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WO2024260422A1 - Tricyclic compound and medical uses thereof - Google Patents

Tricyclic compound and medical uses thereof Download PDF

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Publication number
WO2024260422A1
WO2024260422A1 PCT/CN2024/100408 CN2024100408W WO2024260422A1 WO 2024260422 A1 WO2024260422 A1 WO 2024260422A1 CN 2024100408 W CN2024100408 W CN 2024100408W WO 2024260422 A1 WO2024260422 A1 WO 2024260422A1
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Prior art keywords
alkyl
membered
compound
alternatively
optionally substituted
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PCT/CN2024/100408
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French (fr)
Chinese (zh)
Inventor
敖汪伟
徐斌
李煜
王辉
张钰
Original Assignee
正大天晴药业集团股份有限公司
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Publication of WO2024260422A1 publication Critical patent/WO2024260422A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • the present disclosure relates to a tricyclic compound, a preparation method thereof, a pharmaceutical composition containing the compound, and use thereof in treating diseases.
  • KIF18A is a mitotic kinesin that belongs to the Kinesin-8 family. KIF18A regulates correct chromosome positioning and spindle tension during mitosis. Loss of KIF18A in humans leads to longer spindles and increased chromosome oscillations during the G2/M phase of the cell cycle. Studies have shown that KIF18A is overexpressed in whole-genome doubling (WGD) tumor cells, but is non-essential in normal cells. Inhibition of KIF18A can induce mitotic arrest in WGD tumor cells without affecting normal cells. Therefore, KIF18A is a potential anti-tumor target.
  • WGD whole-genome doubling
  • the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • X1 and Y1 are connected to each other to form a structural unit and Y2 is selected from N or CR Y2 ;
  • X1 and Y2 are linked to each other to form a structural unit and Y1 is selected from N or CR Y1 ;
  • X1 is selected from N or CR X1 ;
  • X2 is selected from N or CR X2 ;
  • X1 and X2 are connected by a single bond
  • Z 1 , Z 2 or Z 3 are each independently selected from N or CR Z1 ;
  • Z4 or Z5 are each independently selected from N or CR Z2 ;
  • Ring A is selected from the following groups optionally substituted by one or more Ra : 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
  • RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is independently selected from H, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, diC1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy, halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated diC1-12 alkylamino, -COC1-12 alkyl, -OC (O) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC (O) OC1-12 alkyl, -SO2C1-12alkyl , -NHSO2C1-12alkyl C
  • Ring B is selected from the following groups optionally substituted by one or more R b : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
  • Each Ra or Rb is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, diC1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy, halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated diC1-12 alkylamino, -COC1-12 alkyl, -OC(O) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC (O) OC1-12 alkyl , -SO2C1-12 alkyl, -NHSO2C1-12 alkyl , -N(C1-12 alkyl ) SO2C -1-12 al
  • Ring C is selected from the following groups optionally substituted by one or more R c1 : 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl;
  • Each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N (C 1-12 alkyl)SO 2 C -1-12 alkyl,
  • R c1 located on the same ring atom and the ring atom to which R c1 is attached together form the following group optionally substituted by one or more R c2 : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl;
  • R c1 located on two adjacent ring atoms and the ring atom to which R c1 is attached together form the following group optionally substituted by one or more R c2 : a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group or a 3-12 membered heterocyclyl group;
  • Each R c2 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N (C 1-12 alkyl)SO 2 C -1-12 alkyl,
  • L1 is selected from a single bond, -O-, -S-, -NR L1 -, C 1-6 alkylene, deuterated C 1-6 alkylene, halogenated C 1-6 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)NR L1 -, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 C(O)O-, -NR L1 C(O)O-, -NR L1 C(O)NR L1 -, -S(O)-, -S(O) 2 -, -S(O) 2 NR L1 -, -NR L1 S(O ) 2 -, -NR L1 S(O) 2 -, -NR L1 S(O) 2 -, -NR L1 S(O) 2 -, -NR L1
  • Each RL1 is independently selected from H, deuterium, or the following groups optionally substituted with one or more RL1a : C1-6 alkyl, deuterated C1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
  • Each RL1a is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, di- C1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy , halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated di- C1-12 alkylamino, -COC1-12 alkyl, -OC ( O ) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC(O) OC1-12 alkyl, -SO2C1-12 alkyl, -NHSO2C1-12 alkyl, -N(C1-12 alkyl ) SO2C1-12
  • R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH , -CN, or C 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkylC 1-6 alkylene, 3-12 membered cycloalkenylC 1-6 alkylene, 3-12 membered heterocyclylC 1-6 alkylene, 6-10 membered arylC 1-6 alkylene, or 5-10 membered heteroarylC 1-6 alkylene, optionally substituted with one or more R 1a ;
  • Each R 1a is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, hydroxy C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O )OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl , -N ( C -12 alkyl
  • RL2 is selected from H, deuterium, C1-6 alkyl, deuterated C1-6 alkyl, or halogenated C1-6 alkyl;
  • RX1 , RX2 , RY1 , RY2, RZ1 , RZ2 , Ra , Rb , Rc1 , Rc2 , RL1 , RL1a , R1 , R1a , or RL2 is optionally substituted with one or more substituents.
  • X1 and Y1 are connected to each other to form a structural unit and Y2 is selected from N or CR Y2 ;
  • X1 and Y2 are linked to each other to form a structural unit and Y1 is selected from N or CR Y1 ;
  • X1 is selected from N or CR X1 ;
  • X2 is selected from N or CR X2 ;
  • X1 and X2 are connected by a single bond
  • Z 1 , Z 2 or Z 3 are each independently selected from N or CR Z1 ;
  • Z4 or Z5 are each independently selected from N or CR Z2 ;
  • Ring A is selected from the following groups optionally substituted by one or more Ra : 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
  • RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is independently selected from H, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, diC1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy, halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated diC1-12 alkylamino, -COC1-12 alkyl, -OC (O) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC (O) OC1-12 alkyl, -SO2C1-12alkyl , -NHSO2C1-12alkyl C
  • Ring B is selected from the following groups optionally substituted by one or more R b : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
  • Each Ra or Rb is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, diC1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy, halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated diC1-12 alkylamino, -COC1-12 alkyl, -OC(O) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC (O) OC1-12 alkyl , -SO2C1-12 alkyl, -NHSO2C1-12 alkyl , -N(C1-12 alkyl ) SO2C -1-12 al
  • Ring C is selected from the following groups optionally substituted by one or more R c1 : 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl;
  • Each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N (C 1-12 alkyl)SO 2 C -1-12 alkyl,
  • R c1 located on the same ring atom and the ring atom to which R c1 is attached together form the following group optionally substituted by one or more R c2 : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl;
  • R c1 located on two adjacent ring atoms and the ring atom to which R c1 is attached together form the following group optionally substituted by one or more R c2 : a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group or a 3-12 membered heterocyclyl group;
  • Each R c2 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N (C 1-12 alkyl)SO 2 C -1-12 alkyl,
  • L1 is selected from a single bond, -O-, -S-, -NR L1 -, C 1-6 alkylene, deuterated C 1-6 alkylene, halogenated C 1-6 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)NR L1 -, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 C(O)O-, -NR L1 C(O)O-, -NR L1 C(O)NR L1 -, -S(O)-, -S(O) 2 -, -S(O) 2 NR L1 -, -NR L1 S(O ) 2 -, -NR L1 S(O) 2 -, -NR L1 S(O) 2 -, -NR L1 S(O) 2 -, -NR L1
  • Each RL1 is independently selected from H, deuterium, or the following groups optionally substituted with one or more RL1a : C1-6 alkyl, deuterated C1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
  • Each RL1a is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, di- C1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy , halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated di- C1-12 alkylamino, -COC1-12 alkyl, -OC ( O ) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC(O) OC1-12 alkyl, -SO2C1-12 alkyl, -NHSO2C1-12 alkyl, -N(C1-12 alkyl ) SO2C1-12
  • R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted by one or more R 1a : C 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; each R 1a is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, hydroxy C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, diC 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthi
  • RL2 is selected from H, deuterium, C1-6 alkyl, deuterated C1-6 alkyl, or halogenated C1-6 alkyl;
  • RX1 , RX2 , RY1 , RY2, RZ1 , RZ2 , Ra , Rb , Rc1 , Rc2 , RL1 , RL1a , R1 , R1a , or RL2 is optionally substituted with one or more substituents.
  • X1 and Y1 are connected to each other to form a structural unit and Y2 is selected from N or CR Y2 ;
  • X1 and Y2 are linked to each other to form a structural unit and Y1 is selected from N or CR Y1 ;
  • X1 is selected from N or CR X1 ;
  • X2 is selected from N or CR X2 ;
  • X1 and X2 are connected by a single bond
  • Z 1 , Z 2 or Z 3 are each independently selected from N or CR Z1 ;
  • Z4 or Z5 are each independently selected from N or CR Z2 ;
  • Ring A is selected from the following groups optionally substituted by one or more Ra : 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
  • RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is independently selected from H, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, diC1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy, halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated diC1-12 alkylamino, -COC1-12 alkyl, -OC (O) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC (O) OC1-12 alkyl, -SO2C1-12alkyl , -NHSO2C1-12alkyl C
  • Ring B is selected from the following groups optionally substituted by one or more R b : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
  • Each Ra or Rb is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, diC1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy, halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated diC1-12 alkylamino, -COC1-12 alkyl, -OC(O) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC (O) OC1-12 alkyl , -SO2C1-12 alkyl, -NHSO2C1-12 alkyl , -N(C1-12 alkyl ) SO2C -1-12 al
  • Ring C is selected from the following groups optionally substituted by one or more R c1 : 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl;
  • Each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N (C 1-12 alkyl)SO 2 C 1-12 alkyl,
  • two R c1 located on the same ring atom together form the following group optionally substituted by one or more R c2 : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl;
  • two R c1 located on two adjacent ring atoms together form the following group optionally substituted by one or more R c2 : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl;
  • Each R c2 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N (C 1-12 alkyl)SO 2 C -1-12 alkyl,
  • Each RL1 is independently selected from H, deuterium, or the following groups optionally substituted with one or more RL1a : C1-6 alkyl, deuterated C1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
  • Each RL1a is independently selected from oxo, deuterium, halogen, -CN, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, diC1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy, halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated diC1-12 alkylamino, -COC1-12 alkyl, -OC ( O ) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC ( O) OC1-12 alkyl , -SO2C1-12 alkyl , -NHSO2C1-12 alkyl, -N( C1-12 alkyl )SO2C1-12 alkyl , -SO2NH2 , -SO 2 NHC 1
  • R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted with one or more R 1a : C 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;
  • Each R 1a is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, hydroxy C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O )OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl , -N ( C -12 alkyl
  • RL2 is selected from H, deuterium, C1-6 alkyl, deuterated C1-6 alkyl, or halogenated C1-6 alkyl;
  • RX1 , RX2 , RY1 , RY2, RZ1 , RZ2 , Ra , Rb , Rc1 , Rc2 , RL1 , RL1a , R1 , R1a , or RL2 is optionally substituted with one or more substituents.
  • the “substituent” is selected from a deuterium atom, a hydroxyl group, a thiol group, a halogen, an amino group, a nitro group, a nitroso group, a cyano group, an azide group, a sulfoxide group, a sulfone group, a sulfone group, a sulfonamide group, a carboxyl group, an aldehyde group, an imine group, a C1-12 alkyl group, a halo- C1-12 alkyl group, a 3-12 membered cycloalkyl group,
  • the “substituents” are selected from a deuterium atom , a hydroxyl group, a thiol group, a halogen, an amino group, a nitro group, a cyano group, a carboxyl group, an aldehyde group, a C1-3 alkyl group, a halo- C1-3 alkyl group, or a C3 cycloalkyl group.
  • X 1 and Y 1 are linked to each other to form a structural unit and Y2 is selected from CR Y2 ; or, X1 and Y2 are connected to each other to form a structural unit And Y1 is selected from CR Y1 .
  • X 1 and Y 1 are linked to each other to form a structural unit and Y2 is selected from CR Y2 ; or, X1 and Y2 are connected to each other to form a structural unit And Y1 is selected from N.
  • X 1 and Y 1 are linked to each other to form a structural unit and Y 2 is selected from N; or, X 1 and Y 2 are connected to each other to form a structural unit And Y1 is selected from CR Y1 .
  • X 1 and Y 1 are linked to each other to form a structural unit and Y 2 is selected from N; or, X 1 and Y 2 are mutually Connect to form structural units And Y1 is selected from N.
  • X 1 and Y 1 are linked to each other to form a structural unit
  • Y2 is selected from N or CR Y2 .
  • X1 and Y2 are linked to each other to form a structural unit
  • Y1 is selected from N or CR Y1 .
  • X 1 and Y 1 are linked to each other to form a structural unit and Y2 is selected from N or CR Y2 ; X1 is selected from CR X1 , and X2 is selected from N. In some embodiments, X1 and Y1 are connected to each other to form a structural unit And Y2 is selected from N or CR Y2 .
  • X1 and Y2 are linked to each other to form a structural unit and Y1 is selected from N or CR Y1 ; X1 is selected from CR X1 , and X2 is selected from N. In some embodiments, X1 and Y2 are connected to each other to form a structural unit And Y1 is selected from N or CR Y1 .
  • X 1 and Y 1 are linked to each other to form a structural unit and Y2 is selected from N; X1 is selected from CR X1 , and X2 is selected from N. In some embodiments, X1 and Y1 are connected to each other to form a structural unit And Y2 is selected from N.
  • X1 and Y2 are linked to each other to form a structural unit and Y 1 is selected from N; X 1 is selected from CR X1 , and X 2 is selected from N. In some embodiments, X 1 and Y 2 are connected to each other to form a structural unit And Y1 is selected from N.
  • X 1 is selected from N.
  • X1 is selected from CR X1 .
  • X 1 is selected from CH.
  • X 2 is selected from N.
  • X2 is selected from CR X2 .
  • X 2 is selected from CH.
  • X1 is selected from CR X1 and X2 is selected from CR X2 .
  • X1 is selected from CR X1
  • X2 is selected from N.
  • X 1 is selected from CH and X 2 is selected from N.
  • X1 is selected from N
  • X2 is selected from CR X2 .
  • X 1 is selected from N
  • X 2 is selected from CH
  • Z 1 , Z 2 and Z 3 are CR Z1 .
  • Z 1 , Z 2 and Z 3 are all CH.
  • Z 1 , Z 2 or Z 3 are not N at the same time.
  • one or both of Z 1 , Z 2 or Z 3 is N.
  • Z1 and Z2 are N, and Z3 is CR Z1 .
  • Z1 and Z3 are N, and Z2 is CRZ1 .
  • Z2 and Z3 are N and Z1 is CRZ1 .
  • Z1 is N, and Z2 and Z3 are CRZ1 .
  • Z2 is N
  • Z1 and Z3 are CRZ1 .
  • Z3 is N, and Z1 and Z2 are CRZ1 .
  • Z4 and Z5 are CRZ2 .
  • Z 4 is CH and Z 5 is CR Z2 .
  • Z4 and Z5 are N.
  • Z 4 or Z 5 are not N at the same time.
  • Z4 is N and Z5 is CRZ2 .
  • Z5 is N and Z4 is CRZ2 .
  • Z 1 , Z 2 and Z 3 are CR Z 1
  • Z 4 and Z 5 are CR Z 2 .
  • Z 1 , Z 2 , Z 3 , Z 4 or Z 5 are not N at the same time.
  • At least one of Z 1 , Z 2 , Z 3 , Z 4 or Z 5 is N.
  • At least two of Z 1 , Z 2 , Z 3 , Z 4 or Z 5 are N.
  • At least three of Z 1 , Z 2 , Z 3 , Z 4 or Z 5 are N.
  • one, two, three, or four of Z 1 , Z 2 , Z 3 , Z 4 , or Z 5 are N.
  • Z1 is N, Z2 and Z3 are CRZ1 , and Z4 and Z5 are CRZ2 .
  • Z2 is N, Z1 and Z3 are CRZ1 , and Z4 and Z5 are CRZ2 .
  • Z3 is N, Z1 and Z2 are CRZ1 , and Z4 and Z5 are CRZ2.
  • Z4 is N, Z1 , Z2 and Z3 are CRZ1
  • Z5 is CRZ2 .
  • Z5 is N, Z1 , Z2 and Z3 are CRZ1 , and Z4 is CRZ2 .
  • Z1 and Z2 are N, Z3 is CRZ1 , and Z4 and Z5 are CRZ2 . In some embodiments, Z1 and Z3 are N, Z2 is CRZ1 , and Z4 and Z5 are CRZ2. In some embodiments, Z2 and Z3 are N, Z1 is CRZ1 , and Z4 and Z5 are CRZ2 . In some embodiments, Z1 and Z4 are N, Z2 and Z3 are CRZ1 , and Z5 is CRZ2 . In some embodiments, Z1 and Z5 are N, Z2 and Z3 are CRZ1 , and Z4 is CRZ2 .
  • Z2 and Z4 are N , Z1 and Z3 are CRZ1 , and Z5 is CRZ2 . In some embodiments, Z2 and Z5 are N, Z1 and Z3 are CRZ1 , and Z4 is CRZ2 . In some embodiments, Z3 and Z4 are N, Z1 and Z2 are CRZ1 , and Z5 is CRZ2. In some embodiments, Z3 and Z5 are N, Z1 and Z2 are CRZ1 , and Z4 is CRZ2 . In some embodiments, Z4 and Z5 are N, Z1 , Z2 and Z3 are CR Z1 .
  • Z 1 , Z 2 and Z 4 are N, Z 3 is CR Z1 , and Z 5 is CR Z2 . In some embodiments, Z 1 , Z 2 and Z 5 are N, Z 3 is CR Z1 , and Z 4 is CR Z2 . In some embodiments, Z 1 , Z 3 and Z 4 are N, Z 2 is CR Z1 , and Z 5 is CR Z2 . In some embodiments, Z 1 , Z 3 and Z 5 are N, Z 2 is CR Z1 , and Z 4 is CR Z2 . In some embodiments, Z 2 , Z 3 and Z 4 are N, Z 1 is CR Z1 , and Z 5 is CR Z2 . In some embodiments, Z 2 , Z 3 and Z 5 are N, Z 1 is CR Z1 , and Z 5 is CR Z2 . In some embodiments, Z 2 , Z 3 and Z 5 are N, Z 1 is CR Z1 , and Z 4 is CR Z2 . In some embodiments, Z 2
  • Y2 is N
  • Z4 and Z5 are CH.
  • Y 1 is N
  • Z 4 is CH
  • Z 5 is CH or CCH 3 .
  • Y 2 is N
  • Z 4 is CH
  • Z 5 is CCH 3 .
  • Y1 and Z5 are N, and Z4 is CH.
  • Y 1 is CH, Z 4 and Z 5 are N.
  • Y 1 is N
  • Z 4 is N
  • Z 5 is CH
  • Y 1 is N
  • Z 4 is CH
  • Z 5 is CCN
  • Ring A is selected from the following groups optionally substituted with one or more Ra : 4-12 membered cycloalkenyl or 4-12 membered heterocycloalkenyl.
  • Ring A is selected from the following groups optionally substituted with one or more Ra : 4-10 membered cycloalkenyl or 4-10 membered heterocycloalkenyl.
  • Ring A is selected from the following groups optionally substituted with one or more Ra : 4-8 membered cycloalkenyl or 4-8 membered heterocycloalkenyl.
  • Ring A is selected from the following groups optionally substituted with one or more Ra : 5-7 membered cycloalkenyl or 5-7 membered heterocycloalkenyl.
  • ring A is selected from 4-12 membered heterocycloalkenyl optionally substituted with one or more Ra .
  • the 4-12 membered heterocycloalkenyl is selected from 4-10 membered heterocycloalkenyl, 4-8 membered heterocycloalkenyl or 5-7 membered heterocycloalkenyl.
  • ring A is selected from 6-7 membered heterocycloalkenyl optionally substituted with one or more Ra .
  • the "cycloalkenyl” or “heterocycloalkenyl” in ring A has only one olefinic bond.
  • the 6-10 membered aryl group in Ring A can be selected from phenyl.
  • the 5-10 membered heteroaryl group in Ring A can be selected from 5-6 membered heteroaryl groups.
  • Ring A is selected from the following groups optionally substituted with one or more Ra :
  • Ring A is selected from the following groups optionally substituted with one or more Ra : In some embodiments, Ring A is selected from the following groups optionally substituted with one or more Ra :
  • Ring A is selected from the following groups:
  • Ring A is selected from the following groups:
  • Ring A is selected from the following groups: In some embodiments, Ring A is selected from the following groups: In some embodiments, Ring A is selected from the following groups: In some embodiments, Ring A is selected from the following groups: In some embodiments, Ring A is selected from the following groups:
  • the "heterocyclyl” described in the present disclosure is selected from “heterocycloalkyl” or “heterocycloalkenyl”.
  • the "heterocyclyl” described in the present disclosure is selected from “heterocycloalkyl”.
  • the 3-12 membered heterocyclyl is selected from 3-12 membered heterocycloalkyl.
  • each RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is independently selected from H, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH , C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, haloC1-6 alkyl, haloC1-6 alkoxy, haloC1-6 alkylthio, haloC1-6 alkylamino, halodiC1-6 alkylamino , -COC1-6 alkyl, -OC (O) C1-6 alkyl, -C (O) OC1-6 alkyl, -OC (O) OC1-6 alkyl, -SO2C1-6 alkyl, -NHSO2C1-6 alkyl , -N ( C1-6 alkyl )SO 2 C
  • the 3-10 membered heterocyclyl is selected from 3-10 membered heterocycloalkyl.
  • each RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is independently selected from H, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH , C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, haloC1-6 alkyl, haloC1-6 alkoxy, haloC1-6 alkylthio, haloC1-6 alkylamino, halodiC1-6 alkylamino , -COC1-6 alkyl, -OC (O) C1-6 alkyl, -C (O) OC1-6 alkyl, -OC (O) OC1-6 alkyl, -SO2C1-6 alkyl, -NHSO2C1-6 alkyl , -N ( C1-6 alkyl )SO 2 C
  • each RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is each independently selected from H, deuterium, halogen, -OH, -NH2 , -CN, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, haloC1-6 alkyl, haloC1-6 alkoxy, haloC1-6 alkylthio, haloC1-6 alkylamino, halodiC1-6 alkylamino, 3-8 membered cycloalkyl, or 3-8 membered heterocyclyl .
  • the 3-8 membered heterocyclyl is selected from 3-8 membered heterocycloalkyl.
  • each RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is independently selected from H, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino, halogenated C1-4 alkyl, halogenated C1-4 alkoxy, halogenated C1-4 alkylthio, halogenated C1-4 alkylamino, halogenated diC1-4 alkylamino, -COC1-4 alkyl, -OC (O) C1-4 alkyl, -C (O) OC1-4 alkyl, -OC (O) OC1-4 alkyl, -SO2C1-4 alkyl, -NHSO2C1-4 alkyl, -N ( C1-4 alkyl ) SO 2 C
  • each RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is independently selected from H, deuterium, halogen, -OH, -NH2 , -CN, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino, haloC1-4 alkyl , haloC1-4 alkoxy, haloC1-4 alkylthio, haloC1-4 alkylamino, halodiC1-4 alkylamino, 3-6 membered cycloalkyl, or 3-6 membered heterocyclyl .
  • the 3-6 membered heterocyclyl is selected from 3-6 membered heterocycloalkyl.
  • each RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is each independently selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n -propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, di(trifluoromethyl)amino, cyclopropyl, cyclobutyl, azetidin
  • each RX1 , RX2 , RY1 , RY2 , RZ1 , or RZ2 is independently selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or cyclopropyl.
  • RX1 is selected from H, -F, -Cl, methyl, or methoxy.
  • RX1 is selected from H.
  • RX2 is selected from H, -F, -Cl, methyl, or methoxy.
  • RX2 is selected from H.
  • R Y1 is selected from H, -F, -Cl, -CN, methyl, methoxy, trifluoromethyl, or cyclopropyl.
  • R Y1 is selected from H.
  • RY2 is selected from H, -F, -Cl, -CN, methyl, methoxy, trifluoromethyl, or cyclopropyl.
  • R Z1 is selected from H, -F, -Cl, methyl, or methoxy.
  • R Z1 is selected from H.
  • R Z2 is selected from H, -F, -Cl, -CN, methyl, methoxy, trifluoromethyl, or cyclopropyl.
  • R Z2 is selected from H, -CN, or methyl.
  • R Z2 is selected from H or methyl.
  • Ring B is selected from the following groups optionally substituted with one or more R b : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, or 3-12 membered heterocyclyl.
  • Ring B is selected from the following groups optionally substituted with one or more R b : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, or 3-12 membered heterocycloalkyl.
  • Ring B is selected from the following groups optionally substituted with one or more R b : 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl.
  • Ring B is selected from the following groups optionally substituted with one or more R b : 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl.
  • Ring B is selected from the following groups optionally substituted with one or more R b : 5-9 membered cycloalkyl or 5-9 membered heterocycloalkyl.
  • Ring B is selected from the following groups optionally substituted with one or more R b : 6-8 membered cycloalkyl or 6-8 membered heterocycloalkyl.
  • Ring B is selected from the following groups optionally substituted with one or more R b : 4-7 membered cycloalkyl or 4-7 membered heterocycloalkyl.
  • Ring B is selected from 3-12 membered heterocycloalkyl optionally substituted with one or more R b .
  • the "3-12 membered” in the "3-12 membered cycloalkyl”, “3-12 membered cycloalkyl”, “3-12 membered cycloalkenyl”, or “3-12 membered heterocycloalkyl” described in Ring B, the “3-12 membered” may be independently selected from 3-10 membered, 5-9 membered, or 6-8 membered. In some embodiments, in the "3-12 membered cycloalkyl”, “3-12 membered cycloalkyl”, “3-12 membered cycloalkenyl", or “3-12 membered heterocycloalkyl” described in Ring B, the “3-12 membered” may be independently selected from 4-7 membered.
  • the 3-12 membered cycloalkyl is selected from 3-10 membered cycloalkyl, 5-9 membered cycloalkyl or 6-8 membered cycloalkyl. In some embodiments, the 3-12 membered cycloalkyl is selected from 4-7 membered cycloalkyl.
  • the 3-12 membered heterocyclyl is selected from a 3-10 membered heterocyclyl, a 5-9 membered heterocyclyl, or a 6-8 membered heterocyclyl. In some embodiments, the 3-12 membered heterocyclyl is selected from a 4-7 membered heterocyclyl.
  • the 3-12 membered heterocycloalkyl is selected from 3-10 membered heterocycloalkyl, 5-9 membered heterocycloalkyl or 6-8 membered heterocycloalkyl. In some embodiments, the 3-12 membered heterocycloalkyl is selected from 4-7 membered heterocycloalkyl.
  • the 3-12 membered heterocycloalkenyl is selected from 3-10 membered heterocycloalkenyl, 5-9 membered heterocycloalkenyl or 6-8 membered heterocycloalkenyl. In some embodiments, the 3-12 membered heterocycloalkenyl is selected from 4-7 membered heterocycloalkenyl.
  • the 6-10 membered aryl groups described in Ring B are independently selected from phenyl.
  • the 5-10 membered heteroaryl described in Ring B is independently selected from 5-6 membered heteroaryl.
  • Ring B is selected from the following groups optionally substituted with one or more R b : cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl,
  • Ring B is selected from the following groups optionally substituted with one or more R b :
  • Ring B is selected from optionally substituted with one or more R
  • Ring B is selected from In some embodiments, Ring B is selected from In some embodiments, Ring B is selected from
  • Ring B is selected from In some embodiments, Ring B is selected from
  • the structural unit is selected from the following groups optionally substituted by one or more R b : in The other end is connected to Y1 or Y2 .
  • the structural unit is selected from optionally substituted with one or more R in The other end is connected to Y1 or Y2 .
  • the structural unit Selected from in The other end of is connected to Y 1 or Y 2 .
  • the structural unit Selected from in The other end of is connected to Y 1 or Y 2 .
  • the structural unit Selected from in The other end is connected to Y1 or Y2 .
  • the structural unit Selected from in The other end is connected to Y1 or Y2 .
  • the 3-12 membered heterocyclyl is selected from 3-12 membered heterocycloalkyl.
  • each Ra or Rb is independently selected from oxo, deuterium, halogen , -OH, -NH2 , -CN, -SH, -COOH, C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, haloC1-6 alkyl, haloC1-6 alkoxy, haloC1-6 alkylthio, haloC1-6 alkylamino, halodiC1-6 alkylamino, -COC1-6 alkyl, -OC (O) C1-6 alkyl, -C (O) OC1-6 alkyl, -OC ( O ) OC1-6 alkyl , -SO2C1-6 alkyl , -NHSO2C1-6 alkyl, -N ( C1-6 alkyl ) SO2C1-6 alkyl, -SO2NH2 , -SO 2 NHC
  • the 3-10 membered heterocyclyl is selected from 3-10 membered heterocycloalkyl.
  • each Ra or Rb is independently selected from oxo, deuterium, halogen , -OH, -NH2 , -CN, -SH, -COOH, C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, haloC1-6 alkyl, haloC1-6 alkoxy, haloC1-6 alkylthio, haloC1-6 alkylamino, halodiC1-6 alkylamino, -COC1-6 alkyl, -OC (O) C1-6 alkyl, -C (O) OC1-6 alkyl, -OC ( O ) OC1-6 alkyl , -SO2C1-6 alkyl , -NHSO2C1-6 alkyl, -N ( C1-6 alkyl ) SO2C1-6 alkyl, -SO2NH2 , -SO 2 NHC
  • each Ra or Rb is independently selected from oxo, deuterium, halogen, -OH , -NH2 , -CN, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, halogenated C1-6 alkylthio, halogenated C1-6 alkylamino, halogenated diC1-6 alkylamino, 3-8 membered cycloalkyl, or 3-8 membered heterocyclyl.
  • each Ra or Rb is independently selected from deuterated C1-6 alkyl.
  • the 3-8 membered heterocyclyl is selected from 3-8 membered heterocycloalkyl.
  • each Ra or Rb is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy , C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino, halogenated C1-4 alkyl, halogenated C1-4 alkoxy, halogenated C1-4 alkylthio, halogenated C1-4 alkylamino, halogenated diC1-4 alkylamino, -COC1-4 alkyl, -OC (O) ...
  • each Ra or Rb is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino, halogenated C1-4 alkyl, halogenated C1-4 alkoxy, halogenated C1-4 alkylthio, halogenated C1-4 alkylamino, halogenated diC1-4 alkylamino, 3-6 membered cycloalkyl, or 3-6 membered heterocyclyl.
  • each Ra or Rb is independently selected from deuterated C1-4 alkyl.
  • the 3-6 membered heterocyclyl is selected from 3-6 membered heterocycloalkyl.
  • each Ra or Rb is each independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, di(trifluoromethyl)amino, cyclopropyl, cyclobutyl, azetidinyl, or oxetanyl.
  • each Ra or Rb is each independently selected
  • each Ra or Rb is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, methoxy, trifluoromethyl , trifluoromethoxy, cyclopropyl, -CD3 , ethyl, or -CD2CD3 .
  • each Ra or Rb is each independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or cyclopropyl.
  • each Ra or Rb is each independently selected from -CD3 .
  • each Ra or Rb is each independently selected from ethyl or -CD2CD3 .
  • each Ra is independently selected from deuterium, oxo, methyl , -CD3 , ethyl, cyclopropyl, or -CD2CD3 .
  • each Ra is each independently selected from deuterium, oxo, or methyl. In some embodiments, each Ra is each independently selected from -CD 3 . In some embodiments, each Ra is each independently selected from ethyl, cyclopropyl, or -CD 2 CD 3 .
  • each R b is independently selected from oxo, deuterium, -F, -Cl, -OH, -NH 2 , -CN, or methyl.
  • each R b is independently selected from -F or -Cl.
  • Ring C is selected from the following groups optionally substituted with one or more R c1 : 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl.
  • Ring C is selected from the following groups optionally substituted with one or more R c1 : 5-9 membered cycloalkyl or 5-9 membered heterocycloalkyl.
  • Ring C is selected from the following groups optionally substituted with one or more R c1 : 4-8 membered cycloalkyl or 4-8 membered heterocycloalkyl.
  • Ring C is selected from the following groups optionally substituted with one or more R c1 : 6-8 membered cycloalkyl or 6-8 membered heterocycloalkyl.
  • Ring C is selected from the following groups optionally substituted with one or more R c1 : 6-10 membered cycloalkyl or 6-10 membered heterocycloalkyl.
  • ring C is selected from 3-12 membered heterocycloalkyl optionally substituted with one or more R c1 .
  • the 3-12 membered heterocycloalkyl is selected from 3-10 membered heterocycloalkyl, 5-9 membered heterocycloalkyl or 6-8 membered heterocycloalkyl.
  • the 3-12 membered heterocycloalkyl is selected from 4-8 membered heterocycloalkyl.
  • the 3-12 membered heterocycloalkyl is selected from 6-10 membered heterocycloalkyl.
  • the 3-12 membered cycloalkyl, 3-10 membered cycloalkyl, 5-9 membered cycloalkyl or 6-8 membered cycloalkyl is selected from monocyclic cycloalkyl. In some embodiments, the 4-8 membered cycloalkyl is selected from monocyclic cycloalkyl.
  • the 3-12 membered cycloalkyl, 3-10 membered cycloalkyl, 5-9 membered cycloalkyl or 6-8 membered cycloalkyl is selected from bridged cycloalkyl.
  • the 4-8 membered cycloalkyl is selected from bridged cycloalkyl.
  • the 3-12 membered heterocycloalkyl, 3-10 membered heterocycloalkyl, 5-9 membered heterocycloalkyl or 6-8 membered heterocycloalkyl is selected from monocyclic heterocycloalkyl.
  • the 4-8 membered heterocycloalkyl is selected from monocyclic heterocycloalkyl.
  • the 3-12 membered heterocycloalkyl, 3-10 membered heterocycloalkyl, 5-9 membered heterocycloalkyl or 6-8 membered heterocycloalkyl is selected from In some embodiments, the 4-8 membered heterocycloalkyl is selected from a bridged heterocycloalkyl.
  • Ring C is selected from the following groups optionally substituted with one or more R c1 :
  • Ring C is selected from the following groups optionally substituted with one or more R c1 : In some embodiments, Ring C is selected from the following groups optionally substituted with one or more R c1 :
  • Ring C is selected from
  • Ring C is selected from In some embodiments, Ring C is selected from
  • Ring C is selected from In some embodiments, Ring C is selected from
  • Ring C is selected from In some embodiments, Ring C is selected from In some embodiments, Ring C is selected from
  • the 3-12 membered heterocyclyl is selected from 3-12 membered heterocycloalkyl.
  • each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-8 alkyl, deuterated C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylthio, C 1-8 alkylamino, diC 1-8 alkylamino, haloC 1-8 alkyl, haloC 1-8 alkoxy, haloC 1-8 alkylthio, haloC 1-8 alkylamino, halodiC 1-8 alkylamino, -COC 1-8 alkyl , -OC(O)C 1-8 alkyl, -C(O)OC 1-8 alkyl, -OC(O)OC 1-8 alkyl, -SO 2 C 1-8 alkyl, -NHSO 2 C 1-8 alkyl, -N(C 1-8 alkyl) SO 2 C 1-8 alkyl, -
  • two R c1 located on the same ring atom (and the ring atom to which R c1 is attached) together form the following group optionally substituted by one or more R c2 : 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl or 3-10 membered heterocyclyl;
  • two R c1 located on two adjacent ring atoms together form a 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl or 3-10 membered heterocyclyl group optionally substituted with one or more R c2 .
  • the 3-10 membered heterocyclyl is selected from 3-10 membered heterocycloalkyl.
  • each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylthio, C 1-8 alkylamino, diC 1-8 alkylamino, haloC 1-8 alkyl, haloC 1-8 alkoxy, haloC 1-8 alkylthio, haloC 1-8 alkylamino, or halodiC 1-8 alkylamino;
  • two R c1 located on the same ring atom together form the following group optionally substituted with one or more R c2 : 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl;
  • two R c1 located on two adjacent ring atoms together form a 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl group optionally substituted with one or more R c2 .
  • each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, diC 1-6 alkylamino, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylthio, haloC 1-6 alkylamino, halodiC 1-6 alkylamino, -COC 1-6 alkyl , -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)OC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -N (C 1-6 alkyl)SO 2 C 1-6 alkyl, -C(O)
  • two R c1 located on the same ring atom (and the ring atom to which R c1 is attached) together form the following group optionally substituted by one or more R c2 : 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl;
  • two R c1 located on two adjacent ring atoms together form a 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl group optionally substituted with one or more R c2 .
  • the 3-8 membered heterocyclyl is selected from 3-8 membered heterocycloalkyl.
  • each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, diC 1-6 alkylamino , haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylthio, haloC 1-6 alkylamino, or halodiC 1-6 alkylamino;
  • two R c1 located on the same ring atom together form the following group optionally substituted by one or more R c2 : 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl;
  • two R c1 located on two adjacent ring atoms together form a 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl group optionally substituted with one or more R c2 .
  • each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino , di-C 1-4 alkylamino, halo-C 1-4 alkyl, halo-C 1-4 alkoxy, halo-C 1-4 alkylthio, halo-C 1-4 alkylamino, halo-di-C 1-4 alkylamino, -COC 1-4 alkyl, -OC(O)C 1-4 alkyl, -C(O)OC 14 alkyl, -OC (O)OC 1-4 alkyl, -SO 2 C 1-4 alkyl, -NHSO 2 C 1-4 alkyl, -N (C 1-4 alkyl)SO 2 C 1-4 alkyl,
  • two R c1 located on the same ring atom (and the ring atom to which R c1 is attached) together form the following group optionally substituted by one or more R c2 : 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl or 3-6 membered heterocyclyl;
  • two R c1 located on two adjacent ring atoms together form a 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl or 3-6 membered heterocyclyl group optionally substituted with one or more R c2 .
  • the 3-6 membered heterocyclyl is selected from 3-6 membered heterocycloalkyl.
  • each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, diC 1-4 alkylamino , haloC 1-4 alkyl, haloC 1-4 alkoxy, haloC 1-4 alkylthio, haloC 1-4 alkylamino, or halodiC 1-4 alkylamino;
  • two R c1 located on the same ring atom (and the ring atom to which R c1 is attached) together form the following group optionally substituted by one or more R c2 : 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
  • two R c1 located on two adjacent ring atoms together form the following group optionally substituted with one or more R c2 : 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl.
  • each R c1 is each independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino;
  • two R c1 located on the same ring atom (and the ring atom to which R c1 is attached) together form a group optionally substituted with one or more R c2 : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl;
  • two R c1 located on two adjacent ring atoms together form the following group optionally substituted with one or more R c2 : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl.
  • each R c1 is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, ethyl, isopropyl, methoxy, methylamino, dimethylamino, trifluoromethyl, trifluoromethoxy;
  • Rc1 on the same ring atom (and the ring atom to which Rc1 is attached) are taken together to form a cyclopropyl group optionally substituted with one or more Rc2 .
  • each R c2 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, diC 1-6 alkylamino, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylthio, haloC 1-6 alkylamino, halodiC 1-6 alkylamino, -COC 1-6 alkyl , -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)OC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -N (C 1-6 alkyl)SO 2 C 1-6 alkyl, -C 1-6 al
  • each R c2 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino , di-C 1-4 alkylamino, halo-C 1-4 alkyl, halo-C 1-4 alkoxy, halo-C 1-4 alkylthio, halo-C 1-4 alkylamino, halo-di-C 1-4 alkylamino, -COC 1-4 alkyl, -OC(O)C 1-4 alkyl, -C(O)OC 14 alkyl, -OC (O)OC 1-4 alkyl, -SO 2 C 1-4 alkyl, -NHSO 2 C 1-4 alkyl, -N (C 1-4 alkyl)SO 2 C 1-4 alkyl,
  • each R c2 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, diC 1-4 alkylamino , haloC 1-4 alkyl, haloC 1-4 alkoxy, haloC 1-4 alkylthio, haloC 1-4 alkylamino, or halodiC 1-4 alkylamino.
  • each R c2 is each independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.
  • each R c2 is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.
  • L 1 is selected from -OC(O)O-, -OC(O)NR L1 -, or
  • L 1 is selected from -S(O) 2 NR L1 -. In some embodiments, L 1 is selected from -NR L1 S(O) 2 -.
  • L1 is read in left-to-right or right-to-left order.
  • L1 is read from left to right.
  • L 1 is -NHS(O) 2 -.
  • each RL1 is independently selected from H, deuterium, or C1-6 alkyl, deuterated C1-6 alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl , which is optionally substituted with one or more RL1a.
  • each RL1 is independently selected from H, deuterium, or C1-6 alkyl, deuterated C1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, which is optionally substituted with one or more RL1a .
  • each RL1 is independently selected from H, deuterium, or C1-4 alkyl, deuterated C1-4 alkyl, 3-7 membered cycloalkyl, 4-7 membered cycloalkenyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, which is optionally substituted with one or more RL1a .
  • the 3-10 membered heterocyclyl, 3-8 membered heterocyclyl or 4-7 membered heterocyclyl are each selected from 3-10 membered heterocycloalkyl, 3-8 membered heterocycloalkyl or 4-7 membered heterocycloalkyl.
  • each RL1 is independently selected from H or C 1-4 alkyl optionally substituted with one or more RL1a .
  • each RL1 is independently selected from H or methyl, ethyl, n-propyl, or isopropyl, optionally substituted with one or more RL1a .
  • each RL1 is independently selected from H or methyl.
  • each RL1 is independently selected from H.
  • each RL1a is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, haloC1-6 alkyl, haloC1-6 alkoxy, haloC1-6 alkylthio, haloC1-6 alkylamino, halodiC1-6 alkylamino, -COC1-6 alkyl, -OC (O) C1-6 alkyl, -C (O) OC1-6 alkyl, -OC ( O ) OC1-6 alkyl , -SO2C1-6 alkyl, -NHSO2C1-6 alkyl , -N ( C1-6 alkyl) SO2C1-6 alkyl, -SO2NH2 , -SO 2 NHC 1-6 al
  • each RL1a is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, haloC1-6 alkyl, haloC1-6 alkoxy, haloC1-6 alkylthio, haloC1-6 alkylamino, halodiC1-6 alkylamino, -COC1-6 alkyl, -OC (O) C1-6 alkyl, -C (O) OC1-6 alkyl, -OC ( O ) OC1-6 alkyl , -SO2C1-6 alkyl, -NHSO2C1-6 alkyl , -N ( C1-6 alkyl) SO2C1-6 alkyl, -SO2NH2 , -SO 2 NHC 1-6 al
  • each RLla is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di-C 1-4 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylthio, halogenated C 1-4 alkylamino , halogenated di-C 1-4 alkylamino, -COC 1-4 alkyl, -OC(O)C 1- 4 alkyl, -C(O)OC 14 alkyl, -OC(O)OC 1-4 alkyl, -SO 2 C 1-4 alkyl, -NHSO 2 C 1-4 alkyl, -N(C 1-4 alkyl)SO 2 C 1-4 alkyl, -
  • each RL1a is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino, haloC1-4 alkyl, haloC1-4 alkoxy, haloC1-4 alkylthio, haloC1-4 alkylamino, or halodiC1-4 alkylamino.
  • each RLla is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.
  • each RLla is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.
  • R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted with one or more R 1a : C 1-6 alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.
  • R 1 is selected from the following groups optionally substituted with one or more R 1a : 3-10 membered cycloalkylC 1-4 alkylene, 3-10 membered cycloalkenylC 1-4 alkylene, 3-10 membered heterocyclylC 1-4 alkylene, 6-10 membered arylC 1-4 alkylene, or 5-10 membered heteroarylC 1-4 alkylene.
  • R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted by one or more R 1a : C 1-4 alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl.
  • R 1 is selected from the following groups optionally substituted by one or more R 1a : 3-8 membered cycloalkyl C 1-4 alkylene, 3-8 membered cycloalkenyl C 1-4 alkylene, 3-8 membered heterocyclyl C 1-4 alkylene, phenyl C 1-4 alkylene, or 5-6 membered heteroaryl C 1-4 alkylene.
  • R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted by one or more R 1a : C 1-4 alkyl, 3-6-membered cycloalkyl, 4-7-membered cycloalkenyl, 4-7-membered heterocyclyl, phenyl, or 5-6-membered heteroaryl.
  • R 1 is selected from the following groups optionally substituted by one or more R 1a : 3-6-membered cycloalkyl C 1-3 alkylene, 4-7-membered cycloalkenyl C 1-3 alkylene, 4-7-membered heterocyclyl C 1-3 alkylene, phenyl C 1-3 alkylene, or 5-6-membered heteroaryl C 1-3 alkylene.
  • R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted with one or more R 1a : C 1-4 alkyl, 3-6 membered cycloalkyl, or 4-7 membered heterocycloalkyl. In some embodiments, R 1 is selected from the following groups optionally substituted with one or more R 1a : 3-6 membered cycloalkylC 1-2 alkylene or 4-7 membered heterocycloalkylC 1-2 alkylene.
  • R 1 is selected from H, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted with one or more R 1a : methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thiazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, piperidinyl, piperazinyl, or morpholinyl.
  • R 1 is selected from the following groups optionally substituted with one or more R 1a : cyclopropylmethylene, cyclobutylmethylene, azetidinylmethylene, or oxetanylmethylene.
  • R 1 is selected from H, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -SH, -COOH, -CN, or methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thiazinyl, isothiazolidinyl, or thiadiazolidinyl , optionally substituted with one or more R 1a.
  • R 1 is selected from tetrahydrofuranyl or cyclopropylmethylene, optionally substituted with one or more R 1a .
  • R 1 is selected from methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, isopropyl, tert-butyl, cyclopropyl,
  • R 1 is selected from methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, isopropyl, tert-butyl, cyclopropyl,
  • R is selected from
  • R 1 is selected from methyl, ethyl, isopropyl, cyclopropyl,
  • R 1 is selected from methyl or
  • R 1 is selected from C 1-4 alkyl optionally substituted with one or more R 1a .
  • R 1 is selected from ethyl optionally substituted with one or more R 1a .
  • the 3-12 membered heterocyclyl is selected from 3-12 membered heterocycloalkyl.
  • each R 1a is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-6 alkyl, deuterated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di-C 1-6 alkylamino, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, halo-C 1-6 alkylthio, halo-C 1-6 alkylamino, halo-di-C 1-6 alkylamino, -COC 1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC (O)OC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -N(C 1-6 al
  • the 3-10 membered heterocyclyl is selected from 3-10 membered heterocycloalkyl.
  • each R 1a is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-6 alkyl, deuterated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, diC 1-6 alkylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylthio, halogenated C 1-6 alkylamino, halogenated di-C 1-6 alkylamino, -COC 1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)OC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -N(C 1-6 alkyl
  • the 3-8 membered heterocyclyl is selected from 3-8 membered heterocycloalkyl.
  • each R 1a is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-4 alkyl, deuterated C 1-4 alkyl, hydroxy C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di-C 1-4 alkylamino, halo-C 1-4 alkyl, halo-C 1-4 alkoxy, halo-C 1-4 alkylthio, halo-C 1-4 alkylamino , halo-di-C 1-4 alkylamino, -COC 1-4 alkyl, -OC(O)C 1-4 alkyl, -C(O)OC 1-4 alkyl, -OC (O)OC 1-4 alkyl, -SO 2 C 1-4 alkyl, -NHSO 2 C 1-4 alkyl, -N(C 1-4
  • each R 1a is independently selected from oxo, halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, deuterated C 1-4 alkyl, hydroxy C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di-C 1-4 alkylamino, halo-C 1-4 alkyl, halo-C 1-4 alkoxy, halo-C 1-4 alkylthio, halo-C 1-4 alkylamino, halo-di-C 1-4 alkylamino, -OC(O)C 1-4 alkyl, -C(O)OC 1-4 alkyl, -CONHC 1-4 alkyl, -NHCOC 1-4 alkyl , 3-6 membered cycloalkyl, or 3-6 membered heterocyclyl. In some embodiments, each R 1a is independently selected from deuterium.
  • the 3-6 membered heterocyclyl is selected from 3-6 membered heterocycloalkyl.
  • each R 1a is each independently selected from oxo, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, hydroxymethyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino, -OC(O)C 1-2 alkyl, -C(O)OC 1-2 alkyl, -CONHC 1-2 al
  • each R 1a is independently selected from oxo, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, hydroxymethyl, methoxy, trifluoromethyl, trifluoromethoxy, -C(O)OCH 3 , -C(O)OCH 2 CH 3 , or cyclopropyl.
  • each R 1a is independently selected from deuterium.
  • each R 1a is independently selected from oxo, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, methoxy, trifluoromethyl, or trifluoromethoxy. In some embodiments, each R 1a is independently selected from deuterium. In some embodiments, R 1a is selected from hydroxymethyl.
  • R 1a is optionally substituted with one or more substituents selected from the group consisting of oxo, deuterium atom, halogen, hydroxyl, amino, cyano, thiol, and carboxyl.
  • R 1a is optionally substituted with one or more substituents selected from hydroxy.
  • R 1a is selected from -OH or methyl, said methyl optionally substituted with one or more hydroxyl groups.
  • R 1a is selected from -OH. In some embodiments, R 1a is selected from methyl or hydroxymethyl.
  • the structural unit -L 1 -R 1 is selected from or
  • the structural unit -L 1 -R 1 is selected from In some embodiments, the structural unit -L 1 -R 1 is selected from or
  • the structural unit -L 1 -R 1 is selected from
  • the structural unit -L 1 -R 1 is selected from or
  • the structural unit -L 1 -R 1 is selected from
  • the structural unit -L 1 -R 1 is selected from In some embodiments, the structural unit -L 1 -R 1 is selected from In some embodiments, the structural unit -L 1 -R 1 is selected from or
  • L2 is selected from -O-, -S-, -NR L2 -, C 1-4 alkylene, deuterated C 1-4 alkylene, halo C 1-4 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L2 -, -NR L2 C(O)-, -S(O)-, -S(O) 2 -, -S(O) 2 NR L2 -, or -NR L2 S(O) 2 -.
  • L2 is selected from -O-, -S-, -NR L2 -, methylene, deuterated methylene, ethylene, deuterated ethylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L2 -, -NR L2 C(O)-, -S(O)-, -S(O) 2 -, -S(O) 2 NR L2 -, or -NR L2 S(O) 2 -.
  • L2 is selected from ethylene, -C(O)O-, -OC(O)-, -C(O)NR L2 -, -NR L2 C(O)-, -S(O) 2 NR L2 -, or -NR L2 S(O) 2 -.
  • L2 is selected from -C(O)NR L2 -, or -NR L2 C(O)-.
  • L2 is read in right-to-left or left-to-right order.
  • L2 is read from right to left.
  • L2 is -NH-C(O)-.
  • RL2 is selected from H, deuterium, C1-4 alkyl, deuterated C1-4 alkyl, or halogenated C1-4 alkyl.
  • RL2 is selected from H, deuterium, methyl, deuterated methyl, monofluoromethyl, difluoromethyl, or trifluoromethyl.
  • RL2 is selected from H, deuterium, or methyl.
  • RL2 is selected from H.
  • the heterocyclic group disclosed herein is selected from heterocyclic alkyl. In some embodiments, the heterocyclic group disclosed herein is selected from partially unsaturated heterocyclic groups.
  • the 3-12-membered, 3-10-membered, 3-8-membered, or 4-7-membered heterocyclyl group disclosed herein is selected from 3-12-membered, 3-10-membered, 3-8-membered, or 4-7-membered heterocycloalkyl groups.
  • the C 1-12 of the present disclosure is selected from C 1-10 , C 1-8 , C 1-6 , C 1-4 , C 1-3 , or C 1-2 .
  • the C 1-6 alkyl group disclosed herein is selected from C 1-4 alkyl group, C 1-3 alkyl group, or C 1-2 alkyl group.
  • the C 1-6 alkylene group disclosed herein is selected from C 1-4 alkylene group, C 1-3 alkylene group, or C 1-2 alkylene group.
  • the halogen described herein is selected from F, Cl, Br, or I.
  • the halo of the present disclosure is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo of the present disclosure is selected from fluoro.
  • the "one or more” described in the present disclosure may refer to an integer from one to ten.
  • “one or more” refers to one, two, three, four, five, six, seven, eight, nine or ten; or, “one or more” refers to one, two, three, four, five or six; or, “one or more” refers to one, two, three or four.
  • the 3-12-membered group of the present disclosure is selected from 3-10-membered, 3-8-membered, 3-6-membered, 4-7-membered, 4-6-membered, 5-8-membered, 5-7-membered, or 5-6-membered.
  • the heterocycloalkyl group disclosed herein contains 1 or 2 heteroatoms selected from N or O.
  • the heterocycloalkyl groups disclosed herein contain 1 N atom.
  • the heterocycloalkyl groups disclosed herein contain 1 O atom.
  • the heterocycloalkyl groups disclosed herein contain 1 N atom and 1 O atom.
  • heterocyclic or heteroaryl groups disclosed herein contain 1 or 2 heteroatoms selected from N, O, or S.
  • heterocyclyl or heteroaryl groups disclosed herein contain 1 or 2 N atoms.
  • the heterocyclyl or heteroaryl groups disclosed herein contain 1 N atom and 1 O atom.
  • the heterocyclyl or heteroaryl groups disclosed herein contain 1 N atom and 1 S atom.
  • the heterocyclic group or heterocycloalkyl group disclosed herein includes a monocyclic ring, a spirocyclic ring, a cyclic ring or a bridged ring. In some embodiments, the heterocyclic group or heterocycloalkyl group disclosed herein includes a monocyclic ring or a spirocyclic ring. In some embodiments, the heterocyclic group or heterocycloalkyl group disclosed herein includes a monocyclic ring or a bridged ring.
  • all hydrogen atoms may be optionally substituted with one or more deuteriums.
  • the present disclosure relates to compounds of formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III), formula (III-1), formula (III-2), formula (III-3) or pharmaceutically acceptable salts thereof,
  • the ring A is selected from 6-7 membered heterocycloalkenyl optionally substituted with one or more Ra .
  • the ring A is selected from 6-7 membered heterocycloalkenyl optionally substituted with one or more Ra , the 6 membered heterocycloalkenyl containing 2 N atoms, the 7 membered heterocycloalkenyl containing 1 or 2 heteroatoms selected from N or O.
  • the structural unit Selected from n is selected from 0, 1, 2, 3, 4, 5, or 6; m is selected from 0, 1, 2, 3, 4, 5, or 6.
  • n is selected from 0, 1, 2, 3, or 4. In some embodiments, n is selected from 0, 1, or 2.
  • n is selected from 0, 1, 2, 3, or 4. In some embodiments, m is selected from 0, 1, or 2.
  • the structural unit Selected from In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from
  • the present disclosure encompasses the above-defined variables and embodiments thereof, and any combination thereof.
  • the compounds of formula (I), (II), (II-1), (II-2), (II-3), (III), (III-1), (III-2), (III-3) or their pharmaceutically acceptable salts disclosed herein do not include the following compounds or their pharmaceutically acceptable salts:
  • the present disclosure also relates to the following compounds or pharmaceutically acceptable salts thereof:
  • the present disclosure also relates to the following compounds or pharmaceutically acceptable salts thereof:
  • the present disclosure provides compounds with longer retention times and compounds with shorter retention times in chiral chromatography among the following compounds:
  • the chiral chromatography uses a whelk-O1 chiral chromatography column.
  • the retention time of the compound with a longer retention time is about 10-11min, and the retention time of the compound with a shorter retention time is about 7-8min.
  • the present disclosure provides compounds with longer retention times and compounds with shorter retention times in chiral chromatography among the following compounds:
  • the chiral chromatography uses a CHIRALART Cellulose-SB chiral chromatography column.
  • the retention time of the compound with a longer retention time is about 12-13 min
  • the retention time of the compound with a shorter retention time is about 10-11 min.
  • the present disclosure provides compounds with longer retention times and compounds with shorter retention times in chiral chromatography among the following compounds:
  • the chiral chromatography uses a chiral chromatography column of CHIRALART Cellulose SC model.
  • the retention time of the compound with a longer retention time is about 22-23min, and the retention time of the compound with a shorter retention time is about 19-20min.
  • the present disclosure provides a structure selected from The compound has the same configuration as the compound with the longer or shorter retention time in chiral chromatography among the following compounds:
  • the chiral chromatography uses a chiral chromatographic column of CHIRALART Amylose-SA model.
  • the retention time of the compound with a longer retention time is about 9-10min, and the retention time of the compound with a shorter retention time is about 6-7min.
  • the present disclosure provides compounds with longer retention times and compounds with shorter retention times in chiral chromatography among the following compounds:
  • the chiral chromatography uses a chiral chromatographic column of CHIRALART Cellulose-SC model.
  • the retention time of the compound with a longer retention time is about 21-22min, and the retention time of the compound with a shorter retention time is about 18-19min.
  • the present disclosure provides compounds with longer retention times and compounds with shorter retention times in chiral chromatography among the following compounds:
  • the chiral chromatography uses a chiral chromatographic column of CHIRALARTCellose-SC model.
  • the retention time of the compound with a longer retention time is about 10-11 min, and the retention time of the compound with a shorter retention time is about 9-10 min.
  • the present disclosure provides compounds with longer retention times in chiral chromatography among the following compounds:
  • the chiral chromatography uses a chiral chromatographic column of the CHIRALPAK IK model.
  • the retention time of the compound with a longer retention time is about 16min
  • the retention time of the compound with a shorter retention time is about 18-19min.
  • the present disclosure provides a structure selected from The compound has the same configuration as the compound with the longer or shorter retention time in chiral chromatography among the following compounds:
  • the chiral chromatography uses a chiral chromatographic column of CHIRALART Amylose-SA model.
  • the retention time of the compound with a longer retention time is about 9-10min, and the retention time of the compound with a shorter retention time is about 6-7min.
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.
  • the present disclosure relates to a method for treating a disease in a mammal, comprising administering a therapeutically effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure to a mammal, preferably a human, in need of such treatment.
  • the present disclosure relates to use of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure in preparing a medicament for treating a disease.
  • the present disclosure relates to use of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure in treating a disease.
  • the present disclosure relates to a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for use in treating a disease.
  • the disease is selected from a KIF18A-related disease.
  • the disease eg, a KIF18A-related disease
  • cancer eg, ovarian cancer, breast cancer
  • the compounds disclosed herein have high KIF18A inhibitory activity (e.g., KIF18A protein motor activity) and cell proliferation inhibitory activity (e.g., OVCAR3 cells, MDA-MB-468 cells), and show good drugability in in vitro and in vivo metabolic stability, pharmacokinetics, bioavailability, and/or pharmacodynamic studies.
  • KIF18A inhibitory activity e.g., KIF18A protein motor activity
  • cell proliferation inhibitory activity e.g., OVCAR3 cells, MDA-MB-468 cells
  • the compounds disclosed herein show good pharmacokinetic properties in terms of oral absorption exposure, half-life, absolute bioavailability, etc.
  • the compounds of the present application can effectively inhibit tumor growth.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • substituteduent includes all substituents mentioned herein, for example, including the definitions of the following terms “alkyl”, “alkylene”, “heteroalkyl”, “alkoxy”, “alkylamino”, “dialkylamino”, “alkylthio”, “alkenyl”, “alkynyl”, “cycloalkyl”, “cycloalkenyl”, “heterocyclyl”, “heterocycloalkyl”, “aryl”, “heteroaryl” and other related groups, and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the “substituent” include deuterium atoms, hydroxyl groups, sulfhydryl groups, halogen groups, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde
  • the substituent is selected from a deuterium atom, a hydroxyl group, a thiol group, a halogen, an amino group, a nitro group, a nitroso group, a cyano group, an azide group, a sulfoxide group, a sulfone group, a sulfone group, a sulfonamide group, a carboxyl group, an aldehyde group, an imine group, a C 1-12 alkyl group, a halo-C 1-12 alkyl group, a 3-12 membered cycloalkyl group, a halo-3-12 membered cycloalkyl group, a C 2-12 alkenyl group, a halo-C 2-12 alkenyl group, a 3-12 membered cycloalkenyl group, a halo-3-12 membered cycloalkenyl group, a C 2-12 alkyn
  • replace or “replaced” means that a specific atom or group can replace or be replaced by another specified atom or group.
  • one, two or three -CH2- in -CH2CH2CH2- can be replaced by O, S or NH to give -O- CH2 - CH2- , -O- CH2- , -CH2 -O- CH2- , -CH2 - O-, -CH2- CH2 -O-, -O-, etc.
  • an ethyl group is "optionally” substituted with a halogen, which means that the ethyl group may be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), polysubstituted (such as CHFCH 2 F, CH 2 CHF 2, etc.) or fully substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or incompatible substituents are introduced. A synthetically capable substitution or substitution pattern.
  • Cmn herein means that the moiety has an integer number of carbon atoms in a given range.
  • C1-12 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms or 12 carbon atoms
  • C1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • C1-3 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • each R has an independent choice.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.
  • connection direction is arbitrary.
  • the connecting group L is -M-W-, which means that the structure can be A-M-W-Z or A-W-M-Z.
  • the substituent When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxy refers to an -OH group.
  • cyano refers to a -CN group.
  • mercapto refers to a -SH group.
  • amino refers to a -NH2 group.
  • nitro refers to a -NO2 group.
  • alkylene refers to a saturated straight or branched divalent hydrocarbon radical of the general formula CnH2n , typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.
  • C1-6 alkylene refers to an alkylene radical containing 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene radicals include, but are not limited to, methylene ( -CH2- ), ethylene ( -CH2CH2- ), propylene ( -CH2CH2CH2- or -CH2CH ( CH3 )-), butylene ( -CH2CH2CH2CH2- , -CH2CH ( CH3 ) CH2- or -CH2CH2CH ( CH3 )-), and the like.
  • the alkylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.
  • substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalky
  • alkyl refers to a saturated hydrocarbon group of the general formula CnH2n +1 , typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.
  • the alkyl group may be straight chain or branched, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • C1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • 1 to 6 carbon atoms e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.
  • the alkyl group is optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, halogenated alkoxy, alkylamino, dialkylamino, halogenated alkylamino, halogenated dialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
  • the alkyl moiety (i.e., alkyl) of alkoxy, alkylamino, dialkylamino and alkylthio has the same definition as above.
  • heteroalkyl refers to an alkyl group in which one or more carbon atoms (and hydrogen atoms connected thereto) are each independently replaced by the same or different heteroatom groups. Unless otherwise indicated, the heteroalkyl group includes 1, 2 or 3 heteroatom groups, non-limiting examples of which include O, S, N or NH, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.
  • C 1-6 heteroalkyl refers to a heteroalkyl group containing 1 to 6 carbon atoms and 1-3 heteroatom groups.
  • the heteroatom group can be placed at any position (e.g., internal or terminal position) of the heteroalkyl group, including the position in which the heteroalkyl group is connected to the rest of the molecule. Typically, in the presence of more than one heteroatom group, the heteroatom groups are not adjacent to each other.
  • exemplary heteroalkyl groups include But not limited to alkoxy, alkoxyalkylene, alkylamino, alkylaminoalkylene, dialkylamino, dialkylaminoalkylene, etc.
  • the heteroalkyl group is optionally substituted with one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
  • substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, hetero
  • alkoxy refers to an -O-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.
  • alkylamino refers to -NH-alkyl groups, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.
  • dialkylamino refers to -N(alkyl) 2 , typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.
  • alkylthio refers to an -S-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.
  • alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one double bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4 or 2 to 3 carbon atoms.
  • alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.
  • the alkenyl is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl, amino, nitro, halogen, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
  • substituents selected from the group consisting of oxo, hydroxyl, amino, nitro, halogen, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, hetero
  • alkynyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4 or 2 to 3 carbon atoms.
  • alkynyl include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 2-propynyl (-CH 2 -C ⁇ CH), 1,3-butadiynyl (-C ⁇ CC ⁇ CH), etc.
  • the alkynyl is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
  • substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyl
  • cycloalkyl refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3-12 ring, a 3 to 10 ring, a 3 to 8 ring, a 4 to 8 ring, a 5 to 8 ring, a 6 to 8 ring or a 5 to 6 ring.
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, etc.
  • the cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 - alkyl , -S(O) 2NH2 , -S(O) 2NH2 , -S(O) 2NH -alkyl,
  • cycloalkenyl refers to a non-aromatic, incompletely saturated, cyclic, bridged or spirocyclic ring having at least one double bond.
  • the carbocyclic ring is typically a 3- to 12-membered ring, a 3- to 10-membered ring, a 3- to 8-membered ring, a 3- to 6-membered ring, a 4- to 8-membered ring, a 5- to 8-membered ring, or a 5- to 6-membered ring.
  • Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc.
  • the cycloalkenyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl )2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 -alkyl, -S(O) 2NH2 , -S(O) 2NH -alkyl, -S(O) 2NH2 ,
  • heterocyclic radical refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged, cyclic or spirocyclic ring.
  • the heterocyclic ring is generally 3 to 12 yuan, 3 to 10 yuan, 3 to 8 yuan, 3 to 6 yuan, 4 to 8 yuan, 5 to 8 yuan, 6 to 8 yuan, 5 to 6 yuan, 3 to 7 yuan or 4 to 6 yuan of heteroatoms (preferably 1 or 2 heteroatoms, preferably heteroatoms are N, O or S) containing 1 to 3 independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and/or boron.
  • heteroatoms preferably 1 or 2 heteroatoms, preferably heteroatoms are N, O or S
  • heterocyclic radicals include but are not limited to oxirane, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc.
  • the heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 - alkyl , -S(O) 2NH2 , -S(O) 2NH -alkyl, -S(O) 2NH2 , -S(
  • heterocyclenyl refers to a partially unsaturated (but not completely unsaturated heteroaromatic) non-aromatic ring that can exist as a monocycle, a bridged ring, a ring or a spirocycle.
  • the heterocycle is generally 3 to 12 yuan, 3 to 10 yuan, 4 to 8 yuan, 6 to 8 yuan, 4 to 10 yuan, 4 to 12 yuan, 5 to 7 yuan, 5 to 8 yuan, 5 to 6 yuan, 3 to 7 yuan or 4 to 6 yuan ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms, preferably heteroatoms are N, O or S) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and/or boron.
  • 1 or 2 heteroatoms preferably heteroatoms are N, O or S
  • heterocyclenyl include but are not limited to dihydrofuranyl, dihydropyrrolyl, 2H-pyranyl, dihydrothienyl etc.
  • the heterocycloalkenyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl )2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 12, 3 to 10, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 5 to 6, 3 to 7 or 4 to 6 ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms, preferably N, O or S) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and/or boron.
  • heteroatoms preferably 1 or 2 heteroatoms, preferably N, O or S
  • 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and cyclonitriles;
  • non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl;
  • examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl;
  • examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl
  • the heterocycloalkyl radical is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 - alkyl , -S(O) 2NH2 , -S(O) 2NH2 , -S(O) 2NH -alkyl,
  • aryl refers to an aromatic ring group of an all-carbon monocyclic or fused polycyclic ring having a conjugated ⁇ electron system.
  • an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, 6-12 carbon atoms or 6-10 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl, etc.
  • the aryl group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 - alkyl, -S(O) 2NH2 , -S(O) 2NH -alkyl, -S(O) 2NH2 , -S(O) 2NH -
  • heteroaryl refers to a monocyclic or fused polycyclic aromatic system containing at least one (e.g., 1, 2 or 3) ring atoms selected from N, O, S, and the remaining ring atoms are C, typically having 5 to 14, 5 to 12, 5 to 10, 5 to 8, 5 to 7 or 5 to 6 rings.
  • Preferred heteroaryls have a single 4 to 8 ring, especially a 5 to 6 ring, or multiple fused rings containing 5 to 14, especially 5 to 10 ring atoms.
  • heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.
  • the heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 - alkyl, -S(O) 2NH2 , -S(O) 2NH -alkyl, -S(O) 2NH2 , -S(O) 2NH -
  • deuterated C 1-12 alkyl means that any number and position of H atoms in the above “C 1-12 alkyl” are replaced by deuterium atoms.
  • the C 1-12 deuterated alkyl may be a C 1-6 deuterated alkyl or a C 1-3 deuterated alkyl. Examples of deuterated alkyl include, but are not limited to, -CH 2 D, -CHD 2 , -CD 3 , wait.
  • the group -L 1 - in the present disclosure is read from left to right or from right to left.
  • the group -L 1 - is connected to the left and right groups connected to the group in the general formula in the reading order from left to right.
  • the structure for Or when -L 1 - is -NHS(O) 2 - the structure for
  • the group -L 2 - in the present disclosure is read from right to left or from left to right.
  • the group -L 2 - is read from right to left and is connected to the right side group and the left side group connected to the group in the general formula.
  • -L 2 - is -C(O)NH-
  • treatment means administering the compounds or formulations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.
  • terapéuticaally effective amount means an amount of a compound of the present disclosure that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein.
  • the amount of a compound of the present disclosure that constitutes a "therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and the present disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts with organic bases for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.
  • composition refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient.
  • the purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, etc.
  • the mammal is a human.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • proton migration such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is an imidazole moiety, in which a proton can migrate between two ring nitrogens.
  • Valence tautomers include interconversions by reorganization of some bonding electrons.
  • the present disclosure also includes isotope-labeled compounds of the present disclosure that are identical to those described herein, but one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature.
  • isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H , 3H , 11C , 13C , 14C , 13N , 15N , 15O , 17O , 18O , 31P , 32P , 35S , 18F , 123I, 125I , and 36Cl , respectively.
  • compounds in which one or more hydrogen atoms in the compounds of formula (I) of the present disclosure are replaced by deuterium atoms are still within the scope of the compounds of formula (I) of the present disclosure.
  • isotopically-labeled compounds of the present disclosure are useful in compound and/or substrate tissue distribution assays. Analysis. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O, 13 N, 11 C, and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an unlabeled reagent.
  • PET positron emission tomography
  • substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, wherein deuterium substitution may be partial or full, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.
  • the compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers.
  • the compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • Non-limiting examples of stereoisomers include, but are not limited to:
  • the compounds of the present disclosure may have one or more atropisomers, and unless otherwise specified, the atropisomers refer to optically active isomers produced due to the obstruction of free rotation between single bonds.
  • the compounds containing chiral axes of the present disclosure can be separated in racemic form. When the energy barrier for free rotation of single bonds of the compounds containing chiral axes of the present disclosure is high enough, the atropisomers thereof can be separated in an optically pure form.
  • compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.
  • the daily dosage is 0.001 to 2000 mg/kg body weight.
  • the compounds of the present disclosure can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples disclosed herein.
  • the compounds of formula (II-2) or (III-2) disclosed herein can be prepared by those skilled in the art of organic synthesis via route 1 or route 2, wherein X1 , X2 , Y1 , Y2 , Z4 , Z5 , R1 , ring A, ring B and ring C are as defined herein.
  • Each product obtained by the reaction in the above route can be obtained by conventional separation techniques, including but not limited to filtration, distillation, crystallization, chromatographic separation, etc.
  • the starting materials can be synthesized by themselves or purchased from commercial institutions (such as, but not limited to Adrich or Sigma). These raw materials can be characterized using conventional means, such as physical constants and spectral data.
  • the compounds described in the present disclosure can be used to obtain a single isomer or a mixture of isomers using synthetic methods.
  • NMP stands for N-methylpyrrolidone
  • DIPEA stands for diisopropylethylamine
  • DIEA stands for diisopropylethylamine
  • Xant-Phos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
  • Pd 2 (dba) 3 stands for tris(dibenzylideneacetone)dipalladium
  • EA stands for ethyl acetate
  • PE stands for petroleum ether
  • DMF stands for N,N-dimethylformamide
  • t-BuXPhos stands for (methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II);
  • DCM stands for dichloromethane; MeOH stands
  • DAST represents diethylaminosulfur trifluoride
  • Boc 2 O represents di-tert-butyl dicarbonate
  • BAST represents bis(2-methoxyethyl)aminosulfur trifluoride
  • 9-BBN represents lithium 9-borabicyclo[3.3.1]nonane hydride
  • TFA represents trifluoroacetic acid
  • THP represents tetrahydropyran
  • TEMPO represents 2,2,6,6-tetramethylpiperidinoxide
  • DCE represents 1,2-dichloroethane.
  • C-4 (0.86g) was dissolved in THF (35mL), and stirred under nitrogen protection in an ice bath.
  • a 0.5M 9-BBN tetrahydrofuran solution (20.8mL) was added, and then the ice bath was removed and stirred at room temperature for 2.5h.
  • Distilled water 40mL was added dropwise, and then sodium perborate tetrahydrate (5.35g) was added, and the reaction was stirred at room temperature for 16h.
  • step F of Example 2 compound 6 was synthesized by replacing compound 2-7 with compound 6-7.
  • step A of Example 2 compound 8-2 was obtained by replacing N-tert-butyloxycarbonyl-2-piperidin-2-ylethanol with compound 8-1.
  • step D of Example 2 compound 8-5 was prepared by replacing compound 2-4 with compound 8-4.
  • step E of Example 2 compound 8-5 was used to replace compound 2-5 to prepare compound 8-6.
  • 1 H NMR 500 MHz, DMSO-d 6 ) ⁇ 11.47 (s, 1H), 8.02 (d, 1H), 7.85 (d, 1H), 7.69–7.59 (m, 3H), 4.34-4.31 (m, 2H), 3.83–3.65 (m, 3H), 3.51–3.38 (m, 4H), 2.99 (t, 4H), 1.99 (q, 2H), 1.53 (s, 4H), 0.34 (s, 4H).
  • step F of Example 2 compound 8 was prepared by replacing compound 2-6 with compound 8-6.
  • 1 H NMR 500MHz, DMSO-d 6 ) ⁇ 11.56(s,1H),10.16(s,1H),8.05(d,1H),7.91(d,1H),7.84(d,1H),7.20(d,1H),7.04(dd,1H),4.93(t,1H),4.40-4.36(m,1H),4.30 -4.27(m,1H),3.80–3.67(m,5H),3.49–3.40(m,4H),3.35(t,2H),2.96(t,4H),2.00(q,2H),1.56(s,4H),0.36(s,4H).
  • step E of Example 3 compound 9 (200 mg) was prepared by replacing compound 3-5 with compound 9-3.
  • step E of Example 4 compound 13-1 was used instead of compound 4-5 to prepare compound 13-2 (480 mg). MS (ESI+, [M+H] + ) m/z: 475.57.
  • step F of Example 2 compound 15 was prepared by replacing compound 2-6 with compound 15-3 and replacing 2-hydroxy-1-sulfonamide with ethylsulfonamide.
  • 1 H NMR 500MHz, DMSO-d 6 ) ⁇ 13.22(s,1H),8.04(d,1H),7.74(d,1H),7.41(d,1H),7.23(d,1H),7.08(m,1H),4.68-4.64(m,1H),4.20(dd,1H),3.27(s,3H) ,3.16(q,2H),2.97(t,4H),2.90-2.86(m,1H),2.42-2.38(m,1H),2.20–1.62(m,7H),1.20(t,3H),0.39(s,4H).
  • HRMS (ESI+,[M+H] + )m/z:589.2418.
  • step F of Example 2 compound 18 was prepared by replacing compound 2-6 with compound 18-5.
  • 1 H NMR 500 MHz, DMSO-d 6 ) ⁇ 11.56 (s, 1H), 8.10 (d, 1H), 7.86 (dd, 2H), 7.13 (s, 1H), 6.98 (d, 1H), 4.50–4.34 (m, 2H), 3.82 (d, 1H), 3.75 (t, 2H), 3.51 (d, 1H), 3.29 (t, 3H), 3.20 (t, 1H), 2.96 (d, 4H), 2.40–1.81 (m, 7H), 1.55 (s, 4H), 0.35 (s, 4H).
  • HRMS (ESI+, [M+H] + ) m/z: 592.2417.
  • step D of Example 14 deuterated iodomethane-D3 was used to replace iodomethane to prepare compound 21-1.
  • 1 H NMR 500 MHz, DMSO-d 6 ) ⁇ 7.24 (d, 1H), 6.99 (d, 1H), 4.57-4.51 (m, 1H), 4.28-4.22 (m, 1H), 2.86-2.79 (m, 1H), 2.48-2.41 (m, 1H), 2.21-2.07 (m, 2H), 2.02-1.88 (m, 1H).
  • compound E-4 was used instead of compound D-4 to prepare compound 22_A (84 mg).
  • 1 HNMR 500 MHz, DMSO-d 6 ) ⁇ 11.58(s,1H),10.10(s,1H),7.90(d,1H),7.74(d,1H),7.41(d,1H),7.08 (d,1H),6.97(dd,1H),4.64(s,1H),4.32–4.05(m,1H),3.84–3.73(m,2H),3.
  • step E of preparation example A-6 compound 24-2 was substituted for compound A-5 to prepare compound 24-3 (110 mg). MS (ESI-, [MH] - ) m/z: 378.16.
  • Compound 24_B 1 H NMR (500 MHz, DMSO-d 6 ) ⁇ 10.98(s,1H),10.05(s,1H),7.85–7.75(m,2H),7.41(d,1H),7.29–7.24(m,1H),7.05(d,1H),4.66(d,1H),4.22–4.16(m,1H),3.79–3.71(m,2H),3.27(s,3H),3.
  • step C of Example 14 compound 25-4 was used to replace compound 14-3 to prepare compound 25-5.
  • 1 H NMR 500 MHz, DMSO-d 6 ) ⁇ 10.33 (s, 1H), 6.83 (s, 1H), 4.55–4.47 (m, 1H), 4.15–4.08 (m, 1H), 2.84–2.75 (m, 1H), 2.47–2.36 (m, 1H), 2.17 (s, 3H), 2.16–1.86 (m, 3H).
  • step D of Example 14 compound 25-5 was used to replace compound 14-4 to prepare compound 25-6.
  • 1 H NMR 500 MHz, DMSO-d 6 ) ⁇ 6.99 (s, 1H), 4.34–4.24 (m, 1H), 3.97–3.91 (m, 1H), 3.29 (s, 3H), 2.88–2.80 (m, 1H), 2.43–2.37 (m, 1H), 2.36 (s, 3H), 2.24–2.14 (m, 1H), 2.14–1.91 (m, 2H).
  • step F of Example 25 compound D-4 was used instead of compound A-6 to prepare compound 28 (220 mg), MS (ESI+, [M+H] + ) m/z: 615.34.
  • compound 29-2 was used instead of compound D-4 to prepare compound 29_A (45 mg).
  • 1 HNMR 500 MHz, DMSO-d 6 ) ⁇ 11.59(s,1H),10.06(s,1H),7.89(d,1H),7.74(d,1H),7.41(d,1H),7.10(d,1H),6.97(dd,1H),4.92(s,1H),4.65(d,1H),4.25–4.06(m,1H),3.84–3.65(m,4H),3.27(s,3H),2.97–2.75 (m,1H),2.53(d,2H),2.49–2.34(m,2H),2.15(d,1H),2.10–1.99(m,3H),1.91(d,2H),1.18(t ,1H),1.05–0.95(m,2H),0.90–0.79(m,1H),0.60(t,2H),0.25
  • compound 37-4 was used to replace compound D-4 to prepare compound 37-5.
  • compound 37-4 was used to replace compound D-4 to prepare compound 37-6.

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Abstract

The present application belongs to the field of medicine, and relates to a tricyclic compound and medical uses thereof, the structure of the compound being represented by formula (I), and specifically relates to a preparation method for the compound, a pharmaceutical composition thereof, and uses thereof in the treatment of diseases.

Description

三并环化合物及其医药用途Tricyclic compounds and their medical uses

相关申请的交叉引用CROSS-REFERENCE TO RELATED APPLICATIONS

本申请要求于2023年6月21日向中国国家知识产权局提交的第202310745248.X号中国专利申请、于2023年9月8日向中国国家知识产权局提交的第202311158909.5号中国专利申请、于2024年3月19日向中国国家知识产权局提交的第202410316232.1号中国专利申请以及于2024年6月13日向中国国家知识产权局提交的第202410761294.3号中国专利申请的优先权和权益，上述申请公开的内容通过引用整体并入本文中。This application claims the priority and rights of Chinese Patent Application No. 202310745248.X filed with the State Intellectual Property Office of China on June 21, 2023, Chinese Patent Application No. 202311158909.5 filed with the State Intellectual Property Office of China on September 8, 2023, Chinese Patent Application No. 202410316232.1 filed with the State Intellectual Property Office of China on March 19, 2024, and Chinese Patent Application No. 202410761294.3 filed with the State Intellectual Property Office of China on June 13, 2024, and the contents disclosed in the above applications are incorporated herein by reference in their entirety.

技术领域Technical Field

本公开涉及三并环化合物、其制备方法、含有该化合物的药物组合物、以及其在治疗疾病中的用途。The present disclosure relates to a tricyclic compound, a preparation method thereof, a pharmaceutical composition containing the compound, and use thereof in treating diseases.

背景技术Background Art

KIF18A是一种有丝分裂驱动蛋白，属于Kinesin-8家族。KIF18A在有丝分裂过程中调控正确的染色体定位和纺锤体张力。人体中KIF18A的缺失导致更长的纺锤体，并导致细胞周期的G2/M期染色体振荡增加。有研究表明，KIF18A在全基因组倍增(Whole-genome doubling,WGD)肿瘤细胞中过表达，但是在正常细胞中却是非必需的。抑制KIF18A可诱导WGD肿瘤细胞的有丝分裂停止，而不影响正常细胞。因此，KIF18A是一个颇具潜力的抗肿瘤靶点。KIF18A is a mitotic kinesin that belongs to the Kinesin-8 family. KIF18A regulates correct chromosome positioning and spindle tension during mitosis. Loss of KIF18A in humans leads to longer spindles and increased chromosome oscillations during the G2/M phase of the cell cycle. Studies have shown that KIF18A is overexpressed in whole-genome doubling (WGD) tumor cells, but is non-essential in normal cells. Inhibition of KIF18A can induce mitotic arrest in WGD tumor cells without affecting normal cells. Therefore, KIF18A is a potential anti-tumor target.

发明详述DETAILED DESCRIPTION OF THE INVENTION

本公开涉及式(I)化合物或其药学上可接受的盐，
The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

其中，in,

X1和Y1相互连接形成结构单元且Y2选自N或CRY2； X1 and Y1 are connected to each other to form a structural unit and Y2 is selected from N or CR Y2 ;

或者，X1和Y2相互连接形成结构单元且Y1选自N或CRY1；Alternatively, X1 and Y2 are linked to each other to form a structural unit and Y1 is selected from N or CR Y1 ;

X1选自N或CRX1； X1 is selected from N or CR X1 ;

X2选自N或CRX2； X2 is selected from N or CR X2 ;

X1与X2通过单键连接； X1 and X2 are connected by a single bond;

Z1、Z2或Z3各自独立地选自N或CRZ1；Z 1 , Z 2 or Z 3 are each independently selected from N or CR Z1 ;

Z4或Z5各自独立地选自N或CRZ2； Z4 or Z5 are each independently selected from N or CR Z2 ;

环A选自任选被一个或多个Ra取代的如下基团：4-12元环烯基、4-12元杂环烯基、6-10元芳基、或5-10元杂芳基；Ring A is selected from the following groups optionally substituted by one or more Ra : 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

每个RX1、RX2、RY1、RY2、RZ1或RZ2各自独立地选自H、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1-12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1- 12烷基)2、-NHCOC1-12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each of RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is independently selected from H, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, diC1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy, halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated diC1-12 alkylamino, -COC1-12 alkyl, -OC (O) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC (O) OC1-12 alkyl, -SO2C1-12alkyl , -NHSO2C1-12alkyl C 1-12 alkyl, -N(C 1-12 alkyl)SO 2 C 1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N (C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

环B选自任选地被一个或多个Rb取代的如下基团：3-12元环烷基、3-12元环烯基、3-12元杂环基、6-10元芳基、或5-10元杂芳基；Ring B is selected from the following groups optionally substituted by one or more R b : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

每个Ra或Rb各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1-12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1- 12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each Ra or Rb is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, diC1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy, halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated diC1-12 alkylamino, -COC1-12 alkyl, -OC(O) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC (O) OC1-12 alkyl , -SO2C1-12 alkyl, -NHSO2C1-12 alkyl , -N(C1-12 alkyl ) SO2C -1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

环C选自任选地被一个或多个Rc1取代的如下基团：3-12元环烷基或3-12元杂环烷基；Ring C is selected from the following groups optionally substituted by one or more R c1 : 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl;

每个Rc1各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1- 12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1-12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N (C 1-12 alkyl)SO 2 C -1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

或者，位于同一个环原子上的两个Rc1和与Rc1相连的环原子一起形成任选被一个或多个Rc2取代的如下基团：3-12元环烷基、3-12元环烯基或3-12元杂环基；Alternatively, two R c1 located on the same ring atom and the ring atom to which R c1 is attached together form the following group optionally substituted by one or more R c2 : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl;

或者，位于相邻两个环原子上的两个Rc1和与Rc1相连的环原子一起形成任选被一个或多个Rc2取代的如下基团：3-12元环烷基、3-12元环烯基或3-12元杂环基；Alternatively, two R c1 located on two adjacent ring atoms and the ring atom to which R c1 is attached together form the following group optionally substituted by one or more R c2 : a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group or a 3-12 membered heterocyclyl group;

每个Rc2各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1- 12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1-12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each R c2 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N (C 1-12 alkyl)SO 2 C -1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

L1选自单键、-O-、-S-、-NRL1-、C1-6亚烷基、氘代C1-6亚烷基、卤代C1-6亚烷基、-C(O)-、-C(O)O-、-OC(O)-、-OC(O)O-、-OC(O)NRL1-、-C(O)NRL1-、-NRL1C(O)-、-NRL1C(O)O-、-NRL1C(O)NRL1-、-S(O)-、-S(O)2-、-S(O)2NRL1-、-NRL1S(O)2-、-NRL1S(O)2NRL1-、-S(O)(＝NH)-、-NRL1S(O)(＝NH)-、或-C＝N(OH)-； L1 is selected from a single bond, -O-, -S-, -NR L1 -, C 1-6 alkylene, deuterated C 1-6 alkylene, halogenated C 1-6 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)NR L1 -, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 C(O)O-, -NR L1 C(O)NR L1 -, -S(O)-, -S(O) 2 -, -S(O) 2 NR L1 -, -NR L1 S(O ) 2 -, -NR L1 S(O) 2 NR L1 -, -S(O)(＝NH)-, -NR L1 S(O)(＝NH)-, or -C＝N(OH)-;

每个RL1各自独立地选自H、氘、或者任选被一个或多个RL1a取代的如下基团：C1-6烷基、氘代C1- 6烷基、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-10元芳基、或5-10元杂芳基；Each RL1 is independently selected from H, deuterium, or the following groups optionally substituted with one or more RL1a : C1-6 alkyl, deuterated C1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

每个RL1a各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1- 12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1-12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、- SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1- 12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each RL1a is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, di- C1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy , halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated di- C1-12 alkylamino, -COC1-12 alkyl, -OC ( O ) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC(O) OC1-12 alkyl, -SO2C1-12 alkyl, -NHSO2C1-12 alkyl, -N(C1-12 alkyl ) SO2C1-12 1-12 alkyl, - SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

R1选自H、卤素、氘、-OH、-NH2、-SH、-COOH、-CN、或者任选被一个或多个R1a取代的如下基团：C1-12烷基、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-10元芳基、5-10元杂芳基、3-12元环烷基C1-6亚烷基、3-12元环烯基C1-6亚烷基、3-12元杂环基C1-6亚烷基、6-10元芳基C1-6亚烷基、或5-10元杂芳基C1-6亚烷基；R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH , -CN, or C 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkylC 1-6 alkylene, 3-12 membered cycloalkenylC 1-6 alkylene, 3-12 membered heterocyclylC 1-6 alkylene, 6-10 membered arylC 1-6 alkylene, or 5-10 membered heteroarylC 1-6 alkylene, optionally substituted with one or more R 1a ;

每个R1a各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1-12烷基、羟基C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1- 12烷基、-C(O)OC1-12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1- 12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1-12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each R 1a is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, hydroxy C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O )OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl , -N ( C -12 alkyl ) SO2C1-12 alkyl, -SO2NH2 , -SO2NHC1-12 alkyl, -SO2N( C1-12 alkyl) 2 , -CONH2 , -CONHC1-12 alkyl, -CON ( C1-12 alkyl ) 2 , -NHCOC1-12 alkyl, -N( C1-12 alkyl ) COC1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl ;

L2选自-O-、-S-、-NRL2-、C1-6亚烷基、氘代C1-6亚烷基、卤代C1-6亚烷基、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NRL2-、-NRL2C(O)-、-S(O)-、-S(O)2-、-S(O)2NRL2-、-NRL2S(O)2-、-S(O)(＝NH)-、-NRL2S(O)(＝NH)-、或-C＝N(OH)-； L2 is selected from -O-, -S-, -NR L2 -, C 1-6 alkylene, deuterated C 1-6 alkylene, halogenated C 1-6 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L2 -, -NR L2 C(O)-, -S(O)-, -S(O) 2 -, -S(O) 2 NR L2 -, -NR L2 S(O) 2 -, -S(O)(＝NH)-, -NR L2 S(O)(＝NH)-, or -C＝N(OH)-;

RL2选自H、氘、C1-6烷基、氘代C1-6烷基、或卤代C1-6烷基； RL2 is selected from H, deuterium, C1-6 alkyl, deuterated C1-6 alkyl, or halogenated C1-6 alkyl;

所述RX1、RX2、RY1、RY2、RZ1、RZ2、Ra、Rb、Rc1、Rc2、RL1、RL1a、R1、R1a、或RL2任选地被一个或多个取代基取代。The RX1 , RX2 , RY1 , RY2, RZ1 , RZ2 , Ra , Rb , Rc1 , Rc2 , RL1 , RL1a , R1 , R1a , or RL2 is optionally substituted with one or more substituents.

