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WO2024235115A1 - Compound containing aromatic bicyclic ring - Google Patents

Compound containing aromatic bicyclic ring Download PDF

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Publication number
WO2024235115A1
WO2024235115A1 PCT/CN2024/092286 CN2024092286W WO2024235115A1 WO 2024235115 A1 WO2024235115 A1 WO 2024235115A1 CN 2024092286 W CN2024092286 W CN 2024092286W WO 2024235115 A1 WO2024235115 A1 WO 2024235115A1
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Prior art keywords
alkyl
alkyls
membered
independently selected
halogen
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PCT/CN2024/092286
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French (fr)
Chinese (zh)
Inventor
敖汪伟
张立
靳辉
韩绪林
张桂铭
Original Assignee
正大天晴药业集团股份有限公司
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Publication of WO2024235115A1 publication Critical patent/WO2024235115A1/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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/54—Spiro-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a compound containing an aromatic bicyclic ring, a preparation method thereof, a pharmaceutical composition containing the compound, and use thereof in treating tumor diseases.
  • the Hippo signaling cascade is an important pathway for cancer biogenesis and tumor maintenance.
  • the Hippo pathway is heavily mutated through loss-of-function mutations in genes such as NF2.
  • These tumor-promoting mutations lead to constitutive activation of downstream transcriptional coactivators YAP and TAZ, which drive the expression of many pro-survival and proliferation genes through essential interactions with members of the TEAD protein family.
  • TEAD proteins are downstream effectors of the Hippo signaling pathway that regulate cell proliferation and stem cell function.
  • this unrestricted transcriptional program also drives enhanced immunosuppression in the tumor microenvironment. Direct inhibition of YAP/TAZ is challenging because YAP/TAZ are intrinsically disordered proteins with high structural flexibility.
  • TEAD inhibitors prevent TEAD palmitoylation, which is essential for the interaction between YAP and TEAD. It indirectly inhibits YAP activity by disrupting TEAD function, thereby suppressing the proliferation of tumor cells.
  • the present disclosure provides a compound of formula IC or a pharmaceutically acceptable salt thereof,
  • X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from N or CH;
  • Xa , Xb , Xc, Xd , Xe and Xf are each independently selected from N or CH optionally substituted by one or more substituents (specifically, each independently selected from N or CH optionally substituted by one substituent);
  • X is selected from O, S, -S(O)-, -S(O) 2- , -C(O)-, -C(O)O-, or the following groups optionally substituted with one or more substituents: NH, -N( C1-6alkyl )-, -NH- C1-6alkyl- , -C1-6alkyl -O-, -C1-6alkyl -S-, or -C(O)NH-;
  • each R 1 is independently selected from CN, halogen, or the following groups optionally substituted by one or more substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, R'O-, R'S-, -SF 5 , R'R"N-, R'OC(O)-, R'C(O)O-, -C(O)NR'R", R'C(O)NH-, R'S(O)NH-, R'R"NS(O)-, R'S(O) 2 NH-, R'R"NS(O) 2 -, R'OC(O)NH-, R'R"NC(O)O-, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl, or 5-12 membered heteroaryl;
  • R' and R" are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C6-12 aryl or 5-12 membered heteroaryl;
  • n and n are independently selected from 0, 1, 2, 3, 4 or 5;
  • Ring A is selected from 3-12 membered heterocycloalkyl or 3-12 membered heterocycloalkenyl (eg, N-containing heterocycloalkyl or heterocycloalkenyl).
  • the compound of formula IC is selected from formula IC-1, or a pharmaceutically acceptable salt thereof,
  • X1 , X2 , X3 , X4, X5 , Xa, Xb , Xc , Xd , Xe , Xf , X , R1 , R2 , m, n and ring A are as defined in the present disclosure.
  • the structural unit (Ring A) contains the structural fragment -NHC(O)-.
  • the structural unit (Ring A) contains the structural fragment -NHCH 2 CH 2 -. In some embodiments, the structural unit (Ring A) contains the structural fragment -NHCH 2 CH 2 *- or -*NHCH 2 CH 2 -, where * indicates that the nitrogen atom or carbon atom at the site is adjacent to the adjacent structure. For example, when the structural fragment -*NHCH 2 CH 2 - is included, it means that the nitrogen atom at this position is connected to the adjacent structure Connection can be formed For example, when the structural fragment -NHCH 2 CH 2 *- is included, it means that the carbon atom at this position is closely related to the adjacent structure. Connection can be formed
  • the compound of formula IC or a pharmaceutically acceptable salt thereof is selected from formula IC-2 or a pharmaceutically acceptable salt thereof,
  • Xa , Xc , X, R1 , R2 , m, n and ring A are as defined in the present disclosure; wherein X6 is selected from N or CH, X7 is selected from NH, O, S or CH2 , and at least one of X6 and X7 contains a nitrogen atom.
  • X7 when X6 is N, X7 is selected from NH, O, S or CH2 ; when X7 is NH, X6 is selected from CH.
  • Xa and Xc are selected from CH. In some embodiments, X is selected from O.
  • R 2 When R 2 is present, it can be located at any position of ring A (provided that the valence bond rules are met), for example R 2 may be located at positions such as X 6 , CH 2 or X 7 .
  • the compound of formula IC or a pharmaceutically acceptable salt thereof is selected from formula IC-3 or a pharmaceutically acceptable salt thereof,
  • X1 , X2 , X3 , X4, X5 , Xa, Xb , Xc , Xd , Xe , Xf , X , R1 , R2 , m, n and ring A are as defined in the present disclosure.
  • the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof,
  • X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from N or CH;
  • Xa , Xb , Xc, Xd , Xe and Xf are each independently selected from N or CH optionally substituted by one or more substituents (specifically, each independently selected from N or CH optionally substituted by one substituent);
  • X is selected from O, S, -S(O)-, -S(O) 2- , -C(O)-, -C(O)O-, or the following groups optionally substituted with one or more substituents: NH, -N( C1-6alkyl )-, -NH- C1-6alkyl- , -C1-6alkyl -O-, -C1-6alkyl -S-, or -C(O)NH-;
  • Each R 1 is independently selected from CN, halogen, or the following groups optionally substituted by one or more substituents: OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOC( O)-, C 1-6 alkylC(O)O-, C 1-6 alkylNHC(O)-, C 1-6 alkylC ( O )NH-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl)
  • n and n are independently selected from 0, 1, 2, 3, 4 or 5;
  • Ring A is selected from 3-12 membered heterocycloalkyl or 3-12 membered heterocycloalkenyl.
  • X 1 , X 2 , X 3 , X 4 , and X 5 are each independently selected from N or CH.
  • X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from N or CH, and X 1 , X 2 , X 3 , X 4 and X 5 are optionally One or two are selected from N.
  • X1 , X2 , X3 , X4 and X5 are each independently selected from N or CH, and one of X1 , X2 , X3 , X4 and X5 is selected from N.
  • X1 , X2, X3 , X4 and X5 are each independently selected from N or CH, and two of X1 , X2 , X3 , X4 and X5 are selected from N.
  • X1, X2 , X3, X4 and X5 are each independently selected from N or CH, and two of X1, X2, X3 , X4 and X5 are selected from N.
  • X1 , X2 , X3 , X4 and X5 are selected from CH.
  • Xa , Xb , Xc , Xd or Xe are each independently selected from N or CH optionally substituted with one or more (one) substituents, and Xf is selected from N or CH.
  • Xa , Xb , Xc , Xd or Xe are each independently selected from N or CH optionally substituted with one or more (one) substituents, and Xf is selected from N or CH.
  • Ra is as defined in the disclosure.
  • Xa , Xb , Xc , Xd , Xe and Xf are each independently selected from N or CH optionally substituted with one or more (one) Ra, wherein Ra is selected from CN, halogen, OH, NH2 , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylO-, C1-6 alkylS-, -SF5, C1-6 alkylNH-, (C1-6 alkyl) 2N- , C1-6 alkylOCO-, C1-6 alkylC(O)O-, C1-6 alkylNHCO-, C1-6 alkylCONH- , ( C1-6 alkyl) 2NCO- , C1-6 alkylNHS(O)-, C1-6 alkylS(O ) NH-, ( C1-6 alkyl) 2NS (O)-, C1-6 alkylNHS(O) 2- , C1-6 alkyl C 1-6 alkylS
  • the Ra is selected from CN, halogen, OH, NH2 , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylO-, C1-6 alkylS-, -SF5 , C1-6 alkylNH-, ( C1-6 alkyl) 2N- , C1-6 alkylOCO-, C1-6 alkylC(O ) O-, C1-6 alkylNHCO-, C1-6 alkylCONH-, ( C1-6 alkyl) 2NCO- , C1-6 alkylNHS(O)-, C1-6 alkylS ( O)NH-, ( C1-6 alkyl)2NS( O )-, C1-6 alkylNHS(O) 2- , C1-6 alkylS(O) 2NH- , (C1-6 alkyl ) 2NS (O) 2- , C1-6 alkyl C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6
  • the Ra is selected from CN, halogen, OH, NH2 , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylO-, C1-6 alkylS-, -SF5 , C1-6 alkylNH-, ( C1-6 alkyl) 2N- , C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C6 aryl or 5-6 membered heteroaryl, the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylO-, C1-6 alkylS-, C1-6 alkylNH-, ( C1-6 alkyl) 2N- , C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C6
  • the 6- membered aryl or 5-6-membered heteroaryl is optionally substituted by one or more of the following groups: CN, halogen, OH, NH 2 , C 1-3 alkyl O-, C 1-3 alkyl S- , -SF 5 , C 1-3 alkyl NH-, or (C 1-3 alkyl) 2 N-.
  • the Ra is selected from CN, halogen, OH, NH2 , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylO-, C1-6 alkylS-, -SF5 , C1-6 alkylNH-, or ( C1-6 alkyl) 2N- , and the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylO-, C1-6 alkylS-, C1-6 alkylNH-, or ( C1-6 alkyl) 2N- are optionally substituted with one or more of the following groups : CN, halogen, OH , NH2 , C1-3 alkylO-, C1-3 alkylS-, -SF5 , C1-3 alkylNH-, or ( C1-3 alkyl ) 2N- .
  • the Ra is selected from CN, halogen, OH, NH2 , C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkylO-, C1-4 alkylS-, -SF5, C1-4 alkylNH-, or ( C1-4 alkyl) 2N- , and the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkylO-, C1-4 alkylS-, -SF5 , C1-4 alkylNH-, or ( C1-4 alkyl) 2N- are optionally substituted with one or more of the following groups : CN, halogen, OH, or NH2 .
  • the Ra is selected from CN, halogen, OH, NH2 , C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, or -SF5 , wherein the C1-4 alkyl, C2-4 alkenyl, or C2-4 alkynyl is optionally substituted with one or more of CN, halogen, OH, or NH2 .
  • the Ra is selected from CN, halogen, OH, NH2 , C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, or -SF5 , wherein the C1-3 alkyl, C2-3 alkenyl, or C2-3 alkynyl is optionally substituted with one or more of the following groups: CN, halogen, OH, or NH2 .
  • the Ra is selected from CN, halogen, OH , NH2 , or C1-3 alkyl, which is optionally substituted with one or more of the following groups: CN, halogen, OH, or NH2 .
  • the Ra is selected from CN, halogen, OH, NH 2 or C 1-3 alkyl. In some embodiments, the Ra is selected from C 1-6 alkyl. In some embodiments, the Ra is selected from C 1-3 alkyl. In some embodiments, the Ra is selected from methyl.
  • Xa , Xb , Xc , Xd , Xe, and Xf are each independently selected from CH or N.
  • Xa , Xb , Xc , Xd , Xe and Xf are each independently selected from CH or N, and optionally one or two of Xa, Xb , Xc , Xd , Xe and Xf are selected from N.
  • Xb , Xd , Xe and Xf are each independently selected from CH, and Xa and Xc are each independently selected from CH or N, wherein CH is optionally substituted with one or more Ra .
  • Xb , Xd , Xe and Xf are each independently selected from CH, and Xa and Xc are each independently selected from CH or N.
  • Xa , Xb , Xd , Xe and Xf are each independently selected from CH, and Xc is selected from N.
  • X b , X d , X e and X f are each independently selected from CH, and X a and X c are each independently selected from N.
  • Xa , Xb , Xc, Xd , Xe , and Xf are selected from CH.
  • Xb when Xb is selected from CH, said CH is optionally substituted with Ra .
  • the structural unit Selected from the following groups optionally substituted by one or more Ra In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from
  • X is selected from O, S, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O-, NH, -N(C 1-6 alkyl)-, -NH-C 1-6 alkyl-, -C 1-6 alkyl-O-, -C 1-6 alkyl-S-, or -C(O)NH-.
  • X is selected from O, S, NH, -N(C 1-3 alkyl)-, -NH-C 1-3 alkyl-, -C 1-3 alkyl-O-, -C 1-3 alkyl-S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)NH-, or -C(O)O-.
  • X is selected from O, S, NH, or -N(C 1-3 alkyl)-.
  • X is selected from O, S, or NH.
  • X is selected from O.
  • X is selected from O, S, NH or -N( C1-3 alkyl)-; Xa , Xb , Xc , Xd , Xe and Xf are selected from CH. In some embodiments, X is selected from O, S or NH; Xa, Xb , Xc , Xd , Xe and Xf are selected from CH. In some embodiments, X is selected from O; Xa , Xb , Xc , Xd , Xe and Xf are selected from CH.
  • R' and R" are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl.
  • R' and R" are each independently selected from hydrogen or C1-3 alkyl. In some embodiments, R' and R" are each independently selected from hydrogen, methyl, -CH2CH2NH2 , or ethyl .
  • each R 1 is independently selected from CN, halogen, or the following groups optionally substituted with one or more substituents: OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl ) 2 N-, HOC(O)-, C 1-6 alkylOC(O)-, C 1-6 alkylC(O)O-, -C(O)NH 2 , C 1-6 alkylNHC(O)-, C 1-6 alkylC(O)NH-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkylNHS(O)-, C 1-6 alkylS (O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkyl
  • each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO- , C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 1-6 alkylNHS(O) 2 -, C
  • each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO- , C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 1-6 alkylNHS(O) 2 -, C
  • each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO- , C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 1-6 alkylNHS(O) 2 -, C
  • each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl,
  • the 6- membered aryl or 5-6-membered heteroaryl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-3 alkyl O-, C 1-3 alkyl S-, -SF 5 , C 1-3 alkyl NH-, or (C 1-3 alkyl) 2 N-.
  • each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, or (C 1-6 alkyl) 2 N-, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, C 1-6 alkylNH-, or (C 1-6 alkyl) 2 N- are optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-3 alkylO-, C 1-3 alkylS-, -SF 5 , C 1-3 alkylNH-, or (C 1-3 alkyl) 2 N-.
  • each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, or (C 1-4 alkyl) 2 N-, and the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, or (C 1-4 alkyl) 2 N- are optionally substituted with one or more of the following groups: CN, halogen, OH, or NH 2 .
  • each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, or -SF 5 , wherein the C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl is optionally substituted with one or more of the following groups: CN, halogen, OH, or NH 2 .
  • each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, or -SF 5 , wherein the C 1-3 alkyl, C 2-3 alkenyl, or C 2-3 alkynyl is optionally substituted with one or more of the following groups: CN, halogen, OH, or NH 2 .
  • each R 1 is independently selected from CN, halogen, OH, NH 2 or C 1-3 alkyl, which is optionally substituted with one or more of the following groups: CN, halogen, OH or NH 2 .
  • each R 1 is independently selected from halo-substituted C 1-6 alkyl or -SF 5 .
  • each R 1 is independently selected from halo-substituted C 1-3 alkyl or -SF 5 .
  • each R 1 is independently selected from fluorinated C 1-3 alkyl or -SF 5 .
  • each R 1 is independently selected from fluorinated C 1-3 alkyl.
  • each R 1 is independently selected from CF 3 or —SF 5 .
  • each R 1 is independently selected from CF 3 .
  • At least one R 2 is selected from ⁇ O.
  • CN halogen
  • R b and R c are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl, or 5-6 membered heteroaryl.
  • R b and R c are each independently selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl.
  • R b and R c are each independently selected from hydrogen or C 1-3 alkyl.
  • CN halogen
  • halogen e.g., F or Cl
  • 3-6 membered cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl is optionally substituted with one or more of the following: CN, halogen, OH, NH 2 , C 1-3 alkyl O-, C 1-3 alkyl S-, -SF 5 , C 1-3 alkyl NH- or (C 1-3 alkyl) 2 N-.
  • each R 2 is independently selected from ⁇ O, OH, —CH 3 or —CH 2 OH.
  • m and n are each independently selected from 0, 1, 2, or 3. In some embodiments, m and n are each independently selected from 1, 2, or 3. In some embodiments, m and n are each independently selected from 1 or 2. In some embodiments, m is selected from 1. In some embodiments, n is selected from 1, 2, or 3. In some embodiments, n is selected from 1 or 2.
  • Ring A is selected from 3-10 membered heterocycloalkyl or 3-10 membered heterocycloalkenyl.
  • Ring A is selected from 3-10 membered heterocycloalkyl or 3-8 membered heterocycloalkenyl.
  • Ring A is selected from 4-10 membered heterocycloalkyl.
  • Ring A is selected from 4-8 or 10-membered heterocycloalkyl.
  • ring A is selected from 4-6 membered monocyclic heterocycloalkyl, 7-8 membered or 10 membered spiroheterocycloalkyl. In some embodiments, ring A is selected from 5 membered monocyclic heterocycloalkyl.
  • ring A is selected from pyrrolidinyl, thiazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, diazaspirodecanyl, monooxa-azaspirooctanyl, azetidinyl, monoazaspiroheptyl or oxazolidinyl. In some specific embodiments, ring A is selected from pyrrolidinyl, thiazolidinyl or imidazolidinyl.
  • Ring A is selected from wherein X t is selected from CH 2 , NH or O.
  • Ring A is selected from t is selected from 1, 2, 3, 4 or 5, and X8 is selected from CH2 , NH, O or S. In some embodiments, t is selected from 1, 2 or 3. In some embodiments, t is selected from 2. In some embodiments, X8 is selected from CH2 . In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from
  • Ring A is selected from wherein Xt is selected from NH or O. In some embodiments, ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from
  • Ring A is selected from 3-8 membered heterocycloalkyl or 3-8 membered heterocycloalkenyl.
  • Ring A is selected from 3-6 membered heterocycloalkyl or 3-6 membered heterocycloalkenyl. In other embodiments, Ring A is selected from 5-6 membered heterocycloalkyl.
  • the heterocycloalkyl or heterocycloalkenyl in ring A wherein the heteroatom is selected from nitrogen, oxygen, sulfur, phosphorus or boron. In some embodiments, the heterocycloalkyl or heterocycloalkenyl in ring A, wherein the heteroatom is selected from nitrogen, oxygen, or sulfur. In some embodiments, the heterocycloalkyl or heterocycloalkenyl in ring A, wherein the number of heteroatoms is selected from 1, 2, 3, 4 or 5. In some embodiments, the heterocycloalkyl or heterocycloalkenyl in ring A, wherein the number of heteroatoms is selected from 1, 2 or 3.
  • the heterocycloalkyl or heterocycloalkenyl group in ring A contains no more than 2 N atoms among the heteroatoms constituting ring A.
  • the heterocycloalkyl or heterocycloalkenyl in ring A has only 1 N atom or only 2 N atoms among the heteroatoms constituting ring A.
  • the heterocycloalkyl or heterocycloalkenyl in ring A has and only has 1 N atom and 1 S atom among the heteroatoms constituting ring A.
  • Ring A is selected from pyrrolidinyl, thiazolidinyl, imidazolidinyl, piperidinyl, or piperazinyl.
  • Ring A is selected from
  • the structural unit Selected from In some embodiments, the structural unit Selected from
  • Ring A is selected from
  • the structural unit Selected from In some embodiments, the structural unit Selected from
  • the present disclosure provides a compound of Formula IA, IA-1, IA-2 or IA-3, or a pharmaceutically acceptable salt thereof,
  • q is selected from 0, 1, 2 or 3;
  • Xa and Xc are each independently selected from CH or N. In some embodiments, Xa and Xc are selected from CH.
  • q is selected from 0, 1 or 2. In some embodiments, q is selected from 0 or 1. In some embodiments, q is selected from 0.
  • the present disclosure provides a compound of formula II, II-1, II-2 or II-3, or a pharmaceutically acceptable salt thereof,
  • the present disclosure provides a compound of formula III, IV, IIIA or IVA, or a pharmaceutically acceptable salt thereof,
  • Ring B is selected from 3-10 membered heterocycloalkyl or 3-10 membered heterocycloalkenyl
  • R 2a is as defined in the disclosure for R 2 ;
  • p is selected from 0, 1, 2 or 3;
  • T is selected from S ⁇ O or C.
  • Xa and Xc are selected from CH or N. In some embodiments, Xa and Xc are selected from CH.
  • Ring B is selected from 3-8 membered heterocycloalkyl or 3-8 membered heterocycloalkenyl.
  • Ring B is selected from 3-6 membered heterocycloalkyl or 3-6 membered heterocycloalkenyl.
  • Ring B is selected from 3-10 membered heterocycloalkyl.
  • Ring B is selected from 4-10 membered heterocycloalkyl.
  • Ring B is selected from 4-8 or 10-membered heterocycloalkyl.
  • Ring B is selected from 4-6 membered monocyclic heterocycloalkyl, 7-8 membered or 10 membered spiroheterocycloalkyl.
  • Ring B is selected from 4-8 membered heterocycloalkyl.
  • Ring B is selected from 4-6 membered heterocycloalkyl.
  • Ring B is selected from 5-6 membered heterocycloalkyl.
  • Ring B is selected from pyrrolidinyl, thiazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, diazaspirodecanyl, monooxa-azaspirooctanyl, azetidinyl, monoazaspiroheptanyl, or oxazolidinyl.
  • Ring B is selected from oxazolidinyl, pyrrolidinyl, thiazolidinyl, imidazolidinyl, piperidinyl, or piperazinyl.
  • Ring B is selected from pyrrolidinyl, thiazolidinyl, imidazolidinyl, piperidinyl, or piperazinyl.
  • the structural unit As structural unit Definition of .
  • each R 2a is as defined for the R 2 group of the present disclosure (ie, the same as R 2 of the present disclosure).
  • each R 2a is independently selected from CN, halogen, OH, NH 2 , C 1-4 alkyl, C 1-4 alkylO-, C 1-4 alkyl C 1-4 alkyl) 2 N—, C 1-4 alkyl OC(O)—, C 1-4 alkyl C(O)O—, C 1-4 alkyl NHC(O)—, C 1-4 alkyl C(O)NH—, (C 1-4 alkyl) 2 NC(O)—, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl O—, C 1-4 alkyl S—, C 1-4 alkyl NH—, (C 1-4 alkyl) 2 N—, C 1-4 alkyl OC(O)—, C 1-4 alkyl C(O)O—, C 1-4 alkyl NHC(O)—, C
  • each R 2a is independently selected from CN, halogen, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylO—, C 1-3 alkylNH—, C 1-3 alkylOC(O)-, or 5-6-membered heterocycloalkyl, and the C 1-3 alkyl, C 1-3 alkylO—, C 1-3 alkylNH—, C 1-3 alkylOC(O)-, or 5-6-membered heterocycloalkyl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-3 alkyl, -COOH, or C 1-3 alkylOC(O)-.
  • each R 2a is independently selected from CN, halogen, OH, NH 2 , methyl, ethyl, CH 3 O-, CH 3 NH-, CH 3 CH 2 NH-, CH 3 OC(O)-, CH 3 CH 2 OC(O)-, or a 5-membered oxygen-containing heterocycloalkyl group, wherein the methyl, ethyl, CH 3 CH 2 NH-, or a 5-membered oxygen-containing heterocycloalkyl group is optionally substituted with one or more of the following groups: halogen (e.g., F or Cl), OH, NH 2 , methyl, -COOH, or CH 3 OC(O)-.
  • halogen e.g., F or Cl
  • each R 2a is independently selected from halogen (e.g., F or Cl), OH, NH 2 , -CH 3 , -CH 2 OH, -CH 2 F, -CH 2 CH 2 OH, -CH(OH)CH 3 , -CH(OH)CH 2 OH, -CH 2 C(O)OCH 3 , -CH 2 C(O)OH, -OCH 3 , -NHCH 3 , -NHCH 2 CH 2 NH 2 , -C(O)OCH 3 , -C(O)OCH 2 CH 3 , or
  • p is selected from 0, 1 or 2.
  • the present disclosure provides a compound of Formula V, VI or VII, or a pharmaceutically acceptable salt thereof,
  • X a , X c , R 1 , R 2a , p and m are as defined in the present disclosure; and X t is selected from CH 2 , NH or O.
  • m is selected from 1, and R1 is substituted at the X3 position.
  • X3 is selected from CH, m is selected from 1, and R1 is substituted at the X3 position.
  • the R1 substitution occurs at the para position of the attached benzene ring, forming the following structural unit
  • X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from CH, and X is selected from O.
  • heterocycloalkyl and heterocycloalkenyl each independently contain 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, heterocycloalkyl and heterocycloalkenyl each independently contain 1 or 2 heteroatoms independently selected from N and O.
  • the heteroaryl group contains 1, 2, or 3 heteroatoms independently selected from N, O, and S.
  • the heterocyclyl contains 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocyclyl contains 1 or 2 heteroatoms independently selected from N and O.
  • the C 1-10 is selected from C 1-9 , C 1-8 , C 1-7 , C 1-6 , C 1-4 , C 1-3 , or C 1-2 .
  • C 1-6 is selected from C 1-4 , C 1-3 , or C 1-2 .
  • the C 1-4 is selected from C 4 , C 3 , C 2 , or C 1.
  • the C 1-3 is selected from C 3 , C 2 , or C 1 .
  • the C 3-6 is selected from C 3-5 , C 3-4 , C 4-6 , C 4-5 , or C 5-6 .
  • the C 6-10 is selected from C 6-9 , C 6-8 , C 6-7 , C 7-10 , C 7-9 , C 7-8 , C 8-10 , C 8-9 , or C 9-10 .
  • the C3-10 is selected from C3-9 , C3-8 , C3-7 , C3-6 , C3-5 , C3-4 , C4-10 , C4-9 , C4-8 , C4-7 , C4-6 , C4-5 , C5-10 , C5-9 , C5-8 , C5-7 , C5-6 , C6-10 , C6-9 , C6-8 , C6-7 , C7-12 , C7-10 , C7-9 , C7-8 , C8-12 , C8-10 , C8-9 , C9-12 , or C9-10 .
  • the C 3-15 is selected from C 3-12 or C 3-10 .
  • the C 3-12 is selected from C 3-10 .
  • the C 6-12 is selected from C 6-10 .
  • the 3-6 yuan is selected from 3-5 yuan, 3-4 yuan, 4-6 yuan, 4-5 yuan, or 5-6 yuan.
  • the 5-10 yuan is selected from 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6-9 yuan, 6-8 yuan, 6-7 yuan, 7-10 yuan, 7-9 yuan, 7-8 yuan, 8-10 yuan, 8-9 yuan, 9-10 yuan.
  • the 3-10 yuan is selected from 3-9 yuan, 3-8 yuan, 3-7 yuan, 3-6 yuan, 3-5 yuan, 3-4 yuan, 4-10 yuan, 4-9 yuan, 4-8 yuan, 4-7 yuan, 4-6 yuan, 4-5 yuan, 5-10 yuan, 5-9 yuan, 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6-9 yuan, 6-8 yuan, 6-7 yuan, 7-10 yuan, 7-9 yuan, 7-8 yuan, 8-10 yuan, 8-9 yuan, 9-10 yuan.
  • the 3-15 yuan is selected from 3-12 yuan or 3-10 yuan. In some embodiments, the 3-12 yuan is selected from 3-10 yuan. In some embodiments, the 5-12 yuan is selected from 5-10 yuan.
  • the compounds of the present disclosure are not selected from the following compounds:
  • the compounds of the present disclosure are not selected from the following compounds:
  • the compounds of the present disclosure are not selected from the following compounds:
  • the present disclosure relates to the following compounds, or pharmaceutically acceptable salts thereof:
  • the present disclosure discloses a compound having an asymmetric carbon atom, the compound comprising a first eluting compound or a last eluting compound after liquid phase separation.
  • the mobile phase for liquid phase separation is the mobile phase in the examples of the present disclosure.
  • the present disclosure relates to a pharmaceutical composition, which contains the above-mentioned compound of the present disclosure or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition of the present disclosure also includes a pharmaceutically acceptable excipient.
  • the present disclosure relates to use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating a disease (eg, a disease associated with TEAD).
  • a disease eg, a disease associated with TEAD
  • the present disclosure relates to a method for treating or preventing a disease (e.g., a disease associated with TEAD), comprising administering a therapeutically effective amount of the above-mentioned compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.
  • a disease e.g., a disease associated with TEAD
  • the present disclosure relates to use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating a disease (eg, a disease associated with TEAD).
  • a disease eg, a disease associated with TEAD
  • the present disclosure relates to the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a disease (eg, a disease associated with TEAD).
  • a disease eg, a disease associated with TEAD.
  • the disease eg, a disease associated with TEAD
  • the disease is selected from cancer; in some more specific embodiments, the disease (eg, a disease associated with TEAD) is selected from mesothelioma and lung cancer.
  • the present disclosure comprises the above-defined variables and embodiments thereof, and any combination thereof.
  • the disclosed compounds have good in vitro protein binding activity, and have binding effects on TEAD1, TEAD2, TEAD3 or TEAD4 proteins. They have proliferation inhibitory activity on NCI-H226 cells or NCI-H2052 cells, and have substantially no proliferation inhibitory activity on NCI-H2452 cells. They have good selectivity for NCI-H226 or NCI-H2052 cells relative to NCI-H2452 cells. They are metabolically stable in vitro and have good in vivo pharmacokinetic properties and in vivo efficacy.
  • the "one or more” is selected from one, two, three, four, five or six. In some embodiments, the “one or more” is selected from one, two, or three. In some embodiments, the “one or more” is selected from one, or two.
  • an ethyl group is "optionally” substituted with 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 ).
  • the C 1-6 alkyl (C 1-4 alkyl) etc. is optionally substituted with one or more of the following groups: CN, halogen, OH or NH 2 , and groups such as -C 1-6 alkyl-OH, -C 1-6 alkyl-NH 2 , etc. can be formed.
  • the "substituent” mentioned herein includes, but is not limited to, the terms “alkyl”, “alkoxy”, “cycloalkyl”, “heterocycloalkyl”, “heteroaryl”, “alkenyl”, “alkynyl”, “cycloalkenyl”, “heterocycloalkenyl”, “heteroaryl ring”, etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent” include protium, deuterium, tritium, -OH, -SF5 , -SH, halogen, -NH2 , nitro, nitroso, -CN, an azide group, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, a carboxaldehyde group, an imine group, an alkyl group, a halo-alkyl group, a cycloal
  • the “substituent” is selected from deuterium, tritium, —SF 5 , hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azido, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 alkyl, halo-C 1-12 alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halo-C 2-12 alkenyl, 3-12 membered cycloalkenyl, halo- 3-12 membered cycloalkenyl, C 2-12 alkynyl , halo-C 2-12 alkynyl, 8-12 membered cycloalkynyl, halo-8-12 membered cycloalkynyl, C 1-12 heteroalkyl, halo
  • Cmn herein means that the moiety has an integer number of carbon atoms in a given range.
  • C1-12 means that the group may 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 may 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 may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.
  • m-n yuan in this article means that the part has an integer number in a given range.
  • 3-12 yuan means 3 yuan, 4 yuan, 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan, 10 yuan, 11 yuan or 12 yuan.
  • 5-10 yuan means 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan or 10 yuan.
  • 3-6 yuan means 3 yuan, 4 yuan, 5 yuan or 6 yuan.
  • any variable e.g., R
  • its definition at each occurrence is independent. For example, if a group contains 2 R's, each R has independent options.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxy refers to an -OH group.
  • amino refers to a -NH2 group.
  • heteroatom includes atoms of any element except carbon or hydrogen.
  • Preferred heteroatoms are boron, nitrogen, oxygen, sulfur, silicon and phosphorus, wherein nitrogen atoms are optionally quaternized or oxidized to N(O), sulfur atoms are optionally oxidized to S(O) or S(O) 2 , and phosphorus atoms are optionally oxidized to P(O) or P(O) 2 .
  • alkyl refers to a hydrocarbon group of the general formula CnH2n +1 .
  • the alkyl group may be straight or branched.
  • 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 portion i.e., alkyl
  • alkyl portion of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.
  • alkoxy refers to an -O-alkyl group.
  • alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one double bond.
  • alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.
  • alkynyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one triple bond.
  • alkynyl include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH3), 2-propynyl (-CH2-C ⁇ CH), 1,3-butadiynyl (-C ⁇ C-C ⁇ CH), etc.
  • cycloalkenyl refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bicyclic bridged ring or spirocyclic ring.
  • carbocyclic ring is generally 3 to 20 rings, 3 to 15 rings or 3 to 10 rings (e.g., 4 to 8 rings).
  • carbocyclic ring is generally 4 to 10 rings (e.g., 5 to 8 rings, specifically such as 5, 6, 7, 8, 9 or 10 rings).
  • Non-limiting examples of cycloalkenyl include but are not limited to cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc.
  • cycloalkyl refers to a fully saturated carbocyclic ring that can exist as a monocyclic ring, a bridged ring or a spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically 3 to 20 rings, 3 to 15 rings or 3 to 10 rings (e.g., 5 to 8 rings, specifically 5, 6, 7, 8, 9 or 10 rings).
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, etc.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spirocyclic ring.
  • the heterocycle is typically a 3 to 20-membered ring, 3 to 15-membered ring, 3 to 7-membered ring, 3 to 6-membered ring or 3 to 5-membered ring containing 1 to 6 or 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, sulfur, silicon and/or phosphorus (preferably sulfur, oxygen and/or nitrogen heteroatoms, preferably 1, 2 or 3 heteroatoms).
  • 3-membered heterocycloalkyl examples include, but are not limited to, oxirane, thioethane, and cyclonitroethane.
  • 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxadiazolyl, and thiadinyl.
  • 5-membered heterocycloalkyl examples include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl.
  • 6-membered heterocycloalkyl examples include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl.
  • 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, and thiepanyl.
  • the monocyclic heterocycloalkyl has 5 or 6 ring atoms.
  • heterocycloalkenyl includes cycloalkenyl groups in which one or more carbon atoms, for example up to 3 carbon atoms, or up to 2 carbon atoms, or 1 carbon atom are independently replaced by B, O, S, S(O), S(O) 2 , N, Si, P or P(O), provided that at least one cycloalkenyl carbon-carbon double bond is retained.
  • the cyclic group which may exist as a monocyclic ring, a bridged ring or a spirocyclic ring, may be a 3-20-membered ring, a 3-15-membered ring or a 3-13-membered ring (e.g., a 5-13-membered ring, a 5-8-membered ring, specifically a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered or 11-membered ring).
  • 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 or spirocyclic ring.
  • the heterocyclic ring is generally 3 to 20 yuan (or 3 to 17 yuan, or 3 to 13 yuan, or 3 to 7 yuan, specifically such as 4 yuan, 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan or 10 yuan ring) ring containing 1 to 3 heteroatoms (preferably 1, 2 or 3 heteroatoms) independently selected from boron, sulfur, oxygen and/or nitrogen.
  • 1 to 3 heteroatoms preferably 1, 2 or 3 heteroatoms
  • 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 heterocyclyl group can be, for example, heterocycloalkenyl, heterocycloalkyl, or benzoheterocycloalkenyl (not a fully saturated heteroaromatic).
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ electron system.
  • an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 (e.g., 6, 7, 8, 9, or 10) carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene, etc.
  • heteroaryl refers to a monocyclic or fused polycyclic system, wherein containing at least one ring atom selected from nitrogen, oxygen, S, the remaining ring atoms are C, and have at least one aromatic ring.
  • Preferred heteroaryl has a single 4 to 8 ring, especially 5 to 8 (e.g., 5, 6, 7 or 8) ring, or comprises 6 to 20, or 6 to 14, especially 6 to 10 (e.g., 6, 7, 8, 9 or 10) ring atoms of a plurality of fused rings.
  • heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.
  • 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 a 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.
  • 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 isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature.
  • isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, etc., respectively .
  • Certain isotopically labeled compounds of the present disclosure can be used in compound and/or substrate tissue distribution assays. 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.
  • substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.
  • deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.
  • deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium.
  • the disclosed compounds may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers.
  • the disclosed compounds containing asymmetric carbon atoms may be isolated in optically pure forms or in racemic forms. Optically pure forms may be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients. Therefore, the compounds of the present disclosure may include pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the present invention 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 dosage administered is 0.001 to 2000 mg/kg body weight per day in single or divided doses.
  • the compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.
  • Ring A, X1 , X2 , X3, X4 , X5 , X, R1 , R2 , Xa , Xb , Xc , Xd , Xe , Xf , m and n are as defined in the present disclosure, and Z1 or Z2 is independently halogen.
  • X is selected from O.
  • DMF stands for dimethylformamide
  • DMSO dimethyl sulfoxide
  • EA stands for ethyl acetate
  • PE petroleum ether
  • MeOH stands for methanol
  • DCM stands for dichloromethane
  • THF stands for tetrahydrofuran
  • NMP stands for
  • Boc stands for tert-butyloxycarbonyl
  • Bn stands for benzyl
  • Xant-Phos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
  • Pd 2 (dba) 3 represents tris(dibenzylideneacetone) dipalladium
  • EDCI represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • DMAP represents 4-dimethylaminopyridine
  • 2-MeTHF represents 2-methyltetrahydrofuran
  • DIPEA represents N,N-diisopropyleth
  • the single crystal growth method was used to confirm the R or S configuration of some isomeric compounds in the following examples.
  • Step A Compound 1-1 (1.00 g), 1-fluoro-4-trifluoromethyl-benzene (3.68 g), cesium carbonate (7.30 g) and DMF (10 mL) were added to a microwave tube in sequence, and microwave heating was performed at 120° C. for 2 h. After the reaction was completed, water was added, extracted with ethyl acetate, the organic layers were combined, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 1-2 (1.45 g).
  • Step B Compound 1-2 (250 mg), Pd 2 (dba) 3 (12.5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (23.5 mg), cesium carbonate (665 mg), 4-hydroxy-2-pyrrolidone (82.5 mg), 1,4-dioxane (10 mL) were added to an eggplant-shaped bottle in sequence, and heated to 110°C under N 2 protection and refluxed for 5 hours. After the reaction was completed, water was added, extracted with ethyl acetate, the organic layers were combined, washed with saturated sodium chloride water, and anhydrous sodium sulfate. The solution was dried and filtered, and the filtrate was concentrated to dryness under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain compound 1 (100 mg).
  • Step C Compound 1 (260 mg) was subjected to chiral separation (YMC high pressure preparative chromatography: CHIRALART Cellulose-SC column, ethanol/n-hexane).
  • the first eluting peak was Example 1_A (112 mg)
  • the later eluting peak was Example 1_B (120 mg).
  • step B 4-hydroxymethyl-2-pyrrolidone was used instead of 4-hydroxy-2-pyrrolidone to obtain compound 2.
  • step B 4-hydroxy-2-pyrrolidone was replaced with isothiazolidine 1,1-dioxide, and the obtained crude product was purified by silica gel column chromatography to obtain compound 3 (238 mg).
  • the first peak was compound 4_A (80 mg), and the last peak was compound 4_B (80 mg).
  • step B 1-methylimidazoline-2-one was used instead of 4-hydroxy-2-pyrrolidone, and the obtained crude product was separated by medium-low pressure preparative liquid phase to obtain compound 5 (215 mg).
  • the first peak was compound 6_A (40 mg), and the last peak was compound 6_B (42 mg).
  • the first peak was compound 7_A (30 mg), and the later peak was compound 7_B (30 mg).
  • step B 4-methylpiperazine-2-one was used instead of 4-hydroxy-2-pyrrolidone, and the obtained crude product was separated by medium-low pressure preparation to obtain compound 8 (246 mg).
  • step B 4-hydroxy-2-piperidone was used instead of 4-hydroxy-2-pyrrolidone.
  • the first peak was compound 9_A (36 mg), and the last peak was compound 9_B (33 mg).
  • the first peak was compound 10_A (15 mg), and the last peak was compound 10_B (15 mg).
  • the first peak was compound 11_A (154 mg), and the last peak was compound 11_B (168 mg).
  • step B pyrrolidone was used instead of 4-hydroxy-2-pyrrolidone.
  • the obtained crude product was purified by silica gel column chromatography to obtain compound 12 (34.5 mg).
  • Step A Referring to the synthesis of Example 1, in step B, 3-oxo-2,8-diazaspiro[4,5]decane-8-carboxylic acid tert-butyl ester is used instead of 4-hydroxy
  • the crude product was purified by silica gel column chromatography (EA/PE) to obtain intermediate 13-1 (250 mg). MS (ESI+, [M+H] + ) m/z: 541.01.
  • Step B Add 13-1 (250 mg) and 4M hydrogen chloride-dioxane solution (5 mL) to a single-mouth bottle, and stir the reaction at room temperature for 0.5 h. After the reaction, the reaction solution was concentrated, diluted with water (50 mL) and adjusted to pH 8-9 with 1M sodium hydroxide solution, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography to obtain compound 13 (125 mg).
  • Step A Referring to the synthesis of Example 1, in step B, 4-hydroxy-2-pyrrolidone was replaced with 14-1, and the obtained crude product was purified by silica gel column chromatography (PE/EA) to obtain compound 14-2 (210 mg).
  • Step B 14-2 (210 mg) and hydrogen chloride (6.9 mL, 4 M 1,4-dioxane solution) were added to an eggplant-shaped bottle in sequence, and the mixture was reacted at room temperature for 2 hours under N2 protection. After the reaction, 20 mL of saturated sodium bicarbonate aqueous solution was added, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 14 (141 mg).
  • Step A Referring to the synthesis of Example 1, in step B, 15-1 was used to replace 4-hydroxy-2-pyrrolidone, and the obtained crude product was purified by silica gel column chromatography (MeOH/DCM) to obtain compound 15-2 (305 mg).
  • Step B Referring to step B of Example 14, intermediate 15-2 was used to replace intermediate 14-2 to obtain compound 15 (220 mg).
  • Step A Refer to the operation of step B in Example 1, replace 4-hydroxy-2-pyrrolidone with 3-hydroxy-2-pyrrolidone, react at 100°C overnight, and after the reaction is completed, filter, wash the filter cake with ethyl acetate, collect the filtrate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain compound 11 (224 mg).
  • Step B 11 (140 mg), dichloromethane (5 mL), pyridine (0.012 mL) and dichlorothionyl (172 mg) were added to the reaction bottle in sequence, and the reaction was allowed to react at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EA) to give 16-1 (127 mg).
  • PE: EA silica gel column chromatography
  • Step C 16-1 (127 mg), K 2 CO 3 (130 mg), KI (120 mgl), acetonitrile (5 mL) and 1,2-ethylenediamine (200 mg) were added to the reaction bottle in sequence. Under N 2 protection, the mixture was heated to 80°C for 6 h. After the reaction, 30 mL of water was added to quench the reaction. Ethyl acetate was then added to extract the mixture. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 16 (120 mg).
  • Step A 11 (80 mg) and THF (2 mL) were added to the reaction bottle in sequence, the reaction solution was placed in an ice bath and cooled, and then NaH (12 mg) was added. After stirring for 10 min, a solution of MeI (0.026 mL) in THF (2 mL) was slowly added dropwise, and the temperature was raised to room temperature under N2 protection for 1.5 h. After the reaction was completed, 10 mL of saturated aqueous ammonium chloride solution was added to quench the reaction, and then extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 17 (10 mg).
  • Step A Referring to the synthesis of Example 1, in step B, tert-butyloxycarbonyl-3-amino-2-pyrrolidone was used to replace 4-hydroxy-2-pyrrolidone.
  • the obtained crude product was purified by silica gel column chromatography (PE/EA) to obtain compound 18-1 (210 mg).
  • Step B 18-1 (210 mg) and 4 M hydrochloric acid dioxane solution (4 mL) were added to an eggplant-shaped bottle in sequence. After stirring at room temperature for 1 h, water (30 mL) was added to the reaction solution. The pH was adjusted to 8-9 with saturated Na 2 CO 3 aqueous solution, and then extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 18 (150 mg).
  • Step A Referring to the synthesis of Example 1, in step B, 4-hydroxy-2-pyrrolidone was replaced with 2-oxa-6-azaspiro[3.4]octan-7-one to obtain compound 19 (120 mg).
  • Step A Add 18-1 (100 mg), dichloromethane (5 mL), iodomethane (30 mg), NaH (20 mg), and DMF (1 mL) to an eggplant-shaped bottle in sequence, stir at room temperature for 6 h, add water (30 mL) to the reaction solution, extract with ethyl acetate, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 20-1 (100 mg).
  • Step B Referring to step B of Example 18, intermediate 20-1 was used instead of 18-1 to obtain compound 20 (150 mg).
  • Step A Referring to the synthesis of Example 1, in step B, 4-hydroxy-2-pyrrolidone was replaced with 4-oxoazetidine-2-carboxylic acid benzyl ester, and the obtained crude product was purified by silica gel column chromatography (EA/PE) to obtain intermediate 21-1 (184 mg). MS (ESI+, [M+H] + ) m/z: 492.13.
  • Step B To a single-necked bottle, 21-1 (184 mg) and MeOH (5 mL) were added in sequence. Under N2 protection, the temperature was lowered to 0°C, and then sodium borohydride (28 mg) was added in batches. After the addition was completed, stirring was continued for 1 h. After the reaction was completed, the reaction solution was slowly poured into an ice-cold saturated ammonium chloride solution (20 mL), extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography to obtain compound 21 (100 mg).
  • Step A Add 22-1 (5.0 g), 1-(4-methoxyphenyl)ethylamine (5.87 g) and NMP (30 mL) to a single-mouth bottle in sequence. Under N2 protection, heat the mixture to 80°C for 1 h, then heat to 120°C and stir for 4 h. After the reaction, cool the reaction solution to room temperature, then slowly pour it into 300 mL of water, filter it, and wash the filter cake with petroleum ether. Dry under reduced pressure to obtain intermediate 22-2 (7.85 g). MS (ESI-, [MH] - ) m/z: 262.19.
  • Step B Add 22-2 (7.7 g), DMF (40 mL), benzyl bromide (5.5 g) and cesium carbonate (10.5 g) to a single-mouth bottle in sequence. After the addition, stir the mixture at room temperature for 1 h. After the reaction is completed, pour the reaction solution into 200 mL of water, extract with EA, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is chromatographed on a silica gel column (EA/PE) to obtain intermediate 22-3 (10.3 g). MS (ESI+, [M+H] + ) m/z: 354.41.
  • Step C Add 22-3 (1.0 g) and DMF (10 mL) to a single-mouth bottle in sequence, and under N2 protection, cool to 0°C, then add sodium hydride (60% wt purity, 0.45 g) in batches. After 10 minutes, add iodomethane (4.02 g) dropwise. After the addition, heat the mixture to 40°C and react for 18 hours. After the reaction, cool the reaction solution to room temperature, then slowly pour it into 100 mL of ice saturated ammonium chloride solution, extract with EA, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is chromatographed on a silica gel column (EA/PE) to obtain intermediate 22-4 (800 mg). MS (ESI+, [M+H] + ) m/z: 368.44.
  • Step D Add 22-4 (800 mg) and MeOH (20 mL) to a single-mouth bottle, and lower the temperature to 0°C under N2 protection. Then add sodium borohydride (285 mg) in batches. After the addition, continue stirring for 2 h. After the reaction is completed, slowly pour the reaction solution into an ice-cold saturated ammonium chloride solution (100 mL), extract with EA, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to remove the solvent. The crude product is purified by silica gel column chromatography (MeOH/DCM) to obtain intermediate 22-5 (570 mg). MS (ESI+, [M+H] + ) m/z: 264.40.
  • Step E Add 22-5 (570 mg) and trifluoroacetic acid (13 g) to a single-mouth bottle, heat the reaction solution to 80°C and stir for 24 hours; after the reaction, directly concentrate the reaction solution under reduced pressure to dryness to obtain intermediate 22-6 (279 mg). MS (ESI+, [M+Na] + ) m/z: 151.95.
  • Step F Referring to the synthesis of Example 1, in step B, 22-6 was used to replace 4-hydroxy-2-pyrrolidone.
  • the obtained crude product was purified by silica gel column chromatography to obtain compound 22 (375 mg), MS (ESI+, [M+H] + ) m/z: 416.26.
  • the first eluting peak was compound 22_A (189 mg), and the later eluting peak was compound 22_B (175 mg).
  • Step A In a nitrogen atmosphere, lithium diisopropylamide (23.3 mL, 2M tetrahydrofuran solution) was added to a three-necked flask in sequence. A tetrahydrofuran solution (50 mL) of 23-1 (4.9 g) was added thereto at -78°C, and the mixture was stirred for 0.5 hours. N-phenylbis(trifluoromethanesulfonimide) (14.8 g) was added thereto, and the mixture was stirred for 0.5 hours and then transferred to 0°C and stirred for 1 hour.
  • Step B 23-2 (9.45 g), N,N-dimethylformamide (40 mL), methanol (80 mL), triethylamine (14.4 mL), bis(triphenylphosphine)palladium(II) chloride (1.07 g) were added to an eggplant-shaped bottle in sequence, and the air in the reaction vessel was replaced with carbon monoxide at normal pressure. The reaction solution was stirred at 50°C for 18 hours. After the reaction was completed, 50 mL of purified water was added, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over medium temperature. The mixture was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 23-3 (6.35 g).
  • Step C 23-3 (6.35 g), toluene (100 mL), and 2,4-dimethoxybenzylamine (5.18 mL) were added to an eggplant-shaped bottle in sequence, and the reaction solution was stirred at 110° C. for 18 hours. After the reaction was completed, the crude product was cooled to room temperature and purified by silica gel column chromatography (PE/EA) to obtain compound 23-4 (330 mg).
  • Step D 23-4 (300 mg) and trifluoroacetic acid (7.2 mL) were added to an eggplant-shaped bottle in sequence, and the reaction solution was stirred at 80° C. for 3 hours. After the reaction was completed and cooled to room temperature, the reaction solution was concentrated under reduced pressure to dryness to obtain compound 23-5 (159 mg).
  • Step E Referring to the synthesis of Example 1, in step B, 23-5 was used to replace 4-hydroxy-2-pyrrolidone, and the obtained crude product was purified by silica gel column chromatography to obtain compound 23-6 (300 mg).
  • Step F Add 23-6 (300 mg), methanol (2 mL), and sodium borohydride (125 mg) to an eggplant-shaped bottle in sequence. Stir the reaction solution at room temperature for 18 hours. After the reaction, add 30 mL of purified water, extract with ethyl acetate, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 23 (170 mg), MS (ESI+, [M+H] + ) m/z: 428.22.
  • Step A Under nitrogen protection, add 24-1 (4.0 g), 24-2 (2.00 g), and potassium fluoride supported on alumina (1.0 g) to the microwave tube in sequence. React at room temperature for 24 h. The system is directly filtered, and the filtrate is collected and concentrated to obtain 24-3 (2.8 g).
  • Step B Under nitrogen protection and ice bath, 24-3 (2.8 g), anhydrous methanol (50 mL), nickel chloride hexahydrate (2.55 g) were added to a single-mouth bottle in sequence, and sodium borohydride (3.24 g) was added in batches. After the addition was completed, the mixture was stirred at room temperature for 1 h. 50 mL of saturated ammonium chloride solution was added to quench the reaction, and the methanol was removed by concentration, and then extracted with EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 24-4 (1.5 g).
  • Step C Under nitrogen protection, 1-2 (300 mg), 24-4 (378 mg), tris(dibenzylideneacetone)dipalladium(0) (112 mg), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (95 mg), cesium carbonate (666 mg), triethylamine (1.12 mL), and toluene (30 mL) were added to a single-necked bottle in sequence; React at 110°C for 4 h.
  • Step D Nitrogen protection, ice bath, add 24-5 (250 mg), THF (10 mL) to a single-mouth bottle, add lithium aluminum hydride tetrahydrofuran solution (0.263 mL, 2.5 M) dropwise, add 0.1 M sodium hydroxide solution 10 mL to quench, then extract with EA, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 24 (120 mg). MS (ESI+, [M+H] + ) m/z: 430.22.
  • Step E Compound 24 (120 mg) was purified by silica gel column chromatography and then subjected to chiral separation (YMC high pressure preparative chromatography: CHIRALART Cellulose-SC column, ethanol/n-hexane). The first eluting peak was compound 24_A (50 mg), and the later eluting peak was compound 24_B (50 mg).
  • Step A Add 25-1 (500 mg) to a single-mouth bottle, dissolve it in methanol (15 mL), add thionyl chloride (0.9 mL) under ice bath conditions, and then transfer to 60°C and heat with stirring for 5 h. After the reaction is completed, stop the reaction, add 20 mL of toluene, and spin dry the solvent to obtain 25-2 (700 mg).
  • 1 HNMR 500 MHz, DMSO-d 6 ) ⁇ 3.65 (s, 3H), 3.61 (s, 3H), 3.51-3.42 (m, 1H), 2.77-2.68 (m, 2H), 2.50-2.36 (m, 2H), 1.95-1.76 (m, 2H).
  • Step B Add 25-2 (700 mg), methanol (15 mL) and triethylamine (1.5 mL) to a single-mouth bottle, heat and reflux at 65 ° C for 3 h. After the reaction is completed, stop the reaction, spin dry the solvent, add ethyl acetate (30 mL), filter, and spin dry the filtrate again to obtain 25-3 (470 mg).
  • Step C Referring to the synthesis of Example 1, in step B, 25-3 was used to replace 4-hydroxy-2-pyrrolidone, and the obtained crude product was purified by silica gel column chromatography to obtain 25-4 (215 mg). MS (ESI+, [M+H] + ) m/z: 444.21.
  • Step D Add 25-4 (180 mg), methanol (6 mL), tetrahydrofuran (2 mL) and sodium hydroxide (640 mg) in water (8 mL) to a single-mouth bottle, and heat and stir at 50 ° C for 2 h. After the reaction is completed, stop heating, cool to room temperature, add 20 mL of water, and adjust the solution pH to about 4 with 1N hydrochloric acid aqueous solution. Extract with ethyl acetate, combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter and spin dry the filtrate to obtain 25-5 (170 mg). MS (ESI+, [M+H] + ) m/z: 430.24.
  • Step E Add 25-5 (200 mg), tetrahydrofuran (10 mL) and N-methylmorpholine (52 mg) to a single-mouth bottle, add isobutyl chloroformate (70 mg) under ice bath conditions, stir at room temperature for 1.5 h, then add sodium borohydride (106 mg), and continue stirring at room temperature for 12 h. After the reaction is completed, stop the reaction, add 30 mL of water, and add 1N hydrochloric acid aqueous solution (2 mL) to quench the reaction.
  • Extract with ethyl acetate combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain compound 25 (100 mg).
  • Step A Referring to the synthesis of Example 1, in step B, 4-hydroxy-2-pyrrolidone was replaced with 26-1 to obtain compound 26 (130 mg).
  • Step B Compound 26 was subjected to chiral separation (YMC high pressure preparative chromatography: CHIRALART Cellulose-SC column, ethanol/n-hexane).
  • the first eluting peak was compound 26_A (58 mg), and the later eluting peak was compound 26_B (58 mg).
  • Step A Under nitrogen protection, add 27-1 (5.0 g), 27-2 (5.87 g), and NMP (30 mL) to a single-mouth bottle in sequence, and heat to 120°C for 4 h. The reaction solution is cooled to room temperature, slowly poured into ice water (300 mL), filtered, and the filter cake is washed with water and PE, and dried to obtain compound 27-3 (8.4 g). MS (ESI+, [M+H]+) m/z: 264.08.
  • Step B Under nitrogen protection, 27-3 (2.00 g), N,O-dimethylhydroxylamine hydrochloride (1.10 g), EDCI (2.18 g), DMAP (1.39 g), and DCM (30 mL) were added to a single-mouth bottle in sequence and reacted at room temperature for 3 h. 0.1 M hydrochloric acid (20 mL) was added to the reaction solution, and the organic phase was separated, washed with saturated sodium bicarbonate, 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 to obtain compound 27-4 (2.3 g). MS (ESI+, [M+H]+) m/z: 307.17.
  • Step C Nitrogen protection, ice bath, add 27-4 (2.2 g), 2-MeTHF (30 mL) to a three-necked flask in sequence, add methylmagnesium bromide (4.33 mL, 3M tetrahydrofuran solution), stir at 0°C for 60 min, and react at room temperature for 2 h. Add 1M hydrochloric acid (20 mL) at 0°C to quench. Separate the organic phase and wash with saturated sodium carbonate solution and saturated brine. Dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the crude product by silica gel column chromatography (PE/EA). Compound 27-5 (1.55 g) is obtained. MS (ESI+, [M+H] + ) m/z: 262.30
  • Step D Nitrogen protection, ice bath, add 27-5 (425 mg), methanol (10 mL) to a single-mouth bottle, add sodium borohydride (73.8 mg) in batches, stir for 30 min, and react at room temperature for 1 h. Add saturated ammonium chloride to quench the reaction. Then concentrate under reduced pressure to remove most of the methanol, add water (10 mL), and extract with EA. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain 27-6 (0.4 g). MS (ESI+, [M+H] + ) m/z: 264.17
  • Step E Under nitrogen protection, add 27-6 (0.4 g) and TFA (3 mL) to a microwave tube, place in a microwave reactor, heat to 90°C and react for 60 min. Add water (0.5 mL), then concentrate and drain to obtain compound 27-7 (0.3 g).
  • Step F Referring to the synthesis of Example 1, in step B, 27-7 was used to replace 4-hydroxy-2-pyrrolidone to obtain compound 27 (90 mg). MS (ESI+, [M+H] + ) m/z: 416.29.
  • Step A Glycine methyl ester hydrochloride (6.70 g), acetonitrile (100 mL), 4-methoxybenzyl chloride (18.39 g), and DIPEA (20.69 g) were added to an eggplant-shaped bottle in sequence, and the mixture was reacted at 110°C overnight. Water (150 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE/EA) to obtain compound 28-1 (17 g). MS (ESI+, [M+H] + ) m/z: 330.14.
  • Step B Add 28-1 (17 g), tetrahydrofuran (20 mL), methanol (20 mL), water (20 mL) and NaOH (10.32 g) to an eggplant-shaped bottle in sequence, stir at room temperature for 2 h, adjust the pH to 6-7 with 6M hydrochloric acid, filter, wash the filter cake with petroleum ether and dry in vacuo to obtain compound 28-2 (16 g).
  • Step C Add 28-2 (16 g), dichloromethane (100 mL), N,O-dimethylhydroxylamine hydrochloride (3.72 g), HATU (28.9 g), and DIPEA (19.67 g) to an eggplant-shaped bottle in sequence, and stir at room temperature for 4 h.
  • the reaction solution was concentrated and purified by silica gel column chromatography (PE/EA) to obtain compound 28-3 (12 g).
  • Step D Add 28-3 (10 g) and tetrahydrofuran (10 mL) to an eggplant-shaped bottle in sequence, and stir under N2 protection in an ice bath for 5 min, then add methylmagnesium bromide in ether (3 mol/L, 13 mL), and continue to react in an ice bath for 1 h. Add water (150 mL) to the reaction solution and extract with ethyl acetate, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is purified by silica gel column chromatography (eluent: PE/EA) to obtain compound 28-4 (7.2 g). MS (ESI+, [M+H] + ) m/z: 314.14.
  • Step E Ethyl acetate (1.23 g) and tetrahydrofuran (30 mL) were added to a two-necked flask in sequence. After N2 protection, the mixture was placed in a -78°C low temperature tank and stirred for 10 min. LDA (2M tetrahydrofuran solution, 7 mL) was added. After stirring for 10 min, a tetrahydrofuran (30 mL) solution of 28-4 (3 g) was added. After 15 min, the reaction solution was moved to room temperature and the reaction was continued to be stirred.
  • LDA 2M tetrahydrofuran solution, 7 mL
  • a tetrahydrofuran (30 mL) solution of 28-4 (3 g) was added. After 15 min, the reaction solution was moved to room temperature and the reaction was continued to be stirred.
  • Step F Add 28-5 (50 mg), ethanol (20 mL), palladium carbon (10% wt, 50 mg) to an eggplant-shaped bottle in sequence, replace with hydrogen, and heat to 80°C for 1 h. Filter the reaction solution and spin dry to obtain compound 28-6 (45 mg). MS (ESI+, [M+H] + ) m/z: 162.11.
  • Step G Add 28-6 (45 mg), water (2 mL) and concentrated aqueous ammonia (2 mL) to an eggplant-shaped bottle in sequence, and stir at room temperature for 1 h. The reaction solution was directly spin-dried to obtain compound 28-7 (30 mg). MS (ESI+, [M+H] + ) m/z: 116.07.
  • Step H Referring to the synthesis of Example 1, in step B, 28-7 was used instead of 4-hydroxy-2-pyrrolidone to obtain compound 28 (40 mg).
  • Step A Referring to the synthesis of Example 1, in step B, 4-hydroxy-2-pyrrolidone was replaced with 5-hydroxymethyl-1,3-oxazolidin-2-one to obtain compound 29 (220 mg), HRMS (ESI+, [M+H] + ) m/z: 404.1113.
  • Step A DMF (15 mL), 7-bromo-4-chloro-2-methylquinazoline (500 mg), 4-trifluoromethylphenol (472 mg) and cesium carbonate (1.90 g) were added to an eggplant-shaped bottle in sequence, and the temperature was raised to 80°C for reaction for 3 h. Water (150 mL) was added to the reaction solution and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE/EA) to obtain compound 30-2 (650 mg). MS (ESI+, [M+H] + ) m/z: 383.09.
  • Step B 30-2 (200 mg), 4-hydroxymethyl-2-pyrrolidone (72 mg), Pd 2 (dba) 3 (10 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (18 mg), cesium carbonate (510 mg), 1,4-dioxane (20 mL) were added to a single-mouth bottle in sequence, and heated to 110°C for 4 h under nitrogen protection.
  • Step A Referring to step A of Example 30, 7-bromo-4-chloro-quinoline was used to replace 7-bromo-4-chloro-2-methylquinazoline to obtain compound 31-2 (670 mg). MS (ESI+, [M+H] + ) m/z: 368.03.
  • Step B Referring to the process of step B of Example 30, compound 31-2 was used to replace compound 30-2 to prepare compound 31 (70 mg).
  • Step A Add 32-1 (5 g) and dimethyl ethylphosphoryl acetate (15.07 g) to an eggplant-shaped bottle in sequence, stir under ice bath for 10 min, then add KOH (53 g) in water (63 mL), after 30 min, move the reaction solution to room temperature and stir overnight.
  • the reaction solution was extracted with DCM, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 32-2 (7.2 g), which was directly used in the next step.
  • Step B Add 32-2 (1 g) and tetrahydrofuran (25 mL) to an eggplant-shaped bottle, place in a -10°C low temperature tank and stir for 10 min, then add nitromethane (0.46 g) and TBAF (1M tetrahydrofuran solution, 7.5 mL), and continue to react at low temperature for 4 h. Add 100 mL of water to the reaction solution, extract with EA, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 32-3 (1.07 g). GC-MS (EI, M + ) m/z: 261.
  • Step C 32-3 (1.07 g), methanol (50 mL), Pd(OH) 2 (0.58 g), and ammonium formate (1.29 g) were added to an eggplant-shaped bottle in sequence, and the temperature was raised to 80°C under a hydrogen atmosphere for reflux reaction overnight.
  • the reaction solution was cooled to room temperature, filtered, and 100 mL of water was added to the filtrate, extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 32-4 (750 mg), which was directly used in the next step.
  • Step D Referring to step B of Example 30, compound 1-2 was substituted for 30-2, and compound 32-4 was substituted for 4-hydroxymethyl-2-pyrrolidone to obtain compound 32-5 (80 mg). MS (ESI + , [M+H] + ) m/z: 472.25.
  • Step A Under nitrogen protection and ice bath, add p-trifluoromethylphenol (399 mg), THF (10 mL), potassium tert-butoxide (323 mg) to a single-mouth bottle, stir for 10 min, add 33-1 (500 mg), and react at 0°C for 3 h.
  • Step B Referring to the reaction process of step B in Example 30, compound 33-2 was used to replace compound 30-2 to obtain compound 33 (130 mg).
  • Step A Add 34-1 (5.0 g), THF (50 mL), H 2 O (50 mL) and sodium carbonate (7.06 g) to a two-necked bottle in sequence. Stir the mixture at room temperature for 0.5 h under N 2 protection. Then cool to 0°C and add a solution of benzyl chloroformate (6.82 g) in THF (20 mL) dropwise. After the addition, stir the mixture at room temperature overnight. After the reaction is completed, pour the reaction solution into 100 mL of water, concentrate under reduced pressure to remove THF, extract with EA, discard the organic phase, place the aqueous phase under an ice bath, adjust the pH to 1-2 with 2M hydrochloric acid, filter, and wash the filter cake with water. Dry under reduced pressure to obtain intermediate 34-2 (6.5 g). MS (ESI+, [M+Na] + )m/z: 289.04.
  • Step B Add 34-2 (6.5 g), DMF (100 mL) and sodium bicarbonate (4.1 g) to a two-necked bottle in sequence. Under N2 protection, cool the mixture to 0°C, add iodomethane (8.66 g) dropwise, and stir the mixture overnight at room temperature. After the reaction is completed, pour the reaction solution into 100 mL of ice water, extract with EA, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to remove the solvent. Add the obtained crude product to a mixed solvent (PE/EA) and beat to obtain intermediate 34-3 (4.0 g). MS (ESI+, [M+Na] + ) m/z: 303.05.
  • Step C Add 34-3 (4.0 g), THF (200 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.34 g) to a single-mouth bottle, cool the mixture to 0°C, add iodophenyldiacetic acid (9.2 g), stir the mixture at 0°C for 20 minutes; after the reaction, pour the reaction solution into 100 mL of ice water, extract with EA, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to remove the solvent, and the obtained crude product is purified by silica gel column chromatography (MeOH/DCM) to obtain intermediate 34-4 (1.58 g). MS (ESI+, [M+H] + ) m/z: 278.95.
  • Step D 1-2 (400 mg), 34-4 (455 mg), Pd(OAc) 2 (36 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (104 mg), cesium carbonate (1.0 g) and 1,4-dioxane (50 mL) were added to a single-mouth bottle in sequence, and heated to 110°C for reflux reaction for 1 h under N 2 protection. After the reaction was completed, 100 mL of water was added, EA was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (PE/EA) to obtain intermediate 34-5 (501 mg). MS (ESI+, [M+H] + ) m/z: 565.31.
  • Step E Add 34-5 (500 mg), MeOH (20 mL), THF (10 mL) and Pd/C (10% wt, 95 mg) to a single-mouth bottle in sequence. After the addition, replace with H 2 5 times, and stir the mixture at room temperature overnight under H 2 atmosphere. After the reaction is completed, filter directly, and concentrate the filtrate under reduced pressure to dryness to obtain intermediate 34-6 (368 mg). MS (ESI-, [MH] - ) m/z: 429.36.
  • Step F Add 34-6 (170 mg) and DMF (5 mL) to a two-necked bottle in sequence. Under N2 protection, cool the mixture to 0°C, add sodium hydride (60% wt purity, 55 mg) in batches, and add iodomethane (84 mg) dropwise after 10 minutes. After the addition, stir the mixture at 0°C for 1 hour. After the reaction is completed, pour the reaction solution into 100 mL of ice saturated ammonium chloride solution, extract with EA, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent to obtain intermediate 34-7 (176 mg). MS (ESI-, [MH] - ) m/z: 443.21.
  • Step G Referring to step B of Example 21, compound 34-7 was used to replace compound 21-1 to obtain compound 34 (150 mg). MS (ESI+, [M+H] + ) m/z: 417.24.
  • Step A Referring to step B of Example 21, compound 34-6 was used to replace compound 21-1 to obtain compound 35 (130 mg). MS (ESI+, [M+H] + ) m/z: 403.26.
  • Step A Add 34-4 (600 mg), THF (20 mL), triethylamine (655 mg), di-tert-butyl dicarbonate (710 mg) and 4-dimethylaminopyridine (26 mg) to a single-mouth bottle in sequence, and stir the mixture at room temperature for 5 h under N2 protection; after the reaction, pour the reaction solution into 100 mL of water, extract with EA, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to remove the solvent, and the obtained crude product is purified by silica gel column chromatography (MeOH/DCM) to obtain intermediate 36-1 (770 mg). MS (ESI+, [M+Na] + ) m/z: 401.27.
  • Step B 36-1 (770 mg), MeOH (20 mL) and Pd/C (10% wt purity, 217 mg) were added to a single-mouth bottle in sequence. After the addition was completed, H 2 was replaced 5 times, and the mixture was stirred at room temperature overnight under H 2 atmosphere; after the reaction was completed, it was directly filtered and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate 36-2 (510 mg). MS (ESI+, [M+H] + ) m/z: 245.05.
  • Step C Referring to step D of Example 34, compound 36-2 was used to replace compound 34-4 to obtain intermediate 36-3 (234 mg). MS (ESI+, [M+Na] + ) m/z: 553.30.
  • Step D Add 36-3 (234 mg) and 4M hydrogen chloride-dioxane solution (5 mL) to a single-mouth bottle, and stir the reaction at room temperature for 0.5 h. After the reaction, slowly add the reaction solution dropwise to a saturated sodium bicarbonate solution (100 mL) under an ice bath, extract with EA, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to remove the solvent. The crude product is purified by silica gel column chromatography to obtain intermediate 36-4 (184 mg). MS (ESI+, [M+H] + ) m/z: 431.00.
  • Step E Referring to step B of Example 21, compound 36-4 was used to replace compound 21-1 to obtain compound 36 (67 mg).
  • Step A Referring to step F of Example 34, intermediate 36-4 was used to replace intermediate 34-6 to obtain intermediate 37-1 (76 mg). MS (ESI+, [M+H] + ) m/z: 445.28.
  • Step B Referring to step B of Example 21, intermediate 37-1 was used to replace intermediate 21-1 to obtain compound 37 (60 mg).
  • Step A Add 38-1 (1 g) and THF (20 mL) to a two-necked bottle. Under N2 protection, slowly add 1M lithium hexamethyldisilazide (17.5 mL) at -78°C, and stir at -20°C for 1 hour. Slowly add benzyl chloromethyl ether (1.15 mL) at -78°C, and stir at -20°C for 2 hours. After the reaction, add 20 mL of saturated aqueous ammonium chloride solution, extract with dichloromethane, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is purified by silica gel column chromatography (DCM/MeOH) to obtain compound 38-2 (1.2 g). MS (ESI+, [M+H] + ) m/z: 264.12.
  • Step B Referring to the synthesis of Example 1, in step B, 38-2 was used to replace 4-hydroxy-2-pyrrolidone to obtain compound 38-3 (220 mg). MS (ESI+, [M+H] + ) m/z: 550.18.
  • Step C 38-3 (220 mg), 10% Pd/C (42.6 mg), and MeOH (20 mL) were added to a round-bottom flask in sequence. The mixture was stirred at room temperature under H2 for 16 hours. After the reaction was completed, the filtrate was filtered and concentrated to dryness under reduced pressure to obtain 38-4 (120 mg). MS (ESI+, [M+H] + ) m/z: 460.18.
  • Step D 38-4 (120 mg), lithium borohydride (8.53 mg), and THF (20 mL) were added to a round-bottom flask in sequence. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, 20 mL of water was added, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 38 (83 mg).
  • Step A 1-1 (0.29 g), 4-fluorophenyl sulfur pentafluoride (0.29 g), cesium carbonate (1.27 g) and DMF (10 mL) were added to a microwave tube in sequence, and microwave heating was performed at 120°C for 2 h. After the reaction was completed, 100 mL of water was added, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE/EA) to obtain compound 39-1 (0.51 g). MS (ESI-, [MH] - ) m/z: 423.00.
  • Step B Referring to step B of Example 38, compound 39-1 was used to replace 1-2, and 4-hydroxymethyl-2-pyrrolidone was used to replace 38-2 to obtain compound 39 (238 mg). MS (ESI+, [M+H] + ) m/z: 460.21.
  • Step A Add benzyl glycidyl ether (2.50 g), dichloromethane (35 mL), benzylamine (1.47 g), and lithium bis(trifluoromethanesulfonyl)imide (0.44 g) to the reaction flask in sequence and react at room temperature overnight.
  • the reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM/MeOH) to obtain compound 40-1 (1.70 g).
  • Step B Add 40-1 (3.00 g), dichloromethane (30 mL), triethylamine (3.36 g), and methanesulfonic anhydride (5.78 g) to the reaction bottle in sequence and react at room temperature for 20 minutes. Add saturated sodium bicarbonate aqueous solution (30 mL) to the reaction solution to quench, extract the resulting mixture with ethyl acetate, combine the organic layers, and purify by silica gel column chromatography (PE/EA) to obtain compound 40-2 (2.90 g). HRMS (ESI+, [M+H] + ) m/z: 428.1210.
  • Step C Add 40-2 (2.70 g) and tetrahydrofuran (78 mL) to the reaction bottle in sequence. After N2 protection, stir at -78°C for 10 min and then add n-butyl lithium (1.6 M tetrahydrofuran solution, 9.87 mL). After the addition, move the reaction solution to room temperature and react for 16 hours. Add saturated aqueous ammonium chloride solution (100 mL) to the reaction solution to quench, extract the resulting mixture with ethyl acetate, combine the organic layers, and purify by silica gel column chromatography (PE/EA) to obtain compound 40-3 (0.35 g). MS (ESI+, [M+H] + ) m/z: 332.25.
  • Step D Add 40-3 (0.22 g), ethanol (2 mL), palladium carbon (1.41 g) to the reaction bottle in sequence, replace the hydrogen three times, and heat to 80 ° C for 17 hours.
  • the reaction solution was filtered and the filtrate was concentrated to dryness under reduced pressure to obtain compound 40-4 (0.16 g).
  • HRMS (ESI+, [M+H] + ) m/z: 242.0852.
  • Step E Add 40-4 (0.16 g), ethanol (2 mL), palladium carbon (1.41 g) to the reaction bottle in sequence, replace the hydrogen three times, heat to 80 ° C for 6.5 hours, transfer to room temperature for 16 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain compound 40-5 (0.10 g).
  • HRMS (ESI+, [M+H] + ) m/z: 152.0365.
  • Step F 1-2 (0.25 g), 40-5 (0.10 g), cesium carbonate (0.67 g), allylpalladium chloride (II) dimer (12.3 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (28.9 mg), 1,4-dioxane (2 mL) were added to the reaction bottle in sequence, and the mixture was replaced with nitrogen three times, and then heated to 110°C for 2.5 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure, purified by silica gel column chromatography, and then separated by high pressure preparative liquid phase separation (Xtimate C18 column) to obtain Example 40 (50 mg).
  • Step A Add 34-6 (250 mg), MeOH (2 mL), THF (2 mL), H 2 O (1 mL) and sodium hydroxide (89 mg) to a single-mouth bottle in sequence. After the addition, stir the mixture at room temperature for 2 h. After the reaction is completed, pour the reaction solution into 20 mL of water, adjust the pH to 1-2 with 2M hydrochloric acid, extract with EA, wash the organic phase with saturated sodium chloride, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to remove the solvent to obtain intermediate 41-1 (242 mg). MS (ESI-, [MH] - ) m/z: 415.20.
  • Step B Add 41-1 (227 mg), DCM (10 mL), N,O-dimethylhydroxylamine hydrochloride (150 mg), HATU (311 mg) and DIPEA (423 mg) to a single-mouth bottle in sequence. After the addition, stir the mixture at room temperature for 1 h. After the reaction, pour the reaction solution into 20 mL of water, extract with EA, and purify by silica gel column chromatography (MeOH/DCM) to obtain compound 41-2 (146 mg). MS (ESI+, [M+H] + ) m/z: 460.18.
  • Step C Add 41-2 (126 mg) and THF (5 mL) to a single-mouth bottle in sequence. Under N2 protection, cool the mixture to 0°C, add 3M methylmagnesium bromide solution (0.27 mL) dropwise, and stir at room temperature overnight. After the reaction is completed, slowly add the reaction solution to saturated sodium bicarbonate solution (20 mL) under ice bath, extract with EA, and purify by silica gel column chromatography (MeOH/DCM) to obtain intermediate 41-3 (88 mg). MS (ESI-, [MH] - ) m/z: 413.23.
  • Step D To a single-necked bottle, 41-3 (80 mg) and MeOH (3 mL) were added in sequence. Under N2 protection, the temperature was lowered to 0°C, and then sodium borohydride (80 mg) was added in batches. After the addition was completed, stirring was continued for 1 h. After the reaction was completed, the reaction solution was slowly poured into an ice-cold saturated ammonium chloride solution (20 mL), extracted with EA, and purified by silica gel column chromatography to obtain Example 41 (74 mg).
  • Example 41 1 H NMR (500 MHz, DMSO-d 6 ) ⁇ 8.21-8.19 (m, 1H), 7.85-7.82 (m, 2H), 7.73-7.71 (m, 3H), 7.49-7.46 (m, 1H), 7.35-7.27 (m, 1H), 7.14-7.12 (m, 2H), 7.06-7.04 (m, 1H), 4.95-4.88 (m, 1H), 4.04-3.98 (m, 1H), 3.85-3.72 (m, 1H), 3.65-3.60 (m, 1H), 3.56-3.51 (m, 1H), 1.12-1.09 (m, 3H). MS (ESI+, [M+H] + ) m/z: 417.24.
  • Step A Add 29 (500 mg), acetonitrile (20 mL), 2,2,6,6-tetramethylpiperidinoxide (291 mg), and iodophenyldiacetic acid (1.20 g) to the reaction bottle in sequence and react at room temperature for 5.5 hours. Add water (50 mL) to the reaction solution, extract the resulting mixture with ethyl acetate, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 42-1 (517 mg). MS (ESI-, [M+H] - ) m/z: 416.19.
  • Step B 42-1 (517 mg), dimethylhydroxylamine hydrochloride (338 mg), HATU (707 mg), N, N-diisopropylethylamine (961 mg) were added to the reaction bottle in sequence and reacted at room temperature for 21.5 hours. Water (50 mL) was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined and purified by silica gel column chromatography (PE/EA) to obtain compound 42-2 (280 mg). HRMS (ESI+, [M+Na] + ) m/z: 483.1139.
  • Step C Add 42-2 (270 mg) and tetrahydrofuran (20 mL) to the reaction bottle in sequence, add methylmagnesium bromide (3M tetrahydrofuran solution, 0.98 mL) dropwise under ice bath, and transfer to room temperature for reaction for 3.5 hours. Add saturated aqueous ammonium chloride solution (50 mL) to the reaction solution, extract the resulting mixture with ethyl acetate, combine the organic layers, and purify by silica gel column chromatography (PE/EA) to obtain compound 42-3 (170 mg). MS (ESI-, [M+H] - ) m/z:414.20.
  • Step D 42-3 (160 mg) and methanol (1 mL) were added to the reaction bottle in sequence, sodium borohydride (146 mg) was added under ice bath, and the mixture was transferred to room temperature for reaction for 2.5 hours. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate, the organic layers were combined, and purified by silica gel column chromatography to obtain compound 42 (150 mg). MS (ESI+, [M+H] + ) m/z: 418.21.
  • Step A Add 43-1 (3.52 g), MeOH (50 mL) and potassium carbonate (6.78 g) to the reaction bottle in sequence, cool to 0°C, then add di-tert-butyl dicarbonate (6.41 g) in batches, and stir at room temperature to react overnight. After the reaction is completed, pour the reaction solution into 100 mL of water, extract with EA, and purify by silica gel column chromatography (PE/EA) to obtain intermediate 43-2 (4.80 g).
  • 1 H NMR 500 MHz, DMSO-d 6 ) ⁇ 3.65-3.60 (m, 2H), 3.45-3.44 (m, 2H), 2.42-2.36 (m, 2H), 1.41 (s, 9H).
  • Step B Add 43-2 (3.80 g), EA (80 mL), H 2 O (80 mL) and ruthenium trichloride (0.23 g) to the reaction bottle in sequence, cool to 0°C, then add sodium periodate (15.7 g) in batches, and stir at room temperature overnight. After the reaction is completed, pour the reaction solution into 100 mL of water, extract with EA, and purify by silica gel column chromatography (PE/EA) to obtain intermediate 43-3 (2.28 g).
  • 1 H NMR 500 MHz, DMSO-d 6 ) ⁇ 4.10-4.04 (m, 2H), 3.26-3.21 (m, 2H), 1.46 (s, 9H).
  • Step C Add 43-3 (330 mg) and 4M hydrogen chloride-dioxane solution (5 mL) to the reaction bottle, and stir the reaction at room temperature for 0.5 h. After the reaction, the reaction solution was directly concentrated to dryness to obtain intermediate 43-4 (181 mg).
  • Step D Referring to the synthesis of Example 1, in step B, 43-4 was used to replace 4-hydroxy-2-pyrrolidone to obtain Example 43 (56 mg).
  • Step A 35 (300 mg) and dichloromethane (6 mL) were added to the reaction flask in sequence, and diethylaminosulfur trifluoride (0.15 mL) was slowly added dropwise under ice bath, and the reaction was continued for 1.5 hours. Water (10 mL) was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate and purified by silica gel column chromatography to obtain the actual Example 44 (120 mg).
  • Step A Compound 45-1 (1.00 g), 1-fluoro-4-trifluoromethyl-benzene (3.68 g), cesium carbonate (7.30 g) and DMF (10 mL) were added to a microwave tube in sequence and heated to 120° C. for 2 h. After the reaction, water was added, extracted with ethyl acetate, the organic layers were combined, and purified by silica gel column chromatography to obtain compound 45-2 (1.45 g).
  • Step B Compound 45-2 (1.0 g), diethyl malonate (0.62 mL), n-butyl di(1-adamantyl) phosphine (78.0 mg), allyl palladium (II) chloride dimer (40.0 mg), cesium carbonate (1.78 g), 1,4-dioxane (20 mL) were added to the reaction bottle in sequence, and heated to 100 ° C for 8 h under N 2 protection. After the reaction, water was added, extracted with ethyl acetate, the organic layers were combined, and purified by silica gel column chromatography to obtain compound 45-3 (370 mg). MS (ESI-, [MH] - ) m/z: 445.19.
  • Step C Compound 45-3 (170 mg), bromoacetonitrile (91 mg), and THF (1 mL) were added to a single-mouth bottle in sequence, and NaH (22.85 mg, 60% w/w) was added at 0°C under nitrogen protection, and then heated to 60°C for 1 h. After the reaction was completed, saturated ammonium chloride was used to quench, and the mixture was extracted with ethyl acetate. The organic layers were combined and purified by silica gel column chromatography to obtain compound 45-4 (130 mg). MS (ESI-, [MH] - ) m/z: 484.22.
  • Step D Compound 45-4 (130 mg), cobalt chloride hexahydrate (127 mg), and methanol (2 mL) were added to a single-mouth bottle in sequence.
  • Sodium borohydride (101 mg) was added in batches at 0°C, and then stirred at room temperature for 1 h. After the reaction was completed, saturated ammonium chloride was used to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined and purified by silica gel column chromatography to obtain compound 45-5 (60 mg).
  • Step E Add 45-5 (60 mg), anhydrous calcium chloride (15 mg), and THF (2 mL) to a single-mouth bottle in sequence, add sodium borohydride (11 mg) in batches at 0°C, and then stir at room temperature for 1 hour. After the reaction is completed, quench with saturated aqueous ammonium chloride solution, extract with ethyl acetate, combine the organic layers, and purify by silica gel column chromatography to obtain compound 45 (40 mg). MS (ESI-, [MH] - ) m/z: 400.23.
  • Step F Compound 45 (30 mg) was separated by supercritical fluid chromatography (CHIRALART Amylose-SA 5 ⁇ m 20*100 mm column; CO 2 -ethanol elution), the first eluting peak was 45_A (10 mg), and the second eluting peak was 45_B (10 mg).
  • Test Example 1 In vitro protein thermal stability
  • the hTEAD1 protein stock solution was diluted to 50 ng/ ⁇ l with phosphate buffered saline (PBS), and the 5000 ⁇ protein dye (SYPRO Orange Dye) was diluted to 20 ⁇ with DMSO. 16 ⁇ l hTEAD1 protein diluent was added to the 96-well plate, and then different compounds dissolved in DMSO were added to the wells using a nanoliter pipette to make the final concentration of the compound 10 ⁇ M and 1 ⁇ M, a total of 2 concentrations. At the same time, blank control wells (without protein) and negative control wells (with protein, with solvent DMSO) were set up, and 2 duplicate wells were set up.
  • PBS phosphate buffered saline
  • SYPRO Orange Dye 5000 ⁇ protein dye
  • the hTEAD2 protein stock solution was diluted to 50 ng/ ⁇ l with phosphate buffered saline (PBS), and the 5000 ⁇ protein dye (SYPRO Orange Dye) was diluted to 20 ⁇ with DMSO. 16 ⁇ l hTEAD2 protein diluent was added to the 96-well plate, and then different compounds dissolved in DMSO were added to the wells using a nanoliter pipette to make the final concentration of the compound 10 ⁇ M and 1 ⁇ M, a total of 2 concentrations. At the same time, blank control wells (without protein) and negative control wells (with protein, with solvent DMSO) were set up, and 2 duplicate wells were set up.
  • PBS phosphate buffered saline
  • SYPRO Orange Dye 5000 ⁇ protein dye
  • the hTEAD3 protein stock solution was diluted to 50 ng/ ⁇ l with phosphate buffered saline (PBS), and the 5000 ⁇ protein dye (SYPRO Orange Dye) was diluted to 20 ⁇ with DMSO. 16 ⁇ l of hTEAD3 protein dilution was added to a 96-well plate, and the DMSO-dissolved solution was pipetted into the wells of the plate using a nanoliter pipette. Different compounds were added to the wells to make the final concentrations of the compounds 10 ⁇ M and 1 ⁇ M, a total of 2 concentrations. At the same time, blank control wells (without protein) and negative control wells (with protein, with solvent DMSO) were set up, and 2 duplicate wells were set up.
  • PBS phosphate buffered saline
  • SYPRO Orange Dye 5000 ⁇ protein dye
  • the hTEAD4 protein stock solution was diluted to 50 ng/ ⁇ l with phosphate buffered saline (PBS), and the 5000 ⁇ protein dye (SYPRO Orange Dye) was diluted to 20 ⁇ with DMSO. 16 ⁇ l hTEAD4 protein diluent was added to the 96-well plate, and then different compounds dissolved in DMSO were added to the wells using a nanoliter pipette to make the final concentration of the compound 10 ⁇ M and 1 ⁇ M, a total of 2 concentrations. At the same time, blank control wells (without protein) and negative control wells (with protein, with solvent DMSO) were set up, and 2 duplicate wells were set up.
  • PBS phosphate buffered saline
  • SYPRO Orange Dye 5000 ⁇ protein dye
  • the disclosed compounds have good binding activity with proteins (TEAD1, TEAD2, TEAD3 and TEAD4 proteins).
  • Test Example 2 In vitro cell proliferation inhibitory activity
  • NCI-H2452 (NF2 wild type) human mesothelioma cells in good growth state were collected into centrifuge tubes, the cell density was adjusted to 4000 cells/mL, and the cells were inoculated on 96-well plates (100 ⁇ L/well). After culturing in a cell culture incubator for 24 hours, the compound was added using a nanoliter pipette to make the final concentration of the compound 10000nM-0.61nM, 2 replicates, and a control was set at the same time. After continuing to culture in the cell culture incubator for 168 hours, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 ⁇ L/well) was added, and the cells were incubated in the cell culture incubator for 2 hours. The absorbance was detected at 450nm using a PerkinElmer Envision microplate reader, and the four-parameter analysis was performed to fit the dose-effect curve and calculate the IC 50 .
  • NCI-H226 (NF2-deficient) human lung squamous cell carcinoma cells in good growth state were collected into centrifuge tubes, the cell density was adjusted to 4000 cells/mL, and the cells were inoculated on 96-well plates (100 ⁇ L/well). After culturing in a cell culture incubator for 24 hours, the compound was added using a nanoliter pipette to make the final concentration of the compound 10000nM-0.61nM, 2 replicate wells, and a control was set at the same time. After continuing to culture in the cell culture incubator for 168 hours, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 ⁇ L/well) was added, and the cells were incubated in the cell culture incubator for 2 hours. The absorbance value was detected at 450nm by a PerkinElmer Envision microplate reader, and the four-parameter analysis was performed to fit the dose-effect curve and calculate the IC 50 .
  • NCI-H2052 NF2 homologous mutation
  • human mesothelioma cells in good growth state, collect them into centrifuge tubes, adjust the cell density to 4000 cells/mL, inoculate them on 96-well plates (100 ⁇ L/well), and culture them in a cell culture incubator for 24 hours. Then use a nanoliter pipette to add compounds, so that the final concentration of the compounds is 10000nM-0.61nM, 2 replicates, and set controls at the same time.
  • test results show that the disclosed compounds have proliferation inhibitory activity against NCI-H226 cells and NCI-H2052 cells, and have substantially no proliferation inhibitory activity against NCI-H2452 cells. Relative to NCI-H2452 cells, the compounds have good selectivity for NCI-H226 and NCI-H2052 cells.
  • the sample preparation for the incubation of liver microsomes was a mixture of PBS buffer (pH 7.4), liver microsome solution (0.5 mg/mL), the test compound and NADPH+MgCl2 solution incubated at 37°C and 300 rpm for 1 hour.
  • the sample preparation for 0 hours was a mixture of PBS buffer (pH 7.4), liver microsome solution (0.5 mg/mL), and the test compound.
  • the sample was added with an acetonitrile solution containing an internal standard to prepare a supernatant by protein precipitation, which was diluted for LC/MS/MS determination.
  • Table 2 The experimental results of some compounds are shown in Table 2.
  • ICR mice weighing 18-22 g were randomly divided into groups after acclimation for 3-5 days, with 9 mice in each group, and were intragastrically administered with a solution of the test compound at a dose of 10 mg/kg (or 2 mg/kg).
  • Blood was collected from the eye sockets at 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h to prepare plasma samples for testing.
  • mice have good pharmacokinetic properties in mice (e.g., AUC, T 1/2 , C max and other parameters)
  • the absolute bioavailability is F>90%).
  • SD rats weighing 180-220g were randomly divided into groups after 3-5 days of adaptation, with 3 rats in each group, and the test compound solution was administered according to the corresponding dose.
  • Blood was collected from the eye socket at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 24h, 30h, and 48h.
  • 30 ⁇ L of the plasma sample to be tested and the standard curve sample were drawn, and the supernatant was obtained by protein precipitation with acetonitrile solution containing internal standard, and diluted for LC/MS/MS determination.
  • the pharmacokinetic parameters were fitted using a non-compartmental model.
  • test results show that the disclosed compounds also have good pharmacokinetic properties in rats (for example, parameters such as AUC, T 1/2 , C max , etc. perform well, and absolute bioavailability F>90%).
  • NCI-H226 cells were subcutaneously inoculated in the right axilla of SPF female nude mice (source: Shanghai Bikeway Biotechnology Co., Ltd.), 5 ⁇ 106 cells/mouse. When the average tumor volume reached about 150 mm3, the animals were divided into groups.
  • the day of grouping was day 0. From day 0 onwards, drugs were administered by gavage once a day. Tumor volume was measured twice 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.
  • the detection indicators and calculation formula are as follows:
  • 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.
  • T/C (%) TRTV / CRTV ⁇ 100%;
  • TRTV is the RTV of the treatment group;
  • CRTV is the RTV of the vehicle control group.
  • 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.
  • 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.
  • test results show that the disclosed compounds can effectively inhibit tumor growth in mice (such as parameters such as T/C or TGI (%) showing the results of effectively inhibiting tumor growth).

