),4.34(t,J＝6.0Hz,2H),3.72(s,2H),3.56(t,J＝6.8Hz,2H),3.21–3.12(m,1H),3.01–2.89(m,4H),2.67–2.58(m,4H),2.50(s,3H),2.42(s,3H).
实施例54：化合物5-(4-((7,8-二氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-(2-氟乙基)-6-甲基吡啶甲酰胺(54)的制备
除使用化合物Int-A24代替实施例52中的化合物Int-A33之外，采用与实施例52中所描述的类似方法合成化合物54的粗品。所得粗品经制备硅胶板纯化得标题化合物54(8.88mg)。
MS m/z(ES)：475.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.50(s,1H),8.61(t,J＝5.6Hz,1H),7.83(d,J＝8.4Hz,1H),7.51(d,J＝8.0Hz,1H),7.21(s,1H),4.54(dt,J＝47.6,4.4Hz,2H),3.67–3.52(m,4H),3.08–2.88(m,4H),2.77–2.57(m,4H),2.51(s,3H),2.44(s,3H).
实施例55：化合物N-环丙基-5-(4-((8-氟-2-甲基-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-6-甲基吡啶甲酰胺(55)的制备
除使用化合物Int-A29代替实施例1中的化合物Int-1之外，采用与实施例1中所描述的类似方法合成化合物55的粗品。所得粗品经制备硅胶板纯化得标题化合物55(6.01mg)。
MS m/z(ES)：451.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),8.32(d,J＝4.8Hz,1H),7.79(d,J＝8.4Hz,1H),7.48(d,J＝8.4Hz,1H),7.14–7.06(m,2H),3.62(s,2H),3.03–2.91(m,4H),2.89–2.80(m,1H),2.63–2.55(m,4H),2.48(s,3H),2.41(s,3H),0.72–0.66(m,2H),0.66–0.60(m,2H)..
实施例56：化合物5-(4-((2-环丙基-8-氟-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N，6- 二甲基吡啶甲酰胺(56)的制备
除使用化合物Int-10代替实施例6中的化合物Int-2之外，采用与实施例6中所描述的类似方法合成化合物55的粗品。所得粗品经制备硅胶板纯化得标题化合物55(40.2mg)。
MS m/z(ES)：451.2[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.45(s,1H),8.46–8.37(m,1H),7.80(d,J＝8.0Hz,1H),7.48(d,J＝8.4Hz,1H),7.12–7.02(m,2H),3.61(s,2H),3.01–2.89(m,4H),2.80(d,J＝4.8Hz,3H),2.73–2.64(m,1H),2.63–2.54(m,4H),2.49(s,3H),1.12–1.03(m,4H).
实施例57：化合物6-氯-5-(4-((2-环丙基-8-氟-3-氧代-3,4-二氢喹喔啉-6-基)甲基)哌嗪-1-基)-N-甲基吡啶甲酰胺(57)的制备
除使用化合物Int-A8代替实施例56中的化合物Int-A7之外，采用与实施例56中所描述的类似方法合成化合物57的粗品。所得粗品经制备硅胶板纯化得标题化合物57(13.4mg)。
MS m/z(ES)：471.1[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),8.46–8.38(m,1H),7.94(d,J＝8.0Hz,1H),7.67(d,J＝8.0Hz,1H),7.11–7.04(m,2H),3.61(s,2H),3.20–3.04(m,4H),2.79(d,J＝4.8Hz,3H),2.73–2.64(m,1H),2.63–2.54(m,4H),1.12–1.03(m,4H).