在一些实施方案中，所述式(I)化合物或其药学上可接受的盐中，In some embodiments, in the compound of formula (I) or a pharmaceutically acceptable salt thereof,

X1和Y1相互连接形成结构单元且Y2选自N或CRY2； X1 and Y1 are connected to each other to form a structural unit and Y2 is selected from N or CR Y2 ;

或者，X1和Y2相互连接形成结构单元且Y1选自N或CRY1；Alternatively, X1 and Y2 are linked to each other to form a structural unit and Y1 is selected from N or CR Y1 ;

X1选自N或CRX1； X1 is selected from N or CR X1 ;

X2选自N或CRX2； X2 is selected from N or CR X2 ;

X1与X2通过单键连接； X1 and X2 are connected by a single bond;

Z1、Z2或Z3各自独立地选自N或CRZ1；Z 1 , Z 2 or Z 3 are each independently selected from N or CR Z1 ;

Z4或Z5各自独立地选自N或CRZ2； Z4 or Z5 are each independently selected from N or CR Z2 ;

环A选自任选被一个或多个Ra取代的如下基团：4-12元环烯基、4-12元杂环烯基、6-10元芳基、或5-10元杂芳基；Ring A is selected from the following groups optionally substituted by one or more Ra : 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

每个RX1、RX2、RY1、RY2、RZ1或RZ2各自独立地选自H、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1-12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1- 12烷基)2、-NHCOC1-12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each of RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is independently selected from H, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, diC1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy, halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated diC1-12 alkylamino, -COC1-12 alkyl, -OC (O) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC (O) OC1-12 alkyl, -SO2C1-12alkyl , -NHSO2C1-12alkyl C 1-12 alkyl, -N(C 1-12 alkyl)SO 2 C 1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N (C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

环B选自任选地被一个或多个Rb取代的如下基团：3-12元环烷基、3-12元环烯基、3-12元杂环基、6-10元芳基、或5-10元杂芳基； Ring B is selected from the following groups optionally substituted by one or more R b : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

每个Ra或Rb各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1-12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1- 12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each Ra or Rb is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, diC1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy, halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated diC1-12 alkylamino, -COC1-12 alkyl, -OC(O) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC (O) OC1-12 alkyl , -SO2C1-12 alkyl, -NHSO2C1-12 alkyl , -N(C1-12 alkyl ) SO2C -1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

环C选自任选地被一个或多个Rc1取代的如下基团：3-12元环烷基或3-12元杂环烷基；Ring C is selected from the following groups optionally substituted by one or more R c1 : 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl;

每个Rc1各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1- 12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1-12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N (C 1-12 alkyl)SO 2 C -1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

或者，位于同一个环原子上的两个Rc1和与Rc1相连的环原子一起形成任选被一个或多个Rc2取代的如下基团：3-12元环烷基、3-12元环烯基或3-12元杂环基；Alternatively, two R c1 located on the same ring atom and the ring atom to which R c1 is attached together form the following group optionally substituted by one or more R c2 : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl;

或者，位于相邻两个环原子上的两个Rc1和与Rc1相连的环原子一起形成任选被一个或多个Rc2取代的如下基团：3-12元环烷基、3-12元环烯基或3-12元杂环基；Alternatively, two R c1 located on two adjacent ring atoms and the ring atom to which R c1 is attached together form the following group optionally substituted by one or more R c2 : a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group or a 3-12 membered heterocyclyl group;

每个Rc2各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1- 12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1-12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each R c2 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N (C 1-12 alkyl)SO 2 C -1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

L1选自单键、-O-、-S-、-NRL1-、C1-6亚烷基、氘代C1-6亚烷基、卤代C1-6亚烷基、-C(O)-、-C(O)O-、-OC(O)-、-OC(O)O-、-OC(O)NRL1-、-C(O)NRL1-、-NRL1C(O)-、-NRL1C(O)O-、-NRL1C(O)NRL1-、-S(O)-、-S(O)2-、-S(O)2NRL1-、-NRL1S(O)2-、-NRL1S(O)2NRL1-、-S(O)(＝NH)-、-NRL1S(O)(＝NH)-、或-C＝N(OH)-； L1 is selected from a single bond, -O-, -S-, -NR L1 -, C 1-6 alkylene, deuterated C 1-6 alkylene, halogenated C 1-6 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)NR L1 -, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 C(O)O-, -NR L1 C(O)NR L1 -, -S(O)-, -S(O) 2 -, -S(O) 2 NR L1 -, -NR L1 S(O ) 2 -, -NR L1 S(O) 2 NR L1 -, -S(O)(＝NH)-, -NR L1 S(O)(＝NH)-, or -C＝N(OH)-;

每个RL1各自独立地选自H、氘、或者任选被一个或多个RL1a取代的如下基团：C1-6烷基、氘代C1- 6烷基、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-10元芳基、或5-10元杂芳基；Each RL1 is independently selected from H, deuterium, or the following groups optionally substituted with one or more RL1a : C1-6 alkyl, deuterated C1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

每个RL1a各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1- 12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1-12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1- 12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each RL1a is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, di- C1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy , halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated di- C1-12 alkylamino, -COC1-12 alkyl, -OC ( O ) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC(O) OC1-12 alkyl, -SO2C1-12 alkyl, -NHSO2C1-12 alkyl, -N(C1-12 alkyl ) SO2C1-12 -1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

R1选自H、卤素、氘、-OH、-NH2、-SH、-COOH、-CN、或者任选被一个或多个R1a取代的如下基团：C1-12烷基、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-10元芳基、或5-10元杂芳基；每个R1a各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1-12烷基、羟基C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1-12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1-12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂 芳基或3-12元杂环基；R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted by one or more R 1a : C 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; each R 1a is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, hydroxy C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, diC 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C C 1-12 alkylamino, halogenated diC 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N(C 1-12 alkyl)SO 2 C 1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 membered alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered hetero Aryl or 3-12 membered heterocyclic group;

L2选自-O-、-S-、-NRL2-、C1-6亚烷基、氘代C1-6亚烷基、卤代C1-6亚烷基、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NRL2-、-NRL2C(O)-、-S(O)-、-S(O)2-、-S(O)2NRL2-、-NRL2S(O)2-、-S(O)(＝NH)-、-NRL2S(O)(＝NH)-、或-C＝N(OH)-； L2 is selected from -O-, -S-, -NR L2 -, C 1-6 alkylene, deuterated C 1-6 alkylene, halogenated C 1-6 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L2 -, -NR L2 C(O)-, -S(O)-, -S(O) 2 -, -S(O) 2 NR L2 -, -NR L2 S(O) 2 -, -S(O)(＝NH)-, -NR L2 S(O)(＝NH)-, or -C＝N(OH)-;

RL2选自H、氘、C1-6烷基、氘代C1-6烷基、或卤代C1-6烷基； RL2 is selected from H, deuterium, C1-6 alkyl, deuterated C1-6 alkyl, or halogenated C1-6 alkyl;

所述RX1、RX2、RY1、RY2、RZ1、RZ2、Ra、Rb、Rc1、Rc2、RL1、RL1a、R1、R1a、或RL2任选地被一个或多个取代基取代。The RX1 , RX2 , RY1 , RY2, RZ1 , RZ2 , Ra , Rb , Rc1 , Rc2 , RL1 , RL1a , R1 , R1a , or RL2 is optionally substituted with one or more substituents.

在一些实施方案中，所述式(I)化合物或其药学上可接受的盐中，In some embodiments, in the compound of formula (I) or a pharmaceutically acceptable salt thereof,

X1和Y1相互连接形成结构单元且Y2选自N或CRY2； X1 and Y1 are connected to each other to form a structural unit and Y2 is selected from N or CR Y2 ;

或者，X1和Y2相互连接形成结构单元且Y1选自N或CRY1；Alternatively, X1 and Y2 are linked to each other to form a structural unit and Y1 is selected from N or CR Y1 ;

X1选自N或CRX1； X1 is selected from N or CR X1 ;

X2选自N或CRX2； X2 is selected from N or CR X2 ;

X1与X2通过单键连接； X1 and X2 are connected by a single bond;

Z1、Z2或Z3各自独立地选自N或CRZ1；Z 1 , Z 2 or Z 3 are each independently selected from N or CR Z1 ;

Z4或Z5各自独立地选自N或CRZ2； Z4 or Z5 are each independently selected from N or CR Z2 ;

环A选自任选被一个或多个Ra取代的如下基团：4-12元环烯基、4-12元杂环烯基、6-10元芳基、或5-10元杂芳基；Ring A is selected from the following groups optionally substituted by one or more Ra : 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

每个RX1、RX2、RY1、RY2、RZ1或RZ2各自独立地选自H、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1-12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1- 12烷基)2、-NHCOC1-12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each of RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is independently selected from H, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, diC1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy, halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated diC1-12 alkylamino, -COC1-12 alkyl, -OC (O) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC (O) OC1-12 alkyl, -SO2C1-12alkyl , -NHSO2C1-12alkyl C 1-12 alkyl, -N(C 1-12 alkyl)SO 2 C 1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N (C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

环B选自任选地被一个或多个Rb取代的如下基团：3-12元环烷基、3-12元环烯基、3-12元杂环基、6-10元芳基、或5-10元杂芳基；Ring B is selected from the following groups optionally substituted by one or more R b : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

每个Ra或Rb各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1-12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1- 12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each Ra or Rb is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, diC1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy, halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated diC1-12 alkylamino, -COC1-12 alkyl, -OC(O) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC (O) OC1-12 alkyl , -SO2C1-12 alkyl, -NHSO2C1-12 alkyl , -N(C1-12 alkyl ) SO2C -1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

环C选自任选地被一个或多个Rc1取代的如下基团：3-12元环烷基或3-12元杂环烷基；Ring C is selected from the following groups optionally substituted by one or more R c1 : 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl;

每个Rc1各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1- 12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1-12烷基、 -N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N (C 1-12 alkyl)SO 2 C 1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

或者，位于同一个环原子上的两个Rc1一起形成任选被一个或多个Rc2取代的如下基团：3-12元环烷基、3-12元环烯基或3-12元杂环基；Alternatively, two R c1 located on the same ring atom together form the following group optionally substituted by one or more R c2 : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl;

或者，位于相邻两个环原子上的两个Rc1一起形成任选被一个或多个Rc2取代的如下基团：3-12元环烷基、3-12元环烯基或3-12元杂环基；Alternatively, two R c1 located on two adjacent ring atoms together form the following group optionally substituted by one or more R c2 : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl;

每个Rc2各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1- 12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1-12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each R c2 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N (C 1-12 alkyl)SO 2 C -1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

L1选自单键、-O-、-S-、-NRL1-、C1-6亚烷基、氘代C1-6亚烷基、卤代C1-6亚烷基、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NRL1-、-NRL1C(O)-、-NRL1C(O)NRL1-、-S(O)-、-S(O)2-、-S(O)2NRL1-、-NRL1S(O)2-、-NRL1S(O)2NRL1-、-S(O)(＝NH)-、-NRL1S(O)(＝NH)-、或-C＝N(OH)-； L1 is selected from a single bond, -O-, -S-, -NR L1 -, C 1-6 alkylene, deuterated C 1-6 alkylene, halogenated C 1-6 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 C(O)NR L1 -, -S(O)-, -S(O) 2 -, -S(O) 2 NR L1 -, -NR L1 S(O) 2 -, -NR L1 S(O) 2 NR L1 -, -S(O)(＝NH)-, -NR L1 S(O)(＝NH)-, or -C＝N(OH)-;

每个RL1各自独立地选自H、氘、或者任选被一个或多个RL1a取代的如下基团：C1-6烷基、氘代C1- 6烷基、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-10元芳基、或5-10元杂芳基；Each RL1 is independently selected from H, deuterium, or the following groups optionally substituted with one or more RL1a : C1-6 alkyl, deuterated C1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

每个RL1a各自独立地选自氧代、氘、卤素、-CN、C1-12烷基、氘代C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1- 12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1-12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1-12烷基、-N(C1-12烷基)COC1- 12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each RL1a is independently selected from oxo, deuterium, halogen, -CN, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, diC1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy, halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated diC1-12 alkylamino, -COC1-12 alkyl, -OC ( O ) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC ( O) OC1-12 alkyl , -SO2C1-12 alkyl , -NHSO2C1-12 alkyl, -N( C1-12 alkyl )SO2C1-12 alkyl , -SO2NH2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1- 12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl;

R1选自H、卤素、氘、-OH、-NH2、-SH、-COOH、-CN、或者任选被一个或多个R1a取代的如下基团：C1-12烷基、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-10元芳基、或5-10元杂芳基；R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted with one or more R 1a : C 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl;

每个R1a各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1-12烷基、羟基C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1- 12烷基、-C(O)OC1-12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1- 12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1-12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each R 1a is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, hydroxy C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O )OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl , -N ( C -12 alkyl ) SO2C1-12 alkyl, -SO2NH2 , -SO2NHC1-12 alkyl, -SO2N( C1-12 alkyl) 2 , -CONH2 , -CONHC1-12 alkyl, -CON ( C1-12 alkyl ) 2 , -NHCOC1-12 alkyl, -N( C1-12 alkyl ) COC1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl ;

L2选自-O-、-S-、-NRL2-、C1-6亚烷基、氘代C1-6亚烷基、卤代C1-6亚烷基、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NRL2-、-NRL2C(O)-、-S(O)-、-S(O)2-、-S(O)2NRL2-、-NRL2S(O)2-、-S(O)(＝NH)-、-NRL2S(O)(＝NH)-、或-C＝N(OH)-； L2 is selected from -O-, -S-, -NR L2 -, C 1-6 alkylene, deuterated C 1-6 alkylene, halogenated C 1-6 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L2 -, -NR L2 C(O)-, -S(O)-, -S(O) 2 -, -S(O) 2 NR L2 -, -NR L2 S(O) 2 -, -S(O)(＝NH)-, -NR L2 S(O)(＝NH)-, or -C＝N(OH)-;

RL2选自H、氘、C1-6烷基、氘代C1-6烷基、或卤代C1-6烷基； RL2 is selected from H, deuterium, C1-6 alkyl, deuterated C1-6 alkyl, or halogenated C1-6 alkyl;

所述RX1、RX2、RY1、RY2、RZ1、RZ2、Ra、Rb、Rc1、Rc2、RL1、RL1a、R1、R1a、或RL2任选地被一个或多个取代基取代。The RX1 , RX2 , RY1 , RY2, RZ1 , RZ2 , Ra , Rb , Rc1 , Rc2 , RL1 , RL1a , R1 , R1a , or RL2 is optionally substituted with one or more substituents.

在一些实施方案中，所述RX1、RX2、RY1、RY2、RZ1、RZ2、Ra、Rb、Rc1、Rc2、RL1、RL1a、R1、R1a、或RL2任选地被一个或多个取代基取代时，其中的“取代基”选自氘原子、羟基、巯基、卤素、氨基、硝基、亚硝基、氰基、叠氮基团、亚砜基团、砜基团、磺酰胺基团、羧基、醛基、亚胺基团、C1-12烷基、卤代-C1-12烷基、3-12元环烷基、卤代-3-12元环烷基、C2-12烯基、卤代-C2-12烯基、3-12元环烯基、卤代-3-12元环烯基、C2-12炔基、卤代-C2-12炔基、8-12元环炔基、卤代-8-12元环炔基、C1-12杂烷基、卤代-C1-12杂烷基、C1-12烷氧基、C1-12烷硫基、6-10元芳基、6-10元芳基氧基、6-10元芳基硫基、6-10元芳基C1-12亚烷基、6-10元芳基C1-12烷氧基、6-10元芳基C1-12烷硫基、5-10元杂芳基、5-10元杂芳基氧基、 5-10元杂芳基硫基、5-10元杂芳基亚烷基、5-10元杂芳基烷氧基、5-10元杂芳基烷硫基、3-12元杂环基、3-12元杂环基氧基、3-12元杂环基硫基、3-12元杂环基C1-12亚烷基、3-12元杂环基C1-12烷氧基、3-12元杂环基C1-12烷硫基、C1-12酰基、C1-12酰氧基、氨基甲酸酯基团、C1-12酰胺基、脲基、环氧基团、C2-12酯基团、氧代和硫代等，所述取代基任选地被一个或多个选自以下的取代基取代：氘原子、氧代、羟基、氨基、硝基、卤素、氰基、C1-12烷基、C2-12烯基、C2-12炔基、C1-12烷氧基、卤代C1-12烷氧基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、羧基、-C(O)O-C1-12烷基、-OC(O)-C1-12烷基、-C(O)NH2、-C(O)NH-C1-12烷基、-C(O)N(C1-12烷基)2、-NHC(O)-C1-12烷基、-C(O)-C1-12烷基、-S(O)-C1-12烷基、-S(O)2-C1-12烷基、-S(O)2NH2、-S(O)2NH-C1-12烷基、-S(O)2N(C1-12烷基)2、3-12元环烷基、3-12元环烷基C1-12亚烷基、3-12元环烷基氧基、3-12元杂环基、3-12元杂环基C1-12亚烷基、3-12元杂环基氧基、3-12元杂环烷基、3-12元杂环烷基C1-12亚烷基、3-12元杂环烷基氧基、5-10元杂芳基、5-10元杂芳基C1-12亚烷基、5-10元杂芳基氧基、6-10元芳基、6-10元芳基C1-12亚烷基或6-10元芳基氧基。In some embodiments, when the RX1 , RX2 , RY1 , RY2, RZ1 , RZ2 , Ra, Rb , Rc1 , Rc2 , RL1 , RL1a , R1 , R1a , or RL2 are optionally substituted with one or more substituents, the “substituent” is selected from a deuterium atom, a hydroxyl group, a thiol group, a halogen, an amino group, a nitro group, a nitroso group, a cyano group, an azide group, a sulfoxide group, a sulfone group, a sulfone group, a sulfonamide group, a carboxyl group, an aldehyde group, an imine group, a C1-12 alkyl group, a halo- C1-12 alkyl group, a 3-12 membered cycloalkyl group, a halo-3-12 membered cycloalkyl group, a C2-12 alkenyl group, a halo- C2-12 alkenyl group, a 3-12 membered cycloalkenyl group, a halo-3-12 membered cycloalkenyl group, a C2-12 alkynyl group, a halo -C1-12 alkyl group, 2-12- membered alkynyl, 8-12-membered cycloalkynyl, halo-8-12-membered cycloalkynyl, C 1-12 heteroalkyl, halo-C 1-12 heteroalkyl, C 1-12 alkoxy, C 1-12 alkylthio, 6-10-membered aryl, 6-10-membered aryloxy, 6-10 -membered arylthio, 6-10-membered arylC 1-12 alkylene, 6-10-membered arylC 1-12 alkoxy, 6-10-membered arylC 1-12 alkylthio, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, 1-12 acyl group, C 1-12 acyloxy group, carbamate group, C 1-12 amide group, urea group, epoxy group, C 2-12 ester group, oxo group and thio group, etc., wherein the substituent is optionally substituted by one or more substituents selected from the following: deuterium atom, oxo group, hydroxyl group, amino group, nitro group, halogen group, cyano group, C 1-12 alkyl group, C 2-12 alkenyl group, C 2-12 alkynyl group, C 1-12 alkyl group, C 2-12 alkynyl group, C 1-12 acyl group, C 1-12 acyloxy group, carbamate group, C 1-12 amide group, urea group, epoxy group, C 2-12 ester group, oxo group and thio group. C 1-12 alkoxy, halogenated C 1-12 alkoxy, C 1-12 alkylamino, diC 1-12 alkylamino, halogenated C 1-12 alkylamino, halogenated diC 1-12 alkylamino, carboxyl, -C(O)OC 1-12 alkyl, -OC(O)-C 1-12 alkyl, -C(O)NH 2 , -C(O)NH-C 1-12 alkyl, -C(O)N(C 1-12 alkyl) 2 , -NHC(O)-C 1-12 alkyl, -C(O)-C 1-12 alkyl, -S(O)-C 1-12 alkyl, -S(O) 2 -C 1-12 alkyl, -S(O) 2 NH 2 , -S(O) 2 NH-C 1-12 alkyl, -S(O) 2 N(C 1-12 alkyl) 2 , 3-12 membered cycloalkyl, 3-12 membered cycloalkylC 1-12 alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclylC 1-12 alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12 alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC 1-12 alkylene, 5-10 membered heteroaryloxy , 6-10 membered aryl, 6-10 membered arylC 1-12 alkylene , or 6-10 membered aryloxy.

在一些实施方案中，所述RX1、RX2、RY1、RY2、RZ1、RZ2、Ra、Rb、Rc1、Rc2、RL1、RL1a、R1、R1a、或RL2任选地被一个或多个取代基取代时，其中的“取代基”选自氘原子、羟基、巯基、卤素、氨基、硝基、氰基、羧基、醛基、C1-3烷基、卤代-C1-3烷基或C3环烷基。In some embodiments, when RX1 , RX2 , RY1 , RY2, RZ1 , RZ2 , Ra, Rb , Rc1 , Rc2 , RL1, RL1a , R1 , R1a , or RL2 are optionally substituted with one or more substituents, the “substituents” are selected from a deuterium atom , a hydroxyl group, a thiol group, a halogen, an amino group, a nitro group, a cyano group, a carboxyl group, an aldehyde group, a C1-3 alkyl group, a halo- C1-3 alkyl group, or a C3 cycloalkyl group.

在一些实施方案中，X1和Y1相互连接形成结构单元且Y2选自CRY2；或者，X1和Y2相互连接形成结构单元且Y1选自CRY1。In some embodiments, X 1 and Y 1 are linked to each other to form a structural unit and Y2 is selected from CR Y2 ; or, X1 and Y2 are connected to each other to form a structural unit And Y1 is selected from CR Y1 .

在一些实施方案中，X1和Y1相互连接形成结构单元且Y2选自CRY2；或者，X1和Y2相互连接形成结构单元且Y1选自N。In some embodiments, X 1 and Y 1 are linked to each other to form a structural unit and Y2 is selected from CR Y2 ; or, X1 and Y2 are connected to each other to form a structural unit And Y1 is selected from N.

在一些实施方案中，X1和Y1相互连接形成结构单元且Y2选自N；或者，X1和Y2相互连接形成结构单元且Y1选自CRY1。In some embodiments, X 1 and Y 1 are linked to each other to form a structural unit and Y 2 is selected from N; or, X 1 and Y 2 are connected to each other to form a structural unit And Y1 is selected from CR Y1 .

在一些实施方案中，X1和Y1相互连接形成结构单元且Y2选自N；或者，X1和Y2相互 连接形成结构单元且Y1选自N。In some embodiments, X 1 and Y 1 are linked to each other to form a structural unit and Y 2 is selected from N; or, X 1 and Y 2 are mutually Connect to form structural units And Y1 is selected from N.

在一些实施方案中，X1和Y1相互连接形成结构单元且Y2选自N或CRY2。In some embodiments, X 1 and Y 1 are linked to each other to form a structural unit And Y2 is selected from N or CR Y2 .

在一些实施方案中，X1和Y2相互连接形成结构单元且Y1选自N或CRY1。In some embodiments, X1 and Y2 are linked to each other to form a structural unit And Y1 is selected from N or CR Y1 .

在一些实施方案中，X1和Y1相互连接形成结构单元且Y2选自N或CRY2；X1选自CRX1，X2选自N。在一些实施方案中，X1和Y1相互连接形成结构单元且Y2选自N或CRY2。In some embodiments, X 1 and Y 1 are linked to each other to form a structural unit and Y2 is selected from N or CR Y2 ; X1 is selected from CR X1 , and X2 is selected from N. In some embodiments, X1 and Y1 are connected to each other to form a structural unit And Y2 is selected from N or CR Y2 .

在一些实施方案中，X1和Y2相互连接形成结构单元且Y1选自N或CRY1；X1选自CRX1，X2选自N。在一些实施方案中，X1和Y2相互连接形成结构单元且Y1选自N或CRY1。In some embodiments, X1 and Y2 are linked to each other to form a structural unit and Y1 is selected from N or CR Y1 ; X1 is selected from CR X1 , and X2 is selected from N. In some embodiments, X1 and Y2 are connected to each other to form a structural unit And Y1 is selected from N or CR Y1 .

在一些实施方案中，X1和Y1相互连接形成结构单元且Y2选自N；X1选自CRX1，X2选自N。在一些实施方案中，X1和Y1相互连接形成结构单元且Y2选自N。In some embodiments, X 1 and Y 1 are linked to each other to form a structural unit and Y2 is selected from N; X1 is selected from CR X1 , and X2 is selected from N. In some embodiments, X1 and Y1 are connected to each other to form a structural unit And Y2 is selected from N.

在一些实施方案中，X1和Y2相互连接形成结构单元且Y1选自N；X1选自CRX1，X2选自N。在一些实施方案中，X1和Y2相互连接形成结构单元且Y1选自N。In some embodiments, X1 and Y2 are linked to each other to form a structural unit and Y 1 is selected from N; X 1 is selected from CR X1 , and X 2 is selected from N. In some embodiments, X 1 and Y 2 are connected to each other to form a structural unit And Y1 is selected from N.

在一些实施方案中，X1选自N。 In some embodiments, X 1 is selected from N.

在一些实施方案中，X1选自CRX1。In some embodiments, X1 is selected from CR X1 .

在一些实施方案中，X1选自CH。In some embodiments, X 1 is selected from CH.

在一些实施方案中，X2选自N。In some embodiments, X 2 is selected from N.

在一些实施方案中，X2选自CRX2。In some embodiments, X2 is selected from CR X2 .

在一些实施方案中，X2选自CH。In some embodiments, X 2 is selected from CH.

在一些实施方案中，X1选自CRX1，X2选自CRX2。In some embodiments, X1 is selected from CR X1 and X2 is selected from CR X2 .

在一些实施方案中，X1选自CRX1，X2选自N。In some embodiments, X1 is selected from CR X1 , and X2 is selected from N.

在一些实施方案中，X1选自CH，X2选自N。In some embodiments, X 1 is selected from CH and X 2 is selected from N.

在一些实施方案中，X1选自N，X2选自CRX2。In some embodiments, X1 is selected from N, and X2 is selected from CR X2 .

在一些实施方案中，X1选自N，X2选自CH。In some embodiments, X 1 is selected from N, and X 2 is selected from CH.

在一些实施方案中，Z1、Z2和Z3为CRZ1。In some embodiments, Z 1 , Z 2 and Z 3 are CR Z1 .

在一些实施方案中，Z1、Z2和Z3均为CH。In some embodiments, Z 1 , Z 2 and Z 3 are all CH.

在一些实施方案中，Z1、Z2或Z3不同时为N。In some embodiments, Z 1 , Z 2 or Z 3 are not N at the same time.

在一些实施方案中，Z1、Z2或Z3中有一个或两个为N。In some embodiments, one or both of Z 1 , Z 2 or Z 3 is N.

在一些实施方案中，Z1和Z2为N，Z3为CRZ1。In some embodiments, Z1 and Z2 are N, and Z3 is CR Z1 .

在一些实施方案中，Z1和Z3为N，Z2为CRZ1。In some embodiments, Z1 and Z3 are N, and Z2 is CRZ1 .

在一些实施方案中，Z2和Z3为N，Z1为CRZ1。In some embodiments, Z2 and Z3 are N and Z1 is CRZ1 .

在一些实施方案中，Z1为N，Z2和Z3为CRZ1。In some embodiments, Z1 is N, and Z2 and Z3 are CRZ1 .

在一些实施方案中，Z2为N，Z1和Z3为CRZ1。In some embodiments, Z2 is N, and Z1 and Z3 are CRZ1 .

在一些实施方案中，Z3为N，Z1和Z2为CRZ1。In some embodiments, Z3 is N, and Z1 and Z2 are CRZ1 .

在一些实施方案中，Z4和Z5为CRZ2。In some embodiments, Z4 and Z5 are CRZ2 .

在一些实施方案中，Z4为CH，Z5为CRZ2。In some embodiments, Z 4 is CH and Z 5 is CR Z2 .

在一些实施方案中，Z4和Z5为N。In some embodiments, Z4 and Z5 are N.

在一些实施方案中，Z4或Z5不同时为N。In some embodiments, Z 4 or Z 5 are not N at the same time.

在一些实施方案中，Z4为N，Z5为CRZ2。In some embodiments, Z4 is N and Z5 is CRZ2 .

在一些实施方案中，Z5为N，Z4为CRZ2。In some embodiments, Z5 is N and Z4 is CRZ2 .

在一些实施方案中，Z1、Z2和Z3为CRZ1，Z4和Z5为CRZ2。In some embodiments, Z 1 , Z 2 and Z 3 are CR Z 1 , and Z 4 and Z 5 are CR Z 2 .

在一些实施方案中，Z1、Z2、Z3、Z4或Z5不同时为N。In some embodiments, Z 1 , Z 2 , Z 3 , Z 4 or Z 5 are not N at the same time.

在一些实施方案中，Z1、Z2、Z3、Z4或Z5中至少有一个为N。In some embodiments, at least one of Z 1 , Z 2 , Z 3 , Z 4 or Z 5 is N.

在一些实施方案中，Z1、Z2、Z3、Z4或Z5中至少有两个为N。In some embodiments, at least two of Z 1 , Z 2 , Z 3 , Z 4 or Z 5 are N.

在一些实施方案中，Z1、Z2、Z3、Z4或Z5中至少有三个为N。In some embodiments, at least three of Z 1 , Z 2 , Z 3 , Z 4 or Z 5 are N.

在一些实施方案中，Z1、Z2、Z3、Z4或Z5中有一个、两个、三个、或四个为N。In some embodiments, one, two, three, or four of Z 1 , Z 2 , Z 3 , Z 4 , or Z 5 are N.

在一些实施方案中，Z1为N，Z2和Z3为CRZ1，Z4和Z5为CRZ2。在一些实施方案中，Z2为N，Z1和Z3为CRZ1，Z4和Z5为CRZ2。在一些实施方案中，Z3为N，Z1和Z2为CRZ1，Z4和Z5为CRZ2。在一些实施方案中，Z4为N，Z1、Z2和Z3为CRZ1，Z5为CRZ2。在一些实施方案中，Z5为N，Z1、Z2和Z3为CRZ1，Z4为CRZ2。In some embodiments, Z1 is N, Z2 and Z3 are CRZ1 , and Z4 and Z5 are CRZ2 . In some embodiments, Z2 is N, Z1 and Z3 are CRZ1 , and Z4 and Z5 are CRZ2 . In some embodiments, Z3 is N, Z1 and Z2 are CRZ1 , and Z4 and Z5 are CRZ2. In some embodiments, Z4 is N, Z1 , Z2 and Z3 are CRZ1 , and Z5 is CRZ2 . In some embodiments, Z5 is N, Z1 , Z2 and Z3 are CRZ1 , and Z4 is CRZ2 .

在一些实施方案中，Z1和Z2为N，Z3为CRZ1，Z4和Z5为CRZ2。在一些实施方案中，Z1和Z3为N，Z2为CRZ1，Z4和Z5为CRZ2。在一些实施方案中，Z2和Z3为N，Z1为CRZ1，Z4和Z5为CRZ2。在一些实施方案中，Z1和Z4为N，Z2和Z3为CRZ1，Z5为CRZ2。在一些实施方案中，Z1和Z5为N，Z2和Z3为CRZ1，Z4为CRZ2。在一些实施方案中，Z2和Z4为N，Z1和Z3为CRZ1，Z5为CRZ2。在一些实施方案中，Z2和Z5为N，Z1和Z3为CRZ1，Z4为CRZ2。在一些实施方案中，Z3和Z4为N，Z1和Z2为CRZ1，Z5为CRZ2。在一些实施方案中，Z3和Z5为N，Z1和Z2为CRZ1，Z4为CRZ2。在一些实施方案中，Z4和Z5为 N，Z1、Z2和Z3为CRZ1。In some embodiments, Z1 and Z2 are N, Z3 is CRZ1 , and Z4 and Z5 are CRZ2 . In some embodiments, Z1 and Z3 are N, Z2 is CRZ1 , and Z4 and Z5 are CRZ2. In some embodiments, Z2 and Z3 are N, Z1 is CRZ1 , and Z4 and Z5 are CRZ2 . In some embodiments, Z1 and Z4 are N, Z2 and Z3 are CRZ1 , and Z5 is CRZ2 . In some embodiments, Z1 and Z5 are N, Z2 and Z3 are CRZ1 , and Z4 is CRZ2 . In some embodiments, Z2 and Z4 are N , Z1 and Z3 are CRZ1 , and Z5 is CRZ2 . In some embodiments, Z2 and Z5 are N, Z1 and Z3 are CRZ1 , and Z4 is CRZ2 . In some embodiments, Z3 and Z4 are N, Z1 and Z2 are CRZ1 , and Z5 is CRZ2. In some embodiments, Z3 and Z5 are N, Z1 and Z2 are CRZ1 , and Z4 is CRZ2 . In some embodiments, Z4 and Z5 are N, Z1 , Z2 and Z3 are CR Z1 .

在一些实施方案中，Z1、Z2和Z4为N，Z3为CRZ1，Z5为CRZ2。在一些实施方案中，Z1、Z2和Z5为N，Z3为CRZ1，Z4为CRZ2。在一些实施方案中，Z1、Z3和Z4为N，Z2为CRZ1，Z5为CRZ2。在一些实施方案中，Z1、Z3和Z5为N，Z2为CRZ1，Z4为CRZ2。在一些实施方案中，Z2、Z3和Z4为N，Z1为CRZ1，Z5为CRZ2。在一些实施方案中，Z2、Z3和Z5为N，Z1为CRZ1，Z4为CRZ2。In some embodiments, Z 1 , Z 2 and Z 4 are N, Z 3 is CR Z1 , and Z 5 is CR Z2 . In some embodiments, Z 1 , Z 2 and Z 5 are N, Z 3 is CR Z1 , and Z 4 is CR Z2 . In some embodiments, Z 1 , Z 3 and Z 4 are N, Z 2 is CR Z1 , and Z 5 is CR Z2 . In some embodiments, Z 1 , Z 3 and Z 5 are N, Z 2 is CR Z1 , and Z 4 is CR Z2 . In some embodiments, Z 2 , Z 3 and Z 4 are N, Z 1 is CR Z1 , and Z 5 is CR Z2 . In some embodiments, Z 2 , Z 3 and Z 5 are N, Z 1 is CR Z1 , and Z 4 is CR Z2 .

在一些实施方案中，Y2为N，Z4和Z5为CH。In some embodiments, Y2 is N, Z4 and Z5 are CH.

在一些实施方案中，Y1为N，Z4为CH，Z5为CH或CCH3。In some embodiments, Y 1 is N, Z 4 is CH, and Z 5 is CH or CCH 3 .

在一些实施方案中，Y2为N，Z4为CH，Z5为CCH3。In some embodiments, Y 2 is N, Z 4 is CH, and Z 5 is CCH 3 .

在一些实施方案中，Y1和Z5为N，Z4为CH。In some embodiments, Y1 and Z5 are N, and Z4 is CH.

在一些实施方案中，Y1为CH，Z4和Z5为N。In some embodiments, Y 1 is CH, Z 4 and Z 5 are N.

在一些实施方案中，Y1为N，Z4为N，Z5为CH。In some embodiments, Y 1 is N, Z 4 is N, and Z 5 is CH.

在一些实施方案中，Y1为N，Z4为CH，Z5为CCN。In some embodiments, Y 1 is N, Z 4 is CH, and Z 5 is CCN.

在一些实施方案中，环A选自任选被一个或多个Ra取代的如下基团：4-12元环烯基或4-12元杂环烯基。In some embodiments, Ring A is selected from the following groups optionally substituted with one or more Ra : 4-12 membered cycloalkenyl or 4-12 membered heterocycloalkenyl.

在一些实施方案中，环A选自任选被一个或多个Ra取代的如下基团：4-10元环烯基或4-10元杂环烯基。In some embodiments, Ring A is selected from the following groups optionally substituted with one or more Ra : 4-10 membered cycloalkenyl or 4-10 membered heterocycloalkenyl.

在一些实施方案中，环A选自任选被一个或多个Ra取代的如下基团：4-8元环烯基或4-8元杂环烯基。In some embodiments, Ring A is selected from the following groups optionally substituted with one or more Ra : 4-8 membered cycloalkenyl or 4-8 membered heterocycloalkenyl.

在一些实施方案中，环A选自任选被一个或多个Ra取代的如下基团：5-7元环烯基或5-7元杂环烯基。In some embodiments, Ring A is selected from the following groups optionally substituted with one or more Ra : 5-7 membered cycloalkenyl or 5-7 membered heterocycloalkenyl.

在一些实施方案中，环A选自任选被一个或多个Ra取代的4-12元杂环烯基。在一些实施方案中，所述4-12元杂环烯基选自4-10元杂环烯基、4-8元杂环烯基或5-7元杂环烯基。在一些实施方案中，环A选自任选被一个或多个Ra取代的6-7元杂环烯基。In some embodiments, ring A is selected from 4-12 membered heterocycloalkenyl optionally substituted with one or more Ra . In some embodiments, the 4-12 membered heterocycloalkenyl is selected from 4-10 membered heterocycloalkenyl, 4-8 membered heterocycloalkenyl or 5-7 membered heterocycloalkenyl. In some embodiments, ring A is selected from 6-7 membered heterocycloalkenyl optionally substituted with one or more Ra .

在一些实施方案中，环A中所述的“环烯基”或“杂环烯基”中，有且仅有一个烯键。In some embodiments, the "cycloalkenyl" or "heterocycloalkenyl" in ring A has only one olefinic bond.

在一些实施方案中，环A中所述的6-10元芳基可选自苯基。In some embodiments, the 6-10 membered aryl group in Ring A can be selected from phenyl.

在一些实施方案中，环A中所述的5-10元杂芳基可选自5-6元杂芳基。In some embodiments, the 5-10 membered heteroaryl group in Ring A can be selected from 5-6 membered heteroaryl groups.

在一些实施方案中，环A选自任选被一个或多个Ra取代的如下基团： In some embodiments, Ring A is selected from the following groups optionally substituted with one or more Ra :

在一些实施方案中，环A选自任选被一个或多个Ra取代的如下基团： 在一些实施方案中，环A选自任选被一个或多个Ra取代的如下基团： In some embodiments, Ring A is selected from the following groups optionally substituted with one or more Ra : In some embodiments, Ring A is selected from the following groups optionally substituted with one or more Ra :

在一些实施方案中，环A选自如下基团： In some embodiments, Ring A is selected from the following groups:

在一些实施方案中，环A选自如下基团： In some embodiments, Ring A is selected from the following groups:

在一些实施方案中，环A选自如下基团： 在一些实施方案中，环A选自如下基团：在一些实施方案中，环A选自如下基团：在一些实施方案中，环A选自如下基团：： In some embodiments, Ring A is selected from the following groups: In some embodiments, Ring A is selected from the following groups: In some embodiments, Ring A is selected from the following groups: In some embodiments, Ring A is selected from the following groups:

在一些实施方案中，本公开所述“杂环基”选自“杂环烷基”或“杂环烯基”。In some embodiments, the "heterocyclyl" described in the present disclosure is selected from "heterocycloalkyl" or "heterocycloalkenyl".

在一些实施方案中，本公开所述“杂环基”选自“杂环烷基”。In some embodiments, the "heterocyclyl" described in the present disclosure is selected from "heterocycloalkyl".

在一些实施方案中，所述3-12元杂环基选自3-12元杂环烷基。In some embodiments, the 3-12 membered heterocyclyl is selected from 3-12 membered heterocycloalkyl.

在一些实施方案中，每个RX1、RX2、RY1、RY2、RZ1或RZ2各自独立地选自H、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-6烷基、氘代C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基氨基、二C1-6烷基氨基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C1-6烷硫基、卤代C1-6烷基氨基、卤代二C1-6烷基氨基、-COC1-6烷基、-OC(O)C1-6烷基、-C(O)OC1-6烷基、-OC(O)OC1-6烷基、-SO2C1-6烷基、-NHSO2C1-6烷基、-N(C1-6烷基)SO2C1-6烷基、-SO2NH2、-SO2NHC1-6烷基、-SO2N(C1-6烷基)2、-CONH2、-CONHC1-6烷基、-CON(C1-6烷基)2、-NHCOC1-6烷基、-N(C1-6烷基)COC1-6烷基、3-10元环烷基、3-10元环烯基、6-10 元芳基、5-10元杂芳基或3-10元杂环基。In some embodiments, each RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is independently selected from H, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH , C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, haloC1-6 alkyl, haloC1-6 alkoxy, haloC1-6 alkylthio, haloC1-6 alkylamino, halodiC1-6 alkylamino , -COC1-6 alkyl, -OC (O) C1-6 alkyl, -C (O) OC1-6 alkyl, -OC (O) OC1-6 alkyl, -SO2C1-6 alkyl, -NHSO2C1-6 alkyl , -N ( C1-6 alkyl )SO 2 C 1-6 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-6 alkyl, -SO 2 N(C 1-6 alkyl) 2 , -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -NHCOC 1-6 alkyl, -N(C 1-6 alkyl)COC 1-6 alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 6-10 The invention also comprises a 5- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, or a 3- to 10-membered heterocyclic group.

在一些实施方案中，所述3-10元杂环基选自3-10元杂环烷基。In some embodiments, the 3-10 membered heterocyclyl is selected from 3-10 membered heterocycloalkyl.

在一些实施方案中，每个RX1、RX2、RY1、RY2、RZ1或RZ2各自独立地选自H、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-6烷基、氘代C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基氨基、二C1-6烷基氨基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C1-6烷硫基、卤代C1-6烷基氨基、卤代二C1-6烷基氨基、-COC1-6烷基、-OC(O)C1-6烷基、-C(O)OC1-6烷基、-OC(O)OC1-6烷基、-SO2C1-6烷基、-NHSO2C1-6烷基、-N(C1-6烷基)SO2C1-6烷基、-SO2NH2、-SO2NHC1-6烷基、-SO2N(C1-6烷基)2、-CONH2、-CONHC1-6烷基、-CON(C1-6烷基)2、-NHCOC1-6烷基、-N(C1-6烷基)COC1-6烷基、3-8元环烷基、3-8元环烯基、6-8元芳基、5-8元杂芳基或3-8元杂环基。In some embodiments, each RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is independently selected from H, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH , C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, haloC1-6 alkyl, haloC1-6 alkoxy, haloC1-6 alkylthio, haloC1-6 alkylamino, halodiC1-6 alkylamino , -COC1-6 alkyl, -OC (O) C1-6 alkyl, -C (O) OC1-6 alkyl, -OC (O) OC1-6 alkyl, -SO2C1-6 alkyl, -NHSO2C1-6 alkyl , -N ( C1-6 alkyl )SO 2 C 1-6 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-6 alkyl, -SO 2 N(C 1-6 alkyl) 2 , -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -NHCOC 1-6 alkyl, -N(C 1-6 alkyl)COC 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 6-8 membered aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclyl.

在一些实施方案中，每个RX1、RX2、RY1、RY2、RZ1或RZ2各自独立地选自H、氘、卤素、-OH、-NH2、-CN、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基氨基、二C1-6烷基氨基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C1-6烷硫基、卤代C1-6烷基氨基、卤代二C1-6烷基氨基、3-8元环烷基、或3-8元杂环基。In some embodiments, each RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is each independently selected from H, deuterium, halogen, -OH, -NH2 , -CN, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, haloC1-6 alkyl, haloC1-6 alkoxy, haloC1-6 alkylthio, haloC1-6 alkylamino, halodiC1-6 alkylamino, 3-8 membered cycloalkyl, or 3-8 membered heterocyclyl .

在一些实施方案中，所述3-8元杂环基选自3-8元杂环烷基。In some embodiments, the 3-8 membered heterocyclyl is selected from 3-8 membered heterocycloalkyl.

在一些实施方案中，每个RX1、RX2、RY1、RY2、RZ1或RZ2各自独立地选自H、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-4烷基、氘代C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基氨基、二C1-4烷基氨基、卤代C1-4烷基、卤代C1-4烷氧基、卤代C1-4烷硫基、卤代C1-4烷基氨基、卤代二C1-4烷基氨基、-COC1-4烷基、-OC(O)C1-4烷基、-C(O)OC1-4烷基、-OC(O)OC1-4烷基、-SO2C1-4烷基、-NHSO2C1-4烷基、-N(C1-4烷基)SO2C1-4烷基、-SO2NH2、-SO2NHC1-4烷基、-SO2N(C1-4烷基)2、-CONH2、-CONHC1-4烷基、-CON(C1-4烷基)2、-NHCOC1-4烷基、-N(C1-4烷基)COC1-4烷基、3-6元环烷基、3-6元环烯基、苯基、5-6元杂芳基或3-6元杂环基。In some embodiments, each RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is independently selected from H, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino, halogenated C1-4 alkyl, halogenated C1-4 alkoxy, halogenated C1-4 alkylthio, halogenated C1-4 alkylamino, halogenated diC1-4 alkylamino, -COC1-4 alkyl, -OC (O) C1-4 alkyl, -C (O) OC1-4 alkyl, -OC (O) OC1-4 alkyl, -SO2C1-4 alkyl, -NHSO2C1-4 alkyl, -N ( C1-4 alkyl ) SO 2 C 1-4 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-4 alkyl, -SO 2 N(C 1-4 alkyl) 2 , -CONH 2 , -CONHC 1-4 alkyl, -CON(C 1-4 alkyl) 2 , -NHCOC 1-4 alkyl, -N(C 1-4 alkyl)COC 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl.

在一些实施方案中，每个RX1、RX2、RY1、RY2、RZ1或RZ2各自独立地选自H、氘、卤素、-OH、-NH2、-CN、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基氨基、二C1-4烷基氨基、卤代C1-4烷基、卤代C1-4烷氧基、卤代C1-4烷硫基、卤代C1-4烷基氨基、卤代二C1-4烷基氨基、3-6元环烷基、或3-6元杂环基。In some embodiments, each RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is independently selected from H, deuterium, halogen, -OH, -NH2 , -CN, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino, haloC1-4 alkyl , haloC1-4 alkoxy, haloC1-4 alkylthio, haloC1-4 alkylamino, halodiC1-4 alkylamino, 3-6 membered cycloalkyl, or 3-6 membered heterocyclyl .

在一些实施方案中，所述3-6元杂环基选自3-6元杂环烷基。In some embodiments, the 3-6 membered heterocyclyl is selected from 3-6 membered heterocycloalkyl.

在一些实施方案中，每个RX1、RX2、RY1、RY2、RZ1或RZ2各自独立地选自H、氘、-F、-Cl、-Br、-OH、-NH2、-CN、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、甲硫基、乙硫基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、单氟甲基、二氟甲基、三氟甲基、三氟乙基、三氟甲氧基、三氟乙氧基、三氟甲硫基、单氟甲基氨基、三氟甲基氨基、二(单氟甲基)氨基、二(三氟甲基)氨基、环丙基、环丁基、氮杂环丁基、或氧杂环丁基。In some embodiments, each RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is each independently selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, ethyl, n -propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, di(trifluoromethyl)amino, cyclopropyl, cyclobutyl, azetidinyl, or oxetanyl.

在一些实施方案中，每个RX1、RX2、RY1、RY2、RZ1或RZ2各自独立地选自H、氘、-F、-Cl、-Br、-OH、-NH2、-CN、甲基、甲氧基、三氟甲基、三氟甲氧基、或环丙基。In some embodiments, each RX1 , RX2 , RY1 , RY2 , RZ1 , or RZ2 is independently selected from H, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or cyclopropyl.

在一些实施方案中，RX1选自H、-F、-Cl、甲基、或甲氧基。In some embodiments, RX1 is selected from H, -F, -Cl, methyl, or methoxy.

在一些实施方案中，RX1选自H。In some embodiments, RX1 is selected from H.

在一些实施方案中，RX2选自H、-F、-Cl、甲基、或甲氧基。In some embodiments, RX2 is selected from H, -F, -Cl, methyl, or methoxy.

在一些实施方案中，RX2选自H。In some embodiments, RX2 is selected from H.

在一些实施方案中，RY1选自H、-F、-Cl、-CN、甲基、甲氧基、三氟甲基、或环丙基。In some embodiments, R Y1 is selected from H, -F, -Cl, -CN, methyl, methoxy, trifluoromethyl, or cyclopropyl.

在一些实施方案中，RY1选自H。In some embodiments, R Y1 is selected from H.

在一些实施方案中，RY2选自H、-F、-Cl、-CN、甲基、甲氧基、三氟甲基、或环丙基。In some embodiments, RY2 is selected from H, -F, -Cl, -CN, methyl, methoxy, trifluoromethyl, or cyclopropyl.

在一些实施方案中，RZ1选自H、-F、-Cl、甲基、或甲氧基。In some embodiments, R Z1 is selected from H, -F, -Cl, methyl, or methoxy.

在一些实施方案中，RZ1选自H。In some embodiments, R Z1 is selected from H.

在一些实施方案中，RZ2选自H、-F、-Cl、-CN、甲基、甲氧基、三氟甲基、或环丙基。In some embodiments, R Z2 is selected from H, -F, -Cl, -CN, methyl, methoxy, trifluoromethyl, or cyclopropyl.

在一些实施方案中，RZ2选自H、-CN、或甲基。In some embodiments, R Z2 is selected from H, -CN, or methyl.

在一些实施方案中，RZ2选自H或甲基。 In some embodiments, R Z2 is selected from H or methyl.

在一些实施方案中，环B选自任选地被一个或多个Rb取代的如下基团：3-12元环烷基、3-12元环烯基或3-12元杂环基。In some embodiments, Ring B is selected from the following groups optionally substituted with one or more R b : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, or 3-12 membered heterocyclyl.

在一些实施方案中，环B选自任选地被一个或多个Rb取代的如下基团：3-12元环烷基、3-12元环烯基或3-12元杂环烷基。In some embodiments, Ring B is selected from the following groups optionally substituted with one or more R b : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, or 3-12 membered heterocycloalkyl.

在一些实施方案中，环B选自任选地被一个或多个Rb取代的如下基团：3-12元环烷基或3-12元杂环烷基。In some embodiments, Ring B is selected from the following groups optionally substituted with one or more R b : 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl.

在一些实施方案中，环B选自任选地被一个或多个Rb取代的如下基团：3-10元环烷基或3-10元杂环烷基。In some embodiments, Ring B is selected from the following groups optionally substituted with one or more R b : 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl.

在一些实施方案中，环B选自任选地被一个或多个Rb取代的如下基团：5-9元环烷基或5-9元杂环烷基。In some embodiments, Ring B is selected from the following groups optionally substituted with one or more R b : 5-9 membered cycloalkyl or 5-9 membered heterocycloalkyl.

在一些实施方案中，环B选自任选地被一个或多个Rb取代的如下基团：6-8元环烷基或6-8元杂环烷基。In some embodiments, Ring B is selected from the following groups optionally substituted with one or more R b : 6-8 membered cycloalkyl or 6-8 membered heterocycloalkyl.

在一些实施方案中，环B选自任选地被一个或多个Rb取代的如下基团：4-7元环烷基或4-7元杂环烷基。In some embodiments, Ring B is selected from the following groups optionally substituted with one or more R b : 4-7 membered cycloalkyl or 4-7 membered heterocycloalkyl.

在一些实施方案中，环B选自任选地被一个或多个Rb取代的3-12元杂环烷基。In some embodiments, Ring B is selected from 3-12 membered heterocycloalkyl optionally substituted with one or more R b .

在一些实施方案中，环B所述的“3-12元环烷基”、“3-12元环烷基”、“3-12元环烯基”、或“3-12元杂环烷基”中，所述“3-12元”可分别独立地选自3-10元、5-9元或6-8元。在一些实施方案中，环B所述的“3-12元环烷基”、“3-12元环烷基”、“3-12元环烯基”、或“3-12元杂环烷基”中，所述“3-12元”可分别独立地选自4-7元。In some embodiments, in the "3-12 membered cycloalkyl", "3-12 membered cycloalkyl", "3-12 membered cycloalkenyl", or "3-12 membered heterocycloalkyl" described in Ring B, the "3-12 membered" may be independently selected from 3-10 membered, 5-9 membered, or 6-8 membered. In some embodiments, in the "3-12 membered cycloalkyl", "3-12 membered cycloalkyl", "3-12 membered cycloalkenyl", or "3-12 membered heterocycloalkyl" described in Ring B, the "3-12 membered" may be independently selected from 4-7 membered.

在一些实施方案中，所述3-12元环烷基选自3-10元环烷基、5-9元环烷基或6-8元环烷基。在一些实施方案中，所述3-12元环烷基选自4-7元环烷基。In some embodiments, the 3-12 membered cycloalkyl is selected from 3-10 membered cycloalkyl, 5-9 membered cycloalkyl or 6-8 membered cycloalkyl. In some embodiments, the 3-12 membered cycloalkyl is selected from 4-7 membered cycloalkyl.

在一些实施方案中，所述3-12元杂环基选自3-10元杂环基、5-9元杂环基或6-8元杂环基。在一些实施方案中，所述3-12元杂环基选自4-7元杂环基。In some embodiments, the 3-12 membered heterocyclyl is selected from a 3-10 membered heterocyclyl, a 5-9 membered heterocyclyl, or a 6-8 membered heterocyclyl. In some embodiments, the 3-12 membered heterocyclyl is selected from a 4-7 membered heterocyclyl.

在一些实施方案中，所述3-12元杂环烷基选自3-10元杂环烷基、5-9元杂环烷基或6-8元杂环烷基。在一些实施方案中，所述3-12元杂环烷基选自4-7元杂环烷基。In some embodiments, the 3-12 membered heterocycloalkyl is selected from 3-10 membered heterocycloalkyl, 5-9 membered heterocycloalkyl or 6-8 membered heterocycloalkyl. In some embodiments, the 3-12 membered heterocycloalkyl is selected from 4-7 membered heterocycloalkyl.

在一些实施方案中，所述3-12元杂环烯基选自3-10元杂环烯基、5-9元杂环烯基或6-8元杂环烯基。在一些实施方案中，所述3-12元杂环烯基选自4-7元杂环烯基。In some embodiments, the 3-12 membered heterocycloalkenyl is selected from 3-10 membered heterocycloalkenyl, 5-9 membered heterocycloalkenyl or 6-8 membered heterocycloalkenyl. In some embodiments, the 3-12 membered heterocycloalkenyl is selected from 4-7 membered heterocycloalkenyl.

在一些实施方案中，环B中所述的6-10元芳基独立地选自苯基。In some embodiments, the 6-10 membered aryl groups described in Ring B are independently selected from phenyl.

在一些实施方案中，环B中所述的5-10元杂芳基独立地选自5-6元杂芳基。In some embodiments, the 5-10 membered heteroaryl described in Ring B is independently selected from 5-6 membered heteroaryl.

在一些实施方案中，环B选自任选地被一个或多个Rb取代的如下基团：环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、噻唑烷基、异噻唑烷基、噁唑烷基、异噁唑烷基、哌啶基、哌嗪基、吗啉基、 In some embodiments, Ring B is selected from the following groups optionally substituted with one or more R b : cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl,

在一些实施方案中，环B选自任选地被一个或多个Rb取代的如下基团： In some embodiments, Ring B is selected from the following groups optionally substituted with one or more R b :

在一些实施方案中，环B选自任选地被一个或多个Rb取代的 In some embodiments, Ring B is selected from optionally substituted with one or more R

在一些实施方案中，环B选自 在一些实施方案中，环B选自在一些实施方案中，环B选自 In some embodiments, Ring B is selected from In some embodiments, Ring B is selected from In some embodiments, Ring B is selected from

在一些实施方案中，环B选自在一些实施方案中，环B选自 In some embodiments, Ring B is selected from In some embodiments, Ring B is selected from

在一些实施方案中，结构单元选自任选地被一个或多个Rb取代的如下基团： 其中的另一端连接Y1或Y2。In some embodiments, the structural unit is selected from the following groups optionally substituted by one or more R b : in The other end is connected to Y1 or Y2 .

在一些实施方案中，结构单元选自任选地被一个或多个Rb取代其中的另一端连接Y1或Y2。In some embodiments, the structural unit is selected from optionally substituted with one or more R in The other end is connected to Y1 or Y2 .

在一些实施方案中，结构单元选自 In some embodiments, the structural unit Selected from

其中的另一端连接Y1或Y2。在一些实施方案中，结构单元选自其中的另一端连接Y1或Y2。在一些实施方案中，结构单元选自其中的另一端连接Y1或Y2。in The other end of is connected to Y 1 or Y 2 . In some embodiments, the structural unit Selected from in The other end of is connected to Y 1 or Y 2 . In some embodiments, the structural unit Selected from in The other end is connected to Y1 or Y2 .

在一些实施方案中，结构单元选自其中的另一端连接Y1或Y2。In some embodiments, the structural unit Selected from in The other end is connected to Y1 or Y2 .

在一些实施方案中，所述3-12元杂环基选自3-12元杂环烷基。In some embodiments, the 3-12 membered heterocyclyl is selected from 3-12 membered heterocycloalkyl.

在一些实施方案中，每个Ra或Rb各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-6烷基、氘代C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基氨基、二C1-6烷基氨基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C1-6烷硫基、卤代C1-6烷基氨基、卤代二C1-6烷基氨基、-COC1-6烷基、-OC(O)C1- 6烷基、-C(O)OC1-6烷基、-OC(O)OC1-6烷基、-SO2C1-6烷基、-NHSO2C1-6烷基、-N(C1-6烷基)SO2C1-6烷基、-SO2NH2、-SO2NHC1-6烷基、-SO2N(C1-6烷基)2、-CONH2、-CONHC1-6烷基、-CON(C1-6烷基)2、-NHCOC1- 6烷基、-N(C1-6烷基)COC1-6烷基、3-10元环烷基、3-10元环烯基、6-10元芳基、5-10元杂芳基或3-10元杂环基。In some embodiments, each Ra or Rb is independently selected from oxo, deuterium, halogen , -OH, -NH2 , -CN, -SH, -COOH, C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, haloC1-6 alkyl, haloC1-6 alkoxy, haloC1-6 alkylthio, haloC1-6 alkylamino, halodiC1-6 alkylamino, -COC1-6 alkyl, -OC (O) C1-6 alkyl, -C (O) OC1-6 alkyl, -OC ( O ) OC1-6 alkyl , -SO2C1-6 alkyl , -NHSO2C1-6 alkyl, -N ( C1-6 alkyl ) SO2C1-6 alkyl, -SO2NH2 , -SO 2 NHC 1-6 alkyl, -SO 2 N(C 1-6 alkyl) 2 , -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -NHCOC 1- 6 alkyl, -N(C 1-6 alkyl)COC 1-6 alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl.

在一些实施方案中，所述3-10元杂环基选自3-10元杂环烷基。In some embodiments, the 3-10 membered heterocyclyl is selected from 3-10 membered heterocycloalkyl.

在一些实施方案中，每个Ra或Rb各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-6烷基、氘代C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基氨基、二C1-6烷基氨基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C1-6烷硫基、卤代C1-6烷基氨基、卤代二C1-6烷基氨基、-COC1-6烷基、-OC(O)C1- 6烷基、-C(O)OC1-6烷基、-OC(O)OC1-6烷基、-SO2C1-6烷基、-NHSO2C1-6烷基、-N(C1-6烷基)SO2C1-6烷基、-SO2NH2、-SO2NHC1-6烷基、-SO2N(C1-6烷基)2、-CONH2、-CONHC1-6烷基、-CON(C1-6烷基)2、-NHCOC1- 6烷基、-N(C1-6烷基)COC1-6烷基、3-8元环烷基、3-8元环烯基、6-8元芳基、5-8元杂芳基或3-8元杂环基。In some embodiments, each Ra or Rb is independently selected from oxo, deuterium, halogen , -OH, -NH2 , -CN, -SH, -COOH, C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, haloC1-6 alkyl, haloC1-6 alkoxy, haloC1-6 alkylthio, haloC1-6 alkylamino, halodiC1-6 alkylamino, -COC1-6 alkyl, -OC (O) C1-6 alkyl, -C (O) OC1-6 alkyl, -OC ( O ) OC1-6 alkyl , -SO2C1-6 alkyl , -NHSO2C1-6 alkyl, -N ( C1-6 alkyl ) SO2C1-6 alkyl, -SO2NH2 , -SO 2 NHC 1-6 alkyl, -SO 2 N(C 1-6 alkyl) 2 , -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -NHCOC 1- 6 alkyl, -N(C 1-6 alkyl)COC 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 6-8 membered aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclyl.

在一些实施方案中，每个Ra或Rb各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基氨基、二C1-6烷基氨基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C1-6烷硫基、卤代C1-6烷基氨基、卤代二C1-6烷基氨基、3-8元环烷基、或3-8元杂环基。在一些实施方案中，每个Ra或Rb各自独立地选自氘代C1-6烷基。In some embodiments, each Ra or Rb is independently selected from oxo, deuterium, halogen, -OH , -NH2 , -CN, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, halogenated C1-6 alkyl, halogenated C1-6 alkoxy, halogenated C1-6 alkylthio, halogenated C1-6 alkylamino, halogenated diC1-6 alkylamino, 3-8 membered cycloalkyl, or 3-8 membered heterocyclyl. In some embodiments, each Ra or Rb is independently selected from deuterated C1-6 alkyl.

在一些实施方案中，所述3-8元杂环基选自3-8元杂环烷基。In some embodiments, the 3-8 membered heterocyclyl is selected from 3-8 membered heterocycloalkyl.

在一些实施方案中，每个Ra或Rb各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-4烷基、氘代C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基氨基、二C1-4烷基氨基、卤代C1-4烷基、卤代C1-4烷氧基、卤代C1-4烷硫基、卤代C1-4烷基氨基、卤代二C1-4烷基氨基、-COC1-4烷基、-OC(O)C1- 4烷基、-C(O)OC1-4烷基、-OC(O)OC1-4烷基、-SO2C1-4烷基、-NHSO2C1-4烷基、-N(C1-4烷基)SO2C1-4烷基、-SO2NH2、-SO2NHC1-4烷基、-SO2N(C1-4烷基)2、-CONH2、-CONHC1-4烷基、-CON(C1-4烷基)2、-NHCOC1- 4烷基、-N(C1-4烷基)COC1-4烷基、3-6元环烷基、3-6元环烯基、苯基、5-6元杂芳基或3-6元杂环基。In some embodiments, each Ra or Rb is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy , C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino, halogenated C1-4 alkyl, halogenated C1-4 alkoxy, halogenated C1-4 alkylthio, halogenated C1-4 alkylamino, halogenated diC1-4 alkylamino, -COC1-4 alkyl, -OC (O) ... -4 alkyl, -C (O) OC1-4 alkyl, -OC(O) OC1-4 alkyl , -SO2C1-4 alkyl, -NHSO2C1-4 alkyl , -N( C1-4 alkyl)SO2C1-4 alkyl, -SO2NH2, -SO2NHC1-4 alkyl, -SO2N ( C1-4 alkyl) 2 , -CONH2 , -CONHC1-4 alkyl, -CON ( C1-4 alkyl) 2 , -NHCOC1-4 alkyl , -N ( C1-4 alkyl ) COC1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, phenyl , 5-6 membered heteroaryl or 3-6 membered heterocyclyl.

在一些实施方案中，每个Ra或Rb各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基氨基、二C1-4烷基氨基、卤代C1-4烷基、卤代C1-4烷氧基、卤代C1-4烷硫基、卤代C1-4烷基氨基、卤代二C1-4烷基氨基、3-6元环烷基、或3-6元杂环基。在一些实施方案中，每个Ra或Rb各自独立地选自氘代C1-4烷基。In some embodiments, each Ra or Rb is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino, halogenated C1-4 alkyl, halogenated C1-4 alkoxy, halogenated C1-4 alkylthio, halogenated C1-4 alkylamino, halogenated diC1-4 alkylamino, 3-6 membered cycloalkyl, or 3-6 membered heterocyclyl. In some embodiments , each Ra or Rb is independently selected from deuterated C1-4 alkyl.

在一些实施方案中，所述3-6元杂环基选自3-6元杂环烷基。In some embodiments, the 3-6 membered heterocyclyl is selected from 3-6 membered heterocycloalkyl.

在一些实施方案中，每个Ra或Rb各自独立地选自氧代、氘、-F、-Cl、-Br、-OH、-NH2、-CN、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、甲硫基、乙硫基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、单氟甲基、二氟甲基、三氟甲基、三氟乙基、三氟甲氧基、三氟乙氧基、三氟甲硫基、单氟甲基氨基、三氟甲基氨基、二(单氟甲基)氨基、二(三氟甲基)氨基、环丙基、环丁基、氮杂环丁基、或氧杂环丁基。在一些实施方案中，每个Ra或Rb各自独立地选自氘代甲基。在一些实施方案中，每个Ra或Rb各自独立地选自氘代乙基。In some embodiments, each Ra or Rb is each independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, di(trifluoromethyl)amino, cyclopropyl, cyclobutyl, azetidinyl, or oxetanyl. In some embodiments, each Ra or Rb is each independently selected from deuterated methyl. In some embodiments, each Ra or Rb is each independently selected from deuterated ethyl.

在一些实施方案中，每个Ra或Rb各自独立地选自氧代、氘、-F、-Cl、-Br、-OH、-NH2、-CN、甲基、甲氧基、三氟甲基、三氟甲氧基、环丙基、-CD3、乙基、或-CD2CD3。In some embodiments, each Ra or Rb is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, methoxy, trifluoromethyl , trifluoromethoxy, cyclopropyl, -CD3 , ethyl, or -CD2CD3 .

在一些实施方案中，每个Ra或Rb各自独立地选自氧代、氘、-F、-Cl、-Br、-OH、-NH2、-CN、甲基、甲氧基、三氟甲基、三氟甲氧基、或环丙基。在一些实施方案中，每个Ra或Rb各自独立地选自-CD3。在一些实施方案中，每个Ra或Rb各自独立地选自乙基或-CD2CD3。In some embodiments, each Ra or Rb is each independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2, -CN, methyl, methoxy, trifluoromethyl, trifluoromethoxy, or cyclopropyl. In some embodiments, each Ra or Rb is each independently selected from -CD3 . In some embodiments, each Ra or Rb is each independently selected from ethyl or -CD2CD3 .

在一些实施方案中，每个Ra各自独立地选自氘、氧代、甲基、-CD3、乙基、环丙基、或-CD2CD3。In some embodiments, each Ra is independently selected from deuterium, oxo, methyl , -CD3 , ethyl, cyclopropyl, or -CD2CD3 .

在一些实施方案中，每个Ra各自独立地选自氘、氧代或甲基。在一些实施方案中，每个Ra各自独立地选自-CD3。在一些实施方案中，每个Ra各自独立地选自乙基、环丙基、或-CD2CD3。In some embodiments, each Ra is each independently selected from deuterium, oxo, or methyl. In some embodiments, each Ra is each independently selected from -CD 3 . In some embodiments, each Ra is each independently selected from ethyl, cyclopropyl, or -CD 2 CD 3 .

在一些实施方案中，每个Rb各自独立地选自氧代、氘、-F、-Cl、-OH、-NH2、-CN、或甲基。In some embodiments, each R b is independently selected from oxo, deuterium, -F, -Cl, -OH, -NH 2 , -CN, or methyl.

在一些实施方案中，每个Rb各自独立地选自-F或-Cl。In some embodiments, each R b is independently selected from -F or -Cl.

在一些实施方案中，环C选自任选地被一个或多个Rc1取代的如下基团：3-10元环烷基或3-10元杂环烷基。In some embodiments, Ring C is selected from the following groups optionally substituted with one or more R c1 : 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl.

在一些实施方案中，环C选自任选地被一个或多个Rc1取代的如下基团：5-9元环烷基或5-9元杂环烷基。In some embodiments, Ring C is selected from the following groups optionally substituted with one or more R c1 : 5-9 membered cycloalkyl or 5-9 membered heterocycloalkyl.

在一些实施方案中，环C选自任选地被一个或多个Rc1取代的如下基团：4-8元环烷基或4-8元杂环烷基。In some embodiments, Ring C is selected from the following groups optionally substituted with one or more R c1 : 4-8 membered cycloalkyl or 4-8 membered heterocycloalkyl.

在一些实施方案中，环C选自任选地被一个或多个Rc1取代的如下基团：6-8元环烷基或6-8元杂环烷基。In some embodiments, Ring C is selected from the following groups optionally substituted with one or more R c1 : 6-8 membered cycloalkyl or 6-8 membered heterocycloalkyl.

在一些实施方案中，环C选自任选地被一个或多个Rc1取代的如下基团：6-10元环烷基或6-10元杂环烷基。In some embodiments, Ring C is selected from the following groups optionally substituted with one or more R c1 : 6-10 membered cycloalkyl or 6-10 membered heterocycloalkyl.

在一些实施方案中，环C选自任选地被一个或多个Rc1取代的3-12元杂环烷基。在一些实施方案中，所述3-12元杂环烷基选自3-10元杂环烷基、5-9元杂环烷基或6-8元杂环烷基。在一些实施方案中，所述3-12元杂环烷基选自4-8元杂环烷基。在一些实施方案中，所述3-12元杂环烷基选自6-10元杂环烷基。In some embodiments, ring C is selected from 3-12 membered heterocycloalkyl optionally substituted with one or more R c1 . In some embodiments, the 3-12 membered heterocycloalkyl is selected from 3-10 membered heterocycloalkyl, 5-9 membered heterocycloalkyl or 6-8 membered heterocycloalkyl. In some embodiments, the 3-12 membered heterocycloalkyl is selected from 4-8 membered heterocycloalkyl. In some embodiments, the 3-12 membered heterocycloalkyl is selected from 6-10 membered heterocycloalkyl.

在一些实施方案中，所述3-12元环烷基、3-10元环烷基、5-9元环烷基或6-8元环烷基选自单环环烷基。在一些实施方案中，所述4-8元环烷基选自单环环烷基。In some embodiments, the 3-12 membered cycloalkyl, 3-10 membered cycloalkyl, 5-9 membered cycloalkyl or 6-8 membered cycloalkyl is selected from monocyclic cycloalkyl. In some embodiments, the 4-8 membered cycloalkyl is selected from monocyclic cycloalkyl.

在一些实施方案中，所述3-12元环烷基、3-10元环烷基、5-9元环烷基或6-8元环烷基选自桥环烷基。在一些实施方案中，所述4-8元环烷基选自桥环烷基。In some embodiments, the 3-12 membered cycloalkyl, 3-10 membered cycloalkyl, 5-9 membered cycloalkyl or 6-8 membered cycloalkyl is selected from bridged cycloalkyl. In some embodiments, the 4-8 membered cycloalkyl is selected from bridged cycloalkyl.

在一些实施方案中，所述3-12元杂环烷基、3-10元杂环烷基、5-9元杂环烷基或6-8元杂环烷基选自单环杂环烷基。在一些实施方案中，所述4-8元杂环烷基选自单环杂环烷基。In some embodiments, the 3-12 membered heterocycloalkyl, 3-10 membered heterocycloalkyl, 5-9 membered heterocycloalkyl or 6-8 membered heterocycloalkyl is selected from monocyclic heterocycloalkyl. In some embodiments, the 4-8 membered heterocycloalkyl is selected from monocyclic heterocycloalkyl.

在一些实施方案中，所述3-12元杂环烷基、3-10元杂环烷基、5-9元杂环烷基或6-8元杂环烷基选 自桥杂环烷基。在一些实施方案中，所述4-8元杂环烷基选自桥杂环烷基。In some embodiments, the 3-12 membered heterocycloalkyl, 3-10 membered heterocycloalkyl, 5-9 membered heterocycloalkyl or 6-8 membered heterocycloalkyl is selected from In some embodiments, the 4-8 membered heterocycloalkyl is selected from a bridged heterocycloalkyl.

在一些实施方案中，环C选自任选地被一个或多个Rc1取代的如下基团： In some embodiments, Ring C is selected from the following groups optionally substituted with one or more R c1 :

在一些实施方案中，环C选自任选地被一个或多个Rc1取代的如下基团：在一些实施方案中，环C选自任选地被一个或多个Rc1取代的如下基团： In some embodiments, Ring C is selected from the following groups optionally substituted with one or more R c1 : In some embodiments, Ring C is selected from the following groups optionally substituted with one or more R c1 :

在一些实施方案中，环C选自 In some embodiments, Ring C is selected from

在一些实施方案中，环C选自在一些实施方案中，环C选自 In some embodiments, Ring C is selected from In some embodiments, Ring C is selected from

在一些实施方案中，环C选自在一些实施方案中，环C选自 In some embodiments, Ring C is selected from In some embodiments, Ring C is selected from

在一些实施方案中，环C选自在一些实施方案中，环C选自 在一些实施方案中，环C选自 In some embodiments, Ring C is selected from In some embodiments, Ring C is selected from In some embodiments, Ring C is selected from

在一些实施方案中，所述3-12元杂环基选自3-12元杂环烷基。In some embodiments, the 3-12 membered heterocyclyl is selected from 3-12 membered heterocycloalkyl.

在一些实施方案中，每个Rc1各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-8烷基、氘代C1-8烷基、C1-8烷氧基、C1-8烷硫基、C1-8烷基氨基、二C1-8烷基氨基、卤代C1-8烷基、卤代C1-8烷氧基、卤代C1-8烷硫基、卤代C1-8烷基氨基、卤代二C1-8烷基氨基、-COC1-8烷基、-OC(O)C1- 8烷基、-C(O)OC1-8烷基、-OC(O)OC1-8烷基、-SO2C1-8烷基、-NHSO2C1-8烷基、-N(C1-8烷基)SO2C1-8烷基、 -SO2NH2、-SO2NHC1-8烷基、-SO2N(C1-8烷基)2、-CONH2、-CONHC1-8烷基、-CON(C1-8烷基)2、-NHCOC1- 8烷基、-N(C1-8烷基)COC1-8烷基、3-10元环烷基、3-10元环烯基、6-10元芳基、5-10元杂芳基或3-10元杂环基；In some embodiments, each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-8 alkyl, deuterated C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylthio, C 1-8 alkylamino, diC 1-8 alkylamino, haloC 1-8 alkyl, haloC 1-8 alkoxy, haloC 1-8 alkylthio, haloC 1-8 alkylamino, halodiC 1-8 alkylamino, -COC 1-8 alkyl , -OC(O)C 1-8 alkyl, -C(O)OC 1-8 alkyl, -OC(O)OC 1-8 alkyl, -SO 2 C 1-8 alkyl, -NHSO 2 C 1-8 alkyl, -N(C 1-8 alkyl) SO 2 C 1-8 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-8 alkyl, -SO 2 N(C 1-8 alkyl) 2 , -CONH 2 , -CONHC 1-8 alkyl, -CON(C 1-8 alkyl) 2 , -NHCOC 1-8 alkyl, -N(C 1-8 alkyl)COC 1-8 alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl;

或者，位于同一个环原子上的两个Rc1(和与Rc1相连的环原子)一起形成任选被一个或多个Rc2取代的如下基团：3-10元环烷基、3-10元环烯基或3-10元杂环基；Alternatively, two R c1 located on the same ring atom (and the ring atom to which R c1 is attached) together form the following group optionally substituted by one or more R c2 : 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl or 3-10 membered heterocyclyl;

或者，位于相邻两个环原子上的两个Rc1(和与Rc1相连的环原子)一起形成任选被一个或多个Rc2取代的如下基团：3-10元环烷基、3-10元环烯基或3-10元杂环基。Alternatively, two R c1 located on two adjacent ring atoms (and the ring atom to which R c1 is attached) together form a 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl or 3-10 membered heterocyclyl group optionally substituted with one or more R c2 .

在一些实施方案中，所述3-10元杂环基选自3-10元杂环烷基。In some embodiments, the 3-10 membered heterocyclyl is selected from 3-10 membered heterocycloalkyl.

在一些实施方案中，每个Rc1各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、C1-8烷基、C1-8烷氧基、C1-8烷硫基、C1-8烷基氨基、二C1-8烷基氨基、卤代C1-8烷基、卤代C1-8烷氧基、卤代C1-8烷硫基、卤代C1-8烷基氨基、或卤代二C1-8烷基氨基；In some embodiments, each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkylthio, C 1-8 alkylamino, diC 1-8 alkylamino, haloC 1-8 alkyl, haloC 1-8 alkoxy, haloC 1-8 alkylthio, haloC 1-8 alkylamino, or halodiC 1-8 alkylamino;

或者，位于同一个环原子上的两个Rc1(和与Rc1相连的环原子)一起形成任选被一个或多个Rc2取代的如下基团：3-10元环烷基或3-10元杂环烷基；Alternatively, two R c1 located on the same ring atom (and the ring atom to which R c1 is attached) together form the following group optionally substituted with one or more R c2 : 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl;

或者，位于相邻两个环原子上的两个Rc1(和与Rc1相连的环原子)一起形成任选被一个或多个Rc2取代的如下基团：3-10元环烷基或3-10元杂环烷基。Alternatively, two R c1 located on two adjacent ring atoms (and the ring atom to which R c1 is attached) together form a 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl group optionally substituted with one or more R c2 .

在一些实施方案中，每个Rc1各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-6烷基、氘代C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基氨基、二C1-6烷基氨基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C1-6烷硫基、卤代C1-6烷基氨基、卤代二C1-6烷基氨基、-COC1-6烷基、-OC(O)C1- 6烷基、-C(O)OC1-6烷基、-OC(O)OC1-6烷基、-SO2C1-6烷基、-NHSO2C1-6烷基、-N(C1-6烷基)SO2C1-6烷基、-SO2NH2、-SO2NHC1-6烷基、-SO2N(C1-6烷基)2、-CONH2、-CONHC1-6烷基、-CON(C1-6烷基)2、-NHCOC1- 6烷基、-N(C1-6烷基)COC1-6烷基、3-8元环烷基、3-8元环烯基、6-8元芳基、5-8元杂芳基或3-8元杂环基；In some embodiments, each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, diC 1-6 alkylamino, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylthio, haloC 1-6 alkylamino, halodiC 1-6 alkylamino, -COC 1-6 alkyl , -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)OC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -N (C 1-6 alkyl)SO 2 C 1-6 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-6 alkyl, -SO 2 N(C 1-6 alkyl) 2 , -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -NHCOC 1- 6 alkyl, -N(C 1-6 alkyl)COC 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 6-8 membered aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclyl;

或者，位于同一个环原子上的两个Rc1(和与Rc1相连的环原子)一起形成任选被一个或多个Rc2取代的如下基团：3-8元环烷基、3-8元环烯基或3-8元杂环基；Alternatively, two R c1 located on the same ring atom (and the ring atom to which R c1 is attached) together form the following group optionally substituted by one or more R c2 : 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl;

或者，位于相邻两个环原子上的两个Rc1(和与Rc1相连的环原子)一起形成任选被一个或多个Rc2取代的如下基团：3-8元环烷基、3-8元环烯基或3-8元杂环基。Alternatively, two R c1 located on two adjacent ring atoms (and the ring atom to which R c1 is attached) together form a 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl or 3-8 membered heterocyclyl group optionally substituted with one or more R c2 .

在一些实施方案中，所述3-8元杂环基选自3-8元杂环烷基。In some embodiments, the 3-8 membered heterocyclyl is selected from 3-8 membered heterocycloalkyl.

在一些实施方案中，每个Rc1各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基氨基、二C1-6烷基氨基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C1-6烷硫基、卤代C1-6烷基氨基、或卤代二C1-6烷基氨基；In some embodiments, each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, diC 1-6 alkylamino , haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylthio, haloC 1-6 alkylamino, or halodiC 1-6 alkylamino;

或者，位于同一个环原子上的两个Rc1(和与Rc1相连的环原子)一起形成任选被一个或多个Rc2取代的如下基团：3-8元环烷基或3-8元杂环烷基；Alternatively, two R c1 located on the same ring atom (and the ring atom to which R c1 is attached) together form the following group optionally substituted by one or more R c2 : 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl;

或者，位于相邻两个环原子上的两个Rc1(和与Rc1相连的环原子)一起形成任选被一个或多个Rc2取代的如下基团：3-8元环烷基或3-8元杂环烷基。Alternatively, two R c1 located on two adjacent ring atoms (and the ring atom to which R c1 is attached) together form a 3-8 membered cycloalkyl or 3-8 membered heterocycloalkyl group optionally substituted with one or more R c2 .

在一些实施方案中，每个Rc1各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-4烷基、氘代C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基氨基、二C1-4烷基氨基、卤代C1-4烷基、卤代C1-4烷氧基、卤代C1-4烷硫基、卤代C1-4烷基氨基、卤代二C1-4烷基氨基、-COC1-4烷基、-OC(O)C1- 4烷基、-C(O)OC14烷基、-OC(O)OC1-4烷基、-SO2C1-4烷基、-NHSO2C1-4烷基、-N(C1-4烷基)SO2C1-4烷基、-SO2NH2、-SO2NHC1-4烷基、-SO2N(C1-4烷基)2、-CONH2、-CONHC1-4烷基、-CON(C1-4烷基)2、-NHCOC1- 4烷基、-N(C1-4烷基)COC1-4烷基、3-6元环烷基、3-6元环烯基、6元芳基、5-6元杂芳基或3-6元杂环基；In some embodiments, each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino , di-C 1-4 alkylamino, halo-C 1-4 alkyl, halo-C 1-4 alkoxy, halo-C 1-4 alkylthio, halo-C 1-4 alkylamino, halo-di-C 1-4 alkylamino, -COC 1-4 alkyl, -OC(O)C 1-4 alkyl, -C(O)OC 14 alkyl, -OC (O)OC 1-4 alkyl, -SO 2 C 1-4 alkyl, -NHSO 2 C 1-4 alkyl, -N (C 1-4 alkyl)SO 2 C 1-4 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-4 alkyl, -SO 2 N(C 1-4 alkyl) 2 , -CONH 2 , -CONHC 1-4 alkyl, -CON(C 1-4 alkyl) 2 , -NHCOC 1- 4 alkyl, -N(C 1-4 alkyl)COC 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 6 membered aryl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl;

或者，位于同一个环原子上的两个Rc1(和与Rc1相连的环原子)一起形成任选被一个或多个Rc2取代的如下基团：3-6元环烷基、3-6元环烯基或3-6元杂环基；Alternatively, two R c1 located on the same ring atom (and the ring atom to which R c1 is attached) together form the following group optionally substituted by one or more R c2 : 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl or 3-6 membered heterocyclyl;

或者，位于相邻两个环原子上的两个Rc1(和与Rc1相连的环原子)一起形成任选被一个或多个Rc2取代的如下基团：3-6元环烷基、3-6元环烯基或3-6元杂环基。Alternatively, two R c1 located on two adjacent ring atoms (and the ring atom to which R c1 is attached) together form a 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl or 3-6 membered heterocyclyl group optionally substituted with one or more R c2 .

在一些实施方案中，所述3-6元杂环基选自3-6元杂环烷基。 In some embodiments, the 3-6 membered heterocyclyl is selected from 3-6 membered heterocycloalkyl.