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Abstract

A compound containing an aromatic bicyclic ring, which has a structure of formula IC, a preparation method therefor, a pharmaceutical composition containing the compound, and use thereof in treating tumor diseases.

Description

含有芳香双并环的化合物Compounds containing aromatic bicyclic rings

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

本公开要求向中国知识产权局提交的第202310547249.3号中国专利申请、第202311268745.1号中国专利申请、第202410070330.1号中国专利申请、第202410233399.1号中国专利申请和第202410561728.5号中国专利申请的优先权和权益，上述中国专利申请的全部内容通过援引并入本文。The present disclosure claims the priority and rights of Chinese Patent Application No. 202310547249.3, Chinese Patent Application No. 202311268745.1, Chinese Patent Application No. 202410070330.1, Chinese Patent Application No. 202410233399.1 and Chinese Patent Application No. 202410561728.5 filed with China Intellectual Property Office, the entire contents of which are incorporated herein by reference.

技术领域Technical Field

本公开涉及含有芳香双并环的化合物、其制备方法、含有该化合物的药物组合物、以及其在治疗肿瘤疾病中的用途。The present invention relates to a compound containing an aromatic bicyclic ring, a preparation method thereof, a pharmaceutical composition containing the compound, and use thereof in treating tumor diseases.

背景技术Background Art

Hippo信号级联是癌症生物发生和肿瘤维持的重要途径。在许多癌症适应症中，Hippo途径经由诸如NF2之类基因的功能缺失突变而出现大量突变。这些促肿瘤突变导致下游转录共活化因子YAP和TAZ的组成性活化，所述共活化因子经由与TEAD蛋白质家族成员的必要相互作用而驱动许多促存活和增殖基因的表达。TEAD蛋白是Hippo信号通路的下游效应子，可调节细胞增殖和干细胞功能。此外，这种不受限制的转录程式还驱动肿瘤微环境中免疫抑制的增强。直接抑制YAP/TAZ具有挑战性，因为YAP/TAZ是内在无序的蛋白，具有高度的结构灵活性。同样，小分子化合物很难干扰YAP-TEAD相互作用中。靶向这一致癌途径，鉴别出选择性结合于TEAD并破坏其YAP和TAZ的相互作用，由此下调YAP依赖性和TAZ依赖性转录的新型小分子抑制剂。TEAD抑制剂防止TEAD棕榈酰化，而TEAD棕榈酰化对于YAP与TEAD之间的相互作用至关重要。通过破坏TEAD功能间接抑制YAP活性，从而抑制肿瘤细胞的增殖。The Hippo signaling cascade is an important pathway for cancer biogenesis and tumor maintenance. In many cancer indications, the Hippo pathway is heavily mutated through loss-of-function mutations in genes such as NF2. These tumor-promoting mutations lead to constitutive activation of downstream transcriptional coactivators YAP and TAZ, which drive the expression of many pro-survival and proliferation genes through essential interactions with members of the TEAD protein family. TEAD proteins are downstream effectors of the Hippo signaling pathway that regulate cell proliferation and stem cell function. In addition, this unrestricted transcriptional program also drives enhanced immunosuppression in the tumor microenvironment. Direct inhibition of YAP/TAZ is challenging because YAP/TAZ are intrinsically disordered proteins with high structural flexibility. Similarly, it is difficult for small molecule compounds to interfere with the YAP-TEAD interaction. Targeting this oncogenic pathway, novel small molecule inhibitors that selectively bind to TEAD and disrupt its YAP and TAZ interactions, thereby downregulating YAP-dependent and TAZ-dependent transcription, were identified. TEAD inhibitors prevent TEAD palmitoylation, which is essential for the interaction between YAP and TEAD. It indirectly inhibits YAP activity by disrupting TEAD function, thereby suppressing the proliferation of tumor cells.

发明内容Summary of the invention

本公开提供式IC化合物或其药学上可接受的盐，
The present disclosure provides a compound of formula IC or a pharmaceutically acceptable salt thereof,

其中，in,

X1、X2、X3、X4及X5分别独立地选自N或CH；X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from N or CH;

Xa、Xb、Xc、Xd、Xe及Xf分别独立地选自N或任选地被一个或多个取代基取代的CH(具体的，分别独立地选自N或任选地被一个取代基取代的CH)； Xa , Xb , Xc, Xd , Xe and Xf are each independently selected from N or CH optionally substituted by one or more substituents (specifically, each independently selected from N or CH optionally substituted by one substituent);

X选自O、S、-S(O)-、-S(O)2-、-C(O)-、-C(O)O-、或任选地被一个或多个取代基取代的以下基团：NH、-N(C1-6烷基)-、-NH-C1-6烷基-、-C1-6烷基-O-、-C1-6烷基-S-或-C(O)NH-；X is selected from O, S, -S(O)-, -S(O) 2- , -C(O)-, -C(O)O-, or the following groups optionally substituted with one or more substituents: NH, -N( C1-6alkyl )-, -NH- C1-6alkyl- , -C1-6alkyl -O-, -C1-6alkyl -S-, or -C(O)NH-;

每一个R1分别独立地选自CN、卤素、或任选地被一个或多个取代基取代的以下基团：C1-6烷基、C2- 6烯基、C2-6炔基、R'O-、R'S-、-SF5、R'R”N-、R'OC(O)-、R'C(O)O-、-C(O)NR'R”、R'C(O)NH-、R'S(O)NH-、R'R”NS(O)-、R'S(O)2NH-、R'R”NS(O)2-、R'OC(O)NH-、R'R”NC(O)O-、C3-12环烷基、3-12元杂环烷基、C3- 12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；each R 1 is independently selected from CN, halogen, or the following groups optionally substituted by one or more substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, R'O-, R'S-, -SF 5 , R'R"N-, R'OC(O)-, R'C(O)O-, -C(O)NR'R", R'C(O)NH-, R'S(O)NH-, R'R"NS(O)-, R'S(O) 2 NH-, R'R"NS(O) 2 -, R'OC(O)NH-, R'R"NC(O)O-, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl, or 5-12 membered heteroaryl;

每一个R2分别独立地选自CN、卤素、＝O、或任选地被一个或多个取代基取代的以下基团：C1-6烷基、C2-6烯基、C2-6炔基、R'O-、R'S-、-SF5、R'R”N-、R'OC(O)-、R'C(O)O-、-C(O)NR'R”、R'C(O)NH-、R'R”NS(O)-、 R'S(O)NH-、R'R”NS(O)-、R'R”NS(O)2-、R'S(O)2NH-、R'R”NS(O)2-、R'OC(O)NH-、R'R”NC(O)O-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Each R 2 is independently selected from CN, halogen, =0, or the following groups optionally substituted by one or more substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, R'O-, R'S-, -SF 5 , R'R"N-, R'OC(O)-, R'C(O)O-, -C(O)NR'R", R'C(O)NH-, R'R"NS(O)-, R'S(O)NH-, R'R"NS(O)-, R'R"NS(O) 2- , R'S(O) 2NH- , R'R"NS(O) 2- , R'OC(O)NH-, R'R"NC(O)O-, C3-12cycloalkyl , 3-12memberedheterocycloalkyl, C3-12cycloalkenyl , 3-12memberedheterocycloalkenyl , C6-12aryl, or 5-12memberedheteroaryl;

R'及R”分别独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；R' and R" are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C6-12 aryl or 5-12 membered heteroaryl;

m及n分别独立地选自0、1、2、3、4或5；m and n are independently selected from 0, 1, 2, 3, 4 or 5;

环A选自3-12元杂环烷基或3-12元杂环烯基(例如含N的杂环烷基或杂环烯基)。Ring A is selected from 3-12 membered heterocycloalkyl or 3-12 membered heterocycloalkenyl (eg, N-containing heterocycloalkyl or heterocycloalkenyl).

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

在一些实施方案中，所述式IC化合物，或其药学上可接受的盐选自式IC-1，或其药学上可接受的盐，
In some embodiments, the compound of formula IC, or a pharmaceutically acceptable salt thereof, is selected from formula IC-1, or a pharmaceutically acceptable salt thereof,

其中，X1、X2、X3、X4、X5、Xa、Xb、Xc、Xd、Xe、Xf、X、R1、R2、m、n及环A的定义如本公开所述。wherein X1 , X2 , X3 , X4, X5 , Xa, Xb , Xc , Xd , Xe , Xf , X , R1 , R2 , m, n and ring A are as defined in the present disclosure.

在一些实施方案中，所述结构单元(环A)中包含结构片段-NHC(O)-。In some embodiments, the structural unit (Ring A) contains the structural fragment -NHC(O)-.

在一些实施方案中，所述结构单元(环A)中包含结构片段-NHCH2CH2-。在一些实施方案中，所述结构单元(环A)中包含结构片段-NHCH2CH2*-或-*NHCH2CH2-，*表示该部位的氮原子或碳原子与相邻结构发生连接。例如包含结构片段-*NHCH2CH2-时候，表示该部位的氮原子与相邻结构发生连接可以形成例如包含结构片段-NHCH2CH2*-时候，表示该部位的碳原子与相邻结构发生连接可以形成 In some embodiments, the structural unit (Ring A) contains the structural fragment -NHCH 2 CH 2 -. In some embodiments, the structural unit (Ring A) contains the structural fragment -NHCH 2 CH 2 *- or -*NHCH 2 CH 2 -, where * indicates that the nitrogen atom or carbon atom at the site is adjacent to the adjacent structure. For example, when the structural fragment -*NHCH 2 CH 2 - is included, it means that the nitrogen atom at this position is connected to the adjacent structure Connection can be formed For example, when the structural fragment -NHCH 2 CH 2 *- is included, it means that the carbon atom at this position is closely related to the adjacent structure. Connection can be formed

在一些实施方案中，所述结构单元选自其中X6选自N或CH，X7选自NH、O、S或CH2，且X6和X7中至少有一个含有氮原子。In some embodiments, the structural unit Selected from wherein X6 is selected from N or CH, X7 is selected from NH, O, S or CH2 , and at least one of X6 and X7 contains a nitrogen atom.

在一些实施方案中，所述式IC化合物或其药学上可接受的盐选自式IC-2或其药学上可接受的盐，
In some embodiments, the compound of formula IC or a pharmaceutically acceptable salt thereof is selected from formula IC-2 or a pharmaceutically acceptable salt thereof,

其中，Xa、Xc、X、R1、R2、m、n及环A的定义如本公开所述；其中X6选自N或CH，X7选自NH、O、S或CH2，且X6和X7中至少有一个含有氮原子。wherein Xa , Xc , X, R1 , R2 , m, n and ring A are as defined in the present disclosure; wherein X6 is selected from N or CH, X7 is selected from NH, O, S or CH2 , and at least one of X6 and X7 contains a nitrogen atom.

在一些实施方案中，当X6为N时，X7选自NH、O、S或CH2；当X7为NH时，X6选自CH。In some embodiments, when X6 is N, X7 is selected from NH, O, S or CH2 ; when X7 is NH, X6 is selected from CH.

在一些实施方案中，Xa及Xc选自CH。在一些实施方案中，X选自O。In some embodiments, Xa and Xc are selected from CH. In some embodiments, X is selected from O.

当R2存在时，其可以发生在环A的任一位置(条件是符合价键规则)，例如针对R2可以发生在X6、CH2或X7等位置。When R 2 is present, it can be located at any position of ring A (provided that the valence bond rules are met), for example R 2 may be located at positions such as X 6 , CH 2 or X 7 .

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

在一些实施方案中，所述式IC化合物或其药学上可接受的盐选自式IC-3或其药学上可接受的盐，
In some embodiments, the compound of formula IC or a pharmaceutically acceptable salt thereof is selected from formula IC-3 or a pharmaceutically acceptable salt thereof,

其中，X1、X2、X3、X4、X5、Xa、Xb、Xc、Xd、Xe、Xf、X、R1、R2、m、n及环A的定义如本公开所述。wherein X1 , X2 , X3 , X4, X5 , Xa, Xb , Xc , Xd , Xe , Xf , X , R1 , R2 , m, n and ring A are as defined in the present disclosure.

本公开提供式I化合物或其药学上可接受的盐，
The present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof,

其中，in,

X1、X2、X3、X4及X5分别独立地选自N或CH；X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from N or CH;

Xa、Xb、Xc、Xd、Xe及Xf分别独立地选自N或任选地被一个或多个取代基取代的CH(具体的，分别独立地选自N或任选地被一个取代基取代的CH)； Xa , Xb , Xc, Xd , Xe and Xf are each independently selected from N or CH optionally substituted by one or more substituents (specifically, each independently selected from N or CH optionally substituted by one substituent);

X选自O、S、-S(O)-、-S(O)2-、-C(O)-、-C(O)O-、或任选地被一个或多个取代基取代的以下基团：NH、-N(C1-6烷基)-、-NH-C1-6烷基-、-C1-6烷基-O-、-C1-6烷基-S-或-C(O)NH-；X is selected from O, S, -S(O)-, -S(O) 2- , -C(O)-, -C(O)O-, or the following groups optionally substituted with one or more substituents: NH, -N( C1-6alkyl )-, -NH- C1-6alkyl- , -C1-6alkyl -O-, -C1-6alkyl -S-, or -C(O)NH-;

每一个R1分别独立地选自CN、卤素、或任选地被一个或多个取代基取代的以下基团：OH、NH2、C1- 6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OC(O)-、C1-6烷基C(O)O-、C1-6烷基NHC(O)-、C1-6烷基C(O)NH-、(C1-6烷基)2NC(O)-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3- 12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Each R 1 is independently selected from CN, halogen, or the following groups optionally substituted by one or more substituents: OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOC( O)-, C 1-6 alkylC(O)O-, C 1-6 alkylNHC(O)-, C 1-6 alkylC ( O )NH-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl;

每一个R2分别独立地选自CN、卤素、＝O、或任选地被一个或多个取代基取代的以下基团：OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OC(O)-、C1-6烷基C(O)O-、C1-6烷基NHC(O)-、C1-6烷基C(O)NH-、(C1-6烷基)2NC(O)-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3- 12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Each R 2 is independently selected from CN, halogen, =O, or the following groups optionally substituted by one or more substituents: OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO- , C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOC(O)-, C 1-6 alkylC(O)O-, C 1-6 alkylNHC(O)-, C 1-6 alkylC(O)NH-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl;

m及n分别独立地选自0、1、2、3、4或5；m and n are independently selected from 0, 1, 2, 3, 4 or 5;

环A选自3-12元杂环烷基或3-12元杂环烯基。Ring A is selected from 3-12 membered heterocycloalkyl or 3-12 membered heterocycloalkenyl.

在一些实施方案中，X1、X2、X3、X4及X5分别独立地选自N或CH。In some embodiments, X 1 , X 2 , X 3 , X 4 , and X 5 are each independently selected from N or CH.

在一些实施方案中，X1、X2、X3、X4及X5分别独立地选自N或CH，X1、X2、X3、X4及X5中任选地 一个或两个选自N。在一些实施方案中，X1、X2、X3、X4及X5分别独立地选自N或CH，X1、X2、X3、X4及X5中一个选自N。在一些实施方案中，X1、X2、X3、X4及X5分别独立地选自N或CH，X1、X2、X3、X4及X5中两个选自N。在一些实施方案中，X1、X2、X3、X4及X5选自CH。In some embodiments, X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from N or CH, and X 1 , X 2 , X 3 , X 4 and X 5 are optionally One or two are selected from N. In some embodiments, X1 , X2 , X3 , X4 and X5 are each independently selected from N or CH, and one of X1 , X2 , X3 , X4 and X5 is selected from N. In some embodiments, X1 , X2, X3 , X4 and X5 are each independently selected from N or CH, and two of X1 , X2 , X3 , X4 and X5 are selected from N. In some embodiments, X1, X2 , X3, X4 and X5 are each independently selected from N or CH, and two of X1, X2, X3 , X4 and X5 are selected from N. In some embodiments, X1 , X2 , X3 , X4 and X5 are selected from CH.

在一些实施方案中，Xa、Xb、Xc、Xd或Xe分别独立地选自N或任选地被一个或多个(一个)取代基取代的CH，Xf选自N或CH。在一些实施方案中，其中所述一个或多个取代基选自Ra，Ra的定义如本公开所述。In some embodiments, Xa , Xb , Xc , Xd or Xe are each independently selected from N or CH optionally substituted with one or more (one) substituents, and Xf is selected from N or CH. In some embodiments, wherein the one or more substituents are selected from Ra , Ra is as defined in the disclosure.

在一些实施方案中，Xa、Xb、Xc、Xd、Xe及Xf分别独立地选自N或任选地被一个或多个(一个)Ra取代的CH，所述Ra选自CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-或(C1-6烷基)2N-。In some embodiments, Xa , Xb , Xc , Xd , Xe and Xf are each independently selected from N or CH optionally substituted with one or more (one) Ra, wherein Ra is selected from CN, halogen, OH, NH2 , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylO-, C1-6 alkylS-, -SF5, C1-6 alkylNH-, (C1-6 alkyl) 2N- , C1-6 alkylOCO-, C1-6 alkylC(O)O-, C1-6 alkylNHCO-, C1-6 alkylCONH- , ( C1-6 alkyl) 2NCO- , C1-6 alkylNHS(O)-, C1-6 alkylS(O ) NH-, ( C1-6 alkyl) 2NS (O)-, C1-6 alkylNHS(O) 2- , C1-6 alkyl C 1-6 alkylS(O) 2 NH—, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO—, C 1-6 alkylS—, C 1-6 alkylNH—, (C 1-6 alkyl) 2 N—, C 1-6 alkylOCO—, C 1-6 alkylC(O)O—, C 1-6 alkylNHCO—, C 1-6 alkylCONH— , (C 1-6 alkyl) 2 NCO—, C 1-6 alkylNHS(O)—, C 1-6 alkylS(O) NH—, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH- or (C 1-6 alkyl) 2 N-.

在一些实施方案中，所述Ra选自CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1- 6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1- 6烷基NH-或(C1-6烷基)2N-。In some embodiments, the Ra is selected from CN, halogen, OH, NH2 , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylO-, C1-6 alkylS-, -SF5 , C1-6 alkylNH-, ( C1-6 alkyl) 2N- , C1-6 alkylOCO-, C1-6 alkylC(O ) O-, C1-6 alkylNHCO-, C1-6 alkylCONH-, ( C1-6 alkyl) 2NCO- , C1-6 alkylNHS(O)-, C1-6 alkylS ( O)NH-, ( C1-6 alkyl)2NS( O )-, C1-6 alkylNHS(O) 2- , C1-6 alkylS(O) 2NH- , (C1-6 alkyl ) 2NS (O) 2- , C1-6 alkyl C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS- , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C The present invention also provides a novel ( C 1-6 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl group, which is optionally substituted by one or more of the following groups: CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH- or (C 1-6 alkyl) 2 N- .

在一些实施方案中，所述Ra选自CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、C1-6烷基NH-、(C1-6烷基)2N-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-3烷基O-、C1-3烷基S-、-SF5、C1-3烷基NH-或(C1- 3烷基)2N-。In some embodiments, the Ra is selected from CN, halogen, OH, NH2 , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylO-, C1-6 alkylS-, -SF5 , C1-6 alkylNH-, ( C1-6 alkyl) 2N- , C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C6 aryl or 5-6 membered heteroaryl, the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylO-, C1-6 alkylS-, C1-6 alkylNH-, ( C1-6 alkyl) 2N- , C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C6 aryl or 5-6 membered heteroaryl. The 6- membered aryl or 5-6-membered heteroaryl is optionally substituted by one or more of the following groups: CN, halogen, OH, NH 2 , C 1-3 alkyl O-, C 1-3 alkyl S- , -SF 5 , C 1-3 alkyl NH-, or (C 1-3 alkyl) 2 N-.

在一些实施方案中，所述Ra选自CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-或(C1-6烷基)2N-，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、C1-6烷基NH-或(C1-6烷基)2N-任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-3烷基O-、C1-3烷基S-、-SF5、C1-3烷基NH-或(C1-3烷基)2N-。In some embodiments, the Ra is selected from CN, halogen, OH, NH2 , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylO-, C1-6 alkylS-, -SF5 , C1-6 alkylNH-, or ( C1-6 alkyl) 2N- , and the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylO-, C1-6 alkylS-, C1-6 alkylNH-, or ( C1-6 alkyl) 2N- are optionally substituted with one or more of the following groups : CN, halogen, OH , NH2 , C1-3 alkylO-, C1-3 alkylS-, -SF5 , C1-3 alkylNH-, or ( C1-3 alkyl ) 2N- .

在一些实施方案中，所述Ra选自CN、卤素、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1- 4烷基S-、-SF5、C1-4烷基NH-或(C1-4烷基)2N-，所述C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-或(C1-4烷基)2N-任选地被一个或多个以下基团取代：CN、卤素、OH或NH2。In some embodiments, the Ra is selected from CN, halogen, OH, NH2 , C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkylO-, C1-4 alkylS-, -SF5, C1-4 alkylNH-, or ( C1-4 alkyl) 2N- , and the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkylO-, C1-4 alkylS-, -SF5 , C1-4 alkylNH-, or ( C1-4 alkyl) 2N- are optionally substituted with one or more of the following groups : CN, halogen, OH, or NH2 .

在一些实施方案中，所述Ra选自CN、卤素、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基或-SF5，所述C1- 4烷基、C2-4烯基或C2-4炔基任选地被一个或多个以下基团取代：CN、卤素、OH或NH2。In some embodiments, the Ra is selected from CN, halogen, OH, NH2 , C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, or -SF5 , wherein the C1-4 alkyl, C2-4 alkenyl, or C2-4 alkynyl is optionally substituted with one or more of CN, halogen, OH, or NH2 .

在一些实施方案中，所述Ra选自CN、卤素、OH、NH2、C1-3烷基、C2-3烯基、C2-3炔基或-SF5，所述C1- 3烷基、C2-3烯基或C2-3炔基任选地被一个或多个以下基团取代：CN、卤素、OH或NH2。 In some embodiments, the Ra is selected from CN, halogen, OH, NH2 , C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, or -SF5 , wherein the C1-3 alkyl, C2-3 alkenyl, or C2-3 alkynyl is optionally substituted with one or more of the following groups: CN, halogen, OH, or NH2 .

在一些实施方案中，所述Ra选自CN、卤素、OH、NH2或C1-3烷基，所述C1-3烷基任选地被一个或多个以下基团取代：CN、卤素、OH或NH2。In some embodiments, the Ra is selected from CN, halogen, OH , NH2 , or C1-3 alkyl, which is optionally substituted with one or more of the following groups: CN, halogen, OH, or NH2 .

在一些实施方案中，所述Ra选自CN、卤素、OH、NH2或C1-3烷基。在一些实施方案中，所述Ra选自C1-6烷基。在一些实施方案中，所述Ra选自C1-3烷基。在一些实施方案中，所述Ra选自甲基。In some embodiments, the Ra is selected from CN, halogen, OH, NH 2 or C 1-3 alkyl. In some embodiments, the Ra is selected from C 1-6 alkyl. In some embodiments, the Ra is selected from C 1-3 alkyl. In some embodiments, the Ra is selected from methyl.

在一些实施方案中，Xa、Xb、Xc、Xd、Xe及Xf分别独立地选自CH或N。In some embodiments, Xa , Xb , Xc , Xd , Xe, and Xf are each independently selected from CH or N.

在一些实施方案中，Xa、Xb、Xc、Xd、Xe及Xf分别独立地选自CH或N，Xa、Xb、Xc、Xd、Xe及Xf中任选地一个或两个选自N。In some embodiments, Xa , Xb , Xc , Xd , Xe and Xf are each independently selected from CH or N, and optionally one or two of Xa, Xb , Xc , Xd , Xe and Xf are selected from N.

在一些实施方案中，Xb、Xd、Xe及Xf分别独立地选自CH，Xa及Xc分别独立地选自CH或N，所述CH任选地被一个或多个Ra取代。In some embodiments, Xb , Xd , Xe and Xf are each independently selected from CH, and Xa and Xc are each independently selected from CH or N, wherein CH is optionally substituted with one or more Ra .

在一些实施方案中，Xb、Xd、Xe及Xf分别独立地选自CH，Xa及Xc分别独立地选自CH或N。In some embodiments, Xb , Xd , Xe and Xf are each independently selected from CH, and Xa and Xc are each independently selected from CH or N.

在一些实施方案中，Xa、Xb、Xd、Xe及Xf分别独立地选自CH，Xc选自N。In some embodiments, Xa , Xb , Xd , Xe and Xf are each independently selected from CH, and Xc is selected from N.

在一些实施方案中，Xb、Xd、Xe及Xf分别独立地选自CH，Xa及Xc分别独立地选自N。In some embodiments, X b , X d , X e and X f are each independently selected from CH, and X a and X c are each independently selected from N.

在一些实施方案中，Xa、Xb、Xc、Xd、Xe及Xf选自CH。In some embodiments, Xa , Xb , Xc, Xd , Xe , and Xf are selected from CH.

在一些实施方案中，当Xb选自CH时，所述CH任选地被Ra取代。In some embodiments, when Xb is selected from CH, said CH is optionally substituted with Ra .

在一些实施方案中，结构单元选自任选地被一个或多个Ra取代的以下基团：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 the following groups optionally substituted by one or more Ra : 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，X选自O、S、-S(O)-、-S(O)2-、-C(O)-、-C(O)O-、或任选地被一个或多个取代基取代的以下基团：NH、-N(C1-3烷基)-、-NH-C1-3烷基-、-C1-3烷基-O-、-C1-3烷基-S-或-C(O)NH-。在一些实施方案中，X选自O、S、或任选地被一个或多个取代基取代的以下基团：NH或-N(C1-3烷基)-。In some embodiments, X is selected from O, S, -S(O)-, -S(O) 2- , -C(O)-, -C(O)O-, or the following groups optionally substituted with one or more substituents: NH, -N(C 1-3 alkyl)-, -NH-C 1-3 alkyl-, -C 1-3 alkyl-O-, -C 1-3 alkyl-S-, or -C(O)NH-. In some embodiments, X is selected from O, S, or the following groups optionally substituted with one or more substituents: NH or -N(C 1-3 alkyl)-.