药理试验评价
试验例1：BRCA1突变的MDA-MB-436细胞增殖抑制测试
1、试验原理
利用CCK-8测定不同药物浓度下细胞中线粒体内脱氢酶的含量，通过发光强度反应细胞活性。用存活率计算不同化合物对BRCA1突变的MDA-MB-436细胞的IC50值，研究本发明化合物对BRCA1突变的MDA-MB-436细胞的增殖抑制作用，用来评价测试化合物在细胞水平的抗肿瘤药效。
2、试验材料
2.1、试验试剂及仪器：
MDA-MB-436细胞专用培养基(DMEM),普诺赛；
胎牛血清：Fetal Bovine Serum(FBS),Hyclone；
磷酸盐缓冲液：Phosphate Buffered Saline(PBS),Gibico；
二甲基亚砜：DMSO，Sigma；
CCK-8,碧云天；
96孔细胞培养板，Coring；
离心机，Eppendorf；
CO2培养箱，Thermo Scientific；
显微镜，OLYMMPUS；
全自动细胞计数仪，Gibco；
多功能酶标仪(Omega),BMG。
2.2、试验细胞：
MDA-MB-436细胞，购至普诺赛。
2.3化合物
受试药：化合物AZD5305和AZD9574购自成都叮当时代医药科技股份有限公司；
受试药：化合物1-57分别依次由实施例1-57合成方法制备获得；
3、试验方法
3.1、试验步骤
Day-1将细胞按照固定的细胞密度接种至96孔细胞培养板中，放到37℃、5％CO2细胞培养箱中过夜培养。
Day 0将待测化合物配制成10mM母液，稀释浓度为1000nM、300nM、100nM、30nM、10nM、3nM、1nM、0.3nM、0.1nM，9个浓度点，两复孔。取固定体积的稀释化合物加入到96孔细胞培养板，放到37℃、5％CO2细胞培养箱中培养5天。
Day 5将固定体积的CCK-8加到96孔细胞培养板，在37℃、5％CO2细胞培养箱中孵育1.5h，用多功能酶标化学发光模块读板。
3.2、数据分析
计算公式
以浓度的对数值作为X轴，百分比存活率为Y轴，采用分析软件Graphpad Prism 9的log(inhibitor)vs.response-Variable slop(Four parameters)公式拟合量效曲线，从而得出各个化合物对BRCA1突变的MDA-MB-436细胞抗增殖抑制活性的IC50值。
4、试验结果
按上述方法测定化合物对BRCA1突变的MDA-MB-436细胞增殖的抑制活性，结果见表1。
表1化合物对BRCA1突变的MDA-MB-436细胞抑制活性
5、试验结论：
从表1化合物对BRCA1突变的MDA-MB-436细胞抑制活性试验数据可知，本申请化合物对BRCA1突变的MDA-MB-436细胞具有较强的细胞增殖抑制活性，且相比阳性对照AZD9574具有明显的优势。
试验例2：BRCA1突变的HCC1395细胞增殖抑制测试
1、试验原理
利用CCK-8测定不同药物浓度下细胞中线粒体内脱氢酶的含量，通过发光强度反应细胞活性。用存活率计算不同化合物对BRCA1突变的HCC1395细胞的IC50值，研究本发明化合物对BRCA1突变的HCC1395细胞的增殖抑制作用，用来评价测试化合物在细胞水平的抗肿瘤药效。
2、试验材料
2.1、试验试剂及仪器：
RPMI-1640培养基，Hyclone；
胎牛血清：Fetal Bovine Serum(FBS)，Gibco；
磷酸盐缓冲液：Phosphate Buffered Saline(PBS)，维森特生物技术(南京)有限公司；
二甲基亚砜：DMSO，Sigma；
CCK-8，碧云天；
96孔细胞培养板，Coring；
离心机，Eppendorf；
CO2培养箱，Thermo Scientific；
显微镜，OLYMMPUS；
全自动细胞计数仪，Gibco；
多功能酶标仪(Omega)，BMG。
2.2、试验细胞：
HCC1395细胞，购至ATCC。
2.3化合物
与试验例1中记载的相同的方法获得所测试的化合物。
3、试验方法
3.1、试验步骤
Day-1将细胞按照固定的细胞密度接种至96孔细胞培养板中，放到37℃、5％CO2细胞培养箱中过夜培养。
Day 0将待测化合物配制成10mM母液，稀释浓度为1000nM、300nM、100nM、30nM、10nM、3nM、1nM、0.3nM、0.1nM，9个浓度点，两复孔。取固定体积的稀释化合物加入到96孔细胞培养板，放到37℃、5％CO2细胞培养箱中培养5天。
Day 5将固定体积的CCK-8加到96孔细胞培养板，在37℃、5％CO2细胞培养箱中孵育1.5h，用多功能酶标化学发光模块读板。
3.2、数据分析
计算公式
以浓度的对数值作为X轴，百分比存活率为Y轴，采用分析软件Graphpad Prism 9的log(inhibitor)vs.response-Variable slop(Four parameters)公式拟合量效曲线，从而得出各个化合物对BRCA1突变的HCC1395细胞抗增殖抑制活性的IC50值。
4、试验结果