在一些实施方案中，每个Rc1各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基氨基、二C1-4烷基氨基、卤代C1-4烷基、卤代C1-4烷氧基、卤代C1-4烷硫基、卤代C1-4烷基氨基、或卤代二C1-4烷基氨基；In some embodiments, each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, diC 1-4 alkylamino , haloC 1-4 alkyl, haloC 1-4 alkoxy, haloC 1-4 alkylthio, haloC 1-4 alkylamino, or halodiC 1-4 alkylamino;

或者，位于同一个环原子上的两个Rc1(和与Rc1相连的环原子)一起形成任选被一个或多个Rc2取代的如下基团：3-6元环烷基或3-6元杂环烷基；Alternatively, two R c1 located on the same ring atom (and the ring atom to which R c1 is attached) together form the following group optionally substituted by one or more R c2 : 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;

或者，位于相邻两个环原子上的两个Rc1(和与Rc1相连的环原子)一起形成任选被一个或多个Rc2取代的如下基团：3-6元环烷基或3-6元杂环烷基。Alternatively, two R c1 located on two adjacent ring atoms (and the ring atom to which R c1 is attached) together form the following group optionally substituted with one or more R c2 : 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl.

在一些实施方案中，每个Rc1各自独立地选自氧代、氘、-F、-Cl、-Br、-OH、-NH2、-CN、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、甲硫基、乙硫基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、单氟甲基、二氟甲基、三氟甲基、三氟乙基、三氟甲氧基、三氟乙氧基、三氟甲硫基、单氟甲基氨基、三氟甲基氨基、二(单氟甲基)氨基、或二(三氟甲基)氨基；In some embodiments, each R c1 is each independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino;

或者，位于同一个环原子上的两个Rc1(和与Rc1相连的环原子)一起形成任选被一个或多个Rc2取代的如下基团：环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、或吗啉基；Alternatively, two R c1 located on the same ring atom (and the ring atom to which R c1 is attached) together form a group optionally substituted with one or more R c2 : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl;

或者，位于相邻两个环原子上的两个Rc1(和与Rc1相连的环原子)一起形成任选被一个或多个Rc2取代的如下基团：环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢吡喃基、哌啶基、哌嗪基、或吗啉基。Alternatively, two R c1 located on two adjacent ring atoms (and the ring atom to which R c1 is attached) together form the following group optionally substituted with one or more R c2 : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, or morpholinyl.

在一些实施方案中，每个Rc1各自独立地选自氧代、氘、-F、-Cl、-Br、-OH、-NH2、-CN、甲基、乙基、异丙基、甲氧基、甲基氨基、二甲基氨基、三氟甲基、三氟甲氧基；In some embodiments, each R c1 is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, ethyl, isopropyl, methoxy, methylamino, dimethylamino, trifluoromethyl, trifluoromethoxy;

或者，位于同一个环原子上的两个Rc1(和与Rc1相连的环原子)一起形成任选被一个或多个Rc2取代的环丙基。Alternatively, two Rc1 on the same ring atom (and the ring atom to which Rc1 is attached) are taken together to form a cyclopropyl group optionally substituted with one or more Rc2 .

在一些实施方案中，每个Rc2各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-6烷基、氘代C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基氨基、二C1-6烷基氨基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C1-6烷硫基、卤代C1-6烷基氨基、卤代二C1-6烷基氨基、-COC1-6烷基、-OC(O)C1- 6烷基、-C(O)OC1-6烷基、-OC(O)OC1-6烷基、-SO2C1-6烷基、-NHSO2C1-6烷基、-N(C1-6烷基)SO2C1-6烷基、-SO2NH2、-SO2NHC1-6烷基、-SO2N(C1-6烷基)2、-CONH2、-CONHC1-6烷基、-CON(C1-6烷基)2、-NHCOC1- 6烷基、-N(C1-6烷基)COC1-6烷基、3-8元环烷基、3-8元环烯基、6-8元芳基、5-8元杂芳基或3-8元杂环基。In some embodiments, each R c2 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-6 alkyl, deuterated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, diC 1-6 alkylamino, haloC 1-6 alkyl, haloC 1-6 alkoxy, haloC 1-6 alkylthio, haloC 1-6 alkylamino, halodiC 1-6 alkylamino, -COC 1-6 alkyl , -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)OC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -N (C 1-6 alkyl)SO 2 C 1-6 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-6 alkyl, -SO 2 N(C 1-6 alkyl) 2 , -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -NHCOC 1- 6 alkyl, -N(C 1-6 alkyl)COC 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 6-8 membered aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclyl.

在一些实施方案中，每个Rc2各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-4烷基、氘代C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基氨基、二C1-4烷基氨基、卤代C1-4烷基、卤代C1-4烷氧基、卤代C1-4烷硫基、卤代C1-4烷基氨基、卤代二C1-4烷基氨基、-COC1-4烷基、-OC(O)C1- 4烷基、-C(O)OC14烷基、-OC(O)OC1-4烷基、-SO2C1-4烷基、-NHSO2C1-4烷基、-N(C1-4烷基)SO2C1-4烷基、-SO2NH2、-SO2NHC1-4烷基、-SO2N(C1-4烷基)2、-CONH2、-CONHC1-4烷基、-CON(C1-4烷基)2、-NHCOC1- 4烷基、-N(C1-4烷基)COC1-4烷基、3-6元环烷基、3-6元环烯基、苯基、5-6元杂芳基或3-6元杂环基。In some embodiments, each R c2 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino , di-C 1-4 alkylamino, halo-C 1-4 alkyl, halo-C 1-4 alkoxy, halo-C 1-4 alkylthio, halo-C 1-4 alkylamino, halo-di-C 1-4 alkylamino, -COC 1-4 alkyl, -OC(O)C 1-4 alkyl, -C(O)OC 14 alkyl, -OC (O)OC 1-4 alkyl, -SO 2 C 1-4 alkyl, -NHSO 2 C 1-4 alkyl, -N (C 1-4 alkyl)SO 2 C 1-4 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-4 alkyl, -SO 2 N(C 1-4 alkyl) 2 , -CONH 2 , -CONHC 1-4 alkyl, -CON(C 1-4 alkyl) 2 , -NHCOC 1-4 alkyl, -N(C 1-4 alkyl)COC 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl.

在一些实施方案中，每个Rc2各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基氨基、二C1-4烷基氨基、卤代C1-4烷基、卤代C1-4烷氧基、卤代C1-4烷硫基、卤代C1-4烷基氨基、或卤代二C1-4烷基氨基。In some embodiments, each R c2 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, diC 1-4 alkylamino , haloC 1-4 alkyl, haloC 1-4 alkoxy, haloC 1-4 alkylthio, haloC 1-4 alkylamino, or halodiC 1-4 alkylamino.

在一些实施方案中，每个Rc2各自独立地选自氧代、氘、-F、-Cl、-Br、-OH、-NH2、-CN、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、甲硫基、乙硫基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、单氟甲基、二氟甲基、三氟甲基、三氟乙基、三氟甲氧基、三氟乙氧基、三氟甲硫基、单氟甲基氨基、三氟甲基氨基、二(单氟甲基)氨基、或二(三氟甲基)氨基。In some embodiments, each R c2 is each independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

在一些实施方案中，每个Rc2各自独立地选自氧代、氘、-F、-Cl、-Br、-OH、-NH2、-CN、甲基、甲氧基、甲基氨基、二甲基氨基、三氟甲基、或三氟甲氧基。In some embodiments, each R c2 is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, methoxy, methylamino, dimethylamino, trifluoromethyl, or trifluoromethoxy.

在一些实施方案中，L1选自单键、-O-、-S-、-NRL1-、C1-4亚烷基、氘代C1-4亚烷基、卤代C1-4亚烷 基、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NRL1-、-NRL1C(O)-、-NRL1C(O)NRL1-、-S(O)-、-S(O)2-、-S(O)2NRL1-、-NRL1S(O)2-、-NRL1S(O)2NRL1-、-S(O)(＝NH)-、-NRL1S(O)(＝NH)-、或-C＝N(OH)-。在一些实施方案中，L1选自-OC(O)O-、-OC(O)NRL1-、或-NRL1C(O)O-。In some embodiments, L1 is selected from a single bond, -O-, -S-, -NR L1 -, C 1-4 alkylene, deuterated C 1-4 alkylene, halogenated C 1-4 alkylene, In some embodiments, L 1 is selected from -OC(O)O-, -OC(O)-, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 C(O)NR L1 -, -S(O)-, -S(O) 2 -, -S(O) 2 NR L1 -, -NR L1 S(O) 2 -, -NR L1 S(O) 2 NR L1 -, -S(O)(＝NH)-, -NR L1 S(O)(＝NH)-, or -C＝N(OH)-. In some embodiments, L 1 is selected from -OC(O)O-, -OC(O)NR L1 -, or -NR L1 C(O)O-.

在一些实施方案中，L1选自单键、-O-、-S-、-NRL1-、亚甲基、氘代亚甲基、亚乙基、氘代亚乙基、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NRL1-、-NRL1C(O)-、-NRL1C(O)NRL1-、-S(O)-、-S(O)2-、-S(O)2NRL1-、-NRL1S(O)2-、-NRL1S(O)2NRL1-、-S(O)(＝NH)-、-NRL1S(O)(＝NH)-、或-C＝N(OH)-。在一些实施方案中，L1选自-OC(O)O-、-OC(O)NRL1-、或-NRL1C(O)O-。In some embodiments, L 1 is selected from a single bond, -O-, -S-, -NR L1 -, methylene, deuterated methylene, ethylene, deuterated ethylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 C(O)NR L1 -, -S(O)-, -S(O) 2 -, -S(O) 2 NR L1 -, -NR L1 S(O) 2 -, -NR L1 S(O) 2 NR L1 -, -S(O)(＝NH)-, -NR L1 S(O)(＝NH)-, or -C＝N(OH)-. In some embodiments, L 1 is selected from -OC(O)O-, -OC(O)NR L1 -, or -NR L1 C(O)O-.

在一些实施方案中，L1选自单键、-O-、-S-、-NRL1-、亚甲基、亚乙基、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NRL1-、-NRL1C(O)-、-S(O)-、-S(O)2-、-S(O)2NRL1-、-NRL1S(O)2-、-NRL1S(O)2NRL1-、或-S(O)(＝NH)-。In some embodiments, L 1 is selected from a single bond, -O-, -S-, -NR L1 -, methylene, ethylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -, -NR L1 C(O)-, -S(O)-, -S(O) 2 -, -S(O) 2 NR L1 -, -NR L1 S(O) 2 -, -NR L1 S(O) 2 NR L1 -, or -S(O)(=NH)-.

在一些实施方案中，L1选自单键、-O-、-S-、-NRL1-、-C(O)NRL1-、-NRL1C(O)-、-S(O)-、-S(O)2-、-S(O)2NRL1-、-NRL1S(O)2-、-NRL1S(O)2NRL1-、或-S(O)(＝NH)-。In some embodiments, L1 is selected from a single bond, -O-, -S-, -NR L1 -, -C(O)NR L1 -, -NR L1 C(O)-, -S(O)-, -S(O) 2- , -S(O) 2NR L1 -, -NR L1 S(O) 2- , -NR L1 S(O) 2NR L1 -, or -S(O)(=NH)-.

在一些实施方案中，L1选自-S(O)2NRL1-。在一些实施方案中，L1选自-NRL1S(O)2-。In some embodiments, L 1 is selected from -S(O) 2 NR L1 -. In some embodiments, L 1 is selected from -NR L1 S(O) 2 -.

在一些实施方案中，L1采用从左至右或从右至左的阅读顺序。In some embodiments, L1 is read in left-to-right or right-to-left order.

在一些实施方案中，L1采用从左至右的阅读顺序。In some embodiments, L1 is read from left to right.

在一些实施方案中，L1为-NHS(O)2-。In some embodiments, L 1 is -NHS(O) 2 -.

在一些实施方案中，每个RL1各自独立地选自H、氘、或者任选被一个或多个RL1a取代的如下基团：C1-6烷基、氘代C1-6烷基、3-10元环烷基、3-10元环烯基、3-10元杂环基、6-10元芳基、或5-10元杂芳基。In some embodiments, each RL1 is independently selected from H, deuterium, or C1-6 alkyl, deuterated C1-6 alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl , which is optionally substituted with one or more RL1a.

在一些实施方案中，每个RL1各自独立地选自H、氘、或者任选被一个或多个RL1a取代的如下基团：C1-6烷基、氘代C1-6烷基、3-8元环烷基、3-8元环烯基、3-8元杂环基、苯基、或5-6元杂芳基。In some embodiments, each RL1 is independently selected from H, deuterium, or C1-6 alkyl, deuterated C1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, which is optionally substituted with one or more RL1a .

在一些实施方案中，每个RL1各自独立地选自H、氘、或者任选被一个或多个RL1a取代的如下基团：C1-4烷基、氘代C1-4烷基、3-7元环烷基、4-7元环烯基、4-7元杂环基、苯基、或5-6元杂芳基。In some embodiments, each RL1 is independently selected from H, deuterium, or C1-4 alkyl, deuterated C1-4 alkyl, 3-7 membered cycloalkyl, 4-7 membered cycloalkenyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, which is optionally substituted with one or more RL1a .

在一些实施方案中，所述3-10元杂环基、3-8元杂环基或4-7元杂环基各自选自3-10元杂环烷基、3-8元杂环烷基或4-7元杂环烷基。In some embodiments, the 3-10 membered heterocyclyl, 3-8 membered heterocyclyl or 4-7 membered heterocyclyl are each selected from 3-10 membered heterocycloalkyl, 3-8 membered heterocycloalkyl or 4-7 membered heterocycloalkyl.

在一些实施方案中，每个RL1各自独立地选自H或者任选被一个或多个RL1a取代的C1-4烷基。In some embodiments, each RL1 is independently selected from H or C 1-4 alkyl optionally substituted with one or more RL1a .

在一些实施方案中，每个RL1各自独立地选自H或者任选被一个或多个RL1a取代的如下基团：甲基、乙基、正丙基、或异丙基。In some embodiments, each RL1 is independently selected from H or methyl, ethyl, n-propyl, or isopropyl, optionally substituted with one or more RL1a .

在一些实施方案中，每个RL1各自独立地选自H或甲基。In some embodiments, each RL1 is independently selected from H or methyl.

在一些实施方案中，每个RL1各自独立地选自H。In some embodiments, each RL1 is independently selected from H.

在一些实施方案中，每个RL1a各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-6烷基、氘代C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基氨基、二C1-6烷基氨基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C1-6烷硫基、卤代C1-6烷基氨基、卤代二C1-6烷基氨基、-COC1-6烷基、-OC(O)C1- 6烷基、-C(O)OC1-6烷基、-OC(O)OC1-6烷基、-SO2C1-6烷基、-NHSO2C1-6烷基、-N(C1-6烷基)SO2C1-6烷基、-SO2NH2、-SO2NHC1-6烷基、-SO2N(C1-6烷基)2、-CONH2、-CONHC1-6烷基、-CON(C1-6烷基)2、-NHCOC1- 6烷基、-N(C1-6烷基)COC1-6烷基、3-10元环烷基、3-10元环烯基、6-10元芳基、5-10元杂芳基或3-10元杂环基。In some embodiments, each RL1a is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, haloC1-6 alkyl, haloC1-6 alkoxy, haloC1-6 alkylthio, haloC1-6 alkylamino, halodiC1-6 alkylamino, -COC1-6 alkyl, -OC (O) C1-6 alkyl, -C (O) OC1-6 alkyl, -OC ( O ) OC1-6 alkyl , -SO2C1-6 alkyl, -NHSO2C1-6 alkyl , -N ( C1-6 alkyl) SO2C1-6 alkyl, -SO2NH2 , -SO 2 NHC 1-6 alkyl, -SO 2 N(C 1-6 alkyl) 2 , -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -NHCOC 1- 6 alkyl, -N(C 1-6 alkyl)COC 1-6 alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl.

在一些实施方案中，每个RL1a各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-6烷基、氘代C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基氨基、二C1-6烷基氨基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C1-6烷硫基、卤代C1-6烷基氨基、卤代二C1-6烷基氨基、-COC1-6烷基、-OC(O)C1- 6烷基、-C(O)OC1-6烷基、-OC(O)OC1-6烷基、-SO2C1-6烷基、-NHSO2C1-6烷基、-N(C1-6烷基)SO2C1-6烷基、-SO2NH2、-SO2NHC1-6烷基、-SO2N(C1-6烷基)2、-CONH2、-CONHC1-6烷基、-CON(C1-6烷基)2、-NHCOC1- 6烷基、-N(C1-6烷基)COC1-6烷基、3-8元环烷基、3-8元环烯基、6-8元芳基、5-8元杂芳基或3-8元杂环基。In some embodiments, each RL1a is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, diC1-6 alkylamino, haloC1-6 alkyl, haloC1-6 alkoxy, haloC1-6 alkylthio, haloC1-6 alkylamino, halodiC1-6 alkylamino, -COC1-6 alkyl, -OC (O) C1-6 alkyl, -C (O) OC1-6 alkyl, -OC ( O ) OC1-6 alkyl , -SO2C1-6 alkyl, -NHSO2C1-6 alkyl , -N ( C1-6 alkyl) SO2C1-6 alkyl, -SO2NH2 , -SO 2 NHC 1-6 alkyl, -SO 2 N(C 1-6 alkyl) 2 , -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -NHCOC 1- 6 alkyl, -N(C 1-6 alkyl)COC 1-6 alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 6-8 membered aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclyl.

在一些实施方案中，每个RL1a各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、 C1-4烷基、氘代C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基氨基、二C1-4烷基氨基、卤代C1-4烷基、卤代C1-4烷氧基、卤代C1-4烷硫基、卤代C1-4烷基氨基、卤代二C1-4烷基氨基、-COC1-4烷基、-OC(O)C1- 4烷基、-C(O)OC14烷基、-OC(O)OC1-4烷基、-SO2C1-4烷基、-NHSO2C1-4烷基、-N(C1-4烷基)SO2C1-4烷基、-SO2NH2、-SO2NHC1-4烷基、-SO2N(C1-4烷基)2、-CONH2、-CONHC1-4烷基、-CON(C1-4烷基)2、-NHCOC1- 4烷基、-N(C1-4烷基)COC1-4烷基、3-6元环烷基、3-6元环烯基、苯基、5-6元杂芳基或3-6元杂环基。In some embodiments, each RLla is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di-C 1-4 alkylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogenated C 1-4 alkylthio, halogenated C 1-4 alkylamino , halogenated di-C 1-4 alkylamino, -COC 1-4 alkyl, -OC(O)C 1- 4 alkyl, -C(O)OC 14 alkyl, -OC(O)OC 1-4 alkyl, -SO 2 C 1-4 alkyl, -NHSO 2 C 1-4 alkyl, -N(C 1-4 alkyl)SO 2 C 1-4 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-4 alkyl, -SO 2 N(C 1-4 alkyl) 2 , -CONH 2 , -CONHC The invention also includes but is not limited to: -C 1-4 alkyl, -CON(C 1-4 alkyl) 2 , -NHCOC 1-4 alkyl, -N(C 1-4 alkyl)COC 1-4 alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl.

在一些实施方案中，每个RL1a各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基氨基、二C1-4烷基氨基、卤代C1-4烷基、卤代C1-4烷氧基、卤代C1-4烷硫基、卤代C1-4烷基氨基、或卤代二C1-4烷基氨基。In some embodiments, each RL1a is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylamino, diC1-4 alkylamino, haloC1-4 alkyl, haloC1-4 alkoxy, haloC1-4 alkylthio, haloC1-4 alkylamino, or halodiC1-4 alkylamino.

在一些实施方案中，每个RL1a各自独立地选自氧代、氘、-F、-Cl、-Br、-OH、-NH2、-CN、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、甲硫基、乙硫基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、单氟甲基、二氟甲基、三氟甲基、三氟乙基、三氟甲氧基、三氟乙氧基、三氟甲硫基、单氟甲基氨基、三氟甲基氨基、二(单氟甲基)氨基、或二(三氟甲基)氨基。In some embodiments, each RLla is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino.

在一些实施方案中，每个RL1a各自独立地选自氧代、氘、-F、-Cl、-Br、-OH、-NH2、-CN、甲基、甲氧基、三氟甲基、或三氟甲氧基。In some embodiments, each RLla is independently selected from oxo, deuterium, -F, -Cl, -Br, -OH, -NH2 , -CN, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.

在一些实施方案中，R1选自H、卤素、氘、-OH、-NH2、-SH、-COOH、-CN、或者任选被一个或多个R1a取代的如下基团：C1-6烷基、3-10元环烷基、3-10元环烯基、3-10元杂环基、6-10元芳基、或5-10元杂芳基。在一些实施方案中，R1选自任选被一个或多个R1a取代的如下基团：3-10元环烷基C1-4亚烷基、3-10元环烯基C1-4亚烷基、3-10元杂环基C1-4亚烷基、6-10元芳基C1-4亚烷基、或5-10元杂芳基C1-4亚烷基。In some embodiments, R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted with one or more R 1a : C 1-6 alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl. In some embodiments, R 1 is selected from the following groups optionally substituted with one or more R 1a : 3-10 membered cycloalkylC 1-4 alkylene, 3-10 membered cycloalkenylC 1-4 alkylene, 3-10 membered heterocyclylC 1-4 alkylene, 6-10 membered arylC 1-4 alkylene, or 5-10 membered heteroarylC 1-4 alkylene.

在一些实施方案中，R1选自H、卤素、氘、-OH、-NH2、-SH、-COOH、-CN、或者任选被一个或多个R1a取代的如下基团：C1-4烷基、3-8元环烷基、3-8元环烯基、3-8元杂环基、苯基、或5-6元杂芳基。在一些实施方案中，R1选自任选被一个或多个R1a取代的如下基团：3-8元环烷基C1-4亚烷基、3-8元环烯基C1-4亚烷基、3-8元杂环基C1-4亚烷基、苯基C1-4亚烷基、或5-6元杂芳基C1-4亚烷基。In some embodiments, R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted by one or more R 1a : C 1-4 alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl. In some embodiments, R 1 is selected from the following groups optionally substituted by one or more R 1a : 3-8 membered cycloalkyl C 1-4 alkylene, 3-8 membered cycloalkenyl C 1-4 alkylene, 3-8 membered heterocyclyl C 1-4 alkylene, phenyl C 1-4 alkylene, or 5-6 membered heteroaryl C 1-4 alkylene.

在一些实施方案中，R1选自H、卤素、氘、-OH、-NH2、-SH、-COOH、-CN、或者任选被一个或多个R1a取代的如下基团：C1-4烷基、3-6元环烷基、4-7元环烯基、4-7元杂环基、苯基、或5-6元杂芳基。在一些实施方案中，R1选自任选被一个或多个R1a取代的如下基团：3-6元环烷基C1-3亚烷基、4-7元环烯基C1-3亚烷基、4-7元杂环基C1-3亚烷基、苯基C1-3亚烷基、或5-6元杂芳基C1-3亚烷基。In some embodiments, R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted by one or more R 1a : C 1-4 alkyl, 3-6-membered cycloalkyl, 4-7-membered cycloalkenyl, 4-7-membered heterocyclyl, phenyl, or 5-6-membered heteroaryl. In some embodiments, R 1 is selected from the following groups optionally substituted by one or more R 1a : 3-6-membered cycloalkyl C 1-3 alkylene, 4-7-membered cycloalkenyl C 1-3 alkylene, 4-7-membered heterocyclyl C 1-3 alkylene, phenyl C 1-3 alkylene, or 5-6-membered heteroaryl C 1-3 alkylene.

在一些实施方案中，R1选自H、卤素、氘、-OH、-NH2、-SH、-COOH、-CN、或者任选被一个或多个R1a取代的如下基团：C1-4烷基、3-6元环烷基、或4-7元杂环烷基。在一些实施方案中，R1选自任选被一个或多个R1a取代的如下基团：3-6元环烷基C1-2亚烷基或4-7元杂环烷基C1-2亚烷基。In some embodiments, R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted with one or more R 1a : C 1-4 alkyl, 3-6 membered cycloalkyl, or 4-7 membered heterocycloalkyl. In some embodiments, R 1 is selected from the following groups optionally substituted with one or more R 1a : 3-6 membered cycloalkylC 1-2 alkylene or 4-7 membered heterocycloalkylC 1-2 alkylene.

在一些实施方案中，R1选自H、氘、-F、-Cl、-Br、-OH、-NH2、-SH、-COOH、-CN、或者任选被一个或多个R1a取代的如下基团：甲基、乙基、正丙基、异丙基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、噻嗪基、吡咯烷基、四氢呋喃基、四氢吡喃基、噻唑烷基、异噻唑烷基、噻二唑烷基、哌啶基、哌嗪基、或吗啉基。在一些实施方案中，R1选自任选被一个或多个R1a取代的如下基团：环丙基亚甲基、环丁基亚甲基、氮杂环丁基亚甲基、或氧杂环丁基亚甲基。In some embodiments, R 1 is selected from H, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted with one or more R 1a : methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thiazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, piperidinyl, piperazinyl, or morpholinyl. In some embodiments, R 1 is selected from the following groups optionally substituted with one or more R 1a : cyclopropylmethylene, cyclobutylmethylene, azetidinylmethylene, or oxetanylmethylene.

在一些实施方案中，R1选自H、氘、-F、-Cl、-Br、-OH、-NH2、-SH、-COOH、-CN、或者任选被一个或多个R1a取代的如下基团：甲基、乙基、正丙基、异丙基、异丁基、仲丁基、叔丁基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、噻嗪基、异噻唑烷基、或噻二唑烷基。在一些实施方案中，R1选自任选被一个或多个R1a取代的如下基团：四氢呋喃基或环丙基亚甲基。In some embodiments, R 1 is selected from H, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -SH, -COOH, -CN, or methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thiazinyl, isothiazolidinyl, or thiadiazolidinyl , optionally substituted with one or more R 1a. In some embodiments, R 1 is selected from tetrahydrofuranyl or cyclopropylmethylene, optionally substituted with one or more R 1a .

在一些实施方案中，R1选自甲基、单氟甲基、二氟甲基、三氟甲基、乙基、异丙基、叔丁基、环丙基、 In some embodiments, R 1 is selected from methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, isopropyl, tert-butyl, cyclopropyl,

在一些实施方案中，R1选自甲基、单氟甲基、二氟甲基、三氟甲基、乙基、异丙基、叔丁基、环丙基、 In some embodiments, R 1 is selected from methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, isopropyl, tert-butyl, cyclopropyl,

在一些实施方案中，R1选自 In some embodiments, R is selected from

在一些实施方案中，R1选自甲基、乙基、异丙基、环丙基、 In some embodiments, R 1 is selected from methyl, ethyl, isopropyl, cyclopropyl,

在一些实施方案中，R1选自甲基或 In some embodiments, R 1 is selected from methyl or

在一些实施方案中，R1选自任选被一个或多个R1a取代的C1-4烷基。In some embodiments, R 1 is selected from C 1-4 alkyl optionally substituted with one or more R 1a .

在一些实施方案中，R1选自任选被一个或多个R1a取代的乙基。In some embodiments, R 1 is selected from ethyl optionally substituted with one or more R 1a .

在一些实施方案中，所述3-12元杂环基选自3-12元杂环烷基。In some embodiments, the 3-12 membered heterocyclyl is selected from 3-12 membered heterocycloalkyl.

在一些实施方案中，每个R1a各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-6烷基、氘代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基氨基、二C1-6烷基氨基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C1-6烷硫基、卤代C1-6烷基氨基、卤代二C1-6烷基氨基、-COC1-6烷基、-OC(O)C1-6烷基、-C(O)OC1-6烷基、-OC(O)OC1-6烷基、-SO2C1-6烷基、-NHSO2C1-6烷基、-N(C1-6烷基)SO2C1-6烷基、-SO2NH2、-SO2NHC1-6烷基、-SO2N(C1-6烷基)2、-CONH2、-CONHC1-6烷基、-CON(C1- 6烷基)2、-NHCOC1-6烷基、-N(C1-6烷基)COC1-6烷基、3-10元环烷基、3-10元环烯基、6-10元芳基、5-10元杂芳基或3-10元杂环基。In some embodiments, each R 1a is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-6 alkyl, deuterated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, di-C 1-6 alkylamino, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, halo-C 1-6 alkylthio, halo-C 1-6 alkylamino, halo-di-C 1-6 alkylamino, -COC 1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC (O)OC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -N(C 1-6 alkyl)SO 2 C 1-6 alkyl, -SO 2 NH2 , -SO2NHC1-6alkyl, -SO2N(C1-6alkyl)2, -CONH2, -CONHC1-6alkyl, -CON(C1-6alkyl)2 , -NHCOC1-6alkyl , -N ( C1-6alkyl ) COC1-6alkyl , 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl.

在一些实施方案中，所述3-10元杂环基选自3-10元杂环烷基。In some embodiments, the 3-10 membered heterocyclyl is selected from 3-10 membered heterocycloalkyl.

在一些实施方案中，每个R1a各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-6烷基、氘代C1-6烷基、羟基C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6烷基氨基、二C1-6烷基氨基、 卤代C1-6烷基、卤代C1-6烷氧基、卤代C1-6烷硫基、卤代C1-6烷基氨基、卤代二C1-6烷基氨基、-COC1-6烷基、-OC(O)C1-6烷基、-C(O)OC1-6烷基、-OC(O)OC1-6烷基、-SO2C1-6烷基、-NHSO2C1-6烷基、-N(C1-6烷基)SO2C1-6烷基、-SO2NH2、-SO2NHC1-6烷基、-SO2N(C1-6烷基)2、-CONH2、-CONHC1-6烷基、-CON(C1- 6烷基)2、-NHCOC1-6烷基、-N(C1-6烷基)COC1-6烷基、3-8元环烷基、3-8元环烯基、6-8元芳基、5-8元杂芳基或3-8元杂环基。In some embodiments, each R 1a is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-6 alkyl, deuterated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, diC 1-6 alkylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, halogenated C 1-6 alkylthio, halogenated C 1-6 alkylamino, halogenated di-C 1-6 alkylamino, -COC 1-6 alkyl, -OC(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -OC(O)OC 1-6 alkyl, -SO 2 C 1-6 alkyl, -NHSO 2 C 1-6 alkyl, -N(C 1-6 alkyl)SO 2 C 1-6 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-6 alkyl, -SO 2 N(C 1-6 alkyl) 2 , -CONH 2 , -CONHC 1-6 alkyl, -CON(C 1-6 alkyl) 2 , -NHCOC 1-6 alkyl, -N(C 1-6 alkyl)COC 1-6 membered alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 6-8 membered aryl, 5-8 membered heteroaryl or 3-8 membered heterocyclyl.

在一些实施方案中，所述3-8元杂环基选自3-8元杂环烷基。In some embodiments, the 3-8 membered heterocyclyl is selected from 3-8 membered heterocycloalkyl.

在一些实施方案中，每个R1a各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-4烷基、氘代C1-4烷基、羟基C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基氨基、二C1-4烷基氨基、卤代C1-4烷基、卤代C1-4烷氧基、卤代C1-4烷硫基、卤代C1-4烷基氨基、卤代二C1-4烷基氨基、-COC1-4烷基、-OC(O)C1-4烷基、-C(O)OC1-4烷基、-OC(O)OC1-4烷基、-SO2C1-4烷基、-NHSO2C1-4烷基、-N(C1-4烷基)SO2C1-4烷基、-SO2NH2、-SO2NHC1-4烷基、-SO2N(C1-4烷基)2、-CONH2、-CONHC1-4烷基、-CON(C1- 4烷基)2、-NHCOC1-4烷基、-N(C1-4烷基)COC1-4烷基、3-6元环烷基、3-6元环烯基、苯基、5-6元杂芳基或3-6元杂环基。In some embodiments, each R 1a is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-4 alkyl, deuterated C 1-4 alkyl, hydroxy C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di-C 1-4 alkylamino, halo-C 1-4 alkyl, halo-C 1-4 alkoxy, halo-C 1-4 alkylthio, halo-C 1-4 alkylamino , halo-di-C 1-4 alkylamino, -COC 1-4 alkyl, -OC(O)C 1-4 alkyl, -C(O)OC 1-4 alkyl, -OC (O)OC 1-4 alkyl, -SO 2 C 1-4 alkyl, -NHSO 2 C 1-4 alkyl, -N(C 1-4 alkyl)SO 2 C 1-4 alkyl, -SO 2 NH2 , -SO2NHC1-4alkyl, -SO2N (C1-4alkyl) 2 , -CONH2 , -CONHC1-4alkyl , -CON ( C1-4alkyl )2 , -NHCOC1-4alkyl , -N( C1-4alkyl ) COC1-4alkyl , 3-6-membered cycloalkyl, 3-6 - membered cycloalkenyl, phenyl, 5-6-membered heteroaryl or 3-6-membered heterocyclyl.

在一些实施方案中，每个R1a各自独立地选自氧代、卤素、-OH、-NH2、-CN、C1-4烷基、氘代C1-4烷基、羟基C1-4烷基、C1-4烷氧基、C1-4烷硫基、C1-4烷基氨基、二C1-4烷基氨基、卤代C1-4烷基、卤代C1-4烷氧基、卤代C1-4烷硫基、卤代C1-4烷基氨基、卤代二C1-4烷基氨基、-OC(O)C1-4烷基、-C(O)OC1-4烷基、-CONHC1-4烷基、-NHCOC1-4烷基、3-6元环烷基、或3-6元杂环基。在一些实施方案中，每个R1a各自独立地选自氘。In some embodiments, each R 1a is independently selected from oxo, halogen, -OH, -NH 2 , -CN, C 1-4 alkyl, deuterated C 1-4 alkyl, hydroxy C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di-C 1-4 alkylamino, halo-C 1-4 alkyl, halo-C 1-4 alkoxy, halo-C 1-4 alkylthio, halo-C 1-4 alkylamino, halo-di-C 1-4 alkylamino, -OC(O)C 1-4 alkyl, -C(O)OC 1-4 alkyl, -CONHC 1-4 alkyl, -NHCOC 1-4 alkyl , 3-6 membered cycloalkyl, or 3-6 membered heterocyclyl. In some embodiments, each R 1a is independently selected from deuterium.

在一些实施方案中，所述3-6元杂环基选自3-6元杂环烷基。In some embodiments, the 3-6 membered heterocyclyl is selected from 3-6 membered heterocycloalkyl.

在一些实施方案中，每个R1a各自独立地选自氧代、-F、-Cl、-Br、-OH、-NH2、-CN、甲基、乙基、正丙基、异丙基、氘代甲基、羟基甲基、甲氧基、乙氧基、甲硫基、乙硫基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、单氟甲基、二氟甲基、三氟甲基、三氟乙基、三氟甲氧基、三氟乙氧基、三氟甲硫基、单氟甲基氨基、三氟甲基氨基、二(单氟甲基)氨基、或二(三氟甲基)氨基、-OC(O)C1-2烷基、-C(O)OC1-2烷基、-CONHC1-2烷基、-NHCOC1-2烷基、环丙基、环丁基、氮杂环丁基、或氧杂环丁基。在一些实施方案中，每个R1a各自独立地选自氘。In some embodiments, each R 1a is each independently selected from oxo, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, hydroxymethyl, methoxy, ethoxy, methylthio, ethylthio, methylamino, ethylamino, dimethylamino, diethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, trifluoromethylthio, monofluoromethylamino, trifluoromethylamino, di(monofluoromethyl)amino, or di(trifluoromethyl)amino, -OC(O)C 1-2 alkyl, -C(O)OC 1-2 alkyl, -CONHC 1-2 alkyl, -NHCOC 1-2 alkyl, cyclopropyl, cyclobutyl, azetidinyl, or oxetanyl. In some embodiments, each R 1a is each independently selected from deuterium.

在一些实施方案中，每个R1a各自独立地选自氧代、-F、-Cl、-Br、-OH、-NH2、-CN、甲基、羟基甲基、甲氧基、三氟甲基、三氟甲氧基、-C(O)OCH3、-C(O)OCH2CH3、或环丙基。在一些实施方案中，每个R1a各自独立地选自氘。In some embodiments, each R 1a is independently selected from oxo, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, hydroxymethyl, methoxy, trifluoromethyl, trifluoromethoxy, -C(O)OCH 3 , -C(O)OCH 2 CH 3 , or cyclopropyl. In some embodiments, each R 1a is independently selected from deuterium.

在一些实施方案中，每个R1a各自独立地选自氧代、-F、-Cl、-Br、-OH、-NH2、-CN、甲基、甲氧基、三氟甲基、或三氟甲氧基。在一些实施方案中，每个R1a各自独立地选自氘。在一些实施方案中，R1a选自羟基甲基。In some embodiments, each R 1a is independently selected from oxo, -F, -Cl, -Br, -OH, -NH 2 , -CN, methyl, methoxy, trifluoromethyl, or trifluoromethoxy. In some embodiments, each R 1a is independently selected from deuterium. In some embodiments, R 1a is selected from hydroxymethyl.

在另一些实施方案中，R1a任选地被一个或多个选自以下的取代基取代：氧代、氘原子、卤素、羟基、氨基、氰基、巯基、羧基。In other embodiments, R 1a is optionally substituted with one or more substituents selected from the group consisting of oxo, deuterium atom, halogen, hydroxyl, amino, cyano, thiol, and carboxyl.

在另一些实施方案中，R1a任选地被一个或多个选自以下的取代基取代：羟基。In other embodiments, R 1a is optionally substituted with one or more substituents selected from hydroxy.

在另一些实施方案中，R1a选自-OH或甲基，所述甲基任选地被一个或多个羟基取代。In other embodiments, R 1a is selected from -OH or methyl, said methyl optionally substituted with one or more hydroxyl groups.

在一些实施方案中，R1a选自-OH。在一些实施方案中，R1a选自甲基或羟基甲基。In some embodiments, R 1a is selected from -OH. In some embodiments, R 1a is selected from methyl or hydroxymethyl.

在一些实施方案中，结构单元-L1-R1选自 或者 In some embodiments, the structural unit -L 1 -R 1 is selected from or

在一些实施方案中，结构单元-L1-R1选自 在一些实施方案中，结构单元-L1-R1选自或者 In some embodiments, the structural unit -L 1 -R 1 is selected from In some embodiments, the structural unit -L 1 -R 1 is selected from or

在一些实施方案中，结构单元-L1-R1选自 In some embodiments, the structural unit -L 1 -R 1 is selected from

在一些实施方案中，结构单元-L1-R1选自或者 In some embodiments, the structural unit -L 1 -R 1 is selected from or

在一些实施方案中，结构单元-L1-R1选自 In some embodiments, the structural unit -L 1 -R 1 is selected from

在一些实施方案中，结构单元-L1-R1选自在一些实施方案中，结构单元-L1-R1选自在一些实施方案中，结构单元-L1-R1选自 或者 In some embodiments, the structural unit -L 1 -R 1 is selected from In some embodiments, the structural unit -L 1 -R 1 is selected from In some embodiments, the structural unit -L 1 -R 1 is selected from or

在一些实施方案中，L2选自-O-、-S-、-NRL2-、C1-4亚烷基、氘代C1-4亚烷基、卤代C1-4亚烷基、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NRL2-、-NRL2C(O)-、-S(O)-、-S(O)2-、-S(O)2NRL2-、或-NRL2S(O)2-。In some embodiments, L2 is selected from -O-, -S-, -NR L2 -, C 1-4 alkylene, deuterated C 1-4 alkylene, halo C 1-4 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L2 -, -NR L2 C(O)-, -S(O)-, -S(O) 2 -, -S(O) 2 NR L2 -, or -NR L2 S(O) 2 -.

在一些实施方案中，L2选自-O-、-S-、-NRL2-、亚甲基、氘代亚甲基、亚乙基、氘代亚乙基、-C(O)-、 -C(O)O-、-OC(O)-、-C(O)NRL2-、-NRL2C(O)-、-S(O)-、-S(O)2-、-S(O)2NRL2-、或-NRL2S(O)2-。In some embodiments, L2 is selected from -O-, -S-, -NR L2 -, methylene, deuterated methylene, ethylene, deuterated ethylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L2 -, -NR L2 C(O)-, -S(O)-, -S(O) 2 -, -S(O) 2 NR L2 -, or -NR L2 S(O) 2 -.

在一些实施方案中，L2选自亚乙基、-C(O)O-、-OC(O)-、-C(O)NRL2-、-NRL2C(O)-、-S(O)2NRL2-、或-NRL2S(O)2-。In some embodiments, L2 is selected from ethylene, -C(O)O-, -OC(O)-, -C(O)NR L2 -, -NR L2 C(O)-, -S(O) 2 NR L2 -, or -NR L2 S(O) 2 -.

在一些实施方案中，L2选自-C(O)NRL2-、或-NRL2C(O)-。In some embodiments, L2 is selected from -C(O)NR L2 -, or -NR L2 C(O)-.

在一些实施方案中，L2采用从右至左或从左至右的阅读顺序。In some embodiments, L2 is read in right-to-left or left-to-right order.

在一些实施方案中，L2采用从右至左的阅读顺序。In some embodiments, L2 is read from right to left.

在一些实施方案中，L2为-NH-C(O)-。In some embodiments, L2 is -NH-C(O)-.

在一些实施方案中，RL2选自H、氘、C1-4烷基、氘代C1-4烷基、或卤代C1-4烷基。In some embodiments, RL2 is selected from H, deuterium, C1-4 alkyl, deuterated C1-4 alkyl, or halogenated C1-4 alkyl.

在一些实施方案中，RL2选自H、氘、甲基、氘代甲基、单氟甲基、二氟甲基、或三氟甲基。In some embodiments, RL2 is selected from H, deuterium, methyl, deuterated methyl, monofluoromethyl, difluoromethyl, or trifluoromethyl.

在一些实施方案中，RL2选自H、氘或甲基。In some embodiments, RL2 is selected from H, deuterium, or methyl.

在一些实施方案中，RL2选自H。In some embodiments, RL2 is selected from H.

在一些实施方案中，本公开所述杂环基选自杂环烷基。在一些实施方案中，本公开所述杂环基选自部分不饱和的杂环基。In some embodiments, the heterocyclic group disclosed herein is selected from heterocyclic alkyl. In some embodiments, the heterocyclic group disclosed herein is selected from partially unsaturated heterocyclic groups.

在一些实施方案中，本公开所述3-12元或3-10元或3-8元或4-7元杂环基选自3-12元或3-10元或3-8元或4-7元杂环烷基。In some embodiments, the 3-12-membered, 3-10-membered, 3-8-membered, or 4-7-membered heterocyclyl group disclosed herein is selected from 3-12-membered, 3-10-membered, 3-8-membered, or 4-7-membered heterocycloalkyl groups.

在一些实施方案中，本公开所述C1-12选自C1-10、C1-8、C1-6、C1-4、C1-3、或C1-2。In some embodiments, the C 1-12 of the present disclosure is selected from C 1-10 , C 1-8 , C 1-6 , C 1-4 , C 1-3 , or C 1-2 .

在一些实施方案中，本公开所述C1-6烷基选自C1-4烷基、C1-3烷基、或C1-2烷基。In some embodiments, the C 1-6 alkyl group disclosed herein is selected from C 1-4 alkyl group, C 1-3 alkyl group, or C 1-2 alkyl group.

在一些实施方案中，本公开所述C1-6亚烷基选自C1-4亚烷基、C1-3亚烷基、或C1-2亚烷基。In some embodiments, the C 1-6 alkylene group disclosed herein is selected from C 1-4 alkylene group, C 1-3 alkylene group, or C 1-2 alkylene group.

在一些实施方案中，本公开所述卤素选自F、Cl、Br、或I。In some embodiments, the halogen described herein is selected from F, Cl, Br, or I.

在一些实施方案中，本公开所述卤代选自氟代、氯代、或溴代。在一些实施方案中，所述卤代选自氟代或氯代。在一些实施方案中，本公开所述卤代选自氟代。In some embodiments, the halo of the present disclosure is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo of the present disclosure is selected from fluoro.

在一些实施方案中，本公开所述的“一个或多个”可以指一个至十个以内的整数。例如“一个或多个”指一个、两个、三个、四个、五个、六个、七个、八个、九个或十个；或者，“一个或多个”指一个、两个、三个、四个、五个或六个；或者，“一个或多个”指一个、两个、三个或四个。In some embodiments, the "one or more" described in the present disclosure may refer to an integer from one to ten. For example, "one or more" refers to one, two, three, four, five, six, seven, eight, nine or ten; or, "one or more" refers to one, two, three, four, five or six; or, "one or more" refers to one, two, three or four.

在一些实施方案中，本公开所述3-12元选自3-10元、3-8元、3-6元、4-7元、4-6元、5-8元、5-7元、或5-6元。In some embodiments, the 3-12-membered group of the present disclosure is selected from 3-10-membered, 3-8-membered, 3-6-membered, 4-7-membered, 4-6-membered, 5-8-membered, 5-7-membered, or 5-6-membered.

在一些实施方案中，本公开所述杂环烷基含有1个或2个选自N或O的杂原子。In some embodiments, the heterocycloalkyl group disclosed herein contains 1 or 2 heteroatoms selected from N or O.

在一些实施方案中，本公开所述杂环烷基含有1个N原子。In some embodiments, the heterocycloalkyl groups disclosed herein contain 1 N atom.

在一些实施方案中，本公开所述杂环烷基含有1个O原子。In some embodiments, the heterocycloalkyl groups disclosed herein contain 1 O atom.

在一些实施方案中，本公开所述杂环烷基含有1个N原子和1个O原子。In some embodiments, the heterocycloalkyl groups disclosed herein contain 1 N atom and 1 O atom.

在一些实施方案中，本公开所述杂环基或杂芳基含有1个或2个选自N、O或S的杂原子。In some embodiments, the heterocyclic or heteroaryl groups disclosed herein contain 1 or 2 heteroatoms selected from N, O, or S.

在一些实施方案中，本公开所述杂环基或杂芳基含有1个或2个N原子。In some embodiments, the heterocyclyl or heteroaryl groups disclosed herein contain 1 or 2 N atoms.

在一些实施方案中，本公开所述杂环基或杂芳基含有1个N原子和1个O原子。In some embodiments, the heterocyclyl or heteroaryl groups disclosed herein contain 1 N atom and 1 O atom.

在一些实施方案中，本公开所述杂环基或杂芳基含有1个N原子和1个S原子。In some embodiments, the heterocyclyl or heteroaryl groups disclosed herein contain 1 N atom and 1 S atom.

在一些实施方案中，本公开所述杂环基或杂环烷基包括单环、螺环、并环或桥环。在一些实施方案中，所述杂环烷基包括单环或螺环。在一些实施方案中，本公开所述杂环基或杂环烷基包括单环或桥环。In some embodiments, the heterocyclic group or heterocycloalkyl group disclosed herein includes a monocyclic ring, a spirocyclic ring, a cyclic ring or a bridged ring. In some embodiments, the heterocyclic group or heterocycloalkyl group disclosed herein includes a monocyclic ring or a spirocyclic ring. In some embodiments, the heterocyclic group or heterocycloalkyl group disclosed herein includes a monocyclic ring or a bridged ring.

在一些实施方案中，本公开所述式(I)化合物或其药学上可接受的盐中，所有的氢原子可任选地被一个或多个氘取代。In some embodiments, in the compounds of formula (I) or pharmaceutically acceptable salts thereof described in the present disclosure, all hydrogen atoms may be optionally substituted with one or more deuteriums.

本公开涉及式(II)、式(II-1)、式(II-2)、式(II-3)、式(III)、式(III-1)、式(III-2)、式(III-3)化合物或其药学上可接受的盐，
The present disclosure relates to compounds of formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III), formula (III-1), formula (III-2), formula (III-3) or pharmaceutically acceptable salts thereof,

其中，X1、X2、Y1、Y2、Z1、Z2、Z3、Z4、Z5、L1、R1、L2、环A、环B和环C部分如本公开所定义。wherein X1 , X2 , Y1, Y2 , Z1 , Z2 , Z3 , Z4 , Z5 , L1 , R1 , L2 , Ring A, Ring B and Ring C moieties are as defined in the present disclosure.

在一些实施方案中，所述环A选自任选被一个或多个Ra取代的6-7元杂环烯基。In some embodiments, the ring A is selected from 6-7 membered heterocycloalkenyl optionally substituted with one or more Ra .

在一些实施方案中，所述环A选自任选被一个或多个Ra取代的6-7元杂环烯基，所述6元杂环烯基包含2个N原子，所述7元杂环烯基包含1个或2个选自N或O的杂原子。In some embodiments, the ring A is selected from 6-7 membered heterocycloalkenyl optionally substituted with one or more Ra , the 6 membered heterocycloalkenyl containing 2 N atoms, the 7 membered heterocycloalkenyl containing 1 or 2 heteroatoms selected from N or O.

在一些实施方案中，所述结构单元选自 n选自0、1、2、3、4、5、或6；m选自0、1、2、3、4、5、或6。In some embodiments, the structural unit Selected from n is selected from 0, 1, 2, 3, 4, 5, or 6; m is selected from 0, 1, 2, 3, 4, 5, or 6.

在一些实施方案中，结构单元选自 In some embodiments, the structural unit Selected from

在一些实施方案中，n选自0、1、2、3、或4。在一些实施方案中，n选自0、1、或2。In some embodiments, n is selected from 0, 1, 2, 3, or 4. In some embodiments, n is selected from 0, 1, or 2.

在一些实施方案中，m选自0、1、2、3、或4。在一些实施方案中，m选自0、1、或2。In some embodiments, m is selected from 0, 1, 2, 3, or 4. In some embodiments, m is selected from 0, 1, or 2.

在一些实施方案中，结构单元选自 In some embodiments, the structural unit Selected from

在一些实施方案中，结构单元选自 在一些实施方案中，结构单元选自 在一些实施方案中，结构单元选自 In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from

在一些实施方案中，本公开包含上述定义的变量及其实施方案，以及它们的任意组合。In some embodiments, the present disclosure encompasses the above-defined variables and embodiments thereof, and any combination thereof.

在一些实施方案中，本公开的式(I)、式(II)、式(II-1)、式(II-2)、式(II-3)、式(III)、式(III-1)、式(III-2)、式(III-3)化合物或其药学上可接受的盐不包含以下化合物或其药学上可接受的盐：
In some embodiments, the compounds of formula (I), (II), (II-1), (II-2), (II-3), (III), (III-1), (III-2), (III-3) or their pharmaceutically acceptable salts disclosed herein do not include the following compounds or their pharmaceutically acceptable salts:

本公开还涉及以下化合物或其药学上可接受的盐：





The present disclosure also relates to the following compounds or pharmaceutically acceptable salts thereof:





本公开还涉及以下化合物或其药学上可接受的盐：









The present disclosure also relates to the following compounds or pharmaceutically acceptable salts thereof:









在一些实施方案中，本公开提供了以下化合物里在手性色谱中保留时间较长的化合物和保留时间较短的化合物：在一些实施方案中，所述手性色谱使用whelk-O1型号的手性色谱柱。在一些实施方案中，所述手性色谱以正己烷：二氯甲烷：乙醇＝40:40:20(体积比)为流动相。在一些实施方案中，所述手性色谱的条件为：手性HPLC(柱：whelk-O1，4.6×250mm，5μm；流动相：正己烷：二氯甲烷：乙醇＝40:40:20；流速：2mL/min；波长：254nm)。在一些实施方案中，所述保留时间较长的化合物的保留时间约为10-11min，所述保留时间较短的化合物的保留时间约为7-8min。In some embodiments, the present disclosure provides compounds with longer retention times and compounds with shorter retention times in chiral chromatography among the following compounds: In some embodiments, the chiral chromatography uses a whelk-O1 chiral chromatography column. In some embodiments, the chiral chromatography uses n-hexane: dichloromethane: ethanol = 40:40:20 (volume ratio) as the mobile phase. In some embodiments, the conditions of the chiral chromatography are: chiral HPLC (column: whelk-O1, 4.6×250mm, 5μm; mobile phase: n-hexane: dichloromethane: ethanol = 40:40:20; flow rate: 2mL/min; wavelength: 254nm). In some embodiments, the retention time of the compound with a longer retention time is about 10-11min, and the retention time of the compound with a shorter retention time is about 7-8min.

在一些实施方案中，本公开提供了以下化合物里在手性色谱中保留时间较长的化合物和保留时间较短的化合物：在一些实施方案中，所述手性色谱使用CHIRALART Cellulose-SB型号的手性色谱柱。在一些实施方案中，所述手性色谱以正己烷:乙醇＝60:40 (体积比)为流动相。在一些实施方案中，所述手性色谱的条件为：手性HPLC(柱：CHIRALART Cellulose-SB柱，4.6×250mm，5μm；流动相：正己烷:乙醇＝60:40；流速：1mL/min；波长：254nm)。在一些实施方案中，所述保留时间较长的化合物的保留时间约为12-13min，所述保留时间较短的化合物的保留时间约为10-11min。In some embodiments, the present disclosure provides compounds with longer retention times and compounds with shorter retention times in chiral chromatography among the following compounds: In some embodiments, the chiral chromatography uses a CHIRALART Cellulose-SB chiral chromatography column. In some embodiments, the chiral chromatography uses n-hexane: ethanol = 60:40. (volume ratio) is the mobile phase. In some embodiments, the conditions of the chiral chromatography are: chiral HPLC (column: CHIRALART Cellulose-SB column, 4.6×250 mm, 5 μm; mobile phase: n-hexane:ethanol=60:40; flow rate: 1 mL/min; wavelength: 254 nm). In some embodiments, the retention time of the compound with a longer retention time is about 12-13 min, and the retention time of the compound with a shorter retention time is about 10-11 min.

在一些实施方案中，本公开提供了以下化合物里在手性色谱中保留时间较长的化合物和保留时间较短的化合物：在一些实施方案中，所述手性色谱使用CHIRALART Cellulose SC型号的手性色谱柱。在一些实施方案中，所述手性色谱以正己烷为流动相A，以二氯甲烷/乙醇＝5/1为流动相B。在一些实施方案中，所述手性色谱的条件为：手性HPLC(柱：CHIRALART Cellulose SC；流动相A：正己烷，流动相B：二氯甲烷/乙醇＝5/1(体积比)；洗脱梯度：A/B＝55/45；流速：1mL/min；波长：254nm)。在一些实施方案中，所述保留时间较长的化合物的保留时间约为22-23min，所述保留时间较短的化合物的保留时间约为19-20min。In some embodiments, the present disclosure provides compounds with longer retention times and compounds with shorter retention times in chiral chromatography among the following compounds: In some embodiments, the chiral chromatography uses a chiral chromatography column of CHIRALART Cellulose SC model. In some embodiments, the chiral chromatography uses n-hexane as mobile phase A and dichloromethane/ethanol=5/1 as mobile phase B. In some embodiments, the conditions of the chiral chromatography are: chiral HPLC (column: CHIRALART Cellulose SC; mobile phase A: n-hexane, mobile phase B: dichloromethane/ethanol=5/1 (volume ratio); elution gradient: A/B=55/45; flow rate: 1mL/min; wavelength: 254nm). In some embodiments, the retention time of the compound with a longer retention time is about 22-23min, and the retention time of the compound with a shorter retention time is about 19-20min.

在一些实施方案中，本公开提供了结构选自的化合物，其构型与以下化合物里在手性色谱中保留时间较长或保留时间较短的化合物一致： 在一些实施方案中，所述手性色谱使用CHIRALART Amylose-SA型号的手性色谱柱。在一些实施方案中，所述手性色谱以正己烷：乙醇＝50:50(体积比)为流动相。在一些实施方案中，所述手性色谱的条件为：手性HPLC(柱：CHIRALART Amylose-SA，30×250mm，5μm；流动相：正己烷：乙醇＝50:50；流速：40mL/min；波长：254nm)。在一些实施方案中，所述保留时间较长的化合物的保留时间约为9-10min，所述保留时间较短的化合物的保留时间约为6-7min。In some embodiments, the present disclosure provides a structure selected from The compound has the same configuration as the compound with the longer or shorter retention time in chiral chromatography among the following compounds: In some embodiments, the chiral chromatography uses a chiral chromatographic column of CHIRALART Amylose-SA model. In some embodiments, the chiral chromatography uses n-hexane: ethanol = 50: 50 (volume ratio) as the mobile phase. In some embodiments, the conditions of the chiral chromatography are: chiral HPLC (column: CHIRALART Amylose-SA, 30×250mm, 5μm; mobile phase: n-hexane: ethanol = 50: 50; flow rate: 40mL/min; wavelength: 254nm). In some embodiments, the retention time of the compound with a longer retention time is about 9-10min, and the retention time of the compound with a shorter retention time is about 6-7min.

在一些实施方案中，本公开提供了以下化合物里在手性色谱中保留时间较长的化合物和保留时间较短的化合物：在一些实施方案中，所述手性色谱使用CHIRALART Cellulose-SC型号的手性色谱柱。在一些实施方案中，所述手性色谱以正己烷:二氯甲烷:乙醇＝60:10:30为流动相。在一些实施方案中，所述手性色谱的条件为：手性HPLC(柱：CHIRALART Cellulose-SC，4.6×250mm，5μm；流动相：正己烷:二氯甲烷:乙醇＝60:10:30(体积比)；流速：1mL/min；波长：254nm)。在一些实施方案中，所述保留时间较长的化合物的保留时间约为21-22min，所述保留时间较短的化合物的保留时间约为18-19min。In some embodiments, the present disclosure provides compounds with longer retention times and compounds with shorter retention times in chiral chromatography among the following compounds: In some embodiments, the chiral chromatography uses a chiral chromatographic column of CHIRALART Cellulose-SC model. In some embodiments, the chiral chromatography uses n-hexane: dichloromethane: ethanol = 60: 10: 30 as the mobile phase. In some embodiments, the conditions of the chiral chromatography are: chiral HPLC (column: CHIRALART Cellulose-SC, 4.6×250mm, 5μm; mobile phase: n-hexane: dichloromethane: ethanol = 60: 10: 30 (volume ratio); flow rate: 1mL/min; wavelength: 254nm). In some embodiments, the retention time of the compound with a longer retention time is about 21-22min, and the retention time of the compound with a shorter retention time is about 18-19min.

在一些实施方案中，本公开提供了以下化合物里在手性色谱中保留时间较长的化合物和保留时间较短的化合物：在一些实施方案中，所述手性色谱使用CHIRALARTCellose-SC型号的手性色谱柱。在一些实施方案中，所述手性色谱以正己烷:二氯甲烷:乙醇＝60:10:30(体积比)为流动相。在一些实施方案中，所述手性色谱的条件为：手性HPLC(柱： CHIRALARTCellose-SC，4.6×250mm，5μm；流动相：正己烷:二氯甲烷:乙醇＝60:10:30；流速：1mL/min；波长：254nm)。在一些实施方案中，所述保留时间较长的化合物的保留时间约为10-11min，所述保留时间较短的化合物的保留时间约为9-10min。In some embodiments, the present disclosure provides compounds with longer retention times and compounds with shorter retention times in chiral chromatography among the following compounds: In some embodiments, the chiral chromatography uses a chiral chromatographic column of CHIRALARTCellose-SC model. In some embodiments, the chiral chromatography uses n-hexane: dichloromethane: ethanol = 60:10:30 (volume ratio) as the mobile phase. In some embodiments, the chiral chromatography conditions are: chiral HPLC (column: CHIRALARTCellose-SC, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 60:10:30; flow rate: 1 mL/min; wavelength: 254 nm). In some embodiments, the retention time of the compound with a longer retention time is about 10-11 min, and the retention time of the compound with a shorter retention time is about 9-10 min.

在一些实施方案中，本公开提供了以下化合物里在手性色谱中保留时间较长的化合物：在一些实施方案中，所述手性色谱使用CHIRALPAK IK型号的手性色谱柱。在一些实施方案中，所述手性色谱以正己烷/二氯甲烷/乙醇＝50/25/25(体积比)为流动相。在一些实施方案中，所述手性色谱的条件为：手性HPLC(柱：CHIRALPAK IK，4.6×250mm，5μm；流动相：正己烷/二氯甲烷/乙醇＝50/25/25；流速：1mL/min)中的保留时间较长。在一些实施方案中，所述保留时间较长的化合物的保留时间约为16min，所述保留时间较短的化合物的保留时间约为18-19min。In some embodiments, the present disclosure provides compounds with longer retention times in chiral chromatography among the following compounds: In some embodiments, the chiral chromatography uses a chiral chromatographic column of the CHIRALPAK IK model. In some embodiments, the chiral chromatography uses n-hexane/dichloromethane/ethanol = 50/25/25 (volume ratio) as the mobile phase. In some embodiments, the conditions of the chiral chromatography are: the retention time in chiral HPLC (column: CHIRALPAK IK, 4.6×250mm, 5μm; mobile phase: n-hexane/dichloromethane/ethanol = 50/25/25; flow rate: 1mL/min) is longer. In some embodiments, the retention time of the compound with a longer retention time is about 16min, and the retention time of the compound with a shorter retention time is about 18-19min.

在一些实施方案中，本公开提供了结构选自的化合物，其构型与以下化合物里在手性色谱中保留时间较长或保留时间较短的化合物一致： 在一些实施方案中，所述手性色谱使用CHIRALART Amylose-SA型号的手性色谱柱。在一些实施方案中，所述手性色谱以正己烷：乙醇＝50:50(体积比)为流动相。在一些实施方案中，所述手性色谱的条件为：手性HPLC(柱：CHIRALART Amylose-SA，30×250mm，5μm；流动相：正己烷：乙醇＝50:50；流速：40mL/min；波长：254nm)。在一些实施方案中，所述保留时间较长的化合物的保留时间约为9-10min，所述保留时间较短的化合物的保留时间约为6-7min。In some embodiments, the present disclosure provides a structure selected from The compound has the same configuration as the compound with the longer or shorter retention time in chiral chromatography among the following compounds: In some embodiments, the chiral chromatography uses a chiral chromatographic column of CHIRALART Amylose-SA model. In some embodiments, the chiral chromatography uses n-hexane: ethanol = 50: 50 (volume ratio) as the mobile phase. In some embodiments, the conditions of the chiral chromatography are: chiral HPLC (column: CHIRALART Amylose-SA, 30×250mm, 5μm; mobile phase: n-hexane: ethanol = 50: 50; flow rate: 40mL/min; wavelength: 254nm). In some embodiments, the retention time of the compound with a longer retention time is about 9-10min, and the retention time of the compound with a shorter retention time is about 6-7min.

另一方面，本公开涉及药物组合物，其包含本公开所述化合物或其药学上可接受的盐。在一些实施方案中，本公开的药物组合物还包括药学上可接受的辅料。In another aspect, the present disclosure relates to a pharmaceutical composition comprising the compound of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

另一方面，本公开涉及治疗哺乳动物疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的本公开所述化合物或其药学上可接受的盐、或本公开的药物组合物。In another aspect, the present disclosure relates to a method for treating a disease in a mammal, comprising administering a therapeutically effective amount of the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure to a mammal, preferably a human, in need of such treatment.

另一方面，本公开涉及本公开所述化合物或其药学上可接受的盐、或本公开的药物组合物在制备治疗疾病的药物中的用途。In another aspect, the present disclosure relates to use of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure in preparing a medicament for treating a disease.

另一方面，本公开涉及本公开所述化合物或其药学上可接受的盐、或本公开的药物组合物在治疗疾病中的用途。In another aspect, the present disclosure relates to use of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present disclosure in treating a disease.

另一方面，本公开涉及用于治疗疾病的本公开所述化合物或其药学上可接受的盐、或本公开的药物组合物。In another aspect, the present disclosure relates to a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for use in treating a disease.

在本公开的一些实施方案中，所述疾病选自KIF18A相关疾病。In some embodiments of the present disclosure, the disease is selected from a KIF18A-related disease.

在本公开的一些实施方案中，所述疾病(例如KIF18A相关疾病)选自癌症(例如卵巢癌、乳腺癌)。In some embodiments of the present disclosure, the disease (eg, a KIF18A-related disease) is selected from cancer (eg, ovarian cancer, breast cancer).

技术效果Technical Effects

本公开的化合物具有较高的KIF18A抑制活性(例如KIF18A蛋白运动活性)和细胞增殖抑制活性(例如OVCAR3细胞、MDA-MB-468细胞)，同时在体内外代谢稳定性、药代动力学、生物利用度和/或药效学研究中表现出良好的成药性。例如，小鼠药代动力学研究中，本公开的化合物在口服吸收暴露量、半衰期、绝对生物利用度等方面表现出良好的药代动力学性质。本申请的化合物可有效抑制肿瘤生长。 The compounds disclosed herein have high KIF18A inhibitory activity (e.g., KIF18A protein motor activity) and cell proliferation inhibitory activity (e.g., OVCAR3 cells, MDA-MB-468 cells), and show good drugability in in vitro and in vivo metabolic stability, pharmacokinetics, bioavailability, and/or pharmacodynamic studies. For example, in a mouse pharmacokinetic study, the compounds disclosed herein show good pharmacokinetic properties in terms of oral absorption exposure, half-life, absolute bioavailability, etc. The compounds of the present application can effectively inhibit tumor growth.

定义definition

除非另有说明，本公开中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise indicated, the following terms used in this disclosure have the following meanings. A particular term should not be considered as indefinite or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient.

术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo will not occur on an aromatic group.

本文所述的“取代基”包括本文上下文中所提及的所有取代基，例如包括下文提及的术语“烷基”、“亚烷基”、“杂烷基”、“烷氧基”、“烷基氨基”、“二烷基氨基”、“烷硫基”、“烯基”、“炔基”、“环烷基”、“环烯基”、“杂环基”、“杂环烷基”、“芳基”、“杂芳基”等相关基团所定义，及相应的非限制性或示例性基团，其中所述“取代基”一些非限制性实例包括氘原子、羟基、巯基、卤素、氨基、硝基、亚硝基、氰基、叠氮基团、亚砜基团、砜基团、磺酰胺基团、羧基、羧醛基团、亚胺基团、烷基、卤代-烷基、环烷基、卤代-环烷基、烯基、卤代-烯基、环烯基、卤代-环烯基、炔基、卤代-炔基、环炔基、卤代-环炔基、杂烷基、卤代-杂烷基、烷氧基、烷硫基、芳基、芳基氧基、芳基硫基、芳烷基、芳基烷氧基、芳基烷硫基、杂芳基、杂芳基氧基、杂芳基硫基、杂芳烷基、杂芳基烷氧基、杂芳基烷硫基、杂环基、杂环基氧基、杂环基硫基、杂环基亚烷基、杂环基烷氧基、杂环基烷硫基、酰基、酰氧基、氨基甲酸酯基团、酰胺基团、脲基、环氧基团和酯基团等，所述基团任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烷基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH2、-C(O)NH-烷基、-C(O)N(烷基)2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O)2-烷基、-S(O)2NH2、-S(O)2NH-烷基、-S(O)2N(烷基)2、环烷基、环烷基亚烷基、环烷基氧基、杂环基、杂环基亚烷基、杂环基氧基、杂环烷基、杂环烷基亚烷基、杂环烷基氧基、杂芳基、杂芳基亚烷基、杂芳基氧基、芳基、芳基亚烷基或芳基氧基。The “substituent” described herein includes all substituents mentioned herein, for example, including the definitions of the following terms “alkyl”, “alkylene”, “heteroalkyl”, “alkoxy”, “alkylamino”, “dialkylamino”, “alkylthio”, “alkenyl”, “alkynyl”, “cycloalkyl”, “cycloalkenyl”, “heterocyclyl”, “heterocycloalkyl”, “aryl”, “heteroaryl” and other related groups, and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the “substituent” include deuterium atoms, hydroxyl groups, sulfhydryl groups, halogen groups, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, cycloalkyl groups, halo-cycloalkyl groups, alkenyl groups, halo-alkenyl groups, cycloalkenyl groups, halo-cycloalkenyl groups, alkynyl groups, halo-alkynyl groups, cyclo alkyl, alkylene, alkyloxy, alkylthio, alkylamino ... 2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O) -alkyl , -S(O) 2 - alkyl, -S(O)2NH2, -S (O)2NH-alkyl, -S(O) 2N (alkyl) 2 , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene, or aryloxy.

在本文的部分实施方案中，所述取代基选自氘原子、羟基、巯基、卤素、氨基、硝基、亚硝基、氰基、叠氮基团、亚砜基团、砜基团、磺酰胺基团、羧基、醛基、亚胺基团、C1-12烷基、卤代-C1-12烷基、3-12元环烷基、卤代-3-12元环烷基、C2-12烯基、卤代-C2-12烯基、3-12元环烯基、卤代-3-12元环烯基、C2-12炔基、卤代-C2-12炔基、8-12元环炔基、卤代-8-12元环炔基、C1-12杂烷基、卤代-C1-12杂烷基、C1-12烷氧基、C1-12烷硫基、6-10元芳基、6-10元芳基氧基、6-10元芳基硫基、6-10元芳基C1-12亚烷基、6-10元芳基C1-12烷氧基、6-10元芳基C1-12烷硫基、5-10元杂芳基、5-10元杂芳基氧基、5-10元杂芳基硫基、5-10元杂芳基亚烷基、5-10元杂芳基烷氧基、5-10元杂芳基烷硫基、3-12元杂环基、3-12元杂环基氧基、3-12元杂环基硫基、3-12元杂环基C1-12亚烷基、3-12元杂环基C1-12烷氧基、3-12元杂环基C1-12烷硫基、C1-12酰基、C1-12酰氧基、氨基甲酸酯基团、C1-12酰胺基、脲基、环氧基团、C2-12酯基团、氧代和硫代等，所述取代基任选地被一个或多个选自以下的取代基取代：氘原子、氧代、羟基、氨基、硝基、卤素、氰基、C1-12烷基、C2-12烯基、C2-12炔基、C1-12烷氧基、卤代C1-12烷氧基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、羧基、-C(O)O-C1-12烷基、-OC(O)-C1-12烷基、-C(O)NH2、-C(O)NH-C1-12烷基、-C(O)N(C1-12烷基)2、-NHC(O)-C1-12烷基、-C(O)-C1-12烷基、-S(O)-C1-12烷基、-S(O)2-C1-12烷基、-S(O)2NH2、-S(O)2NH-C1-12烷基、-S(O)2N(C1-12烷基)2、3-12元环烷基、3-12元环烷基C1-12亚烷基、3-12元环烷基氧基、3-12元杂环基、3-12元杂环基C1-12亚烷基、3-12元杂环基氧基、3-12元杂环烷基、3-12元杂环烷基C1-12亚烷基、3-12元杂环烷基氧基、5-10元杂芳基、5-10元杂芳基C1-12亚烷基、5-10元杂芳基氧基、6-10元芳基、6-10元芳基C1-12亚烷基或6-10元芳基氧基。In some embodiments herein, the substituent is selected from a deuterium atom, a hydroxyl group, a thiol group, a halogen, an amino group, a nitro group, a nitroso group, a cyano group, an azide group, a sulfoxide group, a sulfone group, a sulfone group, a sulfonamide group, a carboxyl group, an aldehyde group, an imine group, a C 1-12 alkyl group, a halo-C 1-12 alkyl group, a 3-12 membered cycloalkyl group, a halo-3-12 membered cycloalkyl group, a C 2-12 alkenyl group, a halo-C 2-12 alkenyl group, a 3-12 membered cycloalkenyl group, a halo-3-12 membered cycloalkenyl group, a C 2-12 alkynyl group, a halo-C 2-12 alkynyl group, an 8-12 membered cycloalkynyl group, a halo-8-12 membered cycloalkynyl group, a C 1-12 heteroalkyl group, a halo-C 1-12 heteroalkyl group, a C 1-12 alkoxy group, a C 1-12 1-12- membered alkylthio, 6-10-membered aryl, 6-10-membered aryloxy, 6-10-membered arylthio, 6-10 -membered arylC 1-12 alkylene, 6-10-membered arylC 1-12 alkoxy, 6-10-membered arylC 1-12 alkylthio, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, 5-10-membered heteroarylthio, 5-10-membered heteroarylalkylene, 5-10-membered heteroarylalkoxy, 5-10-membered heteroarylalkylthio, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, 3-12-membered heterocyclylthio, 3-12-membered heterocyclylC 1-12 alkylene, 3-12-membered heterocyclylC 1-12 alkoxy, 3-12-membered heterocyclylC 1-12 alkylthio, C 1-12 acyl, C The substituents are optionally substituted by one or more substituents selected from the following: a deuterium atom, an oxo, a hydroxyl, an amino, a nitro, a halogen, a cyano, a C 1-12 alkyl, a C 2-12 alkenyl, a C 2-12 alkynyl, a C 1-12 alkoxy, a halogenated C 1-12 alkoxy, a C 1-12 alkylamino, a di-C 1-12 alkylamino, a halogenated C 1-12 alkylamino, a halogenated di-C 1-12 alkylamino, a carboxyl group, a -C(O)OC 1-12 alkyl, a -OC(O)-C 1-12 alkyl, a -C (O)NH 2 , a -C(O)NH-C 1-12 alkyl, a -C(O)N(C 1-12 alkyl) 2 , -NHC(O)-C 1-12 alkyl, -C(O)-C 1-12 alkyl, -S(O)-C 1-12 alkyl, -S(O) 2 -C 1-12 alkyl, -S(O) 2 NH 2 , -S(O) 2 NH-C 1-12 alkyl, -S(O) 2 N(C 1-12 alkyl) 2 , 3-12 -membered cycloalkyl, 3-12-membered cycloalkylC 1-12 alkylene, 3-12-membered cycloalkyloxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclylC 1-12 alkylene, 3-12-membered heterocyclyloxy, 3-12-membered heterocycloalkyl, 3-12-membered heterocycloalkylC 1-12 alkylene, 3-12-membered heterocycloalkyloxy, 5-10-membered heteroaryl, 5-10-membered heteroarylC C 1-12 alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 alkylene or 6-10 membered aryloxy.

术语“置换”或“被置换”指特定的原子或基团可以替换或被替换为指定的其他原子或基团。例如-CH2CH2CH2-中的1个或2个或3个-CH2-可被O、S、NH置换得到-O-CH2-CH2-、-O-CH2-、-CH2-O-CH2-、-CH2-O-、-CH2-CH2-O-、-O-等。The term "replace" or "replaced" means that a specific atom or group can replace or be replaced by another specified atom or group. For example, one, two or three -CH2- in -CH2CH2CH2- can be replaced by O, S or NH to give -O- CH2 - CH2- , -O- CH2- , -CH2 -O- CH2- , -CH2 - O-, -CH2- CH2 -O-, -O-, etc.

术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH2CH3)、单取代的(如CH2CH2F)、多取代的(如CHFCH2F、CH2CHF2等)或完全被取代的(CF2CF3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不 能合成的取代或取代模式。The term "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes both the occurrence of the event or situation and the non-occurrence of the event or situation. For example, an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group may be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), polysubstituted (such as CHFCH 2 F, CH 2 CHF 2, etc.) or fully substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or incompatible substituents are introduced. A synthetically capable substitution or substitution pattern.

本文中的Cm-n，是该部分具有给定范围中的整数个碳原子。例如，“C1-12”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子、10个碳原子、11个碳原子或12个碳原子，“C1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。例如“C1-3”是指该基团可具有1个碳原子、2个碳原子、3个碳原子。 Cmn herein means that the moiety has an integer number of carbon atoms in a given range. For example, " C1-12 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms or 12 carbon atoms, and " C1-6 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. For example, " C1-3 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms.

当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被2个R所取代，则每个R都有独立的选项。When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 2 R's, each R has an independent choice.

当一个连接基团的数量为0时，比如-(CH2)0-，表示该连接基团为共价键。When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a covalent bond.

当其中一个变量选自共价键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表共价键时表示该结构实际上是A-Z。When one of the variables is selected from a covalent bond, it means that the two groups it connects are directly connected. For example, when L in A-L-Z represents a covalent bond, it means that the structure is actually A-Z.

当所列举的连接基团没有指明其连接方向，其连接方向是任意的，比如A-L-Z中，连接基团L为-M-W-，此时表示该结构可以为A-M-W-Z或者A-W-M-Z。When the listed connecting groups do not specify their connection direction, their connection direction is arbitrary. For example, in A-L-Z, the connecting group L is -M-W-, which means that the structure can be A-M-W-Z or A-W-M-Z.

当一个取代基的键交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。例如，结构单元表示其可在环己基或者环己二烯上的任意一个位置发生取代。When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that it can be substituted at any position on the cyclohexyl group or cyclohexadiene.

术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

术语“羟基”指-OH基团。The term "hydroxy" refers to an -OH group.

术语“氰基”指-CN基团。The term "cyano" refers to a -CN group.

术语“巯基”指-SH基团。The term "mercapto" refers to a -SH group.

术语“氨基”指-NH2基团。The term "amino" refers to a -NH2 group.

术语“硝基”指-NO2基团。The term "nitro" refers to a -NO2 group.

术语“亚烷基”是指通式为CnH2n的饱和直链或支链二价烃基，通常具有1至12个、1至8个、1至6个、1至4个、1至3个或1至2个碳原子。例如，术语“C1-6亚烷基”指含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH2-)、亚乙基(-CH2CH2-)、亚丙基(-CH2CH2CH2-或-CH2CH(CH3)-)、亚丁基(-CH2CH2CH2CH2-、-CH2CH(CH3)CH2-或-CH2CH2CH(CH3)-)等。所述亚烷基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。The term "alkylene" refers to a saturated straight or branched divalent hydrocarbon radical of the general formula CnH2n , typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term " C1-6 alkylene" refers to an alkylene radical containing 1 to 6 carbon atoms. Non-limiting examples of alkylene radicals include, but are not limited to, methylene ( -CH2- ), ethylene ( -CH2CH2- ), propylene ( -CH2CH2CH2- or -CH2CH ( CH3 )-), butylene ( -CH2CH2CH2CH2- , -CH2CH ( CH3 ) CH2- or -CH2CH2CH ( CH3 )-), and the like. The alkylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

术语“烷基”是指通式为CnH2n+1的饱和烃基，通常具有1至12个、1至8个、1至6个、1至4个、1至3个或1至2个碳原子。该烷基可以是直链或支链的，通常具有1至12个、1至8个、1至6个、1至4个或1至3个碳原子。例如，术语“C1-6烷基”指含有1至6个碳原子的烷基(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、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。所述烷基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。类似地，烷氧基、烷基氨基、二烷基氨基和烷硫基的烷基部分(即烷基)具有上述相同定义。The term "alkyl" refers to a saturated hydrocarbon group of the general formula CnH2n +1 , typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The alkyl group may be straight chain or branched, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. For example, the term " C1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). The alkyl group is optionally substituted by one or more substituents selected from the group consisting of oxo, hydroxyl, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, halogenated alkoxy, alkylamino, dialkylamino, halogenated alkylamino, halogenated dialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy. Similarly, the alkyl moiety (i.e., alkyl) of alkoxy, alkylamino, dialkylamino and alkylthio has the same definition as above.

术语“杂烷基”指其中一个或多个碳原子(以及与其相连的氢原子)各自独立地被相同或不同杂原子基团置换的烷基。除非另有指示，所述杂烷基包含1个、2个或3个杂原子基团，所述杂原子基团非限制性实例包括O、S、N或NH，通常具有1至12个、1至8个、1至6个、1至4个、1至3个或1至2个碳原子。例如，术语“C1-6杂烷基”指含有1至6个碳原子以及1-3个杂原子基团的杂烷基。所述杂原子基团可以被置于杂烷基的任意位置(例如，内部或末端位置)，包括将杂烷基连接于分子其余部分的位置。通常，在存在超过一个杂原子基团的情况下，所述杂原子基团彼此不相邻。示例性杂烷基包括 但不限于烷氧基、烷氧基亚烷基、烷基氨基、烷基氨基亚烷基、二烷基氨基、二烷基氨基亚烷基等。所述杂烷基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and hydrogen atoms connected thereto) are each independently replaced by the same or different heteroatom groups. Unless otherwise indicated, the heteroalkyl group includes 1, 2 or 3 heteroatom groups, non-limiting examples of which include O, S, N or NH, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. For example, the term "C 1-6 heteroalkyl" refers to a heteroalkyl group containing 1 to 6 carbon atoms and 1-3 heteroatom groups. The heteroatom group can be placed at any position (e.g., internal or terminal position) of the heteroalkyl group, including the position in which the heteroalkyl group is connected to the rest of the molecule. Typically, in the presence of more than one heteroatom group, the heteroatom groups are not adjacent to each other. Exemplary heteroalkyl groups include But not limited to alkoxy, alkoxyalkylene, alkylamino, alkylaminoalkylene, dialkylamino, dialkylaminoalkylene, etc. The heteroalkyl group is optionally substituted with one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.

术语“烷氧基”指-O-烷基，通常具有1至12个、1至8个、1至6个、1至4个、1至3个或1至2个碳原子。其中，烷基部分任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。The term "alkoxy" refers to an -O-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

术语“烷基氨基”指-NH-烷基，通常具有1至12个、1至8个、1至6个、1至4个、1至3个或1至2个碳原子。其中，烷基部分任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。The term "alkylamino" refers to -NH-alkyl groups, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

术语“二烷基氨基”指-N(烷基)2，通常具有1至12个、1至8个、1至6个、1至4个、1至3个或1至2个碳原子。其中，烷基部分任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。The term "dialkylamino" refers to -N(alkyl) 2 , typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

术语“烷硫基”指-S-烷基，通常具有1至12个、1至8个、1至6个、1至4个、1至3个或1至2个碳原子。其中，烷基部分任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。The term "alkylthio" refers to an -S-alkyl group, typically having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms, wherein the alkyl portion is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基，通常具有2至12个、2至8个、2至6个、2至4个或2至3个碳原子。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基、1,3-丁二烯基等。所述烯基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one double bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4 or 2 to 3 carbon atoms. Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc. The alkenyl is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxyl, amino, nitro, halogen, cyano, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.

术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基，通常具有2至12个、2至8个、2至6个、2至4个或2至3个碳原子。炔基的非限制性实例包括但不限于乙炔基(-C≡CH)、1-丙炔基(-C≡C-CH3)、2-丙炔基(-CH2-C≡CH)、1,3-丁二炔基(-C≡C-C≡CH)等。所述炔基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烯基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond, typically having 2 to 12, 2 to 8, 2 to 6, 2 to 4 or 2 to 3 carbon atoms. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH 3 ), 2-propynyl (-CH 2 -C≡CH), 1,3-butadiynyl (-C≡CC≡CH), etc. The alkynyl is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.