在一些实施方案中，X选自O、S、-S(O)-、-S(O)2-、-C(O)-、-C(O)O-、NH、-N(C1-6烷基)-、-NH-C1-6烷基-、-C1-6烷基-O-、-C1-6烷基-S-或-C(O)NH-。在一些实施方案中，X选自O、S、NH、-N(C1-3烷基)-、-NH-C1-3烷基-、-C1-3烷基-O-、-C1-3烷基-S-、-S(O)-、-S(O)2-、-C(O)-、-C(O)NH-或-C(O)O-。在一些实施方案中，X选自O、S、NH或-N(C1-3烷基)-。在一些实施方案中，X选自O、S或NH。在一些实施方案中，X选自O。在一些实施方案中，X选自O、S、-S(O)-、-S(O)2-、NH或-N(C1-6烷基)-；Xa、Xb、Xc、Xd、Xe及Xf选自CH。在一些实施方案中，X选自O、S、-S(O)-、-S(O)2-、NH或-N(C1-3烷基)-；Xa、Xb、Xc、Xd、 Xe及Xf选自CH。在一些实施方案中，X选自O、S、NH或-N(C1-3烷基)-；Xa、Xb、Xc、Xd、Xe及Xf选自CH。在一些实施方案中，X选自O、S或NH；Xa、Xb、Xc、Xd、Xe及Xf选自CH。在一些实施方案中，X选自O；Xa、Xb、Xc、Xd、Xe及Xf选自CH。In some embodiments, X is selected from O, S, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O-, NH, -N(C 1-6 alkyl)-, -NH-C 1-6 alkyl-, -C 1-6 alkyl-O-, -C 1-6 alkyl-S-, or -C(O)NH-. In some embodiments, X is selected from O, S, NH, -N(C 1-3 alkyl)-, -NH-C 1-3 alkyl-, -C 1-3 alkyl-O-, -C 1-3 alkyl-S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)NH-, or -C(O)O-. In some embodiments, X is selected from O, S, NH, or -N(C 1-3 alkyl)-. In some embodiments, X is selected from O, S, or NH. In some embodiments, X is selected from O. In some embodiments, X is selected from O, S, -S(O)-, -S(O) 2- , NH, or -N( C1-6 alkyl)-; Xa, Xb , Xc , Xd , Xe , and Xf are selected from CH. In some embodiments, X is selected from O, S, -S(O)-, -S(O) 2- , NH, or -N( C1-3 alkyl)-; Xa, Xb , Xc , Xd , Xe , and Xf are selected from CH. Xe and Xf are selected from CH. In some embodiments, X is selected from O, S, NH or -N( C1-3 alkyl)-; Xa , Xb , Xc , Xd , Xe and Xf are selected from CH. In some embodiments, X is selected from O, S or NH; Xa, Xb , Xc , Xd , Xe and Xf are selected from CH. In some embodiments, X is selected from O; Xa , Xb , Xc , Xd , Xe and Xf are selected from CH.

在一些实施方案中，R'及R”分别独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基或3-6元杂环烷基。In some embodiments, R' and R" are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, or 3-6 membered heterocycloalkyl.

在一些实施方案中，R'及R”分别独立地选自氢、C1-6烷基、C2-6烯基或C2-6炔基。In some embodiments, R' and R" are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl.

在一些实施方案中，R'及R”分别独立地选自氢或C1-3烷基。在一些实施方案中，R'及R”分别独立地选自氢、甲基、-CH2CH2NH2或乙基。In some embodiments, R' and R" are each independently selected from hydrogen or C1-3 alkyl. In some embodiments, R' and R" are each independently selected from hydrogen, methyl, -CH2CH2NH2 , or ethyl .

在一些实施方案中，每一个R1分别独立地选自CN、卤素、或任选地被一个或多个取代基取代的以下基团：OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、HOC(O)-、C1-6烷基OC(O)-、C1-6烷基C(O)O-、-C(O)NH2、C1-6烷基NHC(O)-、C1-6烷基C(O)NH-、(C1-6烷基)2NC(O)-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基。In some embodiments, each R 1 is independently selected from CN, halogen, or the following groups optionally substituted with one or more substituents: OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl ) 2 N-, HOC(O)-, C 1-6 alkylOC(O)-, C 1-6 alkylC(O)O-, -C(O)NH 2 , C 1-6 alkylNHC(O)-, C 1-6 alkylC(O)NH-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkylNHS(O)-, C 1-6 alkylS (O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl.

在一些实施方案中，每一个R1分别独立地选自CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1- 6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基。In some embodiments, each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO- , C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS ( O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl, or 5-12 membered heteroaryl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkyl C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl.

在一些实施方案中，每一个R1分别独立地选自CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-或(C1-6烷基)2N-。In some embodiments, each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO- , C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS ( O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally substituted with one or more of the following: CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH- or (C 1-6 alkyl) 2 N-.

在一些实施方案中，每一个R1分别独立地选自CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、C1- 6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、 (C1-6烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1- 6烷基S-、-SF5、C1-6烷基NH-或(C1-6烷基)2N-。In some embodiments, each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO- , C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O) -, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS ( O ) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl is optionally substituted with one or more of the following: CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH- or (C 1-6 alkyl) 2 N-.

在一些实施方案中，每一个R1分别独立地选自CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、C1-6烷基NH-、(C1-6烷基)2N-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-3烷基O-、C1-3烷基S-、-SF5、C1-3烷基NH-或(C1-3烷基)2N-。In some embodiments, each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl. The 6- membered aryl or 5-6-membered heteroaryl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-3 alkyl O-, C 1-3 alkyl S-, -SF 5 , C 1-3 alkyl NH-, or (C 1-3 alkyl) 2 N-.

在一些实施方案中，每一个R1分别独立地选自CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-或(C1-6烷基)2N-，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、C1-6烷基NH-或(C1-6烷基)2N-任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-3烷基O-、C1-3烷基S-、-SF5、C1-3烷基NH-或(C1-3烷基)2N-。In some embodiments, each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, or (C 1-6 alkyl) 2 N-, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, C 1-6 alkylNH-, or (C 1-6 alkyl) 2 N- are optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-3 alkylO-, C 1-3 alkylS-, -SF 5 , C 1-3 alkylNH-, or (C 1-3 alkyl) 2 N-.

在一些实施方案中，每一个R1分别独立地选自CN、卤素、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-或(C1-4烷基)2N-，所述C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-或(C1-4烷基)2N-任选地被一个或多个以下基团取代：CN、卤素、OH或NH2。In some embodiments, each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, or (C 1-4 alkyl) 2 N-, and the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, or (C 1-4 alkyl) 2 N- are optionally substituted with one or more of the following groups: CN, halogen, OH, or NH 2 .

在一些实施方案中，每一个R1分别独立地选自CN、卤素、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基或-SF5，所述C1-4烷基、C2-4烯基或C2-4炔基任选地被一个或多个以下基团取代：CN、卤素、OH或NH2。In some embodiments, each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, or -SF 5 , wherein the C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl is optionally substituted with one or more of the following groups: CN, halogen, OH, or NH 2 .

在一些实施方案中，每一个R1分别独立地选自CN、卤素、OH、NH2、C1-3烷基、C2-3烯基、C2-3炔基或-SF5，所述C1-3烷基、C2-3烯基或C2-3炔基任选地被一个或多个以下基团取代：CN、卤素、OH或NH2。In some embodiments, each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, or -SF 5 , wherein the C 1-3 alkyl, C 2-3 alkenyl, or C 2-3 alkynyl is optionally substituted with one or more of the following groups: CN, halogen, OH, or NH 2 .

在一些实施方案中，每一个R1分别独立地选自CN、卤素、OH、NH2或C1-3烷基，所述C1-3烷基任选地被一个或多个以下基团取代：CN、卤素、OH或NH2。In some embodiments, each R 1 is independently selected from CN, halogen, OH, NH 2 or C 1-3 alkyl, which is optionally substituted with one or more of the following groups: CN, halogen, OH or NH 2 .

在一些实施方案中，每一个R1分别独立地选自卤代C1-6烷基或-SF5。In some embodiments, each R 1 is independently selected from halo-substituted C 1-6 alkyl or -SF 5 .

在一些实施方案中，每一个R1分别独立地选自卤代C1-3烷基或-SF5。In some embodiments, each R 1 is independently selected from halo-substituted C 1-3 alkyl or -SF 5 .

在一些实施方案中，每一个R1分别独立地选自氟代C1-3烷基或-SF5。In some embodiments, each R 1 is independently selected from fluorinated C 1-3 alkyl or -SF 5 .

在一些实施方案中，每一个R1分别独立地选自氟代C1-3烷基。In some embodiments, each R 1 is independently selected from fluorinated C 1-3 alkyl.

在一些实施方案中，每一个R1分别独立地选自CF3或-SF5。In some embodiments, each R 1 is independently selected from CF 3 or —SF 5 .

在一些实施方案中，每一个R1分别独立地选自CF3。在一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、或任选地被一个或多个取代基取代的以下基团：OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1- 6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基。In some embodiments, each R 1 is independently selected from CF 3 . In some embodiments, each R 2 is independently selected from CN, halogen, =O, or the following groups optionally substituted with one or more substituents: OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl ) 2 The invention also includes a C 1-6 alkyl) 2 NS(O) 2 -, a C 3-12 cycloalkyl, a 3-12 membered heterocycloalkyl, a C 3-12 cycloalkenyl, a 3-12 membered heterocycloalkenyl, a C 6-12 aryl or a 5-12 membered heteroaryl.

在一些实施方案中，至少有一个R2选自＝O。In some embodiments, at least one R 2 is selected from ═O.

在一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、或任选地被一个或多个取代基取代的以下基团：C1-6烷基、C2-6烯基、C2-6炔基、R'O-、R'S-、-SF5、R'R”N-、R'OC(O)-、R'C(O)O-、-C(O)NR'R”、R'C(O)NH-、R'R”NS(O)-、R'S(O)NH-、R'R”NS(O)-、R'R”NS(O)2-、R'S(O)2NH-、R'R”NS(O)2-、R'OC(O)NH-、R'R”NC(O)O-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、R'O-、R'S-、-SF5、R'R”N-、R'OC(O)-、R'C(O)O-、-C(O)NR'R”、R'C(O)NH-、R'R”NS(O)-、R'S(O)NH-、R'R”NS(O)-、R'R”NS(O)2-、R'S(O)2NH-、R'R”NS(O)2-、R'OC(O)NH-、R'R”NC(O)O-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基任选地被一个或多个以下基团取代：CN、卤素、C1-6烷基、C2-6烯基、C2-6炔基、RbO-、RbS-、-SF5、RbRcN-、RbOC(O)-、RbC(O)O-、RbCONH-、RbRcNCO-、RbS(O)NH-、RbRcNS(O)-、RbS(O)2NH-或RbRcNS(O)2-，Rb及Rc分别独 立地选自氢、C1-6烷基、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基。In some embodiments, each R 2 is independently selected from CN, halogen, =0, or the following groups optionally substituted with one or more substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, R'O-, R'S-, -SF 5 , R'R"N-, R'OC(O)-, R'C(O)O-, -C(O)NR'R", R'C(O)NH-, R'R"NS(O)-, R'S(O)NH-, R'R"NS(O)-, R'R"NS(O) 2 -, R'S(O) 2 NH-, R'R"NS(O) 2 -, R'OC(O)NH-, R'R"NC(O)O-, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, R'O-, R'S-, -SF 5 , R'R"N-, R'OC(O)-, R'C(O)O-, -C (O)NR'R", R'C(O)NH-, R'R"NS(O)-, R'S(O)NH-, R'R"NS(O)-, R'R"NS(O) 2 -, R'S(O) 2 NH-, R'R"NS(O) 2 -, R'OC(O)NH-, R'R"NC(O)O-, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C The 6-12 membered aryl or 5-12 membered heteroaryl is optionally substituted by one or more of the following groups: CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, R b O—, R b S—, -SF 5 , R b R c N—, R b OC(O)—, R b C(O)O—, R b CONH—, R b R c NCO—, R b S(O)NH—, R b R c NS(O)—, R b S(O) 2 NH—, or R b R c NS(O) 2 —, R b and R c are independently is independently selected from hydrogen, C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl.

在一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、或任选地被一个或多个取代基取代的以下基团：OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1- 6烷基)2N-、HOC(O)-、C1-6烷基OC(O)-、C1-6烷基C(O)O-、-C(O)NH2、C1-6烷基NHC(O)-、C1-6烷基C(O)NH-、(C1-6烷基)2NC(O)-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基。In some embodiments, each R 2 is independently selected from CN, halogen, =O, or the following groups optionally substituted with one or more substituents: OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, HOC(O)-, C 1-6 alkylOC(O)-, C 1-6 alkylC(O)O-, -C(O)NH 2 , C 1-6 alkylNHC(O)-, C 1-6 alkylC(O)NH-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkyl C 1-6 alkyl NHS(O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl.

在一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OC(O)-、HOC(O)-、C1-6烷基C(O)O-、-C(O)NH2、C1-6烷基NHC(O)-、C1-6烷基C(O)NH-、(C1-6烷基)2NC(O)-、C1-6烷基NHS(O)-、C1- 6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OC(O)-、C1-6烷基C(O)O-、C1-6烷基NHC(O)-、C1-6烷基C(O)NH-、(C1-6烷基)2NC(O)-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基任选地被一个或多个以下基团取代：CN、卤素、C1-6烷基、C2-6烯基、C2-6炔基、RbO-、RbS-、-SF5、RbRcN-、RbOC(O)-、RbC(O)O-、RbCONH-、RbRcNCO-、RbS(O)NH-、RbRcNS(O)-、RbS(O)2NH-或RbRcNS(O)2-，Rb及Rc分别独立地选自氢、C1-6烷基、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基。In some embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOC(O)-, HOC(O)-, C 1-6 alkylC(O)O-, -C(O) NH 2 , C 1-6 alkylNHC(O)-, C 1-6 alkylC(O)NH-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkylNHS(O)- , C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS ( O ) 2 -, C C 1-6 alkylS(O) 2 NH—, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO—, C 1-6 alkylS—, -SF 5 , C 1-6 alkylNH—, (C 1-6 alkyl) 2 N—, C 1-6 alkylOC(O)—, C 1-6 alkylC(O)O—, C 1-6 alkylNHC(O)—, C 1-6 alkylC(O)NH—, (C 1-6 alkyl) 2 NC(O)—, C 1-6 alkylNHS(O)—, C 1-6 alkyl RbO- , RbS- , -SF5 , RbRcN- , RbOC (O)- , RbC (O) O- , RbCONH- , RbRcNCO- , RbS (O)NH-, RbRcNS(O)-, RbS(O ) NH-, RbRcNS (O)-, RbOC (O)-, RbC (O) O- , RbCONH- , RbRcNCO- , RbS (O ) NH- , RbRcNS ( O ) -, RbS ( O)NH-, RbRcNS (O)- , Rb b S(O) 2 NH- or R b R c NS(O) 2 -, R b and R c are each independently selected from hydrogen, C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl.

在一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、HOC(O)-、C1-6烷基OC(O)-、C1-6烷基C(O)O-、-C(O)NH2、C1-6烷基NHC(O)-、C1-6烷基C(O)NH-、(C1-6烷基)2NC(O)-、C1-6烷基NHS(O)-、C1- 6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基，所述C1-6烷基、C2-6烯基、C2- 6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OC(O)-、C1-6烷基C(O)O-、C1-6烷基NHC(O)-、C1-6烷基C(O)NH-、(C1-6烷基)2NC(O)-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3- 6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基任选地被一个或多个以下基团取代：CN、卤素、C1-6烷基、C2-6烯基、C2-6炔基、RbO-、RbS-、-SF5、RbRcN-、RbOC(O)-、RbC(O)O-、RbCONH-、RbRcNCO-、RbS(O)NH-、RbRcNS(O)-、RbS(O)2NH-或RbRcNS(O)2-。In some embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, HOC(O)-, C 1-6 alkylOC(O)-, C 1-6 alkylC(O)O-, -C(O)NH 2 , C 1-6 alkylNHC(O)-, C 1-6 alkylC(O)NH-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkylNHS(O)- , C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS ( O ) 2 - , C C 1-6 alkylS(O) 2 NH—, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO—, C 1-6 alkylS—, -SF 5 , C 1-6 alkylNH—, (C 1-6 alkyl) 2 N—, C 1-6 alkylOC(O)—, C 1-6 alkylC(O)O—, C 1-6 alkylNHC(O)—, C 1-6 alkylC(O)NH—, (C 1-6 alkyl) 2 NC(O) — , C 1-6 alkylNHS(O)—, C 1-6 alkyl RbO- , RbS- , -SF5 , RbRcN- , RbOC (O)-, RbC ( O ) O- , RbCONH- , RbRcNCO- , RbS ( O ) NH- , RbRcNS ( O ) - , RbS ( O ) 2 NH- or R b R c NS(O) 2 -.

在一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-、(C1-4烷基)2N-、HOC(O)-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、-C(O)NH2、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C1-4烷基NHS(O)-、C1- 4烷基S(O)NH-、(C1-4烷基)2NS(O)-、C1-4烷基NHS(O)2-、C1-4烷基S(O)2NH-、(C1-4烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基，所述C1-4烷基、C2-4烯基、C2- 4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C1-4烷基NHS(O)-、C1-4烷基S(O)NH-、(C1-4烷基)2NS(O)-、C1-4烷基NHS(O)2-、C1-4烷基S(O)2NH-、(C1-4烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3- 6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基任选地被一个或多个以下基团取代：CN、卤素、C1-4烷基、C2-4烯基、C2-4炔基、RbO-、RbS-、-SF5、RbRcN-、RbOC(O)-、RbC(O)O-、RbCONH-、RbRcNCO-、RbS(O)NH-、RbRcNS(O)-、RbS(O)2NH-或RbRcNS(O)2-。In some embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, HOC(O)-, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-, -C(O)NH 2 , C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 1-4 alkylNHS(O)-, C 1-4 alkylS(O)NH-, (C 1-4 alkyl ) 2 NS(O) - , C 1-4 alkylNHS(O) 2 -, C C 1-4 alkylS(O) 2 NH-, (C 1-4 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl, the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-, C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O) - , C 1-4 alkylNHS(O)-, C 1-4 alkyl RbO- , RbS-, -SF5 , RbRcN- , RbOC (O)-, RbC ( O ) O- , RbCONH- , RbRcNCO- , RbS ( O ) NH- , RbRcNS ( O ) - , RbS ( O ) 2 NH- or R b R c NS(O) 2 -.

在一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-、(C1-4烷基)2N-、HOC(O)-、C1-4烷基OC(O)-、C1-4烷 基C(O)O-、-C(O)NH2、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C3-6环烷基或3-6元杂环烷基，所述C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、C1-4烷基NH-、(C1-4烷基)2N-、C1- 4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C3-6环烷基或3-6元杂环烷基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、(C1-4烷基)2N-、C1-4烷基NH-、-COOH、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基CONH-、C1-4烷基NHCO-或(C1-4烷基)2NHCO-。In some embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, ( C 1-4 alkyl) 2 N-, HOC(O)-, C 1-4 alkylOC(O)-, C 1-4 alkyl C1-4 alkylO-, C1-4 alkylS-, C1-4 alkylNH-, (C1-4 alkyl)2N-, C1-4 alkylOC(O)-, C1-4 alkylC(O)O-, C1-4 alkylNHC(O)-, C1-4 alkylC(O)NH-, ( C1-4 alkyl) 2NC ( O )-, C3-6 cycloalkyl or 3-6 membered heterocycloalkyl, the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkylO-, C1-4 alkylS-, C1-4 alkylNH-, (C1-4 alkyl) 2N- , C1-4 alkylOC( O )-, C1-4 alkylC(O)O-, C1-4 alkylNHC(O)-, C1-4 alkylC(O)NH-, ( C1-4 alkyl) 2NC (O)-, C3-6 cycloalkyl or 3-6 membered heterocycloalkyl are optionally substituted by one or more of the following groups: CN, halogen, OH, NH2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , (C 1-4 alkyl) 2 N-, C 1-4 alkylNH-, -COOH, C 1-4 alkylOC(O)-, C 1-4 alkylC (O)O-, C 1-4 alkylCONH-, C 1-4 alkylNHCO- or (C 1-4 alkyl) 2 NHCO-.

在一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-4烷基、C1-4烷基O-、C1-4烷基NH-、(C1-4烷基)2N-、HOC(O)-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、-C(O)NH2、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C3-6环烷基或3-6元杂环烷基，所述C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C3-6环烷基或3-6元杂环烷基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-4烷基、C1-4烷基O-、(C1-4烷基)2N-、C1-4烷基NH-、-COOH、C1-4烷基OC(O)-、C1-4烷基C(O)O-。In some embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-4 alkyl, C 1-4 alkylO-, C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, HOC(O)-, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-, -C(O)NH 2 , C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, C 1-4 alkylOC(O)-, C C 1-4 alkylC(O)O-, C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl are optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-4 alkyl, C 1-4 alkylO-, (C 1-4 alkyl) 2 N-, C 1-4 alkylNH-, -COOH, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-.

在一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-3烷基、C1-3烷基O-、C1-3烷基NH-、HOC(O)-、C1-3烷基OC(O)-、-C(O)NH2或5-6元杂环烷基，所述C1-3烷基、C1-3烷基O-、C1-3烷基NH-、C1-3烷基OC(O)-或5-6元杂环烷基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-3烷基、C1-3烷基NH-、-COOH、或C1-3烷基OC(O)-。In some embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylO-, C 1-3 alkylNH-, HOC(O)-, C 1-3 alkylOC(O)-, -C(O)NH 2 , or 5-6 membered heterocycloalkyl, and the C 1-3 alkyl, C 1-3 alkylO-, C 1-3 alkylNH-, C 1-3 alkylOC(O)- or 5-6 membered heterocycloalkyl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylNH-, -COOH, or C 1-3 alkylOC(O)-.

在一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、甲基、乙基、CH3O-、CH3NH-、CH3CH2NH-、HOC(O)-、CH3OC(O)-、CH3CH2OC(O)-或5元含氧杂环烷基，所述甲基、乙基、CH3O-、CH3NH-、CH3CH2NH-、CH3OC(O)-、CH3CH2OC(O)-、-C(O)NH2或5元含氧杂环烷基任选地被一个或多个以下基团取代：CN、卤素(例如F或Cl)、OH、NH2、甲基、-COOH、C1-2烷基NH-或CH3OC(O)-。In some embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , methyl, ethyl, CH 3 O-, CH 3 NH-, CH 3 CH 2 NH-, HOC(O)-, CH 3 OC(O)-, CH 3 CH 2 OC(O)-, or a 5-membered oxygen-containing heterocycloalkyl group, wherein the methyl, ethyl, CH 3 O-, CH 3 NH-, CH 3 CH 2 NH-, CH 3 OC(O)-, CH 3 CH 2 OC(O)-, -C(O)NH 2 , or a 5-membered oxygen-containing heterocycloalkyl group is optionally substituted with one or more of the following groups: CN, halogen (e.g., F or Cl), OH, NH 2 , methyl, -COOH, C 1-2 alkyl NH-, or CH 3 OC(O)-.

在一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、甲基、乙基、CH3O-、CH3NH-、CH3CH2NH-、HOC(O)-、CH3OC(O)-、CH3CH2OC(O)-、-C(O)NH2或5元含氧杂环烷基，所述甲基、乙基、CH3CH2NH-或5元含氧杂环烷基任选地被一个或多个以下基团取代：卤素(例如F或Cl)、OH、NH2、甲基、-COOH、CH3NH-或CH3OC(O)-。In some embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , methyl, ethyl, CH 3 O-, CH 3 NH-, CH 3 CH 2 NH-, HOC(O)-, CH 3 OC(O)-, CH 3 CH 2 OC(O)-, -C(O)NH 2 , or a 5-membered oxygen-containing heterocycloalkyl group, wherein the methyl, ethyl, CH 3 CH 2 NH- or 5-membered oxygen-containing heterocycloalkyl group is optionally substituted with one or more of the following groups: halogen (e.g., F or Cl), OH, NH 2 , methyl, -COOH, CH 3 NH-, or CH 3 OC(O)-.

在一些实施方案中，每一个R2分别独立地选自卤素(例如F或Cl)、＝O、OH、NH2、-CH3、-CH2OH、-CH2F、-CH2CH2OH、-CH(OH)CH3、-CH(OH)CH2OH、-CH2C(O)OCH3、-CH2C(O)OH、-CH2NH2、-CH2NHCH3、-OCH3、-NHCH3、-NHCH2CH2NH2、-C(O)OH、-C(O)OCH3、-C(O)OCH2CH3、-C(O)NH2或 In some embodiments, each R 2 is independently selected from halogen (e.g., F or Cl), =O, OH, NH 2 , -CH 3 , -CH 2 OH, -CH 2 F, -CH 2 CH 2 OH, -CH(OH)CH 3 , -CH(OH)CH 2 OH, -CH 2 C(O)OCH 3 , -CH 2 C(O)OH, -CH 2 NH 2 , -CH 2 NHCH 3 , -OCH 3 , -NHCH 3 , -NHCH 2 CH 2 NH 2 , -C(O)OH, -C(O)OCH 3 , -C(O)OCH 2 CH 3 , -C(O)NH 2 , or

在一些具体实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OC(O)-、C1-6烷基C(O)O-、C1-6烷基NHC(O)-、C1-6烷基C(O)NH-、(C1-6烷基)2NC(O)-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OC(O)-、C1-6烷基C(O)O-、C1-6烷基NHC(O)-、C1-6烷基C(O)NH-、(C1-6烷基)2NC(O)-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基任选地被一个或多个以下基团取代：CN、卤素、C1-6烷基、C2-6烯基、C2-6炔基、RbO-、RbS-、-SF5、RbRcN-、RbOC(O)-、RbC(O)O-、RbCONH-、RbRcNCO-、RbS(O)NH-、RbRcNS(O)-、RbS(O)2NH-或RbRcNS(O)2-，Rb及Rc分别独立地选自氢、C1-6烷基、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基。在一些具体实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OC(O)-、C1-6烷基C(O)O-、C1-6烷基NHC(O)-、C1-6烷基C(O)NH-、(C1-6烷基)2NC(O)-、 C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基，所述C1- 6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OC(O)-、C1-6烷基C(O)O-、C1-6烷基NHC(O)-、C1-6烷基C(O)NH-、(C1-6烷基)2NC(O)-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基任选地被一个或多个以下基团取代：CN、卤素、C1-6烷基、C2-6烯基、C2-6炔基、RbO-、RbS-、-SF5、RbRcN-、RbOC(O)-、RbC(O)O-、RbCONH-、RbRcNCO-、RbS(O)NH-、RbRcNS(O)-、RbS(O)2NH-或RbRcNS(O)2-。In some specific embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOC ( O)-, C 1-6 alkylC(O)O-, C 1-6 alkylNHC(O)-, C 1-6 alkylC(O)NH-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOC(O)-, C 1-6 alkylC(O)O-, C 1-6 alkylNHC (O)-, C 1-6 alkylC(O)NH-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) R 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl, or 5-12 membered heteroaryl is optionally substituted with one or more of the following groups: CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, R b O-, R b S-, -SF 5 , R b R c N-, R b OC(O)-, R b C(O)O-, R b CONH-, R b R c NCO-, R b S(O)NH-, R b R c NS(O)-, R b S(O) 2 NH-, or R b R c NS(O) R 2 -, R b and R c are independently selected from hydrogen, C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl. In some specific embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl ) 2 N-, C 1-6 alkylOC(O)-, C 1-6 alkylC(O)O-, C 1-6 alkylNHC(O)-, C 1-6 alkylC(O)NH-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl , the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, ( C 1-6 alkyl) 2 N-, C 1-6 alkylOC(O)-, C 1-6 alkylC(O)O-, C C 1-6 alkylNHC(O)-, C 1-6 alkylC(O)NH-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl is optionally substituted with one or more of the following groups: CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, R b O-, R b S-, -SF 5 , R b R c N-, R b OC(O)-, R b C(O)O-, R b CONH-, R b R c NCO-, R b S(O)NH-, R b R c NS(O)-, R b S(O) 2 NH-, or R b R c NS(O) 2 -.

在一些实施方案中，Rb及Rc分别独立地选自氢、C1-6烷基、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基。In some embodiments, R b and R c are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl, or 5-6 membered heteroaryl.

在一些实施方案中，Rb及Rc分别独立地选自氢、C1-4烷基、C3-6环烷基或3-6元杂环烷基。In some embodiments, R b and R c are each independently selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl.

在一些实施方案中，Rb及Rc分别独立地选自氢或C1-3烷基。In some embodiments, R b and R c are each independently selected from hydrogen or C 1-3 alkyl.

在一些具体实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C1-4烷基NHS(O)-、C1-4烷基S(O)NH-、(C1-4烷基)2NS(O)-、C1-4烷基NHS(O)2-、C1-4烷基S(O)2NH-、(C1-4烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基，所述C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C1-4烷基NHS(O)-、C1-4烷基S(O)NH-、(C1-4烷基)2NS(O)-、C1-4烷基NHS(O)2-、C1-4烷基S(O)2NH-、(C1-4烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基任选地被一个或多个以下基团取代：CN、卤素、C1-4烷基、C2-4烯基、C2-4炔基、RbO-、RbS-、-SF5、RbRcN-、RbOC(O)-、RbC(O)O-、RbCONH-、RbRcNCO-、RbS(O)NH-、RbRcNS(O)-、RbS(O)2NH-或RbRcNS(O)2-。在一些具体实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C3-6环烷基或3-6元杂环烷基，所述C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C3-6环烷基或3-6元杂环烷基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、(C1-4烷基)2N-、C1-4烷基NH-、-COOH、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基CONH-、C1-4烷基NHCO-或(C1-4烷基)2NHCO-。In some specific embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, C 1-4 alkylOC ( O)-, C 1-4 alkylC(O)O-, C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 1-4 alkylNHS(O)-, C 1-4 alkylS(O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkylNHS(O) 2 -, C 1-4 alkylS(O) 2 NH-, (C C 1-4 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl, the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-, C 1-4 alkylNHC (O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 1-4 alkylNHS(O)-, C 1-4 alkylS(O)NH-, (C 1-4 alkyl) 2 NS( O )-, C1-4 alkylNHS(O) 2- , C1-4 alkylS(O)2NH-, ( C1-4 alkyl) 2NS (O) 2- , C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C6 aryl or 5-6 membered heteroaryl is optionally substituted with one or more of the following groups: CN, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, RbO- , RbS- , -SF5 , RbRcN- , RbOC (O)-, RbC ( O)O-, RbCONH- , RbRcNCO- , RbS ( O)NH-, RbRcNS (O)- , RbS (O) 2NH- or RbRcNS ( O ) 2- . In some specific embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, C 1-4 alkylOC ( O)-, C 1-4 alkylC(O)O-, C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, C C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-, C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by one or more of the following groups: CN, halogen, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , (C 1-4 alkyl) 2 N-, C 1-4 alkylNH-, -COOH, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O- , C 1-4 alkylCONH-, C 1-4 alkylNHCO- or (C 1-4 alkyl ) 2 NHCO- .

在一些具体实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-4烷基、C1-4烷基O-、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C3-6环烷基或3-6元杂环烷基，所述C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C3-6环烷基或3-6元杂环烷基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-4烷基、C1-4烷基O-、(C1-4烷基)2N-、C1-4烷基NH-、-COOH、C1-4烷基OC(O)-、C1-4烷基C(O)O-。在一些具体实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-3烷基、C1-3烷基O-、C1-3烷基NH-、C1-3烷基OC(O)-或5-6元杂环烷基，所述C1-3烷基、C1-3烷基O-、C1-3烷基NH-、C1- 3烷基OC(O)-或5-6元杂环烷基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-3烷基、-COOH、或C1-3烷基OC(O)-。In some specific embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-4 alkyl, C 1-4 alkylO-, C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-, C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-, C C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-4 alkyl, C 1-4 alkylO-, (C 1-4 alkyl) 2 N-, C 1-4 alkylNH-, -COOH, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-. In some specific embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylO-, C 1-3 alkylNH-, C 1-3 alkylOC(O)-, or 5-6-membered heterocycloalkyl, and the C 1-3 alkyl, C 1-3 alkylO-, C 1-3 alkylNH- , C 1-3 alkylOC (O)-, or 5-6-membered heterocycloalkyl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-3 alkyl, -COOH, or C 1-3 alkylOC(O)-.

在一些具体实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、甲基、乙基、CH3O-、CH3NH-、CH3CH2NH-、CH3OC(O)-、CH3CH2OC(O)-或5元含氧杂环烷基，所述甲基、乙基、CH3O-、CH3NH-、CH3CH2NH-、CH3OC(O)-、CH3CH2OC(O)-或5元含氧杂环烷基任选地被一个或多个以下基团取代：CN、卤素(例如F或Cl)、OH、NH2、甲基、-COOH、或CH3OC(O)-。 In some specific embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , methyl, ethyl, CH 3 O-, CH 3 NH-, CH 3 CH 2 NH-, CH 3 OC(O)-, CH 3 CH 2 OC(O)-, or 5-membered oxygen-containing heterocycloalkyl, wherein the methyl, ethyl, CH 3 O-, CH 3 NH-, CH 3 CH 2 NH-, CH 3 OC(O)-, CH 3 CH 2 OC(O)-, or 5-membered oxygen-containing heterocycloalkyl is optionally substituted with one or more of the following groups: CN, halogen (e.g., F or Cl), OH, NH 2 , methyl, -COOH, or CH 3 OC(O)-.

在一些具体实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、甲基、乙基、CH3O-、CH3NH-、CH3CH2NH-、CH3OC(O)-、CH3CH2OC(O)-或5元含氧杂环烷基，所述甲基、乙基、CH3CH2NH-或5元含氧杂环烷基任选地被一个或多个以下基团取代：卤素(例如F或Cl)、OH、NH2、甲基、-COOH、或CH3OC(O)-。In some specific embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , methyl, ethyl, CH 3 O-, CH 3 NH-, CH 3 CH 2 NH-, CH 3 OC(O)-, CH 3 CH 2 OC(O)-, or a 5-membered oxygen-containing heterocycloalkyl group, wherein the methyl, ethyl, CH 3 CH 2 NH-, or a 5-membered oxygen-containing heterocycloalkyl group is optionally substituted with one or more of the following groups: halogen (e.g., F or Cl), OH, NH 2 , methyl, -COOH, or CH 3 OC(O)-.

在一些具体实施方案中，每一个R2分别独立地选自卤素(例如F或Cl)、＝O、OH、NH2、-CH3、-CH2OH、-CH2F、-CH2CH2OH、-CH(OH)CH3、-CH(OH)CH2OH、-CH2C(O)OCH3、-CH2C(O)OH、-OCH3、-NHCH3、-NHCH2CH2NH2、-C(O)OCH3、-C(O)OCH2CH3或 In some embodiments, each R 2 is independently selected from halogen (e.g., F or Cl), =O, OH, NH 2 , -CH 3 , -CH 2 OH, -CH 2 F, -CH 2 CH 2 OH, -CH(OH)CH 3 , -CH(OH)CH 2 OH, -CH 2 C(O)OCH 3 , -CH 2 C(O)OH, -OCH 3 , -NHCH 3 , -NHCH 2 CH 2 NH 2 , -C(O)OCH 3 , -C(O)OCH 2 CH 3 , or

在另外一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、甲基、乙基、CH3O-、CH3NH-、CH3CH2NH-、CH3OC(O)-、CH3CH2OC(O)-或5元含氧杂环烷基，所述甲基、乙基、CH3CH2NH-或5元含氧杂环烷基任选地被一个或多个以下基团取代：OH、NH2、甲基、-COOH、或CH3OC(O)-。In other embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , methyl, ethyl, CH 3 O-, CH 3 NH-, CH 3 CH 2 NH-, CH 3 OC(O)-, CH 3 CH 2 OC(O)-, or a 5-membered oxygen-containing heterocycloalkyl group, wherein the methyl, ethyl, CH 3 CH 2 NH-, or a 5-membered oxygen-containing heterocycloalkyl group is optionally substituted with one or more of the following groups: OH, NH 2 , methyl, -COOH, or CH 3 OC(O)-.

在另外一些实施方案中，每一个R2分别独立地选自卤素、＝O、OH、NH2、-CH3、-CH2OH、-CH2CH2OH、-CH(OH)CH3、-CH(OH)CH2OH、-CH2C(O)OCH3、-CH2C(O)OH、-OCH3、-NHCH3、-NHCH2CH2NH2、-C(O)OCH3、-C(O)OCH2CH3或 In other embodiments, each R 2 is independently selected from halogen, =O, OH, NH 2 , -CH 3 , -CH 2 OH, -CH 2 CH 2 OH, -CH(OH)CH 3 , -CH(OH)CH 2 OH, -CH 2 C(O)OCH 3 , -CH 2 C(O)OH, -OCH 3 , -NHCH 3 , -NHCH 2 CH 2 NH 2 , -C(O)OCH 3 , -C(O)OCH 2 CH 3 or

在另外一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-或(C1-6烷基)2N-。In other embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)- , C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO- , C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)- , C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C C 1-6 alkylS(O) 2 NH—, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO—, C 1-6 alkylS—, -SF 5 , C 1-6 alkylNH— or (C 1-6 alkyl) 2 N—.

在另外一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3- 6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1- 6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-或(C1-6烷基)2N-。In other embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)- , C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O) -, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS ( O ) 2 - , C C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH- or (C 1-6 alkyl) 2 N-.

在另外一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-3烷基O-、C1-3烷基S-、-SF5、C1-3烷基NH-或(C1-3烷基)2N-。In other embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl. 3-6 membered cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl is optionally substituted with one or more of the following: CN, halogen, OH, NH 2 , C 1-3 alkyl O-, C 1-3 alkyl S-, -SF 5 , C 1-3 alkyl NH- or (C 1-3 alkyl) 2 N-.

在另外一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-6烷基、C2-6烯基、 C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-或(C1-6烷基)2N-，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-或(C1-6烷基)2N-任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-3烷基O-、C1-3烷基S-、-SF5、C1-3烷基NH-或(C1-3烷基)2N-。In other embodiments, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH- or (C 1-6 alkyl) 2 N-, said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH- or (C 1-6 alkyl) 2 N- are optionally substituted by one or more of the following groups: CN, halogen, OH, NH 2 , C 1-3 alkylO-, C 1-3 alkylS-, -SF 5 , C 1-3 alkylNH- or (C 1-3 alkyl) 2 N-.

在一些实施方案中，R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-或(C1-4烷基)2N-，所述C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-或(C1-4烷基)2N-任选地被一个或多个以下基团取代：CN、卤素、OH或NH2。In some embodiments, R 2 is each independently selected from CN, halogen, ＝O, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, or (C 1-4 alkyl) 2 N-, and the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, or (C 1-4 alkyl) 2 N- are optionally substituted with one or more of the following groups: CN, halogen, OH, or NH 2 .

在另外一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-4烷基、C2-4烯基或C2-4炔基-，所述C1-4烷基、C2-4烯基或C2-4炔基-任选地被一个或多个以下基团取代：CN、卤素、OH或NH2。In other embodiments, each R 2 is independently selected from CN, halogen, =0, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl or C 2-4 alkynyl-, said C 1-4 alkyl, C 2-4 alkenyl or C 2-4 alkynyl- optionally substituted with one or more of the following groups: CN, halogen, OH or NH 2 .

在另外一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-3烷基、C2-3烯基或C2-3炔基-，所述C1-3烷基、C2-3烯基或C2-3炔基-任选地被一个或多个以下基团取代：CN、卤素、OH或NH2。In other embodiments, each R 2 is independently selected from CN, halogen, =0, OH, NH 2 , C 1-3 alkyl, C 2-3 alkenyl or C 2-3 alkynyl-, said C 1-3 alkyl, C 2-3 alkenyl or C 2-3 alkynyl- optionally substituted with one or more of the following groups: CN, halogen, OH or NH 2 .

在另外一些实施方案中，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-3烷基，所述C1-3烷基任选地被一个或多个选自CN、卤素、OH或NH2的基团取代。In other embodiments, each R 2 is independently selected from CN, halogen, =0, OH, NH 2 , C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more groups selected from CN, halogen, OH or NH 2 .

在另外一些实施方案中，每一个R2分别独立地选自＝O、OH或C1-3烷基，所述C1-3烷基任选地被一个或多个选自OH或NH2的基团取代。In other embodiments, each R 2 is independently selected from =O, OH or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more groups selected from OH or NH 2 .

在另外一些实施方案中，每一个R2分别独立地选自＝O、OH或任选地被一个或多个OH取代的C1-3烷基(例如-C1-3烷基-OH)。In other embodiments, each R 2 is independently selected from =O, OH, or C 1-3 alkyl optionally substituted with one or more OH (eg, -C 1-3 alkyl-OH).

在另外一些实施方案中，每一个R2分别独立地选自＝O、OH、-CH3或-CH2OH。In other embodiments, each R 2 is independently selected from ═O, OH, —CH 3 or —CH 2 OH.

在一些实施方案中，m及n分别独立地选自0、1、2或3。在一些实施方案中，m及n分别独立地选自1、2或3。在一些实施方案中，m及n分别独立地选自1或2。在一些实施方案中，m选自1。在一些实施方案中，n选自1、2或3。在一些实施方案中，n选自1或2。In some embodiments, m and n are each independently selected from 0, 1, 2, or 3. In some embodiments, m and n are each independently selected from 1, 2, or 3. In some embodiments, m and n are each independently selected from 1 or 2. In some embodiments, m is selected from 1. In some embodiments, n is selected from 1, 2, or 3. In some embodiments, n is selected from 1 or 2.

在一些实施方案中，环A选自3-10元杂环烷基或3-10元杂环烯基。In some embodiments, Ring A is selected from 3-10 membered heterocycloalkyl or 3-10 membered heterocycloalkenyl.

在一些实施方案中，环A选自3-10元杂环烷基或3-8元杂环烯基。In some embodiments, Ring A is selected from 3-10 membered heterocycloalkyl or 3-8 membered heterocycloalkenyl.

在一些实施方案中，环A选自4-10元杂环烷基。In some embodiments, Ring A is selected from 4-10 membered heterocycloalkyl.

在一些实施方案中，环A选自4-8元或10元杂环烷基。In some embodiments, Ring A is selected from 4-8 or 10-membered heterocycloalkyl.

在一些实施方案中，环A选自4-6元单环杂环烷基、7-8元或10元螺杂环烷基。在一些实施方案中，环A选自5元单环杂环烷基。In some embodiments, ring A is selected from 4-6 membered monocyclic heterocycloalkyl, 7-8 membered or 10 membered spiroheterocycloalkyl. In some embodiments, ring A is selected from 5 membered monocyclic heterocycloalkyl.

在一些实施方案中，环A选自吡咯烷基、噻唑烷基、咪唑烷基、哌啶基、哌嗪基、二氮杂螺癸烷基、一氧杂一氮杂螺辛烷基、氮杂环丁烷基、一氮杂螺庚烷基或噁唑烷基。在一些具体实施方案中，环A选自吡咯烷基、噻唑烷基或咪唑烷基。In some embodiments, ring A is selected from pyrrolidinyl, thiazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, diazaspirodecanyl, monooxa-azaspirooctanyl, azetidinyl, monoazaspiroheptyl or oxazolidinyl. In some specific embodiments, ring A is selected from pyrrolidinyl, thiazolidinyl or imidazolidinyl.

在一些实施方案中，环A选自其中Xt选自CH2、NH或O。In some embodiments, Ring A is selected from wherein X t is selected from CH 2 , NH or O.

在一些实施方案中，环A选自t选自1、2、3、4或5，X8选自CH2、NH、O或S。在一些实施方案中，t选自1、2或3。在一些实施方案中，t选自2。在一些实施方案中，X8选自CH2。在一些实施方案中，环A选自 在一些实施方案中，环A选自 在一些实施方案中，环A选自 In some embodiments, Ring A is selected from t is selected from 1, 2, 3, 4 or 5, and X8 is selected from CH2 , NH, O or S. In some embodiments, t is selected from 1, 2 or 3. In some embodiments, t is selected from 2. In some embodiments, X8 is selected from CH2 . In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from

在一些实施方案中，环A选自其中Xt选自NH或O。在一些实施方案中，环A选自 在一些实施方案中，环A选自在一些实施方案中，环A选自 In some embodiments, Ring A is selected from wherein Xt is selected from NH or O. In some embodiments, ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from

在另外一些实施方案中，环A选自3-8元杂环烷基或3-8元杂环烯基。In other embodiments, Ring A is selected from 3-8 membered heterocycloalkyl or 3-8 membered heterocycloalkenyl.

在另外一些实施方案中，环A选自3-6元杂环烷基或3-6元杂环烯基。在另外一些实施方案中，环A选自5-6元杂环烷基。In other embodiments, Ring A is selected from 3-6 membered heterocycloalkyl or 3-6 membered heterocycloalkenyl. In other embodiments, Ring A is selected from 5-6 membered heterocycloalkyl.

在一些实施方案中，环A中的杂环烷基或杂环烯基，其中杂原子选氮、氧、硫、磷或硼。在一些实施方案中，环A中的杂环烷基或杂环烯基，其中杂原子选氮、氧、或硫。在一些实施方案中，环A中的杂环烷基或杂环烯基，其中杂原子个数选自1、2、3、4或5个。在一些实施方案中，环A中的杂环烷基或杂环烯基，其中杂原子个数选自1、2或3个。In some embodiments, the heterocycloalkyl or heterocycloalkenyl in ring A, wherein the heteroatom is selected from nitrogen, oxygen, sulfur, phosphorus or boron. In some embodiments, the heterocycloalkyl or heterocycloalkenyl in ring A, wherein the heteroatom is selected from nitrogen, oxygen, or sulfur. In some embodiments, the heterocycloalkyl or heterocycloalkenyl in ring A, wherein the number of heteroatoms is selected from 1, 2, 3, 4 or 5. In some embodiments, the heterocycloalkyl or heterocycloalkenyl in ring A, wherein the number of heteroatoms is selected from 1, 2 or 3.

在一些实施方案中，环A中的杂环烷基或杂环烯基，其中组成环A的杂原子中，含有不超过2个的N原子。In some embodiments, the heterocycloalkyl or heterocycloalkenyl group in ring A contains no more than 2 N atoms among the heteroatoms constituting ring A.

在一些实施方案中，环A中的杂环烷基或杂环烯基，其中组成环A的杂原子中，有且仅有1个N原子或者有且仅有2个N原子。In some embodiments, the heterocycloalkyl or heterocycloalkenyl in ring A has only 1 N atom or only 2 N atoms among the heteroatoms constituting ring A.

在一些实施方案中，环A中的杂环烷基或杂环烯基，其中组成环A的杂原子中，有且仅有1个N原子和1个S原子。In some embodiments, the heterocycloalkyl or heterocycloalkenyl in ring A has and only has 1 N atom and 1 S atom among the heteroatoms constituting ring A.

在另外一些实施方案中，环A选自吡咯烷基、噻唑烷基、咪唑烷基、哌啶基或哌嗪基。In other embodiments, Ring A is selected from pyrrolidinyl, thiazolidinyl, imidazolidinyl, piperidinyl, or piperazinyl.

在另外一些实施方案中，环A选自 In other embodiments, Ring A is 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 In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from

在另外一些实施方案中，结构单元选自在一些实施方案中，环A选自 In other embodiments, the structural unit Selected from In some embodiments, Ring A is selected from

所述结构单元或者， 或者任选地被一个、两个或三个R2取代。The structural unit or, or Optionally substituted with one, two or three R2 .

在一些实施方案中，环A、结构单元选自
或者 在一些实施方案中，环A、结构单元选自 In some embodiments, Ring A, the building block Selected from
or In some embodiments, Ring A, the building block Selected from

在另外一些实施方案中，结构单元选自 In other 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 In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from

另一方面，本公开提供式I A、IA-1、IA-2或IA-3化合物，或其药学上可接受的盐，

In another aspect, the present disclosure provides a compound of Formula IA, IA-1, IA-2 or IA-3, or a pharmaceutically acceptable salt thereof,

其中，X1、X2、X3、X4、X5、R1、R2、Ra、m及n的定义如本公开所述；wherein X 1 , X 2 , X 3 , X 4 , X 5 , R 1 , R 2 , Ra , m and n are as defined in the present disclosure;

q选自0、1、2或3；q is selected from 0, 1, 2 or 3;

Xa及Xc分别独立地选自CH或N。在一些实施方案中，Xa及Xc选自CH。 Xa and Xc are each independently selected from CH or N. In some embodiments, Xa and Xc are selected from CH.

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

另一方面，本公开提供式II、II-1、II-2或II-3化合物，或其药学上可接受的盐，
In another aspect, the present disclosure provides a compound of formula II, II-1, II-2 or II-3, or a pharmaceutically acceptable salt thereof,

其中，环A、X1、X2、X3、X4、X5、R1、R2、m及n的定义如本公开所述。wherein ring A, X 1 , X 2 , X 3 , X 4 , X 5 , R 1 , R 2 , m and n are as defined in the present disclosure.

另一方面，本公开提供式III、IV、IIIA或IVA化合物，或其药学上可接受的盐，
In another aspect, the present disclosure provides a compound of formula III, IV, IIIA or IVA, or a pharmaceutically acceptable salt thereof,

其中，Xa、Xc、R1、Ra、q及m的定义如本公开所述；wherein X a , X c , R 1 , Ra , q and m are as defined in the present disclosure;

环B选自3-10元杂环烷基或3-10元杂环烯基；Ring B is selected from 3-10 membered heterocycloalkyl or 3-10 membered heterocycloalkenyl;

R2a的定义如本公开R2所述；R 2a is as defined in the disclosure for R 2 ;

或者，每一个R2a分别独立地选自CN、卤素、＝O、或任选地被一个或多个取代基取代的以下基团：OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、HOC(O)-、C1-6烷基OCO-、C1-6烷基C(O)O-、-C(O)NH2、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1- 6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Alternatively, each R 2a is independently selected from CN, halogen, =O, or the following groups optionally substituted by one or more substituents: OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, HOC(O)- , C 1-6 alkylOCO-, C 1-6 alkylC(O) O- , -C(O)NH 2 , C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl;

p选自0、1、2或3；p is selected from 0, 1, 2 or 3;

T选自S＝O或C。T is selected from S═O or C.

在一些实施方案中，Xa及Xc选自CH或N。在一些实施方案中，Xa及Xc选自CH。In some embodiments, Xa and Xc are selected from CH or N. In some embodiments, Xa and Xc are selected from CH.

在一些实施方案中，环B选自3-8元杂环烷基或3-8元杂环烯基。In some embodiments, Ring B is selected from 3-8 membered heterocycloalkyl or 3-8 membered heterocycloalkenyl.

在一些实施方案中，环B选自3-6元杂环烷基或3-6元杂环烯基。In some embodiments, Ring B is selected from 3-6 membered heterocycloalkyl or 3-6 membered heterocycloalkenyl.

在一些实施方案中，环B选自3-10元杂环烷基。In some embodiments, Ring B is selected from 3-10 membered heterocycloalkyl.

在一些实施方案中，环B选自4-10元杂环烷基。In some embodiments, Ring B is selected from 4-10 membered heterocycloalkyl.

在一些实施方案中，环B选自4-8元或10元杂环烷基。In some embodiments, Ring B is selected from 4-8 or 10-membered heterocycloalkyl.

在一些实施方案中，环B选自4-6元单环杂环烷基、7-8元或10元螺杂环烷基。In some embodiments, Ring B is selected from 4-6 membered monocyclic heterocycloalkyl, 7-8 membered or 10 membered spiroheterocycloalkyl.

在一些实施方案中，环B选自4-8元杂环烷基。In some embodiments, Ring B is selected from 4-8 membered heterocycloalkyl.

在一些实施方案中，环B选自4-6元杂环烷基。In some embodiments, Ring B is selected from 4-6 membered heterocycloalkyl.

在一些实施方案中，环B选自5-6元杂环烷基。In some embodiments, Ring B is selected from 5-6 membered heterocycloalkyl.

在一些实施方案中，环B选自吡咯烷基、噻唑烷基、咪唑烷基、哌啶基、哌嗪基、二氮杂螺癸烷基、一氧杂一氮杂螺辛烷基、氮杂环丁烷基、一氮杂螺庚烷基或噁唑烷基。In some embodiments, Ring B is selected from pyrrolidinyl, thiazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, diazaspirodecanyl, monooxa-azaspirooctanyl, azetidinyl, monoazaspiroheptanyl, or oxazolidinyl.

在一些实施方案中，环B选自噁唑烷基、吡咯烷基、噻唑烷基、咪唑烷基、哌啶基或哌嗪基。In some embodiments, Ring B is selected from oxazolidinyl, pyrrolidinyl, thiazolidinyl, imidazolidinyl, piperidinyl, or piperazinyl.

在一些实施方案中，环B选自吡咯烷基、噻唑烷基、咪唑烷基、哌啶基或哌嗪基。 In some embodiments, Ring B is selected from pyrrolidinyl, thiazolidinyl, imidazolidinyl, piperidinyl, or piperazinyl.

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 In some embodiments, the structural unit Selected from In some embodiments, the structural unit Selected from

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，所述结构单元如结构单元的定义。In some embodiments, the structural unit As structural unit Definition of .

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

在一些实施方案中，每一个R2a的定义如本公开R2基团的定义(即与本公开R2相同)。In some embodiments, each R 2a is as defined for the R 2 group of the present disclosure (ie, the same as R 2 of the present disclosure).

在一些实施方案中，每一个R2a分别独立地选自CN、卤素、＝O、或任选地被一个或多个取代基取代的以下基团：OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1- 6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1- 6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基。In some embodiments, each R 2a is independently selected from CN, halogen, =0, or the following groups optionally substituted with one or more substituents: OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O- , C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, ( C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl ) 2 The invention also includes a C 1-6 alkyl) 2 NS(O) 2 -, a C 3-12 cycloalkyl, a 3-12 membered heterocycloalkyl, a C 3-12 cycloalkenyl, a 3-12 membered heterocycloalkenyl, a C 6-12 aryl or a 5-12 membered heteroaryl.

在一些实施方案中，每一个R2a分别独立地选自CN、卤素、OH、NH2、C1-4烷基、C1-4烷基O-、C1-4烷 基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C3-6环烷基或3-6元杂环烷基，所述C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C3-6环烷基或3-6元杂环烷基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-4烷基、C1-4烷基O-、(C1-4烷基)2N-、C1-4烷基NH-、-COOH、C1-4烷基OC(O)-、C1-4烷基C(O)O-。In some embodiments, each R 2a is independently selected from CN, halogen, OH, NH 2 , C 1-4 alkyl, C 1-4 alkylO-, C 1-4 alkyl C 1-4 alkyl) 2 N—, C 1-4 alkyl OC(O)—, C 1-4 alkyl C(O)O—, C 1-4 alkyl NHC(O)—, C 1-4 alkyl C(O)NH—, (C 1-4 alkyl) 2 NC(O)—, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl O—, C 1-4 alkyl S—, C 1-4 alkyl NH—, (C 1-4 alkyl) 2 N—, C 1-4 alkyl OC(O)—, C 1-4 alkyl C(O)O—, C 1-4 alkyl NHC(O)—, C 1-4 alkyl C(O)NH—, (C 1-4 alkyl) 2 NC(O)—, C The 3-6- membered cycloalkyl or 3-6-membered heterocycloalkyl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-4 alkyl, C 1-4 alkylO—, (C 1-4 alkyl) 2 N—, C 1-4 alkylNH—, —COOH, C 1-4 alkylOC(O)—, C 1-4 alkylC(O)O—.

在一些实施方案中，每一个R2a分别独立地选自CN、卤素、OH、NH2、C1-3烷基、C1-3烷基O-、C1-3烷基NH-、C1-3烷基OC(O)-或5-6元杂环烷基，所述C1-3烷基、C1-3烷基O-、C1-3烷基NH-、C1-3烷基OC(O)-或5-6元杂环烷基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-3烷基、-COOH、或C1-3烷基OC(O)-。In some embodiments, each R 2a is independently selected from CN, halogen, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylO—, C 1-3 alkylNH—, C 1-3 alkylOC(O)-, or 5-6-membered heterocycloalkyl, and the C 1-3 alkyl, C 1-3 alkylO—, C 1-3 alkylNH—, C 1-3 alkylOC(O)-, or 5-6-membered heterocycloalkyl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-3 alkyl, -COOH, or C 1-3 alkylOC(O)-.

在一些实施方案中，每一个R2a分别独立地选自CN、卤素、OH、NH2、甲基、乙基、CH3O-、CH3NH-、CH3CH2NH-、CH3OC(O)-、CH3CH2OC(O)-或5元含氧杂环烷基，所述甲基、乙基、CH3O-、CH3NH-、CH3CH2NH-、CH3OC(O)-、CH3CH2OC(O)-或5元含氧杂环烷基任选地被一个或多个以下基团取代：CN、卤素(例如F或Cl)、OH、NH2、甲基、-COOH、或CH3OC(O)-。In some embodiments, each R 2a is independently selected from CN, halogen, OH, NH 2 , methyl, ethyl, CH 3 O-, CH 3 NH-, CH 3 CH 2 NH-, CH 3 OC(O)-, CH 3 CH 2 OC(O)-, or 5-membered oxygen-containing heterocycloalkyl, wherein the methyl, ethyl, CH 3 O-, CH 3 NH-, CH 3 CH 2 NH-, CH 3 OC(O)-, CH 3 CH 2 OC(O)-, or 5-membered oxygen-containing heterocycloalkyl is optionally substituted with one or more of the following groups: CN, halogen (e.g., F or Cl), OH, NH 2 , methyl, -COOH, or CH 3 OC(O)-.

在一些实施方案中，每一个R2a分别独立地选自CN、卤素、OH、NH2、甲基、乙基、CH3O-、CH3NH-、CH3CH2NH-、CH3OC(O)-、CH3CH2OC(O)-或5元含氧杂环烷基，所述甲基、乙基、CH3CH2NH-或5元含氧杂环烷基任选地被一个或多个以下基团取代：卤素(例如F或Cl)、OH、NH2、甲基、-COOH、或CH3OC(O)-。In some embodiments, each R 2a is independently selected from CN, halogen, OH, NH 2 , methyl, ethyl, CH 3 O-, CH 3 NH-, CH 3 CH 2 NH-, CH 3 OC(O)-, CH 3 CH 2 OC(O)-, or a 5-membered oxygen-containing heterocycloalkyl group, wherein the methyl, ethyl, CH 3 CH 2 NH-, or a 5-membered oxygen-containing heterocycloalkyl group is optionally substituted with one or more of the following groups: halogen (e.g., F or Cl), OH, NH 2 , methyl, -COOH, or CH 3 OC(O)-.

在一些实施方案中，每一个R2a分别独立地选自卤素(例如F或Cl)、OH、NH2、-CH3、-CH2OH、-CH2F、-CH2CH2OH、-CH(OH)CH3、-CH(OH)CH2OH、-CH2C(O)OCH3、-CH2C(O)OH、-OCH3、-NHCH3、-NHCH2CH2NH2、-C(O)OCH3、-C(O)OCH2CH3或 In some embodiments, each R 2a is independently selected from halogen (e.g., F or Cl), OH, NH 2 , -CH 3 , -CH 2 OH, -CH 2 F, -CH 2 CH 2 OH, -CH(OH)CH 3 , -CH(OH)CH 2 OH, -CH 2 C(O)OCH 3 , -CH 2 C(O)OH, -OCH 3 , -NHCH 3 , -NHCH 2 CH 2 NH 2 , -C(O)OCH 3 , -C(O)OCH 2 CH 3 , or

在另外一些实施方案中，每一个R2a分别独立地选自CN、卤素、＝O、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-或(C1-6烷基)2N-。In other embodiments, each R 2a is independently selected from CN, halogen, =O, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)- , C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO- , C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)- , C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C C 1-6 alkylS(O) 2 NH—, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO—, C 1-6 alkylS—, -SF 5 , C 1-6 alkylNH— or (C 1-6 alkyl) 2 N—.

