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WO2025218615A1 - Heterocyclic amide compound and use thereof in medicine - Google Patents

Heterocyclic amide compound and use thereof in medicine

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Publication number
WO2025218615A1
WO2025218615A1 PCT/CN2025/088697 CN2025088697W WO2025218615A1 WO 2025218615 A1 WO2025218615 A1 WO 2025218615A1 CN 2025088697 W CN2025088697 W CN 2025088697W WO 2025218615 A1 WO2025218615 A1 WO 2025218615A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
compound
cycloalkyl
substituted
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/088697
Other languages
French (fr)
Chinese (zh)
Inventor
张冯敏
顾东炎
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hangzhou Baicreat Pharma Tech Co Ltd
Original Assignee
Hangzhou Baicreat Pharma Tech Co Ltd
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Filing date
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Application filed by Hangzhou Baicreat Pharma Tech Co Ltd filed Critical Hangzhou Baicreat Pharma Tech Co Ltd
Publication of WO2025218615A1 publication Critical patent/WO2025218615A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates to the field of medical technology, and specifically to a heterocyclic amide compound represented by formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, and use thereof in preparing a medicament for treating related diseases.
  • DSBs DNA damage .
  • chromosomes may experience abnormalities such as breakage, deletions, and rearrangements. Therefore, timely DSB repair plays an important role in maintaining genomic stability, ensuring cell survival, and inhibiting the occurrence and development of tumors.
  • the repair of double-stranded DNA breaks can be roughly divided into three main pathways: homologous recombination (HR), a repair process that uses double-stranded DNA homologous to the damaged DNA as a template to synthesize DNA with high fidelity and low mismatch repair rate; non-homologous end joining (NHEJ), which captures the damaged ends of the broken double-stranded DNA and directly connects the damaged ends through protein interactions, which is an error-prone repair process; microhomology-mediated end joining (MMEJ), a more widespread and error-prone end joining mechanism, also known as alternative end-joining (alt-EJ), is driven by the annealing of microhomologous sequences on the DNA end sides.
  • HR homologous recombination
  • NHEJ non-homologous end joining
  • MMEJ microhomology-mediated end joining
  • alt-EJ alternative end-joining
  • MMEJ an alternative repair method to HR
  • MMEJ becomes the primary DSB repair pathway.
  • HR repair is impaired, and MMEJ becomes the primary DSB repair pathway.
  • DNA polymerase ⁇ plays a crucial role. Pol ⁇ replaces RPA at the resected DSB to promote the annealing of microhomology ssDNA, and then synthesizes DNA to fill the resected gap, completing the connection of the damaged ends.
  • Pol ⁇ inhibitors can be used in combination with PARP inhibitors to achieve a synergistic tumor-killing effect.
  • patients receiving maintenance treatment with PARP inhibitors will develop drug resistance, which may be due to gene mutations that partially restore HR pathway activity, such as the loss of TP53BP1.
  • the main HR repair method is Pol ⁇ -dependent MMEJ. Therefore, Pol ⁇ inhibitors can also overcome resistance to PARP inhibitors, bringing good news to more patients.
  • Pol ⁇ inhibitors could provide a new strategy for the targeted treatment of tumors deficient in homologous recombination repair, representing a significant unmet clinical need.
  • the development of novel and highly effective Pol ⁇ inhibitors holds immense scientific research significance and clinical value.
  • the present invention provides novel heterocyclic amide derivatives and their uses. These compounds possess excellent Pol ⁇ inhibitory activity and can be used as Pol ⁇ inhibitors in the treatment of related tumors or cancers.
  • the technical problem to be solved by the present invention is to provide a novel heterocyclic amide compound that can be used as a Pol ⁇ inhibitor for the preparation of a drug for treating Pol ⁇ -mediated diseases or conditions and related diseases or conditions.
  • the present invention provides the following technical solutions:
  • a heterocyclic amide compound a compound having the following structural formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof:
  • Ring C is selected from
  • U', V', Z', W' are each independently selected from And at least one of U', V', Z', W' is selected from
  • R u , R v , R w , and R x are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, or substituted or unsubstituted C 6-12 aryl; when C
  • Ry and Rz are linked to each other and form a 3-8 membered aliphatic or heterocyclic ring with a common carbon atom, and the aforementioned aliphatic or heterocyclic ring may be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfone, C1-6 alkylthio, C1-6 alkylamino, 4-10 membered heterocyclyl, 5-14 membered heteroaryl or C6-12 aryl ;
  • n 1 is selected from 0, 1, 2 or 3;
  • X', Ya and Yb are each independently selected from N or CR 1a ;
  • R 1a is selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkylfatty, substituted or unsubstituted C 1-6 alkylacyl, substituted or unsubstituted C 1-6 alkylamido, substituted or unsubstituted C 1-6 alkylsulfonyl,
  • Ring B is a 3-18 membered heterocyclyl, a 5-10 membered heteroaryl, a C 6-14 aryl or a 4-10 membered cycloalkenyl; when ring B has a substituent, it may be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxy, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted
  • L is a covalent bond, a substituted or unsubstituted C 1-6 alkylene group, a substituted or unsubstituted C 2-6 alkenylene group, a substituted or unsubstituted C 2-6 alkynylene group, a substituted or unsubstituted C 3-8 cycloalkylene group, a substituted or unsubstituted C 6-10 arylene group, a substituted or unsubstituted C 1-6 alkyleneoxy group, a substituted or unsubstituted C 1-6 alkylenesulfonyl group, a substituted or unsubstituted C 1-6 alkylenethio group, a substituted or unsubstituted C 1-6 alkyleneamino group, when C 1-6 alkylene group, C 2-6 alkenylene group, C 2-6 alkynylene group, C 3-8 cycloalkylene group, C 6-10 arylene group, C 1-6 alkyleneoxy group, C
  • R L is selected from substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 2-9 heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 2-10 heteroaryl; when C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C
  • the heterocyclic group and the heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S.