术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3-12元环、3至10元环、3至8元环、4至8元环、5至8元环、6至8元环或5至6元环。环烷基非限制性实例包括但不限于环丙烷基、环丁烷基、环戊烷基、环己烷基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基等。所述环烷基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烷基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH2、-C(O)NH-烷基、-C(O)N(烷基)2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O)2-烷基、-S(O)2NH2、-S(O)2NH-烷基、-S(O)2N(烷基)2、环烷基、环烷基亚烷基、环烷基氧基、杂环基、杂环基亚烷基、杂环基氧基、杂环烷基、杂环烷基亚烷基、杂环烷基氧基、杂芳基、杂芳基亚烷基、杂芳基氧基、芳基、芳基亚烷基或芳基氧基。The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3-12 ring, a 3 to 10 ring, a 3 to 8 ring, a 4 to 8 ring, a 5 to 8 ring, a 6 to 8 ring or a 5 to 6 ring. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, etc. The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 - alkyl , -S(O) 2NH2 , -S(O) 2NH -alkyl, -S(O) 2N (alkyl) 2 , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

术语“环烯基”是指不完全饱和的具有至少一个双键的并且可以以呈单环、桥环或螺环存在的非芳 族碳环。除非另有指示，该碳环通常为3至12元环、3至10元环、3至8元环、3至6元环、4至8元环、5至8元环或5至6元环。环烯基的非限制性实例包括但不限于环戊烯基、环戊二烯基、环己烯基、环己二烯基、环庚烯基、环庚二烯基等。所述环烯基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烷基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH2、-C(O)NH-烷基、-C(O)N(烷基)2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O)2-烷基、-S(O)2NH2、-S(O)2NH-烷基、-S(O)2N(烷基)2、环烷基、环烷基亚烷基、环烷基氧基、杂环基、杂环基亚烷基、杂环基氧基、杂环烷基、杂环烷基亚烷基、杂环烷基氧基、杂芳基、杂芳基亚烷基、杂芳基氧基、芳基、芳基亚烷基或芳基氧基。The term "cycloalkenyl" refers to a non-aromatic, incompletely saturated, cyclic, bridged or spirocyclic ring having at least one double bond. The carbocyclic ring is typically a 3- to 12-membered ring, a 3- to 10-membered ring, a 3- to 8-membered ring, a 3- to 6-membered ring, a 4- to 8-membered ring, a 5- to 8-membered ring, or a 5- to 6-membered ring. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc. The cycloalkenyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl )2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 -alkyl, -S(O) 2NH2 , -S(O) 2NH -alkyl, -S(O) 2N (alkyl) 2 , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

术语“杂环基”是指完全饱和的或部分不饱和的(但不是完全不饱和的杂芳族)并且可以以单环、桥环、并环或螺环存在的非芳族环。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧、氮、磷、硅和/或硼的杂原子(优选1或2个杂原子，优选杂原子为N、O或S)的3至12元、3至10元、3至8元、3至6元、4至8元、5至8元、6至8元、5至6元、3至7元或4至6元环。杂环基的非限制性实例包括但不限于环氧乙烷基、四氢呋喃基、二氢呋喃基、吡咯烷基、N-甲基吡咯烷基、二氢吡咯基、哌啶基、哌嗪基、吡唑烷基、4H-吡喃基、吗啉基、硫代吗啉基、四氢噻吩基等。所述杂环基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烷基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH2、-C(O)NH-烷基、-C(O)N(烷基)2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O)2-烷基、-S(O)2NH2、-S(O)2NH-烷基、-S(O)2N(烷基)2、环烷基、环烷基亚烷基、环烷基氧基、杂环基、杂环基亚烷基、杂环基氧基、杂环烷基、杂环烷基亚烷基、杂环烷基氧基、杂芳基、杂芳基亚烷基、杂芳基氧基、芳基、芳基亚烷基或芳基氧基。The term "heterocyclic radical" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and can exist as a monocyclic, bridged, cyclic or spirocyclic ring. Unless otherwise indicated, the heterocyclic ring is generally 3 to 12 yuan, 3 to 10 yuan, 3 to 8 yuan, 3 to 6 yuan, 4 to 8 yuan, 5 to 8 yuan, 6 to 8 yuan, 5 to 6 yuan, 3 to 7 yuan or 4 to 6 yuan of heteroatoms (preferably 1 or 2 heteroatoms, preferably heteroatoms are N, O or S) containing 1 to 3 independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and/or boron. Non-limiting examples of heterocyclic radicals include but are not limited to oxirane, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc. The heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 - alkyl , -S(O) 2NH2 , -S(O) 2NH -alkyl, -S(O) 2N (alkyl) 2 , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

术语“杂环烯基”是指部分不饱和的(但不是完全不饱和的杂芳族)并且可以以单环、桥环、并环或螺环存在的非芳族环。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧、氮、磷、硅和/或硼的杂原子(优选1或2个杂原子，优选杂原子为N、O或S)的3至12元、3至10元、4至8元、6至8元、4至10元、4至12元、5至7元、5至8元、5至6元、3至7元或4至6元环。杂环烯基的非限制性实例包括但不限于二氢呋喃基、二氢吡咯基、2H-吡喃基、二氢噻吩基等。所述杂环烯基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烷基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH2、-C(O)NH-烷基、-C(O)N(烷基)2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O)2-烷基、-S(O)2NH2、-S(O)2NH-烷基、-S(O)2N(烷基)2、环烷基、环烷基亚烷基、环烷基氧基、杂环基、杂环基亚烷基、杂环基氧基、杂环烷基、杂环烷基亚烷基、杂环烷基氧基、杂芳基、杂芳基亚烷基、杂芳基氧基、芳基、芳基亚烷基或芳基氧基。The term "heterocyclenyl" refers to a partially unsaturated (but not completely unsaturated heteroaromatic) non-aromatic ring that can exist as a monocycle, a bridged ring, a ring or a spirocycle. Unless otherwise indicated, the heterocycle is generally 3 to 12 yuan, 3 to 10 yuan, 4 to 8 yuan, 6 to 8 yuan, 4 to 10 yuan, 4 to 12 yuan, 5 to 7 yuan, 5 to 8 yuan, 5 to 6 yuan, 3 to 7 yuan or 4 to 6 yuan ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms, preferably heteroatoms are N, O or S) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and/or boron. Non-limiting examples of heterocyclenyl include but are not limited to dihydrofuranyl, dihydropyrrolyl, 2H-pyranyl, dihydrothienyl etc. The heterocycloalkenyl group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl )2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 -alkyl, -S(O) 2NH2 , -S(O) 2NH -alkyl, -S(O) 2N (alkyl) 2 , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

术语“杂环烷基”是指完全饱和的并且可以以单环、桥环或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧、氮、磷、硅和/或硼的杂原子(优选1或2个杂原子，优选杂原子为N、O或S)的3至12元、3至10元、3至8元、4至8元、5至8元、6至8元、5至6元、3至7元或4至6元环。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。所述杂环烷基任选地被一个或多个选自以下的取代基取代：氧代、羟基、氨基、硝基、卤素、氰基、烷基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH2、-C(O)NH-烷基、-C(O)N(烷基)2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O)2-烷基、-S(O)2NH2、-S(O)2NH-烷基、-S(O)2N(烷基)2、环烷基、环烷基亚烷基、环烷基氧基、杂环基、杂环基亚烷基、杂环基氧基、杂环烷基、杂环烷基亚烷基、杂环烷基氧基、杂芳基、杂芳基亚烷基、杂芳基氧基、芳基、芳基亚烷基或芳基氧基。 The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a 3 to 12, 3 to 10, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 5 to 6, 3 to 7 or 4 to 6 ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms, preferably N, O or S) independently selected from sulfur, oxygen, nitrogen, phosphorus, silicon and/or boron. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, thioethane, and cyclonitriles; non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, and thietanyl; examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl; examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl; examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxetanyl, and thiepanyl. The heterocycloalkyl radical is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 - alkyl , -S(O) 2NH2 , -S(O) 2NH -alkyl, -S(O) 2N (alkyl) 2 , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。例如，芳基可以具有6-20个碳原子，6-14个碳原子，6-12个碳原子或6-10个碳原子。芳基的非限制性实例包括但不限于苯基、萘基、和蒽基等。所述芳基任选地被一个或多个选自以下的取代基取代：羟基、氨基、硝基、卤素、氰基、烷基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH2、-C(O)NH-烷基、-C(O)N(烷基)2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O)2-烷基、-S(O)2NH2、-S(O)2NH-烷基、-S(O)2N(烷基)2、环烷基、环烷基亚烷基、环烷基氧基、杂环基、杂环基亚烷基、杂环基氧基、杂环烷基、杂环烷基亚烷基、杂环烷基氧基、杂芳基、杂芳基亚烷基、杂芳基氧基、芳基、芳基亚烷基或芳基氧基。The term "aryl" refers to an aromatic ring group of an all-carbon monocyclic or fused polycyclic ring having a conjugated π electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, 6-12 carbon atoms or 6-10 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl, etc. The aryl group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 - alkyl, -S(O) 2NH2 , -S(O) 2NH -alkyl, -S(O) 2N (alkyl) 2 , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

术语“杂芳基”是指单环或稠合多环的芳香体系，其中含有至少一个(例如，1、2或3个)选自N、O、S的环原子，其余环原子为C，通常具有5至14元、5至12元、5至10元、5至8元、5至7元或5至6元环。优选的杂芳基具有单个4至8元环，尤其是5至6元环，或包含5至14个，尤其是5至10个环原子的多个稠合环。杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三唑基、三嗪基、苯并呋喃基、苯并噻吩基、吲哚基、异吲哚基等。所述杂芳基任选地被一个或多个选自以下的取代基取代：羟基、氨基、硝基、卤素、氰基、烷基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、羧基、-C(O)O-烷基、-OC(O)-烷基、-C(O)NH2、-C(O)NH-烷基、-C(O)N(烷基)2、-NHC(O)-烷基、-C(O)-烷基、-S(O)-烷基、-S(O)2-烷基、-S(O)2NH2、-S(O)2NH-烷基、-S(O)2N(烷基)2、环烷基、环烷基亚烷基、环烷基氧基、杂环基、杂环基亚烷基、杂环基氧基、杂环烷基、杂环烷基亚烷基、杂环烷基氧基、杂芳基、杂芳基亚烷基、杂芳基氧基、芳基、芳基亚烷基或芳基氧基。The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic system containing at least one (e.g., 1, 2 or 3) ring atoms selected from N, O, S, and the remaining ring atoms are C, typically having 5 to 14, 5 to 12, 5 to 10, 5 to 8, 5 to 7 or 5 to 6 rings. Preferred heteroaryls have a single 4 to 8 ring, especially a 5 to 6 ring, or multiple fused rings containing 5 to 14, especially 5 to 10 ring atoms. Non-limiting examples of heteroaryls include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc. The heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O) NH2 , -C(O)NH-alkyl, -C(O)N(alkyl) 2 , -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O) 2 - alkyl, -S(O) 2NH2 , -S(O) 2NH -alkyl, -S(O) 2N (alkyl) 2 , cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

除非另有规定，术语“氘代C1-12烷基”是指上述“C1-12烷基”中任意个数和位置的H原子被氘原子取代。所述C1-12氘代烷基可以为C1-6氘代烷基或C1-3氘代烷基。氘代烷基的实例包括但不限于-CH2D、-CHD2、-CD3、 等。Unless otherwise specified, the term "deuterated C 1-12 alkyl" means that any number and position of H atoms in the above "C 1-12 alkyl" are replaced by deuterium atoms. The C 1-12 deuterated alkyl may be a C 1-6 deuterated alkyl or a C 1-3 deuterated alkyl. Examples of deuterated alkyl include, but are not limited to, -CH 2 D, -CHD 2 , -CD 3 , wait.

本公开中的基团-L1-采用从左至右或从右至左的阅读顺序，例如基团-L1-采用从左至右的阅读顺序对应的与通式中该基团连接的左侧基团及右侧基团连接，具体例如当-L1-为-S(O)2NH-时，结构为或是当-L1-为-NHS(O)2-时，结构为 The group -L 1 - in the present disclosure is read from left to right or from right to left. For example, the group -L 1 - is connected to the left and right groups connected to the group in the general formula in the reading order from left to right. For example, when -L 1 - is -S(O) 2 NH-, the structure for Or when -L 1 - is -NHS(O) 2 -, the structure for

本公开中的基团-L2-采用从右至左或从左至右的阅读顺序，例如基团-L2-采用从右至左的阅读顺序对应的与通式中该基团连接的右侧基团及左侧基团连接，具体例如当-L2-为-C(O)NH-时，结构 为 The group -L 2 - in the present disclosure is read from right to left or from left to right. For example, the group -L 2 - is read from right to left and is connected to the right side group and the left side group connected to the group in the general formula. For example, when -L 2 - is -C(O)NH-, the structure for

术语“治疗”意为将本公开所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：The term "treatment" means administering the compounds or formulations described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i)抑制疾病或疾病状态，即遏制其发展；(i) inhibiting a disease or disease state, i.e. arresting its development;

(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。(ii) ameliorating a disease or condition, even if causing regression of the disease or condition.

术语“预防”意为将本公开所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，包括预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。The term "prevention" means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, including preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本公开化合物的用量。构成“治疗有效量”的本公开化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and the present disclosure.

术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.

作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。As the pharmaceutically acceptable salt, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned.

术语“药物组合物”是指一种或多种本公开的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本公开的化合物。The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。在本文提供的一个有关方法和组合物的实施方案中，所述哺乳动物为人。Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs, etc. In one embodiment of the methods and compositions provided herein, the mammal is a human.

词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。The word "comprise" or "comprises" and its English variations such as comprises or comprising should be construed in an open and non-exclusive sense, ie, "including but not limited to".

本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

本公开还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。例如，应当理解，本公开式(I)化合物中的一个或多个氢原子被替换为氘原子的化合物，仍在本公开式(I)化合物的范围内。The present disclosure also includes isotope-labeled compounds of the present disclosure that are identical to those described herein, but one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H , 3H , 11C , 13C , 14C , 13N , 15N , 15O , 17O , 18O , 31P , 32P , 35S , 18F , 123I, 125I , and 36Cl , respectively. For example, it should be understood that compounds in which one or more hydrogen atoms in the compounds of formula (I) of the present disclosure are replaced by deuterium atoms are still within the scope of the compounds of formula (I) of the present disclosure.

某些同位素标记的本公开化合物(例如用3H及14C标记的那些)可用于化合物和/或底物组织分布分 析中。氚化(即3H)和碳-14(即14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如15O、13N、11C和18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本公开化合物。Certain isotopically-labeled compounds of the present disclosure (eg, those labeled with 3 H and 14 C) are useful in compound and/or substrate tissue distribution assays. Analysis. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O, 13 N, 11 C, and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an unlabeled reagent.

此外，用较重同位素(诸如氘(即2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, wherein deuterium substitution may be partial or full, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.

本公开化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本公开的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。立体异构体的非限制性实例包括但不限于：
The compounds of the present disclosure may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents. Non-limiting examples of stereoisomers include, but are not limited to:

本公开化合物可以具有一个或多个阻转异构体，除非另有说明，所述阻转异构体是指由于单键之间的自由旋转受阻而产生的光活性异构体。本公开的含有手性轴的化合物可以以外消旋形式被分离出来。当本公开含有手性轴化合物的单键自由旋转的能垒足够高时，其阻转异构体可以以光活性纯的形式被分离出来。The compounds of the present disclosure may have one or more atropisomers, and unless otherwise specified, the atropisomers refer to optically active isomers produced due to the obstruction of free rotation between single bonds. The compounds containing chiral axes of the present disclosure can be separated in racemic form. When the energy barrier for free rotation of single bonds of the compounds containing chiral axes of the present disclosure is high enough, the atropisomers thereof can be separated in an optically pure form.

本公开的药物组合物可通过将本公开的化合物与适宜的药学上可接受的辅料组合而制备。The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients.

本公开的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

本文所述的式(I)化合物的所有施用方法中，每天给药的剂量为0.001到2000mg/kg体重，本公开的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本公开的实施例。In all administration methods of the compound of formula (I) described herein, the daily dosage is 0.001 to 2000 mg/kg body weight. The compounds of the present disclosure can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples disclosed herein.

本公开具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本公开的化学变化及其所需的试剂和物料。为了获得本公开的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reactions of the specific embodiments of the present disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

本公开式(II-2)或式(III-2)化合物可由有机合成领域技术人员通过路线1或路线2来制备，其中，X1、X2、Y1、Y2、Z4、Z5、R1、环A、环B和环C部分如本公开定义。
The compounds of formula (II-2) or (III-2) disclosed herein can be prepared by those skilled in the art of organic synthesis via route 1 or route 2, wherein X1 , X2 , Y1 , Y2 , Z4 , Z5 , R1 , ring A, ring B and ring C are as defined herein.

路线1
Route 1

路线2Route 2

上述路线中反应所得的每一个产物可以通过传统分离技术来得到，这种传统技术包括但不限于过滤、蒸馏、结晶、色谱分离等。起始原料可以通过自己合成或从商业机构(例如，但不限于Adrich或Sigma)购买获得。这些原料可以使用常规手段进行表征，比如物理常数和光谱数据。本公开所描述的化合物可以使用合成方法得到单一的异构体或者是异构体的混合物。Each product obtained by the reaction in the above route can be obtained by conventional separation techniques, including but not limited to filtration, distillation, crystallization, chromatographic separation, etc. The starting materials can be synthesized by themselves or purchased from commercial institutions (such as, but not limited to Adrich or Sigma). These raw materials can be characterized using conventional means, such as physical constants and spectral data. The compounds described in the present disclosure can be used to obtain a single isomer or a mixture of isomers using synthetic methods.

本公开采用下述缩略词：This disclosure uses the following abbreviations:

NMP代表N-甲基吡咯烷酮；DIPEA代表二异丙基乙胺；DIEA代表二异丙基乙胺；Xant-Phos代表4,5-双(二苯基膦)-9,9-二甲基氧杂蒽；Pd2(dba)3代表三(二亚苄基丙酮)二钯；EA代表乙酸乙酯；PE代表石油醚；DMF代表N,N-二甲基甲酰胺；t-BuXPhos代表(甲磺酸(2-二叔丁基膦-2',4',6'-三异丙基-1,1'-联苯基)(2'-甲氨基-1,1'-联苯-2-基)钯(II)；DCM代表二氯甲烷；MeOH代表甲醇；Me代表甲基；Et代表乙基；DMSO代表二甲亚砜；HATU代表2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；THF代表四氢呋喃；DEAD代表偶氮二羧酸二乙酯；Boc代表叔丁氧羰基；EDCI代表1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐；DMAP代表4-二甲氨基吡啶；NBS代表N-溴代琥珀酰亚胺；PMB代表对甲氧基苄基；LiHMDS代表二(三甲基硅基)氨基锂。DAST代表二乙胺基三氟化硫；Boc2O代表二碳酸二叔丁酯；BAST代表双(2-甲氧基乙基)氨基三氟化硫；9-BBN代表9-硼杂双环[3.3.1]壬烷氢化锂；TFA代表三氟乙酸；THP代表四氢吡喃；TEMPO代表2,2,6,6-四甲基哌啶氧化物；DCE代表1,2-二氯乙烷。NMP stands for N-methylpyrrolidone; DIPEA stands for diisopropylethylamine; DIEA stands for diisopropylethylamine; Xant-Phos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Pd 2 (dba) 3 stands for tris(dibenzylideneacetone)dipalladium; EA stands for ethyl acetate; PE stands for petroleum ether; DMF stands for N,N-dimethylformamide; t-BuXPhos stands for (methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II); DCM stands for dichloromethane; MeOH stands for methanol; Me stands for methyl; Et stands for ethyl; DMSO stands for dimethyl sulfoxide; HATU stands for 2-(7- =Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; THF represents tetrahydrofuran; DEAD represents diethyl azodicarboxylate; Boc represents tert-butyloxycarbonyl; EDCI represents 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; DMAP represents 4-dimethylaminopyridine; NBS represents N-bromosuccinimide; PMB represents p-methoxybenzyl; LiHMDS represents lithium bis(trimethylsilyl)amide. DAST represents diethylaminosulfur trifluoride; Boc 2 O represents di-tert-butyl dicarbonate; BAST represents bis(2-methoxyethyl)aminosulfur trifluoride; 9-BBN represents lithium 9-borabicyclo[3.3.1]nonane hydride; TFA represents trifluoroacetic acid; THP represents tetrahydropyran; TEMPO represents 2,2,6,6-tetramethylpiperidinoxide; DCE represents 1,2-dichloroethane.

市售化合物采用供应商目录名称。Commercially available compounds were given by their supplier catalog names.

为清楚起见，进一步用实施例来阐述本发明，但是实施例并非限制本公开的范围。本文已详细描述了本公开，并公开了其具体实施例，对本领域的技术人员而言，在不脱离本公开的精神和范围的情况下针对本公开的实施例进行各种变化和改进将是显而易见的。For the sake of clarity, the present invention is further described with examples, but the examples are not intended to limit the scope of the present disclosure. The present disclosure has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications will be made to the embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

本公开所使用的所有试剂是市售的，无需进一步纯化即可使用。All reagents used in this disclosure were commercially available and used without further purification.

实施例Example

制备例A-6
Preparation Example A-6

步骤A:Step A:

100mL单口瓶中，依次加入化合物A-1(2.5g)和6-氮杂螺[2.5]辛烷盐酸盐(2.1g)，用DMSO(30mL)溶解后，加入碳酸钾(5.2g)，油浴140℃加热搅拌20h。反应结束后，冷却至室温，加入100mL水，正己烷(100mL)萃取，保留水相。水相用3N的盐酸水溶液调节pH＝6左右，抽滤，滤饼干燥得到化合物A-2(2.9g)。MS(ESI-,[M-H]-)m/z：356.16.1H NMR(500MHz,DMSO-d6)δ17.07(s,1H),8.06(d,1H),7.75(dd,1H),7.69(d,1H),3.10(t,4H),1.55(s,4H),0.41(s,4H).Compound A-1 (2.5 g) and 6-azaspiro [2.5] octane hydrochloride (2.1 g) were added to a 100 mL single-mouth bottle in sequence, dissolved with DMSO (30 mL), and potassium carbonate (5.2 g) was added. The mixture was heated and stirred in an oil bath at 140 ° C for 20 h. After the reaction was completed, the mixture was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with n-hexane (100 mL), and the aqueous phase was retained. The aqueous phase was adjusted to pH = 6 with 3N hydrochloric acid aqueous solution, filtered, and the filter cake was dried to obtain compound A-2 (2.9 g). MS(ESI-,[MH] - )m/z: 356.16. 1 H NMR(500MHz, DMSO-d 6 )δ17.07(s,1H),8.06(d,1H),7.75(dd,1H),7.69(d,1H),3.10(t,4H),1.55(s,4H),0.41(s,4H).

步骤B:Step B:

100mL单口瓶中，依次加入化合物A-2(1g)和碳酸钾(0.774g)，用DMF(20mL)溶解后，加入碘甲烷(0.795g)，在室温搅拌反应15h。反应结束后向反应液中加入50mL水，EA(100mL)萃取，饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：PE/EA＝10/1)纯化，得到化合物A-3(0.916g)。MS(ESI+,[M+H]+)m/z：371.99.In a 100mL single-mouth bottle, add compound A-2 (1g) and potassium carbonate (0.774g) in turn, dissolve with DMF (20mL), add iodomethane (0.795g), and stir at room temperature for 15h. After the reaction is completed, add 50mL of water to the reaction solution, extract with EA (100mL), wash with saturated brine (50mL×2), and dry with anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent: PE/EA＝10/1) to obtain compound A-3 (0.916g). MS (ESI+, [M+H] + ) m/z: 371.99.

步骤C:Step C:

250mL单口瓶中，依次加入化合物A-3(0.916g)、2-羟基-1-磺酰胺(0.556g)、氯化烯丙基钯(II)二聚物(0.044g)、t-BuXPhos(0.105g)和碳酸钾(0.682g)，用二氧六环(20mL)溶解，氮气保护下，在100℃下加热反应4h。反应结束后向反应液中加入50mL水，EA(100mL)萃取，饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：PE/EA＝1/1)纯化，得到化合物A-4(0.525g)。MS(ESI+,[M+H]+)m/z：369.14.1H NMR(500MHz,DMSO-d6)δ10.00(s,1H),7.59(d,1H),6.91(d,1H),6.77(dd,1H),4.91(t,1H),3.76(s,3H),3.75–3.71(m,2H),3.31–3.29(m,2H),2.99–2.94(m,4H),1.48–1.43(m,4H),0.32(s,4H).Compound A-3 (0.916 g), 2-hydroxy-1-sulfonamide (0.556 g), allylpalladium chloride (II) dimer (0.044 g), t-BuXPhos (0.105 g) and potassium carbonate (0.682 g) were added to a 250 mL single-mouth bottle in sequence, dissolved with dioxane (20 mL), and heated at 100 ° C for 4 h under nitrogen protection. After the reaction, 50 mL of water was added to the reaction solution, extracted with EA (100 mL), washed with saturated brine (50 mL × 2), and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE/EA = 1/1) to obtain compound A-4 (0.525 g). MS(ESI+,[M+H] + )m/z: 369.14. 1 H NMR (500MHz, DMSO-d 6 )δ10.00(s,1H),7.59(d,1H),6.91(d,1H),6.77(dd,1H),4.91(t,1H),3.76(s,3H),3. 75–3.71(m,2H),3.31–3.29(m,2H),2.99–2.94(m,4H),1.48–1.43(m,4H),0.32(s,4H).

步骤D:Step D:

50mL单口瓶中，依次加入化合物A-4(0.525g)、甲醇(16mL)、氢氧化锂一水合物(0.269g)和蒸馏水(4mL)，在60℃下加热反应36h。反应结束后，减压蒸除溶剂，加入蒸馏水(20mL)，在冰浴下搅拌，然后滴加1N稀盐酸(9mL)调节体系pH至2-3左右，冰浴下继续搅拌10min后静置。抽滤，滤饼干燥后得到化合物A-5(0.413g)。MS(ESI+,[M+H]+)m/z：355.10.1H NMR(500MHz,DMSO-d6)δ16.89(s,1H),10.26(s,1H),7.96(d,1H),7.35(d,1H),7.17(dd,1H),5.05–4.80(m,1H),3.79–3.72(m,2H),3.36(t,2H),3.01(t,4H),1.68–1.44(m,4H),0.43(s,4H).Compound A-4 (0.525 g), methanol (16 mL), lithium hydroxide monohydrate (0.269 g) and distilled water (4 mL) were added to a 50 mL single-mouth bottle in sequence, and heated at 60 ° C for 36 h. After the reaction, the solvent was evaporated under reduced pressure, distilled water (20 mL) was added, and the mixture was stirred in an ice bath, and then 1N dilute hydrochloric acid (9 mL) was added dropwise to adjust the pH of the system to about 2-3, and the mixture was stirred for 10 min in an ice bath and then allowed to stand. Filtered with suction, the filter cake was dried to obtain compound A-5 (0.413 g). MS(ESI+,[M+H] + )m/z: 355.10. 1 H NMR (500MHz, DMSO-d 6 )δ16.89(s,1H),10.26(s,1H),7.96(d,1H),7.35(d,1H),7.17(dd,1H),5.05–4.80( m,1H),3.79–3.72(m,2H),3.36(t,2H),3.01(t,4H),1.68–1.44(m,4H),0.43(s,4H).

步骤E:Step E:

100mL单口瓶中，依次加入化合物A-5(0.413g)、氯化铵(0.623g)和HATU(0.886g)，用DMF(15mL)溶解后加入DIPEA(1.506g)，在室温搅拌反应1h。反应结束后向反应液中加入200mL水，EA(300mL)萃取，分别用饱和碳酸氢钠溶液(100mL×2)与饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：DCM/MeOH＝20/1)纯化，得到化合物A-6(0.224g)。MS(ESI+,[M+H]+)m/z：354.41.1H NMR(500MHz,DMSO-d6)δ9.96(s,1H),8.59(d,1H),7.74(d,1H),7.45(d,1H),7.06(d,1H),6.93(dd,1H),4.91(t,1H),3.77–3.71(m,2H),3.31–3.28(m,2H),2.90(t,4H),1.51(t,4H),0.35(s,4H).Compound A-5 (0.413 g), ammonium chloride (0.623 g) and HATU (0.886 g) were added to a 100 mL single-mouth bottle in sequence, dissolved in DMF (15 mL), and DIPEA (1.506 g) was added. The mixture was stirred at room temperature for 1 h. After the reaction, 200 mL of water was added to the reaction solution, extracted with EA (300 mL), washed with saturated sodium bicarbonate solution (100 mL × 2) and saturated brine (100 mL × 2), respectively, and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM/MeOH = 20/1) to obtain compound A-6 (0.224 g). MS(ESI+,[M+H] + )m/z: 354.41. 1 H NMR (500MHz, DMSO-d 6 )δ9.96(s,1H),8.59(d,1H),7.74(d,1H),7.45(d,1H),7.06(d,1H),6.93(dd,1H),4.9 1(t,1H),3.77–3.71(m,2H),3.31–3.28(m,2H),2.90(t,4H),1.51(t,4H),0.35(s,4H).

制备例B-2
Preparation Example B-2

步骤A：Step A:

-78℃，氮气保护下，向DAST(3.58g)中加入B-1(2.6g)的DCM(100mL)溶液，反应液在氮气保护下于-78℃搅拌2小时后恢复至室温搅拌过夜。反应结束，反应液倒入冰水(100mL)中，混合物使用饱和碳酸氢钠水溶液调节pH＝8-9后使用DCM(80ml×3)萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(洗脱剂：PE/EA＝20/1)纯化，得到化合物B-2(2.0g)。1H NMR(500MHz,Chloroform-d)δ5.16–4.83(m,1H),4.13(d,1H),3.75(s,3H),3.31-2.19(m,1H),2.80–2.62(m,1H), 2.21–1.96(m,2H),1.97–1.78(m,1H),1.51–1.43(m,9H).-78 ℃, under nitrogen protection, add DAST (3.58g) DCM (100mL) solution of B-1 (2.6g), the reaction solution was stirred at -78 ℃ under nitrogen protection for 2 hours and then returned to room temperature and stirred overnight. After the reaction was completed, the reaction solution was poured into ice water (100mL), the mixture was adjusted to pH = 8-9 with saturated sodium bicarbonate aqueous solution, and then extracted with DCM (80ml×3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE/EA=20/1) to obtain compound B-2 (2.0g). 1 H NMR (500MHz, Chloroform-d) δ5.16–4.83 (m, 1H), 4.13 (d, 1H), 3.75 (s, 3H), 3.31-2.19 (m, 1H), 2.80–2.62 (m, 1H), 2.21–1.96(m,2H),1.97–1.78(m,1H),1.51–1.43(m,9H).

制备例C-5
Preparation Example C-5

步骤A:Step A:

依次向反应瓶中加入C-1(10g)和THF(100mL)，N2保护，混合物在冰浴条件下搅拌，滴加Boc2O(21g)，然后滴加1M乙烯基溴化镁四氢呋喃溶液(101mL)。撤去冰浴，在室温搅拌反应20h。反应结束后，冰浴下向反应瓶中加入1N稀盐酸(160mL)，并继续在冰浴下搅拌20min。EA(200mL)萃取，分别用饱和碳酸氢钠溶液(50mL×2)和饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，所得粗品经硅胶柱层析(洗脱剂：PE/EA＝10/1)纯化，得到C-2(7.1g)。1H NMR(500MHz,DMSO-d6)δ7.82(dd,1H),5.77(ddd,1H),5.21–5.15(m,2H),5.02–4.97(m,2H),2.95(dd,1H),2.40–2.36(m,1H),1.48(s,9H).C-1 (10 g) and THF (100 mL) were added to the reaction flask in sequence, and N2 was protected. The mixture was stirred under ice bath conditions, and Boc2O (21 g) was added dropwise, and then 1M vinylmagnesium bromide tetrahydrofuran solution (101 mL) was added dropwise. The ice bath was removed, and the reaction was stirred at room temperature for 20 h. After the reaction was completed, 1N dilute hydrochloric acid (160 mL) was added to the reaction flask under ice bath, and the stirring was continued under ice bath for 20 min. EA (200 mL) was extracted, and the mixture was washed with saturated sodium bicarbonate solution (50 mL × 2) and saturated brine (50 mL × 2), respectively, and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA = 10/1) to obtain C-2 (7.1 g). 1 H NMR (500MHz, DMSO-d 6 ) δ7.82(dd,1H),5.77(ddd,1H),5.21–5.15(m,2H),5.02–4.97(m,2H),2.95(dd,1H),2.40–2.36(m,1H),1.48(s,9H).

步骤B:Step B:

250mL单口瓶中，依次加入C-2(3g)，乙酸(35mL)以及锌粉(4.4g)，氮气保护下加热至70℃反应4h。反应结束后，抽滤，滤液用乙酸乙酯(300mL)稀释，加入蒸馏水(600mL)，边搅拌边加入碳酸氢钠固体调节体系pH至7-8左右。分液，取有机相，分别用饱和碳酸氢钠溶液(100mL×2)和饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，所得粗品经硅胶柱层析(洗脱剂：PE/EA＝10/1)纯化，得到C-3(2g)。1H NMR(500MHz,DMSO-d6)δ5.78(ddd,1H),5.20–5.16(m,1H),5.07–5.02(m,1H),4.98–4.85(m,1H),4.00–3.94(m,1H),3.33–3.27(m,1H),2.80(dd,1H),2.48–2.41(m,2H),2.25–2.19(m,1H),1.42(s,9H).In a 250mL single-mouth bottle, add C-2 (3g), acetic acid (35mL) and zinc powder (4.4g) in sequence, and heat to 70℃ under nitrogen protection for 4h. After the reaction is completed, filter, dilute the filtrate with ethyl acetate (300mL), add distilled water (600mL), and add sodium bicarbonate solid while stirring to adjust the pH of the system to about 7-8. Separate the liquid, take the organic phase, wash it with saturated sodium bicarbonate solution (100mL×2) and saturated brine (100mL×2), respectively, and dry it over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (eluent: PE/EA＝10/1) to obtain C-3 (2g). 1 H NMR (500MHz, DMSO-d 6 )δ5.78(ddd,1H),5.20–5.16(m,1H),5.07–5.02(m,1H),4.98–4.85(m,1H),4.00–3.94(m, 1H),3.33–3.27(m,1H),2.80(dd,1H),2.48–2.41(m,2H),2.25–2.19(m,1H),1.42(s,9H).

步骤C:Step C:

250mL单口瓶中，将C-3(1.59g)溶解于DCM(24mL)后在冰浴下搅拌，加入BAST(2.21mL)以及乙醇(0.08mL)。之后逐渐恢复至室温搅拌反应16h。反应结束后，EA(100mL)萃取，分别用饱和碳酸氢钠溶液(50mL×2)与饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，所得粗品经硅胶柱层析(洗脱剂：PE/EA＝20/1)纯化，得到C-4(0.89g)。1H NMR(500MHz,DMSO-d6)δ5.88–5.77(m,1H),5.16–5.10(m,1H),5.00–4.94(m,1H),4.91–4.83(m,1H),4.04–3.97(m,1H),3.01–2.93(m,1H),2.20–2.09(m,2H),2.01–1.82(m,2H),1.40(s,9H).In a 250mL single-mouth bottle, C-3 (1.59 g) was dissolved in DCM (24 mL) and stirred under an ice bath, and BAST (2.21 mL) and ethanol (0.08 mL) were added. Then the temperature was gradually restored to room temperature and stirred for 16 hours. After the reaction was completed, EA (100 mL) was extracted, washed with saturated sodium bicarbonate solution (50 mL × 2) and saturated brine (50 mL × 2), respectively, and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA = 20/1) to obtain C-4 (0.89 g). 1 H NMR (500MHz, DMSO-d 6 )δ5.88–5.77(m,1H),5.16–5.10(m,1H),5.00–4.94(m,1H),4.91–4.83(m,1H),4.04 –3.97(m,1H),3.01–2.93(m,1H),2.20–2.09(m,2H),2.01–1.82(m,2H),1.40(s,9H).

步骤D:Step D:

250mL两口瓶中，将C-4(0.86g)溶解于THF(35mL)，氮气保护，冰浴下搅拌。加入0.5M 9-BBN的四氢呋喃溶液(20.8mL)，然后撤去冰浴在室温搅拌2.5h。滴加蒸馏水(40mL)，然后加入过硼酸钠四水合物(5.35g)，并在室温下搅拌反应16h。反应结束后，抽滤，滤液用EA(100mL)稀释，分别用饱和碳酸氢钠溶液(50mL×2)与饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，所得粗品经硅胶柱层析(洗脱剂：PE/EA＝10/1)纯化，得到C-5(0.9g)。1H NMR(500MHz,DMSO-d6)δ4.48–4.42(m,1H),4.39(t,1H),4.05–3.98(m,1H),3.41–3.34(m,2H),2.98–2.88(m,1H),2.04–1.93(m,3H),1.88–1.70(m,2H),1.66–1.59(m,1H),1.40(s,9H).In a 250mL two-necked flask, C-4 (0.86g) was dissolved in THF (35mL), and stirred under nitrogen protection in an ice bath. A 0.5M 9-BBN tetrahydrofuran solution (20.8mL) was added, and then the ice bath was removed and stirred at room temperature for 2.5h. Distilled water (40mL) was added dropwise, and then sodium perborate tetrahydrate (5.35g) was added, and the reaction was stirred at room temperature for 16h. After the reaction was completed, the filtrate was filtered, and the filtrate was diluted with EA (100mL), washed with saturated sodium bicarbonate solution (50mL×2) and saturated brine (50mL×2), respectively, and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA＝10/1) to obtain C-5 (0.9g). 1 H NMR (500MHz, DMSO-d 6 )δ4.48–4.42(m,1H),4.39(t,1H),4.05–3.98(m,1H),3.41–3.34(m,2H),2.98–2. 88(m,1H),2.04–1.93(m,3H),1.88–1.70(m,2H),1.66–1.59(m,1H),1.40(s,9H).

制备例D-4
Preparation Example D-4

步骤A：Step A:

参考制备例A-6的步骤A，以3-氮杂螺[双环[3.2.1]辛烷-8,1'-环丙烷]盐酸盐代替6-氮杂螺[2.5]辛烷盐酸盐，制备得到化合物D-1(2.2g)。MS(ESI+,[M+H]+)m/z：384.15.Referring to step A of Preparation Example A-6, 3-azaspiro[bicyclo[3.2.1]octane-8,1'-cyclopropane] hydrochloride was used instead of 6-azaspiro[2.5]octane hydrochloride to prepare compound D-1 (2.2 g). MS (ESI+, [M+H] + ) m/z: 384.15.

步骤B：Step B:

参考制备例A-6的步骤B，以化合物D-1代替化合物A-2，制备得到化合物D-2(1.5g)。MS(ESI+,[M+H]+)m/z：398.18.Referring to step B of Preparation Example A-6, Compound D-1 was used instead of Compound A-2 to prepare Compound D-2 (1.5 g). MS (ESI+, [M+H] + ) m/z: 398.18.

步骤C：Step C:

参考制备例A-6的步骤C，以甲基磺酰胺代替2-羟基-1-磺酰胺，制备得到化合物D-3(0.54g)。MS(ESI+,[M+H]+)m/z：365.27.Referring to step C of preparation example A-6, methylsulfonamide was used instead of 2-hydroxy-1-sulfonamide to prepare compound D-3 (0.54 g). MS (ESI+, [M+H] + ) m/z: 365.27.

步骤D：Step D:

30mL微波管中，依次加入化合物D-3(450mg)，甲醇(5mL)和氨水(5mL)，90℃微波加热5h。反应结束，反应液减压旋蒸浓缩后加30mL水，乙酸乙酯(15mL×3)萃取，合并有机相，30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析(洗脱剂DCM/MeOH＝30/1)纯化，得到化合物D-4(147mg)。MS(ESI+,[M+H]+)m/z：350.25.1H NMR(500MHz,DMSO-d6)δ9.87(s,1H),8.31(s,1H),7.53(d,1H),7.49(s,1H),7.05(d,1H),6.91(dd,1H),3.02(s,3H),3.01–2.86(m,4H),1.93–1.74(m,4H),1.48–1.38(m,2H),0.66–0.56(m,2H),0.44–0.32(m,2H).Compound D-3 (450 mg), methanol (5 mL) and aqueous ammonia (5 mL) were added to a 30 mL microwave tube in sequence and heated at 90 ° C for 5 h. After the reaction was completed, the reaction solution was concentrated by rotary evaporation under reduced pressure, and 30 mL of water was added. The mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent DCM/MeOH=30/1) to obtain compound D-4 (147 mg). MS(ESI+,[M+H] + )m/z: 350.25. 1 H NMR (500MHz, DMSO-d 6 )δ9.87(s,1H),8.31(s,1H),7.53(d,1H),7.49(s,1H),7.05(d,1H),6.91(dd,1H),3.02(s,3H), 3.01–2.86(m,4H),1.93–1.74(m,4H),1.48–1.38(m,2H),0.66–0.56(m,2H),0.44–0.32(m,2H).

制备例E-4
Preparation Example E-4

步骤A：Step A:

参考制备例A-6的步骤A，以(1R，5S)-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丙烷]盐酸盐代替6-氮杂螺[2.5]辛烷盐酸盐，制备得到化合物E-1(7.2g)。MS(ESI+,[M+H]+)m/z：384.15.Referring to step A of preparation example A-6, (1R, 5S)-8-azaspiro[bicyclo[3.2.1]octane-3,1'-cyclopropane] hydrochloride was used instead of 6-azaspiro[2.5]octane hydrochloride to prepare compound E-1 (7.2 g). MS (ESI+, [M+H] + ) m/z: 384.15.

步骤B：Step B:

参考制备例A-6的步骤B，以化合物E-1代替化合物A-2，制备得到化合物E-2(5.5g)。MS(ESI+,[M+H]+)m/z：398.18.Referring to step B of Preparation Example A-6, Compound E-1 was used instead of Compound A-2 to prepare Compound E-2 (5.5 g). MS (ESI+, [M+H] + ) m/z: 398.18.

步骤C：Step C:

参考制备例A-6的步骤C，以甲基磺酰胺代替2-羟基-1-磺酰胺，制备得到化合物E-3(0.97g)。MS(ESI+,[M+H]+)m/z：365.27.Referring to step C of preparation example A-6, methylsulfonamide was used instead of 2-hydroxy-1-sulfonamide to prepare compound E-3 (0.97 g). MS (ESI+, [M+H] + ) m/z: 365.27.

步骤D：Step D:

参考制备例D-4的步骤D，以E-3代替D-3，制备得到化合物E-4(0.28g)。MS(ESI+,[M+H]+)m/z：350.25.1H NMR(500MHz,DMSO-d6)δ13.79(s,1H),9.78(s,1H),7.59–7.32(m,2H),6.84(d,1H),6.81–6.66(m,1H),3.88(t,2H),3.01(s,3H),2.29–2.15(m,2H),1.94(d,2H),1.92–1.75(m,2H),0.89(dd,2H),0.56(dd,2H),0.13–0.07(m,2H).Referring to step D of Preparation Example D-4, E-3 was used instead of D-3 to prepare compound E-4 (0.28 g). MS (ESI+, [M+H] + ) m/z: 350.25. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.79 (s, 1H), 9.78 (s, 1H), 7.59–7.32 (m, 2H), 6.84 (d, 1H), 6.81–6.66 (m, 1H), 3.88 (t, 2H), 3.01 (s, 3H), 2.29–2.15 (m, 2H), 1.94 (d, 2H), 1.92–1.75 (m, 2H), 0.89 (dd, 2H), 0.56 (dd, 2H), 0.13–0.07 (m, 2H).

实施例1
Example 1

步骤A：Step A:

向50mL单口瓶中，依次加入化合物1-1(1.2g)，DMSO(10mL)，2-哌啶甲醇(0.713g)和DIPEA(3.24mL)，氮气保护下，加热至120℃反应2h。反应结束后，加入蒸馏水(20mL)，乙酸乙酯(20ml×3)萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(洗脱剂：PE/EA＝4/1)纯化，得到化合物1-2(600mg)。MS(ESI+,[M+H]+)m/z：288.88.1H NMR(500MHz,DMSO-d6)δ7.79(d,1H),7.02(dd,1H),4.60(t,1H),4.19–4.10(m,1H),3.78(d,1H),3.63-3.57(m,2H),3.10-3.05(m,1H),1.81-1.77(m,1H),1.67–1.54(m,4H),1.51-1.45(m,1H).Compound 1-1 (1.2 g), DMSO (10 mL), 2-piperidinemethanol (0.713 g) and DIPEA (3.24 mL) were added to a 50 mL single-mouth bottle in sequence, and heated to 120 ° C for 2 h under nitrogen protection. After the reaction, distilled water (20 mL) was added, ethyl acetate (20 ml × 3) was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE/EA = 4/1) to obtain compound 1-2 (600 mg). MS(ESI+,[M+H] + )m/z: 288.88. 1 H NMR (500MHz, DMSO-d 6 )δ7.79(d,1H),7.02(dd,1H),4.60(t,1H),4.19–4.10(m,1H),3.78(d,1H),3.63-3.5 7(m,2H),3.10-3.05(m,1H),1.81-1.77(m,1H),1.67–1.54(m,4H),1.51-1.45(m,1H).

步骤B：Step B:

向100mL单口瓶中，依次加入化合物1-2(600mg)、叔丁醇(10mL)及叔丁醇钾(815mg)，N2保护下，加热至80℃反应2h。反应结束后，冷却至室温，减压蒸除溶剂，加入蒸馏水(20mL)与乙酸乙酯(20mL)，有机相分离，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(洗脱剂：PE/EA＝9/1)纯化，得到化合物1-3(400mg)。MS(ESI+,[M+H]+)m/z：268.87.1H NMR(500MHz,DMSO-d6)δ7.54(d,1H),6.82(d,1H),4.56–4.51(m,1H),4.33(dd,1H),3.95(dd,1H),3.30–3.23(m,1H),2.60-2.54(m,1H),1.81(d,1H),1.71(t,2H),1.49–1.35(m,2H),1.22–1.11(m,1H).Compound 1-2 (600 mg), tert-butyl alcohol (10 mL) and potassium tert-butylate (815 mg) were added to a 100 mL single-mouth bottle in sequence, and heated to 80 ° C for 2 h under N 2 protection. After the reaction was completed, it was cooled to room temperature, the solvent was evaporated under reduced pressure, distilled water (20 mL) and ethyl acetate (20 mL) were added, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE/EA=9/1) to obtain compound 1-3 (400 mg). MS(ESI+,[M+H] + )m/z: 268.87. 1 H NMR (500MHz, DMSO-d 6 )δ7.54(d,1H),6.82(d,1H),4.56–4.51(m,1H),4.33(dd,1H),3.95(dd,1H),3.30–3.23(m ,1H),2.60-2.54(m,1H),1.81(d,1H),1.71(t,2H),1.49–1.35(m,2H),1.22–1.11(m,1H).

步骤C：Step C:

向50mL单口瓶中，依次加入化合物A-6(0.050g)、Pd2(dba)3(5.18mg)、Xant-Phos(8.21mg)、溶于二氧六环(6mL)的化合物1-3(0.038g)和碳酸铯(0.138g)，N2保护下，加热至100℃反应12h。反应结束后，过滤，减压浓缩，硅胶柱层析(洗脱剂：DCM/MeOH＝20/1)纯化，得到化合物1(20mg)。1H NMR(500MHz,DMSO-d6)δ11.82(s,1H),10.17(s,1H),7.97(d,1H),7.86(d,1H),7.67(d,1H),7.22(d,1H),7.07(dd,1H),4.92(s,1H),4.57(d,1H),4.34(dd,1H),4.01(dd,1H),3.75(t,2H),3.35(t,2H),3.30–3.25(m,1H),2.98–2.89(m,4H),2.60–2.54(m,1H),1.83(d,1H),1.71(t,2H),1.57(s,4H),1.49–1.38(m,2H),1.27-1.24(m,1H),0.37(s,4H).HRMS(ESI+,[M+H]+)m/z：542.2445.Compound A-6 (0.050 g), Pd 2 (dba) 3 (5.18 mg), Xant-Phos (8.21 mg), compound 1-3 (0.038 g) dissolved in dioxane (6 mL) and cesium carbonate (0.138 g) were added to a 50 mL single-mouth bottle in sequence. The mixture was heated to 100°C for 12 h under N 2 protection. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM/MeOH=20/1) to obtain compound 1 (20 mg). 1 H NMR (500 MHz, DMSO-d 6 )δ11.82(s,1H),10.17(s,1H),7.97(d,1H),7.86(d,1H),7.67(d,1H),7.22(d,1H),7. 07(dd,1H),4.92(s,1H),4.57(d,1H),4.34(dd,1H),4.01(dd,1H),3.75(t,2H),3.35( t,2H),3.30–3.25(m,1H),2.98–2.89(m,4H),2.60–2.54(m,1H),1.83(d,1H),1.71(t, 2H),1.57(s,4H),1.49–1.38(m,2H),1.27-1.24(m,1H),0.37(s,4H).HRMS(ESI+,[M+H] + )m/z：542.2445.

实施例2
Example 2

步骤A：Step A:

向250mL三口瓶中依次加入化合物2-1(1.37g)、N-叔丁氧羰基-2-哌啶-2-基乙醇(1.50g)、THF(50mL)、三苯基膦(2.06g)，冰浴且在N2保护下缓慢滴加DEAD(1.37g)的THF(5mL)溶液，加毕，室温搅拌反应15h。向反应液中加入100mL水，乙酸乙酯(3×100mL)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(PE/EA＝20/1)纯化得到化合物2-2(2.72g)。MS(ESI+,[M+H]+)m/z：385.94.1H NMR(500MHz,DMSO-d6)δ8.44(d,1H),7.99(d,1H),4.31(s,1H),4.17(d,1H),4.12–4.01(m,1H),3.83(d,1H),2.80(d,1H),2.13-2.09(m,1H),1.93-1.90(m,1H),1.62–1.50(m,5H),1.36(s,9H),1.29–1.24(m, 1H).Compound 2-1 (1.37 g), N-tert-butyloxycarbonyl-2-piperidin-2-ylethanol (1.50 g), THF (50 mL), and triphenylphosphine (2.06 g) were added to a 250 mL three-necked flask in sequence, and a solution of DEAD (1.37 g) in THF (5 mL) was slowly added dropwise under N 2 protection in an ice bath. After the addition, the mixture was stirred at room temperature for 15 h. 100 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EA=20/1) to obtain compound 2-2 (2.72 g). MS (ESI+, [M+H] + )m/z: 385.94. 1 H NMR (500MHz, DMSO-d 6 )δ8.44(d,1H),7.99(d,1H),4.31(s,1H),4.17(d,1H),4.12–4.01(m,1H),3.83(d,1H),2.80 (d,1H),2.13-2.09(m,1H),1.93-1.90(m,1H),1.62–1.50(m,5H),1.36(s,9H),1.29–1.24(m, 1H).

步骤B：Step B:

向100mL单口瓶中依次加入化合物2-2(2.20g)、乙酸乙酯(20mL)和HCl的乙酸乙酯溶液(4M,12mL)，室温搅拌反应1.5h，浓缩反应液得到化合物2-3(1.7g)。MS(ESI+,[M+H]+)m/z：285.94.Compound 2-2 (2.20 g), ethyl acetate (20 mL) and ethyl acetate solution of HCl (4 M, 12 mL) were added to a 100 mL single-necked bottle in sequence, stirred at room temperature for 1.5 h, and the reaction solution was concentrated to obtain compound 2-3 (1.7 g). MS (ESI+, [M+H] + ) m/z: 285.94.

步骤C：Step C:

向100mL单口瓶中依次加入化合物2-3(1.7g)、NMP(50mL)和DIEA(1.8g)，加热至50℃反应12h，反应结束后，向反应液中加入100mL蒸馏水，乙酸乙酯(3×100mL)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(PE/EA＝10/1)纯化得到化合物2-4(330mg)。MS(ESI+,[M+H]+)m/z：250.02.1H NMR(500MHz,DMSO-d6)δ8.02(d,1H),7.13(d,1H),4.33-4.30(m,1H),4.26-4.21(m,1H),3.92-3.89(m,1H),3.43-3.40(m,1H),3.06-3.01(m,1H),2.16-2.12(m,1H),1.96-1.91(m,1H),1.88–1.79(m,1H),1.65–1.51(m,5H).Compound 2-3 (1.7 g), NMP (50 mL) and DIEA (1.8 g) were added to a 100 mL single-necked bottle in sequence, and the mixture was heated to 50°C for 12 h. After the reaction, 100 mL of distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE/EA=10/1) to obtain compound 2-4 (330 mg). MS(ESI+,[M+H] + )m/z: 250.02. 1 H NMR (500MHz, DMSO-d 6 )δ8.02(d,1H),7.13(d,1H),4.33-4.30(m,1H),4.26-4.21(m,1H),3.92-3.89(m,1H),3.43-3.40(m, 1H),3.06-3.01(m,1H),2.16-2.12(m,1H),1.96-1.91(m,1H),1.88–1.79(m,1H),1.65–1.51(m,5H).

步骤D:Step D:

向100mL单口瓶中依次加入化合物2-4(320mg)、甲醇(20mL)、氯化铵(687mg)、蒸馏水(5mL)和铁粉(720mg)，加热至70℃反应3h，反应结束后，抽滤，滤饼用100mL乙酸乙酯洗涤，有机相浓缩得到化合物2-5(270mg)。MS(ESI+,[M+H]+)m/z：220.04.1H NMR(500MHz,DMSO-d6)δ7.42(d,1H),6.14(d,1H),5.36(s,2H),4.10(dd,2H),3.62-3.59(m,1H),3.23-3.20(m,1H),3.00-2.97(m,1H),1.97–1.89(m,1H),1.86–1.72(m,2H),1.58–1.44(m,5H).Compound 2-4 (320 mg), methanol (20 mL), ammonium chloride (687 mg), distilled water (5 mL) and iron powder (720 mg) were added to a 100 mL single-necked bottle in sequence, and heated to 70 °C for 3 h. After the reaction was completed, the filter was filtered, the filter cake was washed with 100 mL of ethyl acetate, and the organic phase was concentrated to obtain compound 2-5 (270 mg). MS(ESI+,[M+H] + )m/z: 220.04. 1 H NMR (500MHz, DMSO-d 6 )δ7.42(d,1H),6.14(d,1H),5.36(s,2H),4.10(dd,2H),3.62-3.59(m,1H),3.23-3.2 0(m,1H),3.00-2.97(m,1H),1.97–1.89(m,1H),1.86–1.72(m,2H),1.58–1.44(m,5H).

步骤E:Step E:

向50mL单口瓶中依次加入化合物2-5(220mg)、化合物A-2(135mg)、1,2-二氯乙烷(15mL)、EDCI(240mg)和DMAP(150mg)，加热至70℃反应5h，反应结束后，反应液浓缩，硅胶柱层析(PE:EA＝10:1)纯化得到化合物2-6(150mg)。MS(ESI+,[M+H]+)m/z：559.18.1H NMR(500MHz,DMSO-d6)δ11.41(s,1H),7.96(d,1H),7.81(d,1H),7.68–7.64(m,2H),7.64–7.61(m,1H),4.42–4.28(m,2H),3.51-3.48(m,1H),3.35-3.31(m,1H),3.27-3.23(m,1H),2.99(t,4H),2.03-2.00(m,1H),1.98–1.90(m,1H),1.79–1.71(m,1H),1.69–1.48(m,9H),0.34(s,4H).Compound 2-5 (220 mg), compound A-2 (135 mg), 1,2-dichloroethane (15 mL), EDCI (240 mg) and DMAP (150 mg) were added to a 50 mL single-necked bottle in sequence, and heated to 70 °C for 5 h. After the reaction, the reaction solution was concentrated and purified by silica gel column chromatography (PE:EA=10:1) to obtain compound 2-6 (150 mg). MS (ESI+, [M+H] + )m/z: 559.18. 1 H NMR (500MHz, DMSO-d 6 )δ11.41(s,1H),7.96(d,1H),7.81(d,1H),7.68–7.64(m,2H),7.64–7.61(m,1H),4.42–4.28(m,2H),3.51-3.48(m,1H),3.35-3.31 (m,1H),3.27-3.23(m,1H),2.99(t,4H),2.03-2.00(m,1H),1.98–1.90(m,1H),1.79–1.71(m,1H),1.69–1.48(m,9H),0.34(s,4H).

步骤F:Step F:

向50mL单口瓶中，依次加入化合物2-6(120mg)、2-羟基-1-磺酰胺(50mg)、二氧六环(10mL)、碳酸钾(55.2mg)、氯化烯丙基钯(II)二聚物(4.93mg)、t-BuXPhos(8.48mg)，N2保护下，加热至100℃反应4h。反应结束后，冷却至室温，过滤，滤液浓缩，硅胶柱层析(DCM/MeOH＝20/1)纯化，得到化合物2(40mg)。1H NMR(500MHz,DMSO-d6)δ11.51(s,1H),7.99(d,1H),7.90(d,1H),7.80(d,1H),7.18(d,1H),7.03(dd,1H),4.42–4.28(m,2H),3.76(t,2H),3.49-3.44(m,1H),3.34(t,3H),3.30–3.26(m,3H),2.95(t,4H),2.10–1.90(m,2H),1.78–1.72(m,1H),1.70–1.45(m,9H),0.35(s,4H).HRMS(ESI+,[M+H]+)m/z：556.2595.Compound 2-6 (120 mg), 2-hydroxy-1-sulfonamide (50 mg), dioxane (10 mL), potassium carbonate (55.2 mg), allylpalladium (II) chloride dimer (4.93 mg), t-BuXPhos (8.48 mg) were added to a 50 mL single-mouth bottle in sequence, and heated to 100 ° C for 4 h under N 2 protection. After the reaction was completed, it was cooled to room temperature, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain compound 2 (40 mg). 1 H NMR (500MHz, DMSO-d 6 )δ11.51(s,1H),7.99(d,1H),7.90(d,1H),7.80(d,1H),7.18(d,1H),7.03(dd,1H),4.42–4.28(m,2H),3.76(t,2H),3.49-3.44(m,1H) ,3.34(t,3H),3.30–3.26(m,3H),2.95(t,4H),2.10–1.90(m,2H),1.78–1.72(m,1H),1.70–1.45(m,9H),0.35(s,4H).HRMS(ESI+,[M+H] + )m/z：556.2595.

实施例3
Example 3

步骤A:Step A:

100mL单口瓶中依次加入化合物3-1(1g)、乙腈(20mL)和NBS(3.34g)，在氮气保护下，室温搅拌反应18小时。反应结束后向反应液中加入50mL蒸馏水，EA(100mL)萃取，饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：PE/EA＝20/1)纯化，得到化合物3-2(0.8g)。1H NMR(500MHz,DMSO-d6)δ10.00(s,1H),7.45(s,1H),2.24(s,3H).Compound 3-1 (1 g), acetonitrile (20 mL) and NBS (3.34 g) were added to a 100 mL single-mouth bottle in sequence, and the mixture was stirred at room temperature for 18 hours under nitrogen protection. After the reaction, 50 mL of distilled water was added to the reaction solution, extracted with EA (100 mL), washed with saturated brine (50 mL × 2), and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE/EA = 20/1) to obtain compound 3-2 (0.8 g). 1 H NMR (500 MHz, DMSO-d 6 )δ10.00 (s, 1H), 7.45 (s, 1H), 2.24 (s, 3H).

步骤B:Step B:

100mL两口瓶中依次加入化合物3-2(0.2g)、N-叔丁氧羰基-2-哌啶-2-基乙醇(0.189g)、三苯基膦(0.236g)与THF(10mL)，氮气保护下，在冰浴搅拌。之后往其中逐滴滴加溶解于THF(2mL)的DEAD(0.157g)，并逐渐恢复至室温搅拌反应16h。反应结束后向反应液中加入50mL蒸馏水，EA(100mL)萃取，分别用饱和碳酸氢钠溶液(100mL)与饱和食盐水(100mL)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：PE/EA＝10/1)纯化，得到化合物3-3(0.279g)。1H NMR(500MHz,DMSO-d6)δ7.61(s,1H),4.42–4.32(m,1H),3.98–3.90(m,1H),3.86–3.78(m,2H),2.89–2.72(m,1H),2.29(s,3H),2.17–2.10(m,1H),2.00–1.93(m,1H),1.67–1.61(m,1H),1.61–1.51(m,4H),1.37(s,9H),1.29–1.23(m,1H).Compound 3-2 (0.2 g), N-tert-butyloxycarbonyl-2-piperidin-2-ylethanol (0.189 g), triphenylphosphine (0.236 g) and THF (10 mL) were added to a 100 mL two-necked bottle in sequence, and stirred in an ice bath under nitrogen protection. DEAD (0.157 g) dissolved in THF (2 mL) was then added dropwise thereto, and the mixture was gradually returned to room temperature and stirred for 16 h. After the reaction was completed, 50 mL of distilled water was added to the reaction solution, and EA (100 mL) was extracted, and the mixture was washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), respectively, and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE/EA=10/1) to obtain compound 3-3 (0.279 g). 1 H NMR (500MHz, DMSO-d 6 )δ7.61(s,1H),4.42–4.32(m,1H),3.98–3.90(m,1H),3.86–3.78(m,2H),2.89–2.72(m,1H),2.29(s,3H),2 .17–2.10(m,1H),2.00–1.93(m,1H),1.67–1.61(m,1H),1.61–1.51(m,4H),1.37(s,9H),1.29–1.23(m,1H).

步骤C:Step C:

100mL单口瓶中依次加入化合物3-3(0.262g)、乙酸乙酯(6mL)和4M的氯化氢二氧六环溶液(0.7mL)，室温搅拌反应18小时。反应结束后抽滤，滤饼干燥后得到化合物3-4(0.178g)。1H NMR(500MHz,DMSO-d6)δ9.12(s,1H),8.99(s,1H),7.64(s,1H),4.05(t,2H),3.31–3.26(m,1H),3.26–3.21(m,1H),2.94–2.82(m,1H),2.33(s,3H),2.29–2.21(m,1H),2.05–1.94(m,2H),1.81–1.70(m,2H),1.68–1.58(m,1H),1.55–1.42(m,2H).Compound 3-3 (0.262 g), ethyl acetate (6 mL) and 4M hydrogen chloride dioxane solution (0.7 mL) were added to a 100 mL single-mouth bottle in sequence and stirred at room temperature for 18 hours. After the reaction was completed, the mixture was filtered and the filter cake was dried to obtain compound 3-4 (0.178 g). 1 H NMR (500MHz, DMSO-d 6 )δ9.12(s,1H),8.99(s,1H),7.64(s,1H),4.05(t,2H),3.31–3.26(m,1H),3.26–3.21(m,1H),2.94–2.82(m,1H ),2.33(s,3H),2.29–2.21(m,1H),2.05–1.94(m,2H),1.81–1.70(m,2H),1.68–1.58(m,1H),1.55–1.42(m,2H).

步骤D:Step D:

10mL微波管中依次加入化合物3-4(0.14g)、NMP(2mL)和DIPEA(0.175g)，放入微波反应器中,在100瓦下加热至150℃反应40分钟。反应结束后向反应液中加入50mL蒸馏水，EA(100mL)萃取，分别用饱和碳酸氢钠溶液(100mL)与饱和食盐水(100mL)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：PE/EA＝20/1)纯化，得到化合物3-5(0.098g)。MS(ESI+,[M+H]+)m/z：296.90.1H NMR(500MHz,DMSO-d6)δ6.81(s,1H),4.16(dd,2H),3.70–3.60(m,1H),3.38–3.33(m,1H),3.11–3.01(m,1H),2.08(s,3H),2.04–1.97(m,1H),1.91–1.83(m,1H),1.81–1.72(m,1H),1.62–1.44(m,5H).步骤E:Compound 3-4 (0.14 g), NMP (2 mL) and DIPEA (0.175 g) were added to a 10 mL microwave tube in sequence, placed in a microwave reactor, and heated to 150 ° C at 100 watts for 40 minutes. After the reaction was completed, 50 mL of distilled water was added to the reaction solution, extracted with EA (100 mL), washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), respectively, and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE/EA=20/1) to obtain compound 3-5 (0.098 g). MS (ESI+, [M+H] + ) m/z: 296.90. 1 H NMR (500 MHz, DMSO-d 6 ) δ 6.81 (s, 1H), 4.16 (dd, 2H), 3.70–3.60 (m, 1H), 3.38–3.33 (m, 1H), 3.11–3.01 (m, 1H), 2.08 (s, 3H), 2.04–1.97 (m, 1H), 1.91–1.83 (m, 1H), 1.81–1.72 (m, 1H), 1.62–1.44 (m, 5H). Step E:

50mL单口瓶中，依次加入化合物A-6(0.062g)、化合物3-5(0.089g)、Pd2(dba)3(0.007g)、Xant-Phos(0.010g)和碳酸铯(0.194g)，用二氧六环(6mL)溶解，氮气保护下，在100℃下加热反应12h。反应结束后向反应液中加入50mL蒸馏水，EA(100mL)萃取，饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：PE/EA＝1/1)纯化，得到化合物3(0.042g)。1H NMR(500MHz,DMSO-d6)δ12.76(s,1H),10.16(s,1H),8.05(d,1H),7.58(s,1H),7.25(d,1H),7.11(dd,1H),4.93(t,1H),4.20–4.11(m,2H),3.85–3.79(m,1H),3.78–3.74(m,2H),3.36–3.32(m,3H),3.12–3.06(m,1H),2.95(t,4H),2.14(s,3H),2.04–1.99(m,1H),1.93–1.43(m,11H),0.36(s,4H).HRMS(ESI+,[M+H]+)m/z：570.2756.Compound A-6 (0.062 g), compound 3-5 (0.089 g), Pd 2 (dba) 3 (0.007 g), Xant-Phos (0.010 g) and cesium carbonate (0.194 g) were added to a 50 mL single-mouth bottle in sequence, dissolved with dioxane (6 mL), and heated at 100 ° C for 12 h under nitrogen protection. After the reaction, 50 mL of distilled water was added to the reaction solution, extracted with EA (100 mL), washed with saturated brine (50 mL × 2), and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE/EA = 1/1) to obtain compound 3 (0.042 g). 1 H NMR (500MHz, DMSO-d 6 )δ12.76(s,1H),10.16(s,1H),8.05(d,1H),7.58(s,1H),7.25(d,1H),7 .11(dd,1H),4.93(t,1H),4.20–4.11(m,2H),3.85–3.79(m,1H),3.78–3. 74(m,2H),3.36–3.32(m,3H),3.12–3.06(m,1H),2.95(t,4H),2.14(s,3H ),2.04–1.99(m,1H),1.93–1.43(m,11H),0.36(s,4H).HRMS(ESI+,[M+H] + )m/z：570.2756.

步骤F：Step F:

化合物3(134mg)经过制备HPLC(拆分条件：柱：CHIRALART Cellulose-SC，4.6×250mm，5μm；流动相：正己烷：二氯甲烷：乙醇＝64:30:6；流速：1mL/min；波长：254nm)拆分得到化合物3_A(63mg，保留时间为13.363分钟)、化合物3_B(67mg，保留时间为15.056分钟)。Compound 3 (134 mg) was separated by preparative HPLC (separation conditions: column: CHIRALART Cellulose-SC, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 64:30:6; flow rate: 1 mL/min; wavelength: 254 nm) to give compound 3_A (63 mg, retention time: 13.363 minutes) and compound 3_B (67 mg, retention time: 15.056 minutes).

化合物3_A:1H NMR(500MHz,DMSO-d6)δ12.76(s,1H),10.16(s,1H),8.05(d,1H),7.58(s,1H),7.25(d,1H),7.11(dd,1H),4.93(t,1H),4.21–4.11(m,2H),3.85–3.79(m,1H),3.79–3.72(m,2H),3.37–3.33(m,3H),3.12–3.06(m,1H),2.95(t,4H),2.13(s,3H),2.04–1.98(m,1H),1.94–1.40(m,11H),0.36(s,4H).HRMS(ESI+,[M+H]+)m/z：570.2757.Compound 3_A: 1 H NMR (500MHz, DMSO-d 6 )δ12.76(s,1H),10.16(s,1H),8.05(d,1H),7.58(s,1H),7.25(d,1H),7 .11(dd,1H),4.93(t,1H),4.21–4.11(m,2H),3.85–3.79(m,1H),3.79–3. 72(m,2H),3.37–3.33(m,3H),3.12–3.06(m,1H),2.95(t,4H),2.13(s,3H ),2.04–1.98(m,1H),1.94–1.40(m,11H),0.36(s,4H).HRMS(ESI+,[M+H] + )m/z：570.2757.

化合物3_B:1H NMR(500MHz,DMSO-d6)δ12.76(s,1H),10.16(s,1H),8.05(d,1H),7.58(s,1H),7.25(d,1H),7.11(dd,1H),5.03–4.86(m,1H),4.21–4.11(m,2H),3.85–3.79(m,1H),3.79–3.73(m,2H),3.37 –3.33(m,3H),3.12–3.06(m,1H),2.95(t,4H),2.13(s,3H),2.04–1.98(m,1H),1.93–1.43(m,11H),0.36(s,4H).HRMS(ESI+,[M+H]+)m/z：570.2762.Compound 3_B: 1 H NMR (500 MHz, DMSO-d 6 )δ12.76(s,1H),10.16(s,1H),8.05(d,1H),7.58(s,1H),7.25(d,1H),7.11(dd,1H),5.03–4.86(m,1H),4.21–4.11(m,2H),3.85–3.79(m,1H),3.79–3.73(m,2H),3.37 –3.33(m,3H),3.12–3.06(m,1H),2.95(t,4H),2.13(s,3H),2.04–1.98(m,1H),1.93–1.43(m,11H),0.36(s,4H).HRMS(ESI+,[M+H] + )m/z:570.2762.

实施例4
Example 4

步骤A：Step A:

50mL双口瓶中，加入化合物4-1(1g)，DCM(15mL)溶解，冰浴降温后分批多次加入过氧化脲(1.1g)，继续冰浴搅拌15min后缓慢滴加三氟乙酸酐(2.01mL)，滴加完成后室温搅拌15h。反应结束，加入30mL水，用饱和碳酸钠溶液调节水相pH＝9左右，用乙酸乙酯(15mL×3)萃取，合并有机相，依次用10％的亚硫酸钠溶液(30mL)和饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩干，硅胶柱层析(洗脱剂PE/EA＝1/1)纯化，得到化合物4-2(0.77g)。1H NMR(500MHz,DMSO-d6)δ9.11(s,1H),8.07(s,1H),2.50(s,3H).Compound 4-1 (1 g) was added to a 50 mL two-necked flask, dissolved in DCM (15 mL), cooled in an ice bath, urea peroxide (1.1 g) was added in batches, and continued to stir in an ice bath for 15 min, then trifluoroacetic anhydride (2.01 mL) was slowly added dropwise, and stirred at room temperature for 15 h. After the reaction was completed, 30 mL of water was added, and the pH of the aqueous phase was adjusted to about 9 with a saturated sodium carbonate solution, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, washed with 10% sodium sulfite solution (30 mL) and saturated brine (30 mL) in turn, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (eluent PE/EA = 1/1) to obtain compound 4-2 (0.77 g). 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.11 (s, 1H), 8.07 (s, 1H), 2.50 (s, 3H).

步骤B：Step B:

50mL单口瓶中，依次加入化合物4-2(0.76g)、双-(4-甲氧基苄基)-胺(1.5g)、碳酸钾(1.11g)和乙腈(25mL)，80℃加热回流搅拌16h。反应结束，硅藻土助滤抽滤，用EA(30mL)洗涤滤饼，滤液浓缩，硅胶柱层析纯化(洗脱剂：PE/EA＝3/1)得到化合物4-3(1.34g)。MS(ESI+,[M+H]+)m/z：410.17.1H NMR(500MHz,DMSO-d6)δ8.84(s,1H),7.25–7.21(m,4H),7.03(s,1H),6.89–6.85(m,4H),4.67(s,4H),3.71(s,6H),2.42(s,3H).Compound 4-2 (0.76 g), bis-(4-methoxybenzyl)-amine (1.5 g), potassium carbonate (1.11 g) and acetonitrile (25 mL) were added to a 50 mL single-mouth bottle, and heated under reflux at 80°C with stirring for 16 h. After the reaction was completed, filtration was performed with diatomaceous earth, the filter cake was washed with EA (30 mL), the filtrate was concentrated, and purified by silica gel column chromatography (eluent: PE/EA=3/1) to obtain compound 4-3 (1.34 g). MS(ESI+,[M+H] + )m/z: 410.17. 1 H NMR (500MHz, DMSO-d 6 )δ8.84(s,1H),7.25–7.21(m,4H),7.03(s,1H),6.89–6.85(m,4H),4.67(s,4H),3.71(s,6H),2.42(s,3H).

步骤C：Step C:

100mL单口瓶中，加入化合物4-3(1.3g)、甲苯(12mL)和DIPEA(13mL)，冰浴降温后加入三氯氧磷(5.5mL)，70℃加热搅拌20min。反应结束，减压旋蒸除去大部分溶剂，加入蒸馏水(30mL)，用饱和碳酸钠溶液调节水相pH＝9-10左右，用乙酸乙酯(20mL×3)萃取，合并有机相，用30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(洗脱剂PE/EA＝5/1)纯化，得到化合物4-4(0.64g)。1H NMR(500MHz,DMSO-d6)δ7.21–7.16(m,4H),6.92–6.88(m,4H),6.71(s,1H),4.70(s,4H),3.73(s,6H),2.22(s,3H).Compound 4-3 (1.3 g), toluene (12 mL) and DIPEA (13 mL) were added to a 100 mL single-mouth bottle, phosphorus oxychloride (5.5 mL) was added after cooling in an ice bath, and heated at 70°C with stirring for 20 min. After the reaction was completed, most of the solvent was removed by rotary evaporation under reduced pressure, distilled water (30 mL) was added, the pH of the aqueous phase was adjusted to about 9-10 with a saturated sodium carbonate solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE/EA=5/1) to obtain compound 4-4 (0.64 g). 1 H NMR (500MHz, DMSO-d 6 ) δ7.21–7.16(m,4H),6.92–6.88(m,4H),6.71(s,1H),4.70(s,4H),3.73(s,6H),2.22(s,3H).

步骤D：Step D:

30mL微波管中，依次加入化合物4-4(0.57g)、2-哌啶甲酸甲酯(0.76g)、NMP(8mL)和DIPEA(0.34g)，微波140℃加热2h。反应结束，加50mL水，用乙酸乙酯(20mL×3)萃取，合并有机相，用30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(洗脱剂PE/EA＝6.5/1)纯化，得到化合物4-5(0.26g)。MS(ESI+,[M+H]+)m/z：535.29.1H NMR(500MHz,DMSO-d6)δ7.12–7.08(m,4H),6.90–6.86(m,4H),6.13(s,1H),4.73–4.48(m,5H),3.75–3.70(m,7H),3.44(s,3H),3.39–3.33(m,1H),2.20(s, 3H),1.78–1.70(m,1H),1.67–1.54(m,2H),1.54–1.42(m,1H),1.35–1.22(m,2H).Compound 4-4 (0.57 g), methyl 2-piperidinate (0.76 g), NMP (8 mL) and DIPEA (0.34 g) were added to a 30 mL microwave tube in sequence and heated at 140°C for 2 h. After the reaction was completed, 50 mL of water was added, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE/EA=6.5/1) to obtain compound 4-5 (0.26 g). MS(ESI+,[M+H] + )m/z: 535.29. 1 H NMR (500MHz, DMSO-d 6 )δ7.12–7.08(m,4H),6.90–6.86(m,4H),6.13(s,1H),4.73–4.48(m,5H),3.75–3.70(m,7H),3.44(s,3H),3.39–3.33(m,1H),2.20(s, 3H),1.78–1.70(m,1H),1.67–1.54(m,2H),1.54–1.42(m,1H),1.35–1.22(m,2H).

步骤E：Step E:

100mL单口瓶中，加入化合物4-5(2.78g)，乙醇(20mL)溶解后80℃加热搅拌，加入氯化亚锡二水合物(3g)，继续80℃加热搅拌5h。反应结束，加80mL水，用乙酸乙酯(20mL×3)萃取，合并有机相，用30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(洗脱剂PE/EA＝5/1)纯化，得到化合物4-6(0.76g)。MS(ESI+,[M+H]+)m/z：472.89.Compound 4-5 (2.78 g) was added to a 100 mL single-mouth bottle, dissolved in ethanol (20 mL), heated and stirred at 80 ° C, and stannous chloride dihydrate (3 g) was added, and continued to heat and stir at 80 ° C for 5 h. After the reaction was completed, 80 mL of water was added, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE/EA = 5/1) to obtain compound 4-6 (0.76 g). MS (ESI+, [M+H] + ) m/z: 472.89.

步骤F：Step F:

100mL单口瓶中，加入化合物4-6(0.75g)，DMF(5mL)溶解后冰浴降温，加入60％的氢化钠(0.13g)，室温搅拌5min后加入碘甲烷(0.15mL)，室温搅拌2h。反应结束，加50mL水，用乙酸乙酯(15mL×3)萃取，合并有机相，用30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(洗脱剂PE/EA＝5/1)纯化，得到化合物4-7(0.59g)。MS(ESI+,[M+H]+)m/z：487.25.Compound 4-6 (0.75 g) was added to a 100 mL single-mouth bottle, dissolved in DMF (5 mL) and cooled in an ice bath, 60% sodium hydride (0.13 g) was added, stirred at room temperature for 5 min, iodomethane (0.15 mL) was added, and stirred at room temperature for 2 h. After the reaction was completed, 50 mL of water was added, extracted with ethyl acetate (15 mL × 3), the organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE/EA = 5/1) to obtain compound 4-7 (0.59 g). MS (ESI+, [M+H] + ) m/z: 487.25.

步骤G：Step G:

100mL单口瓶中，依次加入化合物4-7(0.59g)、DCM(6mL)、苯甲醚(0.43mL)和三氟乙酸(6mL)，60℃加热搅拌16h。反应结束，减压旋蒸除去大部分溶剂，加50mL水，用乙酸乙酯(15mL×3)萃取，合并有机相，用30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(洗脱剂PE/EA＝1/1)纯化，得到化合物4-8(0.22g)。MS(ESI+,[M+H]+)m/z：247.05.1H NMR(500MHz,DMSO-d6)δ5.74(s,1H),5.43(s,2H),4.20–4.11(m,1H),3.42–3.36(m,1H),3.16(s,3H),2.55–2.51(m,1H),2.18(s,3H),1.95–1.87(m,1H),1.81–1.74(m,1H),1.65–1.58(m,1H),1.46–1.32(m,3H).Compound 4-7 (0.59 g), DCM (6 mL), anisole (0.43 mL) and trifluoroacetic acid (6 mL) were added to a 100 mL single-mouth bottle in sequence, and heated and stirred at 60°C for 16 h. After the reaction was completed, most of the solvent was removed by rotary evaporation under reduced pressure, 50 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE/EA=1/1) to obtain compound 4-8 (0.22 g). MS(ESI+,[M+H] + )m/z: 247.05. 1 H NMR (500MHz, DMSO-d 6 )δ5.74(s,1H),5.43(s,2H),4.20–4.11(m,1H),3.42–3.36(m,1H),3.16(s,3H),2.55–2.51(m, 1H),2.18(s,3H),1.95–1.87(m,1H),1.81–1.74(m,1H),1.65–1.58(m,1H),1.46–1.32(m,3H).

步骤H：Step H:

50mL单口瓶中，依次加入化合物4-8(217mg)、HATU(670mg)、DCM(10mL)和DIPEA(0.31mL)，搅拌均匀后加入化合物A-2(346mg)，室温搅拌12h。反应结束，减压浓缩，硅胶柱层析(洗脱剂PE/EA＝10/1)纯化，得到化合物4-9(467mg)。MS(ESI+,[M+H]+)m/z：586.22.Compound 4-8 (217 mg), HATU (670 mg), DCM (10 mL) and DIPEA (0.31 mL) were added to a 50 mL single-mouth bottle in sequence. After stirring evenly, compound A-2 (346 mg) was added and stirred at room temperature for 12 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent PE/EA=10/1) to obtain compound 4-9 (467 mg). MS (ESI+, [M+H] + ) m/z: 586.22.

步骤I：Step I:

50mL单口瓶中，依次加入化合物4-9(460mg)、2-羟基-1-磺酰胺(151mg)、二氧六环(10mL)、碳酸钾(277mg)、氯化烯丙基钯(II)二聚物(14.44mg)、t-BuXPhos(34.1mg)，N2保护下，加热至100℃反应2h。反应结束后，硅藻土助滤抽滤，减压浓缩，硅胶柱层析(洗脱剂：DCM/MeOH＝40/1)纯化，得到化合物4(250mg)。MS(ESI+,[M+H]+)m/z：583.27.Compound 4-9 (460 mg), 2-hydroxy-1-sulfonamide (151 mg), dioxane (10 mL), potassium carbonate (277 mg), allylpalladium (II) chloride dimer (14.44 mg), t-BuXPhos (34.1 mg) were added to a 50 mL single-mouth bottle in sequence, and heated to 100 ° C for 2 h under N 2 protection. After the reaction, diatomaceous earth was used for filtration, and the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM/MeOH=40/1) to obtain compound 4 (250 mg). MS (ESI+, [M+H] + ) m/z: 583.27.

步骤J：Step J:

化合物4(250mg)经过制备HPLC(拆分条件：柱：whelk-O1，4.6×250mm，5μm；流动相：正己烷：二氯甲烷：乙醇＝40:40:20；流速：2mL/min；波长：254nm)拆分得到化合物4_A(110mg，保留时间为7.199分钟)、化合物4_B(100mg，保留时间为10.291分钟)。Compound 4 (250 mg) was separated by preparative HPLC (separation conditions: column: whelk-O1, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 40:40:20; flow rate: 2 mL/min; wavelength: 254 nm) to give compound 4_A (110 mg, retention time: 7.199 minutes) and compound 4_B (100 mg, retention time: 10.291 minutes).

化合物4_A:1H NMR(500MHz,DMSO-d6)δ13.14(s,1H),10.19(s,1H),8.08(d,1H),7.60(s,1H),7.27(d,1H),7.13(dd,1H),4.93(t,1H),4.36–4.26(m,1H),3.76(t,2H),3.62(dd,1H),3.35(t,2H),3.26(s,3H),3.01–2.92(m,4H),2.75–2.67(m,1H),2.38(s,3H),1.98–1.65(m,5H),1.55–1.22(m,5H),0.37(s,4H)。HRMS(ESI+,[M+H]+)m/z：583.2708.Compound 4_A: 1 H NMR (500MHz, DMSO-d 6 )δ13.14(s,1H),10.19(s,1H),8.08(d,1H),7.60(s,1H),7.27(d,1H),7.13(dd,1H),4.93(t,1H ),4.36–4.26(m,1H),3.76(t,2H),3.62( dd,1H),3.35(t,2H),3.26(s,3H),3.01–2.92(m,4H),2.75–2.67(m,1H),2.38(s,3H),1.98–1.65(m, 5H),1.55–1.22(m,5H),0.37(s,4H). HRMS(ESI+,[M+H] + )m/z: 583.2708.

化合物4_B:1H NMR(500MHz,DMSO-d6)δ13.14(s,1H),10.18(s,1H),8.08(d,1H),7.60(s,1H),7.27(d,1H),7.13(dd,1H),4.93(s,1H),4.37–4.27(m,1H),3.76(t,2H),3.62(dd,1H),3.35(t,2H),3.26(s,3H),2.97(s,4H),2.76–2.67(m,1H),2.38(s,3H),2.00–1.65(m,6H),1.63–1.35(m,4H),0.37(s,4H)。HRMS(ESI+,[M+H]+)m/z：583.2712.Compound 4_B: 1 H NMR (500MHz, DMSO-d 6 )δ13.14(s,1H),10.18(s,1H),8.08(d,1H),7.60(s,1H),7.27(d,1H),7.13(dd,1H),4.93(s,1H ),4.37–4.27(m,1H),3.76(t,2H),3.6 2(dd,1H),3.35(t,2H),3.26(s,3H),2.97(s,4H),2.76–2.67(m,1H),2.38(s,3H),2.00–1.65(m, 6H),1.63–1.35(m,4H),0.37(s,4H). HRMS(ESI+,[M+H] + )m/z: 583.2712.

实施例5
Example 5

步骤A：Step A:

100mL单口瓶中，依次加入化合物5-1(2g)、对甲苯磺酸水合物(0.44g)、2,5-己二酮(1.62mL)和甲苯(25mL)，N2保护下120℃加热搅拌16h。反应结束，停止加热，减压旋蒸除去大部分溶剂，加入40mL水，用乙酸乙酯(20mL×3)萃取，合并有机相，用30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(洗脱剂PE/EA＝50/1)纯化，得到化合物5-2(1.4g)。MS(ESI+,[M+H]+)m/z：251.96.1H NMR(500MHz,DMSO-d6)δ8.89(d,1H),7.85(d,1H),5.87(s,2H),1.93(s,6H).Compound 5-1 (2 g), p-toluenesulfonic acid hydrate (0.44 g), 2,5-hexanedione (1.62 mL) and toluene (25 mL) were added to a 100 mL single-mouth bottle in sequence, and heated and stirred at 120 ° C for 16 h under N 2 protection. After the reaction was completed, the heating was stopped, and most of the solvent was removed by rotary evaporation under reduced pressure. 40 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE/EA＝50/1) to obtain compound 5-2 (1.4 g). MS (ESI+, [M+H] + ) m/z：251.96. 1 H NMR (500 MHz, DMSO-d 6 )δ8.89(d,1H),7.85(d,1H),5.87(s,2H),1.93(s,6H).

步骤B：Step B:

25mL单口瓶中，加入化合物5-2(1g)，2-哌啶甲酸甲酯(3g)，90℃加热搅拌2.5h。反应结束，停止加热，加入40mL蒸馏水，用乙酸乙酯(20mL×3)萃取，合并有机相，依次用1N的稀盐酸溶液(30mL)和饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(洗脱剂PE/EA＝10/1)纯化，得到化合物5-3(1.17g)。MS(ESI+,[M+H]+)m/z：359.12.1H NMR(500MHz,DMSO-d6)δ8.48(d,1H),6.95(d,1H),5.82–5.77(m,2H),4.97–4.91(m,1H),3.66(s,3H),3.39–3.33(m,1H),3.17–3.10(m,1H),2.10–2.03(m,1H),1.95(s,3H),1.86(s,3H),1.86–1.81(m,1H),1.70–1.58(m,2H),1.53–1.33(m,2H).Compound 5-2 (1 g) and methyl 2-piperidinylcarboxylate (3 g) were added to a 25 mL single-mouth bottle, and heated and stirred at 90°C for 2.5 h. After the reaction was completed, heating was stopped, 40 mL of distilled water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with 1N dilute hydrochloric acid solution (30 mL) and saturated brine (30 mL) in sequence, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE/EA = 10/1) to obtain compound 5-3 (1.17 g). MS(ESI+,[M+H] + )m/z: 359.12. 1 H NMR (500MHz, DMSO-d 6 )δ8.48(d,1H),6.95(d,1H),5.82–5.77(m,2H),4.97–4.91(m,1H),3.66(s,3H),3.39–3.33(m,1H),3.17–3.10 (m,1H),2.10–2.03(m,1H),1.95(s,3H),1.86(s,3H),1.86–1.81(m,1H),1.70–1.58(m,2H),1.53–1.33(m,2H).

步骤C：Step C:

100mL单口瓶中，依次加入化合物5-3(1.7g)、乙醇(20mL)、饱和氯化铵水溶液(10mL)和铁粉(1.32g)，N2保护下80℃加热8h。反应结束，停止加热，硅藻土助滤，抽滤，滤液加入40mL蒸馏水，用乙酸乙酯(20mL×3)萃取，合并有机相，用30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(洗脱剂PE/EA＝5/1)纯化，得到化合物5-4(1g)。MS(ESI+,[M+H]+)m/z：297.24.1H NMR(500MHz,DMSO-d6)δ9.26(s,1H),7.87(d,1H),6.47(d,1H),5.86(s,2H),4.59–4.52(m,1H),4.06–3.98(m,1H),2.80–2.71(m,1H),2.05–1.99(m,1H),1.92(s,3H),1.91(s,3H),1.89–1.84(m,1H),1.69–1.63(m,1H),1.59–1.38(m,3H).Compound 5-3 (1.7 g), ethanol (20 mL), saturated aqueous ammonium chloride solution (10 mL) and iron powder (1.32 g) were added to a 100 mL single-mouth bottle in sequence, and heated at 80 ° C for 8 h under N 2 protection. After the reaction was completed, the heating was stopped, diatomaceous earth was used for filtration, and suction filtration was performed. 40 mL of distilled water was added to the filtrate, and it was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE/EA=5/1) to obtain compound 5-4 (1 g). MS(ESI+,[M+H] + )m/z: 297.24. 1 H NMR (500MHz, DMSO-d 6 )δ9.26(s,1H),7.87(d,1H),6.47(d,1H),5.86(s,2H),4.59–4.52(m,1H),4.06–3.98(m,1H),2.80–2.71(m, 1H),2.05–1.99(m,1H),1.92(s,3H),1.91(s,3H),1.89–1.84(m,1H),1.69–1.63(m,1H),1.59–1.38(m,3H).

步骤D：Step D:

100mL单口瓶中，加入化合物5-4(1g)，DMF(5mL)溶解后冰浴降温，加入60％的氢化钠(0.2g)，室温搅拌5min后加入碘甲烷(0.25mL)，室温搅拌2h。反应结束，加50mL水，用乙酸乙酯(20mL×3)萃取，合并有机相，用30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(洗脱剂PE/EA＝5/1)纯化，得到化合物5-5(0.95g)。MS(ESI+,[M+H]+)m/z：311.04.Compound 5-4 (1 g) was added to a 100 mL single-mouth bottle, dissolved in DMF (5 mL) and cooled in an ice bath, 60% sodium hydride (0.2 g) was added, stirred at room temperature for 5 min, iodomethane (0.25 mL) was added, and stirred at room temperature for 2 h. After the reaction was completed, 50 mL of water was added, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE/EA = 5/1) to obtain compound 5-5 (0.95 g). MS (ESI+, [M+H] + ) m/z: 311.04.

步骤E：Step E:

100mL微波瓶中，依次加入化合物5-5(0.95g)、乙醇(20mL)、盐酸羟胺(4.48g)、水(10mL)和三乙胺(1.34mL)，微波140℃加热搅拌6h。反应结束，加50mL水，用乙酸乙酯(20mL×3)萃取，合并有机 相，用30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(洗脱剂PE/EA＝1/1)纯化，得到化合物5-6(0.34g)。MS(ESI+,[M+H]+)m/z：233.03.1H NMR(500MHz,DMSO-d6)δ7.51(d,1H),6.24(t,1H),5.59(s,2H),4.23–4.15(m,1H),3.47–3.38(m,1H),3.19(s,3H),2.60–2.52(m,1H),1.96–1.87(m,1H),1.80–1.70(m,1H),1.67–1.58(m,1H),1.49–1.33(m,3H).Compound 5-5 (0.95 g), ethanol (20 mL), hydroxylamine hydrochloride (4.48 g), water (10 mL) and triethylamine (1.34 mL) were added to a 100 mL microwave vial, and heated at 140 °C with stirring for 6 h. After the reaction was completed, 50 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was combined. The phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE/EA=1/1) to obtain compound 5-6 (0.34 g). MS (ESI+, [M+H] + ) m/z: 233.03. 1 H NMR (500 MHz, DMSO-d 6 ) δ7.51 (d, 1H), 6.24 (t, 1H), 5.59 (s, 2H), 4.23–4.15 (m, 1H), 3.47–3.38 (m, 1H), 3.19 (s, 3H), 2.60–2.52 (m, 1H), 1.96–1.87 (m, 1H), 1.80–1.70 (m, 1H), 1.67–1.58 (m, 1H), 1.49–1.33 (m, 3H).