在另外一些实施方案中，每一个R2a分别独立地选自CN、卤素、＝O、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1- 6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-或(C1-6烷基)2N-。In other embodiments, each R 2a is independently selected from CN, halogen, =O, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)- , C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH- , (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)- , C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS ( O ) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH- or (C 1-6 alkyl) 2 N-.

在另外一些实施方案中，每一个R2a分别独立地选自CN、卤素、＝O、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、 C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-3烷基O-、C1-3烷基S-、-SF5、C1-3烷基NH-或(C1-3烷基)2N-。In other embodiments, each R 2a is independently selected from CN, halogen, =O, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl, wherein the C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkyl S-, -SF 5 , C 1-6 alkyl NH-, (C 1-6 alkyl) 2 N-, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl is optionally substituted with one or more of the following: CN, halogen, OH, NH 2 , C 1-3 alkyl O-, C 1-3 alkyl S-, -SF 5 , C 1-3 alkyl NH- or (C 1-3 alkyl) 2 N-.

在另外一些实施方案中，每一个R2a分别独立地选自CN、卤素、＝O、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-或(C1-6烷基)2N-，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-或(C1-6烷基)2N-任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-3烷基O-、C1-3烷基S-、-SF5、C1-3烷基NH-或(C1-3烷基)2N-。In other embodiments, each R 2a is independently selected from CN, halogen, =O, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, or (C 1-6 alkyl) 2 N-, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, or (C 1-6 alkyl) 2 N- are optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-3 alkylO-, C 1-3 alkylS-, -SF 5 , C 1-3 alkylNH-, or (C 1-3 alkyl) 2 N-.

在一些实施方案中，R2a分别独立地选自CN、卤素、＝O、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-或(C1-4烷基)2N-，所述C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-或(C1-4烷基)2N-任选地被一个或多个以下基团取代：CN、卤素、OH或NH2。在另外一些实施方案中，每一个R2a分别独立地选自CN、卤素、＝O、OH、NH2、C1-4烷基、C2-4烯基或C2-4炔基-，所述C1-4烷基、C2-4烯基或C2-4炔基-任选地被一个或多个以下基团取代：CN、卤素、OH或NH2。In some embodiments, R 2a is each independently selected from CN, halogen, ＝O, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, or (C 1-4 alkyl) 2 N-, and the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, or (C 1-4 alkyl) 2 N- are optionally substituted with one or more of the following groups: CN, halogen, OH, or NH 2 . In other embodiments, each R 2a is independently selected from CN, halogen, =0, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl or C 2-4 alkynyl-, said C 1-4 alkyl, C 2-4 alkenyl or C 2-4 alkynyl- optionally substituted with one or more of the following groups: CN, halogen, OH or NH 2 .

在另外一些实施方案中，每一个R2a分别独立地选自CN、卤素、＝O、OH、NH2、C1-3烷基、C2-3烯基或C2-3炔基-，所述C1-3烷基、C2-3烯基或C2-3炔基-任选地被一个或多个以下基团取代：CN、卤素、OH或NH2。In other embodiments, each R 2a is independently selected from CN, halogen, =0, OH, NH 2 , C 1-3 alkyl, C 2-3 alkenyl or C 2-3 alkynyl-, said C 1-3 alkyl, C 2-3 alkenyl or C 2-3 alkynyl- optionally substituted with one or more of the following groups: CN, halogen, OH or NH 2 .

在另外一些实施方案中，每一个R2a分别独立地选自CN、卤素、＝O、OH、NH2、C1-3烷基，所述C1-3烷基任选地被一个或多个选自CN、卤素、OH或NH2的基团取代。In other embodiments, each R 2a is independently selected from CN, halogen, =0, OH, NH 2 , C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more groups selected from CN, halogen, OH or NH 2 .

在另外一些实施方案中，每一个R2a分别独立地选自卤素、＝O、OH或C1-3烷基，所述C1-3烷基任选地被一个或多个选自卤素、OH或NH2的基团取代。In other embodiments, each R 2a is independently selected from halogen, =0, OH or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more groups selected from halogen, OH or NH 2 .

在另外一些实施方案中，每一个R2a分别独立地选自F、＝O、OH或任选地被一个或多个OH或F取代的C1-3烷基。In other embodiments, each R 2a is independently selected from F, =O, OH, or C 1-3 alkyl optionally substituted with one or more OH or F.

在另外一些实施方案中，每一个R2a分别独立地选自F、＝O、OH、-CH3、-CH(OH)CH3、-CH2OH或-CH2F。In other embodiments, each R 2a is independently selected from F, =0, OH, -CH 3 , -CH(OH)CH 3 , -CH 2 OH, or -CH 2 F.

在另外一些实施方案中，每一个R2a分别独立地选自＝O、OH或C1-3烷基，所述C1-3烷基任选地被一个或多个选自OH或NH2的基团取代。In other embodiments , each R 2a is independently selected from =O, OH or C 1-3 alkyl, which is optionally substituted with one or more groups selected from OH or NH 2 .

在另外一些实施方案中，每一个R2a分别独立地选自＝O、OH或任选地被一个或多个OH取代的C1-3烷基(例如-C1-3烷基-OH)。In other embodiments, each R 2a is independently selected from =O, OH, or C 1-3 alkyl optionally substituted with one or more OH (eg, -C 1-3 alkyl-OH).

在另外一些实施方案中，每一个R2a分别独立地选自＝O、OH、-CH3或-CH2OH。In other embodiments, each R 2a is independently selected from ＝O, OH, -CH 3 or -CH 2 OH.

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

另一方面，本公开提供式V、VI或VII化合物，或其药学上可接受的盐，
In another aspect, the present disclosure provides a compound of Formula V, VI or VII, or a pharmaceutically acceptable salt thereof,

其中，Xa、Xc、R1、R2a、p及m的定义如本公开所述；Xt选自CH2、NH或O。wherein X a , X c , R 1 , R 2a , p and m are as defined in the present disclosure; and X t is selected from CH 2 , NH or O.

在一些实施方案中，m选自1，R1取代在X3位置。在一些实施方案中，X3选自CH，m选自1，R1取代发生在X3位置。 In some embodiments, m is selected from 1, and R1 is substituted at the X3 position. In some embodiments, X3 is selected from CH, m is selected from 1, and R1 is substituted at the X3 position.

在一些实施方案中，R1取代发生在所连接的苯环的对位，形成如下结构单元 In some embodiments, the R1 substitution occurs at the para position of the attached benzene ring, forming the following structural unit

在一些实施方案中，X1、X2、X3、X4及X5分别独立地选自CH，X选自O。In some embodiments, X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from CH, and X is selected from O.

在一些实施方案中，杂环烷基和杂环烯基各自独立地含有1个、2个或3个独立地选自N、O和S的杂原子。在一些实施方案中，杂环烷基和杂环烯基各自独立地含有1个或2个独立地选自N和O的杂原子。In some embodiments, heterocycloalkyl and heterocycloalkenyl each independently contain 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, heterocycloalkyl and heterocycloalkenyl each independently contain 1 or 2 heteroatoms independently selected from N and O.

在一些实施方案中，杂芳基含有1个、2个或3个独立地选自N、O和S的杂原子。In some embodiments, the heteroaryl group contains 1, 2, or 3 heteroatoms independently selected from N, O, and S.

在一些实施方案中，杂环基含有1个、2个或3个独立地选自N、O和S的杂原子。在一些实施方案中，杂环基含有1个或2个独立地选自N和O的杂原子。In some embodiments, the heterocyclyl contains 1, 2, or 3 heteroatoms independently selected from N, O, and S. In some embodiments, the heterocyclyl contains 1 or 2 heteroatoms independently selected from N and O.

在一些实施方案中，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，所述卤代选自氟代。In some embodiments, the halo is selected from fluoro, chloro, or bromo. In some embodiments, the halo is selected from fluoro or chloro. In some embodiments, the halo is selected from fluoro.

在一些实施方案中，所述C1-10选自C1-9、C1-8、C1-7、C1-6、C1-4、C1-3、或C1-2。在一些实施方案中，C1- 6选自C1-4、C1-3、或C1-2。在一些实施方案中，所述C1-4选自C4、C3、C2、或C1。在一些实施方案中，所述C1-3选自C3、C2、或C1。In some embodiments, the C 1-10 is selected from C 1-9 , C 1-8 , C 1-7 , C 1-6 , C 1-4 , C 1-3 , or C 1-2 . In some embodiments, C 1-6 is selected from C 1-4 , C 1-3 , or C 1-2 . In some embodiments, the C 1-4 is selected from C 4 , C 3 , C 2 , or C 1. In some embodiments, the C 1-3 is selected from C 3 , C 2 , or C 1 .

在一些实施方案中，所述C2-10选自C2-8、C2-6、C2-5、C2-4、C2-3。在一些实施方案中，所述C2-6选自C2- 4、或C2-3。在一些实施方案中，所述C2-4选自C4、C3、或C2。In some embodiments, the C 2-10 is selected from C 2-8 , C 2-6 , C 2-5 , C 2-4 , C 2-3 . In some embodiments, the C 2-6 is selected from C 2-4 , or C 2-3 . In some embodiments, the C 2-4 is selected from C 4 , C 3 , or C 2 .

在一些实施方案中，所述C3-6选自C3-5、C3-4、C4-6、C4-5、或C5-6。在一些实施方案中，所述C6-10选自C6-9、C6-8、C6-7、C7-10、C7-9、C7-8、C8-10、C8-9、或C9-10。在一些实施方案中，所述C3-10选自C3-9、C3-8、C3- 7、C3-6、C3-5、C3-4、C4-10、C4-9、C4-8、C4-7、C4-6、C4-5、C5-10、C5-9、C5-8、C5-7、C5-6、C6-10、C6-9、C6-8、C6- 7、C7-12、C7-10、C7-9、C7-8、C8-12、C8-10、C8-9、C9-12、或C9-10。在一些实施方案中，所述C3-15选自C3-12或C3- 10。在一些实施方案中，所述C3-12选自C3-10。在一些实施方案中，所述C6-12选自C6-10。In some embodiments, the C 3-6 is selected from C 3-5 , C 3-4 , C 4-6 , C 4-5 , or C 5-6 . In some embodiments, the C 6-10 is selected from C 6-9 , C 6-8 , C 6-7 , C 7-10 , C 7-9 , C 7-8 , C 8-10 , C 8-9 , or C 9-10 . In some embodiments, the C3-10 is selected from C3-9 , C3-8 , C3-7 , C3-6 , C3-5 , C3-4 , C4-10 , C4-9 , C4-8 , C4-7 , C4-6 , C4-5 , C5-10 , C5-9 , C5-8 , C5-7 , C5-6 , C6-10 , C6-9 , C6-8 , C6-7 , C7-12 , C7-10 , C7-9 , C7-8 , C8-12 , C8-10 , C8-9 , C9-12 , or C9-10 . In some embodiments, the C 3-15 is selected from C 3-12 or C 3-10 . In some embodiments, the C 3-12 is selected from C 3-10 . In some embodiments, the C 6-12 is selected from C 6-10 .

在一些实施方案中，所述3-6元选自3-5元、3-4元、4-6元、4-5元、或5-6元。在一些实施方案中，所述5-10元选自5-8元、5-7元、5-6元、6-10元、6-9元、6-8元、6-7元、7-10元、7-9元、7-8元、8-10元、8-9元、9-10元。在一些实施方案中，所述3-10元选自3-9元、3-8元、3-7元、3-6元、3-5元、3-4元、4-10元、4-9元、4-8元、4-7元、4-6元、4-5元、5-10元、5-9元、5-8元、5-7元、5-6元、6-10元、6-9元、6-8元、6-7元、7-10元、7-9元、7-8元、8-10元、8-9元、9-10元。在一些实施方案中，所述3-15元选自3-12元或3-10元。在一些实施方案中，所述3-12元选自3-10元。在一些实施方案中，所述5-12元选自5-10元。In some embodiments, the 3-6 yuan is selected from 3-5 yuan, 3-4 yuan, 4-6 yuan, 4-5 yuan, or 5-6 yuan. In some embodiments, the 5-10 yuan is selected from 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6-9 yuan, 6-8 yuan, 6-7 yuan, 7-10 yuan, 7-9 yuan, 7-8 yuan, 8-10 yuan, 8-9 yuan, 9-10 yuan. In some embodiments, the 3-10 yuan is selected from 3-9 yuan, 3-8 yuan, 3-7 yuan, 3-6 yuan, 3-5 yuan, 3-4 yuan, 4-10 yuan, 4-9 yuan, 4-8 yuan, 4-7 yuan, 4-6 yuan, 4-5 yuan, 5-10 yuan, 5-9 yuan, 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6-9 yuan, 6-8 yuan, 6-7 yuan, 7-10 yuan, 7-9 yuan, 7-8 yuan, 8-10 yuan, 8-9 yuan, 9-10 yuan. In some embodiments, the 3-15 yuan is selected from 3-12 yuan or 3-10 yuan. In some embodiments, the 3-12 yuan is selected from 3-10 yuan. In some embodiments, the 5-12 yuan is selected from 5-10 yuan.

在一些实施方案中，本公开化合物不选自以下化合物：
In some embodiments, the compounds of the present disclosure are not selected from the following compounds:

在一些实施方案中，本公开化合物不选自以下化合物： In some embodiments, the compounds of the present disclosure are not selected from the following compounds:

在一些实施方案中，本公开化合物不选自以下化合物： In some embodiments, the compounds of the present disclosure are not selected from the following compounds:

另一方面，本公开涉及以下化合物，或其药学上可接受的盐：





In another aspect, the present disclosure relates to the following compounds, or pharmaceutically acceptable salts thereof:





在一些实施方案中，本公开具有一个不对称碳原子的化合物，该化合物包括经液相分离的先出峰化合物或后出峰化合物。在一些具体实施方案中，所述液相分离的流动相为本公开实施例中的流动相。In some embodiments, the present disclosure discloses a compound having an asymmetric carbon atom, the compound comprising a first eluting compound or a last eluting compound after liquid phase separation. In some specific embodiments, the mobile phase for liquid phase separation is the mobile phase in the examples of the present disclosure.

另一方面，本公开涉及一种药物组合物，所述药物组合物含有本公开上述的化合物或其药学上可接受的盐，本公开的药物组合物还包括药学上可接受的辅料。On the other hand, the present disclosure relates to a pharmaceutical composition, which contains the above-mentioned compound of the present disclosure or a pharmaceutically acceptable salt thereof, and the pharmaceutical composition of the present disclosure also includes a pharmaceutically acceptable excipient.

另一方面，本公开涉及上述化合物或其药学上可接受的盐、或其药物组合物在制备预防或者治疗疾病(例如与TEAD相关的疾病)的药物中的用途。In another aspect, the present disclosure relates to use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating a disease (eg, a disease associated with TEAD).

另一方面，本公开涉及治疗或预防疾病(例如与TEAD相关的疾病)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的上述化合物或其药学上可接受的盐、或其药物组合物。In another aspect, the present disclosure relates to a method for treating or preventing a disease (e.g., a disease associated with TEAD), comprising administering a therapeutically effective amount of the above-mentioned compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

另一方面，本公开涉及上述化合物或其药学上可接受的盐、或其药物组合物在预防或者治疗疾病(例如与TEAD相关的疾病)中的用途。In another aspect, the present disclosure relates to use of the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating a disease (eg, a disease associated with TEAD).

另一方面，本公开涉及用于预防或者治疗疾病(例如与TEAD相关的疾病)的上述化合物或其药学上可接受的盐、或其药物组合物。In another aspect, the present disclosure relates to the above-mentioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a disease (eg, a disease associated with TEAD).

在一些具体实施方案中，所述疾病(例如与TEAD相关的疾病)选自癌症；在一些更具体的方案中，所述疾病(例如与TEAD相关的疾病)选自间皮瘤、肺癌。In some specific embodiments, the disease (eg, a disease associated with TEAD) is selected from cancer; in some more specific embodiments, the disease (eg, a disease associated with TEAD) is selected from mesothelioma and lung cancer.

在一些方案中，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 aspects, the present disclosure comprises the above-defined variables and embodiments thereof, and any combination thereof.

技术效果Technical Effects

本公开的化合物具有很好的体外蛋白结合活性，针对TEAD1、TEAD2、TEAD3或TEAD4蛋白具有结合作用。针对NCI-H226细胞或NCI-H2052细胞具有增殖抑制活性，对NCI-H2452细胞基本没有增殖抑制活性，相对于NCI-H2452细胞对NCI-H226或NCI-H2052细胞具有很好的选择性。体外代谢稳定，具有良好的体内药代动力学性质及体内药效。The disclosed compounds have good in vitro protein binding activity, and have binding effects on TEAD1, TEAD2, TEAD3 or TEAD4 proteins. They have proliferation inhibitory activity on NCI-H226 cells or NCI-H2052 cells, and have substantially no proliferation inhibitory activity on NCI-H2452 cells. They have good selectivity for NCI-H226 or NCI-H2052 cells relative to NCI-H2452 cells. They are metabolically stable in vitro and have good in vivo pharmacokinetic properties and in vivo efficacy.

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 specified, the following terms used in this disclosure have the following meanings. A particular term should not be used without special definition. This is considered to be uncertain or unclear, and 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 commercial product or its active ingredient.

在一些实施方案中，所述“一个或多个”选自一个、两个、三个、四个、五个或六个。在一些实施方案中，所述“一个或多个”选自一个、两个、或三个。在一些实施方案中，所述“一个或多个”选自一个、或两个。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。In some embodiments, the "one or more" is selected from one, two, three, four, five or six. In some embodiments, the "one or more" is selected from one, two, or three. In some embodiments, the "one or more" is selected from one, or two. The term "substituted" refers to any one or more hydrogen atoms on a particular atom being 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 an oxo (i.e., =O), it means that two hydrogen atoms are replaced, and the oxo will not occur on the aromatic group.

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。例如，所述C1-6烷基(C1-4烷基)等任选地被一个或多个以下基团取代：CN、卤素、OH或NH2，可以形成例如-C1-6烷基-OH、-C1-6烷基-NH2等基团。The term "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes 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 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 substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will be introduced. For example, the C 1-6 alkyl (C 1-4 alkyl) etc. is optionally substituted with one or more of the following groups: CN, halogen, OH or NH 2 , and groups such as -C 1-6 alkyl-OH, -C 1-6 alkyl-NH 2 , etc. can be formed.

本文所述“取代基”包括但不限于上下文提及的术语“烷基”、“烷氧基”、“环烷基”、“杂环烷基”、“杂芳基”、“烯基”、“炔基”、“环烯基”、“杂环烯基”、“杂芳环”等，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氕、氘、氚、-OH、-SF5、-SH、卤素、-NH2、硝基、亚硝基、-CN、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、环烷基烷基、环烷基氧基、杂环基、杂环基烷基、杂环基氧基、杂环烷基、杂环烷基烷基、杂环烷基氧基、杂芳基、杂芳基烷基、杂芳基氧基、芳基、芳基烷基或芳基氧基。The "substituent" mentioned herein includes, but is not limited to, the terms "alkyl", "alkoxy", "cycloalkyl", "heterocycloalkyl", "heteroaryl", "alkenyl", "alkynyl", "cycloalkenyl", "heterocycloalkenyl", "heteroaryl ring", etc., and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent" include protium, deuterium, tritium, -OH, -SF5 , -SH, halogen, -NH2 , nitro, nitroso, -CN, an azide group, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, a carboxaldehyde group, an imine group, an alkyl group, a halo-alkyl group, a cycloalkyl group, a halo-cycloalkyl group, an alkenyl group, a halo-alkenyl group, a cycloalkenyl group, a halo-cycloalkenyl group, an alkynyl group, a halo-alkynyl group, a cycloalkynyl group, a halo-cycloalkynyl group, a heteroalkyl group, a halo-heteroalkyl group, an alkoxy group, an alkylthio group, an aryl group, an aryloxy group, an arylthio group, an aralkyl group, an arylalkoxy group, an arylalkylthio group, a heteroaryl group, a heteroaryloxy group, a heteroarylthio group, a heteroaralkyl group, a heteroarylalkoxy group, a heteroarylalkylthio group , heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide group, urea group, epoxy group and ester group, etc., which are optionally substituted by one or more substituents selected from the following: oxo, hydroxyl, amino, nitro, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH 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, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyl, heterocyclylalkyl, heterocyclyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, aryl, arylalkyl, or aryloxy.

在本文的部分实施方案中，所述“取代基”选自氘、氚、-SF5、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酯基团和氧代，所述取代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、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 deuterium, tritium, —SF 5 , hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azido, sulfoxide, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 alkyl, halo-C 1-12 alkyl, 3-12 membered cycloalkyl, halo-3-12 membered cycloalkyl, C 2-12 alkenyl, halo-C 2-12 alkenyl, 3-12 membered cycloalkenyl, halo- 3-12 membered cycloalkenyl, C 2-12 alkynyl , halo-C 2-12 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 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 group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 1-12 alkoxy, halogenated C 1-12 alkoxy, C 1-12 alkylamino, di-C 1-12 alkylamino, halogenated C 1-12 alkylamino, halogenated di-C 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 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 heterocyclylalkyl, 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 C 1-12 alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 alkylene or 6-10 membered aryloxy.

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。例如“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 may 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. For example, " C1-6 " means that the group may 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 may have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.

本文中的“m-n元”，是该部分具有给定范围中的整数元。例如“3-12元”是指3元、4元、5元、6元、7元、8元、9元、10元、11元或12元。例如“5-10元”是指5元、6元、7元、8元、9元或10元。例如“3-6元”是指3元、4元、5元或6元。"m-n yuan" in this article means that the part has an integer number in a given range. For example, "3-12 yuan" means 3 yuan, 4 yuan, 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan, 10 yuan, 11 yuan or 12 yuan. For example, "5-10 yuan" means 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan or 10 yuan. For example, "3-6 yuan" means 3 yuan, 4 yuan, 5 yuan or 6 yuan.

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。例如，如果一个基团含2个R，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. For example, if a group contains 2 R's, each R has independent options.

当一个键交叉连接到一个环(包括单环、并环或螺环)的两个原子时，这种键可以与环(包括单环、并环或螺环)上的任意原子相键合。When a bond crosses two atoms in a ring (including a monocyclic, paracyclic or spirocyclic ring), such bond may be bonded to any atom in the ring (including a monocyclic, paracyclic or spirocyclic ring).

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

本公开各含“杂原子”的基团中，“杂原子”包括除碳或氢外的任何元素的原子。优选的杂原子是硼、氮、氧、硫、硅和磷，其中氮原子任选地被季铵化或被氧化为N(O)，硫原子任选被氧化为S(O)或S(O)2，磷原子任选地被氧化为P(O)或P(O)2。In each group containing "heteroatom" in the present disclosure, "heteroatom" includes atoms of any element except carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, sulfur, silicon and phosphorus, wherein nitrogen atoms are optionally quaternized or oxidized to N(O), sulfur atoms are optionally oxidized to S(O) or S(O) 2 , and phosphorus atoms are optionally oxidized to P(O) or P(O) 2 .

术语“烷基”是指通式为CnH2n+1的烃基。该烷基可以是直链或支链的。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)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰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 hydrocarbon group of the general formula CnH2n +1 . The alkyl group may be straight or branched. 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.). Similarly, the alkyl portion (i.e., alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio has the same definition as above.

术语“烷氧基”指-O-烷基。The term "alkoxy" refers to an -O-alkyl group.

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。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。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. Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, etc.

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。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。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. Non-limiting examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C-CH3), 2-propynyl (-CH2-C≡CH), 1,3-butadiynyl (-C≡C-C≡CH), etc.

术语“环烯基”是指不完全饱和的并且可以以呈单环、双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20元环、3至15元环或3至10元环(例如4至8元环)。除非另有指示，该碳环通常为4至10元环(例如5至8元环，具体如5元、6元、7元、8元、9元或10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。The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and can exist as a monocyclic, bicyclic bridged ring or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is generally 3 to 20 rings, 3 to 15 rings or 3 to 10 rings (e.g., 4 to 8 rings). Unless otherwise indicated, the carbocyclic ring is generally 4 to 10 rings (e.g., 5 to 8 rings, specifically such as 5, 6, 7, 8, 9 or 10 rings). Non-limiting examples of cycloalkenyl include but are not limited to cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, etc.

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至20元环、3至15元环或3至10元环(例如5至8元环，具体如5元、6元、7元、8元、9元或10元环)。环烷基非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基等。The term "cycloalkyl" refers to a fully saturated carbocyclic ring that can exist as a monocyclic ring, a bridged ring or a spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically 3 to 20 rings, 3 to 15 rings or 3 to 10 rings (e.g., 5 to 8 rings, specifically 5, 6, 7, 8, 9 or 10 rings). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, etc.

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6个或1至3个独立地选自硼、氮、氧、硫、硅和/或磷的杂原子(优选硫、氧和/或氮的杂原子，优选1个、2个或3个杂原子)的3至20元环、3至15元环、3至7元环、3至6元环或3至5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。优选为具有5或6个环原子的单环杂环烷基。 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 20-membered ring, 3 to 15-membered ring, 3 to 7-membered ring, 3 to 6-membered ring or 3 to 5-membered ring containing 1 to 6 or 1 to 3 heteroatoms independently selected from boron, nitrogen, oxygen, sulfur, silicon and/or phosphorus (preferably sulfur, oxygen and/or nitrogen heteroatoms, preferably 1, 2 or 3 heteroatoms). Examples of 3-membered heterocycloalkyl include, but are not limited to, oxirane, thioethane, and cyclonitroethane. Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxadiazolyl, and thiadinyl. Examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, and tetrahydropyrazolyl. Examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, and 1,4-dithianyl. Examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Preferably, the monocyclic heterocycloalkyl has 5 or 6 ring atoms.

术语"杂环烯基"包括其中一个或多个碳原子，例如至多3个碳原子、或者至多2个碳原子、或者1个碳原子各自独立地被B、O、S、S(O)、S(O)2、N、Si、P或P(O)代替的环烯基，条件是保留至少一个环烯基碳-碳双键。可以以单环、桥环或螺环存在的环状基团，可以是3至20元环、3至15元环或3至13元环(例如5至13元环、5至8元环，具体如5元、6元、7元、8元、9元、10元或11元环)。The term "heterocycloalkenyl" includes cycloalkenyl groups in which one or more carbon atoms, for example up to 3 carbon atoms, or up to 2 carbon atoms, or 1 carbon atom are independently replaced by B, O, S, S(O), S(O) 2 , N, Si, P or P(O), provided that at least one cycloalkenyl carbon-carbon double bond is retained. The cyclic group, which may exist as a monocyclic ring, a bridged ring or a spirocyclic ring, may be a 3-20-membered ring, a 3-15-membered ring or a 3-13-membered ring (e.g., a 5-13-membered ring, a 5-8-membered ring, specifically a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered or 11-membered ring).

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个独立地选自硼、硫、氧和/或氮的杂原子(优选1个、2个或3个杂原子)的3至20元(或者3至17元、或者3至13元、或者3至7元，具体如4元、5元、6元、7元、8元、9元或10元环)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。杂环基可以是例如杂环烯基、杂环烷基、或苯并杂环烯基(不是完全饱和的杂芳族)。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 or spirocyclic ring. Unless otherwise indicated, the heterocyclic ring is generally 3 to 20 yuan (or 3 to 17 yuan, or 3 to 13 yuan, or 3 to 7 yuan, specifically such as 4 yuan, 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan or 10 yuan ring) ring containing 1 to 3 heteroatoms (preferably 1, 2 or 3 heteroatoms) independently selected from boron, sulfur, oxygen and/or nitrogen. 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 heterocyclyl group can be, for example, heterocycloalkenyl, heterocycloalkyl, or benzoheterocycloalkenyl (not a fully saturated heteroaromatic).

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个碳原子或6-12个碳原子，或者6-10个(例如6个、7个、8个、9个或10个)碳原子。芳基的非限制性实例包括但不限于苯基、萘基、蒽基和1,2,3,4-四氢化萘等。The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 (e.g., 6, 7, 8, 9, or 10) carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetrahydronaphthalene, etc.

术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个选自氮、氧、S的环原子，其余环原子为C，并且具有至少一个芳香环。优选的杂芳基具有单个4至8元环，尤其是5至8元(例如5元、6元、7元或8元)环，或包含6至20个，或6至14个，尤其是6至10个(例如6个、7个、8个、9个或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。The term "heteroaryl" refers to a monocyclic or fused polycyclic system, wherein containing at least one ring atom selected from nitrogen, oxygen, S, the remaining ring atoms are C, and have at least one aromatic ring. Preferred heteroaryl has a single 4 to 8 ring, especially 5 to 8 (e.g., 5, 6, 7 or 8) ring, or comprises 6 to 20, or 6 to 14, especially 6 to 10 (e.g., 6, 7, 8, 9 or 10) ring atoms of a plurality of fused rings. Non-limiting examples of heteroaryl include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.

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 a 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.

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。The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, etc., respectively .

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 (e.g., those labeled with 3 H and 14 C) can be used in compound and/or substrate tissue distribution assays. 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。例如，应当理解，本公开式IC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IC化合物的范围内。In addition, substitution with heavier isotopes such as deuterium (i.e., 2H ) may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is replaced by at least one deuterium. For example, it is understood that compounds in which one or more hydrogen atoms in the disclosed IC compounds are replaced by deuterium atoms are still within the scope of the disclosed IC compounds.

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。The disclosed compounds may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers. The disclosed compounds containing asymmetric carbon atoms may be isolated in optically pure forms or in racemic forms. Optically pure forms may be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

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。因此本公开的化合物可以包含药学上可接受的辅料。The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients. Therefore, the compounds of the present disclosure may include 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 invention 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.

本文所述的通式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，以单独或分开剂量的形式。In all methods of administration of the compounds of formula I described herein, the dosage administered is 0.001 to 2000 mg/kg body weight per day in single or divided doses.

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。The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions 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.

本领域合成路线规划中的一个重要考量因素是为反应性官能团(如本公开中的氨基)选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley&Sons,Inc.An important consideration in synthetic route planning in the art is the selection of appropriate protecting groups for reactive functional groups (such as the amino groups in the present disclosure), for example, see Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

本公开的化合物可以采用以下路线，结合领域已知的技术制备得到：

The compounds disclosed herein can be prepared by the following routes in combination with techniques known in the art:

其中环A、X1、X2、X3、X4、X5、X、R1、R2、Xa、Xb、Xc、Xd、Xe、Xf、m及n的定义如本公开所述，Z1或Z2分别独立的为卤素。wherein Ring A, X1 , X2 , X3, X4 , X5 , X, R1 , R2 , Xa , Xb , Xc , Xd , Xe , Xf , m and n are as defined in the present disclosure, and Z1 or Z2 is independently halogen.

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

在一些实施方案中，Z1选自氟；Z2选自溴；R5选自C1-6烷基(例如甲基、乙基或丙基)。In some embodiments, Z 1 is selected from fluorine; Z 2 is selected from bromine; and R 5 is selected from C 1-6 alkyl (eg, methyl, ethyl, or propyl).

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

DMF代表二甲基甲酰胺；DMSO代表二甲基亚砜；EA代表乙酸乙酯；PE代表石油醚；MeOH代表甲醇；DCM代表二氯甲烷；THF代表四氢呋喃；NMP代表；Boc代表叔丁氧羰基；Bn代表苄基；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；EDCI代表1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐；DMAP代表4-二甲氨基吡啶；2-MeTHF代表2-甲基四氢呋喃；DIPEA代表N,N-二异丙基乙胺；HATU代表N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲；LDA代表二异丙基氨基锂；TBAF代表四丁基氟化铵；Cbz代表苄氧羰基；Pd(OAc)2代表醋酸钯；Me代表甲基。DMF stands for dimethylformamide; DMSO stands for dimethyl sulfoxide; EA stands for ethyl acetate; PE stands for petroleum ether; MeOH stands for methanol; DCM stands for dichloromethane; THF stands for tetrahydrofuran; NMP stands for; Boc stands for tert-butyloxycarbonyl; Bn stands for benzyl; Xant-Phos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Pd 2 (dba) 3 represents tris(dibenzylideneacetone) dipalladium; EDCI represents 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; DMAP represents 4-dimethylaminopyridine; 2-MeTHF represents 2-methyltetrahydrofuran; DIPEA represents N,N-diisopropylethylamine; HATU represents N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate; LDA represents lithium diisopropylamide; TBAF represents tetrabutylammonium fluoride; Cbz represents benzyloxycarbonyl; Pd(OAc) 2 represents palladium acetate; Me represents methyl.

具体实施方式DETAILED DESCRIPTION

为清楚起见，进一步用实施例来阐述本公开，但是实施例并非限制本公开的范围。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。For the sake of clarity, the present disclosure is further illustrated with examples, but the examples do not limit the scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

采用单晶培养法，确认下列实施例部分异构体化合物的R或S构型。The single crystal growth method was used to confirm the R or S configuration of some isomeric compounds in the following examples.

实施例1
Example 1

步骤A：向微波管中依次加入化合物1-1(1.00g)，1-氟-4-三氟甲基-苯(3.68g)，碳酸铯(7.30g)和DMF(10mL)，微波加热至120℃反应2h。反应结束后加入水，用乙酸乙酯萃取，合并有机层，饱和氯化钠水洗，无水硫酸钠干燥，抽滤，滤液减压浓缩干，所得粗品经硅胶柱层析纯化，得到化合物1-2(1.45g)。Step A: Compound 1-1 (1.00 g), 1-fluoro-4-trifluoromethyl-benzene (3.68 g), cesium carbonate (7.30 g) and DMF (10 mL) were added to a microwave tube in sequence, and microwave heating was performed at 120° C. for 2 h. After the reaction was completed, water was added, extracted with ethyl acetate, the organic layers were combined, washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 1-2 (1.45 g).

1H NMR(500MHz,DMSO-d6)δ8.35(d,J＝2.0Hz,1H),7.90(d,J＝9.0Hz,1H),7.85(d,J＝8.4Hz,1H),7.74(d,J＝8.7Hz,2H),7.68(dd,J＝9.0,2.0Hz,1H),7.63-7.60(m,1H),7.27(d,J＝7.6Hz,1H),7.17(d,J＝8.6Hz,2H). 1 H NMR (500MHz, DMSO-d 6 )δ8.35(d,J＝2.0Hz,1H),7.90(d,J＝9.0Hz,1H),7.85(d,J＝8.4Hz,1H),7.74(d,J＝8.7Hz,2H) , 7.68(dd,J＝9.0,2.0Hz,1H),7.63-7.60(m,1H),7.27(d,J＝7.6Hz,1H),7.17(d,J＝8.6Hz,2H).

步骤B：向茄型瓶中依次加入化合物1-2(250mg)，Pd2(dba)3(12.5mg)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(23.5mg)，碳酸铯(665mg)，4-羟基-2-吡咯烷酮(82.5mg)，1,4-二氧六环(10mL)，N2保护下加热至110℃回流反应5小时。反应结束后加入水，用乙酸乙酯萃取，合并有机层，饱和氯化钠水洗，无水硫酸钠 干燥，抽滤，滤液减压浓缩干，所得粗品经硅胶柱层析纯化，得到化合物1(100mg)。Step B: Compound 1-2 (250 mg), Pd 2 (dba) 3 (12.5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (23.5 mg), cesium carbonate (665 mg), 4-hydroxy-2-pyrrolidone (82.5 mg), 1,4-dioxane (10 mL) were added to an eggplant-shaped bottle in sequence, and heated to 110°C under N 2 protection and refluxed for 5 hours. After the reaction was completed, water was added, extracted with ethyl acetate, the organic layers were combined, washed with saturated sodium chloride water, and anhydrous sodium sulfate. The solution was dried and filtered, and the filtrate was concentrated to dryness under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain compound 1 (100 mg).

1H NMR(500MHz,DMSO-d6)δ8.11(d,J＝2.1Hz,1H),8.08(dd,J＝9.2,2.2Hz,1H),7.92(d,J＝9.2Hz,1H),7.82(d,J＝8.35Hz,1H),7.73(d,J＝8.70Hz,2H),7.54(t,J＝7.75Hz,1H),7.19-7.10(m,3H),5.40(d,J＝3.90Hz,1H),4.48-4.41(m,1H),4.21-4.15(m,1H),3.74(d,J＝10.45Hz,1H),2.89(dd,J＝17.05,6.15Hz,1H),2.37(dd,J＝17.05,1.65Hz,1H).MS(ESI+,[M+H]+)m/z：388.04。 1 H NMR (500MHz, DMSO-d 6 )δ8.11(d,J＝2.1Hz,1H),8.08(dd,J＝9.2,2.2Hz,1H),7.92(d,J＝9.2Hz,1H),7.82(d ,J＝8.35Hz,1H),7.73(d,J＝8.70Hz,2H),7.54(t,J＝7.75Hz,1H),7.19-7.10(m,3H), 5.40(d,J＝3.90Hz,1H),4.48-4.41(m,1H),4.21-4.15(m,1H),3.74(d,J＝10.45Hz,1 H),2.89(dd,J＝17.05,6.15Hz,1H),2.37(dd,J＝17.05,1.65Hz,1H).MS(ESI+,[M+H] + )m/z: 388.04.

步骤C：化合物1(260mg)经手性拆分(YMC高压制备色谱：CHIRALART Cellulose-SC色谱柱，乙醇/正己烷)先出峰的为实施例1_A(112mg)，后出峰的为实施例1_B(120mg)。Step C: Compound 1 (260 mg) was subjected to chiral separation (YMC high pressure preparative chromatography: CHIRALART Cellulose-SC column, ethanol/n-hexane). The first eluting peak was Example 1_A (112 mg), and the later eluting peak was Example 1_B (120 mg).

实施例1_A：1H NMR(500MHz,DMSO-d6)δ8.11(d,J＝2.1Hz,1H),8.10-8.07(m,1H),7.92(d,J＝9.2Hz,1H),7.82(d,J＝8.3Hz,1H),7.73(d,J＝8.5Hz,2H),7.53(t,J＝7.9Hz,1H),7.17-7.11(m,3H),5.40(d,J＝3.9Hz,1H),4.47-4.43(m,1H),4.22-4.14(m,1H),3.77-3.70(m,1H),2.94-2.85(m,1H),2.39-2.33(m,1H).MS(ESI+,[M+H]+)m/z:388.17.Example 1_A: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.11 (d, J = 2.1 Hz, 1H), 8.10-8.07 (m, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.53 (t, J = 7.9 Hz, 1H), 7.17-7.11 (m, 3H), 5.40 (d, J = 3.9 Hz, 1H), 4.47-4.43 (m, 1H), 4.22-4.14 (m, 1H), 3.77-3.70 (m, 1H), 2.94-2.85 (m, 1H), 2.39-2.33 (m, 1H). MS (ESI+, [M+H] + )m/z:388.17.

实施例1_B：1H NMR(500MHz,DMSO-d6)δ8.11(d,J＝2.2Hz,1H),8.10-8.05(m,1H),7.92(d,J＝9.1Hz,1H),7.82(d,J＝8.3Hz,1H),7.73(d,J＝8.5Hz,2H),7.53(t,J＝7.9Hz,1H),7.17-7.11(m,3H),5.40(d,J＝3.9Hz,1H),4.47-4.44(m,1H),4.22-4.15(m,1H),3.77-3.72(m,1H),2.92-2.86(m,1H),2.39-2.32(m,1H).MS(ESI+,[M+H]+)m/z:388.17.Example 1_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.11 (d, J = 2.2 Hz, 1H), 8.10-8.05 (m, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.53 (t, J = 7.9 Hz, 1H), 7.17-7.11 (m, 3H), 5.40 (d, J = 3.9 Hz, 1H), 4.47-4.44 (m, 1H), 4.22-4.15 (m, 1H), 3.77-3.72 (m, 1H), 2.92-2.86 (m, 1H), 2.39-2.32 (m, 1H). MS (ESI+, [M+H] + )m/z:388.17.

实施例2(2_A和2_B)
Example 2 (2_A and 2_B)

参照实施例1的合成，在步骤B中，以4-羟甲基-2-吡咯烷酮替代4-羟基-2-吡咯烷酮，得到化合物2。Referring to the synthesis of Example 1, in step B, 4-hydroxymethyl-2-pyrrolidone was used instead of 4-hydroxy-2-pyrrolidone to obtain compound 2.

1H NMR(500MHz,DMSO-d6)δ8.10-8.08(m,2H),7.91(d,J＝9.0Hz,1H),7.82(d,J＝8.3Hz,1H),7.73(d,J＝8.4Hz,2H),7.53(t,J＝7.9Hz,1H),7.15-7.13(m,3H),4.90(t,J＝5.2Hz,1H),4.05-4.01(m,1H),3.78-3.75(m,1H),3.53-3.45(m,2H),2.69-2.63(m,1H),2.62-2.55(m,1H),2.39-2.35(m,1H).MS(ESI+,[M+H]+)m/z：402.12。 1 H NMR (500MHz, DMSO-d 6 )δ8.10-8.08(m,2H),7.91(d,J＝9.0Hz,1H),7.82(d,J＝8.3Hz,1H),7.73(d,J＝8.4Hz,2H),7.53( t,J＝7.9Hz,1H),7.15-7.13(m,3H),4.90(t,J＝ 5.2Hz,1H),4.05-4.01(m,1H),3.78-3.75(m,1H),3.53-3.45(m,2H),2 .69-2.63(m,1H),2.62-2.55(m,1H),2.39-2.35(m,1H).MS(ESI+,[M+H] + )m/z：402.12.

化合物2经高压制备液相分离(REFLECT I-Amylose A色谱柱；乙醇：正己烷＝30:70)，先出峰的为化合物2_A(40mg)，后出峰的为化合物2_B(42mg)。Compound 2 was separated by high pressure preparative liquid chromatography (REFLECT I-Amylose A column; ethanol: n-hexane = 30:70). The first peak eluted was compound 2_A (40 mg) and the last peak eluted was compound 2_B (42 mg).

化合物2_A：1H NMR(500MHz,DMSO-d6)δ8.10-8.08(m,2H),7.91(d,J＝9.0Hz,1H),7.82(d,J＝8.3Hz,1H),7.73(d,J＝8.8Hz,2H),7.53(t,J＝7.9Hz,1H),7.15-7.13(m,3H),4.90(t,J＝5.2Hz,1H),4.05-4.01(m,1H),3.78-3.75(m,1H),3.53-3.44(m,2H),2.69-2.64(m,1H),2.61-2.56(m,1H),2.39-2.35(m,1H).MS(ESI+,[M+H]+)m/z：402.16。Compound 2_A: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.10-8.08 (m, 2H), 7.91 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.53 (t, J = 7.9 Hz, 1H), 7.15-7.13 (m, 3H), 4.90 (t, J = 5.2 Hz, 1H), 4.05-4.01 (m, 1H), 3.78-3.75 (m, 1H), 3.53-3.44 (m, 2H), 2.69-2.64 (m, 1H), 2.61-2.56 (m, 1H), 2.39-2.35 (m, 1H). MS (ESI+, [M+H] + )m/z：402.16.

化合物2_B：1H NMR(500MHz,DMSO-d6)δ8.10-8.08(m,2H),7.91(d,J＝9.0Hz,1H),7.82(d,J＝8.3Hz,1H),7.73(d,J＝8.7Hz,2H),7.53(t,J＝7.9Hz,1H),7.15-7.13(m,3H),4.90(t,J＝5.2Hz,1H),4.05-4.01(m,1H),3.78-3.75(m,1H),3.53-3.46(m,2H),2.69-2.63(m,1H),2.61-2.56(m,1H),2.39-2.35(m,1H).MS(ESI+,[M+H]+)m/z：402.16。 Compound 2_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.10-8.08 (m, 2H), 7.91 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.53 (t, J = 7.9 Hz, 1H), 7.15-7.13 (m, 3H), 4.90 (t, J = 5.2 Hz, 1H), 4.05-4.01 (m, 1H), 3.78-3.75 (m, 1H), 3.53-3.46 (m, 2H), 2.69-2.63 (m, 1H), 2.61-2.56 (m, 1H), 2.39-2.35 (m, 1H). MS (ESI+, [M+H] + )m/z：402.16.

实施例3
Example 3

参照实施例1的合成，在步骤B中，以异噻唑烷1,1-二氧化物替代4-羟基-2-吡咯烷酮，所得粗品经硅胶柱层析纯化，得到化合物3(238mg)。Referring to the synthesis of Example 1, in step B, 4-hydroxy-2-pyrrolidone was replaced with isothiazolidine 1,1-dioxide, and the obtained crude product was purified by silica gel column chromatography to obtain compound 3 (238 mg).

1H NMR(500MHz,DMSO-d6)δ7.95(d,J＝9.1Hz,1H),7.80(d,J＝8.3Hz,1H),7.73(d,J＝8.6Hz,2H),7.66(d,J＝2.3Hz,1H),7.61-7.50(m,2H),7.13(dd,J＝12.5,8.0Hz,3H),3.89(t,J＝6.5Hz,2H),3.58(t,J＝7.4Hz,2H),2.46(q,J＝7.0Hz,2H).MS(ESI+,[M+H]+)m/z:408.09。 1 H NMR (500MHz, DMSO-d 6 )δ7.95(d,J＝9.1Hz,1H),7.80(d,J＝8.3Hz,1H),7.73(d,J＝8.6Hz,2H),7.66(d,J＝2.3Hz,1H) ,7.61-7.50(m,2H), 7.13(dd,J＝12.5,8.0Hz,3H), 3.89(t,J＝6.5Hz,2H), 3.58(t,J＝7.4Hz,2H), 2.46(q,J＝7.0Hz,2H). MS(ESI+,[M+H] + )m/z:408.09.

实施例4(4_A和4_B)
Example 4 (4_A and 4_B)

参照实施例1的合成，在步骤B中，以3-(羟甲基)吡咯烷-2-酮替代4-羟基-2-吡咯烷酮，所得粗品经高压制备液相分离(REFLECT I-Amylose A色谱柱；乙醇：正己烷＝22:78)，先出峰的为化合物4_A(80mg)，后出峰的为化合物4_B(80mg)。Referring to the synthesis of Example 1, in step B, 4-hydroxy-2-pyrrolidone was replaced with 3-(hydroxymethyl)pyrrolidin-2-one, and the crude product was separated by high-pressure preparative liquid phase separation (REFLECT I-Amylose A column; ethanol:n-hexane=22:78). The first peak was compound 4_A (80 mg), and the last peak was compound 4_B (80 mg).

化合物4_A：1H NMR(500MHz,DMSO-d6)δ8.13(d,J＝2.1Hz,1H),7.92(d,J＝9.1Hz,1H),7.84-7.77(m,2H),7.76-7.69(m,2H),7.61-7.52(m,1H),7.19-7.12(m,3H),4.86(t,J＝5.3Hz,1H),4.49(ddt,J＝7.9,4.4,3.0Hz,1H),3.58-3.41(m,2H),2.64(ddd,J＝16.9,9.9,8.4Hz,1H),2.40(ddd,J＝16.9,10.1,4.3Hz,1H),2.24(ddt,J＝12.6,10.1,8.5Hz,1H),2.18-2.02(m,1H).MS(ESI+,[M+H]+)m/z：402.24。Compound 4_A: 1 H NMR (500 MHz, DMSO-d 6 ) δ8.13 (d, J=2.1 Hz, 1H), 7.92 (d, J=9.1 Hz, 1H), 7.84-7.77 (m, 2H), 7.76-7.69 (m, 2H), 7.61-7.52 (m, 1H), 7.19-7.12 (m, 3H), 4.86 (t, J=5.3 Hz, 1H), 4.49 (ddt, J=7.9, 4.4, 3. 0Hz,1H),3.58-3.41(m,2H),2.64(ddd,J＝16.9,9.9,8.4Hz,1H),2.40(ddd,J＝16.9,10 .1,4.3Hz,1H),2.24(ddt,J＝12.6,10.1,8.5Hz,1H),2.18-2.02(m,1H).MS(ESI+,[M+H] + )m/z: 402.24.

化合物4_B：1H NMR(500MHz,DMSO-d6)δ8.13(d,J＝2.1Hz,1H),7.92(d,J＝9.1Hz,1H),7.84-7.76(m,2H),7.73(d,J＝8.8Hz,2H),7.54(t,J＝7.9Hz,1H),7.23-7.11(m,3H),4.86(t,J＝5.3Hz,1H),4.58-4.43(m,1H),3.58-3.42(m,2H),2.64(ddd,J＝16.9,9.9,8.5Hz,1H),2.40(ddd,J＝16.9,10.1,4.3Hz,1H),2.24(ddt,J＝12.6,10.0,8.5Hz,1H),2.07(ddt,J＝13.1,9.9,3.7Hz,1H).MS(ESI+,[M+H]+)m/z：402.15。Compound 4_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.13 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 9.1 Hz, 1H), 7.84-7.76 (m, 2H), 7.73 (d, J = 8.8 Hz, 2H), 7.54 (t, J = 7.9 Hz, 1H), 7.23-7.11 (m, 3H), 4.86 (t, J = 5.3 Hz, 1H), 4.58-4.43 (m, 1H), 3.5 8-3.42(m,2H),2.64(ddd,J＝16.9,9.9,8.5Hz,1H),2.40(ddd,J＝16.9,10.1,4.3Hz,1H), 2.24(ddt,J＝12.6,10.0,8.5Hz,1H),2.07(ddt,J＝13.1,9.9,3.7Hz,1H).MS(ESI+,[M+H] + )m/z: 402.15.

实施例5
Example 5

参照实施例1的合成，在步骤B中，以1-甲基咪唑啉-2-酮替代4-羟基-2-吡咯烷酮，所得粗品经中低压制备液相分离，得到化合物5(215mg)。Referring to the synthesis of Example 1, in step B, 1-methylimidazoline-2-one was used instead of 4-hydroxy-2-pyrrolidone, and the obtained crude product was separated by medium-low pressure preparative liquid phase to obtain compound 5 (215 mg).

化合物5：1H NMR(500MHz,DMSO-d6)δ8.18-8.16(m,1H),7.87-7.83(m,2H),7.75-7.71(m,3H),7.51-7.47(m,1H),7.13(d,J＝8.7Hz,2H),7.06(d,J＝7.3Hz,1H),3.93-3.90(m,2H),3.52-3.49(m,2H),2.80(s,3H).MS(ESI+,[M+H]+)m/z：387.16。Compound 5: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.18-8.16 (m, 1H), 7.87-7.83 (m, 2H), 7.75-7.71 (m, 3H), 7.51-7.47 (m, 1H), 7.13 (d, J=8.7 Hz, 2H), 7.06 (d, J=7.3 Hz, 1H), 3.93-3.90 (m, 2H), 3.52-3.49 (m, 2H), 2.80 (s, 3H). MS (ESI+, [M+H] + ) m/z: 387.16.

实施例6(6_A和6_B)
Example 6 (6_A and 6_B)

参照实施例1的合成，在步骤B中，以3-(羟甲基)吡咯烷-2-酮替代4-羟基-2-吡咯烷酮，所得粗品经高压制备液相分离(REFLECT I-Amylose A色谱柱；乙醇：正己烷＝22:78)，先出峰的为化合物6_A(40mg)，后出峰的为化合物6_B(42mg)。Referring to the synthesis of Example 1, in step B, 4-hydroxy-2-pyrrolidone was replaced with 3-(hydroxymethyl)pyrrolidin-2-one, and the crude product was separated by high-pressure preparative liquid phase separation (REFLECT I-Amylose A column; ethanol:n-hexane=22:78). The first peak was compound 6_A (40 mg), and the last peak was compound 6_B (42 mg).

化合物6_A：1H NMR(500MHz,DMSO-d6)δ8.12(d,J＝2.0Hz,1H),8.09(dd,J＝9.2,2.2Hz,1H),7.92(d,J＝9.2Hz,1H),7.81(d,J＝8.3Hz,1H),7.73(d,J＝8.7Hz,2H),7.53(t,J＝7.9Hz,1H),7.20-7.11(m,3H),4.83(t,J＝5.2Hz,1H),3.97-3.88(m,2H),3.76(dt,J＝10.7,6.7Hz,1H),3.69-3.62(m,1H),2.81-2.71(m,1H),2.29-2.20(m,1H),2.12(dq,J＝12.5,8.2Hz,1H).MS(ESI+,[M+H]+)m/z：402.07。Compound 6_A: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.12 (d, J = 2.0 Hz, 1H), 8.09 (dd, J = 9.2, 2.2 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.53 (t, J = 7.9 Hz, 1H), 7.20-7.11 (m, 3H), 4.83 (t,J＝5.2Hz,1H),3.97-3.88(m,2H),3.76(dt,J＝10.7,6.7Hz,1H),3.69-3.62(m,1H) ,2.81-2.71(m,1H),2.29-2.20(m,1H),2.12(dq,J＝12.5,8.2Hz,1H).MS(ESI+,[M+H] + )m/z: 402.07.

化合物6_B：1H NMR(500MHz,DMSO-d6)δ8.12(d,J＝2.0Hz,1H),8.09(dd,J＝9.2,2.1Hz,1H),7.92(d,J＝9.2Hz,1H),7.81(d,J＝8.3Hz,1H),7.73(d,J＝8.7Hz,2H),7.53(t,J＝7.9Hz,1H),7.18-7.11(m,3H),4.83(t,J＝5.2Hz,1H),3.96-3.88(m,2H),3.75(dt,J＝10.7,5.4Hz,1H),3.70-3.62(m,1H),2.83-2.68(m,1H),2.31-2.20(m,1H),2.12(dq,J＝12.4,8.2Hz,1H).MS(ESI+,[M+H]+)m/z：402.16。Compound 6_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.12 (d, J = 2.0 Hz, 1H), 8.09 (dd, J = 9.2, 2.1 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.53 (t, J = 7.9 Hz, 1H), 7.18-7.11 (m, 3H), 4.83 (t,J＝5.2Hz,1H),3.96-3.88(m,2H),3.75(dt,J＝10.7,5.4Hz,1H),3.70-3.62(m,1H) ,2.83-2.68(m,1H),2.31-2.20(m,1H),2.12(dq,J＝12.4,8.2Hz,1H).MS(ESI+,[M+H] + )m/z: 402.16.

实施例7(7_A和7_B)
Example 7 (7_A and 7_B)

参照实施例1的合成，在步骤B中，以5-羟基-2-哌啶酮替代4-羟基-2-吡咯烷酮，所得粗品经高压制备液相分离(REFLECT I-Amylose A色谱柱；乙醇：正己烷＝22:78)，先出峰的为化合物7_A(30mg)，后出峰的为化合物7_B(30mg)。Referring to the synthesis of Example 1, in step B, 4-hydroxy-2-pyrrolidone was replaced with 5-hydroxy-2-piperidone, and the crude product was separated by high-pressure preparative liquid phase separation (REFLECT I-Amylose A column; ethanol:n-hexane=22:78). The first peak was compound 7_A (30 mg), and the later peak was compound 7_B (30 mg).

化合物7_A：1H NMR(500MHz,DMSO-d6)δ7.70(d,J＝8.7Hz,2H),7.61(d,J＝9.1Hz,1H),7.50(d,J＝8.3Hz,1H),7.37-7.31(m,1H),7.09(d,J＝8.6Hz,2H),7.05(dd,J＝9.1,2.3Hz,1H),6.91(d,J＝2.2Hz,1H),6.82(dd,J＝7.5,0.7Hz,1H),6.37(t,J＝5.9Hz,1H),4.75(qd,J＝7.0,4.4Hz,1H),3.48-3.34(m,2H),2.58-2.51(m,2H),2.31(dddd,J＝12.6,9.1,7.0,5.5Hz,1H),2.04-1.94(m,1H).MS(ESI+,[M+H]+)m/z：402.13。Compound 7_A: 1 H NMR (500 MHz, DMSO-d 6 ) δ7.70 (d, J=8.7 Hz, 2H), 7.61 (d, J=9.1 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.37-7.31 (m, 1H), 7.09 (d, J=8.6 Hz, 2H), 7.05 (dd, J=9.1, 2.3 Hz, 1H), 6.91 (d, J=2.2 Hz, 1H), 6.82 (dd, J=7.5 ,0.7Hz,1H),6.37(t,J＝5.9Hz,1H),4.75(qd,J＝7.0,4.4Hz,1H),3.48-3.34(m,2H),2.58- 2.51(m,2H),2.31(dddd,J＝12.6,9.1,7.0,5.5Hz,1H),2.04-1.94(m,1H).MS(ESI+,[M+H] + )m/z: 402.13.

化合物7_B：1H NMR(500MHz,DMSO-d6)δ7.70(d,J＝8.7Hz,2H),7.60(d,J＝9.1Hz,1H),7.50(d,J＝8.3Hz,1H),7.38-7.31(m,1H),7.08(d,J＝8.6Hz,2H),7.04(dd,J＝9.1,2.2Hz,1H),6.91(d,J＝2.1Hz,1H),6.84-6.79(m,1H),6.36(t,J＝5.9Hz,1H),4.79-4.71(m,1H),3.48-3.34(m,2H),2.54(dd,J＝11.1,6.6Hz,2H),2.31(dddd,J＝12.5,9.1,7.0,5.5Hz,1H),2.04-1.93(m,1H).MS(ESI+,[M+H]+)m/z：402.13。Compound 7_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.70 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 9.1 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.38-7.31 (m, 1H), 7.08 (d, J = 8.6 Hz, 2H), 7.04 (dd, J = 9.1, 2.2 Hz, 1H), 6.91 (d, J = 2.1 Hz, 1H), 6.84-6.79 (m,1H),6.36(t,J＝5.9Hz,1H),4.79-4.71(m,1H),3.48-3.34(m,2H),2.54(dd,J＝11.1, 6.6Hz,2H),2.31(dddd,J＝12.5,9.1,7.0,5.5Hz,1H),2.04-1.93(m,1H).MS(ESI+,[M+H] + )m/z: 402.13.

实施例8
Example 8

参照实施例1的合成，在步骤B中，以4-甲基哌嗪-2-酮替代4-羟基-2-吡咯烷酮，所得粗品经中低压制备分离，得到化合物8(246mg)。Referring to the synthesis of Example 1, in step B, 4-methylpiperazine-2-one was used instead of 4-hydroxy-2-pyrrolidone, and the obtained crude product was separated by medium-low pressure preparation to obtain compound 8 (246 mg).

1H NMR(500MHz,DMSO-d6)δ8.19(d,J＝2.0Hz,1H),8.10(d,J＝9.0Hz,1H),8.03(d,J＝8.3Hz,1H),7.92(d,J＝8.7Hz,2H),7.79-7.71(m,2H),7.45-7.42(m,1H),7.33(d,J＝8.6Hz,2H),4.00-3.94(m,2H),3.51(s,2H),3.00-2.93(m,2H),2.73-2.65(m,3H).MS(ESI+,[M+H]+)m/z：401.15。 1 H NMR (500MHz, DMSO-d 6 )δ8.19(d,J＝2.0Hz,1H),8.10(d,J＝9.0Hz,1H),8.03(d,J＝8.3Hz,1H),7.92(d,J＝8.7Hz,2H) ,7.79-7.71(m,2H),7.4 5-7.42(m,1H),7.33(d,J＝8.6Hz,2H),4.00-3.94(m,2H),3.51(s,2H),3.00-2.93(m,2H),2.73-2.65( m,3H).MS(ESI + ,[M+H] + )m/z: 401.15.