  • a heterocyclic amide compound may be a compound represented by the general structural formula (II) or a pharmaceutically acceptable salt thereof:
  • a heterocyclic amide compound may be a compound represented by the general structural formula (IIA) or a pharmaceutically acceptable salt thereof:
  • ring B is selected from
  • RL is selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C6-14 aryl; when C3-6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C6-14 aryl has a substituent, it may be substituted by at least one of the following groups: halogen, hydroxyl, amino, cyano, oxo, C1-6 alkyl;
  • R u is selected from hydrogen, deuterium, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl; when C 1-6 alkyl, C 3-6 cycloalkyl, or 3-8 membered heterocyclyl has a substituent, it may be substituted by at least one of the following groups: hydroxy, amino, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkylsulfone, or substituted or unsubstituted 3-8 membered heterocyclyl; further, when C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylsulfone, or 3-8 membered heterocyclyl has a substituent, it may be substituted by at least one of the following groups:
  • RB and RB ' are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, thiol, oxo, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C1-6 alkylsulfonyl, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C1-6 alkylamino, substituted or unsubstituted C1-6 alkylfatty, substituted or unsubstituted C1-6 alkylacyl, substituted or unsubstituted C1-6 alkylamido, substituted or unsubstituted C1-6 alkylsulfonyl, substituted or un
  • heterocyclic group and heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S;
  • a heterocyclic amide compound may be a compound represented by the general structural formula (IIB) or a pharmaceutically acceptable salt thereof:
  • RL is selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C6-14 aryl, substituted or unsubstituted C2-6 alkynyl; when C3-6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C6-14 aryl, C2-6 alkynyl has a substituent, it may be substituted by at least one of the following groups: halogen, hydroxyl, amino, cyano, oxo, C1-6 alkyl;
  • heterocyclic group and heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S;
  • R y , R z , Ring B and Ru are as defined in the general formula (IIA).
  • a heterocyclic amide compound may be a compound represented by the general structural formula (IIC) or a pharmaceutically acceptable salt thereof:
  • L is selected from -OCH 2 -, -CH 2 -;
  • RL is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C6-14 aryl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C6-14 aryl, substituted or unsubstituted C2-6 alkynyl; when C3-6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C6-14 aryl, C2-6 alkynyl has substituents, they may be substituted by at least one of the following groups: halogen, hydroxyl, amino, cyano, oxo, substituted or unsubstituted C1-6 alkyl; further, when C1-6 alkyl has substituents, they
  • heterocyclic group and heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S;
  • R y , R z , Ring B and Ru are as defined in the general formula (IIA).
  • a heterocyclic amide compound may be a compound represented by the general structural formula (IID) or a pharmaceutically acceptable salt thereof:
  • U', V', Z', W' are each independently selected from And at least one of U', V', Z', W' is selected from
  • n 1 1;
  • R u , R v , R w , R x , R y and R z are as defined in formula (I);
  • Ring B and RL are as defined in the general formula (IIA).
  • a heterocyclic amide compound may be a compound represented by the general structural formula (III) or a pharmaceutically acceptable salt thereof:
  • U', V', Z', W' are each independently selected from And at least one of U', V', Z', W' is selected from
  • n 1 is selected from 0, 1, 2 or 3;
  • R u , R v , R w , and R x are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, or substituted or unsubstituted C 6-12 aryl; when C
  • heterocyclic group and heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S;
  • R y , R z , Ring B and RL are as defined in the general formula (IIA).