步骤F：Step F:

50mL双口瓶中，依次加入化合物A-2(0.68g)、THF(10mL)、N-甲基吗啉(0.31mL)和氯甲酸异丁酯(0.31mL)，室温搅拌0.5h后加入化合物5-6(0.22g)，N2保护下滴加LiHMDS的THF溶液(1M,2.4mL)，滴加完成后室温搅拌12h。反应结束，加入10mL饱和氯化铵溶液，加30mL水，用乙酸乙酯(15mL×3)萃取，合并有机相，用30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(洗脱剂PE/EA＝10/1)纯化，得到化合物5-7(0.33g)。MS(ESI+,[M+H]+)m/z：572.19.1H NMR(500MHz,DMSO-d6)δ11.90(s,1H),7.92(d,1H),7.74(s,1H),7.73–7.66(m,2H),7.44(d,1H),4.40–4.30(m,1H),3.80–3.72(m,1H),3.10(s,3H),3.04–2.95(m,4H),2.81–2.73(m,1H),1.91–1.80(m,2H),1.64–1.46(m,4H),1.38–1.32(m,4H),0.28(s,4H).Compound A-2 (0.68 g), THF (10 mL), N-methylmorpholine (0.31 mL) and isobutyl chloroformate (0.31 mL) were added to a 50 mL two-necked flask in sequence, and the mixture was stirred at room temperature for 0.5 h before adding compound 5-6 (0.22 g). LiHMDS in THF solution (1M, 2.4 mL) was added dropwise under N 2 protection, and the mixture was stirred at room temperature for 12 h after the addition was complete. After the reaction was completed, 10 mL of saturated ammonium chloride solution was added, 30 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE/EA = 10/1) to obtain compound 5-7 (0.33 g). MS (ESI+, [M+H] + )m/z: 572.19. 1 H NMR (500MHz, DMSO-d 6 )δ11.90(s,1H),7.92(d,1H),7.74(s,1H),7.73–7.66(m,2H),7.44(d,1H),4.40–4.30(m,1H),3.80–3.72(m,1H),3.1 0(s,3H),3.04–2.95(m,4H),2.81–2.73(m,1H),1.91–1.80(m,2H),1.64–1.46(m,4H),1.38–1.32(m,4H),0.28(s,4H).

步骤G：Step G:

参考实施例4的步骤I，以化合物5-7代替化合物4-9，合成得到化合物5(200mg)。MS(ESI+,[M+H]+)m/z：569.34.Referring to step I of Example 4, compound 5-7 was used instead of compound 4-9 to synthesize compound 5 (200 mg). MS (ESI+, [M+H] + ) m/z: 569.34.

步骤H：Step H:

化合物5(200mg)经过制备HPLC(拆分条件：柱：REFLECT I-Cellulose C，4.6×250mm，5μm；流动相：正己烷：二氯甲烷：乙醇＝70:15:15；流速：1mL/min；波长：250nm)拆分得到化合物5_A(70mg，保留时间为13.266分钟)、化合物5_B(70mg，保留时间为16.903分钟)。Compound 5 (200 mg) was separated by preparative HPLC (separation conditions: column: REFLECT I-Cellulose C, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 70:15:15; flow rate: 1 mL/min; wavelength: 250 nm) to give compound 5_A (70 mg, retention time: 13.266 minutes) and compound 5_B (70 mg, retention time: 16.903 minutes).

化合物5_A:1H NMR(500MHz,DMSO-d6)δ12.08(s,1H),10.21(s,1H),8.00(d,1H),7.91(d,1H),7.53(d,1H),7.25(d,1H),7.11(dd,1H),4.95(s,1H),4.41–4.32(m,1H),3.82–3.67(m,3H),3.37(t,2H),3.11(s,3H),3.00–2.89(m,4H),2.82–2.73(m,1H),1.91–1.76(m,2H),1.63–1.44(m,4H),1.42–1.32(m,4H),0.29(s,4H)。HRMS(ESI+,[M+H]+)m/z：569.2550.Compound 5_A: 1 H NMR (500MHz, DMSO-d 6 )δ12.08(s,1H),10.21(s,1H),8.00(d,1H),7.91(d,1H),7.53(d,1H), 7.25(d,1H),7.11(dd,1H),4.95(s,1H),4.41–4.32(m,1H),3.82–3.67( m,3H),3.37(t,2H),3.11(s,3H),3.00–2.89(m,4H),2.82–2.73(m,1H) ,1.91–1.76(m,2H),1.63–1.44(m,4H),1.42–1.32(m,4H),0.29(s,4H). HRMS(ESI+,[M+H] + )m/z: 569.2550.

化合物5_B:1H NMR(500MHz,DMSO-d6)δ12.08(s,1H),10.22(s,1H),8.00(d,1H),7.91(d,1H),7.53(d,1H),7.25(d,1H),7.11(dd,1H),4.95(s,1H),4.42–4.30(m,1H),3.85–3.71(m,3H),3.37(t,2H),3.10(s,3H),3.01–2.89(m,4H),2.82–2.73(m,1H),1.91–1.77(m,2H),1.62–1.43(m,4H),1.40–1.32(m,4H),0.28(s,4H)。HRMS(ESI+,[M+H]+)m/z：569.2550.Compound 5_B: 1 H NMR (500MHz, DMSO-d 6 )δ12.08(s,1H),10.22(s,1H),8.00(d,1H),7.91(d,1H),7.53(d,1H), 7.25(d,1H),7.11(dd,1H),4.95(s,1H),4.42–4.30(m,1H),3.85–3.71( m,3H),3.37(t,2H),3.10(s,3H),3.01–2.89(m,4H),2.82–2.73(m,1H) ,1.91–1.77(m,2H),1.62–1.43(m,4H),1.40–1.32(m,4H),0.28(s,4H). HRMS(ESI+,[M+H] + )m/z: 569.2550.

实施例6
Example 6

步骤A:Step A:

100mL单口瓶中依次加入化合物6-1(3g)和浓硫酸(8.6mL)，冰浴搅拌。逐滴滴加硝酸(1.4mL)，滴加完毕后撤去冰浴在室温搅拌反应4h。反应结束后将反应液倒入500mL冰水中，加入乙酸乙酯(250)mL和水(250)mL。有机相分离，饱和食盐水(250mL×2)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：PE/EA＝10/1)纯化，得到化合物6-2(0.843g)。MS(ESI-,[M-H]-)m/z:232.98.1H NMR(500MHz,DMSO-d6)δ11.15(br s,1H),7.74(s,1H),2.44(s,3H).Compound 6-1 (3 g) and concentrated sulfuric acid (8.6 mL) were added to a 100 mL single-mouth bottle in sequence and stirred in an ice bath. Nitric acid (1.4 mL) was added dropwise, and the ice bath was removed after the addition was complete. The reaction mixture was stirred at room temperature for 4 h. After the reaction was completed, the reaction solution was poured into 500 mL of ice water, and ethyl acetate (250) mL and water (250) mL were added. The organic phase was separated, washed with saturated brine (250 mL × 2), and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE/EA＝10/1) to obtain compound 6-2 (0.843 g). MS (ESI-, [MH] - ) m/z: 232.98. 1 H NMR (500 MHz, DMSO-d 6 ) δ11.15 (br s, 1H), 7.74 (s, 1H), 2.44 (s, 3H).

步骤B:Step B:

参考实施例3的步骤B，以化合物6-2替换化合物3-2合成得到化合物6-3。1H NMR(500MHz,DMSO-d6)δ7.87(s,1H),4.34–4.26(m,1H),4.18–4.08(m,1H),4.01–3.95(m,1H),3.88–3.78(m,1H),2.90–2.69(m,1H),2.51(s,3H),2.16–2.07(m,1H),1.98–1.90(m,1H),1.63–1.50(m,5H),1.36(s,9H),1.29–1.23(m,1H).Referring to step B of Example 3, compound 6-2 was used to replace compound 3-2 to synthesize compound 6-3. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.87 (s, 1H), 4.34–4.26 (m, 1H), 4.18–4.08 (m, 1H), 4.01–3.95 (m, 1H), 3.88–3.78 (m, 1H), 2.90–2.69 (m, 1H), 2.51 (s, 3H), 2.16–2.07 (m, 1H), 1.98–1.90 (m, 1H), 1.63–1.50 (m, 5H), 1.36 (s, 9H), 1.29–1.23 (m, 1H).

步骤C:Step C:

250mL单口瓶中，依次加入化合物6-3(0.98g)、DCM(50mL)和三氟乙酸(1.69mL)，在室温搅拌反应5h。反应结束后加入50mL水，DCM(100mL)萃取，依次用饱和碳酸钠溶液(50mL×2)和饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，得到化合物6-4(0.716g)。MS(ESI+,[M+H]+)m/z：344.02.Compound 6-3 (0.98 g), DCM (50 mL) and trifluoroacetic acid (1.69 mL) were added to a 250 mL single-mouth bottle, and the mixture was stirred at room temperature for 5 h. After the reaction, 50 mL of water was added, and the mixture was extracted with DCM (100 mL), washed with saturated sodium carbonate solution (50 mL × 2) and saturated brine (50 mL × 2), and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and compound 6-4 (0.716 g) was obtained. MS (ESI+, [M+H] + ) m/z: 344.02.

步骤D:Step D:

参考实施例3的步骤D，以化合物6-4替换化合物3-4合成得到化合物6-5。MS(ESI+,[M+H]+)m/z：264.07.1H NMR(500MHz,DMSO-d6)δ6.96(s,1H),4.30–4.23(m,1H),4.23–4.15(m,1H),4.00–3.92(m,1H),3.45–3.38(m,1H),3.09–3.00(m,1H),2.33(s,3H),2.17–2.07(m,1H),2.00–1.90(m,1H),1.87–1.78(m,1H),1.66–1.58(m,2H),1.58–1.48(m,3H).Referring to step D of Example 3, compound 6-4 was used to replace compound 3-4 to synthesize compound 6-5. MS (ESI+, [M+H] + ) m/z: 264.07. 1 H NMR (500 MHz, DMSO-d 6 ) δ 6.96 (s, 1H), 4.30–4.23 (m, 1H), 4.23–4.15 (m, 1H), 4.00–3.92 (m, 1H), 3.45–3.38 (m, 1H), 3.09–3.00 (m, 1H), 2.33 (s, 3H), 2.17–2.07 (m, 1H), 2.00–1.90 (m, 1H), 1.87–1.78 (m, 1H), 1.66–1.58 (m, 2H), 1.58–1.48 (m, 3H).

步骤E:Step E:

100mL单口瓶中，依次加入化合物6-5(0.42g)、甲醇(16mL)、蒸馏水(4mL)、铁粉(0.738g)和氯化铵(0.707g)，加热至70℃反应3h。反应结束后加入乙酸乙酯(100)mL，抽滤，依次用饱和碳酸氢钠溶液(50mL×2)和饱和食盐水(50mL×2)洗涤滤液，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：DCM/MeOH＝20/1)纯化，得到化合物6-6(0.337g)。MS(ESI+,[M+H]+)m/z：234.08.1H NMR(500MHz,DMSO-d6)δ5.98(s,1H),5.25(s,2H),4.09–4.00(m,2H),3.69–3.60(m,1H),3.30–3.21(m,1H),3.04–2.95(m,1H),2.07(s,3H),1.93–1.80(m,2H),1.79–1.70(m,1H),1.59–1.42(m,5H).步骤F:Compound 6-5 (0.42 g), methanol (16 mL), distilled water (4 mL), iron powder (0.738 g) and ammonium chloride (0.707 g) were added to a 100 mL single-mouth bottle, and heated to 70 ° C for 3 h. After the reaction, ethyl acetate (100) mL was added, filtered, and the filtrate was washed with saturated sodium bicarbonate solution (50 mL × 2) and saturated brine (50 mL × 2) in turn, and dried over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent: DCM/MeOH = 20/1) to obtain compound 6-6 (0.337 g). MS (ESI+, [M+H] + ) m/z: 234.08. 1 H NMR (500 MHz, DMSO-d 6 ) δ 5.98 (s, 1H), 5.25 (s, 2H), 4.09–4.00 (m, 2H), 3.69–3.60 (m, 1H), 3.30–3.21 (m, 1H), 3.04–2.95 (m, 1H), 2.07 (s, 3H), 1.93–1.80 (m, 2H), 1.79–1.70 (m, 1H), 1.59–1.42 (m, 5H). Step F:

参考实施例2的步骤E，以化合物6-6替换化合物2-6合成得到化合物6-7。MS(ESI+,[M+H]+)m/z：573.2.Referring to step E of Example 2, compound 6-6 was substituted for compound 2-6 to synthesize compound 6-7. MS (ESI+, [M+H] + ) m/z: 573.2.

步骤G:Step G:

参考实施例2的步骤F，以化合物6-7替换化合物2-7合成得到化合物6。MS(ESI+,[M+H]+)m/z：570.33.Referring to step F of Example 2, compound 6 was synthesized by replacing compound 2-7 with compound 6-7. MS (ESI+, [M+H] + ) m/z: 570.33.

步骤H:Step H:

化合物6经过高压制备分离(Cellulose-SC柱，正己烷：乙醇：二氯甲烷＝8:1:1)拆分得到化合物6_A(保留时间为4.053分钟)、化合物6_B(保留时间为4.602分钟)。Compound 6 was separated by high pressure preparative separation (Cellulose-SC column, n-hexane:ethanol:dichloromethane=8:1:1) to give compound 6_A (retention time: 4.053 minutes) and compound 6_B (retention time: 4.602 minutes).

化合物6_A：1H NMR(500MHz,DMSO-d6)δ11.43(s,1H),10.15(s,1H),8.00–7.79(m,2H),7.18(d,1H),7.04(dd,1H),4.93(t,1H),4.35-4.31(m,1H),4.24-4.21(m,1H),3.76(q,2H),3.49-3.44(m,1H),3.35(t,4H),2.95(t,4H),2.28(s,3H),1.99-1.95(m,2H),1.74(s,1H),1.68–1.44(m,9H),0.35(s,4H).HRMS(ESI+,[M+H]+)m/z：570.2754.Compound 6_A: 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.43 (s, 1H), 10.15 (s, 1H), 8.00–7.79 (m, 2H), 7.18 (d, 1H), 7.04 (dd, 1H), 4.93 (t, 1H), 4.35-4.31 (m, 1H), 4.24-4.21 (m, 1H), 3.76 (q, 2H), 3.49-3.44 (m, 1H), 3.35 (t, 4H), 2.95 (t, 4H), 2.28 (s, 3H), 1.99-1.95 (m, 2H), 1.74 (s, 1H), 1.68–1.44 (m, 9H), 0.35 (s, 4H). HRMS (ESI+, [M+H] + )m/z：570.2754.

化合物6_B：1H NMR(500MHz,DMSO-d6)δ11.42(s,1H),10.14(s,1H),8.08–7.77(m,2H),7.18(s,1H),7.04(d,1H),4.93(t,1H),4.34(dd,1H),4.24(s,1H),3.75(q,2H),3.52–3.46(m,1H),3.38(s,4H),2.95(t,4H),2.28(s,3H),2.01–1.94(m,2H),1.74(s,1H),1.68–1.44(m,9H),0.35(s,4H).HRMS(ESI+,[M+H]+)m/z：570.2759. Compound 6_B: 1 H NMR (500MHz, DMSO-d 6 )δ11.42(s,1H),10.14(s,1H),8.08–7.77(m,2H),7.18(s,1H),7.04(d,1H),4.93(t,1H),4.34(dd ,1H),4.24(s,1H),3.75(q,2H),3.52 –3.46(m,1H),3.38(s,4H),2.95(t,4H),2.28(s,3H),2.01–1.94(m,2H),1.74(s,1H),1.68–1.44(m ,9H),0.35(s,4H).HRMS(ESI+,[M+H] + )m/z：570.2759.

实施例7
Example 7

步骤A:Step A:

100mL两口瓶中依次加入化合物7-1(0.3g)、N-叔丁氧羰基-2-哌啶-2-基乙醇(0.430g)、三苯基膦(0.533g)与THF(15mL)，氮气保护下冰浴搅拌。滴加DEAD(0.408g)的THF(5mL)溶液，并逐渐恢复至室温搅拌反应16h。反应结束后，向反应液中加入50mL蒸馏水，EA(100mL)萃取，分别用饱和碳酸氢钠溶液(100mL)与饱和食盐水(100mL)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，所得粗品经硅胶柱层析(洗脱剂：PE/EA＝10/1)纯化，得到化合物7-2(0.587g)。1H NMR(500MHz,DMSO-d6)δ7.65–7.56(m,1H),7.53(d,1H),4.40–4.34(m,1H),4.09–4.05(m,1H),4.03–3.98(m,1H),3.90–3.80(m,1H),2.86–2.69(m,1H),2.20–2.13(m,1H),1.91–1.82(m,1H),1.60–1.50(m,5H),1.29–1.23(m,10H).Compound 7-1 (0.3 g), N-tert-butyloxycarbonyl-2-piperidin-2-ylethanol (0.430 g), triphenylphosphine (0.533 g) and THF (15 mL) were added to a 100 mL two-necked bottle in sequence, and stirred in an ice bath under nitrogen protection. A solution of DEAD (0.408 g) in THF (5 mL) was added dropwise, and the mixture was gradually returned to room temperature and stirred for 16 h. After the reaction was completed, 50 mL of distilled water was added to the reaction solution, and EA (100 mL) was extracted, and the mixture was washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), respectively, and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA=10/1) to obtain compound 7-2 (0.587 g). 1 H NMR (500MHz, DMSO-d 6 )δ7.65–7.56(m,1H),7.53(d,1H),4.40–4.34(m,1H),4.09–4.05(m,1H),4.03–3.98(m,1H),3.90–3.80( m,1H),2.86–2.69(m,1H),2.20–2.13(m,1H),1.91–1.82(m,1H),1.60–1.50(m,5H),1.29–1.23(m,10H).

步骤B:Step B:

250mL单口瓶中依次加入化合物7-2(0.435g)、乙酸乙酯(30mL)和4M的氯化氢二氧六环溶液(4.85mL)，室温搅拌反应16小时。反应结束后，抽滤，滤饼干燥后得到化合物7-3(0.306g)。MS(ESI+,[M+H]+)m/z：303.28.1H NMR(500MHz,DMSO-d6)δ9.15(s,1H),9.03(s,1H),7.69(dd,1H),7.58(d,1H),4.33–4.22(m,2H),3.25–3.13(m,2H),2.91–2.80(m,1H),2.23–2.14(m,1H),2.04–1.97(m,1H),1.96–1.88(m,1H),1.78–1.68(m,2H),1.68–1.58(m,1H),1.53–1.40(m,2H).Compound 7-2 (0.435 g), ethyl acetate (30 mL) and 4M hydrogen chloride dioxane solution (4.85 mL) were added to a 250 mL single-mouth bottle in sequence and stirred at room temperature for 16 hours. After the reaction was completed, the mixture was filtered and the filter cake was dried to obtain compound 7-3 (0.306 g). MS(ESI+,[M+H] + )m/z: 303.28. 1 H NMR (500MHz, DMSO-d 6 )δ9.15(s,1H),9.03(s,1H),7.69(dd,1H),7.58(d,1H),4.33–4.22(m,2H),3.25–3.13(m,2H),2.91–2.80(m,1H), 2.23–2.14(m,1H),2.04–1.97(m,1H),1.96–1.88(m,1H),1.78–1.68(m,2H),1.68–1.58(m,1H),1.53–1.40(m,2H).

步骤C:Step C:

35mL微波管中依次加入化合物7-3(0.335g)、NMP(10mL)和DIPEA(0.319g)，放入微波反应器中,在100瓦下加热至120℃反应30分钟。反应结束后，加入50mL蒸馏水，EA(100mL)萃取，分别用饱和碳酸氢钠溶液(100mL)与饱和食盐水(100mL)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，所得粗品经硅胶柱层析(洗脱剂：PE/EA＝20/1)纯化，得到化合物7-4(0.25g)。MS(ESI+,[M+H]+)m/z：283.28.1H NMR(500MHz,DMSO-d6)δ7.03(d,1H),6.86(d,1H),4.20–4.14(m,2H),3.69–3.63(m,1H),3.41–3.36(m,1H),3.12–3.05(m,1H),2.09–2.02(m,1H),1.93–1.86(m,1H),1.80–1.73(m,1H),1.62–1.54(m,3H),1.53–1.44(m,2H).Compound 7-3 (0.335 g), NMP (10 mL) and DIPEA (0.319 g) were added to a 35 mL microwave tube in sequence, placed in a microwave reactor, and heated to 120°C at 100 watts for 30 minutes. After the reaction was completed, 50 mL of distilled water was added, extracted with EA (100 mL), washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), respectively, and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA=20/1) to obtain compound 7-4 (0.25 g). MS (ESI+, [M+H] + )m/z: 283.28. 1 H NMR (500MHz, DMSO-d 6 )δ7.03(d,1H),6.86(d,1H),4.20–4.14(m,2H),3.69–3.63(m,1H),3.41–3.36(m,1H),3.12–3.05(m, 1H),2.09–2.02(m,1H),1.93–1.86(m,1H),1.80–1.73(m,1H),1.62–1.54(m,3H),1.53–1.44(m,2H).

步骤D:Step D:

100mL单口瓶中，依次加入化合物7-4(0.236g)、化合物A-6(0.23g)、Pd2(dba)3(0.024g)、Xant-Phos(0.038g)、碳酸铯(0.636g)和二氧六环(18mL)，氮气保护，100℃加热反应16h。反应结束后抽滤，所得滤饼粗品经硅胶柱层析(洗脱剂：PE/EA＝1/1)，得到化合物7(0.233g)。MS(ESI+,[M+H]+)m/z：556.54.Compound 7-4 (0.236 g), compound A-6 (0.23 g), Pd 2 (dba) 3 (0.024 g), Xant-Phos (0.038 g), cesium carbonate (0.636 g) and dioxane (18 mL) were added to a 100 mL single-mouth bottle in sequence, and the mixture was heated at 100 °C for 16 h under nitrogen protection. After the reaction was completed, the crude filter cake was filtered and chromatographed on a silica gel column (eluent: PE/EA=1/1) to obtain compound 7 (0.233 g). MS (ESI+, [M+H] + ) m/z: 556.54.

步骤E：Step E:

化合物7(233mg)经过制备HPLC(拆分条件柱：CHIRALART Cellulose-SC，4.6×250mm，5μm；流动相：正己烷：二氯甲烷：乙醇＝64:30:6；流速：1mL/min；波长：254nm)拆分得到，化合物7_A(110mg，保留时间为21.231分钟)，化合物7_B(108mg，保留时间为23.644分钟)。 Compound 7 (233 mg) was separated by preparative HPLC (separation conditions column: CHIRALART Cellulose-SC, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 64:30:6; flow rate: 1 mL/min; wavelength: 254 nm) to obtain compound 7_A (110 mg, retention time of 21.231 minutes) and compound 7_B (108 mg, retention time of 23.644 minutes).

化合物7_A:1H NMR(500MHz,DMSO-d6)δ12.86(s,1H),10.16(s,1H),8.06(d,J＝8.6Hz,1H),7.63(d,J＝8.2Hz,1H),7.26(d,J＝2.1Hz,1H),7.14(d,J＝8.3Hz,1H),7.11(dd,J＝8.6,2.2Hz,1H),5.01–4.86(m,1H),4.22–4.17(m,1H),4.15–4.10(m,1H),3.84–3.79(m,1H),3.78–3.73(m,2H),3.38–3.32(m,3H),3.16–3.10(m,1H),2.96(t,J＝5.3Hz,4H),2.09–2.03(m,1H),2.00–1.41(m,11H),0.37(s,4H).HRMS(ESI+,[M+H]+)m/z：556.2604.Compound 7_A: 1 H NMR (500 MHz, DMSO-d 6 )δ12.86(s,1H),10.16(s,1H),8.06(d,J＝8.6Hz,1H),7.63(d,J＝8.2Hz,1H),7.26(d,J＝2.1Hz,1H),7.14(d,J＝8.3Hz,1H),7.11(dd,J＝8.6,2.2Hz,1H),5.01–4.86(m,1H),4.22–4.17(m,1H), 4.15–4.10(m,1H),3.84–3.79(m,1H),3.78–3.73(m,2H),3.38–3.32(m,3H),3.16–3.10(m,1H) ,2.96(t,J＝5.3Hz,4H),2.09–2.03(m,1H),2.00–1.41(m,11H),0.37(s,4H).HRMS(ESI+,[M+H] + )m/z：556.2604.

化合物7_B:1H NMR(500MHz,DMSO-d6)δ12.86(s,1H),10.16(s,1H),8.06(d,J＝8.6Hz,1H),7.63(d,J＝8.3Hz,1H),7.26(d,J＝2.2Hz,1H),7.14(d,J＝8.3Hz,1H),7.11(dd,J＝8.6,2.2Hz,1H),4.98–4.87(m,1H),4.22–4.17(m,1H),4.16–4.10(m,1H),3.84–3.79(m,1H),3.78–3.73(m,2H),3.39–3.32(m,3H),3.17–3.10(m,1H),2.96(t,J＝5.3Hz,4H),2.09–2.03(m,1H),1.98–1.41(m,11H),0.37(s,4H).HRMS(ESI+,[M+H]+)m/z：556.2596.Compound 7_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.86 (s, 1H), 10.16 (s, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.26 (d, J = 2.2 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 7.11 (dd, J = 8.6, 2.2 Hz, 1H), 4.98–4.87 (m, 1H), 4.22–4.17 (m, 1H), 4.16–4.10(m,1H),3.84–3.79(m,1H),3.78–3.73(m,2H),3.39–3.32(m,3H),3.17–3.10(m,1H) ,2.96(t,J＝5.3Hz,4H),2.09–2.03(m,1H),1.98–1.41(m,11H),0.37(s,4H).HRMS(ESI+,[M+H] + )m/z：556.2596.

实施例8
Example 8

步骤A：Step A:

参考实施例2的步骤A，以化合物8-1替换N-叔丁氧羰基-2-哌啶-2-基乙醇得到化合物8-2。MS(ESI+,[M+H]+)m/z：388.27.Referring to step A of Example 2, compound 8-2 was obtained by replacing N-tert-butyloxycarbonyl-2-piperidin-2-ylethanol with compound 8-1. MS (ESI+, [M+H] + ) m/z: 388.27.

步骤B：Step B:

参考实施例2的步骤B，以化合物8-2替换化合物2-2制备得到化合物8-3。MS(ESI+,[M+H]+)m/z：288.32.Referring to step B of Example 2, compound 8-2 was used to replace compound 2-2 to prepare compound 8-3. MS (ESI+, [M+H] + ) m/z: 288.32.

步骤C：Step C:

参考实施例2的步骤C，以化合物8-3替换化合物2-3制备得到化合物8-4。1H NMR(500MHz,DMSO-d6)δ8.06(d,1H),7.21(d,1H),4.36-4.31(m,1H),4.25-4.21(m,1H),3.87–3.80(m,2H),3.74-3.71(m,1H),3.66–3.58(m,2H),3.35–3.32(m,1H),3.31–3.25(m,1H),2.03–1.95(m,2H).MS(ESI+,[M+H]+)m/z：252.25.Referring to step C of Example 2, compound 8-3 was used to replace compound 2-3 to prepare compound 8-4. 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.06 (d, 1H), 7.21 (d, 1H), 4.36-4.31 (m, 1H), 4.25-4.21 (m, 1H), 3.87–3.80 (m, 2H), 3.74-3.71 (m, 1H), 3.66–3.58 (m, 2H), 3.35–3.32 (m, 1H), 3.31–3.25 (m, 1H), 2.03–1.95 (m, 2H). MS (ESI+, [M+H] + ) m/z: 252.25.

步骤D：Step D:

参考实施例2的步骤D，以化合物8-4替换化合物2-4制备得到化合物8-5。MS(ESI+,[M+H]+)m/z：222.35.Referring to step D of Example 2, compound 8-5 was prepared by replacing compound 2-4 with compound 8-4. MS (ESI+, [M+H] + ) m/z: 222.35.

步骤E：Step E:

参考实施例2的步骤E，以化合物8-5替换化合物2-5制备得到化合物8-6。1H NMR(500MHz,DMSO-d6)δ11.47(s,1H),8.02(d,1H),7.85(d,1H),7.69–7.59(m,3H),4.34-4.31(m,2H),3.83–3.65(m,3H),3.51–3.38(m,4H),2.99(t,4H),1.99(q,2H),1.53(s,4H),0.34(s,4H).MS(ESI+,[M+H]+)m/z：561.40.Referring to step E of Example 2, compound 8-5 was used to replace compound 2-5 to prepare compound 8-6. 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.47 (s, 1H), 8.02 (d, 1H), 7.85 (d, 1H), 7.69–7.59 (m, 3H), 4.34-4.31 (m, 2H), 3.83–3.65 (m, 3H), 3.51–3.38 (m, 4H), 2.99 (t, 4H), 1.99 (q, 2H), 1.53 (s, 4H), 0.34 (s, 4H). MS (ESI+, [M+H] + ) m/z: 561.40.

步骤F：Step F:

参考实施例2的步骤F，以化合物8-6替换化合物2-6制备得到化合物8。1H NMR(500MHz,DMSO-d6)δ11.56(s,1H),10.16(s,1H),8.05(d,1H),7.91(d,1H),7.84(d,1H),7.20(d,1H),7.04(dd,1H),4.93(t,1H),4.40-4.36(m,1H),4.30-4.27(m,1H),3.80–3.67(m,5H),3.49–3.40(m,4H),3.35(t,2H),2.96(t,4H),2.00(q,2H),1.56(s,4H),0.36(s,4H).HRMS(ESI+,[M+H]+)m/z：558.2391. Referring to step F of Example 2, compound 8 was prepared by replacing compound 2-6 with compound 8-6. 1 H NMR (500MHz, DMSO-d 6 )δ11.56(s,1H),10.16(s,1H),8.05(d,1H),7.91(d,1H),7.84(d,1H),7.20(d,1H),7.04(dd,1H),4.93(t,1H),4.40-4.36(m,1H),4.30 -4.27(m,1H),3.80–3.67(m,5H),3.49–3.40(m,4H),3.35(t,2H),2.96(t,4H),2.00(q,2H),1.56(s,4H),0.36(s,4H).HRMS(ESI+,[M+H] + )m/z：558.2391.

实施例9
Example 9

步骤A：Step A:

100mL单口瓶中，依次加入化合物3-2(0.6g)，3-(2-羟乙基)吗啉-4-甲酸叔丁酯(1.04g)，甲苯(15mL)，氰基亚甲基三正丁基膦(1.35g)，N2保护下100℃加热回流搅拌15h。反应结束后，反应液减压旋蒸，加30mL水，乙酸乙酯(15mL×3)萃取，合并有机相，30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析(洗脱剂PE/EA＝10/1)纯化，得到化合物9-1(0.77g)。1H NMR(500MHz,CDCl3)δ7.26(s,1H),4.30–4.20(m,1H),4.06–3.98(m,1H),3.96–3.83(m,3H),3.82–3.73(m,1H),3.62(dd,1H),3.53–3.42(m,1H),3.25–3.09(m,1H),2.31(s,3H),2.29–2.17(m,2H),1.45(s,9H).Compound 3-2 (0.6 g), tert-butyl 3-(2-hydroxyethyl)morpholine-4-carboxylate (1.04 g), toluene (15 mL), cyanomethylenetri-n-butylphosphine (1.35 g) were added in sequence to a 100 mL single-mouth bottle, and heated under reflux at 100 ° C with stirring for 15 h under N 2 protection. After the reaction was completed, the reaction solution was evaporated under reduced pressure, 30 mL of water was added, and ethyl acetate (15 mL×3) was used for extraction. The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent PE/EA=10/1) to obtain compound 9-1 (0.77 g). 1 H NMR (500MHz, CDCl 3 )δ7.26(s,1H),4.30–4.20(m,1H),4.06–3.98(m,1H),3.96–3.83(m,3H),3.82–3.73(m,1H),3. 62(dd,1H),3.53–3.42(m,1H),3.25–3.09(m,1H),2.31(s,3H),2.29–2.17(m,2H),1.45(s,9H).

步骤B：Step B:

参考实施例3的步骤C，以化合物9-1代替化合物3-3制备得到化合物9-2(495mg)。1H NMR(500MHz,DMSO-d6)δ9.54(s,2H),7.65(s,1H),4.10–4.04(m,3H),3.90(dt,1H),3.75–3.69(m,1H),3.61–3.54(m,1H),3.53–3.46(m,1H),3.23(dt,1H),3.16–3.06(m,1H),2.33(s,3H),2.20–2.12(m,1H),2.07–2.00(m,1H).Referring to step C of Example 3, compound 9-1 was used instead of compound 3-3 to prepare compound 9-2 (495 mg). 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.54 (s, 2H), 7.65 (s, 1H), 4.10–4.04 (m, 3H), 3.90 (dt, 1H), 3.75–3.69 (m, 1H), 3.61–3.54 (m, 1H), 3.53–3.46 (m, 1H), 3.23 (dt, 1H), 3.16–3.06 (m, 1H), 2.33 (s, 3H), 2.20–2.12 (m, 1H), 2.07–2.00 (m, 1H).

步骤C：Step C:

参考实施例3的步骤D，以化合物9-2代替化合物3-4制备得到化合物9-3(350mg)。MS(ESI+,[M+H]+)m/z：299.25.Referring to step D of Example 3, compound 9-2 was used instead of compound 3-4 to prepare compound 9-3 (350 mg). MS (ESI+, [M+H] + ) m/z: 299.25.

步骤D：Step D:

参考实施例3的步骤E，以化合物9-3代替化合物3-5制备得到化合物9(200mg)。MS(ESI+,[M+H]+)m/z：572.54.Referring to step E of Example 3, compound 9 (200 mg) was prepared by replacing compound 3-5 with compound 9-3. MS (ESI+, [M+H] + ) m/z: 572.54.

步骤E：Step E:

化合物9(200mg)经过制备HPLC(拆分条件：柱：CHIRALART Cellulose SC，30×250mm，5μm；流动相：正己烷：二氯甲烷：乙醇＝65:30:5；流速：40mL/min；波长：254nm)拆分得到化合物9_A(47mg，保留时间为14.028分钟)、化合物9_B(76mg，保留时间为15.817分钟)。化合物9_A:1H NMR(500MHz,DMSO-d6)δ12.91(s,1H),10.16(s,1H),8.06(d,1H),7.64(s,1H),7.26(d,1H),7.12(dd,1H),5.09–4.70(m,1H),4.25–4.18(m,1H),4.09–4.02(m,1H),3.84(dt,1H),3.80–3.71(m,4H),3.68–3.62(m,1H),3.50–3.42(m,1H),3.36–3.34(m,2H),3.31–3.27(m,2H),3.01–2.88(m,4H),2.16(s,3H),1.88(q,2H),1.85–1.32(m,4H),0.41–0.34(m,4H).HRMS(ESI+,[M+H]+)m/z：572.2546.Compound 9 (200 mg) was separated by preparative HPLC (separation conditions: column: CHIRALART Cellulose SC, 30×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 65:30:5; flow rate: 40 mL/min; wavelength: 254 nm) to give Compound 9_A (47 mg, retention time 14.028 minutes) and Compound 9_B (76 mg, retention time 15.817 minutes). Compound 9_A: 1 H NMR (500 MHz, DMSO-d 6 )δ12.91(s,1H),10.16(s,1H),8.06(d,1H),7.64(s,1H),7.26(d,1H),7.12(dd,1H),5.0 9–4.70(m,1H),4.25–4.18(m,1H),4.09–4.02(m,1H),3.84(dt,1H),3.80–3.71(m,4H),3 .68–3.62(m,1H),3.50–3.42(m,1H),3.36–3.34(m,2H),3.31–3.27(m,2H),3.01–2.88(m ,4H),2.16(s,3H),1.88(q,2H),1.85–1.32(m,4H),0.41–0.34(m,4H).HRMS(ESI+,[M+H] + )m/z：572.2546.

化合物9_B:1H NMR(500MHz,DMSO-d6)δ12.91(s,1H),10.16(s,1H),8.06(d,1H),7.64(s,1H),7.26(d,1H),7.12(dd,1H),5.21–4.71(m,1H),4.25–4.18(m,1H),4.09–4.02(m,1H),3.84(dt,1H),3.79–3.71(m,4H),3.68–3.62(m,1H),3.49–3.43(m,1H),3.36–3.33(m,2H),3.31–3.26(m,2H),3.01–2.88(m,4H),2.16(s,3H),1.88(q,2H),1.84–1.34(m,4H),0.41–0.33(m,4H).HRMS(ESI+,[M+H]+)m/z：572.2553.Compound 9_B: 1 H NMR (500 MHz, DMSO-d 6 )δ12.91(s,1H),10.16(s,1H),8.06(d,1H),7.64(s,1H),7.26(d,1H),7.12(dd,1H),5.21–4.71(m,1H),4.25–4.18(m,1H),4.09–4.02(m,1H),3.84(dt,1H),3.79–3.71(m,4H),3 .68–3.62(m,1H),3.49–3.43(m,1H),3.36–3.33(m,2H),3.31–3.26(m,2H),3.01–2.88(m ,4H),2.16(s,3H),1.88(q,2H),1.84–1.34(m,4H),0.41–0.33(m,4H).HRMS(ESI+,[M+H] + )m/z：572.2553.

实施例10
Example 10

步骤A：Step A:

参考实施例1的步骤A，以3-羟甲基吗啡啉替换2-哌啶甲醇合成得到化合物10-1。MS(ESI+,[M+H]+)m/z：291.24.1H NMR(500MHz,DMSO-d6)δ7.82(d,1H),7.09(d,1H),4.75(t,1H),4.02–3.97(m,1H),3.99–3.80(m,1H),3.89–3.84(m,1H),3.85–3.68(m,1H),3.65–3.59(m,2H),3.58–3.48(m,2H),3.31–3.25(m,1H).Referring to step A of Example 1, 3-hydroxymethylmorpholine was used to replace 2-piperidinol to synthesize compound 10-1. MS (ESI+, [M+H] + ) m/z: 291.24. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.82 (d, 1H), 7.09 (d, 1H), 4.75 (t, 1H), 4.02–3.97 (m, 1H), 3.99–3.80 (m, 1H), 3.89–3.84 (m, 1H), 3.85–3.68 (m, 1H), 3.65–3.59 (m, 2H), 3.58–3.48 (m, 2H), 3.31–3.25 (m, 1H).

步骤B：Step B:

参考实施例1的步骤B，以化合物10-1替换化合物1-2得到化合物10-2。MS(ESI+,[M+H]+)m/z：271.25.1H NMR(500MHz,DMSO-d6)δ7.58(d,1H),6.90(d,1H),4.48–4.30(m,1H),4.25–4.15(m,1H),4.00–3.85(m,3H),3.56–3.43(m,2H),3.16(t,1H),2.95–2.75(m,1H).Referring to step B of Example 1, compound 10-1 was used to replace compound 1-2 to obtain compound 10-2. MS (ESI+, [M+H] + ) m/z: 271.25. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.58 (d, 1H), 6.90 (d, 1H), 4.48–4.30 (m, 1H), 4.25–4.15 (m, 1H), 4.00–3.85 (m, 3H), 3.56–3.43 (m, 2H), 3.16 (t, 1H), 2.95–2.75 (m, 1H).

步骤C：Step C:

参考实施例1的步骤C，以化合物10-2替换化合物1-3得到化合物10。1H NMR(500MHz,DMSO-d6)δ11.86(s,1H),10.18(s,1H),7.97(d,1H),7.92(d,1H),7.70(d,1H),7.23(d,1H),7.15–7.02(m,1H),4.92(t,1H),4.48–4.32(m,1H),4.27–4.20(m,1H),4.06–3.90(m,1H),3.75(q,2H),3.57–3.43(m,2H),3.35(t,2H),3.30–3.15(m,1H),2.99–2.85(m,4H),2.84–2.70(m,1H),1.34(d,2H),1.31–1.21(m,4H),0.37(s,4H).HRMS(ESI+,[M+H]+)m/z：544.2242.Referring to step C of Example 1, compound 10-2 was used to replace compound 1-3 to obtain compound 10. 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.86 (s, 1H), 10.18 (s, 1H), 7.97 (d, 1H), 7.92 (d, 1H), 7.70 (d, 1H), 7.23 (d, 1H), 7.15-7.02 (m, 1H), 4.92 (t, 1H), 4.48-4.32 (m, 1H), 4.27-4.20 (m, 1H), 4.06-3.90 (m, 1 H),3.75(q,2H),3.57–3.43(m,2H),3.35(t,2H),3.30–3.15(m,1H),2.99–2.85(m,4H ),2.84–2.70(m,1H),1.34(d,2H),1.31–1.21(m,4H),0.37(s,4H).HRMS(ESI+,[M+H] + )m/z：544.2242.

实施例11
Embodiment 11

步骤A：Step A:

参考实施例4的步骤I，以乙基磺酰胺替换2-羟基-1-磺酰胺得到化合物11。1H NMR(500MHz,DMSO-d6)δ13.12(s,1H),10.22(s,1H),8.07(d,1H),7.60(s,1H),7.28(d,1H),7.25–7.02(m,1H),4.31(d,1H),3.62(d,1H),3.26(s,4H),3.21(q,2H),2.97(s,4H),2.72(t,1H),2.38(s,3H),1.98(d,2H),1.83(s,2H),1.68(d,1H),1.46(q,3H),1.30–1.15(m,4H),0.37(s,4H).HRMS(ESI+,[M+H]+)m/z：567.2750.With reference to step I of example 4, compound 11 was obtained by replacing 2-hydroxy-1-sulfonamide with ethylsulfonamide. 1 H NMR (500MHz, DMSO-d 6 )δ13.12(s,1H),10.22(s,1H),8.07(d,1H),7.60(s,1H),7.28(d,1H), 7.25–7.02(m,1H),4.31(d,1H),3.62(d,1H),3.26(s,4H),3.21(q,2H), 2.97(s,4H),2.72(t,1H),2.38(s,3H),1.98(d,2H),1.83(s,2H),1.68 (d,1H),1.46(q,3H),1.30–1.15(m,4H),0.37(s,4H).HRMS(ESI+,[M+H] + )m/z：567.2750.

实施例12
Example 12

步骤A：Step A:

参考实施例4的步骤I，以甲基磺酰胺替换2-羟基-1-磺酰胺得到化合物12。1H NMR(500MHz,DMSO-d6)δ13.14(s,1H),10.23(s,1H),8.09(d,1H),7.60(s,1H),7.26(d,1H),7.18–7.06(m,1H),4.31(d,1H),3.26(s,2H),3.11(s,4H),2.98(s,4H),2.73(d,1H),2.38(s,3H),1.99(s,2H),1.57–1.41(m,3H),1.37–1.12(m,6H),0.37(s,4H).HRMS(ESI+,[M+H]+)m/z：553.2599.With reference to step I of example 4, compound 12 was obtained by replacing 2-hydroxy-1-sulfonamide with methanesulfonamide. 1 H NMR (500MHz, DMSO-d 6 )δ13.14(s,1H),10.23(s,1H),8.09(d,1H),7.60(s,1H),7.26(d,1H),7.18–7.06(m,1H),4.31(d,1H),3.26(s,2H),3.11(s,4 H),2.98(s,4H),2.73(d,1H),2.38(s,3H),1.99(s,2H),1.57–1.41(m,3H),1.37–1.12(m,6H),0.37(s,4H).HRMS(ESI+,[M+H] + )m/z：553.2599.

步骤B：Step B:

化合物12(200mg)经过制备HPLC(拆分条件：柱：(R,R)-Whelk O 1，4.6×250mm，5μm；流动 相：正己烷：二氯甲烷：乙醇＝40:45:15；流速：1mL/min；波长：254nm)拆分得到化合物12_A(80mg，保留时间为7.319分钟)、化合物12_B(80mg，保留时间为10.588分钟)。Compound 12 (200 mg) was subjected to preparative HPLC (separation conditions: column: (R,R)-Whelk O 1, 4.6×250 mm, 5 μm; flow The reaction mixture was separated by HPLC (5% CO 2 : 40° C.; phase: n-hexane: dichloromethane: ethanol = 40:45:15; flow rate: 1 mL/min; wavelength: 254 nm) to give compound 12_A (80 mg, retention time: 7.319 minutes) and compound 12_B (80 mg, retention time: 10.588 minutes).

化合物12_A:1H NMR(500MHz,DMSO-d6)δ13.14(s,1H),10.23(s,1H),8.09(d,1H),7.60(s,1H),7.26(d,1H),7.13(dd,1H),4.31(d,1H),3.66–3.26(m,2H),3.20–3.05(m,4H),2.97(s,4H),2.78–2.65(m,1H),2.38(s,3H),1.98(d,2H),1.68(d,2H),1.57–1.41(m,3H),1.29–1.21(m,2H),0.90–0.80(m,2H),0.37(s,4H).HRMS(ESI+,[M+H]+)m/z：553.2602.Compound 12_A: 1 H NMR (500 MHz, DMSO-d 6 )δ13.14(s,1H),10.23(s,1H),8.09(d,1H),7.60(s,1H),7.26(d,1H),7.1 3(dd,1H),4.31(d,1H),3.66–3.26(m,2H),3.20–3.05(m,4H),2.97(s,4H) ,2.78–2.65(m,1H),2.38(s,3H),1.98(d,2H),1.68(d,2H),1.57–1.41(m, 3H),1.29–1.21(m,2H),0.90–0.80(m,2H),0.37(s,4H).HRMS(ESI+,[M+H] + )m/z：553.2602.

化合物12_B:1H NMR(500MHz,DMSO-d6)δ13.14(s,1H),10.23(s,1H),8.09(d,1H),7.60(s,1H),7.26(d,1H),7.13(dd,1H),4.31(d,1H),3.66–3.26(m,2H),3.20–3.05(m,4H),2.98(s,4H),2.77–2.67(m,1H),2.38(s,3H),1.98(d,2H),1.68(d,2H),1.57–1.41(m,3H),1.28–1.21(m,2H),0.91–0.79(m,2H),0.37(s,4H).HRMS(ESI+,[M+H]+)m/z：553.2603.Compound 12_B: 1 H NMR (500 MHz, DMSO-d 6 )δ13.14(s,1H),10.23(s,1H),8.09(d,1H),7.60(s,1H),7.26(d,1H),7.1 3(dd,1H),4.31(d,1H),3.66–3.26(m,2H),3.20–3.05(m,4H),2.98(s,4H) ,2.77–2.67(m,1H),2.38(s,3H),1.98(d,2H),1.68(d,2H),1.57–1.41(m, 3H),1.28–1.21(m,2H),0.91–0.79(m,2H),0.37(s,4H).HRMS(ESI+,[M+H] + )m/z：553.2603.

实施例13
Embodiment 13

步骤A：Step A:

参考实施例4的步骤D，以吗啉-3-甲酸乙酯代替2-哌啶甲酸甲酯，制备得到化合物13-1(650mg)。MS(ESI+,[M+H]+)m/z：551.35.1H NMR(500MHz,DMSO-d6)δ7.13–7.08(m,4H),6.90–6.86(m,4H),6.18(s,1H),4.66–4.53(m,4H),4.11–4.06(m,1H),4.03(q,1H),4.01–3.95(m,1H),3.93–3.85(m,1H),3.79(dd,1H),3.75–3.68(m,8H),3.55–3.45(m,2H),2.21(s,3H),1.05(t,3H).Referring to step D of Example 4, ethyl morpholine-3-carboxylate was used instead of methyl 2-piperidincarboxylate to prepare compound 13-1 (650 mg). MS (ESI+, [M+H] + )m/z: 551.35. 1 H NMR (500MHz, DMSO-d 6 )δ7.13–7.08(m,4H),6.90–6.86(m,4H),6.18(s,1H),4.66–4.53(m,4H),4.11–4.06(m,1H),4.03(q,1H),4.01– 3.95(m,1H),3.93–3.85(m,1H),3.79(dd,1H),3.75–3.68(m,8H),3.55–3.45(m,2H),2.21(s,3H),1.05(t,3H).

步骤B：Step B:

参考实施例4的步骤E，以化合物13-1代替化合物4-5，制备得到化合物13-2(480mg)。MS(ESI+,[M+H]+)m/z：475.57.Referring to step E of Example 4, compound 13-1 was used instead of compound 4-5 to prepare compound 13-2 (480 mg). MS (ESI+, [M+H] + ) m/z: 475.57.

步骤C：Step C:

参考实施例4的步骤F，以化合物13-2代替化合物4-6，制备得到化合物13-3(331mg)。MS(ESI+,[M+H]+)m/z：489.29.Referring to step F of Example 4, compound 13-2 was used instead of compound 4-6 to prepare compound 13-3 (331 mg). MS (ESI+, [M+H] + ) m/z: 489.29.

步骤D：Step D:

参考实施例4的步骤G，以化合物13-3代替化合物4-7，制备得到化合物13-4(160mg)。MS(ESI+,[M+H]+)m/z：249.10.Referring to step G of Example 4, compound 13-3 was used instead of compound 4-7 to prepare compound 13-4 (160 mg). MS (ESI+, [M+H] + ) m/z: 249.10.

步骤E：Step E:

参考实施例4的步骤H，以化合物13-4代替化合物4-8，制备得到化合物13-5(226mg)。MS(ESI+,[M+H]+)m/z：588.26. Referring to step H of Example 4, compound 13-4 was used instead of compound 4-8 to prepare compound 13-5 (226 mg). MS (ESI+, [M+H] + ) m/z: 588.26.

步骤F：Step F:

参考实施例4的步骤I，以化合物13-5代替化合物4-9，制备得到化合物13(150mg)。MS(ESI+,[M+H]+)m/z：585.36.Referring to step I of Example 4, compound 13-5 was used instead of compound 4-9 to prepare compound 13 (150 mg). MS (ESI+, [M+H] + ) m/z: 585.36.

步骤G：Step G:

化合物13(150mg)经过制备HPLC(拆分条件：柱：(R,R)-whelk-O1，30×250mm，10μm；流动相：正己烷：二氯甲烷：乙醇＝50:25:25；流速：2mL/min；波长：254nm)拆分得到化合物13_A(38mg，保留时间为12.000分钟)、化合物13_B(25mg，保留时间为14.500分钟)。Compound 13 (150 mg) was separated by preparative HPLC (separation conditions: column: (R,R)-whelk-O1, 30×250 mm, 10 μm; mobile phase: n-hexane: dichloromethane: ethanol = 50:25:25; flow rate: 2 mL/min; wavelength: 254 nm) to give compound 13_A (38 mg, retention time: 12.000 minutes) and compound 13_B (25 mg, retention time: 14.500 minutes).

化合物13_A:1H NMR(500MHz,DMSO-d6)δ13.29(s,1H),10.17(s,1H),8.07(d,1H),7.68(s,1H),7.27(d,1H),7.13(dd,1H),4.95(s,1H),4.20(dd,1H),3.99(dd,1H),3.89(d,1H),3.76(t,2H),3.68–3.62(m,1H),3.63–3.57(m,1H),3.54(t,1H),3.35(t,2H),3.27(s,3H),3.01–2.92(m,4H),2.90–2.81(m,1H),2.40(s,3H),2.02–1.43(m,4H),0.37(s,4H).HRMS(ESI+,[M+H]+)m/z：585.2502.Compound 13_A: 1 H NMR (500 MHz, DMSO-d 6 )δ13.29(s,1H),10.17(s,1H),8.07(d,1H),7.68(s,1H),7.27(d,1H),7.13(dd,1H),4.95(s,1H),4.20(dd,1H),3.99(dd,1H),3.89(d,1H),3.76(t,2H),3.68–3.62(m ,1H),3.63–3.57(m,1H),3.54(t,1H),3.35(t,2H),3.27(s,3H),3.01–2.92(m,4H) ,2.90–2.81(m,1H),2.40(s,3H),2.02–1.43(m,4H),0.37(s,4H).HRMS(ESI+,[M+H] + )m/z：585.2502.

化合物13_B:1H NMR(500MHz,DMSO-d6)δ13.29(s,1H),10.19(s,1H),8.08(d,1H),7.68(s,1H),7.27(d,1H),7.13(dd,1H),4.93(s,1H),4.20(dd,1H),3.99(dd,1H),3.89(d,1H),3.76(t,2H),3.68–3.62(m,1H),3.63–3.58(m,1H),3.54(t,1H),3.35(t,2H),3.27(s,3H),3.02–2.91(m,4H),2.91–2.81(m,1H),2.40(s,3H),2.08–1.43(m,4H),0.37(s,4H).HRMS(ESI+,[M+H]+)m/z：585.2502.Compound 13_B: 1 H NMR (500 MHz, DMSO-d 6 )δ13.29(s,1H),10.19(s,1H),8.08(d,1H),7.68(s,1H),7.27(d,1H),7.13(dd,1H),4.93(s,1H),4.20(dd,1H),3.99(dd,1H),3.89(d,1H),3.76(t,2H),3.68–3.62(m ,1H),3.63–3.58(m,1H),3.54(t,1H),3.35(t,2H),3.27(s,3H),3.02–2.91(m,4H) ,2.91–2.81(m,1H),2.40(s,3H),2.08–1.43(m,4H),0.37(s,4H).HRMS(ESI+,[M+H] + )m/z：585.2502.

实施例14
Embodiment 14

步骤A：Step A:

向250mL三口瓶中依次加入化合物B-2(7.98g)、化合物14-1(6.0g)和THF(120mL)，N2保护，冰浴下缓慢滴加LiHMDS(1M,60mL)，室温搅拌反应3h，反应结束后，加入200mL饱和氯化铵溶液，EA(3×100mL)萃取，合并有机相，饱和食盐水洗涤后，无水硫酸钠干燥，抽滤，滤液浓缩，所得粗品经硅胶柱层析(PE:EA＝20:1)纯化得到化合物14-2(6.2g)。1H NMR(500MHz,DMSO-d6)δ9.81(s,1H),7.85(s,1H),7.73(d,1H),5.00(s,1H),4.12–3.87(m,1H),3.33(s,1H),2.65(s,1H),2.44(s,1H),2.12–1.89(m,2H),1.41(s,9H).MS(ESI-,[M-H]-)m/z：496.13.Compound B-2 (7.98 g), compound 14-1 (6.0 g) and THF (120 mL) were added to a 250 mL three-necked flask in sequence. Under N2 protection, LiHMDS (1 M, 60 mL) was slowly added dropwise in an ice bath. The reaction was stirred at room temperature for 3 h. After the reaction was completed, 200 mL of saturated ammonium chloride solution was added, and EA (3×100 mL) was used for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (PE:EA=20:1) to obtain compound 14-2 (6.2 g). 1 H NMR (500MHz, DMSO-d 6 )δ9.81(s,1H),7.85(s,1H),7.73(d,1H),5.00(s,1H),4.12–3.87(m,1H),3.33( s,1H),2.65(s,1H),2.44(s,1H),2.12–1.89(m,2H),1.41(s,9H).MS(ESI-,[MH] - )m/z：496.13.

步骤B：Step B:

向500mL三口瓶中依次加入化合物14-2(6.1g)和二氯甲烷(120mL)，冰浴下缓慢加入三氟乙酸(19.14mL)，室温搅拌反应3.0h，反应结束后，加入200mL饱和碳酸氢钠溶液，DCM(3×100mL)萃取，合并有机相，饱和食盐水洗涤后，无水硫酸钠干燥，抽滤，滤液浓缩得到化合物14-3(4.8g)。1H NMR(500MHz,DMSO-d6)δ8.34(d,1H),7.73(d,1H),3.65-3.62(m,1H),3.33(d,1H),3.07-3.03(m,1H),2.77-2.73(m,1H),2.33–2.18(m,1H),2.06-2.01(m,1H),1.92(t,1H),1.88–1.74(m,1H).MS(ESI-,[M-H]-)m/z：396.09.Compound 14-2 (6.1 g) and dichloromethane (120 mL) were added to a 500 mL three-necked flask in sequence, trifluoroacetic acid (19.14 mL) was slowly added under ice bath, and the reaction was stirred at room temperature for 3.0 h. After the reaction, 200 mL of saturated sodium bicarbonate solution was added, and DCM (3×100 mL) was used for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 14-3 (4.8 g). 1 H NMR (500MHz, DMSO-d 6 )δ8.34(d,1H),7.73(d,1H),3.65-3.62(m,1H),3.33(d,1H),3.07-3.03(m,1H),2.77-2.73( m,1H),2.33–2.18(m,1H),2.06-2.01(m,1H),1.92(t,1H),1.88–1.74(m,1H).MS(ESI-,[MH] - )m/z：396.09.

步骤C：Step C:

向100mL微波反应瓶中依次加入化合物14-3(4.7g)、NMP(40mL)和DIEA(4.2mL)，放入微波反应器中，在100瓦下加热至100℃反应150分钟。反应结束后，向反应液中加入300mL水，EA(3×100mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，所得粗品经硅胶柱层析(PE:EA＝4:1)纯化得到化合物14-4(3.6g)。1H NMR(500MHz,DMSO-d6)δ10.82(s,1H),6.94(d,1H),6.88(d,1H),4.55-4.51(m,1H),4.18-4.12(m,1H),2.85–2.73(m,1H),2.42-2.38(m,1H),2.15-2.11(m,2H),2.04–1.85(m,1H).MS(ESI-,[M-H]-)m/z：316.18. Compound 14-3 (4.7 g), NMP (40 mL) and DIEA (4.2 mL) were added to a 100 mL microwave reaction bottle in sequence, placed in a microwave reactor, and heated to 100 ° C at 100 watts for 150 minutes. After the reaction was completed, 300 mL of water was added to the reaction solution, extracted with EA (3×100 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (PE: EA = 4: 1) to obtain compound 14-4 (3.6 g). 1 H NMR (500MHz, DMSO-d 6 )δ10.82(s,1H),6.94(d,1H),6.88(d,1H),4.55-4.51(m,1H),4.18-4.12(m,1H),2.85 –2.73(m,1H),2.42-2.38(m,1H),2.15-2.11(m,2H),2.04–1.85(m,1H).MS(ESI-,[MH] - )m/z: 316.18.

步骤D：Step D:

向100mL单口瓶中依次加入化合物14-4(3.0g)和DMF(20mL)，冰浴下加入NaH(450mg)，搅拌5min后加入碘甲烷(1.6g)，室温反应20min，反应结束后，向反应液中加入饱和的氯化铵溶液200mL，EA(3×100mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，所得粗品用20mL石油醚打浆，抽滤，得到化合物14-5(2.5g)。1H NMR(500MHz,DMSO-d6)δ7.25(d,1H),6.99(d,1H),4.63–4.47(m,1H),4.31–4.17(m,1H),3.24(s,3H),2.82-2.79(m,1H),2.48–2.38(m,1H),2.22–2.06(m,2H),2.05–1.86(m,1H).HRMS(ESI+,[M+H]+)m/z：332.0200.Compound 14-4 (3.0 g) and DMF (20 mL) were added to a 100 mL single-mouth bottle in sequence, and NaH (450 mg) was added under ice bath. After stirring for 5 min, iodomethane (1.6 g) was added and the mixture was reacted at room temperature for 20 min. After the reaction was completed, 200 mL of saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with EA (3×100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was slurried with 20 mL of petroleum ether and filtered to obtain compound 14-5 (2.5 g). 1 H NMR (500MHz, DMSO-d 6 )δ7.25(d,1H),6.99(d,1H),4.63–4.47(m,1H),4.31–4.17(m,1H),3.24(s,3H),2.82-2 .79(m,1H),2.48–2.38(m,1H),2.22–2.06(m,2H),2.05–1.86(m,1H).HRMS(ESI+,[M+H] + )m/z：332.0200.

步骤E：Step E:

参考实施例1的步骤C，以化合物14-5替换化合物1-3，制备得到化合物14。MS(ESI+,[M+H]+)m/z：605.24.Referring to step C of Example 1, compound 14-5 was used to replace compound 1-3 to prepare compound 14. MS (ESI+, [M+H] + ) m/z: 605.24.

步骤F：Step F:

化合物14经过手性制备分离(拆分条件CHIRALART Cellulose-SB柱；流动相：正己烷：乙醇＝60:40)拆分得到化合物14_A(保留时间为3.811分钟)、化合物14_B(保留时间为4.129分钟)。Compound 14 was separated by chiral preparative separation (separation conditions: CHIRALART Cellulose-SB column; mobile phase: n-hexane:ethanol = 60:40) to give compound 14_A (retention time: 3.811 minutes) and compound 14_B (retention time: 4.129 minutes).

化合物14_A:1H NMR(500MHz,DMSO-d6)δ13.20(s,1H),10.20(s,1H),8.08(d,1H),7.74(d,1H),7.42(d,1H),7.28(d,1H),7.13(dd,1H),4.94(s,1H),4.68(d,1H),4.21(dd,1H),3.75(d,2H),3.36(t,2H),3.27(s,3H),3.03–2.86(m,5H),2.43-2.39(m,1H),2.23–1.31(m,7H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：605.2364.Compound 14_A: 1 H NMR (500MHz, DMSO-d 6 )δ13.20(s,1H),10.20(s,1H),8.08(d,1H),7.74(d,1H),7.42(d,1H),7.28(d,1H),7.13(dd,1H ),4.94(s,1H),4.68(d,1H),4.21(dd ,1H),3.75(d,2H),3.36(t,2H),3.27(s,3H),3.03–2.86(m,5H),2.43-2.39(m,1H),2.23–1.31(m,7H ),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：605.2364.

化合物14_B:1H NMR(500MHz,DMSO-d6)δ13.20(s,1H),10.20(s,1H),8.08(d,1H),7.74(d,1H),7.42(d,1H),7.28(d,1H),7.13(dd,1H),4.94(s,1H),4.68(d,1H),4.21(dd,1H),3.75(d,2H),3.36(t,2H),3.27(s,3H),3.03–2.86(m,5H),2.43-2.39(m,1H),2.23–1.31(m,7H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：605.2365.Compound 14_B: 1 H NMR (500MHz, DMSO-d 6 )δ13.20(s,1H),10.20(s,1H),8.08(d,1H),7.74(d,1H),7.42(d,1H),7.28(d,1H),7.13(dd,1H ),4.94(s,1H),4.68(d,1H),4.21(dd ,1H),3.75(d,2H),3.36(t,2H),3.27(s,3H),3.03–2.86(m,5H),2.43-2.39(m,1H),2.23–1.31(m,7H ),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：605.2365.

实施例15
Embodiment 15

步骤A：Step A:

向100mL单口瓶中依次加入化合物14-5(1.0g)、1,4-二氧六环(20mL)、二苯甲酮亚胺(655mg)、碳酸铯(2.45g)、Xant-phos(348mg)和Pd2(dba)3(276mg)，N2保护下100℃反应4.5h。反应结束后，向反应液中加入100mL EA，抽滤，滤液用100mL饱和食盐水洗涤后，无水硫酸钠干燥，抽滤，滤液浓缩，所得粗品经硅胶柱层析(PE:EA＝9:1)纯化，得到化合物15-1(760mg)。1H NMR(500MHz,DMSO-d6)δ7.70–7.64(m,2H),7.59–7.52(m,1H),7.47(dd,2H),7.34(dd,3H),7.24(d,1H),7.14(dd,2H),6.34(d,1H),4.19-4.14(m,1H),4.03(dd,1H),3.19(s,3H),2.56-2.52(m,1H),2.31-2.28(m,1H),1.98–1.78(m,2H),1.54-1.51(m,1H).MS(ESI+,[M+H]+)m/z：433.28.Compound 14-5 (1.0 g), 1,4-dioxane (20 mL), benzophenone imine (655 mg), cesium carbonate (2.45 g), Xant-phos (348 mg) and Pd 2 (dba) 3 (276 mg) were added to a 100 mL single-mouth bottle in sequence, and the mixture was reacted at 100 °C for 4.5 h under N 2 protection. After the reaction, 100 mL of EA was added to the reaction solution, and the mixture was filtered. The filtrate was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (PE:EA=9:1) to obtain compound 15-1 (760 mg). 1 H NMR (500MHz, DMSO-d 6 )δ7.70–7.64(m,2H),7.59–7.52(m,1H),7.47(dd,2H),7.34(dd,3H),7.24(d,1H),7.14(dd,2H),6.34(d,1H),4.19-4.14(m, 1H),4.03(dd,1H),3.19(s,3H),2.56-2.52(m,1H),2.31-2.28(m,1H),1.98–1.78(m,2H),1.54-1.51(m,1H).MS(ESI+,[M+H] + )m/z：433.28.

步骤B：Step B:

向100mL单口瓶中依次加入化合物15-1(700mg)、乙酸乙酯(12mL)和HCl的二氧六环溶液(4M,6mL)，室温反应5.0h，反应结束后，反应液倒入100mL饱和碳酸氢钠溶液中，EA(3×100mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，所得粗品经硅胶柱层析(DCM:MeOH＝50:1)纯化得到化合物15-2(410mg)。MS(ESI+,[M+H]+)m/z：269.03.Compound 15-1 (700 mg), ethyl acetate (12 mL) and HCl in dioxane solution (4 M, 6 mL) were added to a 100 mL single-mouth bottle in sequence, and the mixture was reacted at room temperature for 5.0 h. After the reaction, the reaction solution was poured into 100 mL of saturated sodium bicarbonate solution, extracted with EA (3×100 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (DCM: MeOH = 50: 1) to obtain compound 15-2 (410 mg). MS (ESI+, [M+H] + ) m/z: 269.03.

步骤C： Step C:

参考实施例2的步骤E，以化合物15-2替换化合物2-5制备得到化合物15-3。1H NMR(500MHz,DMSO-d6)δ13.24(s,1H),7.92–7.79(m,2H),7.77–7.70(m,2H),7.43(d,1H),4.68(d,1H),4.28–4.16(m,1H),3.27(s,3H),3.03(t,4H),2.90-2.86(m,1H),2.45–2.39(m,1H),2.25–1.48(m,7H),0.39(s,4H).MS(ESI+,[M+H]+)m/z：608.29.Referring to step E of Example 2, compound 15-2 was used to replace compound 2-5 to prepare compound 15-3. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.24 (s, 1H), 7.92–7.79 (m, 2H), 7.77–7.70 (m, 2H), 7.43 (d, 1H), 4.68 (d, 1H), 4.28–4.16 (m, 1H), 3.27 (s, 3H), 3.03 (t, 4H), 2.90-2.86 (m, 1H), 2.45–2.39 (m, 1H), 2.25–1.48 (m, 7H), 0.39 (s, 4H). MS (ESI+, [M+H] + ) m/z: 608.29.

步骤D：Step D:

参考实施例2的步骤F，以化合物15-3替换化合物2-6，以乙基磺酰胺替换2-羟基-1-磺酰胺，制备得到化合物15。1H NMR(500MHz,DMSO-d6)δ13.22(s,1H),8.04(d,1H),7.74(d,1H),7.41(d,1H),7.23(d,1H),7.08(m,1H),4.68-4.64(m,1H),4.20(dd,1H),3.27(s,3H),3.16(q,2H),2.97(t,4H),2.90-2.86(m,1H),2.42-2.38(m,1H),2.20–1.62(m,7H),1.20(t,3H),0.39(s,4H).HRMS(ESI+,[M+H]+)m/z：589.2418.Referring to step F of Example 2, compound 15 was prepared by replacing compound 2-6 with compound 15-3 and replacing 2-hydroxy-1-sulfonamide with ethylsulfonamide. 1 H NMR (500MHz, DMSO-d 6 )δ13.22(s,1H),8.04(d,1H),7.74(d,1H),7.41(d,1H),7.23(d,1H),7.08(m,1H),4.68-4.64(m,1H),4.20(dd,1H),3.27(s,3H) ,3.16(q,2H),2.97(t,4H),2.90-2.86(m,1H),2.42-2.38(m,1H),2.20–1.62(m,7H),1.20(t,3H),0.39(s,4H).HRMS(ESI+,[M+H] + )m/z：589.2418.

步骤E：Step E:

化合物15经过手性制备分离(拆分条件CHIRALART Cellulose-SB柱，4.6×250mm，5μm；流动相：正己烷:乙醇＝60:40；流速：1mL/min；波长：254nm)拆分得到化合物15_A(保留时间为10.472min)、化合物15_B(保留时间为12.454min)。Compound 15 was separated by chiral preparative separation (separation conditions: CHIRALART Cellulose-SB column, 4.6×250 mm, 5 μm; mobile phase: n-hexane:ethanol=60:40; flow rate: 1 mL/min; wavelength: 254 nm) to give compound 15_A (retention time: 10.472 min) and compound 15_B (retention time: 12.454 min).

化合物15_A:1H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.25(s,1H),8.08(d,1H),7.74(d,1H),7.42(d,1H),7.28(d,1H),7.25–7.04(m,1H),4.68(d,1H),4.29–4.11(m,1H),3.27(s,3H),3.22(q,2H),3.10–2.85(m,4H),2.99–2.81(m,1H),2.23–2.00(m,3H),1.95–1.50(m,4H),1.29–1.12(m,3H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：589.2418.Compound 15_A: 1 H NMR (500MHz, DMSO-d 6 )δ13.18(s,1H),10.25(s,1H),8.08(d,1H),7.74(d,1H),7.42(d,1H),7 .28(d,1H),7.25–7.04(m,1H),4.68(d,1H),4.29–4.11(m,1H),3.27(s, 3H),3.22(q,2H),3.10–2.85(m,4H),2.99–2.81(m,1H),2.23–2.00(m,3 H),1.95–1.50(m,4H),1.29–1.12(m,3H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：589.2418.

化合物15_B:1H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.25(s,1H),8.08(d,1H),7.74(d,1H),7.42(d,1H),7.28(d,1H),7.25–7.04(m,1H),4.68(d,1H),4.29–4.11(m,1H),3.27(s,3H),3.22(q,2H),3.10–2.85(m,4H),2.99–2.81(m,1H),2.23–2.00(m,3H),1.95–1.50(m,4H),1.29–1.12(m,3H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：589.2423.Compound 15_B: 1 H NMR (500MHz, DMSO-d 6 )δ13.18(s,1H),10.25(s,1H),8.08(d,1H),7.74(d,1H),7.42(d,1H),7 .28(d,1H),7.25–7.04(m,1H),4.68(d,1H),4.29–4.11(m,1H),3.27(s, 3H),3.22(q,2H),3.10–2.85(m,4H),2.99–2.81(m,1H),2.23–2.00(m,3 H),1.95–1.50(m,4H),1.29–1.12(m,3H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：589.2423.

实施例16
Example 16

步骤A：Step A:

参考实施例15的步骤D，以甲基磺酰胺替换乙基磺酰胺得到化合物16。1H NMR(500MHz,DMSO-d6)δ13.20(s,1H),10.24(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7.26(d,1H),7.13(dd,1H),4.72–4.64(m,1H),4.23–4.17(m,1H),3.27(s,3H),3.11(s,3H),3.04–2.95(m,4H),2.93–2.87(m,1H),2.46–2.40(m,1H),2.20–1.49(m,7H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：575.2258.Referring to step D of Example 15, Compound 16 was obtained by replacing ethylsulfonamide with methylsulfonamide. 1 H NMR (500MHz, DMSO-d 6 )δ13.20(s,1H),10.24(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7.26(d,1H),7.13(dd,1H),4.72–4.64(m,1H),4.23–4.17(m,1H) ,3.27(s,3H),3.11(s,3H),3.04–2.95(m,4H),2.93–2.87(m,1H),2.46–2.40(m,1H),2.20–1.49(m,7H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：575.2258.

步骤B：Step B:

化合物16(210mg)经过制备HPLC(拆分条件：柱：CHIRALART Cellulose SC；流动相A：正己烷，流动相B：二氯甲烷/乙醇＝5/1,；洗脱梯度：A/B＝55/45；流速：1mL/min；波长：254nm)拆分得到化合物16_A(100mg，保留时间：19.782min)，16_B(100mg，保留时间：22.455min)。Compound 16 (210 mg) was separated by preparative HPLC (separation conditions: column: CHIRALART Cellulose SC; mobile phase A: n-hexane, mobile phase B: dichloromethane/ethanol = 5/1; elution gradient: A/B = 55/45; flow rate: 1 mL/min; wavelength: 254 nm) to give compounds 16_A (100 mg, retention time: 19.782 min) and 16_B (100 mg, retention time: 22.455 min).

化合物16_A:1H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.22(s,1H),8.08(d,1H),7.73(d,1H),7.40(d,1H),7.25(d,1H),7.14-7.10(m,1H),4.69-4.62(m,1H),4.23-4.16(m,1H),3.26(s,3H),3.10(s,3H),3.01-2.95(m,4H),2.92-2.85(m,1H),2.46-2.36(m,1H),2.17-1.45(m,7H),0.37(s,4H).HRMS(ESI+,[M+H]+)m/z：575.2269.Compound 16_A: 1 H NMR (500MHz, DMSO-d 6 )δ13.18(s,1H),10.22(s,1H),8.08(d,1H),7.73(d,1H),7.40(d,1H),7.25(d,1H),7.14-7.10(m ,1H),4.69-4.62(m,1H),4.23-4.16(m,1 H),3.26(s,3H),3.10(s,3H),3.01-2.95(m,4H),2.92-2.85(m,1H),2.46-2.36(m,1H),2.17-1.45(m, 7H),0.37(s,4H).HRMS(ESI+,[M+H] + )m/z：575.2269.

化合物16_B:1H NMR(500MHz,DMSO-d6)δ13.20(s,1H),10.24(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7.26(d,1H),7.15-7.12(m,1H),4.72-4.64(m,1H),4.26-4.17(m,1H),3.27(s,3H),3.12(s,3H),3.03-2.95(m,4H),2.94-2.86(m,1H),2.47-2.39(m,1H),2.21-1.47(m,7H),0.38(s,4H).HRMS(ESI+,[M+H]+)m/z：575.2268. Compound 16_B: 1 H NMR (500MHz, DMSO-d 6 )δ13.20(s,1H),10.24(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7.26(d,1H),7.15-7.12(m ,1H),4.72-4.64(m,1H),4.26-4.17(m,1 H),3.27(s,3H),3.12(s,3H),3.03-2.95(m,4H),2.94-2.86(m,1H),2.47-2.39(m,1H),2.21-1.47(m, 7H),0.38(s,4H).HRMS(ESI+,[M+H] + )m/z：575.2268.

实施例17
Embodiment 17

步骤A：Step A:

100mL单口瓶中，依次加入化合物14-4(350mg)，碳酸钾(304mg)，乙腈(15mL)和4-甲氧基氯苄(224mg)，80℃加热回流搅拌3h。反应结束，抽滤，滤饼用乙酸乙酯(30mL)洗涤，滤液减压浓缩，所得粗品经硅胶柱层析(洗脱剂PE/EA＝20/1)纯化，得到化合物17-1(420mg)。1H NMR(500MHz,DMSO-d6)δ7.21–7.16(m,2H),7.10(d,1H),6.91–6.86(m,3H),5.14–5.00(m,2H),4.60–4.52(m,1H),4.46–4.38(m,1H),3.71(s,3H),2.91–2.82(m,1H),2.55–2.51(m,1H),2.42–2.11(m,2H),2.10–1.88(m,1H).Compound 14-4 (350 mg), potassium carbonate (304 mg), acetonitrile (15 mL) and 4-methoxybenzyl chloride (224 mg) were added to a 100 mL single-mouth bottle in sequence, and the mixture was heated at 80°C and refluxed for 3 h. After the reaction was completed, the mixture was filtered, the filter cake was washed with ethyl acetate (30 mL), the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent PE/EA=20/1) to obtain compound 17-1 (420 mg). 1 H NMR (500MHz, DMSO-d 6 )δ7.21–7.16(m,2H),7.10(d,1H),6.91–6.86(m,3H),5.14–5.00(m,2H),4.60–4.52(m,1H),4.46–4. 38(m,1H),3.71(s,3H),2.91–2.82(m,1H),2.55–2.51(m,1H),2.42–2.11(m,2H),2.10–1.88(m,1H).

步骤B：Step B:

参考实施例3的步骤E，以化合物17-1代替化合物3-5，得到化合物17-2(240mg)。MS(ESI+,[M+H]+)m/z:711.45.1H NMR(500MHz,DMSO-d6)δ13.21(s,1H),10.19(s,1H),8.06(d,1H),7.65–7.60(m,1H),7.33(d,1H),7.27(d,1H),7.23(d,1H),7.21(s,1H),7.12(dd,1H),6.90–6.87(m,2H),5.15–5.05(m,2H),4.93(s,1H),4.73–4.63(m,1H),4.36(dd,1H),3.75(t,2H),3.71(s,3H),3.35(t,2H),2.99–2.90(m,5H),2.39–1.94(m,4H),1.91–1.42(m,4H),0.47–0.34(m,4H).Referring to step E of Example 3, compound 17-1 was used instead of compound 3-5 to obtain compound 17-2 (240 mg). MS (ESI+, [M+H] + ) m/z: 711.45. 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.21 (s, 1H), 10.19 (s, 1H), 8.06 (d, 1H), 7.65–7.60 (m, 1H), 7.33 (d, 1H), 7.27 (d, 1H), 7.23 (d, 1H), 7.21 (s, 1H), 7.12 (dd, 1H), 6.90–6.87 (m, 2H), 5.15–5.05 (m, 2 H),4.93(s,1H),4.73–4.63(m,1H),4.36(dd,1H),3.75(t,2H),3.71(s,3H),3.35( t,2H),2.99–2.90(m,5H),2.39–1.94(m,4H),1.91–1.42(m,4H),0.47–0.34(m,4H).

步骤C：Step C:

100mL单口瓶中，将化合物17-2(240mg)溶于苯甲醚(10mL)，然后加入三氯化铝(675mg)，室温搅拌24h。反应结束，减压旋蒸，加40mL水，乙酸乙酯(20mL×3)萃取，合并有机相，30mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经硅胶柱层析(洗脱剂DCM/MeOH＝30/1)纯化，得到化合物17(16mg)。1H NMR(500MHz,DMSO-d6)δ13.17(s,1H),10.71(s,1H),10.18(s,1H),8.07(d,1H),7.65(d,1H),7.27(d,1H),7.13(dd,1H),7.10(d,1H),4.93(t,1H),4.75–4.65(m,1H),4.17–4.09(m,1H),3.80–3.72(m,2H),3.35(t,2H),3.03–2.93(m,4H),2.92–2.82(m,1H),2.46–2.35(m,1H),2.21–2.05(m,3H),1.95–1.49(m,4H),0.46–0.35(m,4H).HRMS(ESI+,[M+H]+)m/z：591.2216.In a 100 mL single-mouth bottle, compound 17-2 (240 mg) was dissolved in anisole (10 mL), and then aluminum chloride (675 mg) was added and stirred at room temperature for 24 h. After the reaction was completed, the mixture was evaporated under reduced pressure, 40 mL of water was added, and ethyl acetate (20 mL × 3) was used for extraction. The organic phases were combined, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent DCM/MeOH = 30/1) to obtain compound 17 (16 mg). 1 H NMR (500 MHz, DMSO-d 6 )δ13.17(s,1H),10.71(s,1H),10.18(s,1H),8.07(d,1H),7.65(d,1H),7.27(d,1 H),7.13(dd,1H),7.10(d,1H),4.93(t,1H),4.75–4.65(m,1H),4.17–4.09(m,1H), 3.80–3.72(m,2H),3.35(t,2H),3.03–2.93(m,4H),2.92–2.82(m,1H),2.46–2.35( m,1H),2.21–2.05(m,3H),1.95–1.49(m,4H),0.46–0.35(m,4H).HRMS(ESI+,[M+H] + )m/z：591.2216.

实施例18
Embodiment 18

步骤A： Step A:

参考实施例2的步骤A，以化合物C-5替换N-叔丁氧羰基-2-哌啶-2-基乙醇制备得到化合物18-1。1H NMR(500MHz,DMSO-d6)δ8.44(d,1H),7.99(d,1H),4.55(s,1H),4.19(d,1H),4.11–3.97(m,2H),2.99(t,1H),2.15–1.95(m,5H),1.38(s,9H),1.28–1.12(m,1H).MS(ESI+,[M+H]+)m/z：422.09.Referring to step A of Example 2, compound 18-1 was prepared by replacing N-tert-butyloxycarbonyl-2-piperidin-2-ylethanol with compound C-5. 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.44 (d, 1H), 7.99 (d, 1H), 4.55 (s, 1H), 4.19 (d, 1H), 4.11–3.97 (m, 2H), 2.99 (t, 1H), 2.15–1.95 (m, 5H), 1.38 (s, 9H), 1.28–1.12 (m, 1H). MS (ESI+, [M+H] + ) m/z: 422.09.

步骤B：Step B:

参考实施例2的步骤B，以化合物18-1替换化合物2-2制备得到化合物18-2。1H NMR(500MHz,DMSO-d6)δ8.45(d,1H),8.00(d,1H),4.26(t,2H),3.07–2.97(m,1H),2.85–2.76(m,1H),2.56-2.51(m,1H),2.07-2.03(m,1H),1.92-1.90(m,1H),1.84(q,2H),1.70-1.68(m,1H),1.49-1.42(m,1H),1.29–1.13(m,1H).MS(ESI+,[M+H]+)m/z：322.07.Referring to step B of Example 2, compound 18-1 was used to replace compound 2-2 to prepare compound 18-2. 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.45 (d, 1H), 8.00 (d, 1H), 4.26 (t, 2H), 3.07–2.97 (m, 1H), 2.85–2.76 (m, 1H), 2.56-2.51 (m, 1H), 2.07-2.03 (m, 1H), 1.92-1.90 (m, 1H), 1.84 (q, 2H), 1.70-1.68 (m, 1H), 1.49-1.42 (m, 1H), 1.29–1.13 (m, 1H). MS (ESI+, [M+H] + ) m/z: 322.07.

步骤C：Step C:

参考实施例2的步骤C，以化合物18-2替换化合物2-3制备得到化合物18-3。HRMS(ESI+,[M+H]+)m/z：286.1004.Referring to step C of Example 2, compound 18-2 was used to replace compound 2-3 to prepare compound 18-3. HRMS (ESI+, [M+H] + ) m/z: 286.1004.

步骤D：Step D:

参考实施例2的步骤D，以化合物18-3替换化合物2-4制备得到化合物18-4。MS(ESI+,[M+H]+)m/z：256.14.Referring to step D of Example 2, compound 18-3 was used to replace compound 2-4 to prepare compound 18-4. MS (ESI+, [M+H] + ) m/z: 256.14.

步骤E：Step E:

参考实施例2的步骤E，以化合物18-4替换化合物2-5制备得到化合物18-5。MS(ESI+,[M+H]+)m/z：595.28.Referring to step E of Example 2, compound 18-4 was used to replace compound 2-5 to prepare compound 18-5. MS (ESI+, [M+H] + ) m/z: 595.28.

步骤F：Step F:

参考实施例2的步骤F，以化合物18-5替换化合物2-6制备得到化合物18。1H NMR(500MHz,DMSO-d6)δ11.56(s,1H),8.10(d,1H),7.86(dd,2H),7.13(s,1H),6.98(d,1H),4.50–4.34(m,2H),3.82(d,1H),3.75(t,2H),3.51(d,1H),3.29(t,3H),3.20(t,1H),2.96(d,4H),2.40–1.81(m,7H),1.55(s,4H),0.35(s,4H).HRMS(ESI+,[M+H]+)m/z：592.2417.Referring to step F of Example 2, compound 18 was prepared by replacing compound 2-6 with compound 18-5. 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.56 (s, 1H), 8.10 (d, 1H), 7.86 (dd, 2H), 7.13 (s, 1H), 6.98 (d, 1H), 4.50–4.34 (m, 2H), 3.82 (d, 1H), 3.75 (t, 2H), 3.51 (d, 1H), 3.29 (t, 3H), 3.20 (t, 1H), 2.96 (d, 4H), 2.40–1.81 (m, 7H), 1.55 (s, 4H), 0.35 (s, 4H). HRMS (ESI+, [M+H] + ) m/z: 592.2417.

步骤G：Step G:

化合物18经过制备HPLC(拆分条件柱：CHIRALART Cellulose-SC，4.6×250mm，5μm；流动相：正己烷:二氯甲烷:乙醇＝64:30:6；流速：1mL/min；波长：254nm)拆分得到化合物18_A(保留时间：2.762min)、化合物18_B(保留时间：3.108min)。Compound 18 was separated by preparative HPLC (separation conditions: column: CHIRALART Cellulose-SC, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 64:30:6; flow rate: 1 mL/min; wavelength: 254 nm) to give compound 18_A (retention time: 2.762 min) and compound 18_B (retention time: 3.108 min).

化合物18_A:1H NMR(500MHz,DMSO-d6)δ11.56(s,1H),8.10(d,1H),7.86(dd,2H),7.13(s,1H),6.98(d,1H),4.50–4.34(m,2H),3.82(d,1H),3.75(t,2H),3.51(d,1H),3.29(t,3H),3.20(t,1H),2.96(d,4H),2.40–1.81(m,7H),1.55(s,4H),0.35(s,4H).HRMS(ESI+,[M+H]+)m/z：592.2417.Compound 18_A: 1 H NMR (500MHz, DMSO-d 6 )δ11.56(s,1H),8.10(d,1H),7.86(dd,2H),7.13(s,1H),6.98(d,1H),4.50–4.34(m,2H),3.82(d ,1H),3.75(t,2H), 3.51(d,1H),3.29(t,3H),3.20(t,1H),2.96(d,4H),2.40–1.81(m,7H),1.55(s,4H),0.35(s,4H) .HRMS(ESI+,[M+H] + )m/z：592.2417.

化合物18_B:1H NMR(500MHz,DMSO-d6)δ11.56(s,1H),8.10(d,1H),7.86(dd,2H),7.13(s,1H),6.98(d,1H),4.50–4.34(m,2H),3.82(d,1H),3.75(t,2H),3.51(d,1H),3.29(t,3H),3.20(t,1H),2.96(d,4H),2.40–1.81(m,7H),1.55(s,4H),0.35(s,4H).HRMS(ESI+,[M+H]+)m/z：592.2419.Compound 18_B: 1 H NMR (500MHz, DMSO-d 6 )δ11.56(s,1H),8.10(d,1H),7.86(dd,2H),7.13(s,1H),6.98(d,1H),4.50–4.34(m,2H),3.82(d ,1H),3.75(t,2H), 3.51(d,1H),3.29(t,3H),3.20(t,1H),2.96(d,4H),2.40–1.81(m,7H),1.55(s,4H),0.35(s,4H) .HRMS(ESI+,[M+H] + )m/z：592.2419.