按上述方法测定化合物对BRCA1突变的HCC1395细胞增殖的抑制活性，结果见表2。
表2化合物对BRCA1突变的HCC1395细胞抑制活性
5、试验结论：
从表2化合物对BRCA1突变的HCC1395细胞抑制活性试验数据可知，本申请化合物对BRCA1突变的HCC1395细胞具有较强的细胞增殖抑制活性，且相比阳性对照AZD9574具有一定的优势。
试验例3：PARP1和PARP2酶活性测试
1、试验目的
通过本试验评价测试化合物对PARP1和PARP2酶活的影响，同时利用抑制率计算测试化合物对PARP1和PARP2酶的IC50值。
2、试验材料
2.1、化合物：
与试验例1中记载的相同的方法获得所测试的化合物。
2.2、试验试剂及仪器
PARP1Chemiluminescent assay kit，BPS，80551；
PARP2Chemiluminescent assay kit，BPS，80552；
PBS，In house，20210819；
Tween-20，Sigma，P9416；
96-well polypropylene plate，Nunc，249944；
Centrifuge，湘仪，TDZ5-WS；
Plate reader，BMG，PHERAstar FSX。
3、试验方法
3.1、化合物配置
化合物10mM储存液配置：将化合物粉末溶解在100％DMSO中，分别配置成10mM的化合物储存液。
3.2、酶反应过程
(1)用PBS按1:5稀释5x histone mixture，每孔加入50μL，4℃孵育过夜。
(2)用200μL PBST缓冲液洗涤三次，在Blocking buffer中孵育90min。
(3)用200μL PBST缓冲液洗涤三次。
(4)每孔加5μL抑制剂溶液。
(5)每孔加入20μL稀释后的PARP。
(6)每孔加入25μL biotinylated substrate，室温孵育1h。
(7)用200μL PBST缓冲液清洗孔三次，用干净的纸巾吸干。
(8)每孔加入50μL稀释过的Streptavidin-HRP，孵育30分钟。
(9)用200μL PBST缓冲液洗涤三次。
(10)每孔加100μL ELISA ECL substrate A和ELISA ECL substrate B的混合物。
(11)立即读取化学发光信号值。
3.3、数据分析
计算公式
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hillslope))
以化合物浓度的对数值作为X轴，以化学发光信号为Y轴，顶部和底部是与Y相同单位的平台，LogIC50与X相同的对数单位，Hillslop为Slop factor or Hill slope，通过非线性回归方程拟合IC50值。
4、试验结果
按上述方法测定本申请化合物对PARP1和PARP2的酶学抑制活性，结果见表3。
表3化合物对PARP1和PARP2的酶学抑制活性
5、试验结论：
从表3化合物对PARP1和PARP2的酶学抑制活性试验数据可知，本申请化合物在酶学水平对PARP1具有较强抑制活性，对PARP2抑制作用较弱，且部分化合物对PARP1和PARP2的酶学选择性与阳性对照AZD9574相当，相比化合物AZD5305具有明显的优势，可以改善由PARP2引发的血液毒性。
试验例4：大鼠药代动力学的研究
1、试验原理
以SD大鼠为受试动物，应用LC-MS/MS法测定了大鼠口服本发明化合物后不同时刻血浆中的血药浓度。获取本申请的化合物在大鼠体内的药代动力学参数，研究其药代动力学特征。
2、试验材料
2.1、化合物：
与试验例1中记载的相同的方法获得所测试的化合物。
2.2、试验仪器：
岛津LC-30A AB API4500串联质谱仪、真空采血管、采血针、滤纸、注射器等。
2.3、试验动物
SD大鼠，雌性，体重180-220g，每组3只。动物购回后饲养于动物房，适应期至少3天，检疫合格后用于试验。
3、试验方法
3.1、分组：根据表4随机分组，分组后，SD大鼠体重组间无统计学差异。
表4试验分组及给药方案
3.2、溶媒：10％DMSO+90％(20％SBE-β-CD in saline)。
3.3、血样采集测定：
按照表4分别将各化合物用溶媒配制成澄清溶液，对各组灌胃给予相应受试药，给药前、给药后15min、30min、1h、2h、4h、6h、8h、24h，经颈静脉窦采血取固定体积的血量，置于EDTA-K2抗凝管中，4000rpm，离心10min，分离血浆于离心管中，-80℃冰箱冷冻。
3.4、分析方法
取出-80℃保存的各时间点血浆，再加入固定体积的乙腈，涡旋1500转2min后，离心15min(3500r/min)，取固定体积的溶液上清液进行LC-MS/MS分析。
4、药代动力学参数计算：
对受试化合物的药代动力学行为进行非房室模型拟合，并采用DAS3.31软件计算主要药代动力学参数，结果见表5。
表5本申请测试化合物的药代动力学参数

5、试验结论：