实施例9(9_A和9_B)
Example 9 (9_A and 9_B)

参照实施例1的合成，在步骤B中，以4-羟基-2-哌啶酮替代4-羟基-2-吡咯烷酮，所得粗品经高压制备液相分离(REFLECT I-Amylose A色谱柱；乙醇：正己烷＝22:78)，先出峰的为化合物9_A(36mg)，后出峰的为化合物9_B(33mg)。Referring to the synthesis of Example 1, in step B, 4-hydroxy-2-piperidone was used instead of 4-hydroxy-2-pyrrolidone. The crude product was separated by high-pressure preparative liquid phase separation (REFLECT I-Amylose A column; ethanol:n-hexane=22:78). The first peak was compound 9_A (36 mg), and the last peak was compound 9_B (33 mg).

化合物9_A：1H NMR(500MHz,DMSO-d6)δ7.93-7.88(m,2H),7.84(d,J＝8.3Hz,1H),7.73(d,J＝8.6Hz,2H),7.58-7.54(m,1H),7.49-7.47(m,1H),7.22(d,J＝7.5Hz,1H),7.15(d,J＝8.5Hz,2H),5.13(d,J＝3.6Hz,1H),4.17-4.12(m,1H),3.90-3.85(m,1H),3.67-3.62(m,1H),2.71-2.66(m,1H),2.38-2.33(m,1H),2.09-2.07(m,1H),1.91-1.84(m,1H).MS(ESI+,[M+H]+)m/z：402.16。Compound 9_A: 1 H NMR (500 MHz, DMSO-d 6 ) δ7.93-7.88 (m, 2H), 7.84 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.58-7.54 (m, 1H), 7.49-7.47 (m, 1H), 7.22 (d, J=7.5 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H), 5.13 (d, J= 3.6Hz,1H),4.17-4.12(m,1H),3.90-3.85(m,1H),3.67-3.62(m,1H),2.71-2.66 (m,1H),2.38-2.33(m,1H),2.09-2.07(m,1H),1.91-1.84(m,1H).MS(ESI+,[M+H] + )m/z: 402.16.

化合物9_B：1H NMR(500MHz,DMSO-d6)δ7.93-7.88(m,2H),7.84(d,J＝8.3Hz,1H),7.73(d,J＝8.7Hz,2H),7.58-7.54(m,1H),7.49-7.47(m,1H),7.22(d,J＝7.5Hz,1H),7.15(d,J＝8.6Hz,2H),5.13(d,J＝3.6Hz,1H),4.17-4.12(m,1H),3.90-3.85(m,1H),3.67-3.62(m,1H),2.71-2.66(m,1H),2.38-2.33(m,1H),2.09-2.07(m,1H),1.91-1.85(m,1H).MS(ESI+,[M+H]+)m/z：402.15。Compound 9_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.93-7.88 (m, 2H), 7.84 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.58-7.54 (m, 1H), 7.49-7.47 (m, 1H), 7.22 (d, J=7.5 Hz, 1H), 7.15 (d, J=8.6 Hz, 2H), 5.13 (d, J= 3.6Hz,1H),4.17-4.12(m,1H),3.90-3.85(m,1H),3.67-3.62(m,1H),2.71-2.66 (m,1H),2.38-2.33(m,1H),2.09-2.07(m,1H),1.91-1.85(m,1H).MS(ESI+,[M+H] + )m/z: 402.15.

实施例10(10_A和10_B)
Example 10 (10_A and 10_B)

参照实施例1的合成，在步骤B中，以3-羟甲基吡烷替代4-羟基-2-吡咯烷酮，所得粗品经高压制备液相分离(CHIRALPAK IG色谱柱；乙醇：正己烷＝20:80)，先出峰的为化合物10_A(15mg)，后出峰的为化合物10_B(15mg)。Referring to the synthesis of Example 1, in step B, 4-hydroxy-2-pyrrolidone was replaced with 3-hydroxymethylpyridine, and the crude product was separated by high-pressure preparative liquid phase separation (CHIRALPAK IG chromatographic column; ethanol:n-hexane=20:80). The first peak was compound 10_A (15 mg), and the last peak was compound 10_B (15 mg).

化合物10_A：1HNMR(500MHz,CDCl3)δ7.85(d,J＝9.1Hz,1H),7.53(d,J＝8.6Hz,2H),7.49(d,J＝8.3Hz,1H),7.31(d,J＝7.7Hz,1H),7.03(d,J＝8.6Hz,2H),6.96(dd,J＝9.2,2.3Hz,1H),6.80(d,J＝2.1Hz,1H),6.76(d,J＝7.3Hz,1H),3.72(ddd,J＝26.6,10.4,6.9Hz,2H),3.57(dd,J＝9.2,7.7Hz,1H),3.51(td,J＝8.6,4.8Hz,1H),3.43(dd,J＝16.5,7.5Hz,1H),3.26(dd,J＝9.4,6.4Hz,1H),2.63(dt,J＝13.8,6.9Hz,1H),2.20(dtd,J＝12.2,7.4,5.0Hz,1H),1.93-1.85(m,1H).MS(ESI+,[M+H]+)m/z:388.14。Compound 10_A: 1 HNMR (500MHz, CDCl 3 )δ7.85(d,J＝9.1Hz,1H),7.53(d,J＝8.6Hz,2H),7.49(d,J＝8.3Hz,1H),7.31(d,J＝7.7Hz,1H) ,7.03(d,J＝8.6Hz ,2H),6.96(dd,J＝9.2,2.3Hz,1H),6.80(d,J＝2.1Hz,1H),6.76(d,J＝7.3Hz,1H),3.72(ddd,J＝26.6, 10.4,6.9Hz ,2H),3.57(dd,J＝9.2,7.7Hz,1H),3.51(td,J＝8.6,4.8Hz,1H),3.43(dd,J＝16.5,7.5Hz,1H),3.26(dd, J＝9.4,6 .4Hz,1H),2.63(dt,J＝13.8,6.9Hz,1H),2.20(dtd,J＝12.2,7.4,5.0Hz,1H),1.93-1.85(m,1H).MS(ESI+,[ M+H] + )m/z:388.14.

化合物10_B：1HNMR(500MHz,CDCl3)δ7.85(d,J＝9.1Hz,1H),7.53(d,J＝8.7Hz,2H),7.49(d,J＝8.3Hz,1H),7.35(d,J＝2.4Hz,1H),7.03(d,J＝8.6Hz,2H),6.96(dd,J＝9.2,2.4Hz,1H),6.80(d,J＝2.3Hz,1H),6.76(d,J＝7.2Hz,1H),3.73(ddd,J＝26.6,10.4,6.9Hz,2H),3.57(dd,J＝9.4,7.6Hz,1H),3.51(td,J＝8.7,4.8 Hz,1H),3.43(dd,J＝12.0,4.5Hz,1H),3.26(dd,J＝9.4,6.3Hz,1H),2.62(dd,J＝13.9,7.0Hz,1H),2.28-2.16(m,1H),1.88(dd,J＝12.4,7.6Hz,1H).MS(ESI+,[M+H]+)m/z:388.11。Compound 10_B: 1 HNMR (500MHz, CDCl 3 )δ7.85(d,J＝9.1Hz,1H),7.53(d,J＝8.7Hz,2H),7.49(d,J＝8.3Hz,1H),7.35(d,J＝2.4Hz,1H) ,7.03(d,J＝8.6Hz,2H),6.96(dd,J＝9.2,2.4H z,1H),6.80(d,J＝2.3Hz,1H),6.76(d,J＝7.2Hz,1H),3.73(ddd,J＝26.6,10.4,6.9Hz,2H),3.57(dd,J ＝9.4,7.6Hz,1H),3.51(td,J＝8.7,4.8 Hz,1H),3.43(dd,J＝12.0,4.5Hz,1H),3.26(dd,J＝9.4,6.3Hz,1H),2.62(dd,J＝1 3.9,7.0Hz,1H),2.28-2.16(m,1H),1.88(dd,J＝12.4,7.6Hz,1H).MS(ESI+,[M+H] + )m/z:388.11.

实施例11(11_A和11_B)
Example 11 (11_A and 11_B)

参照实施例1的合成，在步骤B中，以4-羟基-2-哌啶酮替代4-羟基-2-吡咯烷酮，所得粗品经高压制备液相分离((R,R)-Whelk-O 1色谱柱；乙醇：正己烷＝50:50)，先出峰的为化合物11_A(154mg)，后出峰的为化合物11_B(168mg)。Referring to the synthesis of Example 1, in step B, 4-hydroxy-2-piperidone was used instead of 4-hydroxy-2-pyrrolidone, and the crude product was separated by high-pressure preparative liquid phase separation ((R,R)-Whelk-O 1 chromatographic column; ethanol:n-hexane=50:50). The first peak was compound 11_A (154 mg), and the last peak was compound 11_B (168 mg).

化合物11_A：1H NMR(500MHz,DMSO-d6)δ8.15(d,J＝2.0Hz,1H),8.12-8.10(m,1H),7.94(d,J＝9.2Hz,1H),7.83(d,J＝8.3Hz,1H),7.73(d,J＝8.7Hz,2H),7.56-7.53(m,1H),7.16-7.13(m,3H),5.81(d,J＝5.9Hz,1H),4.39-4.34(m,1H),3.91-3.87(m,1H),3.85-3.80(m,1H),2.49-2.43(m,1H),1.95-1.87(m,1H).MS(ESI+,[M+H]+)m/z：388.13。Compound 11_A: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.15 (d, J = 2.0 Hz, 1H), 8.12-8.10 (m, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.56-7.53 (m, 1H), 7.16-7.13 (m, 3H), 5.81 (d, J = 5.9 Hz, 1H), 4.39-4.34 (m, 1H), 3.91-3.87 (m, 1H), 3.85-3.80 (m, 1H), 2.49-2.43 (m, 1H), 1.95-1.87 (m, 1H). MS (ESI+, [M+H] + )m/z：388.13.

化合物11_B：1H NMR(500MHz,DMSO-d6)δ8.15(d,J＝2.0Hz,1H),8.12-8.10(m,1H),7.94(d,J＝9.2Hz,1H),7.83(d,J＝8.3Hz,1H),7.73(d,J＝8.8Hz,2H),7.56-7.53(m,1H),7.16-7.13(m,3H),5.81(d,J＝5.9Hz,1H),4.39-4.34(m,1H),3.91-3.87(m,1H),3.85-3.80(m,1H),2.48-2.43(m,1H),1.95-1.87(m,1H).MS(ESI+,[M+H]+)m/z：388.13。Compound 11_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.15 (d, J = 2.0 Hz, 1H), 8.12-8.10 (m, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.8 Hz, 2H), 7.56-7.53 (m, 1H), 7.16-7.13 (m, 3H), 5.81 (d, J = 5.9 Hz, 1H), 4.39-4.34 (m, 1H), 3.91-3.87 (m, 1H), 3.85-3.80 (m, 1H), 2.48-2.43 (m, 1H), 1.95-1.87 (m, 1H). MS (ESI+, [M+H] + )m/z：388.13.

实施例12
Example 12

参照实施例1的合成，在步骤B中，以吡咯烷酮替代4-羟基-2-吡咯烷酮，所得粗品经经硅胶柱层析纯化，得到化合物12(34.5mg)。Referring to the synthesis of Example 1, in step B, pyrrolidone was used instead of 4-hydroxy-2-pyrrolidone. The obtained crude product was purified by silica gel column chromatography to obtain compound 12 (34.5 mg).

1H NMR(500MHz,DMSO-d6)δ8.11(d,J＝1.6Hz,1H),8.08-8.06(m,1H),7.92(d,J＝9.2Hz,1H),7.81(d,J＝8.3Hz,1H),7.73(d,J＝8.6Hz,2H),7.55-7.52(m,1H),7.15-7.13(m,3H),3.98-3.95(m,2H),2.58-2.54(m,2H),2.15-2.09(m,2H).MS(ESI+,[M+H]+)m/z：372.13。 1 H NMR (500MHz, DMSO-d 6 )δ8.11(d,J＝1.6Hz,1H),8.08-8.06(m,1H),7.92(d,J＝9.2Hz,1H),7.81(d,J＝8.3Hz,1H),7.73( d,J＝8.6Hz,2H) ,7.55-7.52(m,1H),7.15-7.13(m,3H),3.98-3.95(m,2H),2.58-2.54(m,2H),2.15-2.09(m,2H).MS(ESI+, [M+H] + )m/z: 372.13.

实施例13
Example 13

步骤A：参照实施例1的合成，在步骤B中，以3-氧代-2,8-二氮杂螺[4,5]癸烷-8-甲酸叔丁酯替代4-羟 基-2-吡咯烷酮，所得粗品经硅胶柱层析纯化(EA/PE)，得到中间体13-1(250mg)。MS(ESI+,[M+H]+)m/z:541.01.Step A: Referring to the synthesis of Example 1, in step B, 3-oxo-2,8-diazaspiro[4,5]decane-8-carboxylic acid tert-butyl ester is used instead of 4-hydroxy The crude product was purified by silica gel column chromatography (EA/PE) to obtain intermediate 13-1 (250 mg). MS (ESI+, [M+H] + ) m/z: 541.01.

步骤B：向单口瓶中，依次加入13-1(250mg)和4M的氯化氢-二氧六环溶液(5mL)，室温下搅拌反应0.5h。反应结束后，将反应液浓缩，用水(50mL)稀释并用1M氢氧化钠溶液调pH至8～9，EA萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，抽滤后减压浓缩除去溶剂，所得粗品经硅胶柱层析纯化，得到化合物13(125mg)。Step B: Add 13-1 (250 mg) and 4M hydrogen chloride-dioxane solution (5 mL) to a single-mouth bottle, and stir the reaction at room temperature for 0.5 h. After the reaction, the reaction solution was concentrated, diluted with water (50 mL) and adjusted to pH 8-9 with 1M sodium hydroxide solution, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography to obtain compound 13 (125 mg).

1H NMR(500MHz,DMSO-d6)δ8.10-8.07(m,2H),7.90(d,J＝9.0Hz,1H),7.81(d,J＝8.2Hz,1H),7.73(d,J＝8.7Hz,2H),7.55-7.52(m,1H),7.15-7.12(m,3H),3.78(s,2H),2.74-2.68(m,4H),2.49(s,2H),1.63-1.55(m,4H).MS(ESI+,[M+H]+)m/z:441.17. 1 H NMR (500MHz, DMSO-d 6 )δ8.10-8.07(m,2H),7.90(d,J＝9.0Hz,1H),7.81(d,J＝8.2Hz,1H),7.73(d,J＝8.7Hz,2H),7.55- 7.52(m, 1H),7.15-7.12(m,3H),3.78(s,2H),2.74-2.68(m,4H),2.49(s,2H),1.63-1.55(m,4H).MS(ESI+,[M +H] + )m/z:441.17.

实施例14
Embodiment 14

步骤A：参照实施例1的合成，在步骤B中，以14-1替代4-羟基-2-吡咯烷酮，所得粗品经硅胶柱层析纯化(PE/EA)，得到化合物14-2(210mg)。Step A: Referring to the synthesis of Example 1, in step B, 4-hydroxy-2-pyrrolidone was replaced with 14-1, and the obtained crude product was purified by silica gel column chromatography (PE/EA) to obtain compound 14-2 (210 mg).

步骤B：向茄型瓶中依次加入14-2(210mg)，氯化氢(6.9mL，4M的1,4-二氧六环溶液)，N2保护下室温反应2小时。反应结束后加入20mL饱和碳酸氢钠水溶液，用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩干，所得粗品经硅胶柱层析纯化，得到化合物14(141mg)。Step B: 14-2 (210 mg) and hydrogen chloride (6.9 mL, 4 M 1,4-dioxane solution) were added to an eggplant-shaped bottle in sequence, and the mixture was reacted at room temperature for 2 hours under N2 protection. After the reaction, 20 mL of saturated sodium bicarbonate aqueous solution was added, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 14 (141 mg).

1H NMR(500MHz,DMSO-d6)δ8.09(d,J＝2.1Hz,1H),8.08-8.04(m,1H),7.91(d,J＝9.1Hz,1H),7.81(d,J＝8.3Hz,1H),7.75-7.70(m,2H),7.53(t,J＝7.9Hz,1H),7.17-7.12(m,3H),4.09-4.04(m,1H),3.72-3.68(m,1H),3.58-3.54(m,1H),2.79-2.75(m,1H),2.28-2.24(m,1H),1.97(d,J＝14.8Hz,2H).MS(ESI+,[M+H]+)m/z:387.13。 1 H NMR (500MHz, DMSO-d 6 )δ8.09(d,J＝2.1Hz,1H),8.08-8.04(m,1H),7.91(d,J＝9.1Hz,1H),7.81(d,J＝8.3Hz,1H),7.75- 7.70(m,2H),7.53(t,J＝7.9Hz,1H),7.17-7.12 (m,3H),4.09-4.04(m,1H),3.72-3.68(m,1H),3.58-3.54(m,1H),2.79- 2.75(m,1H),2.28-2.24(m,1H),1.97(d,J＝14.8Hz,2H).MS(ESI+,[M+H] + )m/z:387.13.

实施例15
Embodiment 15

步骤A：参照实施例1的合成，在步骤B中，以15-1替代4-羟基-2-吡咯烷酮，所得粗品经硅胶柱层析纯化(MeOH/DCM)，得到化合物15-2(305mg)。Step A: Referring to the synthesis of Example 1, in step B, 15-1 was used to replace 4-hydroxy-2-pyrrolidone, and the obtained crude product was purified by silica gel column chromatography (MeOH/DCM) to obtain compound 15-2 (305 mg).

步骤B：参考实施例14的步骤B，以中间体15-2替换中间体14-2，得到化合物15(220mg)。Step B: Referring to step B of Example 14, intermediate 15-2 was used to replace intermediate 14-2 to obtain compound 15 (220 mg).

1H NMR(500MHz,DMSO-d6)δ7.97(d,J＝2.1Hz,1H),7.91(d,J＝9.0Hz,1H),7.84(d,J＝8.3Hz,1H),7.73(d,J＝8.7Hz,2H),7.59-7.53(m,2H),7.25-7.21(m,1H),7.14(d,J＝8.6Hz,2H),3.72(t,J＝5.4Hz,2H),3.44(s,2H),3.09-3.01(m,2H),2.83(s,1H).MS(ESI+,[M+H]+)m/z:387.13。 1 H NMR (500MHz, DMSO-d 6 )δ7.97(d,J＝2.1Hz,1H),7.91(d,J＝9.0Hz,1H),7.84(d,J＝8.3Hz,1H),7.73(d,J＝8.7Hz,2H) ,7.59-7.53(m,2H),7.25- 7.21(m,1H),7.14(d,J＝8.6Hz,2H),3.72(t,J＝5.4Hz,2H),3.44(s,2H),3.09-3.01(m,2H),2.83(s ,1H).MS(ESI+,[M+H] + )m/z:387.13.

实施例16
Example 16

步骤A：参考实施例1步骤B的操作，以3-羟基-2-吡咯烷酮替代4-羟基-2-吡咯烷酮，100℃反应过夜，反应结束后，通过过滤，乙酸乙酯洗涤滤饼，收集滤液，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸除溶剂，经硅胶柱层析纯化，得到化合物11(224mg)。Step A: Refer to the operation of step B in Example 1, replace 4-hydroxy-2-pyrrolidone with 3-hydroxy-2-pyrrolidone, react at 100°C overnight, and after the reaction is completed, filter, wash the filter cake with ethyl acetate, collect the filtrate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain compound 11 (224 mg).

1H NMR(500MHz,DMSO-d6)δ8.15(d,J＝2.2Hz,1H),8.11(dd,J＝9.2,2.2Hz,1H),7.94(d,J＝9.2Hz,1H),7.83(d,J＝8.3Hz,1H),7.73(d,J＝8.9Hz,2H),7.54(t,J＝7.9Hz,1H),7.17-7.13(m,3H),5.81(d,J＝5.9Hz,1H),4.36(ddd,J＝9.1,8.0,5.9Hz,1H),3.90-3.86(m,1H),3.85-3.81(m,1H),2.49-2.41(m,1H),1.93-1.88(m,1H).MS(ESI+,[M+H]+)m/z:388.12。 1 H NMR (500 MHz, DMSO-d 6 )δ8.15(d,J＝2.2Hz,1H),8.11(dd,J＝9.2,2.2Hz,1H),7.94(d,J＝9.2Hz,1H),7 .83(d,J＝8.3Hz,1H),7.73(d,J＝8.9Hz,2H),7.54(t,J＝7.9Hz,1H),7.17-7.13( m,3H),5.81(d,J＝5.9Hz,1H),4.36(ddd,J＝9.1,8.0,5.9Hz,1H),3.90-3.86(m ,1H),3.85-3.81(m,1H),2.49-2.41(m,1H),1.93-1.88(m,1H).MS(ESI+,[M+H] + )m/z:388.12.

步骤B：向反应瓶中依次加入11(140mg)、二氯甲烷(5mL)、吡啶(0.012mL)及二氯亚砜(172mg)，室温反应过夜，反应结束后，加入饱和碳酸氢钠水溶液(20mL)淬灭反应，二氯甲烷萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析纯化(PE:EA)，得到16-1(127mg)。1H NMR(500MHz,DMSO-d6)δ8.20(d,J＝2.2Hz,1H),8.04(dd,J＝9.2,2.2Hz,1H),7.97(d,J＝9.1Hz,1H),7.85(d,J＝8.3Hz,1H),7.74(d,J＝8.7Hz,2H),7.57(t,J＝7.9Hz,1H),7.19(d,J＝7.1Hz,1H),7.15(d,J＝8.6Hz,2H),4.94(dd,J＝7.7,6.0Hz,1H),4.20-3.92(m,2H),2.82-2.78(m,1H),2.34-2.29(m,1H).Step B: 11 (140 mg), dichloromethane (5 mL), pyridine (0.012 mL) and dichlorothionyl (172 mg) were added to the reaction bottle in sequence, and the reaction was allowed to react at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (20 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (PE: EA) to give 16-1 (127 mg). 1 H NMR (500MHz, DMSO-d 6 )δ8.20(d,J＝2.2Hz,1H),8.04(dd,J＝9.2,2.2Hz,1H),7.97(d,J＝9.1Hz,1H),7.85(d,J＝8.3Hz,1H),7.74(d,J＝8.7Hz,2H),7.57(t,J＝7.9H z,1H),7.19(d,J＝7.1Hz,1H),7.15(d,J＝8.6Hz,2H),4.94(dd,J＝7.7,6.0Hz,1H),4.20-3.92(m,2H),2.82-2.78(m,1H),2.34-2.29(m,1H).

步骤C：向反应瓶中依次加入16-1(127mg)、K2CO3(130mg)、KI(120mgl)、乙腈(5mL)及1,2-乙二胺(200mg)，N2保护下，加热至80℃反应6h，反应结束后，加入30mL水淬灭反应，然后加入乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析纯化，得到化合物16(120mg)。Step C: 16-1 (127 mg), K 2 CO 3 (130 mg), KI (120 mgl), acetonitrile (5 mL) and 1,2-ethylenediamine (200 mg) were added to the reaction bottle in sequence. Under N 2 protection, the mixture was heated to 80°C for 6 h. After the reaction, 30 mL of water was added to quench the reaction. Ethyl acetate was then added to extract the mixture. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to give compound 16 (120 mg).

1H NMR(500MHz,DMSO-d6)δ8.14(d,J＝2.2Hz,1H),8.09(dd,J＝9.2,2.2Hz,1H),7.94(d,J＝9.2Hz,1H),7.82(d,J＝8.3Hz,1H),7.73(d,J＝8.5Hz,2H),7.55(t,J＝7.9Hz,1H),7.17-7.13(m,3H),5.58(s,3H),3.96-3.84(m,2H),3.61(t,J＝8.8Hz,1H),2.96-2.88(m,1H),2.89-2.75(m,3H),2.49-2.39(m,1H),1.93-1.80(m,1H).MS(ESI+,[M+H]+)m/z:430.17。 1 H NMR (500 MHz, DMSO-d 6 )δ8.14(d,J＝2.2Hz,1H),8.09(dd,J＝9.2,2.2Hz,1H),7.94(d,J＝9.2Hz,1H),7 .82(d,J＝8.3Hz,1H),7.73(d,J＝8.5Hz,2H),7.55(t,J＝7.9Hz,1H),7.17-7.13 (m,3H),5.58(s,3H),3.96-3.84(m,2H),3.61(t,J＝8.8Hz,1H),2.96-2.88(m, 1H),2.89-2.75(m,3H),2.49-2.39(m,1H),1.93-1.80(m,1H).MS(ESI+,[M+H] + )m/z:430.17.

实施例17
Embodiment 17

步骤A：向的反应瓶中依次加入11(80mg)、THF(2mL)，将反应液置于冰浴下冷却后加入NaH(12mg)，搅拌10min后缓慢滴加MeI(0.026mL)的THF(2mL)溶液，N2保护下，升温至室温反应1.5h。反应结束后，加入10mL饱和氯化铵水溶液淬灭反应，然后用乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压蒸除溶剂，所得粗品经硅胶柱层析纯化，得到化合物17(10mg)。Step A: 11 (80 mg) and THF (2 mL) were added to the reaction bottle in sequence, the reaction solution was placed in an ice bath and cooled, and then NaH (12 mg) was added. After stirring for 10 min, a solution of MeI (0.026 mL) in THF (2 mL) was slowly added dropwise, and the temperature was raised to room temperature under N2 protection for 1.5 h. After the reaction was completed, 10 mL of saturated aqueous ammonium chloride solution was added to quench the reaction, and then extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 17 (10 mg).

1H NMR(500MHz,DMSO-d6)δ8.17(d,J＝2.2Hz,1H),8.06(dd,J＝9.2,2.2Hz,1H),7.94(d,J＝9.2Hz,1H),7.83(d,J＝8.3Hz,1H),7.73(d,J＝8.4Hz,2H),7.55(t,J＝7.9Hz,1H),7.17-7.13(m,3H),4.20(t,J＝8.0Hz,1H),3.95-3.89(m,1H),3.89-3.82(m,1H),3.49(s,3H),2.56-2.51(m,1H),2.04-1.93(m,1H).MS(ESI+,[M+H]+)m/z:402.08。 1 H NMR (500MHz, DMSO-d 6 )δ8.17(d,J＝2.2Hz,1H),8.06(dd,J＝9.2,2.2Hz,1H),7.94(d,J＝9.2Hz,1H),7.83(d,J＝8.3Hz, 1H),7.73(d,J＝8.4Hz,2H),7.55(t,J＝7.9Hz,1H),7 .17-7.13(m,3H),4.20(t,J＝8.0Hz,1H),3.95-3.89(m,1H),3.89-3.82(m ,1H),3.49(s,3H),2.56-2.51(m,1H),2.04-1.93(m,1H).MS(ESI+,[M+H] + )m/z:402.08.

实施例18
Embodiment 18

步骤A：参照实施例1的合成，在步骤B中，以叔丁氧羰基-3-氨基-2-吡咯烷酮替代4-羟基-2-吡咯烷酮，所得粗品经硅胶柱层析纯化(PE/EA)，得到化合物18-1(210mg)。Step A: Referring to the synthesis of Example 1, in step B, tert-butyloxycarbonyl-3-amino-2-pyrrolidone was used to replace 4-hydroxy-2-pyrrolidone. The obtained crude product was purified by silica gel column chromatography (PE/EA) to obtain compound 18-1 (210 mg).

步骤B：向茄型瓶中依次加入18-1(210mg)，4M盐酸二氧六环溶液(4mL)，室温搅拌1h后向反应液加入水(30mL)，用饱和Na2CO3水溶液调pH至8-9后，用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩干，所得粗品经硅胶柱层析纯化，得到化合物18(150mg)。Step B: 18-1 (210 mg) and 4 M hydrochloric acid dioxane solution (4 mL) were added to an eggplant-shaped bottle in sequence. After stirring at room temperature for 1 h, water (30 mL) was added to the reaction solution. The pH was adjusted to 8-9 with saturated Na 2 CO 3 aqueous solution, and then extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 18 (150 mg).

1H NMR(500MHz,DMSO-d6)δ8.19-8.09(m,2H),7.93(d,J＝9.1Hz,1H),7.82(d,J＝8.3Hz,1H),7.73(d,J＝8.6Hz,2H),7.54(t,J＝7.9Hz,1H),7.20-7.09(m,3H),3.92-3.79(m,2H),3.64-3.56(m,1H),2.47-2.37(m,1H),2.03(s,2H),1.88-1.73(m,1H).MS(ESI+,[M+H]+)m/z:387.17。 1 H NMR (500MHz, DMSO-d 6 )δ8.19-8.09(m,2H),7.93(d,J＝9.1Hz,1H),7.82(d,J＝8.3Hz,1H),7.73(d,J＝8.6Hz,2H),7.54( t,J＝7.9Hz,1H),7.20- 7.09(m,3H),3.92-3.79(m,2H),3.64-3.56(m,1H),2.47-2.37(m,1H),2.03(s,2H),1.88-1.73(m,1H). MS(ESI+,[M+H] + )m/z:387.17.

实施例19
Embodiment 19

步骤A：参照实施例1的合成，在步骤B中，以2-氧杂-6-氮杂螺[3.4]辛烷-7-酮替代4-羟基-2-吡咯烷酮，得到化合物19(120mg)。Step A: Referring to the synthesis of Example 1, in step B, 4-hydroxy-2-pyrrolidone was replaced with 2-oxa-6-azaspiro[3.4]octan-7-one to obtain compound 19 (120 mg).

1H NMR(500MHz,DMSO-d6)δ8.11(d,J＝2.2Hz,1H),8.06(dd,J＝9.2,2.2Hz,1H),7.92(d,J＝9.2Hz,1H),7.82(d,J＝8.3Hz,1H),7.73(d,J＝8.5Hz,2H),7.57-7.51(m,1H),7.19-7.09(m,3H),4.71-4.63(m,2H),4.28(s,2H),2.98(s,2H),2.55-2.46(m,2H).MS(ESI-,[M+H]-)m/z:412.31。 1 H NMR (500MHz, DMSO-d 6 )δ8.11(d,J＝2.2Hz,1H),8.06(dd,J＝9.2,2.2Hz,1H),7.92(d,J＝9.2Hz,1H),7.82(d,J＝8.3Hz, 1H),7.73(d,J=8.5Hz,2H ),7.57-7.51(m,1H),7.19-7.09(m,3H),4.71-4.63(m,2H),4.28(s,2H),2.98(s,2H),2.55-2.46(m,2H ).MS(ESI-,[M+H] - )m/z:412.31.

实施例20
Embodiment 20

步骤A：向茄型瓶中依次加入18-1(100mg)，二氯甲烷(5mL)，碘甲烷(30mg)，NaH(20mg)，DMF(1mL)，室温搅拌反应6h后向反应液加入水(30mL)，用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩干，得到化合物20-1(100mg)。MS(ESI+,[M+H]+)m/z:501.46。Step A: Add 18-1 (100 mg), dichloromethane (5 mL), iodomethane (30 mg), NaH (20 mg), and DMF (1 mL) to an eggplant-shaped bottle in sequence, stir at room temperature for 6 h, add water (30 mL) to the reaction solution, extract with ethyl acetate, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 20-1 (100 mg). MS (ESI+, [M+H] + ) m/z: 501.46.

步骤B：参考实施例18的步骤B，以中间体20-1替代18-1，得到化合物20(150mg)。Step B: Referring to step B of Example 18, intermediate 20-1 was used instead of 18-1 to obtain compound 20 (150 mg).

1H NMR(500MHz,DMSO-d6)δ8.14(d,J＝2.2Hz,1H),8.09(dd,J＝9.2,2.2Hz,1H),7.93(d,J＝9.2Hz,1H),7.82(d,J＝8.3Hz,1H),7.73(d,J＝8.6Hz,2H),7.59-7.48(m,1H),7.21-7.08(m,3H),3.98-3.79(m,2H),3.54-3.45(m,1H),2.44-2.32(m,4H),1.96-1.75(m,1H).MS(ESI+,[M+H]+)m/z:401.48。 1 H NMR (500MHz, DMSO-d 6 )δ8.14(d,J＝2.2Hz,1H),8.09(dd,J＝9.2,2.2Hz,1H),7.93(d,J＝9.2Hz,1H),7.82(d,J＝8.3Hz, 1H),7.73(d,J＝8.6Hz,2H),7.5 9-7.48(m,1H),7.21-7.08(m,3H),3.98-3.79(m,2H),3.54-3.45(m,1H),2.44-2.32(m,4H),1.96-1.75(m ,1H).MS(ESI+,[M+H] + )m/z:401.48.

实施例21(21_A和21_B)
Example 21 (21_A and 21_B)

步骤A：参照实施例1的合成，在步骤B中，以4-氧代氮杂环丁烷-2-甲酸苄酯替代4-羟基-2-吡咯烷酮，所得粗品经硅胶柱层析纯化(EA/PE)，得到中间体21-1(184mg)。MS(ESI+,[M+H]+)m/z:492.13.Step A: Referring to the synthesis of Example 1, in step B, 4-hydroxy-2-pyrrolidone was replaced with 4-oxoazetidine-2-carboxylic acid benzyl ester, and the obtained crude product was purified by silica gel column chromatography (EA/PE) to obtain intermediate 21-1 (184 mg). MS (ESI+, [M+H] + ) m/z: 492.13.

步骤B：向单口瓶中，依次加入21-1(184mg)和MeOH(5mL)，N2保护下，降至0℃，然后分批加入硼氢化钠(28mg)，加毕，继续搅拌1h；反应结束后，将反应液缓慢倒入至冰的饱和氯化铵溶液(20mL)中，EA萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，抽滤后减压浓缩除去溶剂，所得粗品经经硅胶柱层析纯化，得到化合物21(100mg)。Step B: To a single-necked bottle, 21-1 (184 mg) and MeOH (5 mL) were added in sequence. Under N2 protection, the temperature was lowered to 0°C, and then sodium borohydride (28 mg) was added in batches. After the addition was completed, stirring was continued for 1 h. After the reaction was completed, the reaction solution was slowly poured into an ice-cold saturated ammonium chloride solution (20 mL), extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography to obtain compound 21 (100 mg).

步骤C：化合物21经过高压制备液相分离(REFLECT I-Amylose A色谱柱；乙醇：正己烷＝30:70)，先出峰的为化合物21_A(49mg)，后出峰的为化合物21_B(49mg)。Step C: Compound 21 was separated by high-pressure preparative liquid separation (REFLECT I-Amylose A column; ethanol:n-hexane=30:70). The first peak was compound 21_A (49 mg) and the last peak was compound 21_B (49 mg).

化合物21_A：1H NMR(500MHz,DMSO-d6)δ7.94-7.92(m,2H),7.83-7.77(m,2H),7.73(d,J＝8.7Hz,2H),7.52(t,J＝7.8Hz,1H),7.14-7.10(m,3H),5.06(t,J＝5.4Hz,1H),4.37-4.34(m,1H),3.98-3.94(m,1H),3.76-3.72(m,1H),3.18-3.14(m,1H),2.97-2.94(m,1H).MS(ESI+,[M+H]+)m/z:387.96。Compound 21_A: 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.94-7.92 (m, 2H), 7.83-7.77 (m, 2H), 7.73 (d, J=8.7 Hz, 2H), 7.52 (t, J=7.8 Hz, 1H), 7.14-7.10 (m, 3H), 5.06 (t, J=5.4 Hz, 1H), 4.37-4.34 (m, 1H), 3.98-3.94 (m, 1H), 3.76-3.72 (m, 1H), 3.18-3.14 (m, 1H), 2.97-2.94 (m, 1H). MS (ESI+, [M+H] + ) m/z: 387.96.

化合物21_B：1H NMR(500MHz,DMSO-d6)δ7.94-7.92(m,2H),7.83-7.77(m,2H),7.73(d,J＝8.7Hz,2H),7.52(t,J＝7.9Hz,1H),7.14-7.10(m,3H),5.06(t,J＝5.4Hz,1H),4.37-4.34(m,1H),3.98-3.94(m,1H),3.76-3.72(m,1H),3.18-3.14(m,1H),2.97-2.93(m,1H).MS(ESI+,[M+H]+)m/z:387.96。Compound 21_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.94-7.92 (m, 2H), 7.83-7.77 (m, 2H), 7.73 (d, J=8.7 Hz, 2H), 7.52 (t, J=7.9 Hz, 1H), 7.14-7.10 (m, 3H), 5.06 (t, J=5.4 Hz, 1H), 4.37-4.34 (m, 1H), 3.98-3.94 (m, 1H), 3.76-3.72 (m, 1H), 3.18-3.14 (m, 1H), 2.97-2.93 (m, 1H). MS (ESI+, [M+H] + ) m/z: 387.96.

实施例22(22_A和22_B)
Example 22 (22_A and 22_B)

步骤A：向单口瓶中，依次加入22-1(5.0g)，1-(4-甲氧基苯基)乙胺(5.87g)和NMP(30mL)，N2保护下，将混合物加热至80℃反应1h，再升温至120℃搅拌4h；反应结束后，将反应液冷却至室温，然后缓慢倒至300mL水中，抽滤，滤饼用石油醚洗涤。减压干燥，得到中间体22-2(7.85g)。MS(ESI-,[M-H]-)m/z:262.19.Step A: Add 22-1 (5.0 g), 1-(4-methoxyphenyl)ethylamine (5.87 g) and NMP (30 mL) to a single-mouth bottle in sequence. Under N2 protection, heat the mixture to 80°C for 1 h, then heat to 120°C and stir for 4 h. After the reaction, cool the reaction solution to room temperature, then slowly pour it into 300 mL of water, filter it, and wash the filter cake with petroleum ether. Dry under reduced pressure to obtain intermediate 22-2 (7.85 g). MS (ESI-, [MH] - ) m/z: 262.19.

步骤B：向单口瓶中，依次加入22-2(7.7g)，DMF(40mL)，溴苄(5.5g)和碳酸铯(10.5g)，加毕，将混合物室温搅拌1h；反应结束后，将反应液倒至200mL水中，EA萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩干，所得粗品经硅胶柱层析(EA/PE)，得到中间体22-3(10.3g)。MS(ESI+,[M+H]+)m/z:354.41. Step B: Add 22-2 (7.7 g), DMF (40 mL), benzyl bromide (5.5 g) and cesium carbonate (10.5 g) to a single-mouth bottle in sequence. After the addition, stir the mixture at room temperature for 1 h. After the reaction is completed, pour the reaction solution into 200 mL of water, extract with EA, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is chromatographed on a silica gel column (EA/PE) to obtain intermediate 22-3 (10.3 g). MS (ESI+, [M+H] + ) m/z: 354.41.

步骤C：向单口瓶中，依次加入22-3(1.0g)和DMF(10mL)，N2保护下，降至0℃，然后分批加入氢化钠(60％wt纯度，0.45g)，10分钟后，往其中滴加碘甲烷(4.02g)，加毕，将混合物加热至40℃反应18h；反应结束后，将反应液冷却至室温，然后缓慢倒至100mL冰的饱和氯化铵溶液中，EA萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩干，所得粗品经硅胶柱层析(EA/PE)，得到中间体22-4(800mg)。MS(ESI+,[M+H]+)m/z:368.44.Step C: Add 22-3 (1.0 g) and DMF (10 mL) to a single-mouth bottle in sequence, and under N2 protection, cool to 0°C, then add sodium hydride (60% wt purity, 0.45 g) in batches. After 10 minutes, add iodomethane (4.02 g) dropwise. After the addition, heat the mixture to 40°C and react for 18 hours. After the reaction, cool the reaction solution to room temperature, then slowly pour it into 100 mL of ice saturated ammonium chloride solution, extract with EA, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product is chromatographed on a silica gel column (EA/PE) to obtain intermediate 22-4 (800 mg). MS (ESI+, [M+H] + ) m/z: 368.44.

步骤D：向单口瓶中，依次加入22-4(800mg)和MeOH(20mL)，N2保护下，降至0℃，然后分批加入硼氢化钠(285mg)，加毕，继续搅拌2h；反应结束后，将反应液缓慢倒入至冰的饱和氯化铵溶液(100mL)中，EA萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，抽滤后减压浓缩除去溶剂，所得粗品经经硅胶柱层析纯化(MeOH/DCM)，得到中间体22-5(570mg)。MS(ESI+,[M+H]+)m/z:264.40.Step D: Add 22-4 (800 mg) and MeOH (20 mL) to a single-mouth bottle, and lower the temperature to 0°C under N2 protection. Then add sodium borohydride (285 mg) in batches. After the addition, continue stirring for 2 h. After the reaction is completed, slowly pour the reaction solution into an ice-cold saturated ammonium chloride solution (100 mL), extract with EA, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to remove the solvent. The crude product is purified by silica gel column chromatography (MeOH/DCM) to obtain intermediate 22-5 (570 mg). MS (ESI+, [M+H] + ) m/z: 264.40.

步骤E：向单口瓶中，依次加入22-5(570mg)和三氟乙酸(13g)，将反应液升温至80℃搅拌24h；反应结束后，将反应液直接减压浓缩干，得到中间体22-6(279mg)。MS(ESI+,[M+Na]+)m/z:151.95.Step E: Add 22-5 (570 mg) and trifluoroacetic acid (13 g) to a single-mouth bottle, heat the reaction solution to 80°C and stir for 24 hours; after the reaction, directly concentrate the reaction solution under reduced pressure to dryness to obtain intermediate 22-6 (279 mg). MS (ESI+, [M+Na] + ) m/z: 151.95.

步骤F：参照实施例1的合成，在步骤B中，以22-6替代4-羟基-2-吡咯烷酮，所得粗品经经硅胶柱层析纯化，得到化合物22(375mg)，MS(ESI+,[M+H]+)m/z:416.26。Step F: Referring to the synthesis of Example 1, in step B, 22-6 was used to replace 4-hydroxy-2-pyrrolidone. The obtained crude product was purified by silica gel column chromatography to obtain compound 22 (375 mg), MS (ESI+, [M+H] + ) m/z: 416.26.

步骤G：化合物22再经过高压制备液相分离(REFLECT I-Amylose A色谱柱；乙醇：正己烷＝30:70)，先出峰的为化合物22_A(189mg)，后出峰的为化合物22_B(175mg)。Step G: Compound 22 was subjected to high pressure preparative liquid separation (REFLECT I-Amylose A column; ethanol:n-hexane=30:70). The first eluting peak was compound 22_A (189 mg), and the later eluting peak was compound 22_B (175 mg).

化合物22_A：1H NMR(500MHz,DMSO-d6)δ8.09-8.07(m,2H),7.92-7.90(m,1H),7.81(d,J＝8.4Hz,1H),7.73(d,J＝8.7Hz,2H),7.53(t,J＝7.8Hz,1H),7.15-7.12(m,3H),5.03(t,J＝5.4Hz,1H),3.88(d,J＝9.7Hz,1H),3.61(d,J＝9.7Hz,1H),3.36-3.34(m,2H),2.55(d,J＝16.9Hz,1H),2.32(d,J＝16.9Hz,1H),1.16(s,3H).MS(ESI+,[M+H]+)m/z:416.26。Compound 22_A: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.09-8.07 (m, 2H), 7.92-7.90 (m, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.15-7.12 (m, 3H), 5.03 (t, J=5.4 Hz, 1H), 3.88 (d, J=9.7 Hz, 1H), 3.61 (d, J=9.7 Hz, 1H), 3.36-3.34 (m, 2H), 2.55 (d, J=16.9 Hz, 1H), 2.32 (d, J=16.9 Hz, 1H), 1.16 (s, 3H). MS (ESI+, [M+H] + )m/z:416.26.

化合物22_B：1H NMR(500MHz,DMSO-d6)δ8.09-8.07(m,2H),7.92-7.90(m,1H),7.81(d,J＝8.3Hz,1H),7.73(d,J＝8.8Hz,2H),7.53(t,J＝7.9Hz,1H),7.15-7.12(m,3H),5.03(t,J＝5.4Hz,1H),3.88(d,J＝9.7Hz,1H),3.61(d,J＝9.7Hz,1H),3.36-3.34(m,2H),2.55(d,J＝16.9Hz,1H),2.32(d,J＝16.9Hz,1H),1.16(s,3H).MS(ESI+,[M+H]+)m/z:416.25。Compound 22_B: 1 H NMR (500MHz, DMSO-d 6 )δ8.09-8.07(m,2H),7.92-7.90(m,1H),7.81(d,J＝8.3Hz,1H),7.73(d,J ＝8.8Hz,2H),7.53(t,J＝7.9Hz,1H),7.15-7.12(m,3H),5.03(t,J＝5.4Hz, 1H),3.88(d,J＝9.7Hz,1H),3.61(d,J＝9.7Hz,1H),3.36-3.34(m,2H),2.5 5(d,J＝16.9Hz,1H),2.32(d,J＝16.9Hz,1H),1.16(s,3H).MS(ESI+,[M+H] + )m/z:416.25.

实施例23(23_A和23_B)
Example 23 (23_A and 23_B)

步骤A：在氮气氛围中，向三口瓶中依次加入二异丙氨基锂(23.3mL，2M的四氢呋喃溶液)。在-78℃，向其中加入23-1(4.9g)的四氢呋喃溶液(50mL)，并将该混合物搅拌0.5小时。向其中加入N-苯基二(三氟甲磺酰亚胺)(14.8g)，该混合物继续搅拌0.5小时后转移至0℃下搅拌1小时。反应结束后加入50mL饱和氯化铵水溶液，用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩干，得到化合物23-2(9.45g)。Step A: In a nitrogen atmosphere, lithium diisopropylamide (23.3 mL, 2M tetrahydrofuran solution) was added to a three-necked flask in sequence. A tetrahydrofuran solution (50 mL) of 23-1 (4.9 g) was added thereto at -78°C, and the mixture was stirred for 0.5 hours. N-phenylbis(trifluoromethanesulfonimide) (14.8 g) was added thereto, and the mixture was stirred for 0.5 hours and then transferred to 0°C and stirred for 1 hour. After the reaction was completed, 50 mL of saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 23-2 (9.45 g).

步骤B：向茄型瓶中依次加入23-2(9.45g)，N,N-二甲基甲酰胺(40mL)，甲醇(80mL)，三乙胺(14.4mL)，二(三苯基膦)二氯化钯(II)(1.07g)，并用常压一氧化碳替换反应容器中的空气，将该反应溶液50℃下搅拌18小时。反应结束后加入50mL纯化水，用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无 水硫酸钠干燥，抽滤，滤液减压浓缩干，得到化合物23-3(6.35g)。Step B: 23-2 (9.45 g), N,N-dimethylformamide (40 mL), methanol (80 mL), triethylamine (14.4 mL), bis(triphenylphosphine)palladium(II) chloride (1.07 g) were added to an eggplant-shaped bottle in sequence, and the air in the reaction vessel was replaced with carbon monoxide at normal pressure. The reaction solution was stirred at 50°C for 18 hours. After the reaction was completed, 50 mL of purified water was added, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over medium temperature. The mixture was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 23-3 (6.35 g).

步骤C：向茄型瓶中依次加入23-3(6.35g)，甲苯(100mL)，2,4-二甲氧基苄胺(5.18mL)，将该反应溶液110℃下搅拌18小时。反应结束冷却至室温后所得粗品经硅胶柱层析纯化(PE/EA)，得到化合物23-4(330mg)。Step C: 23-3 (6.35 g), toluene (100 mL), and 2,4-dimethoxybenzylamine (5.18 mL) were added to an eggplant-shaped bottle in sequence, and the reaction solution was stirred at 110° C. for 18 hours. After the reaction was completed, the crude product was cooled to room temperature and purified by silica gel column chromatography (PE/EA) to obtain compound 23-4 (330 mg).

步骤D：向茄型瓶中依次加入23-4(300mg)，三氟乙酸(7.2mL)，将该反应溶液80℃下搅拌3小时。反应结束冷却至室温后，反应液减压浓缩干，得到化合物23-5(159mg)。Step D: 23-4 (300 mg) and trifluoroacetic acid (7.2 mL) were added to an eggplant-shaped bottle in sequence, and the reaction solution was stirred at 80° C. for 3 hours. After the reaction was completed and cooled to room temperature, the reaction solution was concentrated under reduced pressure to dryness to obtain compound 23-5 (159 mg).

步骤E：参照实施例1的合成，在步骤B中，以23-5替代4-羟基-2-吡咯烷酮，所得粗品经硅胶柱层析纯化，得到化合物23-6(300mg)。Step E: Referring to the synthesis of Example 1, in step B, 23-5 was used to replace 4-hydroxy-2-pyrrolidone, and the obtained crude product was purified by silica gel column chromatography to obtain compound 23-6 (300 mg).

步骤F：向茄型瓶中依次加入23-6(300mg)，甲醇(2mL)，硼氢化钠(125mg)。将该反应溶液室温下搅拌18小时。反应结束后加入30mL纯化水，用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩干，得到化合物23(170mg)，MS(ESI+,[M+H]+)m/z：428.22。Step F: Add 23-6 (300 mg), methanol (2 mL), and sodium borohydride (125 mg) to an eggplant-shaped bottle in sequence. Stir the reaction solution at room temperature for 18 hours. After the reaction, add 30 mL of purified water, extract with ethyl acetate, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 23 (170 mg), MS (ESI+, [M+H] + ) m/z: 428.22.

步骤G：化合物23(170mg)经高压制备液相分离(REFLECT I-Amylose A色谱柱；乙醇：正己烷＝7:93)，先出峰的为化合物23_A(76mg)，后出峰的为化合物23_B(76mg)。Step G: Compound 23 (170 mg) was separated by high pressure preparative liquid separation (REFLECT I-Amylose A column; ethanol:n-hexane=7:93). The first eluting peak was compound 23_A (76 mg), and the later eluting peak was compound 23_B (76 mg).

实施例23_A：1H NMR(500MHz,DMSO)δ8.16-8.09(m,2H),7.91(d,J＝9.1Hz,1H),7.81(d,J＝8.3Hz,1H),7.73(d,J＝8.7Hz,2H),7.55-7.50(m,1H),7.17-7.11(m,3H),4.82-4.78(m,1H),4.16-4.12(m,1H),3.89-3.84(m,1H),3.50-3.45(m,1H),3.43-3.38(m,1H),1.24-1.21(m,1H),1.17-1.11(m,1H),1.02-0.97(m,1H),0.91-0.85(m,2H).MS(ESI+,[M+H]+)m/z：428.15。Example 23_A: 1 H NMR (500 MHz, DMSO) δ 8.16-8.09 (m, 2H), 7.91 (d, J = 9.1 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.55-7.50 (m, 1H), 7.17-7.11 (m, 3H), 4.82-4.78 (m, 1H), 4 .16-4.12(m,1H),3.89-3.84(m,1H),3.50-3.45(m,1H),3.43-3.38(m,1H),1.24-1. 21(m,1H),1.17-1.11(m,1H),1.02-0.97(m,1H),0.91-0.85(m,2H).MS(ESI+,[M+H] + )m/z: 428.15.

实施例23_B：1H NMR(500MHz,DMSO)δ8.16-8.09(m,2H),7.91(d,J＝9.1Hz,1H),7.81(d,J＝8.3Hz,1H),7.76-7.69(m,2H),7.57-7.49(m,1H),7.16-7.12(m,3H),4.82-4.78(m,1H),4.16-4.12(m,1H),3.89-3.84(m,1H),3.52-3.37(m,2H),1.24-1.21(m,1H),1.18-1.13(m,1H),1.02-0.97(m,1H),0.91-0.85(m,2H).MS(ESI+,[M+H]+)m/z：428.15。Example 23_B: 1 H NMR (500MHz, DMSO) δ8.16-8.09(m,2H),7.91(d,J＝9.1Hz,1H),7.81(d,J＝8.3H z,1H),7.76-7.69(m,2H),7.57-7.49(m,1H),7.16-7.12(m,3H),4.82-4.78(m ,1H),4.16-4.12(m,1H),3.89-3.84(m,1H),3.52-3.37(m,2H),1.24-1.21(m, 1H),1.18-1.13(m,1H),1.02-0.97(m,1H),0.91-0.85(m,2H).MS(ESI+,[M+H] + )m/z：428.15.

实施例24(24_A和24_B)
Example 24 (24_A and 24_B)

步骤A：氮气保护，向微波管依次加入24-1(4.0g)，24-2(2.00g)，氧化铝负载氟化钾(1.0g)。室温反应24h。体系直接过滤，收集滤液，浓缩，得到24-3(2.8g)。1H NMR(500MHz,DMSO-d6)δ4.13-4.07(m,2H),4.07-4.00(m,2H),3.53-3.47(m,1H),2.73-2.65(m,1H),2.66-2.58(m,1H),1.58(s,3H),1.53(s,3H),1.17(t,J＝7.1Hz,3H),1.14(t,J＝7.1Hz,3H).Step A: Under nitrogen protection, add 24-1 (4.0 g), 24-2 (2.00 g), and potassium fluoride supported on alumina (1.0 g) to the microwave tube in sequence. React at room temperature for 24 h. The system is directly filtered, and the filtrate is collected and concentrated to obtain 24-3 (2.8 g). 1 H NMR (500 MHz, DMSO-d 6 ) δ 4.13-4.07 (m, 2H), 4.07-4.00 (m, 2H), 3.53-3.47 (m, 1H), 2.73-2.65 (m, 1H), 2.66-2.58 (m, 1H), 1.58 (s, 3H), 1.53 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H).

步骤B：氮气保护，冰浴，向单口瓶依次加入24-3(2.8g)，无水甲醇(50mL)，六水合氯化镍(2.55g)，分批加入硼氢化钠(3.24g)，加毕，室温搅拌1h。加入饱和氯化铵溶液50mL淬灭反应，浓缩除去甲醇，然后用EA萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，得到24-4(1.5g)。1HNMR(500MHz,DMSO-d6)δ7.79(s,1H),4.19-4.12(m,1H),4.12-4.05(m,1H),3.04(t,J＝9.0Hz,1H),2.59-2.51(m,1H),2.31-2.25(m,1H),1.34(s,3H),1.21(t,J＝7.1Hz,3H),1.03(s,3H).GC-MS(EI,M+)m/z:185.Step B: Under nitrogen protection and ice bath, 24-3 (2.8 g), anhydrous methanol (50 mL), nickel chloride hexahydrate (2.55 g) were added to a single-mouth bottle in sequence, and sodium borohydride (3.24 g) was added in batches. After the addition was completed, the mixture was stirred at room temperature for 1 h. 50 mL of saturated ammonium chloride solution was added to quench the reaction, and the methanol was removed by concentration, and then extracted with EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 24-4 (1.5 g). 1 HNMR(500MHz,DMSO-d 6 )δ7.79(s,1H),4.19-4.12(m,1H),4.12-4.05(m,1H),3.04(t,J＝9.0Hz,1H),2.59-2.51 (m,1H),2.31-2.25(m,1H),1.34(s,3H),1.21(t,J＝7.1Hz,3H),1.03(s,3H).GC-MS(EI,M + )m/z:185.

步骤C：氮气保护，向单口瓶中依次加入1-2(300mg)，24-4(378mg)，三(二亚苄基丙酮)二钯(0)(112mg,)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(95mg)，碳酸铯(666mg)，三乙胺(1.12mL)，及甲苯(30mL)； 110℃反应4h。降温至室温，用EA(30mL)稀释，加入30mL水，分出有机相，水相用EA萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，所得粗品经硅胶柱层析(DCM/MeOH)纯化，得到24-5(250mg)。MS(ESI+,[M+H]+)m/z:472.25.Step C: Under nitrogen protection, 1-2 (300 mg), 24-4 (378 mg), tris(dibenzylideneacetone)dipalladium(0) (112 mg), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (95 mg), cesium carbonate (666 mg), triethylamine (1.12 mL), and toluene (30 mL) were added to a single-necked bottle in sequence; React at 110°C for 4 h. Cool to room temperature, dilute with EA (30 mL), add 30 mL of water, separate the organic phase, extract the aqueous phase with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the crude product by silica gel column chromatography (DCM/MeOH) to obtain 24-5 (250 mg). MS (ESI+, [M+H] + ) m/z: 472.25.

步骤D：氮气保护，冰浴，向单口瓶，依次加入24-5(250mg)，THF(10mL)，滴入氢化铝锂的四氢呋喃溶液(0.263mL，2.5M)，滴毕，加入0.1M氢氧化钠溶液10mL淬灭，然后用EA萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，得到化合物24(120mg)。MS(ESI+,[M+H]+)m/z:430.22.Step D: Nitrogen protection, ice bath, add 24-5 (250 mg), THF (10 mL) to a single-mouth bottle, add lithium aluminum hydride tetrahydrofuran solution (0.263 mL, 2.5 M) dropwise, add 0.1 M sodium hydroxide solution 10 mL to quench, then extract with EA, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 24 (120 mg). MS (ESI+, [M+H] + ) m/z: 430.22.

步骤E：化合物24(120mg)经硅胶柱层析纯化，再经手性拆分(YMC高压制备色谱：CHIRALART Cellulose-SC色谱柱，乙醇/正己烷)先出峰的为化合物24_A(50mg)，后出峰的为化合物24_B(50mg)。Step E: Compound 24 (120 mg) was purified by silica gel column chromatography and then subjected to chiral separation (YMC high pressure preparative chromatography: CHIRALART Cellulose-SC column, ethanol/n-hexane). The first eluting peak was compound 24_A (50 mg), and the later eluting peak was compound 24_B (50 mg).

化合物24_A：1H NMR(500MHz,DMSO-d6)δ7.97(d,J＝8.9Hz,1H),7.90(d,J＝8.3Hz,1H),7.84(d,J＝2.0Hz,1H),7.74(d,J＝8.7Hz,2H),7.61-7.56(m,1H),7.32-7.30(m,1H),7.29-7.23(m,1H),7.20-7.16(m,2H),4.74(t,J＝4.9Hz,1H),3.68-3.51(m,2H),2.49-2.43(m,1H),2.43-2.35(m,1H),2.35-2.28(m,1H),1.28(s,3H),1.18(s,3H).MS(ESI+,[M+H]+)m/z:430.26.Compound 24_A: 1 H NMR (500 MHz, DMSO-d 6 )δ7.97(d,J＝8.9Hz,1H),7.90(d,J＝8.3Hz,1H),7.84(d,J＝2.0Hz,1H),7.74(d ,J＝8.7Hz,2H),7.61-7.56(m,1H),7.32-7.30(m,1H),7.29-7.23(m,1H),7.20 -7.16(m,2H),4.74(t,J＝4.9Hz,1H),3.68-3.51(m,2H),2.49-2.43(m,1H),2. 43-2.35(m,1H),2.35-2.28(m,1H),1.28(s,3H),1.18(s,3H).MS(ESI+,[M+H] + )m/z:430.26.