实施例19
Embodiment 19

步骤A:Step A:

250mL两口瓶中依次加入化合物7-1(0.45g)、化合物C-5(0.715g)、三苯基膦(0.8g)与THF(20mL)， 氮气保护，冰浴搅拌，滴加DEAD(0.612g)的THF(5mL)溶液，然后逐渐恢复至室温搅拌反应18h。反应结束后，加入50mL蒸馏水，EA(100mL)萃取，分别用饱和碳酸氢钠溶液(100mL)与饱和食盐水(100mL)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，所得粗品经硅胶柱层析(洗脱剂：PE/EA＝20/1)纯化，得到化合物19-1(0.894g)。1H NMR(500MHz,DMSO-d6)δ7.69–7.56(m,1H),7.53(d,1H),4.72–4.48(m,1H),4.11–3.99(m,3H),3.06–2.90(m,1H),2.16–1.98(m,4H),1.96–1.76(m,2H),1.26(s,9H).Compound 7-1 (0.45 g), compound C-5 (0.715 g), triphenylphosphine (0.8 g) and THF (20 mL) were added to a 250 mL two-necked bottle in sequence. Under nitrogen protection, stirring in an ice bath, dropwise add a solution of DEAD (0.612 g) in THF (5 mL), then gradually return to room temperature and stir to react for 18 h. After the reaction is completed, add 50 mL of distilled water, extract with EA (100 mL), wash with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), respectively, and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (eluent: PE/EA=20/1) to obtain compound 19-1 (0.894 g). 1 H NMR (500MHz, DMSO-d 6 )δ7.69–7.56(m,1H),7.53(d,1H),4.72–4.48(m,1H),4.11–3.99(m,3H) ,3.06–2.90(m,1H),2.16–1.98(m,4H),1.96–1.76(m,2H),1.26(s,9H).

步骤B:Step B:

250mL单口瓶中依次加入化合物19-1(0.864g)、DCM(30mL)和TFA(1.5mL)，室温搅拌反应16小时。反应结束后，加入50mL蒸馏水，EA(100mL)萃取，分别用饱和碳酸氢钠溶液(100mL)与饱和食盐水(100mL)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，所得粗品经硅胶柱层析(洗脱剂：MeOH/DCM＝50/1)纯化，得到化合物19-2(0.656g)。MS(ESI+,[M+H]+)m/z：339.20.1H NMR(500MHz,DMSO-d6)δ7.67(dd,1H),7.54(d,1H),4.25–4.17(m,2H),3.04–2.96(m,1H),2.79–2.71(m,1H),2.57–2.52(m,1H),2.28–2.01(m,2H),1.95–1.88(m,1H),1.87–1.78(m,2H),1.77–1.63(m,1H),1.57–1.42(m,1H).Compound 19-1 (0.864 g), DCM (30 mL) and TFA (1.5 mL) were added to a 250 mL single-mouth bottle in sequence, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, 50 mL of distilled water was added, and EA (100 mL) was used for extraction. The mixture was washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), respectively, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: MeOH/DCM=50/1) to obtain compound 19-2 (0.656 g). MS (ESI+, [M+H] + )m/z: 339.20. 1 H NMR (500MHz, DMSO-d 6 )δ7.67(dd,1H),7.54(d,1H),4.25–4.17(m,2H),3.04–2.96(m,1H),2.79–2.71(m,1H),2.57–2.52(m ,1H),2.28–2.01(m,2H),1.95–1.88(m,1H),1.87–1.78(m,2H),1.77–1.63(m,1H),1.57–1.42(m,1H).

步骤C:Step C:

35mL微波管中依次加入化合物19-2(0.44g)、NMP(10mL)和DIPEA(0.335g)，放入微波反应器中,在100瓦下加热至120℃反应90分钟。反应结束后，加入50mL蒸馏水，EA(100mL)萃取，分别用饱和碳酸氢钠溶液(100mL)与饱和食盐水(100mL)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，所得粗品经硅胶柱层析(洗脱剂：PE/EA＝20/1)纯化，得到化合物19-3(0.25g)。1H NMR(500MHz,DMSO-d6)δ7.11(d,1H),6.99(d,1H),4.28–4.20(m,2H),3.93–3.84(m,1H),3.57–3.52(m,1H),3.15–3.08(m,1H),2.21–1.92(m,6H).Compound 19-2 (0.44 g), NMP (10 mL) and DIPEA (0.335 g) were added to a 35 mL microwave tube in sequence, placed in a microwave reactor, and heated to 120°C at 100 watts for 90 minutes. After the reaction was completed, 50 mL of distilled water was added, extracted with EA (100 mL), washed with saturated sodium bicarbonate solution (100 mL) and saturated brine (100 mL), respectively, and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA=20/1) to obtain compound 19-3 (0.25 g). 1 H NMR (500MHz, DMSO-d 6 )δ7.11(d,1H),6.99(d,1H),4.28–4.20(m,2H),3.93–3.84(m,1H),3.57–3.52(m,1H),3.15–3.08(m,1H),2.21–1.92(m,6H).

步骤D:Step D:

50mL单口瓶中，依次加入化合物A-6(0.231g)、化合物19-3(0.209g)、Pd2(dba)3(0.024g)、Xant-Phos(0.038g)、碳酸铯(0.640g)和二氧六环(20mL)，氮气保护，100℃加热反应8h。反应结束后，加入50mL蒸馏水，EA(100mL)萃取，饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，所得粗品经硅胶柱层析(洗脱剂：PE/EA＝1/1)纯化，得到化合物19(0.210g)。MS(ESI+,[M+H]+)m/z:592.15.Compound A-6 (0.231 g), compound 19-3 (0.209 g), Pd 2 (dba) 3 (0.024 g), Xant-Phos (0.038 g), cesium carbonate (0.640 g) and dioxane (20 mL) were added to a 50 mL single-mouth bottle in sequence, and the mixture was heated at 100 °C for 8 h under nitrogen protection. After the reaction, 50 mL of distilled water was added, and the mixture was extracted with EA (100 mL), washed with saturated brine (50 mL × 2), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: PE/EA = 1/1) to obtain compound 19 (0.210 g). MS (ESI+, [M+H] + ) m/z: 592.15.

步骤E：Step E:

化合物19(150mg)经过制备HPLC(拆分条件柱：whelk-O1，20×250mm，5μm；流动相：正己烷：(二氯甲烷-乙醇)＝66:34(6:1)；流速：22mL/min；波长：254nm)拆分得到化合物19_A(68mg，保留时间为25.02分钟)、化合物19_B(68mg，保留时间为27.13分钟)。Compound 19 (150 mg) was separated by preparative HPLC (separation conditions: column: whelk-O1, 20×250 mm, 5 μm; mobile phase: n-hexane:(dichloromethane-ethanol)=66:34 (6:1); flow rate: 22 mL/min; wavelength: 254 nm) to give compound 19_A (68 mg, retention time: 25.02 minutes) and compound 19_B (68 mg, retention time: 27.13 minutes).

化合物19_A:1H NMR(500MHz,DMSO-d6)δ12.81(s,1H),10.17(s,1H),8.06(d,1H),7.76(d,1H),7.26(d,1H),7.22(d,1H),7.11(dd,1H),4.93(t,1H),4.26–4.17(m,2H),4.04–3.98(m,1H),3.79–3.72(m,2H),3.54–3.47(m,1H),3.35(t,2H),3.22–3.15(m,1H),3.04–2.89(m,4H),2.31–1.55(m,10H),0.38(s,4H).HRMS(ESI+,[M+H]+)m/z：592.2421.Compound 19_A: 1 H NMR (500 MHz, DMSO-d 6 )δ12.81(s,1H),10.17(s,1H),8.06(d,1H),7.76(d,1H),7.26(d,1H),7 .22(d,1H),7.11(dd,1H),4.93(t,1H),4.26–4.17(m,2H),4.04–3.98(m, 1H),3.79–3.72(m,2H),3.54–3.47(m,1H),3.35(t,2H),3.22–3.15(m,1H ),3.04–2.89(m,4H),2.31–1.55(m,10H),0.38(s,4H).HRMS(ESI+,[M+H] + )m/z：592.2421.

化合物19_B:1H NMR(500MHz,DMSO-d6)δ12.81(s,1H),10.17(s,1H),8.06(d,1H),7.76(d,1H),7.26(d,1H),7.22(d,1H),7.11(dd,1H),4.99–4.87(m,1H),4.25–4.16(m,2H),4.04–3.98(m,1H),3.79–3.73(m,2H),3.54–3.47(m,1H),3.35(t,2H),3.22–3.15(m,1H),3.04–2.91(m,4H),2.31–1.58(m,10H),0.38(s,4H).HRMS(ESI+,[M+H]+)m/z：592.2421.Compound 19_B: 1 H NMR (500 MHz, DMSO-d 6 )δ12.81(s,1H),10.17(s,1H),8.06(d,1H),7.76(d,1H),7.26(d,1H),7.2 2(d,1H),7.11(dd,1H),4.99–4.87(m,1H),4.25–4.16(m,2H),4.04–3.98( m,1H),3.79–3.73(m,2H),3.54–3.47(m,1H),3.35(t,2H),3.22–3.15(m,1 H),3.04–2.91(m,4H),2.31–1.58(m,10H),0.38(s,4H).HRMS(ESI+,[M+H] + )m/z：592.2421.

实施例20
Embodiment 20

步骤A：Step A:

化合物14-5(2.09g)经过制备HPLC(拆分条件：柱：CHIRALART Amylose-SA，30×250mm，5μm；流动相：正己烷：乙醇＝50:50；流速：40mL/min；波长：254nm)拆分得到化合物20-1A(0.97g，保留时间为6.313分钟)、化合物20-1B(0.97g，保留时间为9.344分钟)。Compound 14-5 (2.09 g) was separated by preparative HPLC (separation conditions: column: CHIRALART Amylose-SA, 30×250 mm, 5 μm; mobile phase: n-hexane: ethanol = 50:50; flow rate: 40 mL/min; wavelength: 254 nm) to give compound 20-1A (0.97 g, retention time of 6.313 minutes) and compound 20-1B (0.97 g, retention time of 9.344 minutes).

化合物20_1A:1H NMR(500MHz,DMSO-d6)δ7.25(d,1H),6.99(d,1H),4.58–4.51(m,1H),4.31–4.22(m,1H),3.24(s,3H),2.86–2.78(m,1H),2.49–2.40(m,1H),2.23–2.05(m,2H),2.04–1.87(m,1H).Compound 20_1A: 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.25 (d, 1H), 6.99 (d, 1H), 4.58–4.51 (m, 1H), 4.31–4.22 (m, 1H), 3.24 (s, 3H), 2.86–2.78 (m, 1H), 2.49–2.40 (m, 1H), 2.23–2.05 (m, 2H), 2.04–1.87 (m, 1H).

化合物20_1B:1H NMR(500MHz,DMSO-d6)δ7.25(d,1H),6.99(d,1H),4.60–4.52(m,1H),4.30–4.21(m,1H),3.24(s,3H),2.87–2.77(m,1H),2.48–2.40(m,1H),2.22–2.06(m,2H),2.03–1.88(m,1H).Compound 20_1B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.25 (d, 1H), 6.99 (d, 1H), 4.60–4.52 (m, 1H), 4.30–4.21 (m, 1H), 3.24 (s, 3H), 2.87–2.77 (m, 1H), 2.48–2.40 (m, 1H), 2.22–2.06 (m, 2H), 2.03–1.88 (m, 1H).

步骤B：Step B:

依次加入化合物D-4(60mg)、化合物20-1A(68.4mg)、Pd2(dba)3(15.7mg)、Xant-Phos(20mg)、碳酸铯(168mg)和二氧六环(8mL)，氮气保护下，100℃加热反应4h。反应结束后向反应液中加入30mL蒸馏水，EA(20mL×3)萃取，饱和食盐水(30mL)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：PE/EA＝1/1)纯化，得到化合物20_A(68mg)。1H NMR(500MHz,DMSO-d6)δ10.96(s,1H),10.08(s,1H),7.84–7.78(m,2H),7.41(d,1H),7.25(d,1H),7.06(dd,1H),4.70–4.60(m,1H),4.23–4.14(m,1H),3.27(s,3H),3.08(s,3H),3.05–2.98(m,4H),2.87–2.76(m,1H),2.45–2.35(m,1H),2.19–1.92(m,5H),1.87–1.76(m,2H),1.52–1.40(m,2H),0.69–0.59(m,2H),0.46–0.32(m,2H).HRMS(ESI+,[M+H]+)m/z：601.2424.Compound D-4 (60 mg), compound 20-1A (68.4 mg), Pd 2 (dba) 3 (15.7 mg), Xant-Phos (20 mg), cesium carbonate (168 mg) and dioxane (8 mL) were added in sequence, and the mixture was heated at 100°C for 4 h under nitrogen protection. After the reaction, 30 mL of distilled water was added to the reaction solution, and the mixture was extracted with EA (20 mL × 3), washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE/EA = 1/1) to obtain compound 20_A (68 mg). 1 H NMR (500 MHz, DMSO-d 6 )δ10.96(s,1H),10.08(s,1H),7.84–7.78(m,2H),7.41(d,1H),7.25(d,1H),7.06 (dd,1H),4.70–4.60(m,1H),4.23–4.14(m,1H),3.27(s,3H),3.08(s,3H),3.05–2 .98(m,4H),2.87–2.76(m,1H),2.45–2.35(m,1H),2.19–1.92(m,5H),1.87–1.76( m,2H),1.52–1.40(m,2H),0.69–0.59(m,2H),0.46–0.32(m,2H).HRMS(ESI+,[M+H] + )m/z：601.2424.

参考化合物20_A的制备方法，以化合物20-1B代替化合物20-1A，制备得到化合物20_B(80mg)。1H NMR(500MHz,DMSO-d6)δ10.96(s,1H),10.08(s,1H),7.86–7.76(m,2H),7.41(d,1H),7.25(d,1H),7.06(dd,1H),4.75–4.60(m,1H),4.23–4.15(m,1H),3.27(s,3H),3.08(s,3H),3.06–2.95(m,4H),2.86–2.78(m,1H),2.47–2.34(m,1H),2.21–1.98(m,5H),1.88–1.76(m,2H),1.55–1.41(m,2H),0.70–0.60(m,2H),0.48–0.34(m,2H).HRMS(ESI+,[M+H]+)m/z：601.2430.Referring to the preparation method of compound 20_A, compound 20-1B was used instead of compound 20-1A to prepare compound 20_B (80 mg). 1 H NMR (500 MHz, DMSO-d 6 )δ10.96(s,1H),10.08(s,1H),7.86–7.76(m,2H),7.41(d,1H),7.25(d,1H),7.06(dd,1H),4.75–4.60(m,1H),4.23–4.15(m,1H),3.27(s,3H),3.08(s,3H),3.06–2 .95(m,4H),2.86–2.78(m,1H),2.47–2.34(m,1H),2.21–1.98(m,5H),1.88–1.76( m,2H),1.55–1.41(m,2H),0.70–0.60(m,2H),0.48–0.34(m,2H).HRMS(ESI+,[M+H] + )m/z：601.2430.

实施例21
Embodiment 21

步骤A:Step A:

参考实施例14的步骤D，以氘代碘甲烷-D3替换碘甲烷制备得到化合物21-1。1H NMR(500MHz,DMSO-d6)δ7.24(d,1H),6.99(d,1H),4.57–4.51(m,1H),4.28–4.22(m,1H),2.86–2.79(m,1H),2.48–2.41(m,1H),2.21–2.07(m,2H),2.02–1.88(m,1H).Referring to step D of Example 14, deuterated iodomethane-D3 was used to replace iodomethane to prepare compound 21-1. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.24 (d, 1H), 6.99 (d, 1H), 4.57-4.51 (m, 1H), 4.28-4.22 (m, 1H), 2.86-2.79 (m, 1H), 2.48-2.41 (m, 1H), 2.21-2.07 (m, 2H), 2.02-1.88 (m, 1H).

步骤B：Step B:

化合物21-1(0.26g)经过制备HPLC(拆分条件：柱：CHIRALART Amylose-SA(30*250mm,5um)；流动相：乙醇：正己烷＝60:40；流速：40mL/min；波长：254nm)拆分得到化合物21-2A(0.129g，保留时间为6.20分钟)、化合物21-2B(0.126g，保留时间为9.10分钟)。Compound 21-1 (0.26 g) was separated by preparative HPLC (separation conditions: column: CHIRALART Amylose-SA (30*250 mm, 5 um); mobile phase: ethanol: n-hexane = 60:40; flow rate: 40 mL/min; wavelength: 254 nm) to give compound 21-2A (0.129 g, retention time of 6.20 minutes) and compound 21-2B (0.126 g, retention time of 9.10 minutes).

化合物21-2A:1H NMR(500MHz,DMSO-d6)δ7.24(d,1H),6.99(d,1H),4.58–4.51(m,1H),4.28–4.21(m,1H),2.86–2.79(m,1H),2.48–2.41(m,1H),2.21–2.07(m,2H),2.02–1.88(m,1H).HRMS(ESI+,[M+H]+)m/z：335.0388.Compound 21-2A: 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.24 (d, 1H), 6.99 (d, 1H), 4.58–4.51 (m, 1H), 4.28–4.21 (m, 1H), 2.86–2.79 (m, 1H), 2.48–2.41 (m, 1H), 2.21–2.07 (m, 2H), 2.02–1.88 (m, 1H). HRMS (ESI+, [M+H] + ) m/z: 335.0388.

化合物21-2B:1H NMR(500MHz,DMSO-d6)δ7.24(d,1H),6.99(d,1H),4.58–4.51(m,1H),4.28–4.21(m,1H),2.86–2.79(m,1H),2.48–2.41(m,1H),2.21–2.07(m,2H),2.02–1.88(m,1H).HRMS(ESI+,[M+H]+)m/z：335.0380.Compound 21-2B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.24 (d, 1H), 6.99 (d, 1H), 4.58–4.51 (m, 1H), 4.28–4.21 (m, 1H), 2.86–2.79 (m, 1H), 2.48–2.41 (m, 1H), 2.21–2.07 (m, 2H), 2.02–1.88 (m, 1H). HRMS (ESI+, [M+H] + ) m/z: 335.0380.

步骤C:Step C:

参考实施例14的步骤E，以化合物21-2A替换化合物14-5制备得到化合物21_A。1H NMR(500 MHz,DMSO-d6)δ13.20(s,1H),10.19(s,1H),8.08(d,1H),7.74(d,1H),7.41(d,1H),7.28(d,1H),7.13(dd,1H),5.04–4.83(m,1H),4.73–4.63(m,1H),4.25–4.15(m,1H),3.80–3.73(m,2H),3.37–3.34(m,2H),3.06–2.94(m,4H),2.93–2.87(m,1H),2.47–2.39(m,1H),2.31–1.33(m,7H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：608.2556.Referring to step E of Example 14, compound 21-2A was substituted for compound 14-5 to prepare compound 21-A. 1 H NMR (500 MHz, DMSO-d 6 )δ13.20(s,1H),10.19(s,1H),8.08(d,1H),7.74(d,1H),7.41(d,1H),7.28 (d,1H),7.13(dd,1H),5.04–4.83(m,1H),4.73–4.63(m,1H),4.25–4.15(m, 1H),3.80–3.73(m,2H),3.37–3.34(m,2H),3.06–2.94(m,4H),2.93–2.87(m ,1H),2.47–2.39(m,1H),2.31–1.33(m,7H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：608.2556.

参考化合物21_A的制备方法，以化合物21-2B替换化合物21-2A制备得到化合物21_B。1H NMR(500MHz,DMSO-d6)δ13.19(s,1H),10.19(s,1H),8.08(d,1H),7.74(d,1H),7.41(d,1H),7.28(d,1H),7.13(dd,1H),5.06–4.83(m,1H),4.71–4.64(m,1H),4.24–4.17(m,1H),3.79–3.72(m,2H),3.38–3.34(m,2H),3.06–2.94(m,4H),2.93–2.87(m,1H),2.46–2.39(m,1H),2.34–1.30(m,7H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：608.2560.Referring to the preparation method of compound 21-A, compound 21-2B was used to replace compound 21-2A to prepare compound 21-B. 1 H NMR (500 MHz, DMSO-d 6 )δ13.19(s,1H),10.19(s,1H),8.08(d,1H),7.74(d,1H),7.41(d,1H),7.28 (d,1H),7.13(dd,1H),5.06–4.83(m,1H),4.71–4.64(m,1H),4.24–4.17(m, 1H),3.79–3.72(m,2H),3.38–3.34(m,2H),3.06–2.94(m,4H),2.93–2.87(m ,1H),2.46–2.39(m,1H),2.34–1.30(m,7H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：608.2560.

实施例22
Embodiment 22

参考化合物20_A的制备方法，以化合物E-4代替化合物D-4，制备得到化合物22_A(84mg)。1HNMR(500MHz,DMSO-d6)δ11.58(s,1H),10.10(s,1H),7.90(d,1H),7.74(d,1H),7.41(d,1H),7.08(d,1H),6.97(dd,1H),4.64(s,1H),4.32–4.05(m,1H),3.84–3.73(m,2H),3.27(s,3H),3.17(d,1H),3.08(s,3H),2.97–2.75(m,1H),2.48(d,2H),2.23–1.85(m,7H),0.99(t,2H),0.60(t,2H),0.21–0.06(m,2H).HRMS(ESI+,[M+H]+)m/z：601.2420.Referring to the preparation method of compound 20_A, compound E-4 was used instead of compound D-4 to prepare compound 22_A (84 mg). 1 HNMR (500 MHz, DMSO-d 6 )δ11.58(s,1H),10.10(s,1H),7.90(d,1H),7.74(d,1H),7.41(d,1H),7.08 (d,1H),6.97(dd,1H),4.64(s,1H),4.32–4.05(m,1H),3.84–3.73(m,2H),3. 27(s,3H),3.17(d,1H),3.08(s,3H),2.97–2.75(m,1H),2.48(d,2H),2.23– 1.85(m,7H),0.99(t,2H),0.60(t,2H),0.21–0.06(m,2H).HRMS(ESI+,[M+H] + )m/z：601.2420.

参考化合物20_B的制备方法，以化合物E-4代替化合物D-4，制备得到化合物22_B(85mg)。1HNMR(500MHz,DMSO-d6)δ11.58(s,1H),10.10(s,1H),7.90(d,1H),7.74(d,1H),7.41(d,1H),7.08(d,1H),6.97(dd,1H),4.74–4.59(m,1H),4.32–4.05(m,1H),3.87–3.72(m,2H),3.27(s,3H),3.08(s,3H),2.95–2.71(m,1H),2.53(d,1H),2.48(d,2H),2.26–1.85(m,7H),0.99(t,2H),0.60(t,2H),0.21–0.06(m,2H).HRMS(ESI+,[M+H]+)m/z：601.2421.Referring to the preparation method of compound 20_B, compound E-4 was used instead of compound D-4 to prepare compound 22_B (85 mg). 1 HNMR (500 MHz, DMSO-d 6 )δ11.58(s,1H),10.10(s,1H),7.90(d,1H),7.74(d,1H),7.41(d,1H),7.08( d,1H),6.97(dd,1H),4.74–4.59(m,1H),4.32–4.05(m,1H),3.87–3.72(m,2H) ,3.27(s,3H),3.08(s,3H),2.95–2.71(m,1H),2.53(d,1H),2.48(d,2H),2.26 –1.85(m,7H),0.99(t,2H),0.60(t,2H),0.21–0.06(m,2H).HRMS(ESI+,[M+H] + )m/z：601.2421.

实施例23
Embodiment 23

步骤A：Step A:

参考制备例A-6的步骤E，以化合物A-2替换化合物A-5得到化合物23-1。MS(ESI+,[M+H]+)m/z： 357.10.1H NMR(500MHz,DMSO-d6)δ8.44(s,1H),7.58(s,1H),7.50–7.43(m,3H),2.97–2.92(m,4H),1.54–1.45(m,4H),0.33(s,4H).Referring to step E of Preparation Example A-6, Compound A-2 was used to replace Compound A-5 to obtain Compound 23-1. MS (ESI+, [M+H] + ) m/z: 357.10. 1 H NMR (500MHz, DMSO-d 6 ) δ8.44(s,1H),7.58(s,1H),7.50–7.43(m,3H),2.97–2.92(m,4H),1.54–1.45(m,4H),0.33(s,4H).

步骤B:Step B:

100mL单口瓶中，依次加入化合物23-1(0.4g)、甲磺酰胺(0.128g)、碘化亚铜(0.011g)、N'-(2,6-二甲基苯基)-N-(吡啶-2-基甲基)草酰胺(0.016g)和碳酸铯(0.915g)，用叔丁醇(10mL)溶解，氮气保护下，在100℃下加热反应6h。反应结束后减压蒸除溶剂，向反应液中加入50mL水，EA(100mL)萃取，饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：DCM:MeOH＝20:1)纯化，得到化合物23-2(0.363g)。MS(ESI+,[M+H]+)m/z:324.12.1H NMR(500MHz,DMSO-d6)δ10.00(s,1H),8.61(d,1H),7.75(d,1H),7.45(d,1H),7.05(d,1H),6.94(dd,1H),3.05(s,3H),2.93–2.89(m,4H),1.56–1.46(m,4H),0.35(s,4H).Compound 23-1 (0.4 g), methanesulfonamide (0.128 g), cuprous iodide (0.011 g), N'-(2,6-dimethylphenyl)-N-(pyridin-2-ylmethyl)oxalamide (0.016 g) and cesium carbonate (0.915 g) were added to a 100 mL single-mouth bottle in sequence, dissolved with tert-butyl alcohol (10 mL), and heated at 100 ° C for 6 h under nitrogen protection. After the reaction, the solvent was evaporated under reduced pressure, 50 mL of water was added to the reaction solution, extracted with EA (100 mL), washed with saturated brine (50 mL × 2), and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM: MeOH = 20: 1) to obtain compound 23-2 (0.363 g). MS(ESI+,[M+H] + )m/z:324.12. 1 H NMR(500MHz,DMSO-d 6 )δ10.00(s,1H),8.61(d,1H),7.75(d,1H),7.45(d,1H),7.05(d,1H),6.94 (dd,1H),3.05(s,3H),2.93–2.89(m,4H),1.56–1.46(m,4H),0.35(s,4H).

步骤C：Step C:

向100mL单口瓶中，依次加入化合物21-1(0.160g)、化合物23-2(0.154g)、Pd2(dba)3(0.022g)、Xant-Phos(0.028g)和碳酸铯(0.467g)，用二氧六环(10mL)溶解，N2保护下，加热至100℃反应6h。反应结束后，过滤，减压浓缩，硅胶柱层析(洗脱剂：DCM/MeOH＝20/1)纯化，得到化合物23(135mg)。MS(ESI+,[M+H]+)m/z：578.42.Compound 21-1 (0.160 g), compound 23-2 (0.154 g), Pd 2 (dba) 3 (0.022 g), Xant-Phos (0.028 g) and cesium carbonate (0.467 g) were added to a 100 mL single-mouth bottle in sequence, dissolved with dioxane (10 mL), and heated to 100 ° C for 6 h under N 2 protection. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM/MeOH=20/1) to obtain compound 23 (135 mg). MS (ESI+, [M+H] + ) m/z: 578.42.

步骤D：Step D:

化合物23(135mg)经过制备HPLC(拆分条件：柱：CHIRALART Cellulose-SC，4.6×250mm，5μm；流动相：正己烷:二氯甲烷:乙醇＝60:10:30；流速：1mL/min；波长：254nm)拆分得到化合物23_A(61mg，保留时间：18.704min)、化合物23_B(62mg，保留时间：21.194min)。Compound 23 (135 mg) was separated by preparative HPLC (separation conditions: column: CHIRALART Cellulose-SC, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 60:10:30; flow rate: 1 mL/min; wavelength: 254 nm) to give compound 23_A (61 mg, retention time: 18.704 min) and compound 23_B (62 mg, retention time: 21.194 min).

化合物23_A:1H NMR(500MHz,DMSO-d6)δ13.20(s,1H),10.24(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7.26(d,1H),7.13(dd,1H),4.71–4.63(m,1H),4.24–4.18(m,1H),3.12(s,3H),3.04–2.95(m,4H),2.94–2.88(m,1H),2.46–2.40(m,1H),2.21–1.59(m,7H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：578.2465.Compound 23_A: 1 H NMR (500MHz, DMSO-d 6 )δ13.20(s,1H),10.24(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7.26(d,1H),7.13(dd,1H ),4.71–4.63(m,1H),4.24–4.18 (m,1H),3.12(s,3H),3.04–2.95(m,4H),2.94–2.88(m,1H),2.46–2.40(m,1H),2.21–1.59(m,7H),0.40 (s,4H).HRMS(ESI+,[M+H] + )m/z：578.2465.

化合物23_B:1H NMR(500MHz,DMSO-d6)δ13.20(s,1H),10.24(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7.26(d,1H),7.13(dd,1H),4.73–4.64(m,1H),4.24–4.16(m,1H),3.12(s,3H),3.03–2.95(m,4H),2.94–2.88(m,1H),2.45–2.39(m,1H),2.19–1.60(m,7H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：578.2452.Compound 23_B: 1 H NMR (500MHz, DMSO-d 6 )δ13.20(s,1H),10.24(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7.26(d,1H),7.13(dd,1H ),4.73–4.64(m,1H),4.24–4.16 (m,1H),3.12(s,3H),3.03–2.95(m,4H),2.94–2.88(m,1H),2.45–2.39(m,1H),2.19–1.60(m,7H),0.40 (s,4H).HRMS(ESI+,[M+H] + )m/z：578.2452.

实施例24
Embodiment 24

步骤A：Step A:

参考制备例A-6的步骤C，以化合物D-2替换化合物A-3，制备得到化合物24-1(410mg)。MS(ESI+,[M+H]+)m/z：395.16.Referring to step C of Preparation Example A-6, Compound D-2 was used to replace Compound A-3 to prepare Compound 24-1 (410 mg). MS (ESI+, [M+H] + ) m/z: 395.16.

步骤B：Step B:

参考制备例A-6的步骤D，以化合物24-1替换化合物A-4，制备得到化合物24-2(160mg)。MS(ESI-,[M-H]-)m/z：379.14.Referring to step D of Preparation Example A-6, Compound 24-1 was used to replace Compound A-4 to prepare Compound 24-2 (160 mg). MS (ESI-, [MH] - ) m/z: 379.14.

步骤C： Step C:

参考制备例A-6的步骤E，以化合物24-2替换化合物A-5，制备得到化合物24-3(110mg)。MS(ESI-,[M-H]-)m/z：378.16.Referring to step E of preparation example A-6, compound 24-2 was substituted for compound A-5 to prepare compound 24-3 (110 mg). MS (ESI-, [MH] - ) m/z: 378.16.

步骤D：Step D:

参考实施例14的步骤E，以化合物24-3替换化合物A-6，制备得到化合物24(120mg)。MS(ESI+,[M+H]+)m/z：631.24.Referring to step E of Example 14, compound 24-3 was substituted for compound A-6 to prepare compound 24 (120 mg). MS (ESI+, [M+H] + ) m/z: 631.24.

步骤E：Step E:

化合物24(120mg)经过手性HPLC拆分(型号：CHIRALART Cellulose-SC，4.6×250mm，5μm；流动相：正己烷/二氯甲烷/乙醇＝40/30/30；流速：1mL/min)得到化合物24_A(45mg，保留时间：5.982min)、化合物24_B(45mg，保留时间：6.642min)Compound 24 (120 mg) was separated by chiral HPLC (model: CHIRALART Cellulose-SC, 4.6×250 mm, 5 μm; mobile phase: n-hexane/dichloromethane/ethanol=40/30/30; flow rate: 1 mL/min) to obtain compound 24_A (45 mg, retention time: 5.982 min) and compound 24_B (45 mg, retention time: 6.642 min).

化合物24_A：1H NMR(500MHz,DMSO-d6)δ10.97(s,1H),10.05(s,1H),7.86–7.75(m,2H),7.41(d,1H),7.32–7.24(m,1H),7.05(d,1H),4.66(d,1H),4.25–4.14(m,1H),3.79–3.72(m,2H),3.27(s,3H),3.07–2.95(m,4H),2.85–2.77(m,1H),2.43–2.35(m,1H),2.22–1.76(m,8H),1.47(s,2H),1.24–1.23(m,2H),0.68–0.60(m,2H),0.44–0.34(m,2H).HRMS(ESI+,[M+H]+)m/z：631.2532.Compound 24_A: 1 H NMR (500 MHz, DMSO-d 6 )δ10.97(s,1H),10.05(s,1H),7.86–7.75(m,2H),7.41(d,1H),7.32–7.24(m,1H),7.05(d,1H),4.66(d,1H),4.25–4.14(m,1H),3.79–3.72(m,2H),3.27(s,3H),3. 07–2.95(m,4H),2.85–2.77(m,1H),2.43–2.35(m,1H),2.22–1.76(m,8H),1.47(s ,2H),1.24–1.23(m,2H),0.68–0.60(m,2H),0.44–0.34(m,2H).HRMS(ESI+,[M+H] + )m/z：631.2532.

化合物24_B：1H NMR(500MHz,DMSO-d6)δ10.98(s,1H),10.05(s,1H),7.85–7.75(m,2H),7.41(d,1H),7.29–7.24(m,1H),7.05(d,1H),4.66(d,1H),4.22–4.16(m,1H),3.79–3.71(m,2H),3.27(s,3H),3.06–2.93(m,4H),2.89–2.80(m,1H),2.46–2.39(m,1H),2.19–1.82(m,8H),1.47(s,2H),1.24–1.21(m,2H),0.67–0.62(m,2H),0.44–0.34(m,2H).HRMS(ESI+,[M+H]+)m/z：631.2529.Compound 24_B: 1 H NMR (500 MHz, DMSO-d 6 )δ10.98(s,1H),10.05(s,1H),7.85–7.75(m,2H),7.41(d,1H),7.29–7.24(m,1H),7.05(d,1H),4.66(d,1H),4.22–4.16(m,1H),3.79–3.71(m,2H),3.27(s,3H),3. 06–2.93(m,4H),2.89–2.80(m,1H),2.46–2.39(m,1H),2.19–1.82(m,8H),1.47(s ,2H),1.24–1.21(m,2H),0.67–0.62(m,2H),0.44–0.34(m,2H).HRMS(ESI+,[M+H] + )m/z：631.2529.

实施例25
Embodiment 25

步骤A：Step A:

参考实施例14的步骤A，以化合物25-1替换化合物14-1，制备得到化合物25-2。MS(ESI-,[M-H]-)m/z：354.31.Referring to step A of Example 14, compound 25-1 was substituted for compound 14-1 to prepare compound 25-2. MS (ESI-, [MH] - ) m/z: 354.31.

步骤B：Step B:

向250mL单口瓶中加入化合物25-2(7.12g)、DCM(60mL)和氢氧化钠(6.41g)的水(50mL)溶液，搅拌均匀后加入苄基三甲基三溴化铵(25g)，室温反应12h。反应结束后，分液，水相用DCM(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，硅胶柱层析(洗脱剂：PE/EA＝4/1)纯化，得到化合物25-3(7.94g)。1H NMR(500MHz,DMSO-d6)δ9.89(s,1H),7.70(s,1H),5.08–4.82(m,1H),4.18–3.94(m,1H),3.30–3.14(m,1H),2.77–2.68(m,1H),2.47–2.30(m,1H),2.18(s,3H),2.10–1.88(m,2H),1.41(s,9H).Compound 25-2 (7.12 g), DCM (60 mL) and sodium hydroxide (6.41 g) in water (50 mL) were added to a 250 mL single-mouth bottle, and benzyltrimethylammonium tribromide (25 g) was added after stirring evenly, and the mixture was reacted at room temperature for 12 h. After the reaction was completed, the mixture was separated, the aqueous phase was extracted with DCM (3×30 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by silica gel column chromatography (eluent: PE/EA=4/1) to obtain compound 25-3 (7.94 g). 1 H NMR (500MHz, DMSO-d 6 )δ9.89(s,1H),7.70(s,1H),5.08–4.82(m,1H),4.18–3.94(m,1H),3.30–3.14(m,1H) ,2.77–2.68(m,1H),2.47–2.30(m,1H),2.18(s,3H),2.10–1.88(m,2H),1.41(s,9H).

步骤C：Step C:

参考实施例14的步骤B，以化合物25-3替换化合物14-2，制备得到化合物25-4。MS(ESI+,[M+H]+) m/z：412.08.Referring to step B of Example 14, compound 25-3 was substituted for compound 14-2 to prepare compound 25-4. MS (ESI+, [M+H] + ) m/z: 412.08.

步骤D：Step D:

参考实施例14的步骤C，以化合物25-4替换化合物14-3，制备得到化合物25-5。1H NMR(500MHz,DMSO-d6)δ10.33(s,1H),6.83(s,1H),4.55–4.47(m,1H),4.15–4.08(m,1H),2.84–2.75(m,1H),2.47–2.36(m,1H),2.17(s,3H),2.16–1.86(m,3H).Referring to step C of Example 14, compound 25-4 was used to replace compound 14-3 to prepare compound 25-5. 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.33 (s, 1H), 6.83 (s, 1H), 4.55–4.47 (m, 1H), 4.15–4.08 (m, 1H), 2.84–2.75 (m, 1H), 2.47–2.36 (m, 1H), 2.17 (s, 3H), 2.16–1.86 (m, 3H).

步骤E：Step E:

参考实施例14的步骤D，以化合物25-5替换化合物14-4，制备得到化合物25-6。1H NMR(500MHz,DMSO-d6)δ6.99(s,1H),4.34–4.24(m,1H),3.97–3.91(m,1H),3.29(s,3H),2.88–2.80(m,1H),2.43–2.37(m,1H),2.36(s,3H),2.24–2.14(m,1H),2.14–1.91(m,2H).Referring to step D of Example 14, compound 25-5 was used to replace compound 14-4 to prepare compound 25-6. 1 H NMR (500 MHz, DMSO-d 6 ) δ 6.99 (s, 1H), 4.34–4.24 (m, 1H), 3.97–3.91 (m, 1H), 3.29 (s, 3H), 2.88–2.80 (m, 1H), 2.43–2.37 (m, 1H), 2.36 (s, 3H), 2.24–2.14 (m, 1H), 2.14–1.91 (m, 2H).

步骤F：Step F:

参考实施例1的步骤C，以化合物25-6替换化合物1-3，制备得到化合物25。MS(ESI+,[M+H]+)m/z：619.41.Referring to step C of Example 1, compound 25-6 was used to replace compound 1-3 to prepare compound 25. MS (ESI+, [M+H] + ) m/z: 619.41.

步骤G：Step G:

化合物25经过手性制备分离(拆分条件：柱：CHIRALARTCellose-SC，4.6×250mm，5μm；流动相：正己烷:二氯甲烷:乙醇＝60:10:30；流速：1mL/min；波长：254nm)拆分得到化合物25_A(保留时间为9.40分钟)、化合物25_B(保留时间为10.8分钟)。Compound 25 was subjected to chiral preparative separation (separation conditions: column: CHIRALARTCellose-SC, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 60:10:30; flow rate: 1 mL/min; wavelength: 254 nm) to give compound 25_A (retention time: 9.40 minutes) and compound 25_B (retention time: 10.8 minutes).

化合物25_A:1H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.20(s,1H),8.07(d,1H),7.69(s,1H),7.27(d,1H),7.14(dd,1H),4.93(s,1H),4.49–4.37(m,1H),3.91(dd,1H),3.82–3.71(m,2H),3.36(t,2H),3.31(s,3H),3.03–2.88(m,5H),2.41(s,3H),2.40–2.34(m,1H),2.19–2.10(m,2H),2.10–2.03(m,1H),2.03–1.38(m,4H),0.39(s,4H).HRMS(ESI+,[M+H]+)m/z：619.2523.Compound 25_A: 1 H NMR (500 MHz, DMSO-d 6 )δ13.18(s,1H),10.20(s,1H),8.07(d,1H),7.69(s,1H),7.27(d,1H),7.14(dd ,1H),4.93(s,1H),4.49–4.37(m,1H),3.91(dd,1H),3.82–3.71(m,2H),3.36(t ,2H),3.31(s,3H),3.03–2.88(m,5H),2.41(s,3H),2.40–2.34(m,1H),2.19–2. 10(m,2H),2.10–2.03(m,1H),2.03–1.38(m,4H),0.39(s,4H).HRMS(ESI+,[M+H] + )m/z：619.2523.

化合物25_B:1H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.20(s,1H),8.07(d,1H),7.69(s,1H),7.27(d,1H),7.14(dd,1H),4.93(s,1H),4.49–4.39(m,1H),3.91(dd,1H),3.82–3.71(m,2H),3.36(t,2H),3.31(s,3H),3.03–2.88(m,5H),2.41(s,3H),2.40–2.34(m,1H),2.19–2.10(m,2H),2.09–2.00(m,1H),1.98–1.40(m,4H),0.39(s,4H).HRMS(ESI+,[M+H]+)m/z：619.2524.Compound 25_B: 1 H NMR (500 MHz, DMSO-d 6 )δ13.18(s,1H),10.20(s,1H),8.07(d,1H),7.69(s,1H),7.27(d,1H),7.14(dd ,1H),4.93(s,1H),4.49–4.39(m,1H),3.91(dd,1H),3.82–3.71(m,2H),3.36(t ,2H),3.31(s,3H),3.03–2.88(m,5H),2.41(s,3H),2.40–2.34(m,1H),2.19–2. 10(m,2H),2.09–2.00(m,1H),1.98–1.40(m,4H),0.39(s,4H).HRMS(ESI+,[M+H] + )m/z：619.2524.

实施例26
Embodiment 26

步骤A：Step A:

向100mL单口瓶中加入化合物25-5(0.5g)和DMF(8mL)，冰浴下加入NaH(0.07g)，搅拌5min后加入氘代碘甲烷-d3(0.26g)，室温反应2h。反应结束后，向反应液中加入饱和的氯化铵溶液50mL，EA(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，所得粗品用20mL石油醚打浆，抽滤，得到化合物26-1(0.24g)。1H NMR(500MHz,DMSO-d6)δ6.99(s,1H),4.33–4.26(m,1H),3.98–3.92(m,1H),2.89–2.80(m,1H),2.43–2.37(m,1H),2.35(s,3H),2.22–2.15(m,1H),2.10–1.91(m,2H).Compound 25-5 (0.5 g) and DMF (8 mL) were added to a 100 mL single-mouth bottle, and NaH (0.07 g) was added under ice bath. After stirring for 5 min, deuterated iodomethane-d3 (0.26 g) was added and reacted at room temperature for 2 h. After the reaction was completed, 50 mL of saturated ammonium chloride solution was added to the reaction solution, and EA (3×20 mL) was used for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was slurried with 20 mL of petroleum ether and filtered to obtain compound 26-1 (0.24 g). 1 H NMR (500MHz, DMSO-d 6 )δ6.99(s,1H),4.33–4.26(m,1H),3.98–3.92(m,1H),2.89–2.80(m,1H) ,2.43–2.37(m,1H),2.35(s,3H),2.22–2.15(m,1H),2.10–1.91(m,2H).

步骤B：Step B:

向50mL单口瓶中，依次加入化合物23-2(155mg)、Pd2(dba)3(43.9mg)、Xant-Phos(55.5mg)、溶 于二氧六环(8mL)的化合物26-1(176mg)和碳酸铯(390mg)，N2保护下，加热至100℃反应4h。反应结束后，过滤，减压浓缩，硅胶柱层析(洗脱剂：DCM/MeOH＝20/1)纯化，得到化合物26(250mg)。MS(ESI+,[M+H]+)m/z：592.34.In a 50 mL single-necked bottle, compound 23-2 (155 mg), Pd 2 (dba) 3 (43.9 mg), Xant-Phos (55.5 mg), solvent were added in sequence. Compound 26-1 (176 mg) and cesium carbonate (390 mg) in dioxane (8 mL) were heated to 100°C under N2 protection for 4 h. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM/MeOH=20/1) to obtain compound 26 (250 mg). MS (ESI+, [M+H] + ) m/z: 592.34.

步骤C：Step C:

化合物26经过手性制备分离(拆分条件：柱：CHIRALART Cellulose-SC，4.6×250mm，5μm；流动相：正己烷：二氯甲烷：乙醇＝70:15:15；流速：1mL/min；波长：254nm)，拆分得到化合物26_A(保留时间为8.27分钟)、化合物26_B(保留时间为9.43分钟)。Compound 26 was subjected to chiral preparative separation (separation conditions: column: CHIRALART Cellulose-SC, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 70:15:15; flow rate: 1 mL/min; wavelength: 254 nm) to give compound 26_A (retention time: 8.27 minutes) and compound 26_B (retention time: 9.43 minutes).

化合物26_A:1H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.24(s,1H),8.08(d,1H),7.69(s,1H),7.26(d,1H),7.14(dd,1H),4.48–4.39(m,1H),3.91(dd,1H),3.12(s,3H),3.02–2.88(m,5H),2.41(s,3H),2.40–2.35(m,1H),2.17–2.10(m,2H),2.09–2.01(m,1H),1.99–1.35(m,4H),0.39(s,4H).HRMS(ESI+,[M+H]+)m/z：592.2611.Compound 26_A: 1 H NMR (500MHz, DMSO-d 6 )δ13.18(s,1H),10.24(s,1H),8.08(d,1H),7.69(s,1H),7.26(d,1H),7.14(dd,1H),4.48–4.39(m ,1H),3.91(dd,1H),3.12(s,3H),3.0 2–2.88(m,5H),2.41(s,3H),2.40–2.35(m,1H),2.17–2.10(m,2H),2.09–2.01(m,1H),1.99–1.35(m,4H ),0.39(s,4H).HRMS(ESI+,[M+H] + )m/z：592.2611.

化合物26_B:1H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.24(s,1H),8.08(d,1H),7.69(s,1H),7.26(d,1H),7.14(dd,1H),4.47–4.39(m,1H),3.91(dd,1H),3.12(s,3H),3.03–2.87(m,5H),2.41(s,3H),2.40–2.34(m,1H),2.18–2.10(m,2H),2.09–2.02(m,1H),1.99–1.33(m,4H),0.39(s,4H).HRMS(ESI+,[M+H]+)m/z：592.2612.Compound 26_B: 1 H NMR (500MHz, DMSO-d 6 )δ13.18(s,1H),10.24(s,1H),8.08(d,1H),7.69(s,1H),7.26(d,1H),7.14(dd,1H),4.47–4.39(m ,1H),3.91(dd,1H),3.12(s,3H),3.0 3–2.87(m,5H),2.41(s,3H),2.40–2.34(m,1H),2.18–2.10(m,2H),2.09–2.02(m,1H),1.99–1.33(m,4H ),0.39(s,4H).HRMS(ESI+,[M+H] + )m/z：592.2612.

实施例27
Embodiment 27

步骤A：Step A:

参考实施例25的步骤F，以化合物23-2替换化合物A-6制备，得到化合物27(300mg)。MS(ESI+,[M+H]+)m/z：589.23.Referring to step F of Example 25, compound 23-2 was used to replace compound A-6 to obtain compound 27 (300 mg). MS (ESI+, [M+H] + ) m/z: 589.23.

步骤B：Step B:

化合物27(300mg)经过手性HPLC拆分(型号：(R,R)Whelk-O1，4.6×250mm，5μm；流动相：二氯甲烷/乙醇＝1/1；流速：1mL/min)得到化合物27_A(90mg，保留时间：8.329min)、化合物27_B(90mg，保留时间：8.987min)。Compound 27 (300 mg) was separated by chiral HPLC (model: (R,R) Whelk-O1, 4.6×250 mm, 5 μm; mobile phase: dichloromethane/ethanol = 1/1; flow rate: 1 mL/min) to give compound 27_A (90 mg, retention time: 8.329 min) and compound 27_B (90 mg, retention time: 8.987 min).

化合物27_A：1H NMR(500MHz,DMSO-d6)δ13.19(s,1H),10.24(s,1H),8.08(d,1H),7.69(s,1H),7.26(d,1H),7.16–7.12(m,1H),4.43(d,1H),4.08–3.98(m,1H),3.31(s,3H),3.12(s,3H),3.01–2.89(m,4H),2.41(s,4H),2.18–1.67(m,7H),1.20–1.15(m,1H),0.39(s,4H).HRMS(ESI+,[M+H]+)m/z：589.2424.Compound 27_A: 1 H NMR (500MHz, DMSO-d 6 )δ13.19(s,1H),10.24(s,1H),8.08(d,1H),7.69(s,1H),7.26(d,1H),7.16–7.12(m,1H),4.43(d ,1H),4.08–3.98(m,1H),3. 31(s,3H),3.12(s,3H),3.01–2.89(m,4H),2.41(s,4H),2.18–1.67(m,7H),1.20–1.15(m,1H),0.39( s,4H).HRMS(ESI+,[M+H] + )m/z：589.2424.

化合物27_B：1H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.24(s,1H),8.08(d,1H),7.69(s,1H),7.26(d,1H),7.17–7.11(m,1H),4.43(d,1H),3.94–3.87(m,1H),3.30(s,3H),3.12(s,3H),3.02–2.94(m,4H),2.41(s,4H),2.20–1.53(m,7H),1.27–1.22(m,1H),0.39(s,4H).HRMS(ESI+,[M+H]+)m/z：589.2412.Compound 27_B: 1 H NMR (500MHz, DMSO-d 6 )δ13.18(s,1H),10.24(s,1H),8.08(d,1H),7.69(s,1H),7.26(d,1H),7.17–7.11(m,1H),4.43(d ,1H),3.94–3.87(m,1H),3. 30(s,3H),3.12(s,3H),3.02–2.94(m,4H),2.41(s,4H),2.20–1.53(m,7H),1.27–1.22(m,1H),0.39( s,4H).HRMS(ESI+,[M+H] + )m/z：589.2412.

实施例28
Embodiment 28

步骤A：Step A:

参考实施例25的步骤F，以化合物D-4代替化合物A-6，制备得到化合物28(220mg)，MS(ESI+,[M+H]+)m/z：615.34.Referring to step F of Example 25, compound D-4 was used instead of compound A-6 to prepare compound 28 (220 mg), MS (ESI+, [M+H] + ) m/z: 615.34.

步骤B： Step B:

化合物28经过手性制备分离(拆分条件：REFLECT I-Amylose A柱，4.6×250mm，5μm；流动相：正己烷:乙醇＝70:30；流速：1mL/min；波长：254nm)，拆分得到化合物28_A(保留时间为12.807min)、化合物28_B(保留时间为15.227min))。Compound 28 was separated by chiral preparative separation (separation conditions: REFLECT I-Amylose A column, 4.6×250 mm, 5 μm; mobile phase: n-hexane:ethanol=70:30; flow rate: 1 mL/min; wavelength: 254 nm) to give compound 28_A (retention time: 12.807 min) and compound 28_B (retention time: 15.227 min)).

化合物28_A:1H NMR(500MHz,DMSO-d6)δ10.98(s,1H),10.09(s,1H),7.82(d,1H),7.75(s,1H),7.25(d,1H),7.07(dd,1H),4.40(d,1H),3.95–3.85(m,1H),3.30(s,3H),3.08(s,3H),3.01(d,4H),2.84(t,1H),2.41(s,3H),2.36(s,1H),2.19–1.93(m,5H),1.82(s,2H),1.47(s,2H),0.74–0.58(m,2H),0.49–0.30(m,2H).HRMS(ESI+,[M+H]+)m/z：615.2578.Compound 28_A: 1 H NMR (500 MHz, DMSO-d 6 )δ10.98(s,1H),10.09(s,1H),7.82(d,1H),7.75(s,1H),7.25(d,1H),7.0 7(dd,1H),4.40(d,1H),3.95–3.85(m,1H),3.30(s,3H),3.08(s,3H),3.01 (d,4H),2.84(t,1H),2.41(s,3H),2.36(s,1H),2.19–1.93(m,5H),1.82(s ,2H),1.47(s,2H),0.74–0.58(m,2H),0.49–0.30(m,2H).HRMS(ESI+,[M+H] + )m/z：615.2578.

化合物28_B:1H NMR(500MHz,DMSO-d6)δ10.98(s,1H),10.09(s,1H),7.82(d,1H),7.75(s,1H),7.25(d,1H),7.07(dd,1H),4.40(d,1H),3.95–3.85(m,1H),3.30(s,3H),3.08(s,3H),3.01(d,4H),2.84(t,1H),2.41(s,3H),2.36(s,1H),2.17–1.95(m,5H),1.82(s,2H),1.47(s,2H),0.74–0.58(m,2H),0.44–0.33(m,2H).HRMS(ESI+,[M+H]+)m/z：615.2575.Compound 28_B: 1 H NMR (500 MHz, DMSO-d 6 )δ10.98(s,1H),10.09(s,1H),7.82(d,1H),7.75(s,1H),7.25(d,1H),7.0 7(dd,1H),4.40(d,1H),3.95–3.85(m,1H),3.30(s,3H),3.08(s,3H),3.01 (d,4H),2.84(t,1H),2.41(s,3H),2.36(s,1H),2.17–1.95(m,5H),1.82(s ,2H),1.47(s,2H),0.74–0.58(m,2H),0.44–0.33(m,2H).HRMS(ESI+,[M+H] + )m/z：615.2575.

实施例29
Embodiment 29

步骤A：Step A:

参考制备例A-6的步骤C，以化合物E-2代替化合物A-3，制备得到化合物29-1。MS(ESI+,[M+H]+)m/z：395.17.Referring to step C of Preparation Example A-6, Compound E-2 was used instead of Compound A-3 to prepare Compound 29-1. MS (ESI+, [M+H] + ) m/z: 395.17.

步骤B：Step B:

参考制备例D-4的步骤D，以化合物29-1代替化合物D-3，制备得到化合物29-2。MS(ESI+,[M+H]+)m/z：380.18.Referring to step D of Preparation Example D-4, Compound 29-2 was prepared by replacing Compound D-3 with Compound 29-1. MS (ESI+, [M+H] + ) m/z: 380.18.

步骤C：Step C:

参考化合物20_A的制备方法，以化合物29-2代替化合物D-4，制备得到化合物29_A(45mg)。1HNMR(500MHz,DMSO-d6)δ11.59(s,1H),10.06(s,1H),7.89(d,1H),7.74(d,1H),7.41(d,1H),7.10(d,1H),6.97(dd,1H),4.92(s,1H),4.65(d,1H),4.25–4.06(m,1H),3.84–3.65(m,4H),3.27(s,3H),2.97–2.75(m,1H),2.53(d,2H),2.49–2.34(m,2H),2.15(d,1H),2.10–1.99(m,3H),1.91(d,2H),1.18(t,1H),1.05–0.95(m,2H),0.90–0.79(m,1H),0.60(t,2H),0.25–0.10(m,2H).HRMS(ESI+,[M+H]+)m/z：631.2533.Referring to the preparation method of compound 20_A, compound 29-2 was used instead of compound D-4 to prepare compound 29_A (45 mg). 1 HNMR (500 MHz, DMSO-d 6 )δ11.59(s,1H),10.06(s,1H),7.89(d,1H),7.74(d,1H),7.41(d,1H),7.10(d,1H),6.97(dd,1H),4.92(s,1H),4.65(d,1H),4.25–4.06(m,1H),3.84–3.65(m,4H),3.27(s,3H),2.97–2.75 (m,1H),2.53(d,2H),2.49–2.34(m,2H),2.15(d,1H),2.10–1.99(m,3H),1.91(d,2H),1.18(t ,1H),1.05–0.95(m,2H),0.90–0.79(m,1H),0.60(t,2H),0.25–0.10(m,2H).HRMS(ESI+,[M+H] + )m/z：631.2533.

参考化合物20_B的制备方法，以化合物29-2代替化合物D-4，制备得到化合物29_B(43mg)。1HNMR(500MHz,DMSO-d6)δ11.59(s,1H),10.06(s,1H),7.89(d,1H),7.74(d,1H),7.41(d,1H),7.10(d,1H),6.97(dd,1H),4.92(s,1H),4.65(d,1H),4.25–4.06(m,1H),3.84–3.65(m,4H),3.27(s,3H),2.97–2.75(m,1H),2.57–2.51(m,2H),2.49–2.36(m,2H),2.16(d,1H),2.13–2.00(m,3H),1.91(d,2H),1.23(s,1H),1.05–0.95(m,2H),0.90–0.79(m,1H),0.60(t,2H),0.25–0.10(m,2H).HRMS(ESI+,[M+H]+)m/z：631.2519. Referring to the preparation method of compound 20_B, compound 29-2 was used instead of compound D-4 to prepare compound 29_B (43 mg). 1 HNMR (500 MHz, DMSO-d 6 )δ11.59 (s, 1H), 10.06 (s, 1H), 7.89 (d, 1H), 7.74 (d, 1H), 7.41 (d, 1H), 7.10 (d, 1H), 6.97 (dd, 1H), 4.92 (s, 1H), 4.65 (d, 1H), 4.25–4.06 (m, 1H), 3.84–3.65 (m, 4H), 3.27 (s, 3H), 2.97–2.75 (m, 1H),2.57–2.51(m,2H),2.49–2.36(m,2H),2.16(d,1H),2.13–2.00(m,3H),1.91(d,2H),1.23( s,1H),1.05–0.95(m,2H),0.90–0.79(m,1H),0.60(t,2H),0.25–0.10(m,2H).HRMS(ESI+,[M+H] + )m/z：631.2519.

实施例30
Embodiment 30

步骤A：Step A:

向50mL单口瓶中，依次加入化合物29-2(200mg)、Pd2(dba)3(48.3mg)、Xant-Phos(61mg)、溶于二氧六环(8mL)的化合物25-6(219mg)和碳酸铯(429mg)，N2保护下，加热至100℃反应5h。反应结束后，过滤，减压浓缩，硅胶柱层析(洗脱剂：DCM/MeOH＝20/1)纯化，得到化合物30(200mg)。MS(ESI+,[M+H]+)m/z：645.42.Compound 29-2 (200 mg), Pd 2 (dba) 3 (48.3 mg), Xant-Phos (61 mg), compound 25-6 (219 mg) dissolved in dioxane (8 mL) and cesium carbonate (429 mg) were added to a 50 mL single-mouth bottle in sequence, and heated to 100°C for 5 h under N 2 protection. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM/MeOH=20/1) to obtain compound 30 (200 mg). MS (ESI+, [M+H] + ) m/z: 645.42.

步骤B：Step B:

化合物30经过手性制备分离(拆分条件：柱：(R,R)Whelk-O1，4.6×250mm，5μm；流动相：正己烷：二氯甲烷：乙醇＝40:30:30；流速：1mL/min；波长：254nm)拆，分得到化合物30_A(保留时间为8.84分钟)、化合物30_B(保留时间为9.68分钟)。Compound 30 was separated by chiral preparative separation (separation conditions: column: (R,R) Whelk-O1, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 40:30:30; flow rate: 1 mL/min; wavelength: 254 nm) to obtain compound 30_A (retention time: 8.84 minutes) and compound 30_B (retention time: 9.68 minutes).

化合物30_A:1H NMR(500MHz,DMSO-d6)δ11.63(s,1H),10.07(s,1H),7.89(d,1H),7.68(s,1H),7.10(d,1H),6.98(dd,1H),4.91(t,1H),4.44–4.35(m,1H),3.88–3.81(m,1H),3.78–3.71(m,4H),3.30(s,3H),2.89–2.79(m,1H),2.58–2.51(m,2H),2.48–2.35(m,5H),2.20–1.85(m,8H),1.02–0.93(m,2H),0.63–0.56(m,2H),0.17–0.08(m,2H).HRMS(ESI+,[M+H]+)m/z：645.2678.Compound 30_A: 1 H NMR (500 MHz, DMSO-d 6 )δ11.63(s,1H),10.07(s,1H),7.89(d,1H),7.68(s,1H),7.10(d,1H),6.98(dd,1H),4.91(t,1H),4.44–4.35(m,1H),3.88–3.81(m,1H),3.78–3.71(m,4H),3.30 (s,3H),2.89–2.79(m,1H),2.58–2.51(m,2H),2.48–2.35(m,5H),2.20–1.85(m, 8H),1.02–0.93(m,2H),0.63–0.56(m,2H),0.17–0.08(m,2H).HRMS(ESI+,[M+H] + )m/z：645.2678.

化合物30_B:1H NMR(500MHz,DMSO-d6)δ11.63(s,1H),10.07(s,1H),7.89(d,1H),7.68(s,1H),7.10(d,1H),6.98(dd,1H),4.92(t,1H),4.48–4.35(m,1H),3.90–3.81(m,1H),3.79–3.64(m,4H),3.30(s,3H),2.90–2.80(m,1H),2.58–2.51(m,2H),2.48–2.35(m,5H),2.20–1.87(m,8H),1.02–0.94(m,2H),0.63–0.55(m,2H),0.18–0.08(m,2H).HRMS(ESI+,[M+H]+)m/z：645.2673.Compound 30_B: 1 H NMR (500 MHz, DMSO-d 6 )δ11.63(s,1H),10.07(s,1H),7.89(d,1H),7.68(s,1H),7.10(d,1H),6.98(dd,1H),4.92(t,1H),4.48–4.35(m,1H),3.90–3.81(m,1H),3.79–3.64(m,4H),3.30 (s,3H),2.90–2.80(m,1H),2.58–2.51(m,2H),2.48–2.35(m,5H),2.20–1.87(m, 8H),1.02–0.94(m,2H),0.63–0.55(m,2H),0.18–0.08(m,2H).HRMS(ESI+,[M+H] + )m/z：645.2673.

实施例31
Embodiment 31

步骤A：Step A:

参考实施例23的步骤C，以化合物29-2替换化合物23-2制备得到化合物31(170mg)。MS(ESI+,[M+H]+)m/z：634.26.Referring to step C of Example 23, compound 31 (170 mg) was prepared by replacing compound 23-2 with compound 29-2. MS (ESI+, [M+H] + ) m/z: 634.26.

步骤B：Step B:

化合物31(170mg)经过手性HPLC拆分(型号：CHIRALPAK IK，4.6×250mm，5μm；流动相：正己烷/二氯甲烷/乙醇＝50/25/25；流速：1mL/min)得到化合物31_A(60mg，保留时间：8.894min)、化合物31_B(60mg，保留时间：10.344min)Compound 31 (170 mg) was separated by chiral HPLC (model: CHIRALPAK IK, 4.6×250 mm, 5 μm; mobile phase: n-hexane/dichloromethane/ethanol=50/25/25; flow rate: 1 mL/min) to give compound 31_A (60 mg, retention time: 8.894 min) and compound 31_B (60 mg, retention time: 10.344 min).

化合物31_A：1H NMR(500MHz,DMSO-d6)δ11.59(s,1H),10.06(s,1H),7.88(d,1H),7.74(d,1H),7.40(d,1H),7.09(s,1H),6.99–6.94(m,1H),4.96–4.88(m,1H),4.65(d,1H),4.21–4.12(m,1H),3.82–3.69(m,4H),3.34–3.32(m,1H),3.31–3.29(m,1H),2.88–2.78(m,1H),2.56–2.51(m,1H),2.47–2.44(m,1H),2.20–1.87(m,7H),1.32–1.28(m,1H),1.02–0.95(m,2H),0.63–0.55(m,2H),0.18–0.08(m,2H).HRMS(ESI+,[M+H]+)m/z：634.2697.Compound 31_A: 1 H NMR (500 MHz, DMSO-d 6 )δ11.59 (s, 1H), 10.06 (s, 1H), 7.88 (d, 1H), 7.74 (d, 1H), 7.40 (d, 1H), 7.09 (s, 1H), 6.99–6.94 (m, 1H), 4.96–4.88 (m, 1H), 4.65 (d, 1H), 4.21–4.12 (m, 1H), 3.82–3.69 (m, 4H), 3.34–3.32 (m, 1H) ,3.31–3.29(m,1H),2.88–2.78(m,1H),2.56–2.51(m,1H),2.47–2.44(m,1H),2.20–1.87(m,7H) ,1.32–1.28(m,1H),1.02–0.95(m,2H),0.63–0.55(m,2H),0.18–0.08(m,2H).HRMS(ESI+,[M+H] + )m/z：634.2697.

化合物31_B：1H NMR(500MHz,DMSO-d6)δ11.59(s,1H),10.06(s,1H),7.89(d,1H),7.74(d,1H),7.40(d,1H),7.10(d,1H),7.00–6.92(m,1H),4.97–4.87(m,1H),4.65(d,1H),4.20–4.12(m,1H),3.81–3.70(m,4H),3.34–3.32(m,1H),3.31–3.29(m,1H),2.89–2.75(m,1H),2.58–2.52(m,1H),2.48–2.41(m,1H),2.25–1.81(m,7H),1.29–1.26(m,1H),1.03–0.95(m,2H),0.63–0.55(m,2H),0.18–0.10(m,2H). HRMS(ESI+,[M+H]+)m/z：634.2704.Compound 31_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.59 (s, 1H), 10.06 (s, 1H), 7.89 (d, 1H), 7.74 (d, 1H), 7.40 (d, 1H), 7.10 (d, 1H), 7.00–6.92 (m, 1H), 4.97–4.87 (m, 1H), 4.65 (d, 1H), 4.20–4.12 (m, 1H), 3.81–3.70 (m, 4H), 3.34–3. 32(m,1H),3.31–3.29(m,1H),2.89–2.75(m,1H),2.58–2.52(m,1H),2.48–2.41(m,1H),2.2 5–1.81(m,7H),1.29–1.26(m,1H),1.03–0.95(m,2H),0.63–0.55(m,2H),0.18–0.10(m,2H). HRMS(ESI+,[M+H] + )m/z: 634.2704.

实施例32
Embodiment 32

步骤A：Step A:

参考化合物20_A的制备方法，以化合物21-1代替化合物20-1A，制备得到化合物32(45mg)。1HNMR(500MHz,DMSO-d6)δ10.96(s,1H),10.08(s,1H),7.81(t,2H),7.41(d,1H),7.25(d,1H),7.06(dd,1H),4.66(d,1H),4.25–4.14(m,1H),3.08(s,3H),3.05–2.94(m,4H),2.95–2.75(m,1H),2.46–2.32(m,1H),2.22–1.88(m,5H),1.83(d,2H),1.47(s,2H),0.79–0.58(m,2H),0.55–0.26(m,2H).HRMS(ESI+,[M+H]+)m/z：604.2609.Referring to the preparation method of compound 20-A, compound 21-1 was used instead of compound 20-1A to prepare compound 32 (45 mg). 1 HNMR(500MHz,DMSO-d 6 )δ10.96(s,1H),10.08(s,1H),7.81(t,2H),7.41(d,1H),7.25(d,1H),7 .06(dd,1H),4.66(d,1H),4.25–4.14(m,1H),3.08(s,3H),3.05–2.94(m, 4H),2.95–2.75(m,1H),2.46–2.32(m,1H),2.22–1.88(m,5H),1.83(d,2 H),1.47(s,2H),0.79–0.58(m,2H),0.55–0.26(m,2H).HRMS(ESI+,[M+H] + )m/z：604.2609.

实施例33
Embodiment 33

步骤A：Step A:

参考实施例23的步骤C，以化合物E-4替换化合物23-2，制备得到化合物33。HRMS(ESI+,[M+H]+)m/z：604.2597.Referring to step C of Example 23, compound 23-2 was replaced with compound E-4 to prepare compound 33. HRMS (ESI+, [M+H] + ) m/z: 604.2597.

步骤B：Step B:

化合物33(105mg)经过制备HPLC(拆分条件：柱：CHIRALPAK IK,5μm,21.2*250mm；流动相：正己烷:二氯甲烷:乙醇＝60:20:20；流速：20mL/min；波长：254nm)拆分得到化合物33_A(45mg，保留时间为13.5分钟)、化合物33_B(45mg，保留时间为16.1分钟)。Compound 33 (105 mg) was separated by preparative HPLC (separation conditions: column: CHIRALPAK IK, 5 μm, 21.2*250 mm; mobile phase: n-hexane: dichloromethane: ethanol = 60:20:20; flow rate: 20 mL/min; wavelength: 254 nm) to give compound 33_A (45 mg, retention time: 13.5 minutes) and compound 33_B (45 mg, retention time: 16.1 minutes).

化合物33_A:1H NMR(500MHz,DMSO-d6)δ11.58(s,1H),10.10(s,1H),7.89(d,1H),7.74(d,1H),7.40(d,1H),7.08(d,1H),6.97(dd,1H),4.71–4.59(m,1H),4.21–4.12(m,1H),3.83–3.73(m,2H),3.08(s,3H),2.87–2.77(m,1H),2.56–2.51(m,1H),2.49–2.43(m,2H),2.20–1.89(m,7H),1.02–0.96(m,2H),0.65–0.55(m,2H),0.19–0.09(m,2H).HRMS(ESI+,[M+H]+)m/z：604.2601.Compound 33_A: 1 H NMR (500 MHz, DMSO-d 6 )δ11.58(s,1H),10.10(s,1H),7.89(d,1H),7.74(d,1H),7.40(d,1H),7.08(d,1H),6.97(dd,1H),4.71–4.59(m,1H),4.21–4.12(m,1H),3.83–3.73(m,2H),3.08 (s,3H),2.87–2.77(m,1H),2.56–2.51(m,1H),2.49–2.43(m,2H),2.20–1.89(m, 7H),1.02–0.96(m,2H),0.65–0.55(m,2H),0.19–0.09(m,2H).HRMS(ESI+,[M+H] + )m/z：604.2601.

化合物33_B:1H NMR(500MHz,DMSO-d6)δ11.58(s,1H),10.10(s,1H),7.89(d,1H),7.74(d,1H),7.41(d,1H),7.08(d,1H),6.97(dd,1H),4.71–4.60(m,1H),4.22–4.10(m,1H),3.82–3.72(m,2H),3.08(s,3H),2.87–2.79(m,1H),2.56–2.52(m,1H),2.49–2.42(m,2H),2.20–1.89(m,7H),1.03–0.96(m,2H),0.64–0.56(m,2H),0.19–0.09(m,2H).HRMS(ESI+,[M+H]+)m/z：604.2596.Compound 33_B: 1 H NMR (500 MHz, DMSO-d 6 )δ11.58(s,1H),10.10(s,1H),7.89(d,1H),7.74(d,1H),7.41(d,1H),7.08(d,1H),6.97(dd,1H),4.71–4.60(m,1H),4.22–4.10(m,1H),3.82–3.72(m,2H),3.08 (s,3H),2.87–2.79(m,1H),2.56–2.52(m,1H),2.49–2.42(m,2H),2.20–1.89(m, 7H),1.03–0.96(m,2H),0.64–0.56(m,2H),0.19–0.09(m,2H).HRMS(ESI+,[M+H] + )m/z：604.2596.

实施例34
Embodiment 34

步骤A：Step A:

向100mL单口瓶中依次加入双-(4-甲氧基苄基)-胺(3.5g)，DCM(30mL)和DIPEA(2.46mL)，冰浴条件下加入化合物34-1(2.66g)，转移至室温反应1h。反应结束后，加水40mL，DCM(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，所得粗品经硅胶柱层析(PE/EA＝2.5/1)纯化得到化合物34-2(4g)。1H NMR(500MHz,DMSO-d6)δ7.17–7.12(m,4H),6.88–6.84(m,4H),4.28(s,2H),4.25(s,4H),4.15(q,2H),3.73(s,6H),1.21(t,3H).To a 100 mL single-mouth bottle, bis-(4-methoxybenzyl)-amine (3.5 g), DCM (30 mL) and DIPEA (2.46 mL) were added in sequence, and compound 34-1 (2.66 g) was added under ice bath conditions, and the mixture was transferred to room temperature for reaction for 1 h. After the reaction was completed, 40 mL of water was added, and DCM (3×20 mL) was used for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (PE/EA=2.5/1) to obtain compound 34-2 (4 g). 1 H NMR (500MHz, DMSO-d 6 ) δ7.17–7.12(m,4H),6.88–6.84(m,4H),4.28(s,2H),4.25(s,4H),4.15(q,2H),3.73(s,6H),1.21(t,3H).

步骤B：Step B:

向100mL单口瓶中依次加入化合物34-2(4g)，DMF(20mL)和碘甲烷(4.18g)，冰浴条件下加入60％的氢化钠(1g)，转移至室温反应12h。反应结束后，加水80mL，EA(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，所得粗品经硅胶柱层析(PE/EA＝5/1)纯化得到化合物34-3(3g)。1H NMR(500MHz,DMSO-d6)δ7.08–7.03(m,4H),6.81–6.77(m,4H),4.26(s,4H),4.20(q,2H),3.70(s,6H),1.62(s,6H),1.24(t,3H).Compound 34-2 (4 g), DMF (20 mL) and iodomethane (4.18 g) were added to a 100 mL single-mouth bottle in sequence, and 60% sodium hydride (1 g) was added under ice bath conditions, and the mixture was transferred to room temperature for reaction for 12 h. After the reaction, 80 mL of water was added, and EA (3×30 mL) was used for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (PE/EA=5/1) to obtain compound 34-3 (3 g). 1 H NMR (500 MHz, DMSO-d 6 )δ7.08–7.03 (m, 4H), 6.81–6.77 (m, 4H), 4.26 (s, 4H), 4.20 (q, 2H), 3.70 (s, 6H), 1.62 (s, 6H), 1.24 (t, 3H).

步骤C：Step C:

向100mL单口瓶中依次加入34-3(3g)，三氟乙酸(20mL)和苯甲醚(2.42g)，室温搅拌反应3h。反应结束后，减压浓缩，所得粗品经硅胶柱层析(PE/EA＝1/1)纯化得到化合物34-4(1.3g)。1H NMR(500MHz,DMSO-d6)δ7.03(s,2H),4.14(q,2H),1.50(s,6H),1.20(t,3H).34-3 (3 g), trifluoroacetic acid (20 mL) and anisole (2.42 g) were added to a 100 mL single-mouth bottle in sequence, and the mixture was stirred at room temperature for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE/EA=1/1) to obtain compound 34-4 (1.3 g). 1 H NMR (500 MHz, DMSO-d 6 ) δ7.03 (s, 2H), 4.14 (q, 2H), 1.50 (s, 6H), 1.20 (t, 3H).

步骤D：Step D:

向100mL单口瓶中，依次加入化合物23-1(900mg)、化合物34-4(641mg)、碳酸铯(2.06g)、N1-(2,6-二甲基苯基)-N2-(吡啶-2-基甲基)草酰胺(72mg)、碘化亚铜(48mg)和叔丁醇(25mL)，N2保护下，加热至100℃反应5h。反应结束后，加水60mL，DCM(3×20mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩，硅胶柱层析(洗脱剂：DCM/MeOH＝150/1)纯化，得到化合物34-5(708mg)。MS(ESI+,[M+H]+)m/z：424.28.Compound 23-1 (900 mg), compound 34-4 (641 mg), cesium carbonate (2.06 g), N1-(2,6-dimethylphenyl)-N2-(pyridin-2-ylmethyl)oxalamide (72 mg), cuprous iodide (48 mg) and tert-butyl alcohol (25 mL) were added to a 100 mL single-mouth bottle in sequence, and heated to 100 ° C for 5 h under N 2 protection. After the reaction, 60 mL of water was added, and DCM (3×20 mL) was used for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM/MeOH=150/1) to obtain compound 34-5 (708 mg). MS (ESI+, [M+H] + ) m/z: 424.28.

步骤E：Step E:

向50mL双口瓶中，加入化合物34-5(350mg)和THF(10mL)，N2保护冰浴条件下，滴加2M的硼氢化钠溶液(0.85mL)。反应结束后，加5mL甲醇和1mL 2N的盐酸溶液淬灭反应，硅胶柱层析(洗脱剂：DCM/MeOH＝50/1)纯化，得到化合物34-6(310mg)。MS(ESI+,[M+H]+)m/z：382.26.Compound 34-5 (350 mg) and THF (10 mL) were added to a 50 mL two-necked bottle, and 2M sodium borohydride solution (0.85 mL) was added dropwise under N2 protection and ice bath conditions. After the reaction was completed, 5 mL of methanol and 1 mL of 2N hydrochloric acid solution were added to quench the reaction, and purified by silica gel column chromatography (eluent: DCM/MeOH=50/1) to obtain compound 34-6 (310 mg). MS (ESI+, [M+H] + ) m/z: 382.26.

步骤F： Step F:

参考化合物20_A的制备方法，以化合物34-6代替化合物D-4，制备得到化合物34_A。1H NMR(500MHz,DMSO-d6)δ13.25(s,1H),9.97(s,1H),8.05(d,1H),7.74(d,1H),7.45–7.39(m,2H),7.18(dd,1H),5.11(s,1H),4.72–4.64(m,1H),4.21(dd,1H),3.55(s,2H),3.27(s,3H),3.01–2.86(m,5H),2.47–2.38(m,1H),2.19–1.52(m,7H),1.25(s,6H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：633.2681.Referring to the preparation method of compound 20_A, compound 34-6 was used instead of compound D-4 to prepare compound 34_A. 1 H NMR (500MHz, DMSO-d 6 )δ13.25(s,1H),9.97(s,1H),8.05(d,1H),7.74(d,1H),7.45–7.39(m,2H),7.18(dd,1H),5.11(s,1H),4.72–4.64(m,1H),4.21(dd, 1H),3.55(s,2H),3.27(s,3H),3.01–2.86(m,5H),2.47–2.38(m,1H),2.19–1.52(m,7H),1.25(s,6H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：633.2681.

参考化合物20_B的制备方法，以化合物34-6代替化合物D-4，制备得到化合物34_B。1H NMR(500MHz,DMSO-d6)δ13.26(s,1H),9.97(s,1H),8.05(d,1H),7.74(d,1H),7.46–7.37(m,2H),7.18(dd,1H),5.11(s,1H),4.72–4.64(m,1H),4.21(dd,1H),3.55(s,2H),3.27(s,3H),3.01–2.86(m,5H),2.47–2.38(m,1H),2.21–1.46(m,7H),1.25(s,6H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：633.2685.Referring to the preparation method of compound 20_B, compound 34-6 was used instead of compound D-4 to prepare compound 34_B. 1 H NMR (500MHz, DMSO-d 6 )δ13.26(s,1H),9.97(s,1H),8.05(d,1H),7.74(d,1H),7.46–7.37(m,2H),7.18(dd,1H),5.11(s,1H),4.72–4.64(m,1H),4.21(dd, 1H),3.55(s,2H),3.27(s,3H),3.01–2.86(m,5H),2.47–2.38(m,1H),2.21–1.46(m,7H),1.25(s,6H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：633.2685.

实施例35
Embodiment 35

步骤A：Step A:

参考实施例34的步骤B，以1,2-二溴乙烷代替碘甲烷，制备得到化合物35-1。MS(ESI+,[M+H]+)m/z：434.21.Referring to step B of Example 34, 1,2-dibromoethane was used instead of iodomethane to prepare compound 35-1. MS (ESI+, [M+H] + ) m/z: 434.21.

步骤B：Step B:

参考实施例34的步骤C，以35-1代替34-3，制备得到化合物35-2。MS(ESI+,[M+H]+)m/z：194.12.步骤C：Referring to step C of Example 34, 35-1 was used instead of 34-3 to prepare compound 35-2. MS (ESI+, [M+H] + ) m/z: 194.12. Step C:

参考实施例34的步骤D，以35-2代替34-4，制备得到化合物35-3。MS(ESI+,[M+H]+)m/z：422.29.Referring to step D of Example 34, 35-2 was used instead of 34-4 to prepare compound 35-3. MS (ESI+, [M+H] + ) m/z: 422.29.

步骤D：Step D:

参考实施例34的步骤E，以35-3代替34-5，制备得到化合物35-4。1H NMR(500MHz,DMSO-d6)δ9.90(s,1H),8.66(d,1H),7.73(d,1H),7.44(d,1H),7.12(d,1H),6.95(dd,1H),4.94(t,1H),3.74(d,2H),2.88(t,4H),1.52(t,4H),1.09(q,2H),0.95(q,2H),0.35(s,4H).MS(ESI+,[M+H]+)m/z：380.24.Referring to step E of Example 34, 35-3 was used instead of 34-5 to prepare compound 35-4. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.66 (d, 1H), 7.73 (d, 1H), 7.44 (d, 1H), 7.12 (d, 1H), 6.95 (dd, 1H), 4.94 (t, 1H), 3.74 (d, 2H), 2.88 (t, 4H), 1.52 (t, 4H), 1.09 (q, 2H), 0.95 (q, 2H), 0.35 (s, 4H). MS (ESI+, [M+H] + ) m/z: 380.24.

步骤E：Step E:

参考化合物20_A的制备方法，以化合物35-4代替化合物D-4，制备得到化合物35_A(67mg)。1HNMR(500MHz,DMSO-d6)δ13.26(s,1H),10.12(s,1H),8.06(d,1H),7.75(d,1H),7.42(d,1H),7.34(d,1H),7.19 -7.05(m,1H),4.96(t,1H),4.67(s,1H),4.27–4.17(m,1H),3.75(d,2H),3.28(s,3H),3.05–2.85(m,6H),2.43(d,1H),2.20–1.97(m,3H),1.75(s,3H),1.25–1.08(m,2H),1.05–0.94(m,2H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：631.2518.Referring to the preparation method of compound 20_A, compound 35-4 was used instead of compound D-4 to prepare compound 35_A (67 mg). 1 HNMR (500 MHz, DMSO-d 6 )δ13.26(s,1H),10.12(s,1H),8.06(d,1H),7.75(d,1H),7.42(d,1H),7.34(d,1H),7.19 -7.05(m,1H),4.96(t,1H),4.67(s,1H),4.27–4.17(m,1H),3.75(d,2H),3.28(s,3H),3.05–2.85(m,6H),2.43 (d,1H),2.20–1.97(m,3H),1.75(s,3H),1.25–1.08(m,2H),1.05–0.94(m,2H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：631.2518.

参考化合物20_B的制备方法，，以化合物35-4代替化合物D-4，制备得到化合物35_B(57mg)。1H NMR(500MHz,DMSO-d6)δ13.26(s,1H),10.12(s,1H),8.06(d,1H),7.75(d,1H),7.42(d,1H),7.34(d, 1H),7.22–7.02(m,1H),4.97(s,1H),4.68(d,1H),4.35–4.20(m,1H),3.75(s,2H),3.27(s,3H),3.06–2.74(m,5H),2.48–2.39(m,1H),2.22–1.38(m,7H),1.25–1.07(m,2H),1.02–0.93(m,2H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：631.2512.Referring to the preparation method of compound 20_B, compound 35-4 was used instead of compound D-4 to prepare compound 35_B (57 mg). 1 H NMR (500 MHz, DMSO-d 6 )δ13.26(s,1H),10.12(s,1H),8.06(d,1H),7.75(d,1H),7.42(d,1H),7.34(d, 1H),7.22–7.02(m,1H),4.97(s,1H),4.68(d,1H),4.35–4.20(m,1H),3.75(s,2H),3.27(s,3H),3.06–2.74(m,5 H),2.48–2.39(m,1H),2.22–1.38(m,7H),1.25–1.07(m,2H),1.02–0.93(m,2H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：631.2512.

实施例36
Embodiment 36

参考实施例1的步骤C，以化合物21-2A代替化合物1-3，以化合物24-3代替化合物A-6，制备得到化合物36_A。1H NMR(500MHz,DMSO-d6)δ10.97(s,1H),10.05(s,1H),7.81(d,1H),7.79(d,1H),7.41(d,1H),7.26(d,1H),7.05(dd,1H),4.94(t,1H),4.69–4.62(m,1H),4.18(dd,,1H),3.76(q,2H),3.35–3.32(m,2H),3.05–2.97(m,4H),2.86–2.77(m,1H),2.45–2.35(m,1H),2.20–2.02(m,4H),1.99–1.87(m,1H),1.86–1.74(m,2H),1.47(s,2H),0.67–0.59(m,2H),0.43–0.33(m,2H).HRMS(ESI+,[M+H]+)m/z：634.2703.Referring to step C of Example 1, compound 21-2A was used instead of compound 1-3, and compound 24-3 was used instead of compound A-6 to prepare compound 36-A. 1 H NMR (500MHz, DMSO-d 6 )δ10.97(s,1H),10.05(s,1H),7.81(d,1H),7.79(d,1H),7.41(d,1H),7.26(d,1H),7.05(dd,1H),4.94(t,1H),4.69–4.62(m,1H),4.18(dd,,1H),3.76(q,2H),3.35–3.32(m,2H),3. 05–2.97(m,4H),2.86–2.77(m,1H),2.45–2.35(m,1H),2.20–2.02(m,4H),1.99–1.87(m,1H ),1.86–1.74(m,2H),1.47(s,2H),0.67–0.59(m,2H),0.43–0.33(m,2H).HRMS(ESI+,[M+H] + )m/z：634.2703.

参考化合物36_A的制备方法，以21-2B代替21-2A，制备得到化合物36_B。1H NMR(500MHz,DMSO-d6)δ10.97(s,1H),10.05(s,1H),7.81(d,1H),7.79(d,1H),7.41(d,1H),7.26(d,1H),7.05(dd,1H),4.94(t,1H),4.69–4.62(m,1H),4.19(dd,1H),3.76(q,2H),3.35–3.32(m,2H),3.07–2.98(m,4H),2.86–2.77(m,1H),2.45–2.35(m,1H),2.22–2.03(m,4H),1.99–1.88(m,1H),1.86–1.74(m,2H),1.47(s,2H),0.68–0.57(m,2H),0.43–0.34(m,2H).HRMS(ESI+,[M+H]+)m/z：634.2715.Referring to the preparation method of compound 36_A, 21-2B was used instead of 21-2A to prepare compound 36_B. 1 H NMR (500MHz, DMSO-d 6 )δ10.97(s,1H),10.05(s,1H),7.81(d,1H),7.79(d,1H),7.41(d,1H),7.26(d,1H),7.05(dd,1H),4.94(t,1H),4.69–4.62(m,1H),4.19(dd,1H),3.76(q,2H),3.35–3.32(m,2H),3.0 7–2.98(m,4H),2.86–2.77(m,1H),2.45–2.35(m,1H),2.22–2.03(m,4H),1.99–1.88(m,1H ),1.86–1.74(m,2H),1.47(s,2H),0.68–0.57(m,2H),0.43–0.34(m,2H).HRMS(ESI+,[M+H] + )m/z：634.2715.