从表5试验结果可知，相比阳性对照AZD9574，本申请的多个化合物在动物体内的血液暴露量更高、最大血药浓度更高、清除率更低，具有更好的药代动力学性质。

Claims (13)

  1. 化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，所述化合物具有式(I)的结构：
    其中：
    X选自N、CH或CRa，其中Ra选自卤素、C1-4烷基、C3-6环烷基、-O-(C1-4烷基)或卤代C1-4烷基；
    Y选自N、CH或CRb，其中Rb选自卤素、氰基、C1-4烷基、C2-6烯基、C3-6环烷基、4-6元杂环基或-ORz，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自氟、氰基、羟基、C1-4烷基或-O-(C1-4烷基)的取代基取代；
    条件是：当X选自N或CH时，Y选自CRb；
    当X选自CRa时，Y选自N、CH或CRb；
    R1选自氢、卤素、氰基、C1-4烷基、-O-(C1-4烷基)、-O-(卤代C1-4烷基)或卤代C1-4烷基；
    R2选自氢、F、Cl、Br、氰基、C1-4烷基、C3-6环烷基、-O-(C1-4烷基)或卤代C1-4烷基；
    R3选自氰基、C1-4烷基、C3-6环烷基或4-6元杂环基，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自F、氰基、C1-4烷基、C3-6环烷基、4-6元杂环基、-O-(C1-4烷基)或卤代C1-4烷基的取代基取代；
    Q选自N或CRc，其中Rc选自F、羟基、氰基、C1-4烷基、-O-(C1-4烷基)或卤代C1-4烷基；
    R4和R5在每次出现时各自独立地选自氢、C1-4烷基，或R4和R5相互连接成环；
    选自苯基或含有1至2个选自N、O或S原子的五元或六元杂芳基；
    R6在每次出现时各自独立地选自氢、卤素、氰基、-ORz、-C(＝O)-Rz、-C(＝O)-NH-Rz、C1-4烷基、C3-6环烷基或4-6元杂环基，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自F、氰基、羟基、C1-4烷基、-O-(C1-4烷基)或卤代C1-4烷基的取代基取代；
    n为1、2或3；
    Rz在每次出现时各自独立地选自氢、C1-4烷基、C3-6环烷基或4-6元杂环基，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自F、氰基、羟基、C1-4烷基、-O-(C1-4烷基)或氟代C1-4烷基的取代基取代。
  2. 根据权利要求1所述的式(I)的化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，其特征在于：
    X选自N、CH或CRa，其中Ra选自F、Cl、Br、C1-4烷基、C3-6环烷基、-OMe或氟代C1-4烷基；优选地，Ra选自F、Cl、Br、甲基、乙基、异丙基、环丙基、-OMe、-CF3、-CHF2或-CH2F；更为优选地，Ra选自F、Cl、Br、甲基、环丙基、-OMe、-CHF2或-CH2F；
    Y选自N、CH或CRb，其中Rb选自F、Cl、Br、氰基、甲基、乙基、异丙基、环丙基、环丁基、氧杂环丁基、氧杂环己基或-ORz，其中所述甲基、乙基、异丙基、环丙基、环丁基、氧杂环丁基、氧杂环己基是未取代的或各自独立地被一个或多个选自氟、氰基、羟基、甲基或-OMe的取代基取代；优选地，Rb选自F、Cl、Br、氰基、甲基、乙基、异丙基、环丙基、环丁基、氧杂环丁基或-ORz，其中所述甲基、乙基、异丙基、环丙基、环丁基是未取代的或各自独立地被一个或两个选自氟、氰基、羟基或甲基的取代基取代；
    条件是：当X选自N或CH时，Y选自CRb；
    当X选自CRa时，Y选自N、CH或CRb。
  3. 根据权利要求1或2所述的式(I)的化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，其特征在于：
    R1选自氢、F、Cl、Br、氰基、甲基、乙基、异丙基、-OMe、-O-(氟代C1-4烷基)或氟代C1-4烷基； 优选地，R1选自氢、F、Cl、甲基、-OMe、-CHF2或-CH2F。
  4. 根据权利要求1-3任一项所述的式(I)的化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，其特征在于：
    R2选自氢、F、Cl、Br、氰基、甲基、乙基、环丙基、-OMe或氟代C1-4烷基；优选地，R2选自氢、F、Cl、Br、甲基、环丙基、-OMe、-CHF2或-CH2F。
  5. 根据权利要求1-4任一项所述的式(I)的化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，其特征在于：