化合物24_B：1H NMR(500MHz,DMSO-d6)δ7.97(d,J＝8.8Hz,1H),7.90(d,J＝8.3Hz,1H),7.84(d,J＝2.0Hz,1H),7.74(d,J＝8.7Hz,2H),7.61-7.56(m,1H),7.33-7.30(m,1H),7.29-7.23(m,1H),7.18(d,J＝8.6Hz,2H),4.74(t,J＝4.9Hz,1H),3.69-3.60(m,1H),3.60-3.51(m,1H),2.49-2.43(m,1H),2.42-2.35(m,1H),2.35-2.28(m,1H),1.28(s,3H),1.18(s,3H).MS(ESI+,[M+H]+)m/z:430.24.Compound 24_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.97 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 8.7 Hz, 2H), 7.61-7.56 (m, 1H), 7.33-7.30 (m, 1H), 7.29-7.23 (m, 1H), 7.18 (d, J = 8.6 Hz, 2H z,2H),4.74(t,J＝4.9Hz,1H),3.69-3.60(m,1H),3.60-3.51(m,1H),2.49-2.43(m,1 H),2.42-2.35(m,1H),2.35-2.28(m,1H),1.28(s,3H),1.18(s,3H).MS(ESI+,[M+H] + )m/z:430.24.

实施例25(25_A和25_B)
Example 25 (25_A and 25_B)

步骤A：向单口瓶中，加入25-1(500mg)，甲醇(15mL)溶解，冰浴条件下加入氯化亚砜(0.9mL)，之后转移至60℃加热搅拌5h。反应结束，停止反应，加入甲苯20mL，旋干溶剂，得到25-2(700mg)。1HNMR(500MHz,DMSO-d6)δ3.65(s,3H),3.61(s,3H),3.51-3.42(m,1H),2.77-2.68(m,2H),2.50-2.36(m,2H),1.95-1.76(m,2H).Step A: Add 25-1 (500 mg) to a single-mouth bottle, dissolve it in methanol (15 mL), add thionyl chloride (0.9 mL) under ice bath conditions, and then transfer to 60°C and heat with stirring for 5 h. After the reaction is completed, stop the reaction, add 20 mL of toluene, and spin dry the solvent to obtain 25-2 (700 mg). 1 HNMR (500 MHz, DMSO-d 6 )δ3.65 (s, 3H), 3.61 (s, 3H), 3.51-3.42 (m, 1H), 2.77-2.68 (m, 2H), 2.50-2.36 (m, 2H), 1.95-1.76 (m, 2H).

步骤B：向单口瓶中，依次加入25-2(700mg)、甲醇(15mL)和三乙胺(1.5mL)，65℃加热回流搅拌3h。反应结束，停止反应，旋干溶剂后加入乙酸乙酯(30mL)，抽滤，滤液再次旋干得到25-3(470mg)。1HNMR(500MHz,DMSO-d6)δ7.63(s,1H),3.87-3.80(m,1H),3.60(s,3H),2.49(d,J＝3.4Hz,2H),2.22-2.05(m,3H),1.69-1.61(m,1H).Step B: Add 25-2 (700 mg), methanol (15 mL) and triethylamine (1.5 mL) to a single-mouth bottle, heat and reflux at 65 ° C for 3 h. After the reaction is completed, stop the reaction, spin dry the solvent, add ethyl acetate (30 mL), filter, and spin dry the filtrate again to obtain 25-3 (470 mg). 1 HNMR (500 MHz, DMSO-d 6 ) δ7.63 (s, 1H), 3.87-3.80 (m, 1H), 3.60 (s, 3H), 2.49 (d, J＝3.4Hz, 2H), 2.22-2.05 (m, 3H), 1.69-1.61 (m, 1H).

步骤C：参照实施例1的合成，在步骤B中，以25-3替代4-羟基-2-吡咯烷酮，所得粗品经硅胶柱层析纯化，得到25-4(215mg)。MS(ESI+,[M+H]+)m/z:444.21.Step C: Referring to the synthesis of Example 1, in step B, 25-3 was used to replace 4-hydroxy-2-pyrrolidone, and the obtained crude product was purified by silica gel column chromatography to obtain 25-4 (215 mg). MS (ESI+, [M+H] + ) m/z: 444.21.

步骤D：向单口瓶中，依次加入25-4(180mg)、甲醇(6mL)、四氢呋喃(2mL)和氢氧化钠(640mg)的水(8mL)溶液，50℃加热搅拌2h。反应结束，停止加热，冷却至室温，加20mL水，用1N的盐酸水溶液调节溶液pH＝4左右。用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥。抽滤，滤液旋干得到25-5(170mg)。MS(ESI+,[M+H]+)m/z:430.24. Step D: Add 25-4 (180 mg), methanol (6 mL), tetrahydrofuran (2 mL) and sodium hydroxide (640 mg) in water (8 mL) to a single-mouth bottle, and heat and stir at 50 ° C for 2 h. After the reaction is completed, stop heating, cool to room temperature, add 20 mL of water, and adjust the solution pH to about 4 with 1N hydrochloric acid aqueous solution. Extract with ethyl acetate, combine the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter and spin dry the filtrate to obtain 25-5 (170 mg). MS (ESI+, [M+H] + ) m/z: 430.24.

步骤E：向单口瓶中，依次加入25-5(200mg)，四氢呋喃(10mL)和N-甲基吗啉(52mg)，冰浴条件下加入氯甲酸异丁酯(70mg)，室温搅拌1.5h后加入硼氢化钠(106mg)，继续室温搅拌12h。反应结束，停止反应，加入30mL水，加入1N的盐酸水溶液(2mL)淬灭反应。用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩所得粗品经硅胶柱层析纯化，得到化合物25(100mg)。Step E: Add 25-5 (200 mg), tetrahydrofuran (10 mL) and N-methylmorpholine (52 mg) to a single-mouth bottle, add isobutyl chloroformate (70 mg) under ice bath conditions, stir at room temperature for 1.5 h, then add sodium borohydride (106 mg), and continue stirring at room temperature for 12 h. After the reaction is completed, stop the reaction, add 30 mL of water, and add 1N hydrochloric acid aqueous solution (2 mL) to quench the reaction. Extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the resulting crude product by silica gel column chromatography to obtain compound 25 (100 mg).

1H NMR(500MHz,DMSO-d6)δ8.09(d,J＝2.1Hz,1H),7.94(d,J＝9.1Hz,1H),7.81(d,J＝8.3Hz,1H),7.77-7.72(m,3H),7.55(t,J＝7.9Hz,1H),7.20-7.14(m,3H),4.58-4.50(m,2H),3.53-3.44(m,2H),2.68-2.57(m,1H),2.49-2.40(m,1H),2.38-2.26(m,1H),1.95-1.86(m,1H),1.86-1.77(m,1H),1.60-1.50(m,1H)。HRMS(ESI+,[M+H]+)m/z:416.1477. 1 H NMR (500MHz, DMSO-d 6 )δ8.09(d,J＝2.1Hz,1H),7.94(d,J＝9.1Hz,1H),7.81(d,J＝8.3Hz,1H),7.77-7.72(m,3H),7.55( t,J＝7.9Hz,1H),7.20-7.14(m,3H),4.58-4.50 (m,2H),3.53-3.44(m,2H),2.68-2.57(m,1H),2.49-2.40(m,1H),2.38 -2.26(m,1H),1.95-1.86(m,1H),1.86-1.77(m,1H),1.60-1.50(m,1H). HRMS(ESI+,[M+H] + )m/z:416.1477.

步骤F：化合物25(90mg)经过高压制备液相分离(CHIRALART Amylose-SA色谱柱；正己烷：乙醇＝70:30)，先出峰为化合物25_A(30mg)，后出峰为化合物25_B(40mg)。Step F: Compound 25 (90 mg) was subjected to high-pressure preparative liquid separation (CHIRALART Amylose-SA chromatographic column; n-hexane:ethanol=70:30). The first peak was compound 25_A (30 mg) and the second peak was compound 25_B (40 mg).

化合物25_A:1H NMR(500MHz,DMSO-d6)δ8.08(d,J＝2.1Hz,1H),7.94(d,J＝9.1Hz,1H),7.81(d,J＝8.3Hz,1H),7.77-7.70(m,3H),7.55(t,J＝7.9Hz,1H),7.21-7.12(m,3H),4.57-4.50(m,2H),3.51-3.43(m,2H),2.66-2.57(m,1H),2.48-2.40(m,1H),2.37-2.26(m,1H),1.94-1.87(m,1H),1.87-1.76(m,1H),1.60-1.50(m,1H)。HRMS(ESI+,[M+H]+)m/z:416.1475.Compound 25_A: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.08 (d, J = 2.1 Hz, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.77-7.70 (m, 3H), 7.55 (t, J = 7.9 Hz, 1H), 7.21-7.12 (m, 3H), 4.57-4.50 (m, 2H), 3.51-3.43 (m, 2H), 2.66-2.57 (m, 1H), 2.48-2.40 (m, 1H), 2.37-2.26 (m, 1H), 1.94-1.87 (m, 1H), 1.87-1.76 (m, 1H), 1.60-1.50 (m, 1H). HRMS(ESI+,[M+H] + )m/z:416.1475.

化合物25_B:1H NMR(500MHz,DMSO-d6)δ8.08(d,J＝2.1Hz,1H),7.94(d,J＝9.0Hz,1H),7.81(d,J＝8.2Hz,1H),7.79-7.67(m,3H),7.55(t,J＝7.8Hz,1H),7.22-7.11(m,3H),4.63-4.46(m,2H),3.53-3.43(m,2H),2.67-2.57(m,1H),2.48-2.40(m,1H),2.38-2.24(m,1H),1.96-1.86(m,1H),1.86-1.75(m,1H),1.63-1.49(m,1H)。HRMS(ESI+,[M+H]+)m/z:416.1478.Compound 25_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.08 (d, J = 2.1 Hz, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.79-7.67 (m, 3H), 7.55 (t, J = 7.8 Hz, 1H), 7.22-7.11 (m, 3H), 4.63-4.46 (m, 2H), 3.53-3.43 (m, 2H), 2.67-2.57 (m, 1H), 2.48-2.40 (m, 1H), 2.38-2.24 (m, 1H), 1.96-1.86 (m, 1H), 1.86-1.75 (m, 1H), 1.63-1.49 (m, 1H). HRMS(ESI+,[M+H] + )m/z:416.1478.

实施例26(26_A和26_B)
Example 26 (26_A and 26_B)

步骤A：参照实施例1的合成，在步骤B中，以26-1替代4-羟基-2-吡咯烷酮，得到化合物26(130mg)。Step A: Referring to the synthesis of Example 1, in step B, 4-hydroxy-2-pyrrolidone was replaced with 26-1 to obtain compound 26 (130 mg).

1H NMR(500MHz,DMSO-d6)δ8.12(d,J＝2.2Hz,1H),7.95(d,J＝9.1Hz,1H),7.87-7.79(m,1H),7.82(d,J＝8.3Hz,1H),7.78-7.69(m,2H),7.55(t,J＝7.9Hz,1H),7.22-7.12(m,3H),5.08(t,J＝5.3Hz,1H),4.80-4.73(m,1H),4.55(t,J＝8.6Hz,1H),4.40-4.32(m,1H),3.69-3.57(m,1H),3.54-3.47(m,1H).MS(ESI+,[M+H]+)m/z:404.11. 1 H NMR (500MHz, DMSO-d 6 )δ8.12(d,J＝2.2Hz,1H),7.95(d,J＝9.1Hz,1H),7.87-7.79(m,1H),7.82(d,J＝8.3Hz,1H),7.78- 7.69(m,2H),7.55(t,J＝7.9Hz,1H),7.22-7.12( m,3H),5.08(t,J＝5.3Hz,1H),4.80-4.73(m,1H),4.55(t,J＝8.6Hz,1H), 4.40-4.32(m,1H),3.69-3.57(m,1H),3.54-3.47(m,1H).MS(ESI+,[M+H] + )m/z:404.11.

步骤B：化合物26经手性拆分(YMC高压制备色谱：CHIRALART Cellulose-SC色谱柱，乙醇/正己烷)先出峰的为化合物26_A(58mg)，后出峰的为化合物26_B(58mg)。Step B: Compound 26 was subjected to chiral separation (YMC high pressure preparative chromatography: CHIRALART Cellulose-SC column, ethanol/n-hexane). The first eluting peak was compound 26_A (58 mg), and the later eluting peak was compound 26_B (58 mg).

化合物26_A：1H NMR(500MHz,DMSO-d6)δ8.12(d,J＝2.3Hz,1H),7.95(d,J＝9.1Hz,1H),7.90-7.79(m,2H),7.77-7.69(m,2H),7.55(t,J＝7.9Hz,1H),7.22-7.11(m,3H),5.08(t,J＝5.3Hz,1H),4.80-4.73(m,1H),4.55(t,J＝8.6Hz,1H),4.40-4.33(m,1H),3.65-3.57(m,1H),3.54-3.46(m,1H).MS(ESI+,[M+H]+)m/z:404.13.Compound 26_A: 1 H NMR (500MHz, DMSO-d 6 )δ8.12(d,J＝2.3Hz,1H),7.95(d,J＝9.1Hz,1H),7.90-7.79(m,2H),7.77-7.69(m,2H),7.55(t,J ＝7.9Hz,1H),7.22-7.11(m,3H),5.08 (t,J＝5.3Hz,1H),4.80-4.73(m,1H),4.55(t,J＝8.6Hz,1H),4.40-4.33(m,1H),3.65-3.57(m,1H), 3.54-3.46(m,1H).MS(ESI+,[M+H] + )m/z:404.13.

化合物26_B：1H NMR(500MHz,DMSO-d6)δ8.12(d,J＝2.2Hz,1H),7.95(d,J＝9.1Hz,1H),7.90-7.79(m,2H),7.77-7.69(m,2H),7.59-7.52(m,1H),7.20-7.12(m,3H),5.08(t,J＝5.3Hz,1H),4.80-4.73(m,1H),4.55(t,J＝8.6Hz,1H),4.40-4.34(m,1H),3.65-3.57(m,1H),3.54-3.46(m,1H).MS(ESI+,[M+H]+)m/z:404.09.Compound 26_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.12 (d, J = 2.2 Hz, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.90-7.79 (m, 2H), 7.77-7.69 (m, 2H), 7.59-7.52 (m, 1H), 7.20-7.12 (m, 3H), 5.08 (t, J = 5.3 Hz, 1H), 4.80-4.73 (m, 1H), 4.55 (t, J = 8.6 Hz, 1H), 4.40-4.34 (m, 1H), 3.65-3.57 (m, 1H), 3.54-3.46 (m, 1H). MS (ESI+, [M+H] + ) m/z: 404.09.

实施例27(27_A和27_B)
Example 27 (27_A and 27_B)

步骤A：氮气保护，向单口瓶中依次加入27-1(5.0g)，27-2(5.87g)，NMP(30mL)，加热至120℃反应4h。反应液冷却至室温，缓慢倒至冰水(300mL)中，过滤，滤饼用水洗涤，PE洗涤，抽干，得到化合物27-3(8.4g)。MS(ESI+,[M+H]+)m/z:264.08.Step A: Under nitrogen protection, add 27-1 (5.0 g), 27-2 (5.87 g), and NMP (30 mL) to a single-mouth bottle in sequence, and heat to 120°C for 4 h. The reaction solution is cooled to room temperature, slowly poured into ice water (300 mL), filtered, and the filter cake is washed with water and PE, and dried to obtain compound 27-3 (8.4 g). MS (ESI+, [M+H]+) m/z: 264.08.

步骤B：氮气保护，向单口瓶中依次加入27-3(2.00g)，N,O-二甲基羟胺盐酸盐(1.10g)，EDCI(2.18g)，DMAP(1.39g)，DCM(30mL)，室温反应3h。反应液中加入0.1M盐酸(20mL)，分出有机相，用饱和碳酸氢钠洗涤，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，所得粗品经硅胶柱层析纯化，得到化合物27-4(2.3g)。MS(ESI+,[M+H]+)m/z:307.17。Step B: Under nitrogen protection, 27-3 (2.00 g), N,O-dimethylhydroxylamine hydrochloride (1.10 g), EDCI (2.18 g), DMAP (1.39 g), and DCM (30 mL) were added to a single-mouth bottle in sequence and reacted at room temperature for 3 h. 0.1 M hydrochloric acid (20 mL) was added to the reaction solution, and the organic phase was separated, washed with saturated sodium bicarbonate, 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 to obtain compound 27-4 (2.3 g). MS (ESI+, [M+H]+) m/z: 307.17.

步骤C：氮气保护，冰浴，向三口瓶中依次加入27-4(2.2g)，2-MeTHF(30mL)，滴入甲基溴化镁(4.33mL，3M的四氢呋喃溶液)，0℃下搅拌60min，室温反应2h。在0℃下加入1M盐酸(20mL)淬灭。分离有机相并用饱和碳酸钠溶液及饱和食盐水洗涤。用无水硫酸钠干燥，过滤，滤液浓缩，所得粗品经硅胶柱层析(PE/EA)纯化。得到化合物27-5(1.55g)。MS(ESI+,[M+H]+)m/z:262.30Step C: Nitrogen protection, ice bath, add 27-4 (2.2 g), 2-MeTHF (30 mL) to a three-necked flask in sequence, add methylmagnesium bromide (4.33 mL, 3M tetrahydrofuran solution), stir at 0°C for 60 min, and react at room temperature for 2 h. Add 1M hydrochloric acid (20 mL) at 0°C to quench. Separate the organic phase and wash with saturated sodium carbonate solution and saturated brine. Dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the crude product by silica gel column chromatography (PE/EA). Compound 27-5 (1.55 g) is obtained. MS (ESI+, [M+H] + ) m/z: 262.30

步骤D：氮气保护，冰浴，向单口瓶中加入27-5(425mg)，甲醇(10mL)，分批加入硼氢化钠(73.8mg)，搅拌30min，室温反应1h。加入饱和氯化铵淬灭反应。然后减压浓缩，除去大部分甲醇，加入水(10mL)，用EA萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，得到27-6(0.4g)。MS(ESI+,[M+H]+)m/z:264.17Step D: Nitrogen protection, ice bath, add 27-5 (425 mg), methanol (10 mL) to a single-mouth bottle, add sodium borohydride (73.8 mg) in batches, stir for 30 min, and react at room temperature for 1 h. Add saturated ammonium chloride to quench the reaction. Then concentrate under reduced pressure to remove most of the methanol, add water (10 mL), and extract with EA. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain 27-6 (0.4 g). MS (ESI+, [M+H] + ) m/z: 264.17

步骤E：氮气保护，向微波管加入27-6(0.4g)，TFA(3mL)，置于微波反应器中，加热至90℃反应60min。加入水(0.5mL)，然后浓缩、抽干，得到化合物27-7(0.3g)。Step E: Under nitrogen protection, add 27-6 (0.4 g) and TFA (3 mL) to a microwave tube, place in a microwave reactor, heat to 90°C and react for 60 min. Add water (0.5 mL), then concentrate and drain to obtain compound 27-7 (0.3 g).

步骤F：参照实施例1的合成，在步骤B中，以27-7替代4-羟基-2-吡咯烷酮，得到化合物27(90mg)。MS(ESI+,[M+H]+)m/z:416.29.Step F: Referring to the synthesis of Example 1, in step B, 27-7 was used to replace 4-hydroxy-2-pyrrolidone to obtain compound 27 (90 mg). MS (ESI+, [M+H] + ) m/z: 416.29.

步骤G：化合物27(90mg)经硅胶柱层析(洗脱剂：DCM:MeOH＝30:1)分离手性，先出峰的为化合物27_A(36mg)，后出峰的为化合物27_B(38mg)。Step G: Compound 27 (90 mg) was separated by silica gel column chromatography (eluent: DCM:MeOH=30:1). The first eluting peak was compound 27_A (36 mg), and the later eluting peak was compound 27_B (38 mg).

化合物27_A：1H NMR(500MHz,DMSO-d6)δ8.14-8.08(m,2H),7.94-7.89(m,1H),7.82(d,J＝8.3Hz,1H),7.73(d,J＝8.5Hz,2H),7.53(t,J＝7.9Hz,1H),7.17-7.11(m,3H),4.85(d,J＝5.0Hz,1H),4.05-3.93(m,1H),3.91-3.81(m,1H),3.72-3.63(m,1H),2.63-2.53(m,1H),2.47-2.36(m,2H),1.13(d,J＝6.3Hz,3H).MS(ESI+,[M+H]+)m/z:416.27.Compound 27_A: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.14-8.08 (m, 2H), 7.94-7.89 (m, 1H), 7.82 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.5 Hz, 2H), 7.53 (t, J=7.9 Hz, 1H), 7.17-7.11 (m, 3H), 4.85 (d, J=5.0 Hz, 1H), 4.05-3.93 (m, 1H), 3.91-3.81 (m, 1H), 3.72-3.63 (m, 1H), 2.63-2.53 (m, 1H), 2.47-2.36 (m, 2H), 1.13 (d, J=6.3 Hz, 3H). MS (ESI+, [M+H] + )m/z:416.27.

化合物27_B：1H NMR(500MHz,DMSO-d6)δ8.14-8.08(m,2H),7.91(d,J＝9.7Hz,1H),7.81(d,J＝8.3Hz,1H),7.73(d,J＝8.6Hz,2H),7.53(t,J＝7.9Hz,1H),7.14(d,J＝8.1Hz,3H),4.81(d,J＝4.8Hz,1H),4.02-3.91(m,1H),3.80-3.66(m,2H),2.65-2.52(m,2H),2.49-2.40(m,1H),1.11(d,J＝6.2Hz,3H).MS(ESI+,[M+H]+)m/z:416.31.Compound 27_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.14-8.08 (m, 2H), 7.91 (d, J=9.7 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.53 (t, J=7.9 Hz, 1H), 7.14 (d, J=8.1 Hz, 3H), 4.81 (d, J=4.8 Hz, 1H), 4.02-3.91 (m, 1H), 3.80-3.66 (m, 2H), 2.65-2.52 (m, 2H), 2.49-2.40 (m, 1H), 1.11 (d, J=6.2 Hz, 3H). MS (ESI+, [M+H] + ) m/z: 416.31.

实施例28(28_A和28_B)
Example 28 (28_A and 28_B)

步骤A：向茄型瓶中依次加入甘氨酸甲酯盐酸盐(6.70g)，乙腈(100mL)，4-甲氧基氯苄(18.39g)，DIPEA(20.69g)，110℃反应过夜。向反应液加入水(150mL)后用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩干，所得粗品经硅胶柱层析纯化(PE/EA)，得到化合物28-1(17g)。MS(ESI+,[M+H]+)m/z:330.14。Step A: Glycine methyl ester hydrochloride (6.70 g), acetonitrile (100 mL), 4-methoxybenzyl chloride (18.39 g), and DIPEA (20.69 g) were added to an eggplant-shaped bottle in sequence, and the mixture was reacted at 110°C overnight. Water (150 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE/EA) to obtain compound 28-1 (17 g). MS (ESI+, [M+H] + ) m/z: 330.14.

步骤B：向茄型瓶中依次加入28-1(17g)，四氢呋喃(20mL)，甲醇(20mL)，水(20mL)和NaOH(10.32g)，室温搅拌反应2h后用6M盐酸调pH至6-7，抽滤，滤饼用石油醚洗涤后真空干燥，得到化合物28-2(16g)。MS(ESI+,[M+H]+)m/z:316.10。Step B: Add 28-1 (17 g), tetrahydrofuran (20 mL), methanol (20 mL), water (20 mL) and NaOH (10.32 g) to an eggplant-shaped bottle in sequence, stir at room temperature for 2 h, adjust the pH to 6-7 with 6M hydrochloric acid, filter, wash the filter cake with petroleum ether and dry in vacuo to obtain compound 28-2 (16 g). MS (ESI+, [M+H] + ) m/z: 316.10.

步骤C：向茄型瓶中依次加入28-2(16g)，二氯甲烷(100mL)，N,O-二甲基羟胺盐酸盐(3.72g)，HATU(28.9g)，DIPEA(19.67g)，室温搅拌反应4h。反应液浓缩后经硅胶柱层析纯化(PE/EA)，得到化合物28-3(12g)。MS(ESI+,[M+H]+)m/z:359.21。Step C: Add 28-2 (16 g), dichloromethane (100 mL), N,O-dimethylhydroxylamine hydrochloride (3.72 g), HATU (28.9 g), and DIPEA (19.67 g) to an eggplant-shaped bottle in sequence, and stir at room temperature for 4 h. The reaction solution was concentrated and purified by silica gel column chromatography (PE/EA) to obtain compound 28-3 (12 g). MS (ESI+, [M+H] + ) m/z: 359.21.

步骤D：向茄型瓶中依次加入28-3(10g)，四氢呋喃(10mL)，N2保护后置于冰浴下搅拌5min后，加入甲基溴化镁的乙醚溶液(3mol/L,13mL)，继续冰浴反应1h。向反应液加入水(150mL)后用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩干，所得粗品经硅胶柱层析纯化(洗脱剂：PE/EA)，得到化合物28-4(7.2g)。MS(ESI+,[M+H]+)m/z:314.14。Step D: Add 28-3 (10 g) and tetrahydrofuran (10 mL) to an eggplant-shaped bottle in sequence, and stir under N2 protection in an ice bath for 5 min, then add methylmagnesium bromide in ether (3 mol/L, 13 mL), and continue to react in an ice bath for 1 h. Add water (150 mL) to the reaction solution and extract with ethyl acetate, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is purified by silica gel column chromatography (eluent: PE/EA) to obtain compound 28-4 (7.2 g). MS (ESI+, [M+H] + ) m/z: 314.14.

步骤E：向两颈瓶中依次加入乙酸乙酯(1.23g)，四氢呋喃(30mL)，N2保护后置于-78℃低温槽中搅拌10min后加入LDA(2M的四氢呋喃溶液，7mL)，继续搅拌10min后加入28-4(3g)的四氢呋喃(30mL)溶液。15min后将反应液移至室温继续搅拌反应。30min后向反应液加入水(150mL)，用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩干，得到化合物28-5(2.7g)。MS(ESI+,[M+H]+)m/z:402.30。Step E: Ethyl acetate (1.23 g) and tetrahydrofuran (30 mL) were added to a two-necked flask in sequence. After N2 protection, the mixture was placed in a -78°C low temperature tank and stirred for 10 min. LDA (2M tetrahydrofuran solution, 7 mL) was added. After stirring for 10 min, a tetrahydrofuran (30 mL) solution of 28-4 (3 g) was added. After 15 min, the reaction solution was moved to room temperature and the reaction was continued to be stirred. After 30 min, water (150 mL) was added to the reaction solution, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 28-5 (2.7 g). MS (ESI+, [M+H] + ) m/z: 402.30.

步骤F：向茄型瓶中依次加入28-5(50mg)，乙醇(20mL)，钯碳(10％wt，50mg)，氢气置换后，升温至80℃反应1h。反应液抽滤后旋干，得到化合物28-6(45mg)。MS(ESI+,[M+H]+)m/z:162.11。Step F: Add 28-5 (50 mg), ethanol (20 mL), palladium carbon (10% wt, 50 mg) to an eggplant-shaped bottle in sequence, replace with hydrogen, and heat to 80°C for 1 h. Filter the reaction solution and spin dry to obtain compound 28-6 (45 mg). MS (ESI+, [M+H] + ) m/z: 162.11.

步骤G：向茄型瓶中依次加入28-6(45mg)，水(2mL)和浓氨水(2mL)，室温搅拌反应1h。反应液直接旋干，得到化合物28-7(30mg)。MS(ESI+,[M+H]+)m/z:116.07。Step G: Add 28-6 (45 mg), water (2 mL) and concentrated aqueous ammonia (2 mL) to an eggplant-shaped bottle in sequence, and stir at room temperature for 1 h. The reaction solution was directly spin-dried to obtain compound 28-7 (30 mg). MS (ESI+, [M+H] + ) m/z: 116.07.

步骤H：参照实施例1的合成，在步骤B中，以28-7替代4-羟基-2-吡咯烷酮，得到化合物28(40mg)。Step H: Referring to the synthesis of Example 1, in step B, 28-7 was used instead of 4-hydroxy-2-pyrrolidone to obtain compound 28 (40 mg).

1H NMR(500MHz,DMSO-d6)δ8.10-8.03(m,2H),7.95-7.89(m,1H),7.81(d,J＝8.3Hz,1H),7.79-7.70(m,2H),7.53(t,J＝7.9Hz,1H),7.19-7.11(m,3H),5.27(s,1H),3.96(d,J＝10.0Hz,1H),3.77(d,J＝10.0Hz,1H),2.74(d,J＝16.7Hz,1H),2.48(d,J＝16.1Hz,1H),1.42(s,3H).MS(ESI+,[M+H]+)m/z:402.13。 1 H NMR (500MHz, DMSO-d 6 )δ8.10-8.03(m,2H),7.95-7.89(m,1H),7.81(d,J＝8.3Hz,1H),7.79-7.70(m,2H),7.53(t,J＝7.9Hz ,1H),7.19-7.11(m,3H),5.27( s,1H),3.96(d,J＝10.0Hz,1H),3.77(d,J＝10.0Hz,1H),2.74(d,J＝16.7Hz,1H),2.48(d,J＝16.1Hz, 1H),1.42(s,3H).MS(ESI+,[M+H] + )m/z:402.13.

步骤I：将化合物28(170mg)进行高压制备液相分离(REFLECT I-Amylose A色谱柱；乙醇：正己烷＝22:78)，先出峰的为化合物28_A(40mg)，后出峰的为化合物28_B(60mg)。Step I: Compound 28 (170 mg) was subjected to high pressure preparative liquid separation (REFLECT I-Amylose A column; ethanol:n-hexane=22:78). The first eluting peak was compound 28_A (40 mg), and the later peak was compound 28_B (60 mg).

化合物28_A：1H NMR(500MHz,DMSO-d6)δ8.12-8.05(m,2H),7.92(d,J＝9.0Hz,1H),7.81(d,J＝8.3Hz,1H),7.75-7.69(m,2H),7.53(t,J＝7.9Hz,1H),7.19-7.10(m,3H),5.28(s,1H),3.96(d,J＝10.0Hz,1H),3.77(d,J＝10.0Hz,1H),2.74(d,J＝16.7Hz,1H),2.50-2.44(m,1H),1.42(s,3H).MS(ESI+,[M+H]+)m/z:402.13。 Compound 28_A: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.12-8.05 (m, 2H), 7.92 (d, J=9.0 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.75-7.69 (m, 2H), 7.53 (t, J=7.9 Hz, 1H), 7.19-7.10 (m, 3H), 5.28 (s, 1H), 3.96 (d, J=10.0 Hz, 1H), 3.77 (d, J=10.0 Hz, 1H), 2.74 (d, J=16.7 Hz, 1H), 2.50-2.44 (m, 1H), 1.42 (s, 3H). MS (ESI+, [M+H] + ) m/z: 402.13.

化合物28_B：1H NMR(500MHz,DMSO-d6)δ8.10-8.05(m,2H),7.94-7.89(m,1H),7.81(d,J＝8.3Hz,1H),7.77-7.70(m,2H),7.57-7.51(m,1H),7.18-7.11(m,3H),5.27(s,1H),3.96(d,J＝10.0Hz,1H),3.77(d,J＝10.1Hz,1H),2.74(d,J＝16.6Hz,1H),2.50-2.44(m,1H),1.42(s,3H).MS(ESI+,[M+H]+)m/z:402.13。Compound 28_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.10-8.05 (m, 2H), 7.94-7.89 (m, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.77-7.70 (m, 2H), 7.57-7.51 (m, 1H), 7.18-7.11 (m, 3H), 5.27 (s, 1H), 3.96 (d, J=10.0 Hz, 1H), 3.77 (d, J=10.1 Hz, 1H), 2.74 (d, J=16.6 Hz, 1H), 2.50-2.44 (m, 1H), 1.42 (s, 3H). MS (ESI+, [M+H] + ) m/z: 402.13.

实施例29(29_A和29_B)
Example 29 (29_A and 29_B)

步骤A：参照实施例1的合成，在步骤B中，以5-羟甲基-1,3-噁唑烷-2-酮替代4-羟基-2-吡咯烷酮，得到化合物29(220mg)，HRMS(ESI+,[M+H]+)m/z：404.1113。Step A: Referring to the synthesis of Example 1, in step B, 4-hydroxy-2-pyrrolidone was replaced with 5-hydroxymethyl-1,3-oxazolidin-2-one to obtain compound 29 (220 mg), HRMS (ESI+, [M+H] + ) m/z: 404.1113.

步骤B：化合物29(220mg)经高压制备液相分离(REFLECT I-Amylose A色谱柱；乙醇：正己烷＝40:60)，先出峰的为化合物29_A(46mg)，后出峰的为化合物29_B(96mg)。Step B: Compound 29 (220 mg) was separated by high pressure preparative liquid separation (REFLECT I-Amylose A column; ethanol:n-hexane=40:60). The first eluting peak was compound 29_A (46 mg), and the later eluting peak was compound 29_B (96 mg).

化合物29_A：1H NMR(500MHz,DMSO-d6)δ8.05(dd,J＝9.2,2.2Hz,1H),7.99(d,J＝2.3Hz,1H),7.95(d,J＝9.3Hz,1H),7.81(d,J＝8.3Hz,1H),7.76-7.69(m,2H),7.61-7.51(m,1H),7.18-7.08(m,3H),5.27-5.17(m,1H),4.74-4.79(m,1H),4.22(t,J＝8.9Hz,1H),4.12-3.95(m,1H),3.70-3.74(m,1H),3.58-3.63(m,1H).MS(ESI+,[M+H]+)m/z：404.11。Compound 29_A: 1 H NMR (500 MHz, DMSO-d 6 )δ8.05(dd,J＝9.2,2.2Hz,1H),7.99(d,J＝2.3Hz,1H),7.95(d,J＝9.3Hz,1H),7.81(d,J＝8.3Hz,1H),7.76-7.69(m,2H),7.61-7.51(m,1H),7.18-7 .08(m,3H),5.27-5.17(m,1H),4.74-4.79(m,1H),4.22(t,J＝8.9Hz,1H), 4.12-3.95(m,1H),3.70-3.74(m,1H),3.58-3.63(m,1H).MS(ESI+,[M+H] + )m/z: 404.11.

化合物29_B：1H NMR(500MHz,DMSO-d6)δ8.05(dd,J＝9.2,2.2Hz,1H),7.99(d,J＝2.3Hz,1H),7.95(d,J＝9.3Hz,1H),7.81(d,J＝8.3Hz,1H),7.76-7.69(m,2H),7.61-7.51(m,1H),7.18-7.08(m,3H),5.27-5.17(m,1H),4.74-4.79(m,1H),4.22(t,J＝8.9Hz,1H),4.12-3.95(m,1H),3.70-3.74(m,1H),3.58-3.63(m,1H).MS(ESI+,[M+H]+)m/z：404.11。Compound 29_B: 1 H NMR (500 MHz, DMSO-d 6 )δ8.05(dd,J＝9.2,2.2Hz,1H),7.99(d,J＝2.3Hz,1H),7.95(d,J＝9.3Hz,1H),7.81(d,J＝8.3Hz,1H),7.76-7.69(m,2H),7.61-7.51(m,1H),7.18-7 .08(m,3H),5.27-5.17(m,1H),4.74-4.79(m,1H),4.22(t,J＝8.9Hz,1H), 4.12-3.95(m,1H),3.70-3.74(m,1H),3.58-3.63(m,1H).MS(ESI+,[M+H] + )m/z: 404.11.

实施例30
Embodiment 30

步骤A：向茄型瓶中依次加入DMF(15mL)，7-溴-4-氯-2-甲基喹唑啉(500mg)，4-三氟甲基苯酚(472mg)和碳酸铯(1.90g)，升温至80℃反应3h。反应液中加水(150mL)后用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩干，所得粗品经硅胶柱层析纯化(PE/EA)，得到化合物30-2(650mg)。MS(ESI+,[M+H]+)m/z:383.09。Step A: DMF (15 mL), 7-bromo-4-chloro-2-methylquinazoline (500 mg), 4-trifluoromethylphenol (472 mg) and cesium carbonate (1.90 g) were added to an eggplant-shaped bottle in sequence, and the temperature was raised to 80°C for reaction for 3 h. Water (150 mL) was added to the reaction solution and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE/EA) to obtain compound 30-2 (650 mg). MS (ESI+, [M+H] + ) m/z: 383.09.

步骤B：向单口瓶中依次加入30-2(200mg)，4-羟甲基-2-吡咯烷酮(72mg)，Pd2(dba)3(10mg)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(18mg)，碳酸铯(510mg)，1,4-二氧六环(20mL)，氮气保护下加热至110℃反应4h。降温至室温，用EA(30mL)稀释，加入30mL水，分出有机相，水相用EA萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，所得粗品经硅胶柱层析纯化，得到化合物30(110mg)。Step B: 30-2 (200 mg), 4-hydroxymethyl-2-pyrrolidone (72 mg), Pd 2 (dba) 3 (10 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (18 mg), cesium carbonate (510 mg), 1,4-dioxane (20 mL) were added to a single-mouth bottle in sequence, and heated to 110°C for 4 h under nitrogen protection. The mixture was cooled to room temperature, diluted with EA (30 mL), 30 mL of water was added, the organic phase was separated, the aqueous phase was extracted with EA, 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 to obtain compound 30 (110 mg).

1H NMR(500MHz,DMSO-d6)δ8.35-8.23(m,2H),7.99(d,J＝2.1Hz,1H),7.88(d,J＝8.5Hz,2H),7.61(d,J＝8.4Hz,2H),4.91(t,J＝5.3Hz,1H),4.12-4.05(m,1H),3.81-3.76(m,1H),3.56-3.44(m,2H),2.77-2.70(m,1H),2.66-2.55(m,1H),2.49(s,3H),2.47-2.38(m,1H).MS(ESI+,[M+H]+)m/z:418.26。 1 H NMR (500MHz, DMSO-d 6 )δ8.35-8.23(m,2H),7.99(d,J＝2.1Hz,1H),7.88(d,J＝8.5Hz,2H),7.61(d,J＝8.4Hz,2H),4.91( t,J＝5.3Hz,1H),4.12-4.05 (m,1H),3.81-3.76(m,1H),3.56-3.44(m,2H),2.77-2.70(m,1H),2.66-2.55(m,1H),2.49(s,3H),2.47 -2.38(m,1H).MS(ESI + ,[M+H] + )m/z:418.26.

实施例31
Embodiment 31

步骤A：参考实施例30的步骤A，以7-溴-4-氯-喹啉替换7-溴-4-氯-2-甲基喹唑啉，得到化合物31-2(670mg)。MS(ESI+,[M+H]+)m/z:368.03。Step A: Referring to step A of Example 30, 7-bromo-4-chloro-quinoline was used to replace 7-bromo-4-chloro-2-methylquinazoline to obtain compound 31-2 (670 mg). MS (ESI+, [M+H] + ) m/z: 368.03.

步骤B：参考实施例30步骤B的过程，用化合物31-2替换化合物30-2，制备得到化合物31(70mg)。Step B: Referring to the process of step B of Example 30, compound 31-2 was used to replace compound 30-2 to prepare compound 31 (70 mg).

1H NMR(500MHz,DMSO-d6)δ8.74(d,J＝5.1Hz,1H),8.27-8.20(m,2H),8.14(s,1H),7.88(d,J＝8.6Hz,2H),7.48(d,J＝8.4Hz,2H),6.77(d,J＝5.1Hz,1H),4.91(t,J＝5.3Hz,1H),4.12-4.05(m,1H),3.84-3.75(m,1H),3.56-3.45(m,2H),2.75-2.67(m,1H),2.67-2.55(m,1H),2.44-2.37(m,1H).MS(ESI+,[M+H]+)m/z:403.27。 1 H NMR (500MHz, DMSO-d 6 )δ8.74(d,J＝5.1Hz,1H),8.27-8.20(m,2H),8.14(s,1H),7.88(d,J＝8.6Hz,2H),7.48(d,J＝8.4 Hz,2H),6.77(d,J=5.1Hz,1H),4.91(t,J ＝5.3Hz,1H),4.12-4.05(m,1H),3.84-3.75(m,1H),3.56-3.45(m,2H),2.75-2.67(m,1H),2.67-2.55(m,1H) ),2.44-2.37(m,1H).MS(ESI + ,[M+H] + )m/z:403.27.

实施例32
Embodiment 32

步骤A：向茄型瓶中依次加入32-1(5g)，乙基磷酰基乙酸二甲酯(15.07g)，冰浴下搅拌10min后加入KOH(53g)的水(63mL)溶液，30min后将反应液移至室温搅拌过夜。反应液用DCM萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，得化合物32-2(7.2g)，直接用于下一步反应。Step A: Add 32-1 (5 g) and dimethyl ethylphosphoryl acetate (15.07 g) to an eggplant-shaped bottle in sequence, stir under ice bath for 10 min, then add KOH (53 g) in water (63 mL), after 30 min, move the reaction solution to room temperature and stir overnight. The reaction solution was extracted with DCM, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 32-2 (7.2 g), which was directly used in the next step.

步骤B：向茄型瓶中依次加入32-2(1g)，四氢呋喃(25mL)，置于-10℃低温槽中搅拌10min后依次加入硝基甲烷(0.46g)和TBAF(1M的四氢呋喃液，7.5mL)，继续低温反应4h。反应液加水100mL，用EA萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，得化合物32-3(1.07g)。GC-MS(EI,M+)m/z:261.Step B: Add 32-2 (1 g) and tetrahydrofuran (25 mL) to an eggplant-shaped bottle, place in a -10°C low temperature tank and stir for 10 min, then add nitromethane (0.46 g) and TBAF (1M tetrahydrofuran solution, 7.5 mL), and continue to react at low temperature for 4 h. Add 100 mL of water to the reaction solution, extract with EA, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 32-3 (1.07 g). GC-MS (EI, M + ) m/z: 261.

步骤C：向茄型瓶中依次加入32-3(1.07g)，甲醇(50mL)，Pd(OH)2(0.58g)，和甲酸铵(1.29g)，氢气氛围下升温至80℃回流反应过夜。反应液降至室温，抽滤后滤液加水100mL，用EA萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，得化合物32-4(750mg)，直接用于下一步反应。Step C: 32-3 (1.07 g), methanol (50 mL), Pd(OH) 2 (0.58 g), and ammonium formate (1.29 g) were added to an eggplant-shaped bottle in sequence, and the temperature was raised to 80°C under a hydrogen atmosphere for reflux reaction overnight. The reaction solution was cooled to room temperature, filtered, and 100 mL of water was added to the filtrate, extracted with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 32-4 (750 mg), which was directly used in the next step.

步骤D：参照实施例30的步骤B，以化合物1-2替换30-2，化合物32-4替换4-羟甲基-2-吡咯烷酮，得到化合物32-5(80mg)。MS(ESI+,[M+H]+)m/z:472.25。Step D: Referring to step B of Example 30, compound 1-2 was substituted for 30-2, and compound 32-4 was substituted for 4-hydroxymethyl-2-pyrrolidone to obtain compound 32-5 (80 mg). MS (ESI + , [M+H] + ) m/z: 472.25.

步骤E：向茄型瓶中依次加入32-5(80mg)，4M的盐酸二氧六环溶液(4mL)，室温搅拌反应2h。反应液直接浓缩后所得粗品经高压制备液相分离(Ultimate Polar RP8色谱柱，水：乙腈＝20:80)，得到化合物32(40mg)。Step E: Add 32-5 (80 mg) and 4M dioxane hydrochloride solution (4 mL) to an eggplant-shaped bottle, and stir at room temperature for 2 h. The reaction solution was directly concentrated and the resulting crude product was separated by high-pressure preparative liquid separation (Ultimate Polar RP8 column, water: acetonitrile = 20:80) to obtain compound 32 (40 mg).

1H NMR(500MHz,DMSO-d6)δ8.14-8.07(m,2H),7.91(d,J＝8.9Hz,1H),7.85-7.79(m,1H),7.73(d,J＝8.7Hz,2H),7.53(t,J＝8.0Hz,1H),7.18-7.11(m,3H),4.95-4.90(m,1H),4.69-4.61(m,1H),4.03-3.88(m,2H),3.57-3.49(m,1H),3.47-3.35(m,2H),2.68-2.52(m,3H).MS(ESI+,[M+H]+)m/z:432.26。 1 H NMR (500MHz, DMSO-d 6 )δ8.14-8.07(m,2H),7.91(d,J＝8.9Hz,1H),7.85-7.79(m,1H),7.73(d,J＝8.7Hz,2H),7.53(t,J ＝8.0Hz,1H),7.18-7.11(m,3 H),4.95-4.90(m,1H),4.69-4.61(m,1H),4.03-3.88(m,2H),3.57-3.49(m,1H),3.47-3.35(m,2H),2.68- 2.52(m,3H).MS(ESI + ,[M+H] + )m/z:432.26.

实施例33
Embodiment 33

步骤A：氮气保护，冰浴，向单口瓶中加入对三氟甲基苯酚(399mg)，THF(10mL)，叔丁醇钾(323mg)，搅拌10min，加入33-1(500mg)，0℃反应3h。加入EA(10Ml)用0.1M盐酸调pH至中性，然后分出有机相，水相用EA萃取，合并有机相，饱和碳酸氢钠溶液洗涤，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，所得粗品经硅胶柱层析(PE/EA)纯化，得到化合物33-2(0.6g)。MS(ESI+,[M+H]+)m/z:369.10。Step A: Under nitrogen protection and ice bath, add p-trifluoromethylphenol (399 mg), THF (10 mL), potassium tert-butoxide (323 mg) to a single-mouth bottle, stir for 10 min, add 33-1 (500 mg), and react at 0°C for 3 h. Add EA (10 mL) and adjust the pH to neutral with 0.1 M hydrochloric acid, then separate the organic phase, extract the aqueous phase with EA, combine the organic phases, wash with saturated sodium bicarbonate solution, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the crude product by silica gel column chromatography (PE/EA) to obtain compound 33-2 (0.6 g). MS (ESI+, [M+H] + ) m/z: 369.10.

步骤B：参考实施例30步骤B反应过程，以化合物33-2替换化合物30-2，得到化合物33(130mg)。Step B: Referring to the reaction process of step B in Example 30, compound 33-2 was used to replace compound 30-2 to obtain compound 33 (130 mg).

1H NMR(500MHz,DMSO-d6)δ8.70(s,1H),8.41-8.32(m,2H),8.09(d,J＝2.1Hz,1H),7.93-7.87(m,2H),7.66-7.60(m,2H),4.92(t,J＝5.3Hz,1H),4.15-4.06(m,1H),3.88-3.76(m,1H),3.56-3.45(m,2H),2.79-2.70(m,1H),2.67-2.56(m,1H),2.49-2.38(m,1H).MS(ESI+,[M+H]+)m/z:404.23. 1 H NMR (500MHz, DMSO-d 6 )δ8.70(s,1H),8.41-8.32(m,2H),8.09(d,J＝2.1Hz,1H),7.93-7.87(m,2H),7.66-7.60(m,2H),4.92 (t,J＝5.3Hz,1H),4.15- 4.06(m,1H),3.88-3.76(m,1H),3.56-3.45(m,2H),2.79-2.70(m,1H),2.67-2.56(m,1H),2.49-2.38(m,1H ).MS(ESI+,[M+H] + )m/z:404.23.

实施例34(34_A和34_B)
Example 34 (34_A and 34_B)

步骤A：向两口瓶中，依次加入34-1(5.0g)，THF(50mL)，H2O(50mL)和碳酸钠(7.06g)，N2保护下，将混合物室温搅拌0.5h；然后降至0℃，往其中滴加氯甲酸苄酯(6.82g)的THF(20mL)溶液，加毕，将混合物室温搅拌过夜；反应结束后，将反应液倒至100mL水中，减压浓缩除去THF，EA萃取，弃去有机相，将水相置于冰浴下，用2M盐酸调pH至1～2，过滤，滤饼用水洗涤。减压干燥，得到中间体34-2(6.5g)。MS(ESI+,[M+Na]+)m/z:289.04.Step A: Add 34-1 (5.0 g), THF (50 mL), H 2 O (50 mL) and sodium carbonate (7.06 g) to a two-necked bottle in sequence. Stir the mixture at room temperature for 0.5 h under N 2 protection. Then cool to 0°C and add a solution of benzyl chloroformate (6.82 g) in THF (20 mL) dropwise. After the addition, stir the mixture at room temperature overnight. After the reaction is completed, pour the reaction solution into 100 mL of water, concentrate under reduced pressure to remove THF, extract with EA, discard the organic phase, place the aqueous phase under an ice bath, adjust the pH to 1-2 with 2M hydrochloric acid, filter, and wash the filter cake with water. Dry under reduced pressure to obtain intermediate 34-2 (6.5 g). MS (ESI+, [M+Na] + )m/z: 289.04.

步骤B：向两口瓶中，依次加入34-2(6.5g)，DMF(100mL)和碳酸氢钠(4.1g)，N2保护下，将混合物降至0℃，往其中滴加碘甲烷(8.66g)，加毕，将混合物室温搅拌过夜；反应结束后，将反应液倒至100mL冰水中，EA萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，抽滤后减压浓缩除去溶剂，所得粗品加入混合溶剂(PE/EA)打浆，得到中间体34-3(4.0g)。MS(ESI+,[M+Na]+)m/z:303.05.Step B: Add 34-2 (6.5 g), DMF (100 mL) and sodium bicarbonate (4.1 g) to a two-necked bottle in sequence. Under N2 protection, cool the mixture to 0°C, add iodomethane (8.66 g) dropwise, and stir the mixture overnight at room temperature. After the reaction is completed, pour the reaction solution into 100 mL of ice water, extract with EA, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to remove the solvent. Add the obtained crude product to a mixed solvent (PE/EA) and beat to obtain intermediate 34-3 (4.0 g). MS (ESI+, [M+Na] + ) m/z: 303.05.

步骤C：向单口瓶中，依次加入34-3(4.0g)，THF(200mL)和1,8-二氮杂二环[5.4.0]十一碳-7-烯(4.34g)，将混合物降至0℃，往其中加入碘苯二乙酸(9.2g)，加毕，将混合物0℃搅拌20分钟；反应结束后，将反应液倒至100mL冰水中，EA萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，抽滤后减压浓缩除去溶剂，所得粗品经经硅胶柱层析纯化(MeOH/DCM)，得到中间体34-4(1.58g)。MS(ESI+,[M+H]+)m/z:278.95.Step C: Add 34-3 (4.0 g), THF (200 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.34 g) to a single-mouth bottle, cool the mixture to 0°C, add iodophenyldiacetic acid (9.2 g), stir the mixture at 0°C for 20 minutes; after the reaction, pour the reaction solution into 100 mL of ice water, extract with EA, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to remove the solvent, and the obtained crude product is purified by silica gel column chromatography (MeOH/DCM) to obtain intermediate 34-4 (1.58 g). MS (ESI+, [M+H] + ) m/z: 278.95.

步骤D：向单口瓶中依次加入1-2(400mg)，34-4(455mg)，Pd(OAc)2(36mg)，2-二环己基膦-2',4',6'-三异丙基联苯(104mg)，碳酸铯(1.0g)和1,4-二氧六环(50mL)，N2保护下加热至110℃回流反应1h。反应结束后，加入100mL水，EA萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，抽滤后减压浓缩除去溶 剂，所得粗品经硅胶柱层析纯化(PE/EA)，得到中间体34-5(501mg)。MS(ESI+,[M+H]+)m/z:565.31.Step D: 1-2 (400 mg), 34-4 (455 mg), Pd(OAc) 2 (36 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (104 mg), cesium carbonate (1.0 g) and 1,4-dioxane (50 mL) were added to a single-mouth bottle in sequence, and heated to 110°C for reflux reaction for 1 h under N 2 protection. After the reaction was completed, 100 mL of water was added, EA was extracted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (PE/EA) to obtain intermediate 34-5 (501 mg). MS (ESI+, [M+H] + ) m/z: 565.31.

步骤E：向单口瓶中依次加入34-5(500mg)，MeOH(20mL)，THF(10mL)和Pd/C(10％wt，95mg)，加毕，H2置换5次后，在H2氛围下，将混合物室温搅拌过夜；反应结束后，直接抽滤，滤液减压浓缩干，得到中间体34-6(368mg)。MS(ESI-,[M-H]-)m/z:429.36.Step E: Add 34-5 (500 mg), MeOH (20 mL), THF (10 mL) and Pd/C (10% wt, 95 mg) to a single-mouth bottle in sequence. After the addition, replace with H 2 5 times, and stir the mixture at room temperature overnight under H 2 atmosphere. After the reaction is completed, filter directly, and concentrate the filtrate under reduced pressure to dryness to obtain intermediate 34-6 (368 mg). MS (ESI-, [MH] - ) m/z: 429.36.

步骤F：向两口瓶中，依次加入34-6(170mg)和DMF(5mL)，N2保护下，将混合物降至0℃，往其中分批加入氢化钠(60％wt纯度，55mg)，10分钟后，往其中滴加碘甲烷(84mg)，加毕，将混合物0℃搅拌1h；反应结束后，将反应液倒至100mL冰的饱和氯化铵溶液中，EA萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，抽滤后减压浓缩除去溶剂，得到中间体34-7(176mg)。MS(ESI-,[M-H]-)m/z:443.21.Step F: Add 34-6 (170 mg) and DMF (5 mL) to a two-necked bottle in sequence. Under N2 protection, cool the mixture to 0°C, add sodium hydride (60% wt purity, 55 mg) in batches, and add iodomethane (84 mg) dropwise after 10 minutes. After the addition, stir the mixture at 0°C for 1 hour. After the reaction is completed, pour the reaction solution into 100 mL of ice saturated ammonium chloride solution, extract with EA, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent to obtain intermediate 34-7 (176 mg). MS (ESI-, [MH] - ) m/z: 443.21.

步骤G：参考实施例21的步骤B，以化合物34-7替换化合物21-1，得到化合物34(150mg)。MS(ESI+,[M+H]+)m/z:417.24.Step G: Referring to step B of Example 21, compound 34-7 was used to replace compound 21-1 to obtain compound 34 (150 mg). MS (ESI+, [M+H] + ) m/z: 417.24.

步骤H：化合物34(150mg)经过高压制备液相分离(REFLECT I-Amylose A色谱柱；乙醇：正己烷＝30:70)，先出峰的为化合物34_A(58mg)，后出峰的为化合物34_B(68mg)。Step H: Compound 34 (150 mg) was subjected to high pressure preparative liquid separation (REFLECT I-Amylose A column; ethanol:n-hexane=30:70). The first eluting peak was compound 34_A (58 mg), and the later eluting peak was compound 34_B (68 mg).

化合物34_A：1H NMR(500MHz,DMSO-d6)δ8.22-8.20(m,1H),7.86-7.81(m,2H),7.74-7.71(m,3H),7.48(t,J＝7.8Hz,1H),7.13(d,J＝8.7Hz,2H),7.05(d,J＝7.4Hz,1H),5.00(t,J＝5.5Hz,1H),4.05-3.97(m,1H),3.74-3.65(m,3H),3.58-3.54(m,1H),2.82(s,3H).MS(ESI+,[M+H]+)m/z:417.27。Compound 34_A: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.22-8.20 (m, 1H), 7.86-7.81 (m, 2H), 7.74-7.71 (m, 3H), 7.48 (t, J=7.8 Hz, 1H), 7.13 (d, J=8.7 Hz, 2H), 7.05 (d, J=7.4 Hz, 1H), 5.00 (t, J=5.5 Hz, 1H), 4.05-3.97 (m, 1H), 3.74-3.65 (m, 3H), 3.58-3.54 (m, 1H), 2.82 (s, 3H). MS (ESI+, [M+H] + ) m/z: 417.27.

化合物34_B：1H NMR(500MHz,DMSO-d6)δ8.22-8.19(m,1H),7.86-7.81(m,2H),7.74-7.71(m,3H),7.48(t,J＝7.8Hz,1H),7.13(d,J＝8.6Hz,2H),7.05(d,J＝7.5Hz,1H),4.99(t,J＝5.5Hz,1H),4.04-3.97(m,1H),3.74-3.65(m,3H),3.58-3.54(m,1H),2.82(s,3H).MS(ESI+,[M+H]+)m/z:417.31。Compound 34_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.22-8.19 (m, 1H), 7.86-7.81 (m, 2H), 7.74-7.71 (m, 3H), 7.48 (t, J=7.8 Hz, 1H), 7.13 (d, J=8.6 Hz, 2H), 7.05 (d, J=7.5 Hz, 1H), 4.99 (t, J=5.5 Hz, 1H), 4.04-3.97 (m, 1H), 3.74-3.65 (m, 3H), 3.58-3.54 (m, 1H), 2.82 (s, 3H). MS (ESI+, [M+H] + ) m/z: 417.31.

实施例35(35_A和35_B)
Example 35 (35_A and 35_B)

步骤A：参考实施例21的步骤B，以化合物34-6替换化合物21-1，得到化合物35(130mg)。MS(ESI+,[M+H]+)m/z:403.26.Step A: Referring to step B of Example 21, compound 34-6 was used to replace compound 21-1 to obtain compound 35 (130 mg). MS (ESI+, [M+H] + ) m/z: 403.26.

步骤B：化合物35(130mg)经过高压制备液相分离(REFLECT I-Amylose A色谱柱；乙醇：正己烷＝30:70)，先出峰的为化合物35_A(60mg)，后出峰的为化合物35_B(62mg)。Step B: Compound 35 (130 mg) was subjected to high pressure preparative liquid separation (REFLECT I-Amylose A column; ethanol: n-hexane = 30:70). The first eluting peak was compound 35_A (60 mg), and the later eluting peak was compound 35_B (62 mg).

化合物35_A：1H NMR(500MHz,DMSO-d6)δ8.19-8.17(m,1H),7.85-7.82(m,2H),7.75-7.71(m,3H),7.48(t,J＝7.9Hz,1H),7.24(s,1H),7.13(d,J＝8.5Hz,2H),7.05(d,J＝7.5Hz,1H),4.99(t,J＝5.5Hz,1H),4.05-4.01(m,1H),3.78-3.73(m,2H),3.49-3.40(m,2H).MS(ESI+,[M+H]+)m/z:403.30。Compound 35_A: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.19-8.17 (m, 1H), 7.85-7.82 (m, 2H), 7.75-7.71 (m, 3H), 7.48 (t, J=7.9 Hz, 1H), 7.24 (s, 1H), 7.13 (d, J=8.5 Hz, 2H), 7.05 (d, J=7.5 Hz, 1H), 4.99 (t, J=5.5 Hz, 1H), 4.05-4.01 (m, 1H), 3.78-3.73 (m, 2H), 3.49-3.40 (m, 2H). MS (ESI+, [M+H] + ) m/z: 403.30.

化合物35_B：1H NMR(500MHz,DMSO-d6)δ8.19-8.17(m,1H),7.85-7.81(m,2H),7.75-7.71(m,3H),7.48(t,J＝7.8Hz,1H),7.24(s,1H),7.13(d,J＝8.7Hz,2H),7.06-7.05(m,1H),4.98(t,J＝5.5Hz,1H),4.05-4.01(m,1H),3.79-3.73(m,2H),3.49-3.40(m,2H).MS(ESI+,[M+H]+)m/z:403.26。Compound 35_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.19-8.17 (m, 1H), 7.85-7.81 (m, 2H), 7.75-7.71 (m, 3H), 7.48 (t, J=7.8 Hz, 1H), 7.24 (s, 1H), 7.13 (d, J=8.7 Hz, 2H), 7.06-7.05 (m, 1H), 4.98 (t, J=5.5 Hz, 1H), 4.05-4.01 (m, 1H), 3.79-3.73 (m, 2H), 3.49-3.40 (m, 2H). MS (ESI+, [M+H] + ) m/z: 403.26.