实施例37

Embodiment 37

步骤A：Step A:

向100mL单口瓶中依次加入化合物34-2(3.500g)，DMF(20mL)、碘甲烷(1.340g)和碳酸钾(1.78g)，室温搅拌反应12h。反应结束后，加水80mL，EA(3×30mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，所得粗品经硅胶柱层析(PE/EA＝5/1)纯化得到化合物37-1(3g)。1H NMR(500MHz,DMSO-d6)δ7.08–7.03(m,4H),6.81–6.77(m,4H),4.33–4.11(m,7H),3.72(s,6H),1.46(d,3H),1.20(t,3H).Compound 34-2 (3.500 g), DMF (20 mL), iodomethane (1.340 g) and potassium carbonate (1.78 g) were added to a 100 mL single-mouth bottle in sequence, and the mixture was stirred at room temperature for 12 h. After the reaction, 80 mL of water was added, and EA (3×30 mL) was used for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (PE/EA=5/1) to obtain compound 37-1 (3 g). 1 H NMR (500 MHz, DMSO-d 6 )δ7.08–7.03 (m, 4H), 6.81–6.77 (m, 4H), 4.33–4.11 (m, 7H), 3.72 (s, 6H), 1.46 (d, 3H), 1.20 (t, 3H).

步骤B：Step B:

向100mL单口瓶中依次加入化合物37-1(2.300g)，三氟乙酸(20mL)和苯甲醚(1.92g)，室温搅拌反应3h。反应结束后，减压浓缩，所得粗品经硅胶柱层析(PE/EA＝1/1)纯化得到化合物37-2(0.9g)。1HNMR(500MHz,DMSO-d6)δ7.12(s,2H),4.14(q,2H),3.97(q,1H),1.45(d,3H),1.21(t,3H).Compound 37-1 (2.300 g), trifluoroacetic acid (20 mL) and anisole (1.92 g) were added to a 100 mL single-mouth bottle in sequence and stirred at room temperature for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (PE/EA=1/1) to obtain compound 37-2 (0.9 g). 1 HNMR (500 MHz, DMSO-d 6 )δ7.12 (s, 2H), 4.14 (q, 2H), 3.97 (q, 1H), 1.45 (d, 3H), 1.21 (t, 3H).

步骤C：Step C:

参考实施例23的步骤B，以化合物37-2替换甲磺酰胺，制备得到化合物37-3。MS(ESI+,[M+H]+)m/z：410.25.1H NMR(500MHz,DMSO-d6)δ10.41(s,1H),8.57(d,1H),7.74(d,1H),7.46(d,1H),7.09(d,1H),6.95(dd,1H),4.22(q,1H),4.10–4.02(m,2H),2.90(t,4H),1.56–1.48(m,4H),1.45(d,3H),1.14(t,3H),0.35(s,4H).Referring to step B of Example 23, methanesulfonamide was replaced with compound 37-2 to prepare compound 37-3. MS (ESI+, [M+H] + ) m/z: 410.25. 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.41 (s, 1H), 8.57 (d, 1H), 7.74 (d, 1H), 7.46 (d, 1H), 7.09 (d, 1H), 6.95 (dd, 1H), 4.22 (q, 1H), 4.10-4.02 (m, 2H), 2.90 (t, 4H), 1.56-1.48 (m, 4H), 1.45 (d, 3H), 1.14 (t, 3H), 0.35 (s, 4H).

步骤D：Step D:

50mL两口瓶中，依次加入化合物37-3(0.330g)和THF(30mL)溶解，氮气保护冰浴条件下滴加2M的硼氢化锂溶液(0.80mL)下，转移至室温搅拌16h。反应结束后向反应液中加入5mL甲醇淬灭反应，加入30mL蒸馏水，EA(2×20mL)萃取，饱和食盐水(30mL)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：DCM/MeOH＝20/1)纯化，得到化合物37-4(0.180g)。MS(ESI+,[M+H]+)m/z：368.32.1H NMR(500MHz,DMSO-d6)δ9.98(s,1H),8.57(d,1H),7.72(d,1H),7.44(d,1H),7.08(d,1H),6.95(dd,1H),4.99(br s,1H),3.83(dd,1H),3.45(dd,1H),3.24–3.18(m,1H),2.95–2.87(m,4H),1.57–1.46(m,4H),1.27(d,3H),0.35(s,4H).Compound 37-3 (0.330 g) and THF (30 mL) were added to a 50 mL two-necked bottle to dissolve, and 2 M lithium borohydride solution (0.80 mL) was added dropwise under nitrogen protection in an ice bath, and the mixture was transferred to room temperature and stirred for 16 h. After the reaction was completed, 5 mL of methanol was added to the reaction solution to quench the reaction, 30 mL of distilled water was added, EA (2×20 mL) was added for extraction, saturated brine (30 mL) was washed, and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM/MeOH=20/1) to obtain compound 37-4 (0.180 g). MS(ESI+,[M+H] + )m/z: 368.32. 1 H NMR(500MHz, DMSO-d 6 )δ9.98(s,1H),8.57(d,1H),7.72(d,1H),7.44(d,1H),7.08(d,1H),6.95(dd,1H),4.99(br s,1H),3.83(dd,1H),3.45(dd,1H),3.24–3.18(m,1H),2.95–2.87(m,4H),1.57–1.46(m,4H),1.27(d,3H),0.35(s,4H).

步骤E：
Step E:

参考化合物20_A的制备方法，以化合物37-4替换化合物D-4，制备得到化合物37-5。MS(ESI+,[M+H]+)m/z：619.50.Referring to the preparation method of compound 20_A, compound 37-4 was used to replace compound D-4 to prepare compound 37-5. MS (ESI+, [M+H] + ) m/z: 619.50.

参考化合物20_B的制备方法，以化合物37-4替换化合物D-4，制备得到化合物37-6。MS(ESI+,[M+H]+)m/z：619.37.Referring to the preparation method of compound 20_B, compound 37-4 was used to replace compound D-4 to prepare compound 37-6. MS (ESI+, [M+H] + ) m/z: 619.37.

步骤F： Step F:

化合物37-5(155mg)经过制备HPLC(拆分条件：柱：CHIRALPAK IG，4.6×250mm，5μm；流动相：正己烷:二氯甲烷:乙醇＝60:30:10；流速：1mL/min；波长：254nm)拆分得到化合物37_A(41mg，保留时间为8.381分钟)、化合物37_B(56mg，保留时间为10.409分钟)。Compound 37-5 (155 mg) was separated by preparative HPLC (separation conditions: column: CHIRALPAK IG, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 60:30:10; flow rate: 1 mL/min; wavelength: 254 nm) to give compound 37_A (41 mg, retention time 8.381 minutes) and compound 37_B (56 mg, retention time 10.409 minutes).

化合物37-6(160mg)经过制备HPLC(拆分条件：柱：CHIRALART Cellulose SB，5μm，30*250mm；流动相：乙醇:二氯甲烷＝1:5(A相)，正己烷(B相)，35A65B等度洗脱；流速：40mL/min；波长：254nm)拆分得到化合物37_C(49mg，保留时间为10.8分钟)、化合物37_D(70mg，保留时间为13.2分钟)。Compound 37-6 (160 mg) was separated by preparative HPLC (separation conditions: column: CHIRALART Cellulose SB, 5 μm, 30*250 mm; mobile phase: ethanol: dichloromethane = 1:5 (phase A), n-hexane (phase B), 35A65B isocratic elution; flow rate: 40 mL/min; wavelength: 254 nm) to give compound 37_C (49 mg, retention time 10.8 minutes) and compound 37_D (70 mg, retention time 13.2 minutes).

化合物37_A:1H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.19(s,1H),8.07(d,1H),7.74(d,1H),7.42(d,1H),7.30(d,1H),7.15(dd,1H),5.16–4.86(m,1H),4.73–4.62(m,1H),4.25–4.14(m,1H),3.93–3.76(m,1H),3.56–3.42(m,1H),3.30–3.25(m,4H),3.09–2.93(m,4H),2.93–2.87(m,1H),2.46–2.39(m,1H),2.21–1.50(m,7H),1.29(d,3H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：619.2519.Compound 37_A: 1 H NMR (500 MHz, DMSO-d 6 )δ13.18(s,1H),10.19(s,1H),8.07(d,1H),7.74(d,1H),7.42(d,1H),7.30(d,1H),7.15(dd,1H),5.16–4.86(m,1H),4.73–4.62(m,1H),4.25–4.14(m,1H),3.93–3.76 (m,1H),3.56–3.42(m,1H),3.30–3.25(m,4H),3.09–2.93(m,4H),2.93–2.87(m,1H) ,2.46–2.39(m,1H),2.21–1.50(m,7H),1.29(d,3H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：619.2519.

化合物37_B:1H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.19(s,1H),8.07(d,1H),7.74(d,1H),7.42(d,1H),7.30(d,1H),7.15(dd,1H),5.16–4.87(m,1H),4.74–4.59(m,1H),4.26–4.15(m,1H),3.87–3.80(m,1H),3.55–3.45(m,1H),3.30–3.25(m,4H),3.11–2.94(m,4H),2.93–2.87(m,1H),2.46–2.39(m,1H),2.24–1.50(m,7H),1.29(d,3H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：619.2512.Compound 37_B: 1 H NMR (500 MHz, DMSO-d 6 )δ13.18(s,1H),10.19(s,1H),8.07(d,1H),7.74(d,1H),7.42(d,1H),7.30(d,1H),7.15(dd,1H),5.16–4.87(m,1H),4.74–4.59(m,1H),4.26–4.15(m,1H),3.87–3.80 (m,1H),3.55–3.45(m,1H),3.30–3.25(m,4H),3.11–2.94(m,4H),2.93–2.87(m,1H) ,2.46–2.39(m,1H),2.24–1.50(m,7H),1.29(d,3H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：619.2512.

化合物37_C:1H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.19(s,1H),8.07(d,1H),7.74(d,1H),7.42(d,1H),7.30(d,1H),7.15(dd,1H),5.01(t,1H),4.72–4.64(m,1H),4.24–4.18(m,1H),3.87–3.81(m,1H),3.52–3.45(m,1H),3.29–3.25(m,4H),3.03–2.93(m,4H),2.93–2.87(m,1H),2.46–2.39(m,1H),2.18–1.54(m,7H),1.29(d,3H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：619.2502.Compound 37_C: 1 H NMR (500 MHz, DMSO-d 6 )δ13.18(s,1H),10.19(s,1H),8.07(d,1H),7.74(d,1H),7.42(d,1H),7.30(d,1H),7.15(dd,1H),5.01(t,1H),4.72–4.64(m,1H),4.24–4.18(m,1H),3.87–3.81(m, 1H),3.52–3.45(m,1H),3.29–3.25(m,4H),3.03–2.93(m,4H),2.93–2.87(m,1H), 2.46–2.39(m,1H),2.18–1.54(m,7H),1.29(d,3H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：619.2502.

化合物37_D:1H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.19(s,1H),8.07(d,1H),7.74(d,1H),7.42(d,1H),7.30(d,1H),7.15(dd,1H),5.01(t,1H),4.71–4.64(m,1H),4.23–4.18(m,1H),3.87–3.81(m,1H),3.52–3.45(m,1H),3.30–3.25(m,4H),3.03–2.93(m,4H),2.93–2.87(m,1H),2.47–2.40(m,1H),2.23–1.50(m,7H),1.29(d,3H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：619.2487.Compound 37_D: 1 H NMR (500 MHz, DMSO-d 6 )δ13.18(s,1H),10.19(s,1H),8.07(d,1H),7.74(d,1H),7.42(d,1H),7.30(d,1H),7.15(dd,1H),5.01(t,1H),4.71–4.64(m,1H),4.23–4.18(m,1H),3.87–3.81(m, 1H),3.52–3.45(m,1H),3.30–3.25(m,4H),3.03–2.93(m,4H),2.93–2.87(m,1H), 2.47–2.40(m,1H),2.23–1.50(m,7H),1.29(d,3H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：619.2487.

实施例38
Embodiment 38

步骤A：Step A:

参考实施例23的步骤B，以异丙基磺酰胺代替甲磺酰胺，得到化合物38-1。MS(ESI+,[M+H]+)m/z：352.22.Referring to step B of Example 23, methanesulfonamide was replaced with isopropylsulfonamide to obtain compound 38-1. MS (ESI+, [M+H] + ) m/z: 352.22.

步骤B：Step B:

参考实施例14的步骤E，以化合物38-1代替化合物A-6，得到化合物38。MS(ESI+,[M+H]+)m/z：603.31Referring to step E of Example 14, compound 38-1 was used instead of compound A-6 to obtain compound 38. MS (ESI+, [M+H] + ) m/z: 603.31

步骤C：Step C:

化合物38经过手性制备分离(柱：REFLECT Cellulose B，4.6×250mm，5μm；流动相：正己烷:二氯甲烷:乙醇＝70:15:15；流速：1mL/min；波长：254nm)，拆分得到化合物38_A(保留时间为8.997min)、化合物38_B(保留时间为10.442min)。Compound 38 was subjected to chiral preparative separation (column: REFLECT Cellulose B, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 70:15:15; flow rate: 1 mL/min; wavelength: 254 nm) to give compound 38_A (retention time: 8.997 min) and compound 38_B (retention time: 10.442 min).

化合物38_A:1H NMR(500MHz,DMSO)δ13.18(s,1H),10.18(s,1H),8.07(d,J＝8.6Hz,1H),7.74(d, J＝8.4Hz,1H),7.42(d,J＝8.5Hz,1H),7.31(d,J＝2.3Hz,1H),7.16(dd,J＝8.7,2.1Hz,1H),4.72–4.64(m,1H),4.24–4.17(m,1H),3.42–3.31(m,1H),3.27(s,3H),3.00–2.94(m,4H),2.95–2.86(m,1H),2.47–2.37(m,1H),2.19–2.00(m,3H),1.87–1.49(m,4H),1.27(d,J＝6.8Hz,6H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：603.2556.Compound 38_A: 1 H NMR (500 MHz, DMSO) δ 13.18 (s, 1H), 10.18 (s, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.74 (d, J＝8.4Hz,1H),7.42(d,J＝8.5Hz,1H),7.31(d,J＝2.3Hz,1H),7.16(dd,J＝8.7, 2.1Hz,1H),4.72–4.64(m,1H),4.24–4.17(m,1H),3.42–3.31(m,1H),3.27(s, 3H),3.00–2.94(m,4H),2.95–2.86(m,1H),2.47–2.37(m,1H),2.19–2.00(m, 3H),1.87–1.49(m,4H),1.27(d,J＝6.8Hz,6H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：603.2556.

化合物38_B:.1H NMR(500MHz,DMSO)δ13.18(s,1H),10.18(s,1H),8.07(d,J＝8.6Hz,1H),7.74(d,J＝8.5Hz,1H),7.42(d,J＝8.5Hz,1H),7.31(d,J＝2.2Hz,1H),7.16(dd,J＝8.6,2.2Hz,1H),4.74–4.62(m,1H),4.24–4.17(m,1H),3.42–3.32(m,1H),3.27(s,3H),3.01–2.94(m,4H),2.94–2.86(m,1H),2.47–2.36(m,1H),2.20–2.00(m,3H),1.93–1.48(m,4H),1.27(d,J＝6.8Hz,6H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：603.2554.Compound 38_B: 1 H NMR (500 MHz, DMSO) δ 13.18 (s, 1H), 10.18 (s, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.16 (dd, J = 8.6, 2.2 Hz, 1H), 4.74–4.62 (m, 1H), 4.24– 4.17(m,1H),3.42–3.32(m,1H),3.27(s,3H),3.01–2.94(m,4H),2.94–2.86(m,1H),2.47–2.36(m ,1H),2.20–2.00(m,3H),1.93–1.48(m,4H),1.27(d,J＝6.8Hz,6H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：603.2554.

实施例39
Embodiment 39

步骤A：Step A:

参考实施例23的步骤B，以环丙基磺酰胺代替甲磺酰胺，得到化合物39-1。MS(ESI+,[M+H]+)m/z：350.21.Referring to step B of Example 23, cyclopropylsulfonamide was used instead of methanesulfonamide to obtain compound 39-1. MS (ESI+, [M+H] + ) m/z: 350.21.

步骤B：Step B:

参考实施例14的步骤E，以化合物39-1代替化合物A-6，得到化合物39。MS(ESI+,[M+H]+)m/z：601.40.Referring to step E of Example 14, compound 39-1 was used instead of compound A-6 to obtain compound 39. MS (ESI+, [M+H] + ) m/z: 601.40.

步骤C：Step C:

化合物39经过手性制备分离(拆分条件：柱：CHIRALART Cellulose-SB，4.6×250mm，S-5μm氘代103#；流动相：正己烷:乙醇＝60:40；流速：1mL/min；波长：254nm)，拆分得到化合物39_A(保留时间为8.72分钟)、化合物39_B(保留时间为9.96分钟)。Compound 39 was subjected to chiral preparative separation (separation conditions: column: CHIRALART Cellulose-SB, 4.6×250mm, S-5μm deuterated 103#; mobile phase: n-hexane:ethanol=60:40; flow rate: 1mL/min; wavelength: 254nm) to obtain compound 39_A (retention time: 8.72 minutes) and compound 39_B (retention time: 9.96 minutes).

化合物39_A:1H NMR(500MHz,DMSO-d6)δ13.23(s,1H),10.22(s,1H),8.09(d,1H),7.75(d,1H),7.42(d,1H),7.32(d,1H),7.16(dd,1H),4.71–4.63(m,1H),4.21(dd,1H),3.28(s,3H),3.03–2.95(m,4H),2.95–2.87(m,1H),2.81–2.74(m,1H),2.47–2.39(m,1H),2.20–2.10(m,2H),2.09–2.01(m,1H),1.99–1.47(m,4H),1.04–0.98(m,4H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：601.2418.Compound 39_A: 1 H NMR (500MHz, DMSO-d 6 )δ13.23(s,1H),10.22(s,1H),8.09(d,1H),7.75(d,1H),7.42(d,1H),7.32(d,1H ),7.16(dd,1H),4.71–4.63(m,1H),4.21(dd,1H),3.28(s,3H),3.03–2.95(m,4H), 2.95–2.87(m,1H),2.81–2.74(m,1H),2.47–2.39(m,1H),2.20–2.10(m,2H),2.09– 2.01(m,1H),1.99–1.47(m,4H),1.04–0.98(m,4H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：601.2418.

化合物39_B:1H NMR(500MHz,DMSO-d6)δ13.23(s,1H),10.22(s,1H),8.09(d,1H),7.75(d,1H),7.42(d,1H),7.32(d,1H),7.16(dd,1H),4.71–4.63(m,1H),4.21(dd,1H),3.28(s,3H),3.03–2.95(m,4H),2.94–2.87(m,1H),2.80–2.74(m,1H),2.47–2.39(m,1H),2.18–2.09(m,2H),2.08–2.00(m,1H),1.99–1.47(m,4H),1.05–0.97(m,4H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：601.2412.Compound 39_B: 1 H NMR (500MHz, DMSO-d 6 )δ13.23(s,1H),10.22(s,1H),8.09(d,1H),7.75(d,1H),7.42(d,1H),7.32(d,1H ),7.16(dd,1H),4.71–4.63(m,1H),4.21(dd,1H),3.28(s,3H),3.03–2.95(m,4H), 2.94–2.87(m,1H),2.80–2.74(m,1H),2.47–2.39(m,1H),2.18–2.09(m,2H),2.08– 2.00(m,1H),1.99–1.47(m,4H),1.05–0.97(m,4H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：601.2412.

实施例40
Embodiment 40

步骤A：Step A:

向250mL单口瓶中依次加入化合物40-1(4.4g)、二氯甲烷(100mL)、三苯基膦(26.2g)、碘单质(6.8g)，氮气保护、50℃下搅拌16h。反应结束后，加入饱和亚硫酸钠水溶液200mL，二氯甲烷(3×150mL)萃取，合并有机相，无水硫酸钠干燥，抽滤，滤液减压蒸干溶剂，硅胶柱层析(PE/EA＝95/5)纯化得到化合物40-2(6.9g)。1H NMR(500MHz,CDCl3)δ4.78–4.41(m,2H),4.24–4.18(m,1H),4.11–3.83(m,2H),2.42–2.23(m,2H).Compound 40-1 (4.4 g), dichloromethane (100 mL), triphenylphosphine (26.2 g), and iodine (6.8 g) were added to a 250 mL single-mouth bottle in sequence, and stirred at 50°C for 16 h under nitrogen protection. After the reaction, 200 mL of saturated sodium sulfite aqueous solution was added, and the mixture was extracted with dichloromethane (3×150 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness under reduced pressure, and purified by silica gel column chromatography (PE/EA＝95/5) to obtain compound 40-2 (6.9 g). 1 H NMR (500 MHz, CDCl 3 )δ4.78–4.41 (m, 2H), 4.24–4.18 (m, 1H), 4.11–3.83 (m, 2H), 2.42–2.23 (m, 2H).

步骤B：Step B:

向250mL单口瓶中依次加入化合物40-2(2g)、乙腈(60mL)、硫代乙酸(1.2g)、碳酸钾(2.8g)、18-冠-6(113mg)，氮气保护下85℃反应12h。反应结束后，减压蒸干溶剂，加水100mL，乙醚(3×25mL)萃取，合并有机相，无水硫酸钠干燥，抽滤，滤液减压蒸干溶剂，得到化合物40-3(1.4g)，直接投入后续反应。Compound 40-2 (2 g), acetonitrile (60 mL), thioacetic acid (1.2 g), potassium carbonate (2.8 g), and 18-crown-6 (113 mg) were added to a 250 mL single-mouth bottle in sequence, and the mixture was reacted at 85 ° C for 12 h under nitrogen protection. After the reaction, the solvent was evaporated under reduced pressure, 100 mL of water was added, and ether (3×25 mL) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to dry the solvent to obtain compound 40-3 (1.4 g), which was directly used for subsequent reactions.

步骤C：Step C:

向100mL单口瓶中依次加入化合物40-3(1g)、乙腈(30mL)、N-氯代丁二酰亚胺(3.7g)、稀盐酸(2mol/L,6mL)，氮气保护、25℃下搅拌2h。反应结束后，加水70mL，乙醚(3×25mL)萃取，合并有机相，无水硫酸钠干燥，抽滤，滤液减压蒸干溶剂，硅胶柱层析(PE/EA＝95/5)纯化得到化合物40-4(820mg)。1H NMR(500MHz,CDCl3)δ3.61–3.56(m,2H),3.49–3.31(m,2H),2.98–2.87(m,1H),1.90–1.85(m,2H).Compound 40-3 (1 g), acetonitrile (30 mL), N-chlorosuccinimide (3.7 g), and dilute hydrochloric acid (2 mol/L, 6 mL) were added to a 100 mL single-mouth bottle in sequence, and stirred at 25°C for 2 h under nitrogen protection. After the reaction, 70 mL of water was added, and the mixture was extracted with ether (3×25 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness under reduced pressure, and purified by silica gel column chromatography (PE/EA＝95/5) to obtain compound 40-4 (820 mg). 1 H NMR (500 MHz, CDCl 3 )δ3.61–3.56 (m, 2H), 3.49–3.31 (m, 2H), 2.98–2.87 (m, 1H), 1.90–1.85 (m, 2H).

步骤D：Step D:

向100mL单口瓶中依次加入化合物40-4(500mg)、氨-二氧六环溶液(0.4mol/L,5mL)，25℃下搅拌4h。反应结束后，减压蒸干溶剂，60℃真空干燥6h，得到化合物40-5(470mg)，直接投入后续反应。1H NMR(500MHz,DMSO)δ7.36(s,2H),3.84–3.60(m,4H),3.25–3.07(m,1H),2.05–1.90(m,2H).Compound 40-4 (500 mg) and ammonia-dioxane solution (0.4 mol/L, 5 mL) were added to a 100 mL single-mouth bottle and stirred at 25°C for 4 h. After the reaction, the solvent was evaporated under reduced pressure and dried under vacuum at 60°C for 6 h to obtain compound 40-5 (470 mg), which was directly used in the subsequent reaction. 1 H NMR (500 MHz, DMSO) δ7.36 (s, 2H), 3.84–3.60 (m, 4H), 3.25–3.07 (m, 1H), 2.05–1.90 (m, 2H).

步骤E：Step E:

参考实施例23的步骤B，以化合物40-5替换甲磺酰胺制备得到化合物40-6(120mg)。MS(ESI-,[M-H]-)m/z:378.16.Referring to step B of Example 23, compound 40-5 was used to replace methanesulfonamide to prepare compound 40-6 (120 mg). MS (ESI-, [MH] - ) m/z: 378.16.

步骤F：
Step F:

参考化合物20_A的制备方法，以化合物40-6替换化合物D-4，制备得到化合物40-7(110mg)。MS(ESI+,[M+H]+)m/z:631.33.Referring to the preparation method of compound 20_A, compound 40-6 was used to replace compound D-4 to prepare compound 40-7 (110 mg). MS (ESI+, [M+H] + ) m/z: 631.33.

参考化合物20_B的制备方法，以化合物40-6替换化合物D-4，制备得到化合物40-8(110mg)。MS(ESI+,[M+H]+)m/z:631.12.Referring to the preparation method of compound 20_B, compound 40-6 was used to replace compound D-4 to prepare compound 40-8 (110 mg). MS (ESI+, [M+H] + ) m/z: 631.12.

步骤G：Step G:

化合物40-7(110mg)经过手性HPLC拆分(型号：CHIRALART Cellulose-SB，30×250mm，5μm；流动相：正己烷/二氯甲烷/乙醇＝65/17.5/17.5；流速：40mL/min)得到化合物40_A(30mg，保留时间：13.2min)、化合物40_B(30mg，保留时间：15.5min)。Compound 40-7 (110 mg) was separated by chiral HPLC (model: CHIRALART Cellulose-SB, 30×250 mm, 5 μm; mobile phase: n-hexane/dichloromethane/ethanol = 65/17.5/17.5; flow rate: 40 mL/min) to obtain compound 40_A (30 mg, retention time: 13.2 min) and compound 40_B (30 mg, retention time: 15.5 min).

化合物40-8(100mg)经过手性HPLC拆分(型号：CHIRALART Cellulose-SB，30×250mm，5μm；流动相：正己烷/二氯甲烷/乙醇＝65/17.5/17.5；流速：40mL/min)得到化合物40_C(30mg，保留时间：14.1min)、化合物40_D(30mg，保留时间：16.0min)。Compound 40-8 (100 mg) was separated by chiral HPLC (model: CHIRALART Cellulose-SB, 30×250 mm, 5 μm; mobile phase: n-hexane/dichloromethane/ethanol = 65/17.5/17.5; flow rate: 40 mL/min) to obtain compound 40_C (30 mg, retention time: 14.1 min) and compound 40_D (30 mg, retention time: 16.0 min).

化合物40_A：1H NMR(500MHz,DMSO-d6)δ13.18(s,1H),10.38(s,1H),8.08(d,1H),7.74(d,1H),7.42(d,1H),7.28(d,1H),7.19–7.12(m,1H),4.68(d,1H),4.26–4.17(m,1H),4.07–3.98(m,2H),3.90–3.77(m,2H),3.69–3.60(m,1H),3.27(s,3H),3.06–2.87(m,5H),2.47–2.38(m,1H),2.20–1.52(m,9H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：631.2501.Compound 40_A: 1 H NMR (500 MHz, DMSO-d 6 )δ13.18(s,1H),10.38(s,1H),8.08(d,1H),7.74(d,1H),7.42(d,1H),7. 28(d,1H),7.19–7.12(m,1H),4.68(d,1H),4.26–4.17(m,1H),4.07–3.98( m,2H),3.90–3.77(m,2H),3.69–3.60(m,1H),3.27(s,3H),3.06–2.87(m, 5H),2.47–2.38(m,1H),2.20–1.52(m,9H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：631.2501.

化合物40_B：1H NMR(500MHz,DMSO-d6)δ13.17(s,1H),10.36(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7.30(d,1H),7.20–7.14(m,1H),4.67(d,1H),4.26–4.18(m,1H),4.10–3.98(m,2H),3.90–3.80(m,2H),3.68–3.61(m,1H),3.27(s,3H),3.05–2.87(m,5H),2.46–2.35(m,1H),2.20–1.52(m,9H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：631.2502.Compound 40_B: 1 H NMR (500 MHz, DMSO-d 6 )δ13.17(s,1H),10.36(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7. 30(d,1H),7.20–7.14(m,1H),4.67(d,1H),4.26–4.18(m,1H),4.10–3.98( m,2H),3.90–3.80(m,2H),3.68–3.61(m,1H),3.27(s,3H),3.05–2.87(m, 5H),2.46–2.35(m,1H),2.20–1.52(m,9H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：631.2502.

化合物40_C：1H NMR(500MHz,DMSO-d6)δ13.17(s,1H),10.36(s,1H),8.08(d,1H),7.74(d,1H),7.42(d,1H),7.29(d,1H),7.21–7.12(m,1H),4.68(d,1H),4.25–4.18(m,1H),4.09–3.98(m,2H),3.89–3.78(m,2H),3.70–3.59(m,1H),3.27(s,3H),3.06–2.82(m,5H),2.47–2.36(m,1H),2.24–1.53(m,9H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：631.2531.Compound 40_C: 1 H NMR (500 MHz, DMSO-d 6 )δ13.17(s,1H),10.36(s,1H),8.08(d,1H),7.74(d,1H),7.42(d,1H),7. 29(d,1H),7.21–7.12(m,1H),4.68(d,1H),4.25–4.18(m,1H),4.09–3.98( m,2H),3.89–3.78(m,2H),3.70–3.59(m,1H),3.27(s,3H),3.06–2.82(m, 5H),2.47–2.36(m,1H),2.24–1.53(m,9H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：631.2531.

化合物40_D：1H NMR(500MHz,DMSO-d6)δ13.17(s,1H),10.36(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7.30(d,1H),7.19–7.14(m,1H),4.68(d,1H),4.26–4.17(m,1H),4.11–3.98(m,2H),3.93–3.78(m,2H),3.70–3.60(m,1H),3.27(s,3H),3.04–2.87(m,5H),2.47–2.36(m,1H),2.24–1.55(m,9H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：631.2530.Compound 40_D: 1 H NMR (500 MHz, DMSO-d 6 )δ13.17(s,1H),10.36(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7. 30(d,1H),7.19–7.14(m,1H),4.68(d,1H),4.26–4.17(m,1H),4.11–3.98( m,2H),3.93–3.78(m,2H),3.70–3.60(m,1H),3.27(s,3H),3.04–2.87(m, 5H),2.47–2.36(m,1H),2.24–1.55(m,9H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：631.2530.

实施例41
Embodiment 41

步骤A：Step A:

参考实施例34的步骤D，以化合物41-1代替化合物34-4，制备得到化合物41-2。MS(ESI+,[M+H]+)m/z：464.27.Referring to step D of Example 34, compound 41-1 was used instead of compound 34-4 to prepare compound 41-2. MS (ESI+, [M+H] + ) m/z: 464.27.

步骤B：Step B:

参考化合物20_A的制备方法，以化合物41-2代替化合物D-4，制备得到化合物41-3A。MS(ESI+,[M+H]+)m/z：715.32.Referring to the preparation method of compound 20_A, compound 41-2 was used instead of compound D-4 to prepare compound 41-3A. MS (ESI+, [M+H] + ) m/z: 715.32.

参考化合物20_B的制备方法，以化合物41-2代替化合物D-4，制备得到化合物41-3B。MS(ESI+,[M+H]+)m/z：715.38.Referring to the preparation method of compound 20_B, compound 41-2 was used instead of compound D-4 to prepare compound 41-3B. MS (ESI+, [M+H] + ) m/z: 715.38.

步骤C：Step C:

向100mL单口瓶中依次加入化合物41-3A(170mg)、乙醇(12mL)和对甲苯磺酸(9mg)，反应液在氮气保护下60℃下反应3h，反应结束后，反应液倒入50mL水中，EA(3×50mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，硅胶柱层析(DCM:MeOH＝50:1)纯化得到化合物41_A(105mg)。1H NMR(500MHz,DMSO-d6)δ13.24(s,1H),10.10(s,1H),8.06(d,1H),7.75(d,1H),7.42(d,1H),7.30(d,1H),7.20–7.04(m,1H),5.46(s,1H),4.67(s,1H),4.39–4.22(m,1H),3.42(s,2H),3.27(s,3H),3.07–2.78(m,4H),2.48–2.40(m,1H),2.21–1.46(m,8H),0.78–0.60(m,4H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：631.2525.Compound 41-3A (170 mg), ethanol (12 mL) and p-toluenesulfonic acid (9 mg) were added sequentially to a 100 mL single-necked bottle, and the reaction solution was reacted at 60 ° C for 3 h under nitrogen protection. After the reaction, the reaction solution was poured into 50 mL of water, extracted with EA (3×50 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (DCM:MeOH=50:1) to obtain compound 41_A (105 mg). 1 H NMR(500MHz,DMSO-d6)δ13.24(s,1H),10.10(s,1H),8.06(d,1H),7.75(d,1 H),7.42(d,1H),7.30(d,1H),7.20–7.04(m,1H),5.46(s,1H),4.67(s,1H),4 .39–4.22(m,1H),3.42(s,2H),3.27(s,3H),3.07–2.78(m,4H),2.48–2.40( m,1H),2.21–1.46(m,8H),0.78–0.60(m,4H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：631.2525.

参考化合物41_A的制备方法，以化合物41-3B代替化合物41-3A，制备得到化合物41_B。1H NMR(500MHz,DMSO-d6)δ13.24(s,1H),10.10(s,1H),8.06(d,1H),7.75(d,1H),7.42(d,1H),7.30(d,1H),7.20–7.04(m,1H),5.47(s,1H),4.67(s,1H),4.27–4.17(m,1H),3.42(s,2H),3.27(s,3H),3.03–2.92(m,4H),2.43(d,1H),2.20–1.46(m,8H),0.72–0.60(m,4H),0.40(s,4H).MS(ESI+,[M+H]+)m/z：631.2530.Referring to the preparation method of compound 41_A, compound 41-3B was used instead of compound 41-3A to prepare compound 41_B. 1 H NMR(500MHz,DMSO-d6)δ13.24(s,1H),10.10(s,1H),8.06(d,1H),7.75(d ,1H),7.42(d,1H),7.30(d,1H),7.20–7.04(m,1H),5.47(s,1H),4.67(s,1 H),4.27–4.17(m,1H),3.42(s,2H),3.27(s,3H),3.03–2.92(m,4H),2.43( d,1H),2.20–1.46(m,8H),0.72–0.60(m,4H),0.40(s,4H).MS(ESI+,[M+H] + )m/z：631.2530.

实施例42
Embodiment 42

步骤A：Step A:

向100mL单口瓶中，依次加入甲胺盐酸盐(0.573g)和碳酸钾(1.174g)，用甲醇(15mL)溶解，再向体系中加入化合物42-1(0.750g)，室温搅拌0.5h后在冰浴下向体系中中加入硼氢化钠(0.139g)，并逐渐恢复至室温搅拌过夜反应18h。用10mL饱和氯化铵溶液淬灭反应，向反应液中加入50mL水，DCM(100mL)萃取，饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：DCM:MeOH＝20:1)纯化，得到化合物42-2(0.611g)。1H NMR(500MHz,DMSO-d6)δ7.80(d,1H),7.71(d,1H),3.63(s,2H),2.37(br s,1H),2.29(s,3H).In a 100mL single-mouth bottle, methylamine hydrochloride (0.573g) and potassium carbonate (1.174g) were added in sequence, dissolved with methanol (15mL), and compound 42-1 (0.750g) was added to the system. After stirring at room temperature for 0.5h, sodium borohydride (0.139g) was added to the system under an ice bath, and the temperature was gradually restored to room temperature and stirred overnight for 18h. The reaction was quenched with 10mL saturated ammonium chloride solution, 50mL water was added to the reaction solution, extracted with DCM (100mL), washed with saturated brine (50mL×2), and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH＝20:1) to obtain compound 42-2 (0.611g). 1 H NMR (500MHz, DMSO-d 6 ) δ7.80(d,1H),7.71(d,1H),3.63(s,2H),2.37(br s,1H),2.29(s,3H).

步骤B：Step B:

向100mL单口瓶中，依次加入化合物42-2(0.611g)、1-(叔丁氧基羰基)-4,4-二氟哌啶-2-羧酸(0.614g)、HATU(1.162g)、DIPEA(0.564g)，用DCM(15mL)溶解，在30℃下加热反应18h。结束后向反应液中加入50mL水，EA(100mL)萃取，饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：PE:EA＝10:1)纯化，得到化合物42-3(0.709g)。HRMS(ESI+,[M+H]+)m/z：526.0147.Compound 42-2 (0.611 g), 1-(tert-butoxycarbonyl)-4,4-difluoropiperidine-2-carboxylic acid (0.614 g), HATU (1.162 g), and DIPEA (0.564 g) were added to a 100 mL single-mouth bottle, dissolved in DCM (15 mL), and heated at 30°C for 18 h. After completion, 50 mL of water was added to the reaction solution, extracted with EA (100 mL), washed with saturated brine (50 mL×2), and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE:EA=10:1) to obtain compound 42-3 (0.709 g). HRMS (ESI+, [M+H] + ) m/z: 526.0147.

步骤C：Step C:

向100mL单口瓶中依次加入化合物42-3(0.507g)和二氯甲烷(20mL)，冰浴下缓慢加入三氟乙酸(1.1mL)，室温搅拌反应18h。反应结束后，加入100mL饱和碳酸氢钠溶液，DCM(3×100mL)萃取，合并有机相，饱和食盐水洗涤后，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：DCM:MeOH＝20:1)纯化，得到化合物42-4(0.380g)。MS(ESI+,[M+H]+)m/z：425.82.Compound 42-3 (0.507 g) and dichloromethane (20 mL) were added to a 100 mL single-mouth bottle in sequence, trifluoroacetic acid (1.1 mL) was slowly added under ice bath, and the reaction was stirred at room temperature for 18 h. After the reaction was completed, 100 mL of saturated sodium bicarbonate solution was added, and DCM (3×100 mL) was used for extraction. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM: MeOH = 20:1) to obtain compound 42-4 (0.380 g). MS (ESI+, [M+H] + ) m/z: 425.82.

步骤D：Step D:

向100mL单口瓶中，依次加入化合物42-4(0.438g)、NMP(8mL)和DIPEA(0.199g)，在120℃下加热反应6h。结束后向反应液中加入100mL水，EA(50*2mL)萃取，饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：PE:EA＝2:1)纯化，得到化合物42-5(0.208g)。1H NMR(500MHz,DMSO-d6)δ7.52(d,1H),7.04(d,1H),4.65(d,1H),4.46–4.41(m,1H),4.31(d,1H),3.86–3.80(m,1H),3.50–3.42(m,1H),2.94(s,3H),2.59–2.47(m,1H),2.29–2.13(m,3H).Compound 42-4 (0.438 g), NMP (8 mL) and DIPEA (0.199 g) were added to a 100 mL single-mouth bottle in sequence, and the mixture was heated at 120°C for 6 h. After completion, 100 mL of water was added to the reaction solution, extracted with EA (50*2 mL), washed with saturated brine (50 mL×2), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE:EA=2:1) to obtain compound 42-5 (0.208 g). 1 H NMR (500MHz, DMSO-d 6 )δ7.52(d,1H),7.04(d,1H),4.65(d,1H),4.46–4.41(m,1H),4.31(d,1H),3.86–3 .80(m,1H),3.50–3.42(m,1H),2.94(s,3H),2.59–2.47(m,1H),2.29–2.13(m,3H).

步骤E：Step E:

参考实施例1的步骤C，以化合物42-5替换化合物1-3，制备得到化合物42。MS(ESI+,[M+H]+)m/z：619.33.Referring to step C of Example 1, compound 42-5 was used to replace compound 1-3 to prepare compound 42. MS (ESI+, [M+H] + ) m/z: 619.33.

步骤F：Step F:

化合物42(110mg)经过制备HPLC(拆分条件：柱：CHIRALART Amylose-SA，4.6×250mm，5μm；流动相：正己烷:二氯甲烷:乙醇＝60:20:20；流速：1mL/min；波长：254nm)拆分得到化合物42_A(43mg，保留时间为7.102分钟)、化合物42_B(45mg，保留时间为8.575分钟)。Compound 42 (110 mg) was separated by preparative HPLC (separation conditions: column: CHIRALART Amylose-SA, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 60:20:20; flow rate: 1 mL/min; wavelength: 254 nm) to give compound 42_A (43 mg, retention time: 7.102 minutes) and compound 42_B (45 mg, retention time: 8.575 minutes).

化合物42_A:1H NMR(500MHz,DMSO-d6)δ13.16(s,1H),10.20(s,1H),8.06(d,1H),7.75(d,1H),7.65(d,1H),7.27(d,1H),7.13(dd,1H),4.97–4.90(m,1H),4.54(d,1H),4.40(d,1H),4.27–4.21(m,1H), 3.94–3.87(m,1H),3.78–3.74(m,2H),3.51–3.45(m,1H),3.37–3.34(m,2H),3.01–2.93(m,7H),2.59–2.45(m,1H),2.34–2.17(m,3H),1.99–1.37(m,4H),0.38(s,4H).HRMS(ESI+,[M+H]+)m/z：619.2521.Compound 42_A: 1 H NMR (500 MHz, DMSO-d 6 )δ13.16(s,1H),10.20(s,1H),8.06(d,1H),7.75(d,1H),7.65(d,1H),7.27(d,1H),7.13(dd,1H),4.97–4.90(m,1H),4.54(d,1H),4.40(d,1H),4.27–4.21(m,1H), 3.94–3.87(m,1H),3.78–3.74(m,2H),3.51–3.45(m,1H),3.37–3.34(m,2H),3.01–2.93(m,7 H),2.59–2.45(m,1H),2.34–2.17(m,3H),1.99–1.37(m,4H),0.38(s,4H).HRMS(ESI+,[M+H] + )m/z：619.2521.

化合物42_B:1H NMR(500MHz,DMSO-d6)δ13.16(s,1H),10.20(s,1H),8.06(d,1H),7.75(d,1H),7.65(d,1H),7.27(d,1H),7.13(dd,1H),5.00–4.88(m,1H),4.54(d,1H),4.40(d,1H),4.27–4.21(m,1H),3.94–3.87(m,1H),3.79–3.73(m,2H),3.51–3.45(m,1H),3.37–3.34(m,2H),3.01–2.93(m,7H),2.59–2.45(m,1H),2.34–2.17(m,3H),2.02–1.36(m,4H),0.38(s,4H).HRMS(ESI+,[M+H]+)m/z：619.2520.Compound 42_B: 1 H NMR (500 MHz, DMSO-d 6 )δ13.16(s,1H),10.20(s,1H),8.06(d,1H),7.75(d,1H),7.65(d,1H),7.27(d,1H),7.13(dd,1H),5.00–4.88(m,1H),4.54(d,1H),4.40(d,1H),4.27–4.21(m,1H),3.94–3.87 (m,1H),3.79–3.73(m,2H),3.51–3.45(m,1H),3.37–3.34(m,2H),3.01–2.93(m,7H),2 .59–2.45(m,1H),2.34–2.17(m,3H),2.02–1.36(m,4H),0.38(s,4H).HRMS(ESI+,[M+H] + )m/z：619.2520.

实施例43
Embodiment 43

参考化合物34_B的制备方法，以化合物21-2B替换化合物20-1B，制备得到化合物43。1H NMR(500MHz,DMSO-d6)δ13.25(s,1H),9.97(s,1H),8.05(d,1H),7.74(d,1H),7.43–7.40(m,2H),7.18(dd,1H),5.11(s,1H),4.72–4.64(m,1H),4.23–4.14(m,1H),3.55(s,2H),3.00–2.93(m,4H),2.93–2.86(m,1H),2.47–2.39(m,1H),2.18–2.02(m,3H),2.01–1.50(m,4H),1.27–1.23(m,6H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：636.2862.Referring to the preparation method of compound 34-B, compound 21-2B was used to replace compound 20-1B to prepare compound 43. 1 H NMR (500 MHz, DMSO-d 6 )δ13.25(s,1H),9.97(s,1H),8.05(d,1H),7.74(d,1H),7.43–7.40(m,2H) ,7.18(dd,1H),5.11(s,1H),4.72–4.64(m,1H),4.23–4.14(m,1H),3.55(s, 2H),3.00–2.93(m,4H),2.93–2.86(m,1H),2.47–2.39(m,1H),2.18–2.02(m ,3H),2.01–1.50(m,4H),1.27–1.23(m,6H),0.40(s,4H).HRMS(ESI+,[M+H] + )m/z：636.2862.

实施例44
Embodiment 44

步骤A：Step A:

参考制备例A-6的步骤E，以化合物E-1替换化合物A-5制备得到化合物44-1(600mg)。MS(ESI+,[M+H]+)m/z：383.05.Referring to step E of Preparation Example A-6, Compound E-1 was used to replace Compound A-5 to prepare Compound 44-1 (600 mg). MS (ESI+, [M+H] + ) m/z: 383.05.

步骤B：Step B:

向50mL单口瓶中依次加入化合物44-1(300mg)、环丙基磺酰胺(143mg)、碘化亚铜(15mg)、N1-(2,6-二甲基苯基)-N2-(吡啶-2-基甲基)草酰胺(11mg)、碳酸铯(640mg)、异丙醇(5mL)，氮气保护下100℃反应8h。反应结束后将反应体系抽滤，滤液减压蒸干溶剂，硅胶柱层析(DCM/MeOH＝95/5)纯化得到化合物44-2(220mg)。MS(ESI-,[M-H]-)m/z：374.16.Compound 44-1 (300 mg), cyclopropylsulfonamide (143 mg), cuprous iodide (15 mg), N1-(2,6-dimethylphenyl)-N2-(pyridin-2-ylmethyl)oxalamide (11 mg), cesium carbonate (640 mg), and isopropanol (5 mL) were added to a 50 mL single-mouth bottle in sequence, and the mixture was reacted at 100 °C for 8 h under nitrogen protection. After the reaction, the reaction system was filtered, the filtrate was evaporated under reduced pressure, and the solvent was purified by silica gel column chromatography (DCM/MeOH=95/5) to obtain compound 44-2 (220 mg). MS (ESI-, [MH] - ) m/z: 374.16.

步骤C： Step C:

参考化合物20_A的制备方法，以化合物44-2替代化合物D-4制备得到化合物44_A(70mg)。1H NMR(500MHz,DMSO-d6)δ11.57(s,1H),10.06(s,1H),7.87(d,1H),7.73(d,1H),7.40(d,1H),7.11(d,1H),7.03–6.96(m,1H),4.63(d,1H),4.21–4.12(m,1H),3.81–3.70(m,2H),3.25(s,3H),2.85–2.69(m,2H),2.56–2.51(m,1H),2.46–2.42(m,1H),2.21–1.82(m,8H),1.02–0.93(m,6H),0.61–0.55(m,2H),0.18–0.08(m,2H).HRMS(ESI+,[M+H]+)m/z：627.2572.Referring to the preparation method of compound 20_A, compound 44-2 was used instead of compound D-4 to prepare compound 44_A (70 mg). 1 H NMR (500 MHz, DMSO-d 6 )δ11.57 (s, 1H), 10.06 (s, 1H), 7.87 (d, 1H), 7.73 (d, 1H), 7.40 (d, 1H), 7.11 (d, 1H), 7.03–6.96 (m, 1H), 4.63 (d, 1H), 4.21–4.12 (m, 1H), 3.81–3.70 (m, 2H), 3.25 (s,3H),2.85–2.69(m,2H),2.56–2.51(m,1H),2.46–2.42(m,1H),2.21–1.82(m, 8H),1.02–0.93(m,6H),0.61–0.55(m,2H),0.18–0.08(m,2H).HRMS(ESI+,[M+H] + )m/z：627.2572.

参考化合物20_B的制备方法，以化合物44-2替代化合物D-4制备得到化合物44_B(70mg)。1H NMR(500MHz,DMSO-d6)δ11.57(s,1H),10.06(s,1H),7.87(d,1H),7.73(d,1H),7.40(d,1H),7.11(d,1H),7.03–6.96(m,1H),4.64(d,1H),4.21–4.12(m,1H),3.84–3.72(m,2H),3.25(s,3H),2.86–2.70(m,2H),2.56–2.52(m,1H),2.48–2.44(m,1H),2.24–1.81(m,8H),1.07–0.92(m,6H),0.65–0.55(m,2H),0.17–0.10(m,2H).HRMS(ESI+,[M+H]+)m/z：627.2581.Referring to the preparation method of compound 20_B, compound 44-2 was used instead of compound D-4 to prepare compound 44_B (70 mg). 1 H NMR (500 MHz, DMSO-d 6 )δ11.57 (s, 1H), 10.06 (s, 1H), 7.87 (d, 1H), 7.73 (d, 1H), 7.40 (d, 1H), 7.11 (d, 1H), 7.03–6.96 (m, 1H), 4.64 (d, 1H), 4.21–4.12 (m, 1H), 3.84–3.72 (m, 2H), 3.25 (s,3H),2.86–2.70(m,2H),2.56–2.52(m,1H),2.48–2.44(m,1H),2.24–1.81(m, 8H),1.07–0.92(m,6H),0.65–0.55(m,2H),0.17–0.10(m,2H).HRMS(ESI+,[M+H] + )m/z：627.2581.

实施例45
Embodiment 45

步骤A：Step A:

参考实施例14的步骤A，以化合物45-1代替化合物14-1，得到化合物45-2。MS(ESI-,[M-H]-)m/z：402.23.Referring to step A of Example 14, compound 45-1 was used instead of compound 14-1 to obtain compound 45-2. MS (ESI-, [MH] - ) m/z: 402.23.

步骤B：Step B:

参考实施例14的步骤B，以化合物45-2代替化合物14-2，得到化合物45-3。MS(ESI-,[M-H]-)m/z：302.09.Referring to step B of Example 14, compound 45-2 was used instead of compound 14-2 to obtain compound 45-3. MS (ESI-, [MH] - ) m/z: 302.09.

步骤C：Step C:

参考实施例14的步骤C，以化合物45-3代替化合物14-3，得到化合物45-4。MS(ESI-,[M-H]-)m/z：281.99.Referring to step C of Example 14, compound 45-3 was substituted for compound 14-3 to obtain compound 45-4. MS (ESI-, [MH] - ) m/z: 281.99.

步骤D：Step D:

参考实施例14的步骤D，以化合物45-4代替化合物14-4，得到化合物45-5。1H NMR(500MHz,DMSO-d6)δ7.83(dd,1H),7.71(d,1H),7.30(d,1H),4.11–4.04(m,1H),4.01–3.96(m,1H),3.36(s,3H),3.03–2.94(m,1H),2.49–2.41(m,1H),2.25–2.17(m,1H),2.17–2.02(m,2H).Referring to step D of Example 14, compound 45-4 was used instead of compound 14-4 to obtain compound 45-5. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.83 (dd, 1H), 7.71 (d, 1H), 7.30 (d, 1H), 4.11-4.04 (m, 1H), 4.01-3.96 (m, 1H), 3.36 (s, 3H), 3.03-2.94 (m, 1H), 2.49-2.41 (m, 1H), 2.25-2.17 (m, 1H), 2.17-2.02 (m, 2H).

步骤E：Step E:

向100mL双口瓶中，依次加入化合物45-5(610mg)、THF(5mL)、甲醇(5mL)和10％的干钯/碳(109mg)，H2氛围下室温搅拌3h。反应结束后，硅藻土抽滤，甲醇洗涤，滤液浓缩干燥得到化合物45-6(500mg)。MS(ESI+,[M+H]+)m/z：268.29.Compound 45-5 (610 mg), THF (5 mL), methanol (5 mL) and 10% dry palladium/carbon (109 mg) were added to a 100 mL two-necked bottle in sequence and stirred at room temperature for 3 h under H 2 atmosphere. After the reaction was completed, the mixture was filtered through diatomaceous earth, washed with methanol, and the filtrate was concentrated and dried to obtain compound 45-6 (500 mg). MS (ESI+, [M+H] + ) m/z: 268.29.

步骤F：Step F:

参考实施例4的步骤H，以化合物45-6代替化合物4-8，得到化合物45-7。1H NMR(500MHz,DMSO- d6)δ11.26(s,1H),7.69(d,1H),7.47(d,1H),7.45(d,1H),7.38(dd,1H),7.34(dd,1H),7.12(d,1H),3.87–3.78(m,2H),3.30(s,3H),3.06–3.00(m,4H),2.98–2.91(m,1H),2.44–2.36(m,1H),2.26–2.18(m,1H),2.18–1.91(m,2H),1.54–1.46(m,4H),0.32(s,4H).Referring to step H of Example 4, compound 45-6 was used instead of compound 4-8 to obtain compound 45-7. 1 H NMR (500 MHz, DMSO- d 6 )δ11.26(s,1H),7.69(d,1H),7.47(d,1H),7.45(d,1H),7.38(dd,1H),7.34(dd,1H),7.12(d,1H),3.87–3.78(m,2H),3.30(s,3H) ,3.06–3.00(m,4H),2.98–2.91(m,1H),2.44–2.36(m,1H),2.26–2.18(m,1H),2.18–1.91(m,2H),1.54–1.46(m,4H),0.32(s,4H).

步骤G：Step G:

参考实施例4的步骤I，以化合物45-7代替化合物4-9，得到化合物45。MS(ESI+,[M+H]+)m/z：604.41.Referring to step I of Example 4, compound 45-7 was used instead of compound 4-9 to obtain compound 45. MS (ESI+, [M+H] + ) m/z: 604.41.

步骤H：Step H:

化合物45经过手性制备分离(拆分条件：柱：CHIRALPAK IK，4.6×250mm，5μm；流动相：正己烷:二氯甲烷:乙醇＝60:20:20；流速：1mL/min；波长：254nm)，拆分得到化合物45_A(保留时间为10.9分钟)、化合物45_B(保留时间为12.08分钟)。Compound 45 was subjected to chiral preparative separation (separation conditions: column: CHIRALPAK IK, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 60:20:20; flow rate: 1 mL/min; wavelength: 254 nm) to give compound 45_A (retention time: 10.9 minutes) and compound 45_B (retention time: 12.08 minutes).

化合物45_A:1H NMR(500MHz,DMSO-d6)δ11.62(s,1H),10.08(s,1H),7.83(d,1H),7.50(d,1H),7.32(dd,1H),7.16(d,1H),7.13(d,1H),7.03(dd,1H),4.95(s,1H),3.88–3.81(m,2H),3.79–3.73(m,2H),3.34–3.33(m,2H),3.30(s,3H),3.00–2.96(m,4H),2.96–2.91(m,1H),2.44–2.35(m,1H),2.27–2.18(m,1H),2.17–1.93(m,2H),1.54(s,4H),0.35(s,4H).HRMS(ESI+,[M+H]+)m/z：604.2385.Compound 45_A: 1 H NMR (500 MHz, DMSO-d 6 )δ11.62(s,1H),10.08(s,1H),7.83(d,1H),7.50(d,1H),7.32(dd,1H),7.16(d,1H),7.13(d,1H),7.03(dd,1H),4.95(s,1H),3.88–3.81(m,2H),3.79–3.73(m,2H),3.3 4–3.33(m,2H),3.30(s,3H),3.00–2.96(m,4H),2.96–2.91(m,1H),2.44–2.35(m,1H ),2.27–2.18(m,1H),2.17–1.93(m,2H),1.54(s,4H),0.35(s,4H).HRMS(ESI+,[M+H] + )m/z：604.2385.

化合物45_B:1H NMR(500MHz,DMSO-d6)δ11.62(s,1H),10.08(s,1H),7.83(d,1H),7.50(d,1H),7.32(dd,1H),7.16(d,1H),7.13(d,1H),7.03(dd,1H),4.95(s,1H),3.87–3.81(m,2H),3.79–3.72(m,2H),3.34–3.33(m,2H),3.30(s,3H),3.00–2.96(m,4H),2.96–2.90(m,1H),2.43–2.34(m,1H),2.26–2.17(m,1H),2.15–1.92(m,2H),1.55(s,4H),0.35(s,4H).HRMS(ESI+,[M+H]+)m/z：604.2404.Compound 45_B: 1 H NMR (500 MHz, DMSO-d 6 )δ11.62(s,1H),10.08(s,1H),7.83(d,1H),7.50(d,1H),7.32(dd,1H),7.16(d,1H),7.13(d,1H),7.03(dd,1H),4.95(s,1H),3.87–3.81(m,2H),3.79–3.72(m,2H),3.3 4–3.33(m,2H),3.30(s,3H),3.00–2.96(m,4H),2.96–2.90(m,1H),2.43–2.34(m,1H ),2.26–2.17(m,1H),2.15–1.92(m,2H),1.55(s,4H),0.35(s,4H).HRMS(ESI+,[M+H] + )m/z：604.2404.

实施例46
Embodiment 46

步骤A：Step A:

向100mL双口瓶中，依次加入化合物C-5(4.76g)、DCM(30mL)、水(15mL)、碘苯二乙酸(11.56g)和TEMPO(0.28g)，室温搅拌12h。反应结束后，加入水60mL，加入饱和碳酸氢钠溶液调节水相pH＝9-10左右，DCM(2×40mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，减压浓缩干燥得到化合物46-1(4.4g)。1H NMR(500MHz,DMSO-d6)δ12.28(s,1H),4.75–4.65(m,1H),4.09–3.96(m,1H),3.00–2.89(m,1H),2.57–2.51(m,1H),2.47–2.39(m,1H),2.15–1.77(m,4H),1.40(s,9H).Compound C-5 (4.76 g), DCM (30 mL), water (15 mL), iodophenyl diacetic acid (11.56 g) and TEMPO (0.28 g) were added to a 100 mL two-necked bottle in sequence and stirred at room temperature for 12 h. After the reaction was completed, 60 mL of water was added, and a saturated sodium bicarbonate solution was added to adjust the pH of the aqueous phase to about 9-10, and DCM (2×40 mL) was used for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 46-1 (4.4 g). 1 H NMR (500MHz, DMSO-d 6 )δ12.28(s,1H),4.75–4.65(m,1H),4.09–3.96(m,1H),3.00–2.89(m,1H ),2.57–2.51(m,1H),2.47–2.39(m,1H),2.15–1.77(m,4H),1.40(s,9H).

步骤B:Step B:

100mL单口瓶中，依次加入化合物46-1(4.4g)和碳酸钾(4.35g)，用DMF(20mL)溶解后，加入碘甲烷(5.59g)，室温搅拌反应12h。反应结束后向反应液中加入70mL水，EA(3×25mL)萃取，饱和食盐水(2×50mL)洗涤，无水硫酸钠干燥。过滤，减压浓缩干燥得到化合物46-2(4.23g)。1H NMR(500MHz,DMSO-d6)δ4.79–4.69(m,1H),4.07–3.98(m,1H),3.59(s,3H),3.02–2.91(m,1H),2.65–2.53(m,2H),2.17–1.97(m,3H),1.94–1.76(m,1H),1.39(s,9H).Compound 46-1 (4.4 g) and potassium carbonate (4.35 g) were added to a 100 mL single-mouth bottle in sequence, dissolved with DMF (20 mL), and iodomethane (5.59 g) was added. The mixture was stirred at room temperature for 12 h. After the reaction, 70 mL of water was added to the reaction solution, extracted with EA (3 × 25 mL), washed with saturated brine (2 × 50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and dried to obtain compound 46-2 (4.23 g). 1 H NMR (500MHz, DMSO-d 6 )δ4.79–4.69(m,1H),4.07–3.98(m,1H),3.59(s,3H),3.02–2.91(m,1H) ,2.65–2.53(m,2H),2.17–1.97(m,3H),1.94–1.76(m,1H),1.39(s,9H).

步骤C：Step C:

参考实施例14的步骤A，以化合物46-2代替化合物B-2，得到化合物46-3。MS(ESI-,[M-H]-)m/z：510.07.Referring to step A of Example 14, compound 46-2 was used instead of compound B-2 to obtain compound 46-3. MS (ESI-, [MH] - ) m/z: 510.07.

步骤D： Step D:

参考实施例14的步骤B，以化合物46-3代替化合物14-2，得到化合物46-4。MS(ESI-,[M-H]-)m/z：409.99.Referring to step B of Example 14, compound 46-3 was used instead of compound 14-2 to obtain compound 46-4. MS (ESI-, [MH] - ) m/z: 409.99.

步骤E：Step E:

参考实施例14的步骤C，以化合物46-4代替化合物14-3，得到化合物46-5。MS(ESI-,[M-H]-)m/z：330.02.Referring to step C of Example 14, compound 46-4 was used instead of compound 14-3 to obtain compound 46-5. MS (ESI-, [MH] - ) m/z: 330.02.

步骤F：Step F:

参考实施例14的步骤D，以化合物46-5代替化合物14-4，得到化合物46-6。1H NMR(500MHz,DMSO-d6)δ7.63(d,1H),7.33(d,1H),3.82–3.59(m,2H),3.18(s,3H),3.06–2.96(m,1H),2.83–2.59(m,1H),2.37–2.24(m,1H),2.22–1.85(m,4H).Referring to step D of Example 14, compound 46-5 was used instead of compound 14-4 to obtain compound 46-6. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.63 (d, 1H), 7.33 (d, 1H), 3.82-3.59 (m, 2H), 3.18 (s, 3H), 3.06-2.96 (m, 1H), 2.83-2.59 (m, 1H), 2.37-2.24 (m, 1H), 2.22-1.85 (m, 4H).

步骤G：Step G:

参考实施例1的步骤C，以化合物46-6代替化合物1-3，得到化合物46。1H NMR(500MHz,DMSO-d6)δ13.37(s,1H),10.21(s,1H),8.09(d,1H),8.03(d,1H),7.75(d,1H),7.28(d,1H),7.14(dd,1H),4.94(s,1H),3.87–3.54(m,4H),3.36(t,2H),3.20(s,3H),3.16–3.08(m,1H),3.02–2.94(m,4H),2.85–2.62(m,1H),2.34–2.05(m,4H),2.02–1.37(m,5H),0.42–0.35(m,4H).HRMS(ESI+,[M+H]+)m/z：619.2513.Referring to step C of Example 1, compound 46-6 was used instead of compound 1-3 to obtain compound 46. 1 H NMR (500MHz, DMSO-d 6 )δ13.37(s,1H),10.21(s,1H),8.09(d,1H),8.03(d,1H),7.75(d,1H),7 .28(d,1H),7.14(dd,1H),4.94(s,1H),3.87–3.54(m,4H),3.36(t,2H),3 .20(s,3H),3.16–3.08(m,1H),3.02–2.94(m,4H),2.85–2.62(m,1H),2. 34–2.05(m,4H),2.02–1.37(m,5H),0.42–0.35(m,4H).HRMS(ESI+,[M+H] + )m/z：619.2513.

实施例47
Embodiment 47

步骤A：Step A:

参考实施例45的步骤G，以甲基磺酰胺代替2-羟基-1-磺酰胺，得到化合物47。MS(ESI+,[M+H]+)m/z：574.35.Referring to step G of Example 45, 2-hydroxy-1-sulfonamide was replaced with methylsulfonamide to obtain compound 47. MS (ESI+, [M+H] + ) m/z: 574.35.

步骤B：Step B:

化合物47经过手性制备分离(拆分条件：柱：CHIRALPAK IK，4.6×250mm，5μm；流动相：正己烷:二氯甲烷:乙醇＝70:15:15；流速：1mL/min；波长：254nm)拆分得到化合物47_A(保留时间为23.0分钟)、化合物47_B(保留时间为26.1分钟)。Compound 47 was separated by chiral preparative separation (separation conditions: column: CHIRALPAK IK, 4.6×250 mm, 5 μm; mobile phase: n-hexane: dichloromethane: ethanol = 70:15:15; flow rate: 1 mL/min; wavelength: 254 nm) to give compound 47_A (retention time: 23.0 minutes) and compound 47_B (retention time: 26.1 minutes).

化合物47_A:1H NMR(500MHz,DMSO-d6)δ11.64(s,1H),10.11(s,1H),7.85(d,1H),7.50(d,1H),7.32(dd,1H),7.15(d,1H),7.13(d,1H),7.04(dd,1H),3.88–3.80(m,2H),3.30(s,3H),3.09(s,3H),3.00–2.96(m,4H),2.96–2.91(m,1H),2.43–2.35(m,1H),2.27–2.17(m,1H),2.17–1.99(m,2H),1.59–1.48(m,4H),0.35(s,4H).HRMS(ESI+,[M+H]+)m/z：574.2291.Compound 47_A: 1 H NMR (500 MHz, DMSO-d 6 )δ11.64(s,1H),10.11(s,1H),7.85(d,1H),7.50(d,1H),7.32(dd,1H),7.1 5(d,1H),7.13(d,1H),7.04(dd,1H),3.88–3.80(m,2H),3.30(s,3H),3.09(s ,3H),3.00–2.96(m,4H),2.96–2.91(m,1H),2.43–2.35(m,1H),2.27–2.17( m,1H),2.17–1.99(m,2H),1.59–1.48(m,4H),0.35(s,4H).HRMS(ESI+,[M+H] + )m/z：574.2291.

化合物47_B:1H NMR(500MHz,DMSO-d6)δ11.64(s,1H),10.11(s,1H),7.85(d,1H),7.50(d,1H),7.32(dd,1H),7.15(d,1H),7.13(d,1H),7.04(dd,1H),3.87–3.80(m,2H),3.30(s,3H),3.09(s,3H),3.00–2.96(m,4H),2.96–2.91(m,1H),2.44–2.35(m,1H),2.27–2.17(m,1H),2.16–1.99(m,2H),1.59–1.48(m,4H),0.35(s,4H).HRMS(ESI+,[M+H]+)m/z：574.2301.Compound 47_B: 1 H NMR (500 MHz, DMSO-d 6 )δ11.64(s,1H),10.11(s,1H),7.85(d,1H),7.50(d,1H),7.32(dd,1H),7.1 5(d,1H),7.13(d,1H),7.04(dd,1H),3.87–3.80(m,2H),3.30(s,3H),3.09(s ,3H),3.00–2.96(m,4H),2.96–2.91(m,1H),2.44–2.35(m,1H),2.27–2.17( m,1H),2.16–1.99(m,2H),1.59–1.48(m,4H),0.35(s,4H).HRMS(ESI+,[M+H] + )m/z：574.2301.

实施例48
Embodiment 48

步骤A：Step A:

向100mL单口瓶中，依次加入化合物48-1(1.700g)、DIPEA(1.971g)和DCM(20mL)，冰浴下再向体系中加入甲磺酸酐(2.125g)，并逐渐恢复至室温搅拌过夜反应18h。反应结束后向反应液中加入50mL水，DCM(100mL)萃取，饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：DCM)纯化，得到化合物48-2(1.520g)。1H NMR(500MHz,DMSO-d6)δ7.22–7.16(m,2H),6.55(d,1H),6.50(dd,1H),4.04(d,2H),3.78(s,3H),3.75(s,3H),2.81(s,3H).Compound 48-1 (1.700 g), DIPEA (1.971 g) and DCM (20 mL) were added to a 100 mL single-mouth bottle in sequence, and methanesulfonic anhydride (2.125 g) was added to the system under ice bath, and the mixture was gradually returned to room temperature and stirred overnight for 18 h. After the reaction, 50 mL of water was added to the reaction solution, and DCM (100 mL) was used for extraction, washed with saturated brine (50 mL × 2), and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM) to obtain compound 48-2 (1.520 g). 1 H NMR (500MHz, DMSO-d 6 ) δ7.22–7.16(m,2H),6.55(d,1H),6.50(dd,1H),4.04(d,2H),3.78(s,3H),3.75(s,3H),2.81(s,3H).

步骤B：Step B:

-78℃，氮气保护下，向装有化合物48-2(3.58g)以及THF(60mL)的250mL两口瓶中，滴加正丁基锂2.5M溶液(12.02mL)。15min后，继续滴加丙酮(16.39mL)，然后将体系转移至0℃下反应2h。用20mL饱和氯化铵溶液淬灭反应，EA(200mL)萃取，分别用饱和碳酸氢钠溶液(50mL×2)和饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：PE/EA＝2/1)纯化，得到化合物48-3(0.788g)。1H NMR(500MHz,DMSO-d6)δ7.20(d,1H),7.06(t,1H),6.55(d,1H),6.50(dd,1H),4.74(s,1H),4.04(d,2H),3.78(s,3H),3.75(s,3H),3.07(s,2H),1.27(s,6H).-78 ℃, under nitrogen protection, to a 250mL two-necked bottle containing compound 48-2 (3.58g) and THF (60mL), n-butyl lithium 2.5M solution (12.02mL) was added dropwise. After 15min, acetone (16.39mL) was added dropwise, and then the system was transferred to 0℃ for reaction for 2h. The reaction was quenched with 20mL saturated ammonium chloride solution, extracted with EA (200mL), washed with saturated sodium bicarbonate solution (50mL×2) and saturated brine (50mL×2), respectively, and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, purified by silica gel column chromatography (eluent: PE/EA＝2/1), and compound 48-3 (0.788g) was obtained. 1 H NMR (500MHz, DMSO-d 6 )δ7.20(d,1H),7.06(t,1H),6.55(d,1H),6.50(dd,1H),4.74(s,1H),4.04(d,2H),3.78(s,3H),3.75(s,3H),3.07(s,2H),1.27(s,6H).

步骤C：Step C:

向100mL单口瓶中，依次加入化合物48-3(0.380g)、DCM(10mL)和TFA(0.714g)，室温搅拌反应2h。反应结束后，向反应液中加入DCM(20mL)稀释体系，抽滤，滤液减压浓缩，向残留物中加入二氯甲烷(15)mL和正己烷(15)mL，在室温下搅拌1h。抽滤收集滤饼得到化合物48-4(0.141g)。1HNMR(500MHz,DMSO-d6)δ6.71(s,2H),4.77(s,1H),3.15(s,2H),1.29(s,6H).Compound 48-3 (0.380 g), DCM (10 mL) and TFA (0.714 g) were added to a 100 mL single-mouth bottle in sequence, and the mixture was stirred at room temperature for 2 h. After the reaction was completed, DCM (20 mL) was added to the reaction solution to dilute the system, and the mixture was filtered and concentrated under reduced pressure. Dichloromethane (15) mL and n-hexane (15) mL were added to the residue, and the mixture was stirred at room temperature for 1 h. The filter cake was collected by filtration to obtain compound 48-4 (0.141 g). 1 HNMR (500 MHz, DMSO-d 6 )δ6.71 (s, 2H), 4.77 (s, 1H), 3.15 (s, 2H), 1.29 (s, 6H).

步骤D：Step D:

参考实施例23的步骤B，以化合物48-4替换甲磺酰胺，制备得到化合物48-5。MS(ESI+,[M+H]+)m/z：382.23.1H NMR(500MHz,DMSO-d6)δ9.95(s,1H),8.60(d,1H),7.74(d,1H),7.45(d,1H),7.06(d,1H),6.93(dd,1H),4.84(s,1H),3.22(s,2H),2.95–2.87(m,4H),1.57–1.47(m,4H),1.30(s,6H),0.35(s,4H).Referring to step B of Example 23, methanesulfonamide was replaced with compound 48-4 to prepare compound 48-5. MS (ESI+, [M+H] + ) m/z: 382.23. 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.60 (d, 1H), 7.74 (d, 1H), 7.45 (d, 1H), 7.06 (d, 1H), 6.93 (dd, 1H), 4.84 (s, 1H), 3.22 (s, 2H), 2.95-2.87 (m, 4H), 1.57-1.47 (m, 4H), 1.30 (s, 6H), 0.35 (s, 4H).

步骤E：Step E:

参考实施例14的步骤E，以化合物48-5替换化合物A-6，制备得到化合物48。MS(ESI+,[M+H]+)m/z：633.43.Referring to step E of Example 14, compound 48-5 was substituted for compound A-6 to prepare compound 48. MS (ESI+, [M+H] + ) m/z: 633.43.

步骤F：Step F:

化合物48(168mg)经过制备HPLC(拆分条件：柱：CHIRALPAK IK,5μm,21.2*250mm；流动相：正己烷:二氯甲烷:乙醇＝40:10:30；流速：20mL/min；波长：254nm)拆分得到化合物48_A(77mg，保留时间为12.5分钟)、化合物48_B(60mg，保留时间为14.6分钟)。Compound 48 (168 mg) was separated by preparative HPLC (separation conditions: column: CHIRALPAK IK, 5 μm, 21.2*250 mm; mobile phase: n-hexane: dichloromethane: ethanol = 40:10:30; flow rate: 20 mL/min; wavelength: 254 nm) to give compound 48_A (77 mg, retention time: 12.5 minutes) and compound 48_B (60 mg, retention time: 14.6 minutes).

化合物48_A:1H NMR(500MHz,DMSO-d6)δ13.19(s,1H),10.18(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7.27(d,1H),7.12(dd,1H),4.86(s,1H),4.72–4.65(m,1H),4.23–4.13(m,1H),3.30–3.24(m,5H),3.05–2.94(m,4H),2.94–2.87(m,1H),2.46–2.39(m,1H),2.21–1.52(m,7H),1.31(s,6H),0.39(s, 4H).HRMS(ESI+,[M+H]+)m/z：633.2683.Compound 48_A: 1 H NMR (500MHz, DMSO-d 6 )δ13.19(s,1H),10.18(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7.27(d,1H),7.12(dd,1H ),4.86(s,1H),4.72–4.65(m,1H),4. 23–4.13(m,1H),3.30–3.24(m,5H),3.05–2.94(m,4H),2.94–2.87(m,1H),2.46–2.39(m,1H),2.21–1.52(m ,7H),1.31(s,6H),0.39(s, 4H).HRMS(ESI+,[M+H] + )m/z: 633.2683.

化合物48_B:1H NMR(500MHz,DMSO-d6)δ13.19(s,1H),10.18(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7.27(d,1H),7.12(dd,1H),4.86(s,1H),4.72–4.64(m,1H),4.24–4.17(m,1H),3.29–3.25(m,5H),3.06–2.94(m,4H),2.93–2.87(m,1H),2.46–2.40(m,1H),2.19–1.50(m,7H),1.31(s,6H),0.39(s,4H).HRMS(ESI+,[M+H]+)m/z：633.2677.Compound 48_B: 1 H NMR (500MHz, DMSO-d 6 )δ13.19(s,1H),10.18(s,1H),8.09(d,1H),7.74(d,1H),7.42(d,1H),7 .27(d,1H),7.12(dd,1H),4.86(s,1H),4.72–4.64(m,1H),4.24–4.17(m, 1H),3.29–3.25(m,5H),3.06–2.94(m,4H),2.93–2.87(m,1H),2.46–2.4 0(m,1H),2.19–1.50(m,7H),1.31(s,6H),0.39(s,4H).HRMS(ESI+,[M+H] + )m/z：633.2677.

实施例49
Embodiment 49

步骤A：Step A:

参考制备例A-6的步骤A，以8-氮杂双环[3.2.1]辛烷盐酸盐代替6-氮杂螺[2.5]辛烷盐酸盐，得到化合物49-1。MS(ESI+,[M+H]+)m/z：357.98.Referring to step A of Preparation Example A-6, 8-azabicyclo[3.2.1]octane hydrochloride was used instead of 6-azaspiro[2.5]octane hydrochloride to obtain compound 49-1. MS (ESI+, [M+H] + ) m/z: 357.98.

步骤B：Step B:

参考制备例A-6的步骤E，以化合物49-1代替化合物A-5，得到化合物49-2。MS(ESI+,[M+H]+)m/z：356.99.Referring to step E of preparation example A-6, compound 49-1 was used instead of compound A-5 to obtain compound 49-2. MS (ESI+, [M+H] + ) m/z: 356.99.

步骤C：Step C:

参考制备例D-4的步骤C，以化合物49-2代替化合物D-2，得到化合物49-3。MS(ESI+,[M+H]+)m/z：324.01.Referring to step C of Preparation Example D-4, compound 49-2 was used instead of compound D-2 to obtain compound 49-3. MS (ESI+, [M+H] + ) m/z: 324.01.

步骤D：Step D:

参考化合物20_A的制备方法，以化合物49-3代替化合物D-4，制备得到化合物49_A。1H NMR(500MHz,DMSO-d6)δ11.57(s,1H),10.09(s,1H),7.88(d,1H),7.73(d,1H),7.41(d,1H),7.06(d,1H),6.95(dd,1H),4.60–4.51(m,1H),4.23–4.16(m,1H),3.77–3.66(m,2H),3.27(s,3H),3.08(s,3H),2.87–2.79(m,1H),2.44–2.35(m,1H),2.21–2.04(m,4H),2.03–1.92(m,3H),1.78–1.64(m,3H),1.58–1.45(m,3H).HRMS(ESI+,[M+H]+)m/z：575.2268.Referring to the preparation method of compound 20_A, compound 49-3 was used instead of compound D-4 to prepare compound 49_A. 1 H NMR (500 MHz, DMSO-d 6 )δ11.57(s,1H),10.09(s,1H),7.88(d,1H),7.73(d,1H),7.41(d,1H),7.06(d ,1H),6.95(dd,1H),4.60–4.51(m,1H),4.23–4.16(m,1H),3.77–3.66(m,2H),3 .27(s,3H),3.08(s,3H),2.87–2.79(m,1H),2.44–2.35(m,1H),2.21–2.04(m,4 H),2.03–1.92(m,3H),1.78–1.64(m,3H),1.58–1.45(m,3H).HRMS(ESI+,[M+H] + )m/z：575.2268.

参考化合物20_B的制备方法，以化合物49-3代替化合物D-4，制备得到化合物49_B。1H NMR(500MHz,DMSO-d6)δ11.57(s,1H),10.09(s,1H),7.87(d,1H),7.73(d,1H),7.41(d,1H),7.06(d,1H),6.95(dd,1H),4.60–4.51(m,1H),4.22–4.15(m,1H),3.77–3.67(m,2H),3.27(s,3H),3.08(s,3H),2.87–2.78(m,1H),2.44–2.35(m,1H),2.20–2.03(m,4H),2.01–1.89(m,3H),1.78–1.63(m,3H),1.57–1.44(m,3H).HRMS(ESI+,[M+H]+)m/z：575.2254.Referring to the preparation method of compound 20_B, compound 49-3 was used instead of compound D-4 to prepare compound 49_B. 1 H NMR (500 MHz, DMSO-d 6 )δ11.57(s,1H),10.09(s,1H),7.87(d,1H),7.73(d,1H),7.41(d,1H),7.06(d ,1H),6.95(dd,1H),4.60–4.51(m,1H),4.22–4.15(m,1H),3.77–3.67(m,2H),3 .27(s,3H),3.08(s,3H),2.87–2.78(m,1H),2.44–2.35(m,1H),2.20–2.03(m,4 H),2.01–1.89(m,3H),1.78–1.63(m,3H),1.57–1.44(m,3H).HRMS(ESI+,[M+H] + )m/z：575.2254.

实施例50
Embodiment 50

步骤A：Step A:

参考实施例42的步骤E，以化合物23-2代替化合物A-6，制备得到化合物50。MS(ESI+,[M+H]+)m/z：589.34.Referring to step E of Example 42, compound 23-2 was used instead of compound A-6 to prepare compound 50. MS (ESI+, [M+H] + ) m/z: 589.34.

步骤B：Step B:

化合物50经过手性制备分离(拆分条件CHIRALART Cellulose-SB柱；30×250mm，5μm；流动相：正己烷:乙醇＝68:32；流速：40mL/min；波长：254nm)拆分得到化合物50_A(保留时间为9.102min)、化合物50_B(保留时间为13.454min)。Compound 50 was separated by chiral preparative separation (separation conditions: CHIRALART Cellulose-SB column; 30×250 mm, 5 μm; mobile phase: n-hexane:ethanol=68:32; flow rate: 40 mL/min; wavelength: 254 nm) to give compound 50_A (retention time: 9.102 min) and compound 50_B (retention time: 13.454 min).

化合物50_A:1H NMR(500MHz,DMSO-d6)δ13.17(s,1H),10.27(s,1H),8.08(d,1H),7.89–7.54(m,2H),7.43–7.03(m,2H),4.54(d,1H),4.41(d,1H),4.24(d,1H),4.02(t,1H),3.90(d,1H),3.47(s,1H),3.12(s,3H),2.97(s,6H),2.25(d,3H),1.99(s,2H),1.72(s,3H),0.38(s,4H).HRMS(ESI+,[M+H]+)m/z：589.2402.Compound 50_A: 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.17 (s, 1H), 10.27 (s, 1H), 8.08 (d, 1H), 7.89–7.54 (m, 2H), 7.43–7.03 (m, 2H), 4.54 (d, 1H), 4.41 (d, 1H), 4.24 (d, 1H), 4.02 (t, 1H), 3.90 (d, 1H), 3.47 (s, 1H), 3.12 (s, 3H), 2.97 (s, 6H), 2.25 (d, 3H), 1.99 (s, 2H), 1.72 (s, 3H), 0.38 (s, 4H). HRMS (ESI+, [M+H] + ) m/z: 589.2402.

化合物50_B:1H NMR(500MHz,DMSO-d6)δ13.16(s,1H),10.25(s,1H),8.08(d,1H),7.76(d,1H),7.65(d,1H),7.25(d,1H),7.13(dd,1H),4.54(d,1H),4.40(d,1H),4.35–4.05(m,1H),4.03–3.97(m,1H),3.95–3.86(m,1H),3.65–3.45(m,1H),3.12(s,3H),3.10–2.84(m,6H),2.38–2.13(m,3H),1.99(s,1H),1.97–1.22(m,4H),0.38(s,4H).HRMS(ESI+,[M+H]+)m/z：589.2411.Compound 50_B: 1 H NMR (500 MHz, DMSO-d 6 )δ13.16(s,1H),10.25(s,1H),8.08(d,1H),7.76(d,1H),7.65(d,1H),7.25(d, 1H),7.13(dd,1H),4.54(d,1H),4.40(d,1H),4.35–4.05(m,1H),4.03–3.97(m, 1H),3.95–3.86(m,1H),3.65–3.45(m,1H),3.12(s,3H),3.10–2.84(m,6H),2.3 8–2.13(m,3H),1.99(s,1H),1.97–1.22(m,4H),0.38(s,4H).HRMS(ESI+,[M+H] + )m/z：589.2411.

实施例51
Embodiment 51

步骤A：Step A:

参考制备例A-6的步骤A，以(1R，5S)-3-氮杂双环[3.2.1]辛烷盐酸盐代替6-氮杂螺[2.5]辛烷盐酸盐，制备得到化合物51-1(1.9g)。MS(ESI+,[M+H]+)m/z：358.12.Referring to step A of Preparation Example A-6, (1R, 5S)-3-azabicyclo[3.2.1]octane hydrochloride was used instead of 6-azaspiro[2.5]octane hydrochloride to prepare compound 51-1 (1.9 g). MS (ESI+, [M+H] + ) m/z: 358.12.

步骤B：Step B:

参考制备例A-6的步骤B，以化合物51-1代替化合物A-2，制备得到化合物52-2(1.8g)。MS(ESI+,[M+H]+)m/z：372.16.Referring to step B of Preparation Example A-6, Compound 51-1 was used instead of Compound A-2 to prepare Compound 52-2 (1.8 g). MS (ESI+, [M+H] + ) m/z: 372.16.

步骤C：Step C:

参考制备例A-6的步骤C，以化合物51-2代替化合物A-3，以甲基磺酰胺代替2-羟基-1-磺酰胺，制备得到化合物51-3(0.75g)。MS(ESI+,[M+H]+)m/z：339.27.Referring to step C of Preparation Example A-6, Compound 51-2 was used instead of Compound A-3, and methylsulfonamide was used instead of 2-hydroxy-1-sulfonamide to prepare Compound 51-3 (0.75 g). MS (ESI+, [M+H] + ) m/z: 339.27.

步骤D：Step D:

参考制备例D-4的步骤D，以化合物51-3代替化合物D-3，制备得到化合物51-4(0.47g)。MS(ESI+, [M+H]+)m/z：324.28.Referring to step D of Preparation Example D-4, Compound 51-3 was substituted for Compound D-3 to prepare Compound 51-4 (0.47 g). MS (ESI+, [M+H] + )m/z：324.28.

步骤E：Step E:

参考化合物20_A的制备方法，以化合物51-4代替化合物D-4，制备得到化合物51-A。1H NMR(500MHz,DMSO-d6)δ10.85(s,1H),10.07(s,1H),7.78(dd,2H),7.41(d,1H),7.19(d,1H),7.02(dd,1H),4.65(d,1H),4.26–4.10(m,1H),3.27(s,3H),3.08(s,3H),2.98(d,2H),2.88–2.75(m,3H),2.44–2.35(m,1H),2.26(s,2H),2.20–2.03(m,2H),2.02–1.91(m,3H),1.67–1.46(m,4H).HRMS(ESI+,[M+H]+)m/z：575.2263.Referring to the preparation method of compound 20_A, compound 51-4 was used instead of compound D-4 to prepare compound 51-A. 1 H NMR (500MHz, DMSO-d 6 )δ10.85(s,1H),10.07(s,1H),7.78(dd,2H),7.41(d,1H),7.19(d,1H) ,7.02(dd,1H),4.65(d,1H),4.26–4.10(m,1H),3.27(s,3H),3.08(s,3H ),2.98(d,2H),2.88–2.75(m,3H),2.44–2.35(m,1H),2.26(s,2H),2.20–2.03(m,2H),2.02–1.91(m,3H),1.67–1.46(m,4H).HRMS(ESI+,[M+H] + )m/z：575.2263.

参考化合物20_B的制备方法，以化合物51-4代替化合物D-4，制备得到化合物51-B。1H NMR(500MHz,DMSO-d6)δ10.85(s,1H),10.07(s,1H),7.85–7.60(m,2H),7.41(d,1H),7.19(d,1H),7.02(dd,1H),4.65(d,1H),4.23–4.15(m,1H),3.27(s,3H),3.08(s,3H),2.98(d,2H),2.81(q,3H),2.38(d,1H),2.26(s,2H),2.20–2.05(m,2H),2.05–1.80(m,3H),1.65–1.48(m,4H).HRMS(ESI+,[M+H]+)m/z：575.2268.Referring to the preparation method of compound 20-B, compound 51-4 was used instead of compound D-4 to prepare compound 51-B. 1 H NMR (500MHz, DMSO-d 6 )δ10.85(s,1H),10.07(s,1H),7.85–7.60(m,2H),7.41(d,1H),7.19(d,1H),7.02(dd,1H),4.65(d,1H),4.23–4.15(m,1H),3.27(s,3H),3. 08(s,3H),2.98(d,2H),2.81(q,3H),2.38(d,1H),2.26(s,2H),2.20–2.05(m,2H),2.05–1.80(m,3H),1.65–1.48(m,4H).HRMS(ESI+,[M+H] + )m/z：575.2268.