    R3选自氰基、甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基，其中所述甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基是未取代的或各自独立地被一个或多个选自F、氰基、甲基、环丙基、-OMe或氟代C1-4烷基的取代基取代；
    优选地，R3选自氰基、甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基，其中所述甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基是未取代的或各自独立地被一个或两个选自F、氰基、-OMe、-CHF2或-CH2F的取代基取代。
  6. 根据权利要求1-5任一项所述的式(I)的化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，其特征在于：
    Q选自N或CRc，其中Rc选自F、羟基、氰基、甲基、乙基、-OMe或氟代C1-4烷基；
    优选地，Q选自N或CRc，其中Rc选自F、羟基、氰基、甲基、-OMe、-CHF2或-CH2F；
    更为优选地，Q选自N或CRc，其中Rc选自F、羟基、-OMe或甲基；
    R4和R5在每次出现时各自独立地选自氢、甲基、乙基，或R4和R5相互连接成环；
    优选地，R4和R5在每次出现时各自独立地选自氢或甲基，或R4和R5相互连接成环，形成
    更为优选地，所述R4和R5在每次出现时各自独立地选自氢或甲基，或R4和R5相互连接成环，形成
  7. 根据权利要求1-6任一项所述的式(I)的化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，其特征在于：
    选自苯基、吡啶、嘧啶、吡嗪、哒嗪、吡唑、噁唑、异噁唑、噻吩或噻唑；
    优选地，选自苯基、吡啶、吡唑、噁唑、噻吩或噻唑；
    更为优选地，选自
    R6在每次出现时各自独立地选自氢、F、Cl、Br、氰基、-ORz、-C(＝O)-Rz、-C(＝O)-NH-Rz、甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基，其中所述甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基是未取代的或各自独立地被一个或多个选自F、氰基、羟基、甲基、-OMe、-CF3或-CHF2的取代基取代；
    优选地，R6在每次出现时各自独立地选自氢、F、Cl、Br、氰基、-ORz、-C(＝O)-Rz、-C(＝O)-NH-Rz、甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基，其中所述甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基是未取代的或各自独立地被一个或两个选自F、羟基或-OMe的取代基取代；
    Rz在每次出现时各自独立地选自氢、甲基、乙基、异丙基、环丙基、环丁基、氧杂环丁基或氧杂环戊基，其中所述甲基、乙基、异丙基、环丙基、环丁基或氧杂环戊基是未取代的或各自独立地被一个或多个选自氟、氰基、-OH、-OMe、氧杂环丁基或甲基的取代基取代；
    n为1或2。
  8. 化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，所述化合物具有式(II)的结构：
    其中：
    R1选自氢、F、Cl、Br、氰基、甲基、乙基、异丙基或-OMe；
    R2选自氢、卤素、氰基、C1-4烷基、C3-6环烷基、-O-(C1-4烷基)或氟代C1-4烷基；
    R3选自氰基、甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基，其中所述甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基是未取代的或各自独立地被一个或多个选自F、氰基、甲基、环丙基或-OMe的取代基取代；
    Rb选自F、Cl、Br、氰基、C1-4烷基、C3-6环烷基、4-6元杂环基或-ORz，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自氟、氰基、羟基、C1-4烷基或-O-(C1-4烷基)的取代基取代；
    R4和R5在每次出现时各自独立地选自氢、C1-4烷基，或R4和R5相互连接成环，形成
    选自苯基、吡啶、嘧啶、吡嗪、哒嗪、吡唑、噁唑、异噁唑、噻吩或噻唑；
    R6在每次出现时各自独立地选自氢、卤素、氰基、-ORz、-C(＝O)-Rz、-C(＝O)-NH-Rz、C1-4烷基、C3-6环烷基或4-6元杂环基，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自F、氰基、羟基、C1-4烷基、-O-(C1-4烷基)或卤代C1-4烷基的取代基取代；