实施例36
Embodiment 36

步骤A：向单口瓶中，依次加入34-4(600mg)，THF(20mL)，三乙胺(655mg)，二碳酸二叔丁酯(710mg)和4-二甲氨基吡啶(26mg)，N2保护下，将混合物室温搅拌5h；反应结束后，将反应液倒至100mL水中，EA萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，抽滤后减压浓缩除去溶剂，所得粗品经经硅胶柱层析纯化(MeOH/DCM)，得到中间体36-1(770mg)。MS(ESI+,[M+Na]+)m/z:401.27.Step A: Add 34-4 (600 mg), THF (20 mL), triethylamine (655 mg), di-tert-butyl dicarbonate (710 mg) and 4-dimethylaminopyridine (26 mg) to a single-mouth bottle in sequence, and stir the mixture at room temperature for 5 h under N2 protection; after the reaction, pour the reaction solution into 100 mL of water, extract with EA, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to remove the solvent, and the obtained crude product is purified by silica gel column chromatography (MeOH/DCM) to obtain intermediate 36-1 (770 mg). MS (ESI+, [M+Na] + ) m/z: 401.27.

步骤B：向单口瓶中依次加入36-1(770mg)，MeOH(20mL)和Pd/C(10％wt纯度，217mg)，加毕，H2置换5次后，在H2氛围下，将混合物室温搅拌过夜；反应结束后，直接抽滤，滤液减压浓缩干，得到中间体36-2(510mg)。MS(ESI+,[M+H]+)m/z:245.05.Step B: 36-1 (770 mg), MeOH (20 mL) and Pd/C (10% wt purity, 217 mg) were added to a single-mouth bottle in sequence. After the addition was completed, H 2 was replaced 5 times, and the mixture was stirred at room temperature overnight under H 2 atmosphere; after the reaction was completed, it was directly filtered and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate 36-2 (510 mg). MS (ESI+, [M+H] + ) m/z: 245.05.

步骤C：参照实施例34的步骤D，以化合物36-2替换化合物34-4，得到中间体36-3(234mg)。MS(ESI+,[M+Na]+)m/z:553.30.Step C: Referring to step D of Example 34, compound 36-2 was used to replace compound 34-4 to obtain intermediate 36-3 (234 mg). MS (ESI+, [M+Na] + ) m/z: 553.30.

步骤D：向单口瓶中，依次加入36-3(234mg)和4M的氯化氢-二氧六环溶液(5mL)，室温下搅拌反应0.5h；反应结束后，冰浴下将反应液缓慢滴加至饱和碳酸氢钠溶液(100mL)中，EA萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥，抽滤后减压浓缩除去溶剂，所得粗品经硅胶柱层析纯化，得到中间体36-4(184mg)。MS(ESI+,[M+H]+)m/z:431.00.Step D: Add 36-3 (234 mg) and 4M hydrogen chloride-dioxane solution (5 mL) to a single-mouth bottle, and stir the reaction at room temperature for 0.5 h. After the reaction, slowly add the reaction solution dropwise to a saturated sodium bicarbonate solution (100 mL) under an ice bath, extract with EA, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to remove the solvent. The crude product is purified by silica gel column chromatography to obtain intermediate 36-4 (184 mg). MS (ESI+, [M+H] + ) m/z: 431.00.

步骤E：参考实施例21的步骤B，以化合物36-4替换化合物21-1，得到化合物36(67mg)。Step E: Referring to step B of Example 21, compound 36-4 was used to replace compound 21-1 to obtain compound 36 (67 mg).

1H NMR(500MHz,DMSO-d6)δ8.00(d,J＝2.0Hz,1H),7.95-7.93(m,1H),7.85(d,J＝9.2Hz,1H),7.74-7.72(m,3H),7.49(t,J＝7.9Hz,1H),7.14(d,J＝8.6Hz,2H),7.08(d,J＝7.5Hz,1H),7.00(s,1H),4.96(t,J＝5.6Hz,1H),4.59-4.54(m,1H),3.57-3.49(m,3H),3.38-3.35(m,1H).MS(ESI+,[M+H]+)m/z:403.25。 1 H NMR (500MHz, DMSO-d 6 )δ8.00(d,J＝2.0Hz,1H),7.95-7.93(m,1H),7.85(d,J＝9.2Hz,1H),7.74-7.72(m,3H),7.49(t,J ＝7.9Hz,1H),7.14(d,J＝8.6Hz,2H), 7.08(d,J＝7.5Hz,1H),7.00(s,1H),4.96(t,J＝5.6Hz,1H),4.59-4.54(m,1H),3.57-3.49(m,3H),3.38 -3.35(m,1H).MS(ESI+,[M+H] + )m/z:403.25.

实施例37
Embodiment 37

步骤A：参考实施例34的步骤F，以中间体36-4替换中间体34-6，得到中间体37-1(76mg)。MS(ESI+,[M+H]+)m/z:445.28.Step A: Referring to step F of Example 34, intermediate 36-4 was used to replace intermediate 34-6 to obtain intermediate 37-1 (76 mg). MS (ESI+, [M+H] + ) m/z: 445.28.

步骤B：参考实施例21的步骤B，以中间体37-1替换中间体21-1，得到化合物37(60mg)。Step B: Referring to step B of Example 21, intermediate 37-1 was used to replace intermediate 21-1 to obtain compound 37 (60 mg).

1H NMR(500MHz,DMSO-d6)δ7.99(d,J＝1.7Hz,1H),7.95-7.93(m,1H),7.85(d,J＝9.2Hz,1H),7.74-7.72(m,3H),7.51-7.48(m,1H),7.14(d,J＝8.6Hz,2H),7.09(d,J＝7.5Hz,1H),4.97(t,J＝5.5Hz,1H),4.53-4.49(m,1H),3.60-3.48(m,3H),3.43-3.40(m,1H),2.79(s,3H).MS(ESI+,[M+H]+)m/z:417.26。 1 H NMR (500MHz, DMSO-d 6 )δ7.99(d,J＝1.7Hz,1H),7.95-7.93(m,1H),7.85(d,J＝9.2Hz,1H),7.74-7.72(m,3H),7.51-7.48(m ,1H),7.14(d,J=8.6Hz,2H),7 .09(d,J＝7.5Hz,1H),4.97(t,J＝5.5Hz,1H),4.53-4.49(m,1H),3.60-3.48(m,3H),3.43-3.40(m,1H ),2.79(s,3H).MS(ESI+,[M+H] + )m/z:417.26.

实施例38
Embodiment 38

步骤A:向两口瓶中加入38-1(1g)，THF(20mL)。N2保护下于-78℃缓慢滴加1M六甲基二硅基胺基锂(17.5mL)，-20℃搅拌反应1小时。-78℃下缓慢滴加苄基氯甲基醚(1.15mL)，-20℃搅拌反应2小时。反应结束后加入20mL饱和氯化铵水溶液，用二氯甲烷萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩干，所得粗品经硅胶柱层析纯化(DCM/MeOH)，得到化合物38-2(1.2g)。MS(ESI+,[M+H]+)m/z:264.12。Step A: Add 38-1 (1 g) and THF (20 mL) to a two-necked bottle. Under N2 protection, slowly add 1M lithium hexamethyldisilazide (17.5 mL) at -78°C, and stir at -20°C for 1 hour. Slowly add benzyl chloromethyl ether (1.15 mL) at -78°C, and stir at -20°C for 2 hours. After the reaction, add 20 mL of saturated aqueous ammonium chloride solution, extract with dichloromethane, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is purified by silica gel column chromatography (DCM/MeOH) to obtain compound 38-2 (1.2 g). MS (ESI+, [M+H] + ) m/z: 264.12.

步骤B:参照实施例1的合成，在步骤B中，以38-2替代4-羟基-2-吡咯烷酮，得到化合物38-3(220mg)。MS(ESI+,[M+H]+)m/z:550.18。Step B: Referring to the synthesis of Example 1, in step B, 38-2 was used to replace 4-hydroxy-2-pyrrolidone to obtain compound 38-3 (220 mg). MS (ESI+, [M+H] + ) m/z: 550.18.

步骤C:向圆底烧瓶中依次加入38-3(220mg)，10％ Pd/C(42.6mg)，MeOH(20mL)。H2条件下室温搅拌反应16小时。反应结束后抽滤，滤液减压浓缩干，得到38-4(120mg)。MS(ESI+,[M+H]+)m/z:460.18。Step C: 38-3 (220 mg), 10% Pd/C (42.6 mg), and MeOH (20 mL) were added to a round-bottom flask in sequence. The mixture was stirred at room temperature under H2 for 16 hours. After the reaction was completed, the filtrate was filtered and concentrated to dryness under reduced pressure to obtain 38-4 (120 mg). MS (ESI+, [M+H] + ) m/z: 460.18.

步骤D:向圆底烧瓶中依次加入38-4(120mg)，硼氢化锂(8.53mg)，THF(20mL)。室温条件下搅拌16小时。反应结束后加入20mL水，用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩干，所得粗品经硅胶柱层析纯化，得到化合物38(83mg)。Step D: 38-4 (120 mg), lithium borohydride (8.53 mg), and THF (20 mL) were added to a round-bottom flask in sequence. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, 20 mL of water was added, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 38 (83 mg).

1H NMR(500MHz,DMSO-d6)δ7.95(d,J＝8.9Hz,1H),7.89(d,J＝1.9Hz,1H),7.83(d,J＝8.3Hz,1H),7.79-7.67(m,2H),7.58(t,J＝7.9Hz,1H),7.41(m,1H),7.26(m,1H),7.17(s,2H),5.05(t,J＝5.0Hz,2H),3.31-3.24(m,4H),2.42(m,2H),2.17(m,2H).MS(ESI+,[M+H]+)m/z:432.14。 1 H NMR (500MHz, DMSO-d 6 )δ7.95(d,J＝8.9Hz,1H),7.89(d,J＝1.9Hz,1H),7.83(d,J＝8.3Hz,1H),7.79-7.67(m,2H),7.58( t,J＝7.9Hz,1H),7.41 (m,1H),7.26(m,1H),7.17(s,2H),5.05(t,J＝5.0Hz,2H),3.31-3.24(m,4H),2.42(m,2H),2.17( m,2H).MS(ESI+,[M+H] + )m/z:432.14.

实施例39(39_A和39_B)
Example 39 (39_A and 39_B)

步骤A：向微波管中依次加入1-1(0.29g)，4-氟苯基五氟化硫(0.29g)，碳酸铯(1.27g)和DMF(10mL)，微波加热至120℃反应2h。反应结束后加入100mL水，用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩干，所得粗品经硅胶柱层析纯化(PE/EA)，得到化合物39-1(0.51g)。MS(ESI-,[M-H]-)m/z:423.00.Step A: 1-1 (0.29 g), 4-fluorophenyl sulfur pentafluoride (0.29 g), cesium carbonate (1.27 g) and DMF (10 mL) were added to a microwave tube in sequence, and microwave heating was performed at 120°C for 2 h. After the reaction was completed, 100 mL of water was added, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE/EA) to obtain compound 39-1 (0.51 g). MS (ESI-, [MH] - ) m/z: 423.00.

步骤B：参考实施例38步骤B，以化合物39-1替换1-2，以4-羟甲基-2-吡咯烷酮替换38-2，得到化合物39(238mg)。MS(ESI+,[M+H]+)m/z:460.21。Step B: Referring to step B of Example 38, compound 39-1 was used to replace 1-2, and 4-hydroxymethyl-2-pyrrolidone was used to replace 38-2 to obtain compound 39 (238 mg). MS (ESI+, [M+H] + ) m/z: 460.21.

步骤C：化合物39(238mg)经过高压制备液相分离(REFLECT I-Amylose A色谱柱；乙醇：正己烷＝30:70)，先出峰的为化合物39_A(97mg)，后出峰的为化合物39_B(104mg)。 Step C: Compound 39 (238 mg) was separated by high pressure preparative liquid separation (REFLECT I-Amylose A column; ethanol:n-hexane=30:70). The first eluting peak was compound 39_A (97 mg), and the last eluting peak was compound 39_B (104 mg).

化合物39_A：1H NMR(500MHz,DMSO-d6)δ8.11-8.08(m,2H),7.90-7.88(m,3H),7.84(d,J＝8.3Hz,1H),7.56-7.53(m,1H),7.19(d,J＝7.5Hz,1H),7.11(d,J＝9.0Hz,2H),4.90(t,J＝5.3Hz,1H),4.05-4.01(m,1H),3.78-3.75(m,1H),3.53-3.44(m,2H),2.69-2.61(m,1H),2.60-2.54(m,1H),2.39-2.34(m,1H).MS(ESI+,[M+H]+)m/z:460.10。Compound 39_A: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.11-8.08 (m, 2H), 7.90-7.88 (m, 3H), 7.84 (d, J=8.3 Hz, 1H), 7.56-7.53 (m, 1H), 7.19 (d, J=7.5 Hz, 1H), 7.11 (d, J=9.0 Hz, 2H), 4.90 (t, J=5.3 Hz, 1H), 4.05-4.01 (m, 1H), 3.78-3.75 (m, 1H), 3.53-3.44 (m, 2H), 2.69-2.61 (m, 1H), 2.60-2.54 (m, 1H), 2.39-2.34 (m, 1H). MS (ESI+, [M+H] + )m/z:460.10.

化合物39_B：1H NMR(500MHz,DMSO-d6)δ8.12-8.08(m,2H),7.91-7.88(m,3H),7.84(d,J＝8.3Hz,1H),7.56-7.53(m,1H),7.20(d,J＝7.5Hz,1H),7.11(d,J＝9.1Hz,2H),4.90(t,J＝5.3Hz,1H),4.05-4.01(m,1H),3.78-3.75(m,1H),3.53-3.44(m,2H),2.69-2.61(m,1H),2.60-2.55(m,1H),2.39-2.35(m,1H).MS(ESI+,[M+H]+)m/z:460.21。Compound 39_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.12-8.08 (m, 2H), 7.91-7.88 (m, 3H), 7.84 (d, J=8.3 Hz, 1H), 7.56-7.53 (m, 1H), 7.20 (d, J=7.5 Hz, 1H), 7.11 (d, J=9.1 Hz, 2H), 4.90 (t, J=5.3 Hz, 1H), 4.05-4.01 (m, 1H), 3.78-3.75 (m, 1H), 3.53-3.44 (m, 2H), 2.69-2.61 (m, 1H), 2.60-2.55 (m, 1H), 2.39-2.35 (m, 1H). MS (ESI+, [M+H] + )m/z:460.21.

实施例40
Embodiment 40

步骤A：向反应瓶中依次加入苄基缩水甘油醚(2.50g)，二氯甲烷(35mL)，苄胺(1.47g)，双三氟甲烷磺酰亚胺锂(0.44g)，室温反应过夜。反应液减压浓缩干，所得粗品经硅胶柱层析纯化(DCM/MeOH)，得到化合物40-1(1.70g)。MS(ESI+,[M+H]+)m/z:272.31.Step A: Add benzyl glycidyl ether (2.50 g), dichloromethane (35 mL), benzylamine (1.47 g), and lithium bis(trifluoromethanesulfonyl)imide (0.44 g) to the reaction flask in sequence and react at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM/MeOH) to obtain compound 40-1 (1.70 g). MS (ESI+, [M+H] + ) m/z: 272.31.

步骤B：向反应瓶中依次加入40-1(3.00g)，二氯甲烷(30mL)，三乙胺(3.36g)，甲基磺酸酐(5.78g)，室温反应20分钟。向反应液加入饱和碳酸氢钠水溶液(30mL)淬灭，所得混合物用乙酸乙酯萃取，合并有机层，经硅胶柱层析纯化(PE/EA)，得到化合物40-2(2.90g)。HRMS(ESI+,[M+H]+)m/z:428.1210.Step B: Add 40-1 (3.00 g), dichloromethane (30 mL), triethylamine (3.36 g), and methanesulfonic anhydride (5.78 g) to the reaction bottle in sequence and react at room temperature for 20 minutes. Add saturated sodium bicarbonate aqueous solution (30 mL) to the reaction solution to quench, extract the resulting mixture with ethyl acetate, combine the organic layers, and purify by silica gel column chromatography (PE/EA) to obtain compound 40-2 (2.90 g). HRMS (ESI+, [M+H] + ) m/z: 428.1210.

步骤C：向反应瓶中依次加入40-2(2.70g)，四氢呋喃(78mL)，N2保护后于-78℃条件下搅拌10min后加入正丁基锂(1.6M的四氢呋喃溶液，9.87mL)，加完后将反应液移至室温反应16小时。向反应液加入饱和氯化铵水溶液(100mL)淬灭，所得混合物用乙酸乙酯萃取，合并有机层，经硅胶柱层析纯化(PE/EA)，得到化合物40-3(0.35g)。MS(ESI+,[M+H]+)m/z:332.25.Step C: Add 40-2 (2.70 g) and tetrahydrofuran (78 mL) to the reaction bottle in sequence. After N2 protection, stir at -78°C for 10 min and then add n-butyl lithium (1.6 M tetrahydrofuran solution, 9.87 mL). After the addition, move the reaction solution to room temperature and react for 16 hours. Add saturated aqueous ammonium chloride solution (100 mL) to the reaction solution to quench, extract the resulting mixture with ethyl acetate, combine the organic layers, and purify by silica gel column chromatography (PE/EA) to obtain compound 40-3 (0.35 g). MS (ESI+, [M+H] + ) m/z: 332.25.

步骤D：向反应瓶中依次加入40-3(0.22g)，乙醇(2mL)，钯碳(1.41g)，氢气置换三次后，加热至80℃反应17小时。反应液抽滤，滤液减压浓缩干，得到化合物40-4(0.16g)。HRMS(ESI+,[M+H]+)m/z:242.0852.Step D: Add 40-3 (0.22 g), ethanol (2 mL), palladium carbon (1.41 g) to the reaction bottle in sequence, replace the hydrogen three times, and heat to 80 ° C for 17 hours. The reaction solution was filtered and the filtrate was concentrated to dryness under reduced pressure to obtain compound 40-4 (0.16 g). HRMS (ESI+, [M+H] + ) m/z: 242.0852.

步骤E：向反应瓶中依次加入40-4(0.16g)，乙醇(2mL)，钯碳(1.41g)，氢气置换三次后，加热至80℃反应6.5小时，转移至室温反应16小时。反应液抽滤，滤液减压浓缩干，得到化合物40-5(0.10g)。HRMS(ESI+,[M+H]+)m/z:152.0365.Step E: Add 40-4 (0.16 g), ethanol (2 mL), palladium carbon (1.41 g) to the reaction bottle in sequence, replace the hydrogen three times, heat to 80 ° C for 6.5 hours, transfer to room temperature for 16 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain compound 40-5 (0.10 g). HRMS (ESI+, [M+H] + ) m/z: 152.0365.

步骤F：向反应瓶中依次加入1-2(0.25g)，40-5(0.10g)，碳酸铯(0.67g)，氯化烯丙基钯(II)二聚物(12.3mg)，2-二-叔丁膦基-2',4',6'-三异丙基联苯(28.9mg)，1,4-二氧六环(2mL)，氮气置换三次后，加热至110℃反应2.5小时。反应液抽滤，滤液减压浓缩干，经硅胶柱层析纯化后再经过高压制备液相分离(Xtimate C18色谱柱)得到实施例40(50mg)。Step F: 1-2 (0.25 g), 40-5 (0.10 g), cesium carbonate (0.67 g), allylpalladium chloride (II) dimer (12.3 mg), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (28.9 mg), 1,4-dioxane (2 mL) were added to the reaction bottle in sequence, and the mixture was replaced with nitrogen three times, and then heated to 110°C for 2.5 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure, purified by silica gel column chromatography, and then separated by high pressure preparative liquid phase separation (Xtimate C18 column) to obtain Example 40 (50 mg).

1H NMR(500MHz,DMSO-d6)δ7.95(d,J＝9.2Hz,1H),7.80(d,J＝8.3Hz,1H),7.73(d,J＝8.5Hz,2H),7.68(d,J＝2.3Hz,1H),7.59(dd,J＝9.2,2.4Hz,1H),7.54(t,J＝7.9Hz,1H),7.13(t,J＝8.8Hz,3H),5.14(s,1H),3.90(dd,J＝9.2,6.9Hz,1H),3.76-3.68(m,2H),3.63(d,J＝6.1Hz,2H),3.40(dd,J＝13.0,9.1Hz,1H),2.94-2.86(m,1H).HRMS(ESI+,[M+H]+)m/z:438.0989. 1 H NMR (500 MHz, DMSO-d 6 )δ7.95(d,J＝9.2Hz,1H),7.80(d,J＝8.3Hz,1H),7.73(d,J＝8.5Hz,2H),7.68(d, J＝2.3Hz,1H),7.59(dd,J＝9.2,2.4Hz,1H),7.54(t,J＝7.9Hz,1H),7.13(t,J＝8.8 Hz,3H),5.14(s,1H),3.90(dd,J＝9.2,6.9Hz,1H),3.76-3.68(m,2H),3.63(d,J ＝6.1Hz,2H),3.40(dd,J＝13.0,9.1Hz,1H),2.94-2.86(m,1H).HRMS(ESI+,[M+H] + )m/z:438.0989.

实施例41
Embodiment 41

步骤A：向单口瓶中，依次加入34-6(250mg)，MeOH(2mL)，THF(2mL)，H2O(1mL)和氢氧化钠(89mg)，加毕，将混合物室温搅拌2h；反应结束后，将反应液倒至20mL水中，用2M盐酸调pH至1～2，EA萃取，饱和氯化钠洗涤有机相，无水硫酸钠干燥，抽滤后减压浓缩除去溶剂，得到中间体41-1(242mg)。MS(ESI-,[M-H]-)m/z：415.20.Step A: Add 34-6 (250 mg), MeOH (2 mL), THF (2 mL), H 2 O (1 mL) and sodium hydroxide (89 mg) to a single-mouth bottle in sequence. After the addition, stir the mixture at room temperature for 2 h. After the reaction is completed, pour the reaction solution into 20 mL of water, adjust the pH to 1-2 with 2M hydrochloric acid, extract with EA, wash the organic phase with saturated sodium chloride, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure to remove the solvent to obtain intermediate 41-1 (242 mg). MS (ESI-, [MH] - ) m/z: 415.20.

步骤B：向单口瓶中，依次加入41-1(227mg)，DCM(10mL)，N,O-二甲基羟胺盐酸盐(150mg)，HATU(311mg)和DIPEA(423mg)，加毕，将混合物室温搅拌1h；反应结束后，将反应液倒至20mL水中，EA萃取，经硅胶柱层析纯化(MeOH/DCM)，得到化合物41-2(146mg)。MS(ESI+,[M+H]+)m/z：460.18.Step B: Add 41-1 (227 mg), DCM (10 mL), N,O-dimethylhydroxylamine hydrochloride (150 mg), HATU (311 mg) and DIPEA (423 mg) to a single-mouth bottle in sequence. After the addition, stir the mixture at room temperature for 1 h. After the reaction, pour the reaction solution into 20 mL of water, extract with EA, and purify by silica gel column chromatography (MeOH/DCM) to obtain compound 41-2 (146 mg). MS (ESI+, [M+H] + ) m/z: 460.18.

步骤C：向单口瓶中，依次加入41-2(126mg)和THF(5mL)，N2保护下，将混合物降至0℃，往其中滴加3M的甲基溴化镁溶液(0.27mL)，加毕，室温下搅拌反应过夜；反应结束后，冰浴下将反应液缓慢加至饱和碳酸氢钠溶液(20mL)中，EA萃取，经硅胶柱层析纯化(MeOH/DCM)，得到中间体41-3(88mg)。MS(ESI-,[M-H]-)m/z：413.23.Step C: Add 41-2 (126 mg) and THF (5 mL) to a single-mouth bottle in sequence. Under N2 protection, cool the mixture to 0°C, add 3M methylmagnesium bromide solution (0.27 mL) dropwise, and stir at room temperature overnight. After the reaction is completed, slowly add the reaction solution to saturated sodium bicarbonate solution (20 mL) under ice bath, extract with EA, and purify by silica gel column chromatography (MeOH/DCM) to obtain intermediate 41-3 (88 mg). MS (ESI-, [MH] - ) m/z: 413.23.

步骤D：向单口瓶中，依次加入41-3(80mg)和MeOH(3mL)，N2保护下，降至0℃，然后分批加入硼氢化钠(80mg)，加毕，继续搅拌1h；反应结束后，将反应液缓慢倒入至冰的饱和氯化铵溶液(20mL)中，EA萃取，经硅胶柱层析纯化，得到实施例41(74mg)。Step D: To a single-necked bottle, 41-3 (80 mg) and MeOH (3 mL) were added in sequence. Under N2 protection, the temperature was lowered to 0°C, and then sodium borohydride (80 mg) was added in batches. After the addition was completed, stirring was continued for 1 h. After the reaction was completed, the reaction solution was slowly poured into an ice-cold saturated ammonium chloride solution (20 mL), extracted with EA, and purified by silica gel column chromatography to obtain Example 41 (74 mg).

实施例41：1H NMR(500MHz,DMSO-d6)δ8.21-8.19(m,1H),7.85-7.82(m,2H),7.73-7.71(m,3H),7.49-7.46(m,1H),7.35-7.27(m,1H),7.14-7.12(m,2H),7.06-7.04(m,1H),4.95-4.88(m,1H),4.04-3.98(m,1H),3.85-3.72(m,1H),3.65-3.60(m,1H),3.56-3.51(m,1H),1.12-1.09(m,3H).MS(ESI+,[M+H]+)m/z：417.24。Example 41: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.21-8.19 (m, 1H), 7.85-7.82 (m, 2H), 7.73-7.71 (m, 3H), 7.49-7.46 (m, 1H), 7.35-7.27 (m, 1H), 7.14-7.12 (m, 2H), 7.06-7.04 (m, 1H), 4.95-4.88 (m, 1H), 4.04-3.98 (m, 1H), 3.85-3.72 (m, 1H), 3.65-3.60 (m, 1H), 3.56-3.51 (m, 1H), 1.12-1.09 (m, 3H). MS (ESI+, [M+H] + ) m/z: 417.24.

实施例42(42_A和42_B)
Example 42 (42_A and 42_B)

步骤A：向反应瓶中依次加入29(500mg)，乙腈(20mL)，2,2,6,6-四甲基哌啶氧化物(291mg)，碘苯二乙酸(1.20g)，室温反应5.5小时。向反应液加入水(50mL)，所得混合物用乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩干，得到化合物42-1(517mg)。MS(ESI-,[M+H]-)m/z:416.19。Step A: Add 29 (500 mg), acetonitrile (20 mL), 2,2,6,6-tetramethylpiperidinoxide (291 mg), and iodophenyldiacetic acid (1.20 g) to the reaction bottle in sequence and react at room temperature for 5.5 hours. Add water (50 mL) to the reaction solution, extract the resulting mixture with ethyl acetate, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 42-1 (517 mg). MS (ESI-, [M+H] - ) m/z: 416.19.

步骤B：向反应瓶中依次加入42-1(517mg)，二甲羟胺盐酸盐(338mg)，HATU(707mg)，N,N-二异丙基乙胺(961mg)，室温反应21.5小时。向反应液加入水(50mL)，所得混合物用乙酸乙酯萃取，合并有机层，经硅胶柱层析纯化(PE/EA)，得到化合物42-2(280mg)。HRMS(ESI+,[M+Na]+)m/z:483.1139。Step B: 42-1 (517 mg), dimethylhydroxylamine hydrochloride (338 mg), HATU (707 mg), N, N-diisopropylethylamine (961 mg) were added to the reaction bottle in sequence and reacted at room temperature for 21.5 hours. Water (50 mL) was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined and purified by silica gel column chromatography (PE/EA) to obtain compound 42-2 (280 mg). HRMS (ESI+, [M+Na] + ) m/z: 483.1139.

步骤C：向反应瓶中依次加入42-2(270mg)，四氢呋喃(20mL)，冰浴下滴加甲基溴化镁(3M的四氢呋喃溶液，0.98mL)，转移至室温反应3.5小时。向反应液加入饱和氯化铵水溶液(50mL)，所得混合物用乙酸乙酯萃取，合并有机层，经硅胶柱层析纯化(PE/EA)，得到化合物42-3(170mg)。MS(ESI-,[M+H]-) m/z:414.20。Step C: Add 42-2 (270 mg) and tetrahydrofuran (20 mL) to the reaction bottle in sequence, add methylmagnesium bromide (3M tetrahydrofuran solution, 0.98 mL) dropwise under ice bath, and transfer to room temperature for reaction for 3.5 hours. Add saturated aqueous ammonium chloride solution (50 mL) to the reaction solution, extract the resulting mixture with ethyl acetate, combine the organic layers, and purify by silica gel column chromatography (PE/EA) to obtain compound 42-3 (170 mg). MS (ESI-, [M+H] - ) m/z:414.20.

步骤D：向反应瓶中依次加入42-3(160mg)，甲醇(1mL)，冰浴下加入硼氢化钠(146mg)，转移至室温反应2.5小时。向反应液加入饱和氯化铵水溶液(20mL)，所得混合物用乙酸乙酯萃取，合并有机层，经硅胶柱层析纯化，得到化合物42(150mg)。MS(ESI+,[M+H]+)m/z:418.21。Step D: 42-3 (160 mg) and methanol (1 mL) were added to the reaction bottle in sequence, sodium borohydride (146 mg) was added under ice bath, and the mixture was transferred to room temperature for reaction for 2.5 hours. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate, the organic layers were combined, and purified by silica gel column chromatography to obtain compound 42 (150 mg). MS (ESI+, [M+H] + ) m/z: 418.21.

步骤E：化合物42(150mg)经高压制备液相分离(CHIRALART cellulose-SB色谱柱；二氧化碳：乙醇＝82:18)，先出峰的为实施例42_A(35mg)，后出峰的为实施例42_B(35mg)。Step E: Compound 42 (150 mg) was separated by high pressure preparative liquid separation (CHIRALART cellulose-SB column; carbon dioxide:ethanol=82:18). The first peak was Example 42_A (35 mg), and the last peak was Example 42_B (35 mg).

实施例42_A：1H NMR(500MHz,DMSO-d6)δ8.08(dd,J＝9.2,2.3Hz,1H),8.01(d,J＝2.3Hz,1H),7.95(d,J＝9.2Hz,1H),7.81(d,J＝8.3Hz,1H),7.75-7.71(m,2H),7.54(t,J＝7.9Hz,1H),7.16-7.12(m,3H),5.26(d,J＝5.1Hz,1H),4.55(ddd,J＝9.0,6.2,4.3Hz,1H),4.18(t,J＝9.0Hz,1H),4.07(dd,J＝9.0,6.3Hz,1H),3.85-3.77(m,1H),1.13(d,J＝6.4Hz,3H).HRMS(ESI+,[M+H]+)m/z：418.1269.Example 42_A: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.08 (dd, J=9.2, 2.3 Hz, 1H), 8.01 (d, J=2.3 Hz, 1H), 7.95 (d, J=9.2 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.75-7.71 (m, 2H), 7.54 (t, J=7.9 Hz, 1H), 7.16-7.12 (m, 3H), 5.2 6(d,J＝5.1Hz,1H),4.55(ddd,J＝9.0,6.2,4.3Hz,1H),4.18(t,J＝9.0Hz,1H),4.07( dd,J＝9.0,6.3Hz,1H),3.85-3.77(m,1H),1.13(d,J＝6.4Hz,3H).HRMS(ESI+,[M+H] + )m/z：418.1269.

实施例42_B：1H NMR(500MHz,DMSO-d6)δ8.06(dd,J＝9.2,2.3Hz,1H),8.00(d,J＝2.2Hz,1H),7.95(d,J＝9.2Hz,1H),7.81(d,J＝8.3Hz,1H),7.75-7.71(m,2H),7.54(t,J＝7.9Hz,1H),7.17-7.11(m,3H),5.17(d,J＝5.4Hz,1H),4.58(ddd,J＝9.0,6.4,3.8Hz,1H),4.19(t,J＝9.0Hz,1H),3.99(dd,J＝8.9,6.4Hz,1H),3.84-3.77(m,1H),1.17(d,J＝6.4Hz,3H).HRMS(ESI+,[M+H]+)m/z：418.1269。Example 42_B: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.06 (dd, J = 9.2, 2.3 Hz, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.75-7.71 (m, 2H), 7.54 (t, J = 7.9 Hz, 1H), 7.17-7.11 (m, 3H), 5.1 7(d,J＝5.4Hz,1H),4.58(ddd,J＝9.0,6.4,3.8Hz,1H),4.19(t,J＝9.0Hz,1H),3.99( dd,J＝8.9,6.4Hz,1H),3.84-3.77(m,1H),1.17(d,J＝6.4Hz,3H).HRMS(ESI+,[M+H] + )m/z: 418.1269.

实施例43
Embodiment 43

步骤A：向反应瓶中，依次加入43-1(3.52g)，MeOH(50mL)和碳酸钾(6.78g)，降至0℃，然后分批加入二碳酸二叔丁酯(6.41g)，加毕，室温下搅拌反应过夜。反应结束后，将反应液倒至100mL水中，EA萃取，经硅胶柱层析纯化(PE/EA)，得到中间体43-2(4.80g)。1H NMR(500MHz,DMSO-d6)δ3.65-3.60(m,2H),3.45-3.44(m,2H),2.42-2.36(m,2H),1.41(s,9H).Step A: Add 43-1 (3.52 g), MeOH (50 mL) and potassium carbonate (6.78 g) to the reaction bottle in sequence, cool to 0°C, then add di-tert-butyl dicarbonate (6.41 g) in batches, and stir at room temperature to react overnight. After the reaction is completed, pour the reaction solution into 100 mL of water, extract with EA, and purify by silica gel column chromatography (PE/EA) to obtain intermediate 43-2 (4.80 g). 1 H NMR (500 MHz, DMSO-d 6 )δ3.65-3.60 (m, 2H), 3.45-3.44 (m, 2H), 2.42-2.36 (m, 2H), 1.41 (s, 9H).

步骤B：向反应瓶中，依次加入43-2(3.80g)，EA(80mL)，H2O(80mL)和三氯化钌(0.23g)，降至0℃，然后分批加入高碘酸钠(15.7g)，加毕，室温下搅拌反应过夜。反应结束后，将反应液倒至100mL水中，EA萃取，经硅胶柱层析纯化(PE/EA)，得到中间体43-3(2.28g)。1H NMR(500MHz,DMSO-d6)δ4.10-4.04(m,2H),3.26-3.21(m,2H),1.46(s,9H).Step B: Add 43-2 (3.80 g), EA (80 mL), H 2 O (80 mL) and ruthenium trichloride (0.23 g) to the reaction bottle in sequence, cool to 0°C, then add sodium periodate (15.7 g) in batches, and stir at room temperature overnight. After the reaction is completed, pour the reaction solution into 100 mL of water, extract with EA, and purify by silica gel column chromatography (PE/EA) to obtain intermediate 43-3 (2.28 g). 1 H NMR (500 MHz, DMSO-d 6 )δ4.10-4.04 (m, 2H), 3.26-3.21 (m, 2H), 1.46 (s, 9H).

步骤C：向反应瓶中，依次加入43-3(330mg)和4M的氯化氢-二氧六环溶液(5mL)，室温下搅拌反应0.5h。反应结束后，将反应液直接浓缩干，得到中间体43-4(181mg)。1H NMR(500MHz,DMSO-d6)δ8.12(s,1H),3.69-3.63(m,2H),2.90-2.83(m,2H).Step C: Add 43-3 (330 mg) and 4M hydrogen chloride-dioxane solution (5 mL) to the reaction bottle, and stir the reaction at room temperature for 0.5 h. After the reaction, the reaction solution was directly concentrated to dryness to obtain intermediate 43-4 (181 mg). 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.12 (s, 1H), 3.69-3.63 (m, 2H), 2.90-2.83 (m, 2H).

步骤D：参照实施例1的合成，在步骤B中，以43-4替代4-羟基-2-吡咯烷酮，得到实施例43(56mg)。Step D: Referring to the synthesis of Example 1, in step B, 43-4 was used to replace 4-hydroxy-2-pyrrolidone to obtain Example 43 (56 mg).

1H NMR(500MHz,DMSO-d6)δ8.29-8.28(m,1H),8.06-8.01(m,2H),7.90-7.88(m,1H),7.75-7.73(m,2H),7.61-7.58(m,1H),7.23-7.22(m,1H),7.17-7.15(m,2H),4.11-4.08(m,2H),2.84-2.75(m,2H).MS(ESI-,[M-H]-)m/z：406.17. 1 H NMR (500MHz, DMSO-d 6 )δ8.29-8.28(m,1H),8.06-8.01(m,2H),7.90-7.88(m,1H),7.75-7.73(m,2H),7.61-7.58(m,1 H),7.23-7.22(m,1H),7.17-7.15(m,2H),4.11-4.08(m,2H),2.84-2.75(m,2H).MS(ESI-,[MH] - )m/z：406.17.

实施例44
Embodiment 44

步骤A：向反应瓶中依次加入35(300mg)，二氯甲烷(6mL)，冰浴下缓慢滴入二乙胺基三氟化硫(0.15mL)，反应1.5小时。向反应液加入水(10mL)，所得混合物用乙酸乙酯萃取，经硅胶柱层析纯化，得到实 施例44(120mg)。Step A: 35 (300 mg) and dichloromethane (6 mL) were added to the reaction flask in sequence, and diethylaminosulfur trifluoride (0.15 mL) was slowly added dropwise under ice bath, and the reaction was continued for 1.5 hours. Water (10 mL) was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate and purified by silica gel column chromatography to obtain the actual Example 44 (120 mg).

1H NMR(500MHz,DMSO-d6)δ8.17(dd,J＝9.3,2.2Hz,1H),7.89-7.82(m,2H),7.74(dd,J＝16.0,8.4Hz,3H),7.50(dd,J＝15.3,7.4Hz,2H),7.13(d,J＝8.4Hz,2H),7.06(d,J＝7.5Hz,1H),4.18-4.07(m,2H),3.81-3.69(m,3H).HRMS(ESI-,[M+H]-)m/z:403.1072. 1 H NMR (500MHz, DMSO-d 6 )δ8.17(dd,J＝9.3,2.2Hz,1H),7.89-7.82(m,2H),7.74(dd,J＝16.0,8.4Hz,3H),7.50(dd,J＝15.3,7.4Hz , 2H),7.13(d,J＝8.4Hz,2H),7.06(d,J＝7.5Hz,1H),4.18-4.07(m,2H),3.81-3.69(m,3H).HRMS(ESI-, [M+H] - )m/z:403.1072.

实施例45
Embodiment 45

步骤A：向微波管中依次加入化合物45-1(1.00g)，1-氟-4-三氟甲基-苯(3.68g)，碳酸铯(7.30g)和DMF(10mL)，加热至120℃反应2h。反应结束后加入水，用乙酸乙酯萃取，合并有机层，经硅胶柱层析纯化得到化合物45-2(1.45g)。Step A: Compound 45-1 (1.00 g), 1-fluoro-4-trifluoromethyl-benzene (3.68 g), cesium carbonate (7.30 g) and DMF (10 mL) were added to a microwave tube in sequence and heated to 120° C. for 2 h. After the reaction, water was added, extracted with ethyl acetate, the organic layers were combined, and purified by silica gel column chromatography to obtain compound 45-2 (1.45 g).

1H NMR(500MHz,DMSO-d6)δ8.35(d,J＝2.0Hz,1H),7.90(d,J＝9.0Hz,1H),7.85(d,J＝8.4Hz,1H),7.74(d,J＝8.7Hz,2H),7.68(dd,J＝9.0,2.0Hz,1H),7.63-7.60(m,1H),7.27(d,J＝7.6Hz,1H),7.17(d,J＝8.6Hz,2H). 1 H NMR (500MHz, DMSO-d 6 )δ8.35(d,J＝2.0Hz,1H),7.90(d,J＝9.0Hz,1H),7.85(d,J＝8.4Hz,1H),7.74(d,J＝8.7Hz,2H) , 7.68(dd,J＝9.0,2.0Hz,1H),7.63-7.60(m,1H),7.27(d,J＝7.6Hz,1H),7.17(d,J＝8.6Hz,2H).

步骤B：向反应瓶中依次加入化合物45-2(1.0g)，丙二酸二乙酯(0.62mL)，正丁基二(1-金刚烷基)膦(78.0mg)，氯化烯丙基钯(II)二聚物(40.0mg)，碳酸铯(1.78g)，1,4-二氧六环(20mL)，N2保护下加热至100℃反应8h。反应结束后加入水，用乙酸乙酯萃取，合并有机层，经硅胶柱层析纯化得到化合物45-3(370mg)。MS(ESI-,[M-H]-)m/z:445.19.Step B: Compound 45-2 (1.0 g), diethyl malonate (0.62 mL), n-butyl di(1-adamantyl) phosphine (78.0 mg), allyl palladium (II) chloride dimer (40.0 mg), cesium carbonate (1.78 g), 1,4-dioxane (20 mL) were added to the reaction bottle in sequence, and heated to 100 ° C for 8 h under N 2 protection. After the reaction, water was added, extracted with ethyl acetate, the organic layers were combined, and purified by silica gel column chromatography to obtain compound 45-3 (370 mg). MS (ESI-, [MH] - ) m/z: 445.19.

步骤C：向单口瓶中依次加入化合物45-3(170mg)，溴乙腈(91mg)，THF(1mL)，氮气保护，0℃下加入NaH(22.85mg，60％w/w)，然后加热至60℃反应1h。反应完毕用饱和氯化铵淬灭，用乙酸乙酯萃取，合并有机层，经硅胶柱层析纯化得到化合物45-4(130mg)。MS(ESI-,[M-H]-)m/z:484.22.Step C: Compound 45-3 (170 mg), bromoacetonitrile (91 mg), and THF (1 mL) were added to a single-mouth bottle in sequence, and NaH (22.85 mg, 60% w/w) was added at 0°C under nitrogen protection, and then heated to 60°C for 1 h. After the reaction was completed, saturated ammonium chloride was used to quench, and the mixture was extracted with ethyl acetate. The organic layers were combined and purified by silica gel column chromatography to obtain compound 45-4 (130 mg). MS (ESI-, [MH] - ) m/z: 484.22.

步骤D：向单口瓶中依次加入化合物45-4(130mg)，六水合氯化钴(127mg)，甲醇(2mL)，0℃下，分批加入硼氢化钠(101mg)，然后室温搅拌1h。反应完毕用饱和氯化铵淬灭，用乙酸乙酯萃取，合并有机层，经硅胶柱层析纯化得到化合物45-5(60mg)。MS(ESI-,[M-H]-)m/z:442.18.Step D: Compound 45-4 (130 mg), cobalt chloride hexahydrate (127 mg), and methanol (2 mL) were added to a single-mouth bottle in sequence. Sodium borohydride (101 mg) was added in batches at 0°C, and then stirred at room temperature for 1 h. After the reaction was completed, saturated ammonium chloride was used to quench the mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined and purified by silica gel column chromatography to obtain compound 45-5 (60 mg). MS (ESI-, [MH] - ) m/z: 442.18.

步骤E：向单口瓶中依次加入45-5(60mg)，无水氯化钙(15mg)，THF(2mL)，0℃下，分批加入硼氢化钠(11mg)，然后室温搅拌1h。反应完毕用饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，合并有机层，经硅胶柱层析纯化得到化合物45(40mg)。MS(ESI-,[M-H]-)m/z:400.23.Step E: Add 45-5 (60 mg), anhydrous calcium chloride (15 mg), and THF (2 mL) to a single-mouth bottle in sequence, add sodium borohydride (11 mg) in batches at 0°C, and then stir at room temperature for 1 hour. After the reaction is completed, quench with saturated aqueous ammonium chloride solution, extract with ethyl acetate, combine the organic layers, and purify by silica gel column chromatography to obtain compound 45 (40 mg). MS (ESI-, [MH] - ) m/z: 400.23.

1H NMR(500MHz,DMSO-d6)δ8.07(d,J＝1.9Hz,1H),7.87(d,J＝8.9Hz,1H),7.84(d,J＝8.3Hz,2H),7.72(d,J＝8.6Hz,2H),7.67(dd,J＝8.9,1.9Hz,1H),7.54(t,J＝7.9Hz,1H),7.21(dd,J＝7.6,1.0Hz,1H),7.12(d,J＝8.5Hz,2H),5.07(t,J＝5.3Hz,1H),3.87-3.79(m,1H),3.70-3.63(m,1H),3.29-3.23(m,1H),3.19- 3.10(m,1H),2.71-2.62(m,1H),2.48-2.38(m,1H). 1 H NMR (500MHz, DMSO-d 6 )δ8.07(d,J＝1.9Hz,1H),7.87(d,J＝8.9Hz,1H),7.84(d,J＝8.3Hz,2H),7.72(d,J＝8.6Hz,2H) ,7.67(dd,J＝8.9,1.9Hz,1H),7.54(t,J＝7.9Hz,1 H),7.21(dd,J＝7.6,1.0Hz,1H),7.12(d,J＝8.5Hz,2H),5.07(t,J＝5.3Hz,1H),3.87-3.79(m,1H), 3.70-3.63(m,1H),3.29-3.23(m,1H),3.19- 3.10(m,1H),2.71-2.62(m,1H),2.48-2.38(m,1H).

步骤F：将化合物45(30mg)经超临界流体色谱仪分离(CHIRALART Amylose-SA 5μm 20*100mm色谱柱；CO2-乙醇洗脱)，先出峰为45_A(10mg)，后出峰为45_B(10mg)。Step F: Compound 45 (30 mg) was separated by supercritical fluid chromatography (CHIRALART Amylose-SA 5 μm 20*100 mm column; CO 2 -ethanol elution), the first eluting peak was 45_A (10 mg), and the second eluting peak was 45_B (10 mg).

45_A:MS(ESI-,[M-H]-)m/z：400.26；1H NMR(500MHz,DMSO-d6)δ8.07(d,J＝1.8Hz,1H),7.90-7.81(m,3H),7.75-7.69(m,2H),7.67(dd,J＝8.9,1.9Hz,1H),7.54(dd,J＝8.3,7.5Hz,1H),7.21(dd,J＝7.5,1.0Hz,1H),7.16-7.09(m,2H),5.07(t,J＝5.3Hz,1H),3.84(dd,J＝10.5,5.6Hz,1H),3.67(dd,J＝10.4,5.1Hz,1H),3.30-3.24(m,1H),3.19-3.10(m,1H),2.71-2.62(m,1H),2.47-2.38(m,1H).45_A:MS(ESI - ,[MH] - )m/z: 400.26; 1 H NMR (500MHz, DMSO-d 6 )δ8.07(d,J＝1.8Hz,1H),7.90-7.81(m,3H),7.75-7.69(m,2H),7.67(dd,J＝8.9,1 .9Hz,1H),7.54(dd,J＝8.3,7.5Hz,1H),7.21(dd,J＝7.5,1.0Hz,1H),7.16-7.09(m, 2H),5.07(t,J＝5.3Hz,1H),3.84(dd,J＝10.5,5.6Hz,1H),3.67(dd,J＝10.4,5.1Hz ,1H),3.30-3.24(m,1H),3.19-3.10(m,1H),2.71-2.62(m,1H),2.47-2.38(m,1H).

45_B：MS(ESI-,[M-H]-)m/z：400.25；1H NMR(500MHz,DMSO-d6)δ8.07(d,J＝1.8Hz,1H),7.92-7.81(m,3H),7.74-7.70(m,2H),7.67(dd,J＝8.9,1.9Hz,1H),7.54(dd,J＝8.2,7.5Hz,1H),7.21(dd,J＝7.5,1.0Hz,1H),7.16-7.09(m,2H),5.07(t,J＝5.3Hz,1H),3.84(dd,J＝10.5,5.5Hz,1H),3.67(dd,J＝10.4,5.1Hz,1H),3.30-3.23(m,1H),3.19-3.10(m,1H),2.72-2.62(m,1H),2.47-2.37(m,1H).45_B: MS (ESI - ,[MH] - )m/z: 400.25; 1 H NMR (500MHz, DMSO-d 6 )δ8.07(d,J＝1.8Hz,1H),7.92-7.81(m,3H),7.74-7.70(m,2H),7.67(dd,J＝8.9,1 .9Hz,1H),7.54(dd,J＝8.2,7.5Hz,1H),7.21(dd,J＝7.5,1.0Hz,1H),7.16-7.09(m, 2H),5.07(t,J＝5.3Hz,1H),3.84(dd,J＝10.5,5.5Hz,1H),3.67(dd,J＝10.4,5.1Hz ,1H),3.30-3.23(m,1H),3.19-3.10(m,1H),2.72-2.62(m,1H),2.47-2.37(m,1H).

实施例46
Embodiment 46

向单口瓶中依次加入45-5(70mg)，乙醇(2mL)，氢氧化钠水溶液(2mL，1M)，氮气保护下加热至110℃反应1h，然后冷却至室温，加入盐酸(1mL,4M)，用乙酸乙酯萃取，合并有机层，经硅胶柱层析纯化，得到化合物46(27mg)。MS(ESI-,[M-H]-)m/z:370.17.45-5 (70 mg), ethanol (2 mL), and sodium hydroxide aqueous solution (2 mL, 1 M) were added to a single-mouth bottle in sequence, heated to 110 ° C under nitrogen protection for 1 h, then cooled to room temperature, hydrochloric acid (1 mL, 4 M) was added, extracted with ethyl acetate, the organic layers were combined, and purified by silica gel column chromatography to obtain compound 46 (27 mg). MS (ESI-, [MH] - ) m/z: 370.17.

1H NMR(500MHz,DMSO-d6)δ7.91-7.85(m,3H),7.83(d,J＝8.2Hz,1H),7.72(d,J＝8.5Hz,2H),7.55(t,J＝7.9Hz,1H),7.44(dd,J＝8.7,1.8Hz,1H),7.22(d,J＝7.5Hz,1H),7.12(d,J＝8.5Hz,2H),3.74(t,J＝9.1Hz,1H),3.45-3.33(m,2H),2.59-2.54(m,1H),2.26-2.15(m,1H). 1 H NMR (500MHz, DMSO-d 6 )δ7.91-7.85(m,3H),7.83(d,J＝8.2Hz,1H),7.72(d,J＝8.5Hz,2H),7.55(t,J＝7.9Hz,1H),7.44( dd,J＝8.7,1.8Hz,1H),7.2 2(d,J＝7.5Hz,1H),7.12(d,J＝8.5Hz,2H),3.74(t,J＝9.1Hz,1H),3.45-3.33(m,2H),2.59-2.54(m ,1H),2.26-2.15(m,1H).

试验例1：体外蛋白热稳定性Test Example 1: In vitro protein thermal stability

1.1 hTEAD11.1 hTEAD1

用磷酸盐缓冲液(PBS)将hTEAD1蛋白母液稀释至50ng/μl，同时用DMSO将5000×的蛋白染料(SYPRO Orange Dye)稀释至20×，在96孔板中加入16μl hTEAD1蛋白稀释液，然后用纳升加样仪将DMSO溶解的不同化合物加入孔中，使化合物终浓度为10μM和1μM，共2个浓度，同时设空白对照孔(不含蛋白)与阴性对照孔(含蛋白，加溶媒DMSO)，设置2个复孔，最后每孔加入4μl 20×SYPRO Orange Dye蛋白染料，离心混匀。Roche LightCycler480荧光定量PCR仪中，运行程序为20℃15s；30℃--90℃0.02℃/s；20℃15s。使用LightCycler Thermal Shift Analysis软件分析得到熔解温度(Tm)，计算熔解温度差ΔTm。The hTEAD1 protein stock solution was diluted to 50 ng/μl with phosphate buffered saline (PBS), and the 5000× protein dye (SYPRO Orange Dye) was diluted to 20× with DMSO. 16μl hTEAD1 protein diluent was added to the 96-well plate, and then different compounds dissolved in DMSO were added to the wells using a nanoliter pipette to make the final concentration of the compound 10μM and 1μM, a total of 2 concentrations. At the same time, blank control wells (without protein) and negative control wells (with protein, with solvent DMSO) were set up, and 2 duplicate wells were set up. Finally, 4μl 20× SYPRO Orange Dye protein dye was added to each well, and centrifuged to mix. In the Roche LightCycler480 fluorescence quantitative PCR instrument, the operating program was 20℃15s; 30℃--90℃0.02℃/s; 20℃15s. The melting temperature (Tm) was obtained by analysis using LightCycler Thermal Shift Analysis software, and the melting temperature difference ΔTm was calculated.

1.2 hTEAD21.2 hTEAD2

用磷酸盐缓冲液(PBS)将hTEAD2蛋白母液稀释至50ng/μl，同时用DMSO将5000×的蛋白染料(SYPRO Orange Dye)稀释至20×，在96孔板中加入16μl hTEAD2蛋白稀释液，然后用纳升加样仪将DMSO溶解的不同化合物加入孔中，使化合物终浓度为10μM和1μM，共2个浓度，同时设空白对照孔(不含蛋白)与阴性对照孔(含蛋白，加溶媒DMSO)，设置2个复孔，最后每孔加入4μl 20×SYPRO Orange Dye蛋白染料，离心混匀。Roche LightCycler480荧光定量PCR仪中，运行程序为20℃15s；30℃--90℃0.02℃/s；20℃15s。使用LightCycler Thermal Shift Analysis软件分析得到熔解温度(Tm)，计算熔解温度差ΔTm。The hTEAD2 protein stock solution was diluted to 50 ng/μl with phosphate buffered saline (PBS), and the 5000× protein dye (SYPRO Orange Dye) was diluted to 20× with DMSO. 16μl hTEAD2 protein diluent was added to the 96-well plate, and then different compounds dissolved in DMSO were added to the wells using a nanoliter pipette to make the final concentration of the compound 10μM and 1μM, a total of 2 concentrations. At the same time, blank control wells (without protein) and negative control wells (with protein, with solvent DMSO) were set up, and 2 duplicate wells were set up. Finally, 4μl 20× SYPRO Orange Dye protein dye was added to each well and centrifuged to mix. In the Roche LightCycler480 fluorescence quantitative PCR instrument, the operating program was 20℃15s; 30℃--90℃0.02℃/s; 20℃15s. The melting temperature (Tm) was obtained by analysis using LightCycler Thermal Shift Analysis software, and the melting temperature difference ΔTm was calculated.

1.3 hTEAD31.3 hTEAD3

用磷酸盐缓冲液(PBS)将hTEAD3蛋白母液稀释至50ng/μl，同时用DMSO将5000×的蛋白染料(SYPRO Orange Dye)稀释至20×，在96孔板中加入16μl hTEAD3蛋白稀释液，然后用纳升加样仪将DMSO溶解的 不同化合物加入孔中，使化合物终浓度为10μM和1μM，共2个浓度，同时设空白对照孔(不含蛋白)与阴性对照孔(含蛋白，加溶媒DMSO)，设置2个复孔，最后每孔加入4μl 20×SYPRO Orange Dye蛋白染料，离心混匀。Roche LightCycler480荧光定量PCR仪中，运行程序为20℃15s；30℃--90℃0.02℃/s；20℃15s。使用LightCycler Thermal Shift Analysis软件分析得到熔解温度(Tm)，计算熔解温度差ΔTm。The hTEAD3 protein stock solution was diluted to 50 ng/μl with phosphate buffered saline (PBS), and the 5000× protein dye (SYPRO Orange Dye) was diluted to 20× with DMSO. 16 μl of hTEAD3 protein dilution was added to a 96-well plate, and the DMSO-dissolved solution was pipetted into the wells of the plate using a nanoliter pipette. Different compounds were added to the wells to make the final concentrations of the compounds 10μM and 1μM, a total of 2 concentrations. At the same time, blank control wells (without protein) and negative control wells (with protein, with solvent DMSO) were set up, and 2 duplicate wells were set up. Finally, 4μl 20×SYPRO Orange Dye protein dye was added to each well and centrifuged to mix. In the Roche LightCycler480 fluorescence quantitative PCR instrument, the operating program was 20℃15s; 30℃--90℃0.02℃/s; 20℃15s. The melting temperature (Tm) was obtained by analysis using the LightCycler Thermal Shift Analysis software, and the melting temperature difference ΔTm was calculated.

1.4 hTEAD41.4 hTEAD4

用磷酸盐缓冲液(PBS)将hTEAD4蛋白母液稀释至50ng/μl，同时用DMSO将5000×的蛋白染料(SYPRO Orange Dye)稀释至20×，在96孔板中加入16μl hTEAD4蛋白稀释液，然后用纳升加样仪将DMSO溶解的不同化合物加入孔中，使化合物终浓度为10μM和1μM，共2个浓度，同时设空白对照孔(不含蛋白)与阴性对照孔(含蛋白，加溶媒DMSO)，设置2个复孔，最后每孔加入4μl 20×SYPRO Orange Dye蛋白染料，离心混匀。Roche LightCycler480荧光定量PCR仪中，运行程序为20℃15s；30℃--90℃0.02℃/s；20℃15s。使用LightCycler Thermal Shift Analysis软件分析得到熔解温度(Tm)，计算熔解温度差ΔTm。ΔTm＝Tm(实验组)-Tm(空白组)。The hTEAD4 protein stock solution was diluted to 50 ng/μl with phosphate buffered saline (PBS), and the 5000× protein dye (SYPRO Orange Dye) was diluted to 20× with DMSO. 16μl hTEAD4 protein diluent was added to the 96-well plate, and then different compounds dissolved in DMSO were added to the wells using a nanoliter pipette to make the final concentration of the compound 10μM and 1μM, a total of 2 concentrations. At the same time, blank control wells (without protein) and negative control wells (with protein, with solvent DMSO) were set up, and 2 duplicate wells were set up. Finally, 4μl 20× SYPRO Orange Dye protein dye was added to each well, and centrifuged to mix. In the Roche LightCycler480 fluorescence quantitative PCR instrument, the operating program was 20℃15s; 30℃--90℃0.02℃/s; 20℃15s. The melting temperature (Tm) was obtained by analysis using LightCycler Thermal Shift Analysis software, and the melting temperature difference ΔTm was calculated. ΔTm = Tm (experimental group) - Tm (blank group).

本公开化合物与蛋白(TEAD1、TEAD2、TEAD3及TEAD4蛋白)具有很好的结合活性。The disclosed compounds have good binding activity with proteins (TEAD1, TEAD2, TEAD3 and TEAD4 proteins).

试验例2：体外细胞增殖抑制活性Test Example 2: In vitro cell proliferation inhibitory activity

2.1 NCI-H2452细胞增殖抑制活性测定2.1 NCI-H2452 cell proliferation inhibitory activity assay

取处于生长状态良好的NCI-H2452(NF2野生型)人间皮瘤细胞，收集至离心管，调整细胞密度至4000个/mL，接种于96孔板上(100μL/孔)，细胞培养箱中培养24h后使用纳升加样仪进行化合物加样，使化合物终浓度为10000nM-0.61nM，2个复孔，同时设置对照。细胞培养箱中继续培养168小时后，加入检测试剂CCK-8(厂家：北京同仁化学，10μL/孔)，细胞培养箱中孵育2小时后，PerkinElmer 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。NCI-H2452 (NF2 wild type) human mesothelioma cells in good growth state were collected into centrifuge tubes, the cell density was adjusted to 4000 cells/mL, and the cells were inoculated on 96-well plates (100 μL/well). After culturing in a cell culture incubator for 24 hours, the compound was added using a nanoliter pipette to make the final concentration of the compound 10000nM-0.61nM, 2 replicates, and a control was set at the same time. After continuing to culture in the cell culture incubator for 168 hours, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL/well) was added, and the cells were incubated in the cell culture incubator for 2 hours. The absorbance was detected at 450nm using a PerkinElmer Envision microplate reader, and the four-parameter analysis was performed to fit the dose-effect curve and calculate the IC 50 .