实施例52
Embodiment 52

步骤A：Step A:

向250mL单口瓶中，依次加入化合物52-1(2g)、化合物B-2(2.2g)、三甲基铝(2mol/L甲苯溶液，5mL)、甲苯(50mL)，氮气保护下120℃加热回流2h。反应结束后，加入饱和氯化铵水溶液150mL，二氯甲烷(50mL×3)萃取，合并有机相，干燥，抽滤，滤液减压浓缩，硅胶柱层析(PE/EA＝90/10)纯化得到化合物52-2(1.5g)。MS(ESI+,[M+H]+)m/z：498.97.Compound 52-1 (2 g), compound B-2 (2.2 g), trimethylaluminum (2 mol/L toluene solution, 5 mL), toluene (50 mL) were added to a 250 mL single-mouth bottle in sequence, and heated to reflux at 120 ° C for 2 h under nitrogen protection. After the reaction, 150 mL of saturated ammonium chloride aqueous solution was added, and dichloromethane (50 mL × 3) was used for extraction. The organic phases were combined, dried, filtered, and the filtrate was concentrated under reduced pressure. The compound 52-2 (1.5 g) was purified by silica gel column chromatography (PE/EA = 90/10). MS (ESI+, [M+H] + ) m/z: 498.97.

步骤B：Step B:

向100mL三口瓶中依次加入化合物52-2(1.5g)和二氯甲烷(30mL)，冰浴下缓慢加入三氟乙酸(19.14mL)，室温搅拌反应3h，反应结束后，加入100mL饱和碳酸氢钠溶液，DCM(3×50mL)萃取，合并有机相，无水硫酸钠干燥，抽滤，滤液浓缩得到化合物52-3(1.2g)。MS(ESI+,[M+H]+)m/z：398.92Compound 52-2 (1.5 g) and dichloromethane (30 mL) were added to a 100 mL three-necked flask in sequence, trifluoroacetic acid (19.14 mL) was slowly added under ice bath, and the mixture was stirred at room temperature for 3 h. After the reaction, 100 mL of saturated sodium bicarbonate solution was added, and DCM (3×50 mL) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 52-3 (1.2 g). MS (ESI+, [M+H] + ) m/z: 398.92

步骤C：Step C:

向100mL单口瓶中依次加入化合物52-3(1.2g)、NMP(10mL)和DIEA(1mL)，加热至120℃反应8h。反应结束后，向反应液中加入100mL水，EA(3×50mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，硅胶柱层析(PE/EA＝4/1)纯化得到化合物52-4(820mg)。MS(ESI+,[M+H]+)m/z：318.99.Compound 52-3 (1.2 g), NMP (10 mL) and DIEA (1 mL) were added to a 100 mL single-mouth bottle in sequence, and heated to 120°C for 8 h. After the reaction, 100 mL of water was added to the reaction solution, and EA (3×50 mL) was used for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography (PE/EA=4/1) to obtain compound 52-4 (820 mg). MS (ESI+, [M+H] + ) m/z: 318.99.

步骤D：Step D:

向100mL单口瓶中依次加入化合物52-4(820mg)和DMF(10mL)，冰浴下加入NaH(125mg)，搅拌5min后加入碘甲烷(480mg)，室温反应1h。反应结束后，向反应液中加入饱和的氯化铵溶液100mL，EA(3×50mL)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，20mL石油醚打浆，抽滤，得到化合物52-5(310mg)。MS(ESI+,[M+H]+)m/z：333.01.Compound 52-4 (820 mg) and DMF (10 mL) were added to a 100 mL single-mouth bottle in sequence, NaH (125 mg) was added under ice bath, iodomethane (480 mg) was added after stirring for 5 min, and the mixture was reacted at room temperature for 1 h. After the reaction was completed, 100 mL of saturated ammonium chloride solution was added to the reaction solution, and EA (3×50 mL) was used for extraction. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, slurried with 20 mL of petroleum ether, and filtered to obtain compound 52-5 (310 mg). MS (ESI+, [M+H] + ) m/z: 333.01.

步骤E：Step E:

参考实施例23的步骤C，以化合物52-5替换化合物21-1制备得到化合物52(180mg)。MS(ESI+,[M+H]+)m/z：576.21.Referring to step C of Example 23, compound 52-5 was substituted for compound 21-1 to prepare compound 52 (180 mg). MS (ESI+, [M+H] + ) m/z: 576.21.

步骤F： Step F:

化合物52(180mg)经过手性HPLC拆分(型号：(R,R)Whelk-O1，4.6×250mm，5μm；流动相：正己烷/二氯甲烷/乙醇＝45/40/15；流速：1mL/min)得到化合物52_A(60mg，保留时间：8.889min)、化合物52_B(60mg，保留时间：10.070min)Compound 52 (180 mg) was separated by chiral HPLC (model: (R,R) Whelk-O1, 4.6×250 mm, 5 μm; mobile phase: n-hexane/dichloromethane/ethanol=45/40/15; flow rate: 1 mL/min) to give Compound 52_A (60 mg, retention time: 8.889 min) and Compound 52_B (60 mg, retention time: 10.070 min).

化合物52_A：1H NMR(500MHz,DMSO-d6)δ13.47(s,1H),10.27(s,1H),8.55(s,1H),8.10(d,1H),7.28(d,1H),7.21–7.12(m,1H),4.70–4.61(m,1H),4.45–4.36(m,1H),3.33(s,3H),3.13(s,3H),3.04–2.88(m,5H),2.49–2.42(m,1H),2.37–1.59(m,7H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：576.2209.Compound 52_A: 1 H NMR (500MHz, DMSO-d 6 )δ13.47(s,1H),10.27(s,1H),8.55(s,1H),8.10(d,1H),7.28(d,1H),7.21–7.12(m,1H),4.70–4.61 (m,1H),4.45–4.36( m,1H),3.33(s,3H),3.13(s,3H),3.04–2.88(m,5H),2.49–2.42(m,1H),2.37–1.59(m,7H),0.40(s, 4H).HRMS(ESI+,[M+H] + )m/z：576.2209.

化合物52_B：1H NMR(500MHz,DMSO-d6)δ13.47(s,1H),10.27(s,1H),8.55(s,1H),8.10(d,1H),7.28(d,1H),7.18–7.13(m,1H),4.70–4.61(m,1H),4.44–4.38(m,1H),3.33(s,3H),3.13(s,3H),3.05–2.90(m,5H),2.49–2.42(m,1H),2.35–1.64(m,7H),0.40(s,4H).HRMS(ESI+,[M+H]+)m/z：576.2210.Compound 52_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.47 (s, 1H), 10.27 (s, 1H), 8.55 (s, 1H), 8.10 (d, 1H), 7.28 (d, 1H), 7.18–7.13 (m, 1H), 4.70–4.61 (m, 1H), 4.44–4.38 (m, 1H), 3.33 (s, 3H), 3.13 (s, 3H), 3.05–2.90 (m, 5H), 2.49–2.42 (m, 1H), 2.35–1.64 (m, 7H), 0.40 (s, 4H). HRMS (ESI+, [M+H] + ) m/z: 576.2210.

实施例53
Embodiment 53

50mL单口瓶中，依次加入化合物51-4(300mg)、化合物21-2A(342mg)、Pd2(dba)3(85mg)、Xant-Phos(107mg)、碳酸铯(907mg)和二氧六环(15mL)溶解，氮气保护下，在100℃下加热反应4h。反应结束后向反应液中加入30mL蒸馏水，EA(20mL×3)萃取，饱和食盐水(30mL)洗涤，无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：PE/EA＝1/1)纯化，得到化合物53_A(254mg)。1H NMR(500MHz,DMSO-d6)δ10.85(s,1H),10.07(s,1H),7.89–7.70(m,2H),7.41(d,1H),7.19(d,1H),7.10–6.91(m,1H),4.65(d,1H),4.28–4.05(m,1H),3.08(s,3H),2.98(d,2H),2.89–2.71(m,3H),2.49–2.32(m,1H),2.26(s,2H),2.19–2.04(m,2H),1.98–1.79(m,3H),1.64–1.51(m,4H).HRMS(ESI+,[M+H]+)m/z：578.2458.Compound 51-4 (300 mg), compound 21-2A (342 mg), Pd 2 (dba) 3 (85 mg), Xant-Phos (107 mg), cesium carbonate (907 mg) and dioxane (15 mL) were added to a 50 mL single-mouth bottle and dissolved. The mixture was heated at 100 °C for 4 h under nitrogen protection. After the reaction, 30 mL of distilled water was added to the reaction solution, extracted with EA (20 mL × 3), washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE/EA = 1/1) to obtain compound 53_A (254 mg). 1 H NMR (500MHz, DMSO-d 6 )δ10.85(s,1H),10.07(s,1H),7.89–7.70(m,2H),7.41(d,1H),7.19( d,1H),7.10–6.91(m,1H),4.65(d,1H),4.28–4.05(m,1H),3.08(s,3H) ,2.98(d,2H),2.89–2.71(m,3H),2.49–2.32(m,1H),2.26(s,2H),2.19–2.04(m,2H),1.98–1.79(m,3H),1.64–1.51(m,4H).HRMS(ESI+,[M+H] + )m/z：578.2458.

参考化合物53_A的制备方法，以化合物21-2B代替化合物21-2A，制备得到化合物53_B。1H NMR(500MHz,DMSO-d6)δ10.85(s,1H),10.07(s,1H),7.87–7.69(m,2H),7.41(d,1H),7.19(d,1H),7.12–6.95(m,1H),4.65(d,1H),4.29–4.15(m,1H),3.08(s,3H),2.98(d,2H),2.89–2.65(m,3H),2.40(s,1H),2.26(s,2H),2.20–1.87(m,5H),1.67–1.49(m,4H).HRMS(ESI+,[M+H]+)m/z：578.2470.Referring to the preparation method of compound 53_A, compound 21-2B was used instead of compound 21-2A to prepare compound 53_B. 1 H NMR (500MHz, DMSO-d 6 )δ10.85(s,1H),10.07(s,1H),7.87–7.69(m,2H),7.41(d,1H),7.19(d,1H),7.12–6.95(m,1H),4.65(d,1H),4.29–4.15(m,1H), 3.08(s,3H),2.98(d,2H),2.89–2.65(m,3H),2.40(s,1H),2.26(s,2H),2.20–1.87(m,5H),1.67–1.49(m,4H).HRMS(ESI+,[M+H] + )m/z：578.2470.

实施例54
Embodiment 54

步骤A：Step A:

参考实施例49的步骤C，以2-羟基-1-磺酰胺代替甲基磺酰胺，得到化合物54-1。MS(ESI+,[M+H]+)m/z：354.05Referring to step C of Example 49, 2-hydroxy-1-sulfonamide was used instead of methylsulfonamide to obtain compound 54-1. MS (ESI+, [M+H] + ) m/z: 354.05

步骤B：Step B:

参考实施例43的制备方法，以化合物54-1替换化合物34-6，制备得到化合物54。1H NMR(500MHz,DMSO-d6)δ11.58(s,1H),10.05(s,1H),7.87(d,1H),7.73(d,1H),7.41(d,1H),7.07(d,1H),6.95(dd,1H),4.92(s,1H),4.60–4.51(m,1H),4.25–4.13(m,1H),3.74(t,2H),3.72–3.66(m,2H),3.30(s,1H),2.90–2.79(m,1H),2.44–2.34(m,1H),2.25–1.82(m,8H),1.78–1.64(m,3H),1.59–1.44(m,3H).HRMS(ESI+,[M+H]+)m/z：608.2554.Referring to the preparation method of Example 43, Compound 54 was prepared by replacing Compound 34-6 with Compound 54-1. 1 H NMR (500 MHz, DMSO-d 6 )δ11.58(s,1H),10.05(s,1H),7.87(d,1H),7.73(d,1H),7.41(d,1H),7.07( d,1H),6.95(dd,1H),4.92(s,1H),4.60–4.51(m,1H),4.25–4.13(m,1H),3.74 (t,2H),3.72–3.66(m,2H),3.30(s,1H),2.90–2.79(m,1H),2.44–2.34(m,1H ),2.25–1.82(m,8H),1.78–1.64(m,3H),1.59–1.44(m,3H).HRMS(ESI+,[M+H] + )m/z：608.2554.

实施例55
Embodiment 55

步骤A：Step A:

参考制备例A-6的步骤E，以化合物51-1替换化合物A-5，制备得到化合物55-1。MS(ESI+,[M+H]+)m/z：357.00.Referring to step E of Preparation Example A-6, Compound 51-1 was substituted for Compound A-5 to prepare Compound 55-1. MS (ESI+, [M+H] + ) m/z: 357.00.

步骤B：Step B:

参考制备例A-6的步骤C，以化合物55-1替换化合物A-3，制备得到化合物55-2。MS(ESI-,[M-H]-)m/z：354.07.Referring to step C of Preparation Example A-6, Compound 55-1 was substituted for Compound A-3 to prepare Compound 55-2. MS (ESI-, [MH] - ) m/z: 354.07.

步骤C：Step C:

参考实施例54的步骤B，以化合物55-2替换化合物54-1，制备得到化合物55。1H NMR(500MHz,DMSO-d6)δ10.85(s,1H),10.04(s,1H),7.91–7.59(m,2H),7.41(d,1H),7.20(d,1H),7.02(dd,1H),5.09–4.77(m,1H),4.72–4.54(m,1H),4.24–4.09(m,1H),3.80–3.71(m,2H),3.33–3.30(m,2H),3.02–2.94(m,2H),2.87–2.75(m,3H),2.43–2.36(m,1H),2.26(s,2H),2.18–1.90(m,5H),1.63–1.50(m,4H).HRMS(ESI+,[M+H]+)m/z：608.2543.Referring to step B of Example 54, Compound 55 was prepared by replacing Compound 54-1 with Compound 55-2. 1 H NMR (500 MHz, DMSO-d 6 )δ10.85(s,1H),10.04(s,1H),7.91–7.59(m,2H),7.41(d,1H),7.20(d,1H),7 .02(dd,1H),5.09–4.77(m,1H),4.72–4.54(m,1H),4.24–4.09(m,1H),3.80–3. 71(m,2H),3.33–3.30(m,2H),3.02–2.94(m,2H),2.87–2.75(m,3H),2.43–2.3 6(m,1H),2.26(s,2H),2.18–1.90(m,5H),1.63–1.50(m,4H).HRMS(ESI+,[M+H] + )m/z：608.2543.

实施例56
Embodiment 56

步骤A： Step A:

参考实施例14的步骤D，以碘乙烷替换碘甲烷，制备得到化合物56-1。1H NMR(500MHz,DMSO-d6)δ7.32(d,1H),6.98(d,1H),4.55–4.51(m,1H),4.25–4.22(m,1H),3.95–3.84(m,2H),2.84–2.79(m,1H),2.47–2.40(m,1H),2.20–2.07(m,2H),2.03–1.89(m,1H),1.10(t,3H).Referring to step D of Example 14, iodoethane was used to replace iodomethyl to prepare compound 56-1. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.32 (d, 1H), 6.98 (d, 1H), 4.55-4.51 (m, 1H), 4.25-4.22 (m, 1H), 3.95-3.84 (m, 2H), 2.84-2.79 (m, 1H), 2.47-2.40 (m, 1H), 2.20-2.07 (m, 2H), 2.03-1.89 (m, 1H), 1.10 (t, 3H).

步骤B：Step B:

向100mL单口瓶中，依次加入化合物56-1(0.214g)、化合物51-4(0.200g)、Pd2(dba)3(0.028g)、Xant-Phos(0.036g)和碳酸铯(0.604g)，用二氧六环(10mL)溶解，N2保护下，加热至100℃反应6h。反应结束后，过滤，减压浓缩，硅胶柱层析(洗脱剂：DCM/MeOH＝20/1)纯化，得到化合物56(265mg)。1H NMR(500MHz,DMSO-d6)δ10.85(s,1H),10.07(s,1H),7.80–7.77(m,2H),7.47(d,1H),7.19(d,1H),7.02(dd,1H),4.65–4.62(m,1H),4.18–4.15(m,1H),4.04–3.86(m,2H),3.08(s,3H),2.98(d,2H),2.85–2.77(m,3H),2.41–2.36(m,1H),2.26(s,2H),2.13–1.90(m,5H),1.64–1.51(m,4H),1.14(t,3H).HRMS(ESI+,[M+H]+)m/z：589.2385.Compound 56-1 (0.214 g), compound 51-4 (0.200 g), Pd 2 (dba) 3 (0.028 g), Xant-Phos (0.036 g) and cesium carbonate (0.604 g) were added to a 100 mL single-necked bottle in sequence, dissolved with dioxane (10 mL), and heated to 100° C. for 6 h under N 2 protection. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM/MeOH=20/1) to obtain compound 56 (265 mg). 1 H NMR (500MHz, DMSO-d 6 )δ10.85(s,1H),10.07(s,1H),7.80–7.77(m,2H),7.47(d,1H),7.19(d,1 H),7.02(dd,1H),4.65–4.62(m,1H),4.18–4.15(m,1H),4.04–3.86(m,2H) ,3.08(s,3H),2.98(d,2H),2.85–2.77(m,3H),2.41–2.36(m,1H),2.26(s, 2H),2.13–1.90(m,5H),1.64–1.51(m,4H),1.14(t,3H).HRMS(ESI+,[M+H] + )m/z：589.2385.

实施例57
Embodiment 57

向100mL单口瓶中，依次加入化合物56-1(0.198g)、化合物E-4(0.200g)、Pd2(dba)3(0.026g)、Xant-Phos(0.033g)和碳酸铯(0.559g)，用二氧六环(10mL)溶解，N2保护下，加热至100℃反应6h。反应结束后，过滤，减压浓缩，硅胶柱层析(洗脱剂：DCM/MeOH＝20/1)纯化，得到化合物57(223mg)。1H NMR(500MHz,DMSO-d6)δ11.59(s,1H),10.10(s,1H),7.90(d,1H),7.75(d,1H),7.47(d,1H),7.08(d,1H),6.97(dd,1H),4.66–4.62(m,1H),4.16–4.13(m,1H),3.97–3.86(m,2H),3.79–3.77(m,2H),3.08(s,3H),2.85–2.80(m,1H),2.55–2.52(m,1H),2.47–2.43(m,2H),2.16–1.88(m,7H),1.14(t,3H),1.00–0.98(m,2H),0.62–0.59(m,2H),0.15–0.12(m,2H).HRMS(ESI+,[M+H]+)m/z：615.2542.Compound 56-1 (0.198 g), compound E-4 (0.200 g), Pd 2 (dba) 3 (0.026 g), Xant-Phos (0.033 g) and cesium carbonate (0.559 g) were added to a 100 mL single-mouth bottle in sequence, dissolved with dioxane (10 mL), and heated to 100 ° C for 6 h under N 2 protection. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM/MeOH=20/1) to obtain compound 57 (223 mg). 1 H NMR (500 MHz, DMSO-d 6 )δ11.59(s,1H),10.10(s,1H),7.90(d,1H),7.75(d,1H),7.47(d,1H),7.08(d,1H),6.9 7(dd,1H),4.66–4.62(m,1H),4.16–4.13(m,1H),3.97–3.86(m,2H),3.79–3.77(m,2H),3 .08(s,3H),2.85–2.80(m,1H),2.55–2.52(m,1H),2.47–2.43(m,2H),2.16–1.88(m,7H), 1.14(t,3H),1.00–0.98(m,2H),0.62–0.59(m,2H),0.15–0.12(m,2H).HRMS(ESI+,[M+H] + )m/z：615.2542.

实施例58
Embodiment 58

步骤A：Step A:

参考实施例14的步骤D，以d5-氘代碘乙烷替换碘甲烷，制备得到化合物58-1。MS(ESI+,[M+H]+)m/z：351.07.Referring to step D of Example 14, iodomethane was replaced with d5-deuterated iodoethane to prepare compound 58-1. MS (ESI+, [M+H] + ) m/z: 351.07.

步骤B：Step B:

参考实施例55的步骤C，以化合物58-1替换化合物21-2B，制备得到化合物58。1H NMR(500MHz,DMSO-d6)δ10.85(s,1H),10.04(s,1H),7.79(d,1H),7.77(d,1H),7.47(d,1H),7.20(d,1H),7.02(dd,1H),4.93(s,1H),4.68–4.60(m,1H),4.19–4.13(m,1H),3.78–3.69(m,2H),3.33(s,1H),3.01–2.93(m,2H),2.86–2.75(m,3H),2.43–2.35(m,1H),2.26(s,2H),2.18–2.04(m,2H),2.04–1.89(m,4H),1.64–1.48(m,4H).HRMS(ESI+,[M+H]+)m/z：624.2824.Referring to step C of Example 55, compound 58-1 was used to replace compound 21-2B to prepare compound 58. 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.85 (s, 1H), 10.04 (s, 1H), 7.79 (d, 1H), 7.77 (d, 1H), 7.47 (d, 1H), 7.20 (d, 1H), 7.02 (dd, 1H), 4.93 (s, 1H), 4.68-4.60 (m, 1H), 4.19-4.13 (m, 1H), 3.78-3.69 (m, 2H),3.33(s,1H),3.01–2.93(m,2H),2.86–2.75(m,3H),2.43–2.35(m,1H),2.26( s,2H),2.18–2.04(m,2H),2.04–1.89(m,4H),1.64–1.48(m,4H).HRMS(ESI+,[M+H] + )m/z：624.2824.

实施例59
Embodiment 59

参考实施例29_A的制备方法，以化合物58-1替换化合物20-1A，制备得到化合物59。1H NMR(500MHz,DMSO-d6)δ11.60(s,1H),10.06(s,1H),7.89(d,1H),7.74(d,1H),7.47(d,1H),7.10(d,1H),6.97(dd,1H),4.92(t,1H),4.69–4.58(m,1H),4.21–4.11(m,1H),3.81–3.70(m,4H),3.34–3.30(m,2H),2.89–2.75(m,1H),2.54–2.42(m,2H),2.20–2.07(m,2H),2.06–1.97(m,4H),1.94–1.85(m,2H),1.05–0.95(m,2H),0.63–0.54(m,2H),0.18–0.10(m,2H).HRMS(ESI+,[M+H]+)m/z：650.2970.Referring to the preparation method of Example 29_A, Compound 58-1 was used to replace Compound 20-1A to prepare Compound 59. 1 H NMR (500 MHz, DMSO-d 6 )δ11.60(s,1H),10.06(s,1H),7.89(d,1H),7.74(d,1H),7.47(d,1H),7.10(d,1H),6.97(dd,1H),4.92(t,1H),4.69-4.58(m,1H),4.21-4.11(m,1H),3.81-3.70(m,4H),3.34-3.30 (m,2H),2.89–2.75(m,1H),2.54–2.42(m,2H),2.20–2.07(m,2H),2.06–1.97(m,4H),1.94 –1.85(m,2H),1.05–0.95(m,2H),0.63–0.54(m,2H),0.18–0.10(m,2H).HRMS(ESI+,[M+H] + )m/z：650.2970.

实施例60
Embodiment 60

参考实施例56的步骤B，以化合物58-1替换化合物56-1，制备得到化合物60。1H NMR(500MHz,DMSO-d6)δ10.85(s,1H),10.07(s,1H),7.79(dd,2H),7.47(d,1H),7.19(d,1H),7.02(dd,1H),4.64(d,1H),4.23–4.13(m,1H),3.08(s,3H),2.98(d,2H),2.88–2.74(m,3H),2.45–2.34(s,1H),2.26(s,2H),2.20–1.85(m,5H),1.67–1.48(m,4H).HRMS(ESI+,[M+H]+)m/z：594.2713.Referring to step B of Example 56, compound 60 was prepared by replacing compound 56-1 with compound 58-1. 1 H NMR (500MHz, DMSO-d 6 )δ10.85(s,1H),10.07(s,1H),7.79(dd,2H),7.47(d,1H),7.19(d,1H),7.02(dd,1H),4.64(d,1H),4.23–4.13(m,1H),3.08(s ,3H),2.98(d,2H),2.88–2.74(m,3H),2.45–2.34(s,1H),2.26(s,2H),2.20–1.85(m,5H),1.67–1.48(m,4H).HRMS(ESI+,[M+H] + )m/z：594.2713.

实施例61
Embodiment 61

参考实施例57的制备方法，以化合物58-1替换化合物56-1，制备得到化合物61。1H NMR(500MHz,DMSO-d6)δ11.59(s,1H),10.10(s,1H),7.90(d,1H),7.75(d,1H),7.47(d,1H),7.08(d,1H),6.97(dd,1H),4.64(d,1H),4.15(dd,1H),3.86–3.70(m,2H),3.08(s,3H),2.87–2.76(m,1H),2.56–2.52(m,1H),2.49–2.40(m,2H),2.26–1.81(m,7H),1.07–0.95(m,2H),0.68–0.53(m,2H),0.25–0.08(m,2H).HRMS(ESI+,[M+H]+)m/z：620.2866.Referring to the preparation method of Example 57, Compound 58-1 was used to replace Compound 56-1 to prepare Compound 61. 1 H NMR (500 MHz, DMSO-d 6 )δ11.59(s,1H),10.10(s,1H),7.90(d,1H),7.75(d,1H),7.47(d,1H),7.08( d,1H),6.97(dd,1H),4.64(d,1H),4.15(dd,1H),3.86–3.70(m,2H),3.08(s,3 H),2.87–2.76(m,1H),2.56–2.52(m,1H),2.49–2.40(m,2H),2.26–1.81(m,7H ),1.07–0.95(m,2H),0.68–0.53(m,2H),0.25–0.08(m,2H).HRMS(ESI+,[M+H] + )m/z：620.2866.

实施例62
Embodiment 62

步骤A： Step A:

100mL单口瓶中依次加入化合物14-4(0.5g)，环丙基硼酸(0.15g,)，吡啶(0.13)，碳酸钠(0.37g)，醋酸铜(0.31g)，DCE(30mL)，加热至60℃反应4h。反应结束后使用硅藻土过滤，滤液依次使用饱和碳酸氢钠水溶液(20mL)、2N盐酸水溶液(20mL)、饱和食盐水(30mL)洗涤后使用无水硫酸钠干燥。过滤，减压浓缩干，硅胶柱层析(洗脱剂：PE/EA＝1/3)纯化，得到化合物62-1(420mg)。1H NMR(500MHz,DMSO-d6)δ7.46(d,1H),7.04(d,1H),4.49–4.39(m,1H),4.19–4.10(m,1H),2.85–2.76(m,1H),2.75–2.67(m,1H),2.45–2.37(m,1H),2.19–1.87(m,3H),1.14–1.03(m,2H),0.69–0.60(m,1H),0.58–0.47(m,1H).Compound 14-4 (0.5 g), cyclopropylboronic acid (0.15 g), pyridine (0.13), sodium carbonate (0.37 g), copper acetate (0.31 g), DCE (30 mL) were added to a 100 mL single-mouth bottle, and heated to 60 ° C for 4 h. After the reaction, it was filtered using diatomaceous earth, and the filtrate was washed with saturated sodium bicarbonate aqueous solution (20 mL), 2N hydrochloric acid aqueous solution (20 mL), and saturated brine (30 mL) in turn, and then dried over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent: PE/EA=1/3) to obtain compound 62-1 (420 mg). 1 H NMR (500MHz, DMSO-d 6 )δ7.46(d,1H),7.04(d,1H),4.49–4.39(m,1H),4.19–4.10(m,1H),2.85–2.76(m,1H),2.75–2.67(m, 1H),2.45–2.37(m,1H),2.19–1.87(m,3H),1.14–1.03(m,2H),0.69–0.60(m,1H),0.58–0.47(m,1H).

步骤B：Step B:

参考化合物53_A的制备方法，以化合物62-1替换化合物21-2A，制备得到化合物62。1H NMR(500MHz,DMSO-d6)δ10.88(s,1H),10.07(s,1H),7.89–7.72(m,2H),7.63(d,1H),7.19(d,1H),7.13–6.92(m,1H),4.53(d,1H),4.15–4.01(m,1H),3.08(s,3H),2.98(d,2H),2.89–2.79(m,2H),2.79–2.60(m,2H),2.42–2.33(m,1H),2.26(s,2H),2.19–2.05(m,2H),2.07–1.88(m,5H),1.67–1.45(m,2H),1.25–1.02(m,2H),0.66–0.56(m,2H).HRMS(ESI+,[M+H]+)m/z：601.2405.Referring to the preparation method of compound 53_A, compound 62-1 was used to replace compound 21-2A to prepare compound 62. 1 H NMR (500MHz, DMSO-d 6 )δ10.88(s,1H),10.07(s,1H),7.89–7.72(m,2H),7.63(d,1H),7.19(d,1H),7.13–6.92(m,1H),4.53(d,1H),4.15–4.01(m,1H),3.08(s,3H),2.98(d,2H),2.89–2.79(m, 2H),2.79–2.60(m,2H),2.42–2.33(m,1H),2.26(s,2H),2.19–2.05(m,2H),2.07–1.8 8(m,5H),1.67–1.45(m,2H),1.25–1.02(m,2H),0.66–0.56(m,2H).HRMS(ESI+,[M+H] + )m/z：601.2405.

实施例63
Embodiment 63

参考实施例55的步骤C，以化合物62-1替换化合物21-2B，制备得到化合物63。1H NMR(500MHz,DMSO-d6)δ10.89(s,1H),10.04(s,1H),7.83(d,1H),7.78(d,1H),7.63(d,1H),7.21(d,1H),7.12–6.94(m,1H),4.93(s,1H),4.53(d,1H),4.15–4.04(m,1H),3.85–3.69(m,2H),2.97(d,2H),2.88–2.66(m,4H),2.37(s,1H),2.26(s,2H),2.17–1.87(m,5H),1.69–1.41(m,4H),1.25(d,2H),1.20–1.01(m,2H),0.66–0.56(m,2H).HRMS(ESI+,[M+H]+)m/z：631.2485.Referring to step C of Example 55, compound 62-1 was used to replace compound 21-2B to prepare compound 63. 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.89 (s, 1H), 10.04 (s, 1H), 7.83 (d, 1H), 7.78 (d, 1H), 7.63 (d, 1H), 7.21 (d, 1H), 7.12-6.94 (m, 1H), 4.93 (s, 1H), 4.53 (d, 1H), 4.15-4.04 (m, 1H), 3.85-3.69 (m, 2H) ,2.97(d,2H),2.88–2.66(m,4H),2.37(s,1H),2.26(s,2H),2.17–1.87(m,5H),1.69 –1.41(m,4H),1.25(d,2H),1.20–1.01(m,2H),0.66–0.56(m,2H).HRMS(ESI+,[M+H] + )m/z：631.2485.

实施例64
Embodiment 64

参考化合物61的制备方法，以化合物62-1替换化合物58-1，制备得到化合物64。1H NMR(500MHz,DMSO-d6)δ11.63(s,1H),10.10(s,1H),7.91(d,1H),7.78(d,1H),7.62(d,1H),7.08(d,1H),6.97(dd,1H),4.62–4.50(m,1H),4.09–4.02(m,1H),3.82–3.73(m,2H),3.08(s,3H),2.85–2.76(m,1H),2.75–2.70(m,1H),2.57–2.38(m,3H),2.18–1.89(m,7H),1.17–1.07(m,2H),1.02–0.95(m,2H),0.69–0.63(m,1H),0.63–0.52(m,3H),0.19–0.10(m,2H).HRMS(ESI+,[M+H]+)m/z：627.2548.Referring to the preparation method of compound 61, compound 62-1 was used to replace compound 58-1 to prepare compound 64. 1 H NMR (500 MHz, DMSO-d 6 )δ11.63(s,1H),10.10(s,1H),7.91(d,1H),7.78(d,1H),7.62(d,1H),7.08(d,1H),6.97(dd,1H),4.62–4.50(m,1H),4.09–4.02(m,1H),3.82–3.73(m,2H),3.08(s,3H),2.85–2.76 (m,1H),2.75–2.70(m,1H),2.57–2.38(m,3H),2.18–1.89(m,7H),1.17–1.07(m,2H),1.02 –0.95(m,2H),0.69–0.63(m,1H),0.63–0.52(m,3H),0.19–0.10(m,2H).HRMS(ESI+,[M+H] + )m/z：627.2548.

实施例65
Embodiment 65

参考化合物64的制备方法，以化合物29-2替换化合物E-4，制备得到化合物65。1H NMR(500MHz,DMSO-d6)δ11.63(s,1H),10.06(s,1H),7.90(d,1H),7.77(d,1H),7.62(d,1H),7.10(d,1H),6.97(dd,1H),4.92(t,1H),4.62–4.49(m,1H),4.10–4.02(m,1H),3.81–3.70(m,4H),3.34–3.29(m,2H),2.86–2.76(m,1H),2.75–2.70(m,1H),2.57–2.36(m,3H),2.19–1.88(m,7H),1.15–1.06(m,2H),1.03–0.95(m,2H),0.70–0.52(m,4H),0.19–0.05(m,2H).HRMS(ESI+,[M+H]+)m/z：657.2664.Referring to the preparation method of compound 64, compound 29-2 was used to replace compound E-4 to prepare compound 65. 1 H NMR (500 MHz, DMSO-d 6 )δ11.63 (s, 1H), 10.06 (s, 1H), 7.90 (d, 1H), 7.77 (d, 1H), 7.62 (d, 1H), 7.10 (d, 1H), 6.97 (dd, 1H), 4.92 (t, 1H), 4.62–4.49 (m, 1H), 4.10–4.02 (m, 1H), 3.81–3.70 (m, 4H), 3.34–3.29 (m,2H),2.86–2.76(m,1H),2.75–2.70(m,1H),2.57–2.36(m,3H),2.19–1.88(m,7H),1.15 –1.06(m,2H),1.03–0.95(m,2H),0.70–0.52(m,4H),0.19–0.05(m,2H).HRMS(ESI+,[M+H] + )m/z：657.2664.

实施例66
Embodiment 66

步骤A：Step A:

100mL单口瓶中依次加入化合物66-1(2g)、甲醇(30mL)，氮气保护，冰浴降温后加入NBS(6.57g)，室温搅拌2h。反应结束后，减压蒸出溶剂，经硅胶柱层析(PE/EA＝90/10)纯化得到化合物66-2(2.3g)。MS(ESI-,[M-H]-)m/z：273.75.Compound 66-1 (2 g) and methanol (30 mL) were added to a 100 mL single-mouth bottle in sequence, and NBS (6.57 g) was added after cooling in an ice bath, and stirred at room temperature for 2 h. After the reaction was completed, the solvent was evaporated under reduced pressure, and compound 66-2 (2.3 g) was obtained by purification by silica gel column chromatography (PE/EA=90/10). MS (ESI-, [MH] - ) m/z: 273.75.

步骤B：Step B:

参考实施例14的步骤A，以化合物66-2替换化合物14-1，制备得到化合物66-3。MS(ESI-,[M-H]-)m/z：520.98.Referring to step A of Example 14, compound 66-2 was substituted for compound 14-1 to prepare compound 66-3. MS (ESI-, [MH] - ) m/z: 520.98.

步骤C：Step C:

参考实施例14的步骤B，以化合物66-3替换化合物14-2，制备得到化合物66-4。MS(ESI-,[M-H]-)m/z：420.88.Referring to step B of Example 14, compound 66-3 was substituted for compound 14-2 to prepare compound 66-4. MS (ESI-, [MH] - ) m/z: 420.88.

步骤D：Step D:

参考实施例14的步骤C，以化合物66-4替换化合物14-3，制备得到化合物66-5。MS(ESI-,[M-H]-)m/z：340.95.Referring to step C of Example 14, compound 66-4 was substituted for compound 14-3 to prepare compound 66-5. MS (ESI-, [MH] - ) m/z: 340.95.

步骤E：Step E:

参考实施例14的步骤D，以化合物66-5替换化合物14-4，制备得到化合物66-6(120mg)。MS(ESI+,[M+H]+)m/z：357.01.Referring to step D of Example 14, compound 66-5 was substituted for compound 14-4 to prepare compound 66-6 (120 mg). MS (ESI+, [M+H] + ) m/z: 357.01.

步骤F：Step F:

参考化合物53_A的制备方法，以化合物66-6替换化合物21-2A，制备得到化合物66(30mg)。MS(ESI+,[M+H]+)m/z：600.21.Referring to the preparation method of compound 53_A, compound 66-6 was used to replace compound 21-2A to prepare compound 66 (30 mg). MS (ESI+, [M+H] + ) m/z: 600.21.

实施例67
Embodiment 67

参考实施例33的步骤A，以化合物66-6替换化合物21-1，制备得到化合物67。Referring to step A of Example 33, compound 67 was prepared by replacing compound 21-1 with compound 66-6.

1H NMR(500MHz,DMSO-d6)δ11.90(s,1H),10.15(s,1H),7.96–7.86(m,2H),7.09(d,1H),7.03–6.96(m, 1H),4.55(d,1H),4.28–4.21(m,1H),3.82–3.72(m,2H),3.55(s,3H),3.09(s,3H),2.96–2.87(m,1H),2.48–2.36(m,3H),2.22–1.88(m,7H),1.05–0.96(m,2H),0.64–0.53(m,2H),0.18–0.09(m,2H).HRMS(ESI+,[M+H]+)m/z：626.2342. 1 H NMR (500MHz, DMSO-d 6 ) δ11.90(s,1H),10.15(s,1H),7.96–7.86(m,2H),7.09(d,1H),7.03–6.96(m, 1H),4.55(d,1H),4.28–4.21(m,1H),3.82–3.72(m,2H),3.55(s,3H),3.09(s,3H),2.96–2.87(m,1H) ,2.48– 2.36(m,3H),2.22–1.88(m,7H),1.05–0.96(m,2H),0.64–0.53(m,2H),0.18–0.09(m,2H).HRMS(ESI+,[M+ H] + )m/z：626.2342.

试验例1 KIF18A蛋白运动活性抑制实验Experimental Example 1 KIF18A protein motor activity inhibition experiment

用含有微管蛋白(厂家：Cytoskeleton Inc)和紫杉醇的缓冲液将KIF18A(1-374)蛋白(厂家：Cytoskeleton Inc)稀释到50nM，按每孔3μL加入至检测孔中，用纳升加样仪将DMSO溶解的不同化合物加入到检测孔中，使化合物终浓度为1000nM-0.244nM，2个复孔，同时设对照，上述体系孵育15min。将ATP(187.5nM)按每孔2μL加入检测孔中，室温反应15min，后将ADP-Glo reagent(厂家：Promega)，按每孔5μL加入至检测孔中，室温孵育40min。再加入Kinase Detection reagent(厂家：Promega)，每孔10μL，室温孵育40min，Envision多功能酶标仪进行Luminescence模块检测，采用四参数拟合，计算IC50。KIF18A (1-374) protein (manufacturer: Cytoskeleton Inc) was diluted to 50 nM with a buffer containing tubulin (manufacturer: Cytoskeleton Inc) and paclitaxel, and 3 μL was added to each well. Different compounds dissolved in DMSO were added to the test wells using a nanoliter pipette to make the final concentration of the compound 1000 nM-0.244 nM. Two replicate wells were set up at the same time, and the above system was incubated for 15 min. ATP (187.5 nM) was added to the test wells at 2 μL per well, reacted at room temperature for 15 min, and then ADP-Glo reagent (manufacturer: Promega) was added to the test wells at 5 μL per well, and incubated at room temperature for 40 min. Kinase Detection reagent (manufacturer: Promega) was then added at 10 μL per well, and incubated at room temperature for 40 min. Luminescence module detection was performed using Envision multifunctional microplate reader, and IC 50 was calculated using four-parameter fitting.

实验结果参见表1。The experimental results are shown in Table 1.

表1
Table 1

注：A表示IC50≤150nM；B表示150nM＜IC50≤500nM。Note: A means IC 50 ≤150nM; B means 150nM＜IC 50 ≤500nM.

试验例2细胞增殖抑制实验 Experimental Example 2 Cell proliferation inhibition experiment

2.1 OVCAR3细胞增殖抑制活性测定2.1 Determination of OVCAR3 cell proliferation inhibitory activity

取处于生长状态良好的OVCAR3细胞，收集至离心管，调整细胞密度至4×104个/mL，接种于96孔板上(100μL/孔)，细胞培养箱中培养过夜，使用纳升加样仪进行化合物加样，使化合物终浓度为2000nM-0.91nM，2个复孔，同时设置对照。细胞培养箱中继续培养7天后，加入检测试剂CCK-8(北京同仁化学，10μL/孔)，细胞培养箱中孵育2小时后，Envision酶标仪450nm处检测其吸光值，四参数分析，拟合量效曲线，计算IC50。OVCAR3 cells in good growth state were collected into centrifuge tubes, the cell density was adjusted to 4×10 4 cells/mL, and inoculated on 96-well plates (100 μL/well), cultured overnight in a cell culture incubator, and the compound was added using a nanoliter pipette to make the final concentration of the compound 2000nM-0.91nM, 2 replicates, and a control was set at the same time. After continuing to culture in the cell culture incubator for 7 days, the detection reagent CCK-8 (Beijing Tongren Chemical, 10 μL/well) was added, and after incubation in the cell culture incubator for 2 hours, the absorbance value was detected at 450nm by Envision microplate reader, and the four-parameter analysis was performed to fit the dose-effect curve and calculate IC 50 .

部分实验结果参见表2A。Some experimental results are shown in Table 2A.

表2A
Table 2A

注：A表示IC50≤150nM；B表示150nM＜IC50≤500nM；C表示500nM＜IC50≤1000nM。Note: A means IC 50 ≤150nM; B means 150nM＜IC 50 ≤500nM; C means 500nM＜IC 50 ≤1000nM.

2.2 MDA-MB-468细胞增殖抑制活性测定2.2 Determination of MDA-MB-468 cell proliferation inhibitory activity

取处于生长状态良好的MDA-MB-468细胞，收集至离心管，调整细胞密度至2×104个/mL，接种于96孔板上(100μL/孔)，细胞培养箱中培养过夜，使用纳升加样仪进行化合物加样，使化合物终浓度为2000nM-0.91nM，2个复孔，同时设置对照。细胞培养箱中继续培养7天后，加入检测试剂CCK-8(北京同仁化学，10μL/孔)，细胞培养箱中孵育2小时后，Envision酶标仪450nm处检测其吸光值，四参数分析，拟合量效曲线，计算IC50。MDA-MB-468 cells in good growth state were collected into centrifuge tubes, the cell density was adjusted to 2×10 4 cells/mL, and inoculated on 96-well plates (100 μL/well), cultured overnight in a cell culture incubator, and the compound was added using a nanoliter pipette to make the final concentration of the compound 2000nM-0.91nM, 2 replicates, and a control was set at the same time. After continuing to culture in the cell culture incubator for 7 days, the detection reagent CCK-8 (Beijing Tongren Chemical, 10 μL/well) was added, and after incubation in the cell culture incubator for 2 hours, the absorbance value was detected at 450nm by Envision microplate reader, and the four-parameter analysis was performed to fit the dose-effect curve and calculate IC 50 .

实验结果参见表2B。 The experimental results are shown in Table 2B.

表2B
Table 2B

注：A表示IC50≤150nM；B表示150nM＜IC50≤500nM；C表示500nM＜IC50≤1000nM。Note: A means IC 50 ≤150nM; B means 150nM＜IC 50 ≤500nM; C means 500nM＜IC 50 ≤1000nM.

试验例3肝微粒体稳定性实验Test Example 3 Liver microsome stability test

肝微粒体温孵样本制备为混合PBS缓冲液(pH7.4)，肝微粒体溶液(0.5mg/ml)，受试化合物及NADPH+MgCl2溶液于37℃及300rpm孵育1小时。0小时样本制备为混合PBS缓冲液(pH7.4)，肝微粒体溶液(0.5mg/ml)，受试化合物。样本加入含内标的乙腈溶液经蛋白沉淀制备上清液，稀释后用于LC/MS/MS测定。The liver microsome incubation sample was prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.5 mg/ml), test compound and NADPH+ MgCl2 solution at 37°C and 300 rpm for 1 hour. The 0 hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.5 mg/ml), test compound. The sample was added with acetonitrile solution containing internal standard to prepare supernatant by protein precipitation, and diluted for LC/MS/MS determination.

部分实验结果参见表3和表4。Some experimental results are shown in Tables 3 and 4.

表3人肝微粒体稳定性
Table 3 Stability of human liver microsomes

表4小鼠肝微粒体稳定性
Table 4 Mouse liver microsome stability

试验例4小鼠药代动力学Experimental Example 4 Pharmacokinetics in mice

ICR小鼠，体重18～22g，适应3～5天后，随机分组，每组9只，按1mg/kg体重的剂量静脉注射受试化合物溶液，按10mg/kg体重的剂量灌胃受试化合物溶液。ICR mice weighing 18-22 g were randomly divided into groups of 9 after acclimation for 3-5 days. The test compound solution was injected intravenously at a dose of 1 mg/kg body weight and was gavaged orally at a dose of 10 mg/kg body weight.

静脉注射采血时间点0.083h、0.25h、0.5h、1h、2h、4h、6h、8h、10h、24h，灌胃采血时间点0.25h、0.5h、1h、2h、4h、6h、8h、10h、24h，于眼眶取血制备待测血浆样品。The time points for intravenous blood collection were 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, and 24h. The time points for intragastric blood collection were 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, and 24h. Blood was collected from the eye sockets to prepare the plasma samples to be tested.

吸取30μL待测血浆样品和标曲样品，加入含内标的乙腈溶液经蛋白沉淀得到上清液，稀释后用于LC/MS/MS测定。30 μL of the plasma sample to be tested and the standard curve sample were taken, and acetonitrile solution containing the internal standard was added to obtain the supernatant after protein precipitation, which was diluted for LC/MS/MS determination.

采用非房室模型拟合药代参数。The non-compartmental model was used to fit the pharmacokinetic parameters.

结论：本申请的化合物具有良好的药代动力学性质。例如，本申请的部分实施例化合物在小鼠体内表现出较高的暴露量、较长的半衰期及较高的生物利用度。Conclusion: The compounds of the present application have good pharmacokinetic properties. For example, some of the compounds of the present application showed higher exposure, longer half-life and higher bioavailability in mice.

试验例5体内药效评价Test Example 5 In vivo efficacy evaluation

5.1 OVCAR-3人卵巢癌B-NDG小鼠移植瘤模型中的药效学评价5.1 Pharmacodynamic evaluation in the OVCAR-3 human ovarian cancer B-NDG mouse transplant tumor model

在SPF级雌性B-NDG小鼠(来源：百奥赛图)右侧腋窝皮下接种OVCAR-3细胞(来源：浙江美森)，1×107个/只(PBS:基质胶＝1:1)，为F1代。使用F1代小鼠肿瘤组织，采用插块法接种于SPF级雌性裸小鼠(来源：上海灵畅生物科技有限公司)右侧腋窝皮下。待肿瘤平均体积达100-200mm3时，将动物分为对照组和给药组，每组6只。OVCAR-3 cells (source: Zhejiang Meisen) were inoculated subcutaneously in the right axilla of SPF female B-NDG mice (source: Biocytogen), 1×10 7 cells/mouse (PBS: Matrigel = 1:1), which is the F1 generation. F1 generation mouse tumor tissue was used and inoculated subcutaneously in the right axilla of SPF female nude mice (source: Shanghai Lingchang Biotechnology Co., Ltd.) using the plug method. When the average tumor volume reached 100-200 mm 3 , the animals were divided into a control group and a treatment group, with 6 mice in each group.

分组当天为第0天，第0天给药，每天灌胃给药一次。每周测2-3次瘤体积，同时称小鼠体重，记录数据；每日观察与记录小鼠一般表现。实验结束后剥取肿瘤并称重、拍照。The day of grouping was day 0, and drugs were administered by gavage once a day. The tumor volume was measured 2-3 times a week, and the mice were weighed and the data were recorded; the general performance of the mice was observed and recorded daily. After the experiment, the tumor was removed, weighed, and photographed.

检测指标及计算公式如下：The detection indicators and calculation formula are as follows:

肿瘤体积，TV(mm3)＝1/2×(a×b2)；其中，a为肿瘤长径，b为肿瘤短径。 Tumor volume, TV (mm 3 ) = 1/2 × (a × b 2 ); where a is the long diameter of the tumor, and b is the short diameter of the tumor.

相对肿瘤体积，RTV＝TVt/TV0；其中，TV0为第0天肿瘤体积，TVt为每一次测量时的肿瘤体积。Relative tumor volume, RTV=TV t /TV 0 ; wherein TV 0 is the tumor volume on day 0, and TV t is the tumor volume at each measurement.

相对肿瘤增殖率，T/C(％)＝TRTV/CRTV×100％；其中，TRTV为治疗组RTV；CRTV为溶媒对照组RTV。Relative tumor proliferation rate, T/C (%) = TRTV / CRTV × 100%; TRTV is the RTV of the treatment group; CRTV is the RTV of the vehicle control group.

肿瘤生长抑制率，TGI(％)＝(1-TW/TW0)×100％；其中，TW为治疗组瘤重，TW0为溶媒对照组瘤重。Tumor growth inhibition rate, TGI (%) = (1-TW/TW 0 ) × 100%; wherein, TW is the tumor weight of the treatment group, and TW 0 is the tumor weight of the vehicle control group.

体重变化率，WCR(％)＝(Wtt-Wt0)/Wt0×100％；其中，Wt0为第0天小鼠体重，Wtt为每一次测量时的小鼠体重。Body weight change rate, WCR (%) = (Wt t - Wt 0 )/Wt 0 × 100%; wherein Wt 0 is the body weight of mice on day 0, and Wt t is the body weight of mice at each measurement.

5.2 JIMT-1人乳腺癌裸小鼠移植瘤模型中的药效学评价5.2 Pharmacodynamic evaluation in the JIMT-1 human breast cancer xenograft model in nude mice

在SPF级雌性裸小鼠(来源：杭州医学院)右侧腋窝皮下接种JIMT-1细胞(来源：AddexBio)，2×106个/只。待肿瘤平均体积达100-200mm3时，将动物分为对照组和给药组，每组5只。JIMT-1 cells (source: AddexBio) were subcutaneously inoculated in the right axilla of SPF female nude mice (source: Hangzhou Medical College), 2×10 6 cells/mouse. When the average tumor volume reached 100-200 mm 3 , the animals were divided into a control group and a treatment group, with 5 mice in each group.

分组当天为第0天，第0天给药，每天灌胃给药一次，给药组按如下方案给药待测试化合物：d0-d1820mpk、d19-d24 30mpk、d25-d28 40mpk。每周测2-3次瘤体积，同时称小鼠体重，记录数据；每日观察与记录小鼠一般表现。实验结束后剥取肿瘤并称重、拍照。The day of grouping was day 0, and the drug was administered on day 0. The drug was administered by gavage once a day. The drug-dosing group was administered with the test compound according to the following scheme: 20 mpk on d0-d18, 30 mpk on d19-d24, and 40 mpk on d25-d28. The tumor volume was measured 2-3 times a week, and the mice were weighed and the data were recorded; the general performance of the mice was observed and recorded daily. After the experiment, the tumor was removed, weighed, and photographed.

检测指标及计算公式如下：The detection indicators and calculation formula are as follows:

肿瘤体积，TV(mm3)＝1/2×(a×b2)；其中，a为肿瘤长径，b为肿瘤短径。Tumor volume, TV (mm 3 ) = 1/2 × (a × b 2 ); where a is the long diameter of the tumor, and b is the short diameter of the tumor.

相对肿瘤体积，RTV＝TVt/TV0；其中，TV0为第0天肿瘤体积，TVt为每一次测量时的肿瘤体积。Relative tumor volume, RTV=TV t /TV 0 ; wherein TV 0 is the tumor volume on day 0, and TV t is the tumor volume at each measurement.

相对肿瘤增殖率，T/C(％)＝TRTV/CRTV×100％；其中，TRTV为治疗组RTV；CRTV为溶媒对照组RTV。Relative tumor proliferation rate, T/C (%) = TRTV / CRTV × 100%; TRTV is the RTV of the treatment group; CRTV is the RTV of the vehicle control group.

肿瘤生长抑制率，TGI(％)＝(1-TW/TW0)×100％；其中，TW为治疗组瘤重，TW0为溶媒对照组瘤重。Tumor growth inhibition rate, TGI (%) = (1-TW/TW 0 ) × 100%; wherein, TW is the tumor weight of the treatment group, and TW 0 is the tumor weight of the vehicle control group.

体重变化率，WCR(％)＝(Wtt-Wt0)/Wt0×100％；其中，Wt0为第0天小鼠体重，Wtt为每一次测量时的小鼠体重。Body weight change rate, WCR (%) = (Wt t - Wt 0 )/Wt 0 × 100%; wherein Wt 0 is the body weight of mice on day 0, and Wt t is the body weight of mice at each measurement.

结论：本申请的化合物可有效抑制肿瘤生长。例如，每天给药20-40mg/kg体重时，本申请的部分实施例化合物的肿瘤生长抑制率不小于50％，优选地，不小于70％。 Conclusion: The compounds of the present application can effectively inhibit tumor growth. For example, when 20-40 mg/kg body weight is administered daily, the tumor growth inhibition rate of some of the compounds of the present application is not less than 50%, preferably, not less than 70%.

Claims (15)

式(I)化合物或其药学上可接受的盐，
A compound of formula (I) or a pharmaceutically acceptable salt thereof,
其中，in, X1和Y1相互连接形成结构单元且Y2选自N或CRY2； X1 and Y1 are connected to each other to form a structural unit and Y2 is selected from N or CR Y2 ; 或者，X1和Y2相互连接形成结构单元且Y1选自N或CRY1；Alternatively, X1 and Y2 are linked to each other to form a structural unit and Y1 is selected from N or CR Y1 ; X1选自N或CRX1； X1 is selected from N or CR X1 ; X2选自N或CRX2； X2 is selected from N or CR X2 ; X1与X2通过单键连接； X1 and X2 are connected by a single bond; Z1、Z2或Z3各自独立地选自N或CRZ1；Z 1 , Z 2 or Z 3 are each independently selected from N or CR Z1 ; Z4或Z5各自独立地选自N或CRZ2； Z4 or Z5 are each independently selected from N or CR Z2 ; 环A选自任选被一个或多个Ra取代的如下基团：4-12元环烯基、4-12元杂环烯基、6-10元芳基、或5-10元杂芳基；Ring A is selected from the following groups optionally substituted by one or more Ra : 4-12 membered cycloalkenyl, 4-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-10 membered heteroaryl; 每个RX1、RX2、RY1、RY2、RZ1或RZ2各自独立地选自H、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1- 12烷基、-OC(O)C1-12烷基、-C(O)OC1-12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1-12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each of RX1 , RX2 , RY1 , RY2 , RZ1 or RZ2 is independently selected from H, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, diC1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy, halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated diC1-12 alkylamino, -COC1-12 alkyl, -OC (O) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC (O) OC1-12 alkyl, -SO2C1-12 alkyl , -NHSO2C1-12 C 1-12 alkyl, -N(C 1-12 alkyl)SO 2 C 1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; 环B选自任选地被一个或多个Rb取代的如下基团：3-12元环烷基、3-12元环烯基、3-12元杂环基、6-10元芳基、或5-10元杂芳基；Ring B is selected from the following groups optionally substituted by one or more R b : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; 每个Ra或Rb各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1-12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1- 12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each Ra or Rb is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, diC1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy, halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated diC1-12 alkylamino, -COC1-12 alkyl, -OC(O) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC (O) OC1-12 alkyl , -SO2C1-12 alkyl, -NHSO2C1-12 alkyl , -N(C1-12 alkyl ) SO2C -1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; 环C选自任选地被一个或多个Rc1取代的如下基团：3-12元环烷基或3-12元杂环烷基；Ring C is selected from the following groups optionally substituted by one or more R c1 : 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl; 每个Rc1各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1- 12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1-12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1- 12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3- 12元杂环基；Each R c1 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N (C 1-12 alkyl)SO 2 C -1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N ( C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3- 12-membered heterocyclic group; 或者，位于同一个环原子上的两个Rc1和与Rc1相连的环原子一起形成任选被一个或多个Rc2取代的如下基团：3-12元环烷基、3-12元环烯基或3-12元杂环基；Alternatively, two R c1 located on the same ring atom and the ring atom to which R c1 is attached together form the following group optionally substituted by one or more R c2 : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl; 或者，位于相邻两个环原子上的两个Rc1和与Rc1相连的环原子一起形成任选被一个或多个Rc2取代的如下基团：3-12元环烷基、3-12元环烯基或3-12元杂环基；Alternatively, two R c1 located on two adjacent ring atoms and the ring atom to which R c1 is attached together form the following group optionally substituted by one or more R c2 : a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group or a 3-12 membered heterocyclyl group; 每个Rc2各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1- 12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1-12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1- 12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each R c2 is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N (C 1-12 alkyl)SO 2 C -1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; L1选自单键、-O-、-S-、-NRL1-、C1-6亚烷基、氘代C1-6亚烷基、卤代C1-6亚烷基、-C(O)-、-C(O)O-、-OC(O)-、-OC(O)O-、-OC(O)NRL1-、-C(O)NRL1-、-NRL1C(O)-、-NRL1C(O)O-、-NRL1C(O)NRL1-、-S(O)-、-S(O)2-、-S(O)2NRL1-、-NRL1S(O)2-、-NRL1S(O)2NRL1-、-S(O)(＝NH)-、-NRL1S(O)(＝NH)-、或-C＝N(OH)-； L1 is selected from a single bond, -O-, -S-, -NR L1 -, C 1-6 alkylene, deuterated C 1-6 alkylene, halogenated C 1-6 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)NR L1 -, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 C(O)O-, -NR L1 C(O)NR L1 -, -S(O)-, -S(O) 2 -, -S(O) 2 NR L1 -, -NR L1 S(O ) 2 -, -NR L1 S(O) 2 NR L1 -, -S(O)(＝NH)-, -NR L1 S(O)(＝NH)-, or -C＝N(OH)-; 每个RL1各自独立地选自H、氘、或者任选被一个或多个RL1a取代的如下基团：C1-6烷基、氘代C1- 6烷基、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-10元芳基、或5-10元杂芳基；Each RL1 is independently selected from H, deuterium, or the following groups optionally substituted with one or more RL1a : C1-6 alkyl, deuterated C1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; 每个RL1a各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1- 12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1-12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1-12烷基)2、-NHCOC1- 12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each RL1a is independently selected from oxo, deuterium, halogen, -OH, -NH2 , -CN, -SH, -COOH, C1-12 alkyl, deuterated C1-12 alkyl, C1-12 alkoxy, C1-12 alkylthio, C1-12 alkylamino, di- C1-12 alkylamino, halogenated C1-12 alkyl, halogenated C1-12 alkoxy , halogenated C1-12 alkylthio, halogenated C1-12 alkylamino, halogenated di- C1-12 alkylamino, -COC1-12 alkyl, -OC ( O ) C1-12 alkyl, -C (O) OC1-12 alkyl, -OC(O) OC1-12 alkyl, -SO2C1-12 alkyl, -NHSO2C1-12 alkyl, -N(C1-12 alkyl ) SO2C1-12 -1-12 alkyl, -SO 2 NH 2 , -SO 2 NHC 1-12 alkyl, -SO 2 N(C 1-12 alkyl) 2 , -CONH 2 , -CONHC 1-12 alkyl, -CON(C 1-12 alkyl) 2 , -NHCOC 1-12 alkyl, -N(C 1-12 alkyl)COC 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl; R1选自H、卤素、氘、-OH、-NH2、-SH、-COOH、-CN、或者任选被一个或多个R1a取代的如下基团：C1-12烷基、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-10元芳基、5-10元杂芳基、3-12元环烷基C1-6亚烷基、3-12元环烯基C1-6亚烷基、3-12元杂环基C1-6亚烷基、6-10元芳基C1-6亚烷基、或5-10元杂芳基C1-6亚烷基；R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN , or C 1-12 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkylC 1-6 alkylene, 3-12 membered cycloalkenylC 1-6 alkylene, 3-12 membered heterocyclylC 1-6 alkylene, 6-10 membered arylC 1-6 alkylene, or 5-10 membered heteroarylC 1-6 alkylene, optionally substituted with one or more R 1a; 每个R1a各自独立地选自氧代、氘、卤素、-OH、-NH2、-CN、-SH、-COOH、C1-12烷基、氘代C1- 12烷基、羟基C1-12烷基、C1-12烷氧基、C1-12烷硫基、C1-12烷基氨基、二C1-12烷基氨基、卤代C1-12烷基、卤代C1-12烷氧基、卤代C1-12烷硫基、卤代C1-12烷基氨基、卤代二C1-12烷基氨基、-COC1-12烷基、-OC(O)C1-12烷基、-C(O)OC1-12烷基、-OC(O)OC1-12烷基、-SO2C1-12烷基、-NHSO2C1-12烷基、-N(C1-12烷基)SO2C1-12烷基、-SO2NH2、-SO2NHC1-12烷基、-SO2N(C1-12烷基)2、-CONH2、-CONHC1-12烷基、-CON(C1- 12烷基)2、-NHCOC1-12烷基、-N(C1-12烷基)COC1-12烷基、3-12元环烷基、3-12元环烯基、6-10元芳基、5-10元杂芳基或3-12元杂环基；Each R 1a is independently selected from oxo, deuterium, halogen, -OH, -NH 2 , -CN, -SH, -COOH, C 1-12 alkyl, deuterated C 1-12 alkyl, hydroxy C 1-12 alkyl, C 1-12 alkoxy, C 1-12 alkylthio, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkyl, halogenated C 1-12 alkoxy, halogenated C 1-12 alkylthio, halogenated C 1-12 alkylamino, halogenated di-C 1-12 alkylamino, -COC 1-12 alkyl, -OC(O)C 1-12 alkyl, -C(O)OC 1-12 alkyl, -OC(O)OC 1-12 alkyl, -SO 2 C 1-12 alkyl, -NHSO 2 C 1-12 alkyl, -N (C -12 alkyl ) SO2C1-12 alkyl, -SO2NH2 , -SO2NHC1-12 alkyl, -SO2N(C1-12 alkyl)2, -CONH2, -CONHC1-12 alkyl, -CON(C1-12 alkyl)2 , -NHCOC1-12 alkyl , -N ( C1-12 alkyl ) COC1-12 alkyl , 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 6-10 membered aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclyl ; L2选自-O-、-S-、-NRL2-、C1-6亚烷基、氘代C1-6亚烷基、卤代C1-6亚烷基、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NRL2-、-NRL2C(O)-、-S(O)-、-S(O)2-、-S(O)2NRL2-、-NRL2S(O)2-、-S(O)(＝NH)-、-NRL2S(O)(＝NH)-、或-C＝N(OH)-； L2 is selected from -O-, -S-, -NR L2 -, C 1-6 alkylene, deuterated C 1-6 alkylene, halogenated C 1-6 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L2 -, -NR L2 C(O)-, -S(O)-, -S(O) 2 -, -S(O) 2 NR L2 -, -NR L2 S(O) 2 -, -S(O)(＝NH)-, -NR L2 S(O)(＝NH)-, or -C＝N(OH)-; RL2选自H、氘、C1-6烷基、氘代C1-6烷基、或卤代C1-6烷基； RL2 is selected from H, deuterium, C1-6 alkyl, deuterated C1-6 alkyl, or halogenated C1-6 alkyl; 所述RX1、RX2、RY1、RY2、RZ1、RZ2、Ra、Rb、Rc1、Rc2、RL1、RL1a、R1、R1a、或RL2任选地被一个或多个取代基取代。The RX1 , RX2 , RY1 , RY2, RZ1 , RZ2 , Ra , Rb , Rc1 , Rc2 , RL1 , RL1a , R1 , R1a , or RL2 is optionally substituted with one or more substituents. 根据权利要求1所述的式(I)化合物或其药学上可接受的盐，其中，X1选自N；The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X 1 is selected from N; 或者，X1选自CRX1；Alternatively, X1 is selected from CR X1 ; 或者，X1选自CH；Alternatively, X 1 is selected from CH; 或者，X2选自N；Alternatively, X2 is selected from N; 或者，X2选自CRX2；Alternatively, X2 is selected from CR X2 ; 或者，X2选自CH。Alternatively, X2 is selected from CH. 根据权利要求1或2所述的式(I)化合物或其药学上可接受的盐，其中，X1和Y1相互连接形成结 构单元且Y2选自CRY2；或者，X1和Y2相互连接形成结构单元且Y1选自CRY1；The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X1 and Y1 are connected to each other to form a Structural unit and Y2 is selected from CR Y2 ; or, X1 and Y2 are connected to each other to form a structural unit and Y1 is selected from CR Y1 ; 或者，X1和Y1相互连接形成结构单元且Y2选自CRY2；或者，X1和Y2相互连接形成结构单元且Y1选自N；Alternatively, X1 and Y1 are linked to each other to form a structural unit and Y2 is selected from CR Y2 ; or, X1 and Y2 are connected to each other to form a structural unit and Y 1 is selected from N; 或者，X1和Y1相互连接形成结构单元且Y2选自N；或者，X1和Y2相互连接形成结构单元且Y1选自CRY1；Alternatively, X1 and Y1 are linked to each other to form a structural unit and Y 2 is selected from N; or, X 1 and Y 2 are connected to each other to form a structural unit and Y1 is selected from CR Y1 ; 或者，X1和Y1相互连接形成结构单元且Y2选自N；或者，X1和Y2相互连接形成结构单元且Y1选自N；Alternatively, X1 and Y1 are linked to each other to form a structural unit and Y 2 is selected from N; or, X 1 and Y 2 are connected to each other to form a structural unit and Y 1 is selected from N; 或者，X1和Y1相互连接形成结构单元且Y2选自N或CRY2；Alternatively, X1 and Y1 are linked to each other to form a structural unit and Y2 is selected from N or CR Y2 ; 或者，X1和Y2相互连接形成结构单元且Y1选自N或CRY1。Alternatively, X1 and Y2 are linked to each other to form a structural unit And Y1 is selected from N or CR Y1 . 根据权利要求1-3任意一项所述的式(I)化合物或其药学上可接受的盐，其中，Z1、Z2和Z3为CRZ1；The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein Z 1 , Z 2 and Z 3 are CR Z1 ; 或者，Z1和Z2为N，Z3为CRZ1；Alternatively, Z1 and Z2 are N, and Z3 is CR Z1 ; 或者，Z1和Z3为N，Z2为CRZ1；Alternatively, Z1 and Z3 are N, and Z2 is CR Z1 ; 或者，Z2和Z3为N，Z1为CRZ1；Alternatively, Z2 and Z3 are N, and Z1 is CR Z1 ; 或者，Z1为N，Z2和Z3为CRZ1；Alternatively, Z1 is N, Z2 and Z3 are CR Z1 ; 或者，Z2为N，Z1和Z3为CRZ1；Alternatively, Z2 is N, Z1 and Z3 are CR Z1 ; 或者，Z3为N，Z1和Z2为CRZ1；Alternatively, Z3 is N, Z1 and Z2 are CR Z1 ; 或者，Z4和Z5为CRZ2；Alternatively, Z 4 and Z 5 are CR Z2 ; 或者，Z4为CH，Z5为CRZ2；Alternatively, Z 4 is CH, Z 5 is CR Z2 ; 或者，Z4和Z5为N；Alternatively, Z 4 and Z 5 are N; 或者，Z4为N，Z5为CRZ2； Alternatively, Z4 is N, Z5 is CR Z2 ; 或者，Z5为N，Z4为CRZ2。Alternatively, Z5 is N and Z4 is CR Z2 . 根据权利要求1-4任意一项所述的式(I)化合物或其药学上可接受的盐，其中，环A选自任选被一个或多个Ra取代的如下基团：4-12元环烯基或4-12元杂环烯基；The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein ring A is selected from the following groups optionally substituted by one or more Ra : 4-12 membered cycloalkenyl or 4-12 membered heterocycloalkenyl; 或者，环A选自任选被一个或多个Ra取代的如下基团：4-10元环烯基或4-10元杂环烯基；Alternatively, Ring A is selected from the following groups optionally substituted by one or more Ra : 4-10 membered cycloalkenyl or 4-10 membered heterocycloalkenyl; 或者，环A选自任选被一个或多个Ra取代的如下基团：4-8元环烯基或4-8元杂环烯基；Alternatively, Ring A is selected from the following groups optionally substituted by one or more Ra : 4-8 membered cycloalkenyl or 4-8 membered heterocycloalkenyl; 或者，环A选自任选被一个或多个Ra取代的如下基团：5-7元环烯基或5-7元杂环烯基；Alternatively, Ring A is selected from the following groups optionally substituted by one or more Ra : 5-7 membered cycloalkenyl or 5-7 membered heterocycloalkenyl; 或者，环A选自任选被一个或多个Ra取代的4-12元杂环烯基；Alternatively, Ring A is selected from 4-12 membered heterocycloalkenyl groups optionally substituted with one or more Ra ; 或者，环A选自任选被一个或多个Ra取代的6-7元杂环烯基，所述6元杂环烯基包含2个N原子，所述7元杂环烯基包含1个或2个选自N或O的杂原子；Alternatively, Ring A is selected from 6-7 membered heterocycloalkenyl optionally substituted by one or more Ra , wherein the 6 membered heterocycloalkenyl contains 2 N atoms, and the 7 membered heterocycloalkenyl contains 1 or 2 heteroatoms selected from N or O; 或者，环A选自任选被一个或多个Ra取代的如下基团： Alternatively, Ring A is selected from the following groups optionally substituted by one or more Ra : 或者，环A选自任选被一个或多个Ra取代的如下基团： Alternatively, Ring A is selected from the following groups optionally substituted by one or more Ra : 或者，环A选自如下基团： Alternatively, ring A is selected from the following groups: 根据权利要求1-5任意一项所述的式(I)化合物或其药学上可接受的盐，其中，环B选自任选地被一个或多个Rb取代的如下基团：3-12元环烷基、3-12元环烯基或3-12元杂环基；The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein ring B is selected from the following groups optionally substituted by one or more R b : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocyclyl; 或者，环B选自任选地被一个或多个Rb取代的如下基团：3-12元环烷基、3-12元环烯基或3-12元杂环烷基；Alternatively, Ring B is selected from the following groups optionally substituted by one or more R b : 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl or 3-12 membered heterocycloalkyl; 或者，环B选自任选地被一个或多个Rb取代的如下基团：3-12元环烷基或3-12元杂环烷基；Alternatively, Ring B is selected from the following groups optionally substituted by one or more R b : 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl; 或者，环B选自任选地被一个或多个Rb取代的如下基团：3-10元环烷基或3-10元杂环烷基；Alternatively, Ring B is selected from the following groups optionally substituted by one or more R b : 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl; 或者，环B选自任选地被一个或多个Rb取代的如下基团：5-9元环烷基或5-9元杂环烷基；Alternatively, Ring B is selected from the following groups optionally substituted by one or more R b : 5-9 membered cycloalkyl or 5-9 membered heterocycloalkyl; 或者，环B选自任选地被一个或多个Rb取代的如下基团：6-8元环烷基或6-8元杂环烷基；Alternatively, Ring B is selected from the following groups optionally substituted by one or more R b : 6-8 membered cycloalkyl or 6-8 membered heterocycloalkyl; 或者，环B选自任选地被一个或多个Rb取代的如下基团：4-7元环烷基或4-7元杂环烷基；Alternatively, Ring B is selected from the following groups optionally substituted by one or more R b : 4-7 membered cycloalkyl or 4-7 membered heterocycloalkyl; 或者，环B选自任选地被一个或多个Rb取代的3-12元杂环烷基；Alternatively, Ring B is selected from 3-12 membered heterocycloalkyl optionally substituted with one or more R b ; 或者，环B选自任选地被一个或多个Rb取代的如下基团：环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、噻唑烷基、异噻唑烷基、噁唑烷基、异噁唑烷基、哌啶基、哌嗪基、吗啉基、 Alternatively, Ring B is selected from the following groups optionally substituted by one or more R b : cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, 或者，环B选自任选地被一个或多个Rb取代的如下基团： Alternatively, Ring B is selected from the following groups optionally substituted with one or more R b : 或者，环B选自 Alternatively, ring B is selected from 或者，所述结构单元选自任选地被一个或多个Rb取代的如下基团： 其中的另一端连接Y1或Y2；Alternatively, the structural unit is selected from the following groups optionally substituted by one or more R b : in The other end is connected to Y1 or Y2 ; 或者，所述结构单元选自 Alternatively, the structural unit Selected from 其中的另一端连接Y1或Y2。in The other end is connected to Y1 or Y2 . 根据权利要求1-6任意一项所述的式(I)化合物或其药学上可接受的盐，其中，环C选自任选地被一个或多个Rc1取代的如下基团：3-10元环烷基或3-10元杂环烷基；The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring C is selected from the following groups optionally substituted by one or more R c1 : 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl; 或者，环C选自任选地被一个或多个Rc1取代的如下基团：5-9元环烷基或5-9元杂环烷基；Alternatively, Ring C is selected from the following groups optionally substituted by one or more R c1 : 5-9 membered cycloalkyl or 5-9 membered heterocycloalkyl; 或者，环C选自任选地被一个或多个Rc1取代的如下基团：4-8元环烷基或4-8元杂环烷基；Alternatively, Ring C is selected from the following groups optionally substituted by one or more R c1 : 4-8 membered cycloalkyl or 4-8 membered heterocycloalkyl; 或者，环C选自任选地被一个或多个Rc1取代的如下基团：6-8元环烷基或6-8元杂环烷基； Alternatively, Ring C is selected from the following groups optionally substituted by one or more R c1 : 6-8 membered cycloalkyl or 6-8 membered heterocycloalkyl; 或者，环C选自任选地被一个或多个Rc1取代的3-12元杂环烷基；Alternatively, Ring C is selected from 3-12 membered heterocycloalkyl optionally substituted with one or more R c1 ; 或者，环C选自任选地被一个或多个Rc1取代的如下基团： Alternatively, Ring C is selected from the following groups optionally substituted by one or more R c1 : 或者，环C选自任选地被一个或多个Rc1取代的如下基团： Alternatively, Ring C is selected from the following groups optionally substituted by one or more R c1 : 或者，环C选自 Alternatively, ring C is selected from 或者，环C选自 Alternatively, ring C is selected from 根据权利要求1-7任意一项所述的式(I)化合物或其药学上可接受的盐，其中，L1选自单键、-O-、-S-、-NRL1-、C1-4亚烷基、氘代C1-4亚烷基、卤代C1-4亚烷基、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NRL1-、-NRL1C(O)-、-NRL1C(O)NRL1-、-S(O)-、-S(O)2-、-S(O)2NRL1-、-NRL1S(O)2-、-NRL1S(O)2NRL1-、-S(O)(＝NH)-、-NRL1S(O)(＝NH)-、-C＝N(OH)-、-OC(O)O-、-OC(O)NRL1-、或-NRL1C(O)O-；The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein L1 is selected from a single bond, -O-, -S-, -NR L1 -, C 1-4 alkylene, deuterated C 1-4 alkylene, halogenated C 1-4 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 C(O)NR L1 -, -S(O)-, -S(O) 2 -, -S(O) 2 NR L1 -, -NR L1 S(O) 2 -, -NR L1 S(O) 2 NR L1 -, -S(O)(＝NH)-, -NR L1 S(O)(＝NH)-, -C＝N(OH)-, -OC(O)O-, -OC(O)NR L1 -, or -NR L1 C(O)O-; 或者，L1选自单键、-O-、-S-、-NRL1-、亚甲基、氘代亚甲基、亚乙基、氘代亚乙基、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NRL1-、-NRL1C(O)-、-NRL1C(O)NRL1-、-S(O)-、-S(O)2-、-S(O)2NRL1-、-NRL1S(O)2-、-NRL1S(O)2NRL1-、-S(O)(＝NH)-、-NRL1S(O)(＝NH)-、-C＝N(OH)-、-OC(O)O-、-OC(O)NRL1-、或-NRL1C(O)O-；Alternatively, L1 is selected from a single bond, -O-, -S-, -NR L1 -, methylene, deuterated methylene, ethylene, deuterated ethylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -, -NR L1 C(O)-, -NR L1 C(O)NR L1 -, -S(O)-, -S(O) 2 -, -S(O) 2 NR L1 -, -NR L1 S(O) 2 -, -NR L1 S(O) 2 NR L1 -, -S(O)(＝NH)-, -NR L1 S(O)(＝NH)-, -C＝N(OH)-, -OC(O)O-, -OC(O)NR L1 -, or -NR L1 C(O)O-; 或者，L1选自单键、-O-、-S-、-NRL1-、亚甲基、亚乙基、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NRL1-、-NRL1C(O)-、-S(O)-、-S(O)2-、-S(O)2NRL1-、-NRL1S(O)2-、-NRL1S(O)2NRL1-、或-S(O)(＝NH)-；Alternatively, L 1 is selected from a single bond, -O-, -S-, -NR L1 -, methylene, ethylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L1 -, -NR L1 C(O)-, -S(O)-, -S(O) 2 -, -S(O) 2 NR L1 -, -NR L1 S(O) 2 -, -NR L1 S(O) 2 NR L1 -, or -S(O)(=NH)-; 或者，L1选自单键、-O-、-S-、-NRL1-、-C(O)NRL1-、-NRL1C(O)-、-S(O)-、-S(O)2-、-S(O)2NRL1-、-NRL1S(O)2-、-NRL1S(O)2NRL1-、或-S(O)(＝NH)-；Alternatively, L1 is selected from a single bond, -O-, -S-, -NR L1 -, -C(O)NR L1 -, -NR L1 C(O)-, -S(O)-, -S(O) 2 -, -S(O) 2 NR L1 -, -NR L1 S(O) 2 -, -NR L1 S(O) 2 NR L1 -, or -S(O)(=NH)-; 或者，L1选自-S(O)2NRL1-或-NRL1S(O)2-。Alternatively, L1 is selected from -S(O) 2NRL1- or -NRL1S ( O) 2- . 根据权利要求1-8任意一项所述的式(I)化合物或其药学上可接受的盐，其中，R1选自H、卤素、氘、-OH、-NH2、-SH、-COOH、-CN、或者任选被一个或多个R1a取代的如下基团：C1-6烷基、3-10元环烷基、3-10元环烯基、3-10元杂环基、6-10元芳基、或5-10元杂芳基；The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted by one or more R 1a : C 1-6 alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; 或者，R1选自H、卤素、氘、-OH、-NH2、-SH、-COOH、-CN、或者任选被一个或多个R1a取代的如下基团：C1-6烷基、3-10元环烷基、3-10元环烯基、3-10元杂环基、6-10元芳基、5-10元杂芳基、3-10元环烷基C1-4亚烷基、3-10元环烯基C1-4亚烷基、3-10元杂环基C1-4亚烷基、6-10元芳基C1-4亚烷基、或5-10元杂芳基C1-4亚烷基；Alternatively, R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN , or a C 1-6 alkyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkylC 1-4 alkylene, 3-10 membered cycloalkenylC 1-4 alkylene, 3-10 membered heterocyclylC 1-4 alkylene, 6-10 membered arylC 1-4 alkylene, or 5-10 membered heteroarylC 1-4 alkylene, optionally substituted with one or more R 1a; 或者，R1选自H、卤素、氘、-OH、-NH2、-SH、-COOH、-CN、或者任选被一个或多个R1a取代的如下基团：C1-4烷基、3-8元环烷基、3-8元环烯基、3-8元杂环基、苯基、5-6元杂芳基、3-8元环烷基C1-4亚烷基、3-8元环烯基C1-4亚烷基、3-8元杂环基C1-4亚烷基、苯基C1-4亚烷基、或5-6元杂芳基C1- 4亚烷基；Alternatively, R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted with one or more R 1a : C 1-4 alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 3-8 membered cycloalkylC 1-4 alkylene, 3-8 membered cycloalkenylC 1-4 alkylene, 3-8 membered heterocyclylC 1-4 alkylene, phenylC 1-4 alkylene, or 5-6 membered heteroarylC 1-4 alkylene ; 或者，R1选自H、卤素、氘、-OH、-NH2、-SH、-COOH、-CN、或者任选被一个或多个R1a取代的如下基团：C1-4烷基、3-6元环烷基、4-7元环烯基、4-7元杂环基、苯基、5-6元杂芳基、3-6元环烷基C1-3亚烷基、4-7元环烯基C1-3亚烷基、4-7元杂环基C1-3亚烷基、苯基C1-3亚烷基、或5-6元杂芳基C1- 3亚烷基；Alternatively, R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted with one or more R 1a : C 1-4 alkyl, 3-6 membered cycloalkyl, 4-7 membered cycloalkenyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 3-6 membered cycloalkylC 1-3 alkylene, 4-7 membered cycloalkenylC 1-3 alkylene, 4-7 membered heterocyclylC 1-3 alkylene, phenylC 1-3 alkylene, or 5-6 membered heteroarylC 1-3 alkylene ; 或者，R1选自H、卤素、氘、-OH、-NH2、-SH、-COOH、-CN、或者任选被一个或多个R1a取代的如下基团：C1-4烷基、3-6元环烷基、4-7元杂环烷基、3-6元环烷基C1-2亚烷基、或4-7元杂环烷基C1- 2亚烷基；Alternatively, R 1 is selected from H, halogen, deuterium, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted with one or more R 1a : C 1-4 alkyl, 3-6 membered cycloalkyl, 4-7 membered heterocycloalkyl , 3-6 membered cycloalkylC 1-2 alkylene, or 4-7 membered heterocycloalkylC 1-2 alkylene; 或者，R1选自H、氘、-F、-Cl、-Br、-OH、-NH2、-SH、-COOH、-CN、或者任选被一个或多个R1a 取代的如下基团：甲基、乙基、正丙基、异丙基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、噻嗪基、吡咯烷基、四氢呋喃基、四氢吡喃基、噻唑烷基、异噻唑烷基、噻二唑烷基、哌啶基、哌嗪基、吗啉基、环丙基亚甲基、环丁基亚甲基、氮杂环丁基亚甲基、或氧杂环丁基亚甲基；Alternatively, R 1 is selected from H, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -SH, -COOH, -CN, or is optionally replaced by one or more R 1a substituted with: methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, thiazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, piperidinyl, piperazinyl, morpholinyl, cyclopropylmethylene, cyclobutylmethylene, azetidinylmethylene, or oxetanylmethylene; 或者，R1选自H、氘、-F、-Cl、-Br、-OH、-NH2、-SH、-COOH、-CN、或者任选被一个或多个R1a取代的如下基团：甲基、乙基、正丙基、异丙基、异丁基、仲丁基、叔丁基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、噻嗪基、异噻唑烷基、噻二唑烷基、四氢呋喃基、或环丙基亚甲基；Alternatively, R 1 is selected from H, deuterium, -F, -Cl, -Br, -OH, -NH 2 , -SH, -COOH, -CN, or the following groups optionally substituted with one or more R 1a : methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, thiazinyl, isothiazolidinyl, thiadiazolidinyl, tetrahydrofuranyl, or cyclopropylmethylene; 或者，R1选自甲基、单氟甲基、二氟甲基、三氟甲基、乙基、异丙基、叔丁基、环丙基、 Alternatively, R1 is selected from methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, isopropyl, tert-butyl, cyclopropyl, 根据权利要求1-9任意一项所述的式(I)化合物或其药学上可接受的盐，其中，L2选自-O-、-S-、-NRL2-、C1-4亚烷基、氘代C1-4亚烷基、卤代C1-4亚烷基、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NRL2-、-NRL2C(O)-、-S(O)-、-S(O)2-、-S(O)2NRL2-、或-NRL2S(O)2-；The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein L2 is selected from -O-, -S-, -NR L2 -, C 1-4 alkylene, deuterated C 1-4 alkylene, halogenated C 1-4 alkylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L2 -, -NR L2 C(O)-, -S(O)-, -S(O) 2 -, -S(O) 2 NR L2 -, or -NR L2 S(O) 2 -; 或者，L2选自-O-、-S-、-NRL2-、亚甲基、氘代亚甲基、亚乙基、氘代亚乙基、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NRL2-、-NRL2C(O)-、-S(O)-、-S(O)2-、-S(O)2NRL2-、或-NRL2S(O)2-；Alternatively, L2 is selected from -O-, -S-, -NR L2 -, methylene, deuterated methylene, ethylene, deuterated ethylene, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR L2 -, -NR L2 C(O)-, -S(O)-, -S(O) 2 -, -S(O) 2 NR L2 -, or -NR L2 S(O) 2 -; 或者，L2选自亚乙基、-C(O)O-、-OC(O)-、-C(O)NRL2-、-NRL2C(O)-、-S(O)2NRL2-、或-NRL2S(O)2-；Alternatively, L2 is selected from ethylene, -C(O)O-, -OC(O)-, -C(O)NR L2 -, -NR L2 C(O)-, -S(O) 2 NR L2 -, or -NR L2 S(O) 2 -; 或者，L2选自-C(O)NRL2-、或-NRL2C(O)-。Alternatively, L2 is selected from -C(O)NR L2 -, or -NR L2 C(O)-. 根据权利要求1-10任意一项所述的式(I)化合物或其药学上可接受的盐，其选自式(II)或式(II-1)或式(II-2)或式(II-3)或式(III)或式(III-1)或式(III-2)或式(III-3)化合物或其药学上可接受的盐，
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, which is selected from a compound of formula (II) or formula (II-1) or formula (II-2) or formula (II-3) or formula (III) or formula (III-1) or formula (III-2) or formula (III-3) or a pharmaceutically acceptable salt thereof,
其中，X1、X2、Y1、Y2、Z1、Z2、Z3、Z4、Z5、L1、R1、L2、环A、环B和环C部分如权利要求1-10任意一项所定义；wherein X 1 , X 2 , Y 1 , Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , L 1 , R 1 , L 2 , Ring A, Ring B and Ring C are as defined in any one of claims 1 to 10; 或者，结构单元选自 n选自0、1、2、3、4、5、或6；m选自0、1、2、3、4、5、或6；Alternatively, the structural unit Selected from n is selected from 0, 1, 2, 3, 4, 5, or 6; m is selected from 0, 1, 2, 3, 4, 5, or 6; 或者，结构单元选自 Alternatively, the structural unit Selected from 根据权利要求1-11任意一项所述的式(I)化合物或其药学上可接受的盐，其选自：




The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, which is selected from:




根据权利要求1-12任意一项所述的式(I)化合物或其药学上可接受的盐，其选自：









The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, which is selected from:









一种药物组合物，其包含权利要求1-13任意一项所述的式(I)化合物或其药学上可接受的盐；任选地，还包括药学上可接受的辅料。A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13; optionally, further comprising a pharmaceutically acceptable excipient. 权利要求1-13任意一项所述的式(I)化合物或其药学上可接受的盐或者权利要求14所述的药物组合物在制备治疗疾病的药物中的用途。 Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 14 in the preparation of a medicament for treating a disease.
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