    n为1、2或3；
    Rz在每次出现时各自独立地选自氢、C1-4烷基、C3-6环烷基或4-6元杂环基，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自F、氰基、羟基、C1-4烷基、-O-(C1-4烷基)、4-6元杂环基或氟代C1-4烷基的取代基取代。
  9. 化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，所述化合物具有式(III)的结构：
    其中：
    R1选自氢、F、Cl、甲基、-OMe、-CHF2或-CH2F；
    R2选自氢、卤素、氰基、C1-4烷基、C3-6环烷基、-O-(C1-4烷基)或卤代C1-4烷基；
    R3选自氰基、甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基，其中所述甲基、乙基、异丙基、环丙基、环丁基或氧杂环丁基是未取代的或各自独立地被一个或两个选自F、氰基、甲基、环丙基或-OMe的取代基取代；
    Rb选自F、Cl、Br、氰基、甲基、乙基、异丙基、环丙基、环丁基、氧杂环丁基或-ORz，其中所述甲基、乙基、异丙基、环丙基、环丁基是未取代的或各自独立地被一个或两个选自氟、氰基、羟基或甲基的取代基取代；
    R4和R5在每次出现时各自独立地选自氢、C1-4烷基，或R4和R5相互连接成环，形成
    选自
    R7选自氢、F、Cl、Br、氰基、C1-4烷基、C3-6环烷基、4-6元杂环基或-ORz，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自F、氰基、羟基、C1-4烷基、-O-(C1-4烷基)或卤代C1-4烷基的取代基取代；
    n为1或2；
    Rz在每次出现时各自独立地选自氢、C1-4烷基、C3-6环烷基或4-6元杂环基，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自F、氰基、羟基、C1-4烷基、-O-(C1-4烷基)、4-6元杂环基或氟代C1-4烷基的取代基取代。
  10. 化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，所述化合物具有式(IV)的结构：
    其中，
    R2选自氢、F、Cl、Br、氰基、C1-4烷基、C3-6环烷基、-O-(C1-4烷基)或氟代C1-4烷基；
    R3选自氰基、甲基、乙基、正丙基、异丙基、环丙基、环丁基或4-6元杂环基，其中所述甲基、乙基、正丙基、异丙基、环丙基、环丁基或4-6元杂环基是未取代的或各自独立地被一个或多个F、氰基、甲基或-OMe的取代基取代；
    Rb选自F、Cl、Br、氰基、甲基、乙基、正丙基、异丙基、环丙基、环丁基、氧杂环丁基或-ORz，其中所述甲基、乙基、正丙基、异丙基、环丙基、环丁基是未取代的或各自独立地被一个或两个选自氟、氰基、羟基或甲基的取代基取代；
    R4和R5在每次出现时各自独立地选自氢、甲基或乙基，或R4和R5相互连接成环，形成
    R7选自氢、卤素、氰基、-ORz、C1-4烷基、C3-6环烷基或4-6元杂环基，其中所述C1-4烷基、C3-6环烷基或4-6元杂环基是未取代的或各自独立地被一个或多个选自F、羟基、甲基、乙基、甲氧基或乙氧基的取代基取代；
    n为1或2；
    Rz在每次出现时各自独立地选自氢、甲基、乙基、正丙基、异丙基、环丙基、环丁基、氧杂环丁基或氧杂环戊基，其中所述甲基、乙基、正丙基、异丙基、环丙基或环丁基是未取代的或各自独立地被一个或多个选自F、氰基、羟基、甲基、乙基、甲氧基、乙氧基、氧杂环丁基或氟甲基的取代基取代。
  11. 根据权利要求1、8、9或10任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，其中所述化合物选自：






  12. 一种药物组合物，所述组合物包括：有效剂量的根据权利要求1-11任一项所述的式(I)的化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，以及药学上可接受的载体和/或赋形剂；或进一步包括一种或多种其他治疗剂。
  13. 根据权利要求1-11中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体或N-氧化物，或根据权利要求12所述的药物组合物在制备PARP1抑制剂中的用途；所述PARP1抑制剂在制备用于治疗癌症的药物中的用途；优选地，所述癌症为由PARP1介导的BRCA基因缺陷型肿瘤；更为优选地，所述肿瘤选自乳腺癌、卵巢癌、胰腺癌、前列腺癌、结直肠癌、膀胱癌、胃肠道癌、肺癌或血液瘤。
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