2.2 NCI-H226细胞增殖抑制活性测定2.2 NCI-H226 cell proliferation inhibitory activity assay

取处于生长状态良好的NCI-H226(NF2缺失)人肺鳞癌细胞，收集至离心管，调整细胞密度至4000个/mL，接种于96孔板上(100μL/孔)，细胞培养箱中培养24h后使用纳升加样仪进行化合物加样，使化合物终浓度为10000nM-0.61nM，2个复孔，同时设置对照。细胞培养箱中继续培养168小时后，加入检测试剂CCK-8(厂家：北京同仁化学，10μL/孔)，细胞培养箱中孵育2小时后，PerkinElmer 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。NCI-H226 (NF2-deficient) human lung squamous cell carcinoma cells in good growth state were collected into centrifuge tubes, the cell density was adjusted to 4000 cells/mL, and the cells were inoculated on 96-well plates (100 μL/well). After culturing in a cell culture incubator for 24 hours, the compound was added using a nanoliter pipette to make the final concentration of the compound 10000nM-0.61nM, 2 replicate wells, and a control was set at the same time. After continuing to culture in the cell culture incubator for 168 hours, the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL/well) was added, and the cells were incubated in the cell culture incubator for 2 hours. The absorbance value was detected at 450nm by a PerkinElmer Envision microplate reader, and the four-parameter analysis was performed to fit the dose-effect curve and calculate the IC 50 .

2.3 NCI-H2052细胞增殖抑制活性测定2.3 NCI-H2052 cell proliferation inhibitory activity assay

取处于生长状态良好的NCI-H2052(NF2同源突变)人间皮瘤细胞，收集至离心管，调整细胞密度至4000个/mL，接种于96孔板上(100μL/孔)，细胞培养箱中培养24h后使用纳升加样仪进行化合物加样，使化合物终浓度为10000nM-0.61nM，2个复孔，同时设置对照。细胞培养箱中继续培养168小时后，加入检测试剂CCK-8(厂家：北京同仁化学，10μL/孔)，细胞培养箱中孵育2小时后，PerkinElmer 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。Take NCI-H2052 (NF2 homologous mutation) human mesothelioma cells in good growth state, collect them into centrifuge tubes, adjust the cell density to 4000 cells/mL, inoculate them on 96-well plates (100 μL/well), and culture them in a cell culture incubator for 24 hours. Then use a nanoliter pipette to add compounds, so that the final concentration of the compounds is 10000nM-0.61nM, 2 replicates, and set controls at the same time. After continuing to culture in the cell culture incubator for 168 hours, add the detection reagent CCK-8 (manufacturer: Beijing Tongren Chemical, 10 μL/well), incubate in the cell culture incubator for 2 hours, and detect its absorbance at 450nm using a PerkinElmer Envision microplate reader. Four-parameter analysis, fitting of the dose-effect curve, and calculation of IC 50 .

本公开部分化合物的上述试验结果如表1所示。The above test results of some compounds disclosed in the present invention are shown in Table 1.

表1 体外细胞增殖抑制实验结果

Table 1 Results of in vitro cell proliferation inhibition experiment

试验结果表明，本公开化合物针对NCI-H226细胞及NCI-H2052细胞具有增殖抑制活性，对NCI-H2452细胞基本没有增殖抑制活性，相对于NCI-H2452细胞，对NCI-H226及NCI-H2052细胞具有很好的选择性。The test results show that the disclosed compounds have proliferation inhibitory activity against NCI-H226 cells and NCI-H2052 cells, and have substantially no proliferation inhibitory activity against NCI-H2452 cells. Relative to NCI-H2452 cells, the compounds have good selectivity for NCI-H226 and NCI-H2052 cells.

试验例3：体外肝微粒体稳定性Test Example 3: In vitro liver microsome stability

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。部分化合物的实验结果见表2。The sample preparation for the incubation of liver microsomes was a mixture of PBS buffer (pH 7.4), liver microsome solution (0.5 mg/mL), the test compound and NADPH+MgCl2 solution incubated at 37°C and 300 rpm for 1 hour. The sample preparation for 0 hours was a mixture of PBS buffer (pH 7.4), liver microsome solution (0.5 mg/mL), and the test compound. The sample was added with an acetonitrile solution containing an internal standard to prepare a supernatant by protein precipitation, which was diluted for LC/MS/MS determination. The experimental results of some compounds are shown in Table 2.

表2
Table 2

试验结果表明，本公开化合物体外肝微粒代谢稳定。The test results show that the compounds disclosed herein are stable in the in vitro liver microsome metabolism.

试验例4：体内药代动力学Test Example 4: In vivo pharmacokinetics

4.1小鼠药代动力学4.1 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10mg/kg(或2mg/kg)剂量灌胃受试化合物溶液。ICR mice weighing 18-22 g were randomly divided into groups after acclimation for 3-5 days, with 9 mice in each group, and were intragastrically administered with a solution of the test compound at a dose of 10 mg/kg (or 2 mg/kg).

采血时间点15min、0.5h、1h、2h、4h、6h、8h、10h、24h，于眼眶取血制备待测血浆样品。Blood was collected from the eye sockets at 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h to prepare plasma samples for testing.

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。本公开部分化合物的结果见表3。The pharmacokinetic parameters were fitted using a non-compartmental model. The results of some compounds disclosed in this disclosure are shown in Table 3.

表3
Table 3

试验结果表明，本公开化合物在小鼠体内具有良好的药代动力学性质(例如AUC、T1/2、Cmax等参数表 现良好，绝对生物利用度F＞90％)。The test results show that the disclosed compounds have good pharmacokinetic properties in mice (e.g., AUC, T 1/2 , C max and other parameters) The absolute bioavailability is F＞90%).

4.2大鼠体内药代动力学4.2 Pharmacokinetics in rats

SD大鼠，体重180～220g，适应3～5天后，随机分组，每组3只，按对应剂量给药受试化合物溶液。采血时间点0.25h、0.5h、1h、2h、4h、6h、8h、10h、24h、30h、48h，于眼眶取血制备待测血浆样品。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。采用非房室模型拟合药代参数。SD rats weighing 180-220g were randomly divided into groups after 3-5 days of adaptation, with 3 rats in each group, and the test compound solution was administered according to the corresponding dose. Blood was collected from the eye socket at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 24h, 30h, and 48h. 30μL of the plasma sample to be tested and the standard curve sample were drawn, and the supernatant was obtained by protein precipitation with acetonitrile solution containing internal standard, and diluted for LC/MS/MS determination. The pharmacokinetic parameters were fitted using a non-compartmental model.

试验结果表明，本公开化合物在大鼠体内同样具有良好的药代动力学性质(例如AUC、T1/2、Cmax等参数表现良好，绝对生物利用度F＞90％)。The test results show that the disclosed compounds also have good pharmacokinetic properties in rats (for example, parameters such as AUC, T 1/2 , C max , etc. perform well, and absolute bioavailability F>90%).

试验例5：体内药效Test Example 5: In vivo efficacy

在NCI-H226人肺鳞癌裸小鼠皮下移植瘤模型中的药效学评价Pharmacodynamic evaluation of NCI-H226 human lung squamous cell carcinoma subcutaneous transplant tumor model in nude mice

在SPF级雌性裸小鼠(来源：上海必凯科翼生物科技有限公司)右侧腋窝皮下接种NCI-H226细胞，5×106个/只。待肿瘤平均体积达150mm3左右时，将动物分组。NCI-H226 cells were subcutaneously inoculated in the right axilla of SPF female nude mice (source: Shanghai Bikeway Biotechnology Co., Ltd.), 5×106 cells/mouse. When the average tumor volume reached about 150 mm3, the animals were divided into groups.

分组当天为第0天，从第0天开始，每天灌胃给药一次。每周测2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. From day 0 onwards, drugs were administered by gavage once a day. Tumor volume was measured twice 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.

试验结果表明，本公开化合物在小鼠体内可以有效抑制肿瘤的生长(如T/C或TGI(％)等参数表现出有效抑制肿瘤的生长的结果)。 The test results show that the disclosed compounds can effectively inhibit tumor growth in mice (such as parameters such as T/C or TGI (%) showing the results of effectively inhibiting tumor growth).

Claims (15)

式IC化合物，或其药学上可接受的盐，
A compound of formula IC, or a pharmaceutically acceptable salt thereof,
其中，in, X1、X2、X3、X4及X5分别独立地选自N或CH；X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from N or CH; Xa、Xb、Xc、Xd、Xe及Xf分别独立地选自N或任选地被一个取代基取代的CH； Xa , Xb , Xc , Xd , Xe and Xf are each independently selected from N or CH optionally substituted with one substituent; X选自O、S、-S(O)-、-S(O)2-、-C(O)-、-C(O)O-、或任选地被一个或多个取代基取代的以下基团：NH、-N(C1-6烷基)-、-NH-C1-6烷基-、-C1-6烷基-O-、-C1-6烷基-S-或-C(O)NH-；X is selected from O, S, -S(O)-, -S(O) 2- , -C(O)-, -C(O)O-, or the following groups optionally substituted with one or more substituents: NH, -N( C1-6alkyl )-, -NH- C1-6alkyl- , -C1-6alkyl -O-, -C1-6alkyl -S-, or -C(O)NH-; 每一个R1分别独立地选自CN、卤素、或任选地被一个或多个取代基取代的以下基团：C1-6烷基、C2- 6烯基、C2-6炔基、R'O-、R'S-、-SF5、R'R”N-、R'OC(O)-、R'C(O)O-、-C(O)NR'R”、R'C(O)NH-、R'S(O)NH-、R'R”NS(O)-、R'S(O)2NH-、R'R”NS(O)2-、R'OC(O)NH-、R'R”NC(O)O-、C3-12环烷基、3-12元杂环烷基、C3- 12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；each R 1 is independently selected from CN, halogen, or the following groups optionally substituted by one or more substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, R'O-, R'S-, -SF 5 , R'R"N-, R'OC(O)-, R'C(O)O-, -C(O)NR'R", R'C(O)NH-, R'S(O)NH-, R'R"NS(O)-, R'S(O) 2 NH-, R'R"NS(O) 2 -, R'OC(O)NH-, R'R"NC(O)O-, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl, or 5-12 membered heteroaryl; 每一个R2分别独立地选自CN、卤素、＝O、或任选地被一个或多个取代基取代的以下基团：C1-6烷基、C2-6烯基、C2-6炔基、R'O-、R'S-、-SF5、R'R”N-、R'OC(O)-、R'C(O)O-、-C(O)NR'R”、R'C(O)NH-、R'R”NS(O)-、R'S(O)NH-、R'R”NS(O)-、R'R”NS(O)2-、R'S(O)2NH-、R'R”NS(O)2-、R'OC(O)NH-、R'R”NC(O)O-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Each R 2 is independently selected from CN, halogen, =0, or the following groups optionally substituted by one or more substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, R'O-, R'S-, -SF 5 , R'R"N-, R'OC(O)-, R'C(O)O-, -C(O)NR'R", R'C(O)NH-, R'R"NS(O)-, R'S(O)NH-, R'R"NS(O)-, R'R"NS(O) 2 -, R'S(O) 2 NH-, R'R"NS(O) 2 -, R'OC(O)NH-, R'R"NC(O)O-, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12- membered aryl or 5-12-membered heteroaryl; R'及R”分别独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；R' and R" are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C6-12 aryl or 5-12 membered heteroaryl; m及n分别独立地选自0、1、2、3、4或5；m and n are independently selected from 0, 1, 2, 3, 4 or 5; 环A选自3-12元杂环烷基或3-12元杂环烯基。Ring A is selected from 3-12 membered heterocycloalkyl or 3-12 membered heterocycloalkenyl. 如权利要求1所述的化合物、或其药学上可接受的盐，其选自式I化合物，或其药学上可接受的盐，
The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is selected from a compound of formula I, or a pharmaceutically acceptable salt thereof,
其中，in, X1、X2、X3、X4及X5分别独立地选自N或CH；X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from N or CH; Xa、Xb、Xc、Xd、Xe及Xf分别独立地选自N或任选地被一个取代基取代的CH； Xa , Xb , Xc , Xd , Xe and Xf are each independently selected from N or CH optionally substituted with one substituent; X选自O、S、-S(O)-、-S(O)2-、-C(O)-、-C(O)O-、或任选地被一个或多个取代基取代的以下基团：NH、-N(C1-6烷基)-、-NH-C1-6烷基-、-C1-6烷基-O-、-C1-6烷基-S-或-C(O)NH-；X is selected from O, S, -S(O)-, -S(O) 2- , -C(O)-, -C(O)O-, or the following groups optionally substituted with one or more substituents: NH, -N( C1-6alkyl )-, -NH- C1-6alkyl- , -C1-6alkyl -O-, -C1-6alkyl -S-, or -C(O)NH-; 每一个R1分别独立地选自CN、卤素、或任选地被一个或多个取代基取代的以下基团：OH、NH2、C1- 6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OC(O)-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基C(O)NH-、(C1-6烷基)2NC(O)-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Each R 1 is independently selected from CN, halogen, or the following groups which are optionally substituted by one or more substituents: OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOC(O)-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylC(O)NH-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkylNHS(O)-, C 1-6 alkylS (O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl; 每一个R2分别独立地选自CN、卤素、＝O、或任选地被一个或多个取代基取代的以下基团：OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OC(O)-、C1-6烷基C(O)O-、C1-6烷基NHC(O)-、C1-6烷基C(O)NH-、(C1-6烷基)2NC(O)-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Each R 2 is independently selected from CN, halogen, =O, or the following groups optionally substituted by one or more substituents: OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO- , C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOC(O)-, C 1-6 alkylC(O)O-, C 1-6 alkylNHC(O)-, C 1-6 alkylC(O)NH-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl; m及n分别独立地选自0、1、2、3、4或5；m and n are independently selected from 0, 1, 2, 3, 4 or 5; 环A选自3-12元杂环烷基或3-12元杂环烯基。Ring A is selected from 3-12 membered heterocycloalkyl or 3-12 membered heterocycloalkenyl. 如权利要求1或2所述的化合物、或其药学上可接受的盐，其中X1、X2、X3、X4及X5分别独立地选自N或CH；The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , X 4 and X 5 are independently selected from N or CH; 或者，X1、X2、X3、X4及X5分别独立地选自N或CH，X1、X2、X3、X4及X5中任选地一个或两个选自N；Alternatively, X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from N or CH, and one or two of X 1 , X 2 , X 3 , X 4 and X 5 are optionally selected from N; 或者，X1、X2、X3、X4及X5分别独立地选自N或CH，X1、X2、X3、X4及X5中一个选自N；Alternatively, X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from N or CH, and one of X 1 , X 2 , X 3 , X 4 and X 5 is selected from N; 或者，X1、X2、X3、X4及X5分别独立地选自N或CH，X1、X2、X3、X4及X5中两个选自N；Alternatively, X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from N or CH, and two of X 1 , X 2 , X 3 , X 4 and X 5 are selected from N; 或者，X1、X2、X3、X4及X5选自CH。Alternatively, X 1 , X 2 , X 3 , X 4 and X 5 are selected from CH. 如权利要求1-3任一项所述的化合物、或其药学上可接受的盐，其中Xa、Xb、Xc、Xd、Xe及Xf分别独立地选自N或任选地被一个或多个Ra取代的CH，所述Ra选自CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基，所述C1-6烷基、C2- 6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-或(C1-6烷基)2N-；或者，Xa、Xb、Xc、Xd、Xe及Xf分别独立地选自CH或N；The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Xa , Xb , Xc , Xd, Xe and Xf are independently selected from N or CH optionally substituted by one or more Ra , wherein Ra is selected from CN, halogen, OH, NH2 , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylO-, C1-6 alkylS-, -SF5 , C1-6 alkylNH-, ( C1-6 alkyl)2N-, C1-6 alkylOCO-, C1-6 alkylC(O ) O- , C1-6 alkylNHCO-, C1-6 alkylCONH-, ( C1-6 alkyl)2NCO-, C1-6 alkylNHS(O)-, C1-6 alkylS(O)NH-, ( C1-6 alkyl) 2NS (O)-, C1-6 alkyl C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl , 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkyl C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS- , -SF 5 , C 1-6 alkylNH- or (C 1-6 alkyl) 2 N-; or, X a , X b , X c , X d , X e and X f are each independently selected from CH or N; 或者，Xa、Xb、Xc、Xd、Xe及Xf分别独立地选自CH或N，Xa、Xb、Xc、Xd、Xe及Xf中任选地一个或两个选自N；Alternatively, Xa , Xb , Xc , Xd, Xe and Xf are each independently selected from CH or N, and one or two of Xa, Xb , Xc , Xd , Xe and Xf are optionally selected from N ; 或者，Xa、Xb、Xc、Xd、Xe及Xf选自CH；Alternatively, Xa , Xb , Xc , Xd , Xe and Xf are selected from CH; 或者，Xb、Xd、Xe及Xf分别独立地选自CH，Xa及Xc分别独立地选自CH或N，所述CH任选地被一个Ra取代；Alternatively, Xb , Xd , Xe and Xf are each independently selected from CH, Xa and Xc are each independently selected from CH or N, and the CH is optionally substituted with one Ra ; 或者，Xb、Xd、Xe及Xf分别独立地选自CH，Xa及Xc分别独立地选自CH或N；Alternatively, X b , X d , X e and X f are each independently selected from CH, and X a and X c are each independently selected from CH or N; 任选地，所述Ra选自CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-或(C1-6烷基)2N-，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、 C1-6烷基NH-或(C1-6烷基)2N-任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-3烷基O-、C1- 3烷基S-、-SF5、C1-3烷基NH-或(C1-3烷基)2N-；Optionally, the Ra is selected from CN, halogen, OH, NH2 , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylO-, C1-6 alkylS-, -SF5 , C1-6 alkylNH- or ( C1-6 alkyl) 2N- , the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , C1-6 alkylO-, C1-6 alkylS-, C 1-6 alkylNH- or (C 1-6 alkyl) 2 N- is optionally substituted with one or more of the following: CN, halogen, OH, NH 2 , C 1-3 alkylO-, C 1-3 alkylS-, -SF 5 , C 1-3 alkylNH- or (C 1-3 alkyl) 2 N- ; 或者，所述Ra选自CN、卤素、OH、NH2或C1-3烷基。Alternatively, said Ra is selected from CN, halogen, OH, NH2 or C1-3 alkyl. 如权利要求1-4任一项所述的化合物、或其药学上可接受的盐，其中X选自O、S、-S(O)-、-S(O)2-、-C(O)-、-C(O)O-、或任选地被一个或多个取代基取代的以下基团：NH、-N(C1-3烷基)-、-NH-C1-3烷基-、-C1-3烷基-O-、-C1-3烷基-S-或-C(O)NH-；The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is selected from O, S, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)O-, or the following groups optionally substituted with one or more substituents: NH, -N(C 1-3 alkyl)-, -NH-C 1-3 alkyl-, -C 1-3 alkyl-O-, -C 1-3 alkyl-S- or -C(O)NH-; 或者，X选自O、S、或任选地被一个或多个取代基取代的以下基团：NH或-N(C1-3烷基)-；Alternatively, X is selected from O, S, or the following groups optionally substituted by one or more substituents: NH or -N(C 1-3 alkyl)-; 或者，X选自O、S、-S(O)-、-S(O)2-、-C(O)-、-C(O)O-、NH、-N(C1-6烷基)-、-NH-C1-6烷基-、-C1-6烷基-O-、-C1-6烷基-S-或-C(O)NH-；Alternatively, X is selected from O, S, -S(O)-, -S(O) 2- , -C(O)-, -C(O)O-, NH, -N( C1-6alkyl )-, -NH- C1-6alkyl- , -C1-6alkyl -O-, -C1-6alkyl -S-, or -C(O)NH-; 或者，X选自O、S、NH、-N(C1-3烷基)-、-NH-C1-3烷基-、-C1-3烷基-O-、-C1-3烷基-S-、-S(O)-、-S(O)2-、-C(O)-、-C(O)NH-或-C(O)O-；Alternatively, X is selected from O, S, NH, -N(C 1-3 alkyl)-, -NH-C 1-3 alkyl-, -C 1-3 alkyl-O-, -C 1-3 alkyl-S-, -S(O)-, -S(O) 2 -, -C(O)-, -C(O)NH- or -C(O)O-; 或者，X选自O、S、NH或-N(C1-3烷基)-；Alternatively, X is selected from O, S, NH or -N(C 1-3 alkyl)-; 或者，X选自O、S或NH；Alternatively, X is selected from O, S or NH; 或者，X选自O。Alternatively, X is selected from O. 如权利要求1-5任一项所述的化合物、或其药学上可接受的盐，其中R'及R”分别独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基或3-6元杂环烷基；The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R' and R" are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl or 3-6 membered heterocycloalkyl; 或者，R'及R”分别独立地选自氢、C1-6烷基、C2-6烯基或C2-6炔基；Alternatively, R' and R" are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; 或者，R'及R”分别独立地选自氢或C1-3烷基；Alternatively, R' and R" are each independently selected from hydrogen or C 1-3 alkyl; 或者，R'及R”分别独立地选自氢、甲基、-CH2CH2NH2或乙基。Alternatively, R ' and R" are each independently selected from hydrogen, methyl, -CH2CH2NH2 or ethyl . 如权利要求1-6任一项所述的化合物、或其药学上可接受的盐，其中每一个R1分别独立地选自CN、卤素、或任选地被一个或多个取代基取代的以下基团：OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、HOC(O)-、C1-6烷基OC(O)-、C1-6烷基C(O)O-、-C(O)NH2、C1-6烷基NHC(O)-、C1-6烷基C(O)NH-、(C1-6烷基)2NC(O)-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently selected from CN, halogen, or the following groups optionally substituted by one or more substituents: OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS- , -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, HOC(O)-, C 1-6 alkylOC(O)-, C 1-6 alkylC(O)O-, -C(O)NH 2 , C 1-6 alkylNHC(O)-, C 1-6 alkylC(O)NH-, (C 1-6 alkyl) 2 NC(O)-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C1-6 alkyl NHS(O) 2- , C1-6 alkyl S(O) 2NH- , ( C1-6 alkyl) 2NS (O) 2- , C3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C6-12 aryl or 5-12 membered heteroaryl; 或者，每一个R1分别独立地选自CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1- 6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1- 6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Alternatively, each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O) - , C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) The following groups are optionally substituted with one or more of the following groups: CN , halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, ( C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC ( O) O- , C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS ( O ) - , C 1-6 alkyl C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl; 或者，每一个R1分别独立地选自CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1- 6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1- 6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-或(C1-6烷基)2N-；Alternatively, each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C The C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkyl C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl 1-6 alkylNH- or (C 1-6 alkyl) 2 N-; 或者，每一个R1分别独立地选自CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1- 6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-或(C1-6烷基)2N-；Alternatively, each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS ( O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS- , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C C 1-6 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH- or (C 1-6 alkyl) 2 N-; 或者，每一个R1分别独立地选自CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、C1-6烷基NH-、(C1-6烷基)2N-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-3烷基O-、C1-3烷基S-、-SF5、C1-3烷基NH-或(C1- 3烷基)2N-；Alternatively, each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl. 6- membered aryl or 5-6-membered heteroaryl is optionally substituted by one or more of the following groups: CN, halogen, OH, NH 2 , C 1-3 alkyl O-, C 1-3 alkyl S- , -SF 5 , C 1-3 alkyl NH-, or (C 1-3 alkyl) 2 N-; 或者，每一个R1分别独立地选自CN、卤素、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-或(C1-6烷基)2N-，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、C1-6烷基NH-或(C1-6烷基)2N-任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-3烷基O-、C1-3烷基S-、-SF5、C1-3烷基NH-或(C1-3烷基)2N-；Alternatively, each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH- or (C 1-6 alkyl) 2 N-, and the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, C 1-6 alkylNH- or (C 1-6 alkyl) 2 N- is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-3 alkylO-, C 1-3 alkylS-, -SF 5 , C 1-3 alkylNH- or (C 1-3 alkyl) 2 N-; 或者，每一个R1分别独立地选自CN、卤素、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-或(C1-4烷基)2N-，所述C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-或(C1-4烷基)2N-任选地被一个或多个以下基团取代：CN、卤素、OH或NH2；Alternatively, each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH- or (C 1-4 alkyl) 2 N-, and the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH- or (C 1-4 alkyl) 2 N- is optionally substituted with one or more of the following groups: CN, halogen, OH or NH 2 ; 或者，每一个R1分别独立地选自CN、卤素、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基或-SF5，所述C1-4烷基、C2-4烯基或C2-4炔基任选地被一个或多个以下基团取代：CN、卤素、OH或NH2；Alternatively, each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl or -SF 5 , wherein the C 1-4 alkyl, C 2-4 alkenyl or C 2-4 alkynyl is optionally substituted with one or more of the following groups: CN, halogen, OH or NH 2 ; 或者，每一个R1分别独立地选自CN、卤素、OH、NH2、C1-3烷基、C2-3烯基、C2-3炔基或-SF5，所述C1-3烷基、C2-3烯基或C2-3炔基任选地被一个或多个以下基团取代：CN、卤素、OH或NH2；Alternatively, each R 1 is independently selected from CN, halogen, OH, NH 2 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl or -SF 5 , wherein the C 1-3 alkyl, C 2-3 alkenyl or C 2-3 alkynyl is optionally substituted with one or more of the following groups: CN, halogen, OH or NH 2 ; 或者，每一个R1分别独立地选自CN、卤素、OH、NH2或C1-3烷基，所述C1-3烷基任选地被一个或多个以下基团取代：CN、卤素、OH或NH2；Alternatively, each R 1 is independently selected from CN, halogen, OH, NH 2 or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more of the following groups: CN, halogen, OH or NH 2 ; 或者，每一个R1分别独立地选自卤代C1-6烷基或-SF5；Alternatively, each R 1 is independently selected from halogenated C 1-6 alkyl or -SF 5 ; 或者，每一个R1分别独立地选自卤代C1-3烷基或-SF5；Alternatively, each R 1 is independently selected from halogenated C 1-3 alkyl or -SF 5 ; 或者，每一个R1分别独立地选自氟代C1-3烷基或-SF5；Alternatively, each R 1 is independently selected from fluorinated C 1-3 alkyl or -SF 5 ; 或者，每一个R1分别独立地选自氟代C1-3烷基；Alternatively, each R 1 is independently selected from fluorinated C 1-3 alkyl; 或者，每一个R1分别独立地选自CF3或-SF5；Alternatively, each R 1 is independently selected from CF 3 or -SF 5 ; 或者，每一个R1分别独立地选自CF3。Alternatively, each R 1 is independently selected from CF 3 . 如权利要求1-7任一项所述的化合物、或其药学上可接受的盐，其中每一个R2分别独立地选自CN、卤素、＝O、或任选地被一个或多个取代基取代的以下基团：C1-6烷基、C2-6烯基、C2-6炔基、R'O-、R'S-、-SF5、R'R”N-、R'OC(O)-、R'C(O)O-、-C(O)NR'R”、R'C(O)NH-、R'R”NS(O)-、R'S(O)NH-、R'R”NS(O)-、R'R”NS(O)2-、R'S(O)2NH-、R'R”NS(O)2-、R'OC(O)NH-、R'R”NC(O)O-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、R'O-、 R'S-、-SF5、R'R”N-、R'OC(O)-、R'C(O)O-、-C(O)NR'R”、R'C(O)NH-、R'R”NS(O)-、R'S(O)NH-、R'R”NS(O)-、R'R”NS(O)2-、R'S(O)2NH-、R'R”NS(O)2-、R'OC(O)NH-、R'R”NC(O)O-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基任选地被一个或多个以下基团取代：CN、卤素、C1-6烷基、C2-6烯基、C2-6炔基、RbO-、RbS-、-SF5、RbRcN-、RbOC(O)-、RbC(O)O-、RbCONH-、RbRcNCO-、RbS(O)NH-、RbRcNS(O)-、RbS(O)2NH-或RbRcNS(O)2-，Rb及Rc分别独立地选自氢、C1-6烷基、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected from CN, halogen, =O, or the following groups optionally substituted by one or more substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, R'O-, R'S-, -SF 5 , R'R"N-, R'OC(O)-, R'C(O)O-, -C(O)NR'R", R'C(O)NH-, R'R"NS(O)-, R'S(O)NH-, R'R"NS(O)-, R'R"NS(O) 2 -, R'S(O) 2 NH-, R'R"NS(O) 2 -, R'OC(O)NH-, R'R"NC(O)O-, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, R'O-, R'S-, -SF5 , R'R"N-, R'OC(O)-, R'C(O)O-, -C(O)NR'R", R'C(O)NH-, R'R"NS(O)-, R'S(O)NH-, R'R"NS(O) - , R'R"NS(O) 2- , R'S(O)2NH-, R'R"NS(O) 2- , R'OC(O)NH-, R'R"NC(O ) O-, C3-12cycloalkyl , 3-12memberedheterocycloalkyl, C3-12cycloalkenyl, 3-12memberedheterocycloalkenyl , C6-12aryl , or 5-12memberedheteroaryl is optionally substituted with one or more of the following groups: CN , halogen, C1-6alkyl, C2-6alkenyl , C2-6alkynyl , RbO- , RbS- , -SF5 RbRcN- , RbOC ( O)-, RbC (O)O-, RbCONH- , RbRcNCO- , RbS ( O)NH-, RbRcNS(O)-, RbS(O)2NH- or RbRcNS ( O ) 2- , Rb and Rc are each independently selected from hydrogen, C1-6 alkyl, C3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C6-12 aryl or 5-12 membered heteroaryl; 或者，每一个R2分别独立地选自CN、卤素、＝O、或任选地被一个或多个取代基取代的以下基团：OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、HOC(O)-、C1-6烷基OCO-、C1-6烷基C(O)O-、-C(O)NH2、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Alternatively, each R 2 is independently selected from CN, halogen, =O, or the following groups optionally substituted by one or more substituents: OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, HOC(O)- , C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, -C(O)NH 2 , C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl; 或者，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、HOC(O)-、C1-6烷基OCO-、C1-6烷基C(O)O-、-C(O)NH2、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1- 6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基任选地被一个或多个以下基团取代：CN、卤素、C1-6烷基、C2- 6烯基、C2-6炔基、RbO-、RbS-、-SF5、RbRcN-、RbOC(O)-、RbC(O)O-、RbCONH-、RbRcNCO-、RbS(O)NH-、RbRcNS(O)-、RbS(O)2NH-或RbRcNS(O)2-，Rb及Rc分别独立地选自氢、C1-6烷基、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Alternatively, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, HOC(O)-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, -C(O)NH 2 , C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O) - , C RbO- , RbS- , -SF5 , RbRcN-, RbOC (O)-, RbC (O ) O- , RbCONH-, RbRcNCO- , RbS ( O ) NH- , RbRcNS ( O )- , RbS ( O ) 2NH- or RbRcNS ( O ) 2- , Rb and R c are each independently selected from hydrogen, C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl; 或者，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、HOC(O)-、C1-6烷基OCO-、C1-6烷基C(O)O-、-C(O)NH2、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基任选地被一个或多个以下基团取代：CN、卤素、C1-6烷基、C2-6烯基、C2-6炔基、RbO-、RbS-、-SF5、RbRcN-、RbOC(O)-、RbC(O)O-、RbCONH-、RbRcNCO-、RbS(O)NH-、RbRcNS(O)-、RbS(O)2NH-或RbRcNS(O)2-；Alternatively, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, HOC(O)-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, -C(O)NH 2 , C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C C 1-6 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) R 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl is optionally substituted with one or more of the following groups: CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , R b O-, R b S-, -SF 5 , R b R c N-, R b OC(O)-, R b C(O)O-, R b CONH-, R b R c NCO-, R b S(O)NH-, R b R c NS(O)-, R b S(O) 2 NH- or R b R c NS(O) 2 -; 或者，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-、(C1-4烷基)2N-、HOC(O)-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、-C(O)NH2、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C1-4烷基NHS(O)-、C1-4烷基S(O)NH-、(C1-4烷基)2NS(O)-、C1-4烷基NHS(O)2-、C1-4烷基S(O)2NH-、(C1-4烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基，所述C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C1-4烷基NHS(O)-、C1-4烷基S(O)NH-、(C1-4烷基)2NS(O)-、C1-4烷基NHS(O)2-、C1-4烷基S(O)2NH-、(C1-4烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基任选地被一个或多个以下基团取代：CN、卤素、C1-4烷基、C2-4烯 基、C2-4炔基、RbO-、RbS-、-SF5、RbRcN-、RbOC(O)-、RbC(O)O-、RbCONH-、RbRcNCO-、RbS(O)NH-、RbRcNS(O)-、RbS(O)2NH-或RbRcNS(O)2-；Alternatively, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, HOC(O)-, C 1-4 alkylOC(O)-, C 1-4 alkylC (O)O-, -C(O)NH 2 , C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 1-4 alkylNHS(O)-, C 1-4 alkylS(O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkylNHS(O) 2 -, C C 1-4 alkylS(O) 2 NH-, (C 1-4 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl, the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS- , -SF 5 , C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-, C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 1-4 alkylNHS(O)-, C 1-4 alkyl C 1-4 alkylS(O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkylNHS(O) 2 -, C 1-4 alkylS(O) 2 NH-, (C 1-4 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl is optionally substituted with one or more of the following groups: CN, halogen, C 1-4 alkyl, C 2-4 alkene, C 2-4 alkyl ... alkyl, C 2-4 alkynyl, R b O-, R b S-, -SF 5 , R b R c N-, R b OC(O)-, R b C(O)O-, R b CONH-, R b R c NCO-, R b S(O)NH-, R b R c NS(O)-, R b S(O) 2 NH- or R b R c NS(O) 2 -; 或者，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-、(C1-4烷基)2N-、HOC(O)-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、-C(O)NH2、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C3-6环烷基或3-6元杂环烷基，所述C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C3-6环烷基或3-6元杂环烷基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、(C1-4烷基)2N-、C1-4烷基NH-、-COOH、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基CONH-、C1-4烷基NHCO-或(C1-4烷基)2NHCO-；Alternatively, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, HOC(O)-, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-, -C(O)NH 2 , C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, C The present invention relates to a C 1-4 alkyl NH-, (C 1-4 alkyl) 2 N-, C 1-4 alkyl OC(O)-, C 1-4 alkyl C(O)O-, C 1-4 alkyl NHC(O)-, C 1-4 alkyl C(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, which is optionally substituted by one or more of the following groups: CN, halogen, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , (C 1-4 alkyl) 2 N-, C 1-4 alkylNH-, -COOH, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-, C 1-4 alkylCONH-, C 1-4 alkylNHCO- or (C 1-4 alkyl) 2 1-4 alkyl) 2 NHCO-; 或者，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-4烷基、C1-4烷基O-、C1-4烷基NH-、(C1-4烷基)2N-、HOC(O)-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、-C(O)NH2、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C3-6环烷基或3-6元杂环烷基，所述C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C3-6环烷基或3-6元杂环烷基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-4烷基、C1-4烷基O-、(C1-4烷基)2N-、C1-4烷基NH-、-COOH、C1-4烷基OC(O)-、C1-4烷基C(O)O-；Alternatively, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-4 alkyl, C 1-4 alkylO-, C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, HOC(O)-, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-, -C(O)NH 2 , C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, C 1-4 alkylOC(O)-, C C 1-4 alkylC(O)O-, C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-4 alkyl, C 1-4 alkylO-, (C 1-4 alkyl) 2 N-, C 1-4 alkylNH-, -COOH, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-; 或者，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、C1-3烷基、C1-3烷基O-、C1-3烷基NH-、HOC(O)-、C1-3烷基OC(O)-、-C(O)NH2或5-6元杂环烷基，所述C1-3烷基、C1-3烷基O-、C1-3烷基NH-、C1-3烷基OC(O)-或5-6元杂环烷基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-3烷基、-C1-3烷基NH-、COOH、或C1-3烷基OC(O)-；Alternatively, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylO-, C 1-3 alkylNH-, HOC(O)-, C 1-3 alkylOC(O)-, -C(O)NH 2 , or 5-6 membered heterocycloalkyl, wherein the C 1-3 alkyl, C 1-3 alkylO-, C 1-3 alkylNH-, C 1-3 alkylOC(O)-, or 5-6 membered heterocycloalkyl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-3 alkyl, -C 1-3 alkylNH-, COOH, or C 1-3 alkylOC(O)-; 或者，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、甲基、乙基、CH3O-、CH3NH-、CH3CH2NH-、HOC(O)-、CH3OC(O)-、CH3CH2OC(O)-、-C(O)NH2或5元含氧杂环烷基，所述甲基、乙基、CH3O-、CH3NH-、CH3CH2NH-、CH3OC(O)-、CH3CH2OC(O)-或5元含氧杂环烷基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、甲基、-COOH、C1-2烷基NH-或CH3OC(O)-；Alternatively, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , methyl, ethyl, CH 3 O-, CH 3 NH-, CH 3 CH 2 NH-, HOC(O)-, CH 3 OC(O)-, CH 3 CH 2 OC(O)-, -C(O)NH 2 or 5-membered oxygen-containing heterocycloalkyl, wherein the methyl, ethyl, CH 3 O-, CH 3 NH-, CH 3 CH 2 NH-, CH 3 OC(O)-, CH 3 CH 2 OC(O)- or 5-membered oxygen-containing heterocycloalkyl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , methyl, -COOH, C 1-2 alkylNH- or CH 3 OC(O)-; 或者，每一个R2分别独立地选自CN、卤素、＝O、OH、NH2、甲基、乙基、CH3O-、CH3NH-、CH3CH2NH-、HOC(O)-、CH3OC(O)-、CH3CH2OC(O)-、-C(O)NH2或5元含氧杂环烷基，所述甲基、乙基、CH3CH2NH-或5元含氧杂环烷基任选地被一个或多个以下基团取代：卤素、OH、NH2、甲基、-COOH、CH3NH-或CH3OC(O)-；Alternatively, each R 2 is independently selected from CN, halogen, =O, OH, NH 2 , methyl, ethyl, CH 3 O-, CH 3 NH-, CH 3 CH 2 NH-, HOC(O)-, CH 3 OC(O)-, CH 3 CH 2 OC(O)-, -C(O)NH 2 or 5-membered oxygen-containing heterocycloalkyl, wherein the methyl, ethyl, CH 3 CH 2 NH- or 5-membered oxygen-containing heterocycloalkyl is optionally substituted with one or more of the following groups: halogen, OH, NH 2 , methyl, -COOH, CH 3 NH- or CH 3 OC(O)-; 或者，每一个R2分别独立地选自卤素、＝O、OH、NH2、-CH3、-CH2OH、-CH2F、-CH2CH2OH、-CH(OH)CH3、-CH(OH)CH2OH、-CH2C(O)OCH3、-CH2C(O)OH、-CH2NH2、-CH2NHCH3、-OCH3、-NHCH3、-NHCH2CH2NH2、-C(O)OH、-C(O)OCH3、-C(O)OCH2CH3、-C(O)NH2或 Alternatively, each R 2 is independently selected from halogen, =O, OH, NH 2 , -CH 3 , -CH 2 OH, -CH 2 F, -CH 2 CH 2 OH, -CH(OH)CH 3 , -CH(OH)CH 2 OH, -CH 2 C(O)OCH 3 , -CH 2 C(O)OH, -CH 2 NH 2 , -CH 2 NHCH 3 , -OCH 3 , -NHCH 3 , -NHCH 2 CH 2 NH 2 , -C(O)OH, -C(O)OCH 3 , -C(O)OCH 2 CH 3 , -C(O)NH 2 or 任选地，Rb及Rc分别独立地选自氢、C1-6烷基、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基；Optionally, R b and R c are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl; 或者，Rb及Rc分别独立地选自氢、C1-4烷基、C3-6环烷基或3-6元杂环烷基；Alternatively, R b and R c are each independently selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; 或者，Rb及Rc分别独立地选自氢或C1-3烷基。Alternatively, R b and R c are each independently selected from hydrogen or C 1-3 alkyl. 如权利要求1-8任一项所述的化合物、或其药学上可接受的盐，其中m及n分别独立地选自0、1、2或3；The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein m and n are independently selected from 0, 1, 2 or 3; 或者，m及n分别独立地选自1或2；Alternatively, m and n are independently selected from 1 or 2; 或者，m选自1；Alternatively, m is selected from 1; 可选地，n选自1或2。Optionally, n is selected from 1 or 2. 如权利要求1-9任一项所述的化合物、或其药学上可接受的盐，其中环A选自3-10元杂环烷基或3-10 元杂环烯基；The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from a 3-10 membered heterocycloalkyl group or a 3-10 1-membered heterocycloalkenyl; 或者，环A选自3-10元杂环烷基或3-8元杂环烯基；Alternatively, ring A is selected from 3-10 membered heterocycloalkyl or 3-8 membered heterocycloalkenyl; 或者，环A选自4-10元杂环烷基；Alternatively, ring A is selected from 4-10 membered heterocycloalkyl; 或者，环A选自4-8元或10元杂环烷基；Alternatively, ring A is selected from 4-8 or 10-membered heterocycloalkyl; 或者，环A选自4-6元单环杂环烷基、7-8元或10元螺杂环烷基；Alternatively, ring A is selected from 4-6 membered monocyclic heterocycloalkyl, 7-8 membered or 10 membered spiroheterocycloalkyl; 或者，环A选自5元单环杂环烷基；Alternatively, Ring A is selected from 5-membered monocyclic heterocycloalkyl; 或者，环A选自吡咯烷基、噻唑烷基、咪唑烷基、哌啶基、哌嗪基、二氮杂螺癸烷基、一氧杂一氮杂螺辛烷基、氮杂环丁烷基、一氮杂螺庚烷基或噁唑烷基；Alternatively, ring A is selected from pyrrolidinyl, thiazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, diazaspirodecanyl, monooxa-azaspirooctanyl, azetidinyl, monoazaspiroheptyl or oxazolidinyl; 或者，环A选自其中Xt选自CH2、NH或O。Alternatively, ring A is selected from wherein X t is selected from CH 2 , NH or O. 如权利要求1-10任一项所述的化合物、或其药学上可接受的盐，所述式I化合物或其药学上可接受的盐选自式IC-1、IC-2、IC-3、IA、IA-1、IA-2、IA-3、II、II-1、II-2、II-3、III、IV、IIIA、IVA、V、VI或VII化合物，或其药学上可接受的盐，

A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is selected from a compound of formula IC-1, IC-2, IC-3, IA, IA-1, IA-2, IA-3, II, II-1, II-2, II-3, III, IV, IIIA, IVA, V, VI or VII, or a pharmaceutically acceptable salt thereof,

其中，in, q选自0、1、2或3；q is selected from 0, 1, 2 or 3; Xa及Xc分别独立地选自CH或N； Xa and Xc are each independently selected from CH or N; X6选自N或CH，X7选自NH、O、S或CH2，且X6和X7中至少有一个含有氮原子；X 6 is selected from N or CH, X 7 is selected from NH, O, S or CH 2 , and at least one of X 6 and X 7 contains a nitrogen atom; 环B选自3-10元杂环烷基或3-10元杂环烯基；Ring B is selected from 3-10 membered heterocycloalkyl or 3-10 membered heterocycloalkenyl; 每一个R2a分别独立地选自CN、卤素、＝O、或任选地被一个或多个取代基取代的以下基团：OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、HOC(O)-、C1-6烷基OCO-、C1-6烷基C(O)O-、-C(O)NH2、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1- 6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Each R 2a is independently selected from CN, halogen, =O, or the following groups optionally substituted by one or more substituents: OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO- , C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, HOC(O)-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, -C (O)NH 2 , C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkyl S(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl; p选自0、1、2或3；p is selected from 0, 1, 2 or 3; T选自S＝O或C；T is selected from S=O or C; Xt选自CH2、NH或O。 Xt is selected from CH2 , NH or O. 如权利要求11所述的化合物、或其药学上可接受的盐，其中环B选自3-8元杂环烷基或3-8元杂环烯基；The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from a 3-8 membered heterocycloalkyl or a 3-8 membered heterocycloalkenyl; 或者，环B选自3-6元杂环烷基或3-6元杂环烯基；Alternatively, Ring B is selected from 3-6 membered heterocycloalkyl or 3-6 membered heterocycloalkenyl; 或者，环B选自3-10元杂环烷基； Alternatively, Ring B is selected from 3-10 membered heterocycloalkyl; 或者，环B选自4-10元杂环烷基；Alternatively, Ring B is selected from 4-10 membered heterocycloalkyl; 或者，环B选自4-8元或10元杂环烷基；Alternatively, Ring B is selected from 4-8 or 10-membered heterocycloalkyl; 或者，环B选自4-6元单环杂环烷基、7-8元或10元螺杂环烷基；Alternatively, Ring B is selected from 4-6 membered monocyclic heterocycloalkyl, 7-8 membered or 10 membered spiroheterocycloalkyl; 或者，环B选自4-8元杂环烷基；Alternatively, Ring B is selected from 4-8 membered heterocycloalkyl; 或者，环B选自4-6元杂环烷基；Alternatively, Ring B is selected from 4-6 membered heterocycloalkyl; 或者，环B选自5-6元杂环烷基；Alternatively, Ring B is selected from 5-6 membered heterocycloalkyl; 或者，环B选自吡咯烷基、噻唑烷基、咪唑烷基、哌啶基、哌嗪基、二氮杂螺癸烷基、一氧杂一氮杂螺辛烷基、氮杂环丁烷基、一氮杂螺庚烷基或噁唑烷基；Alternatively, ring B is selected from pyrrolidinyl, thiazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, diazaspirodecanyl, monooxa-azaspirooctanyl, azetidinyl, monoazaspiroheptyl or oxazolidinyl; 任选地，每一个R2a分别独立地选自CN、卤素、＝O、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1- 6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1- 6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基任选地被一个或多个以下基团取代：CN、卤素、C1-6烷基、C2-6烯基、C2-6炔基、RbO-、RbS-、-SF5、RbRcN-、RbOC(O)-、RbC(O)O-、RbCONH-、RbRcNCO-、RbS(O)NH-、RbRcNS(O)-、RbS(O)2NH-或RbRcNS(O)2-，Rb及Rc分别独立地选自氢、C1-6烷基、C3-12环烷基、3-12元杂环烷基、C3-12环烯基、3-12元杂环烯基、C6-12芳基或5-12元杂芳基；Optionally, each R 2a is independently selected from CN, halogen, =O, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO- , C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl ) 2 NS (O) 2 -, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO- , C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O) - , C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C The group consisting of: RbO-, RbS-, -SF5 , RbRcN-, RbOC(O)- , RbC(O)O-, RbCONH-, RbRcNCO-, RbS(O)NH-, RbRcNS(O)-, RbS (O) 2NH- or RbRcNS (O)2-, Rb and Rc are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, RbO- , RbS- , -SF5 , RbRcN-, RbOC(O)-, RbC(O) O-, RbCONH-, RbRcNCO-, RbS(O)NH- , RbRcNS ( O)-, RbS(O)2NH- or RbRcNS (O)2-, Rb and Rc are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, RbO-, RbS-, -SF5, RbRcN-, RbOC(O)-, RbC (O)O-, RbCONH- , RbRcNCO-, RbS(O)NH-, RbRcNS ( O)-, RbS (O) 2NH- or RbRcNS (O) 2- , Rb and Rc are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, RbO-, RbS- , -SF5, RbRc C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocycloalkenyl, C 6-12 aryl or 5-12 membered heteroaryl; 或者，每一个R2a分别独立地选自CN、卤素、＝O、OH、NH2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基，所述C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷基O-、C1-6烷基S-、-SF5、C1-6烷基NH-、(C1-6烷基)2N-、C1-6烷基OCO-、C1-6烷基C(O)O-、C1-6烷基NHCO-、C1-6烷基CONH-、(C1-6烷基)2NCO-、C1-6烷基NHS(O)-、C1-6烷基S(O)NH-、(C1-6烷基)2NS(O)-、C1-6烷基NHS(O)2-、C1-6烷基S(O)2NH-、(C1-6烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基任选地被一个或多个以下基团取代：CN、卤素、C1-6烷基、C2-6烯基、C2-6炔基、RbO-、RbS-、-SF5、RbRcN-、RbOC(O)-、RbC(O)O-、RbCONH-、RbRcNCO-、RbS(O)NH-、RbRcNS(O)-、RbS(O)2NH-或RbRcNS(O)2-；Alternatively, each R 2a is independently selected from CN, halogen, =O, OH, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS-, -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 -, C 1-6 alkylS(O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylO-, C 1-6 alkylS- , -SF 5 , C 1-6 alkylNH-, (C 1-6 alkyl) 2 N-, C 1-6 alkylOCO-, C 1-6 alkylC(O)O-, C 1-6 alkylNHCO-, C 1-6 alkylCONH-, (C 1-6 alkyl) 2 NCO-, C 1-6 alkylNHS(O)-, C 1-6 alkylS(O)NH-, (C 1-6 alkyl) 2 NS(O)-, C 1-6 alkylNHS(O) 2 - , C 1-6 alkylS (O) 2 NH-, (C 1-6 alkyl) 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl, or 5-6 membered heteroaryl is optionally substituted with one or more of the following: CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, R b O-, R b S-, -SF 5 , R b R c N-, R b OC(O)-, R b C(O)O-, R b CONH-, R b R c NCO-, R b S(O)NH-, R b R c NS(O)-, R b S(O) 2 NH-, or R b R c NS(O) 2 -; 或者，每一个R2a分别独立地选自CN、卤素、＝O、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C1-4烷基NHS(O)-、C1-4烷基S(O)NH-、(C1-4烷基)2NS(O)-、C1-4烷基NHS(O)2-、C1-4烷基S(O)2NH-、(C1-4烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基，所述C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C1-4烷基NHS(O)-、C1-4烷基S(O)NH-、(C1-4烷基)2NS(O)-、C1-4烷基NHS(O)2-、C1-4烷基S(O)2NH-、(C1-4烷基)2NS(O)2-、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基任选地被一个或多个以下基团取代：CN、卤素、C1-4烷基、C2-4烯基、C2-4炔基、RbO-、RbS-、-SF5、RbRcN-、RbOC(O)-、RbC(O)O-、RbCONH-、RbRcNCO-、RbS(O)NH-、RbRcNS(O)-、RbS(O)2NH-或RbRcNS(O)2-；Alternatively, each R 2a is independently selected from CN, halogen, =O, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-, C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 1-4 alkylNHS(O)-, C 1-4 alkylS(O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkylNHS(O) 2 -, C 1-4 alkylS(O) 2 NH-, (C 1-4 alkyl) C 2 NS(O) 2 -, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl, the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-, C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 1-4 alkylNHS(O)-, C 1-4 alkylS(O)NH-, (C 1-4 alkyl) 2 NS(O)-, C 1-4 alkyl RbO- , RbS-, -SF5 , RbRcN- , RbOC (O) - , RbC ( O )O-, RbCONH- , RbRcNCO- , RbS ( O ) NH- , RbRcNS ( O )- , RbS ( O ) 2NH- , or RbRcNS ( O ) 2- ; 或者，每一个R2a分别独立地选自CN、卤素、＝O、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C3-6环烷基或3-6元杂环烷基，所述C1-4烷基、C2-4烯 基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C3-6环烷基或3-6元杂环烷基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、-SF5、(C1-4烷基)2N-、C1-4烷基NH-、-COOH、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基CONH-、C1-4烷基NHCO-或(C1-4烷基)2NHCO-；Alternatively, each R 2a is independently selected from CN, halogen, =O, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-, C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-, C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC( O )-, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-, C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS-, -SF 5 , (C 1-4 alkyl) 2 N-, C 1-4 alkylNH-, -COOH, C 1-4 alkylOC(O)-, C C 1-4 alkyl C(O)O-, C 1-4 alkyl CONH-, C 1-4 alkyl NHCO- or (C 1-4 alkyl) 2 NHCO-; 或者，每一个R2a分别独立地选自CN、卤素、＝O、OH、NH2、C1-4烷基、C1-4烷基O-、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C3-6环烷基或3-6元杂环烷基，所述C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷基O-、C1-4烷基S-、C1-4烷基NH-、(C1-4烷基)2N-、C1-4烷基OC(O)-、C1-4烷基C(O)O-、C1-4烷基NHC(O)-、C1-4烷基C(O)NH-、(C1-4烷基)2NC(O)-、C3-6环烷基或3-6元杂环烷基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1- 4烷基、C1-4烷基O-、(C1-4烷基)2N-、C1-4烷基NH-、-COOH、C1-4烷基OC(O)-、C1-4烷基C(O)O-；Alternatively, each R 2a is independently selected from CN, halogen, =O, OH, NH 2 , C 1-4 alkyl, C 1-4 alkylO-, C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-, C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl, the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylO-, C 1-4 alkylS- , C 1-4 alkylNH-, (C 1-4 alkyl) 2 N-, C 1-4 alkylOC(O)-, C 1-4 alkylC(O)O-, C C 1-4 alkylNHC(O)-, C 1-4 alkylC(O)NH-, (C 1-4 alkyl) 2 NC(O)-, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-4 alkyl, C 1-4 alkylO-, (C 1-4 alkyl) 2 N-, C 1-4 alkylNH-, -COOH, C 1-4 alkylOC(O)-, C 1-4 alkylC(O ) O-; 或者，每一个R2a分别独立地选自CN、卤素、＝O、OH、NH2、C1-3烷基、C1-3烷基O-、C1-3烷基NH-、C1-3烷基OC(O)-或5-6元杂环烷基，所述C1-3烷基、C1-3烷基O-、C1-3烷基NH-、C1-3烷基OC(O)-或5-6元杂环烷基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、C1-3烷基、-COOH、或C1-3烷基OC(O)-；Alternatively, each R 2a is independently selected from CN, halogen, =O, OH, NH 2 , C 1-3 alkyl, C 1-3 alkylO-, C 1-3 alkylNH-, C 1-3 alkylOC(O)-, or 5-6 membered heterocycloalkyl, wherein the C 1-3 alkyl, C 1-3 alkylO-, C 1-3 alkylNH-, C 1-3 alkylOC(O)-, or 5-6 membered heterocycloalkyl is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , C 1-3 alkyl, -COOH, or C 1-3 alkylOC(O)-; 或者，每一个R2a分别独立地选自CN、卤素、＝O、OH、NH2、甲基、乙基、CH3O-、CH3NH-、CH3CH2NH-、CH3OC(O)-、CH3CH2OC(O)-或5元含氧杂环烷基，所述甲基、乙基、CH3O-、CH3NH-、CH3CH2NH-、CH3OC(O)-、CH3CH2OC(O)-或5元含氧杂环烷基任选地被一个或多个以下基团取代：CN、卤素、OH、NH2、甲基、-COOH、或CH3OC(O)-；Alternatively, each R 2a is independently selected from CN, halogen, =O, OH, NH 2 , methyl, ethyl, CH 3 O-, CH 3 NH-, CH 3 CH 2 NH-, CH 3 OC(O)-, CH 3 CH 2 OC(O)-, or a 5-membered oxygen-containing heterocycloalkyl group, wherein the methyl, ethyl, CH 3 O-, CH 3 NH-, CH 3 CH 2 NH-, CH 3 OC(O)-, CH 3 CH 2 OC(O)-, or a 5-membered oxygen-containing heterocycloalkyl group is optionally substituted with one or more of the following groups: CN, halogen, OH, NH 2 , methyl, -COOH, or CH 3 OC(O)-; 或者，每一个R2a分别独立地选自CN、卤素、＝O、OH、NH2、甲基、乙基、CH3O-、CH3NH-、CH3CH2NH-、CH3OC(O)-、CH3CH2OC(O)-或5元含氧杂环烷基，所述甲基、乙基、CH3CH2NH-或5元含氧杂环烷基任选地被一个或多个以下基团取代：卤素、OH、NH2、甲基、-COOH、或CH3OC(O)-；Alternatively, each R 2a is independently selected from CN, halogen, =O, OH, NH 2 , methyl, ethyl, CH 3 O-, CH 3 NH-, CH 3 CH 2 NH-, CH 3 OC(O)-, CH 3 CH 2 OC(O)-, or a 5-membered oxygen-containing heterocycloalkyl group, wherein the methyl, ethyl, CH 3 CH 2 NH-, or a 5-membered oxygen-containing heterocycloalkyl group is optionally substituted with one or more of the following groups: halogen, OH, NH 2 , methyl, -COOH, or CH 3 OC(O)-; 或者，每一个R2a分别独立地选自卤素、＝O、OH、NH2、-CH3、-CH2OH、-CH2F、-CH2CH2OH、-CH(OH)CH3、-CH(OH)CH2OH、-CH2C(O)OCH3、-CH2C(O)OH、-OCH3、-NHCH3、-NHCH2CH2NH2、-C(O)OCH3、-C(O)OCH2CH3或 Alternatively, each R 2a is independently selected from halogen, =O, OH, NH 2 , -CH 3 , -CH 2 OH, -CH 2 F, -CH 2 CH 2 OH, -CH(OH)CH 3 , -CH(OH)CH 2 OH, -CH 2 C(O)OCH 3 , -CH 2 C(O)OH, -OCH 3 , -NHCH 3 , -NHCH 2 CH 2 NH 2 , -C(O)OCH 3 , -C(O)OCH 2 CH 3 or 可选地，p选自0、1或2；Optionally, p is selected from 0, 1 or 2; 任选地，Rb及Rc分别独立地选自氢、C1-6烷基、C3-6环烷基、3-6元杂环烷基、C3-6环烯基、3-6元杂环烯基、C6芳基或5-6元杂芳基；Optionally, R b and R c are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3-6 cycloalkenyl, 3-6 membered heterocycloalkenyl, C 6 aryl or 5-6 membered heteroaryl; 或者，Rb及Rc分别独立地选自氢、C1-4烷基、C3-6环烷基或3-6元杂环烷基；Alternatively, R b and R c are each independently selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl; 或者，Rb及Rc分别独立地选自氢或C1-3烷基。Alternatively, R b and R c are each independently selected from hydrogen or C 1-3 alkyl. 以下化合物，或其药学上可接受的盐：




The following compound, or a pharmaceutically acceptable salt thereof:




一种药物组合物，所述药物组合物含有权利要求1-13任一项所述的化合物或其药学上可接受的盐，任 选地，包括药学上可接受的辅料。A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, Optionally, include pharmaceutically acceptable excipients. 权利要求1-13任一项所述的化合物或其药学上可接受的盐、或权利要求14所述的药物组合物在制备预防或者治疗疾病的药物中的用途；可选地，上述疾病选自癌症。 Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14 in the preparation of a medicament for preventing or treating a disease; optionally, the disease is selected from cancer.
PCT/CN2024/092286 2023-05-12 2024-05-10 Compound containing aromatic bicyclic ring WO2024235115A1 (en)

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