  • the present invention provides a heterocyclic amide compound represented by general formula (Ia) or (Ib), and its stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts:
  • Ring A is selected from a 3-14 membered heterocyclyl, a 5-14 membered heteroaryl, a C 6-14 aryl or a 4-10 membered cycloalkenyl; the 3-14 membered heterocyclyl, the 5-14 membered heteroaryl, the C 6 -C 14 aryl or the 4-10 membered cycloalkenyl may be optionally further substituted with one or more Ra ;
  • the X is selected from N or CR 2 ; the R 2 are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl;
  • Said Y 1 and Y 2 are each independently selected from N or CR 4 ; said R 4 are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl;
  • n is selected from 0, 1, 2 or 3;
  • R e , R f and the atoms to which they are connected together form a C 3-12 cycloalkyl group or a 3-12 membered heterocyclic group; the C 3-12 cycloalkyl group or the 3-12 membered heterocyclic group may be optionally further substituted by one or more R a ;
  • Ra , Rb , Rc , and Rd are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylester, C1-6 alkylacyl, C1-6 alkylamide, C1-6 alkylsulfonyl, C1-6 alkylsulfonamido, C1-6 phosphoryl, 3-8 membered heterocyclyl , 5-14 membered heteroaryl or C6-12 aryl ; said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl , C1-6 C 1-6 C
  • R 1 is selected from halogen, cyano, amino, -OR g -, C 1-6 alkyl substituted by one or more R g , C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-14 membered heteroaryl, C 6-10 aryl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylsulfone, C 1-6 alkylthio or C 1-6 alkylamino;
  • the Rg is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylester, C1-6 alkylacyl , C1-6 alkylamide, C1-6 alkylsulfonyl, C1-6 phosphoryl, C6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl; the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl , C1-6 alkoxy , C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylester, C1-6 alkylacyl
  • the compound represented by general formula (Ia) or (Ib), or a stereoisomer, tautomer, deuterated form or pharmaceutically acceptable salt thereof wherein R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-14 membered heteroaryl, C 6-10 aryl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio or C 1-6 alkylamino substituted with one or more R g ;
  • the Rg is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylester, C1-6 alkylacyl , C1-6 alkylamide, C1-6 alkylsulfonyl, C1-6 phosphoryl, C6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl; the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylester, C1-6 alkylacyl, C
  • the compound has a structure represented by the following formula (IIa) or (IIb), or a stereoisomer, tautomer, deuterated compound, or pharmaceutically acceptable salt thereof:
  • the compound has a structure represented by the following formula (IIIa) or (IIIb), or a stereoisomer, tautomer, deuterated compound, or pharmaceutically acceptable salt thereof:
  • the ring A, Y 1 , Y 2 , R 1 , R b , R c , R d , Re , and R f are as defined in the general formula (Ia) or (Ib).
  • the compound has a structure represented by the following formula (IVa), (IVb), (IVc), (IVd), (IVe) or (IVf), or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof:
  • n and t are each independently selected from 0, 1, 2, 3, 4 or 5, and m and t are not 0 at the same time;
  • Q is selected from O, S, SO 2 , C(R 3 ) 2 or NR 3 ; each of the R 3 groups is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl;
  • Ring A, Y 1 , Y 2 , R 1 , R b , R c , and R d are as defined in the general formula (Ia) or (Ib).
  • the compound has a structure represented by Formula (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv) or (Vw), or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof:
  • R 3 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl;
  • Ring A, R 1 and R b are as defined in the general formula (Ia) or (Ib).
  • the compound has a structure represented by Formula (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), or (Vv):
  • R 3 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl;
  • Ring A, R 1 and R b are as defined in the general formula (Ia) or (Ib).
  • the compound has a structure represented by the following formula (IIIc) or (IIId), or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof:
  • Ring A, Y 1 , Y 2 , R 1 , R b , R c , R d , Re , and R f are as defined in the general formula (Ia) or (Ib).
  • the compound has a structure represented by the following formula (IVg), (IVh), (IVi), (IVj) or (IVk), or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof:
  • n and t are each independently selected from 0, 1, 2, 3, 4 or 5, and m and t are not 0 at the same time;
  • Q is selected from O, S, SO 2 , C(R 3 ) 2 or NR 3 ; each of the R 3 groups is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl;
  • Ring A, Y 1 , Y 2 , R 1 , R b , R c , and R d are as defined in the general formula (Ia) or (Ib).
  • the compound has a structure represented by Formula (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), (VIn), (VIo), (VIp), (VIq), (VIr), (VIs), (VIt), (VIu), (VIv) or (VIw), or a stereoisomer, tautomer, deuterated form or pharmaceutically acceptable salt thereof:
  • ring A, R 1 , and R b are as defined in the general formula (Ia) or (Ib).
  • the ring A is selected from phenyl, pyridyl, morpholinyl, pyridonyl or cyclohexenyl; the phenyl, pyridyl, morpholinyl, pyridonyl or cyclohexenyl may be optionally further substituted with one or more Ra , each of which is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl or 3-8 membered heterocyclyl.
  • the ring A is selected from phenyl, which may be optionally further substituted with one or more Ra , wherein Ra is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl or 3-8 membered heterocyclyl.
  • the ring A is selected from pyridinyl, which may be optionally further substituted with one or more Ra , wherein Ra is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl or 3-8 membered heterocyclyl.
  • the ring A is selected from
  • the ring A is selected from
  • the ring A is selected from
  • the R 1 is selected from ethynyl substituted by R g , wherein the R g is selected from hydrogen, deuterium, C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, and the C 1-6 alkyl, C 3-12 cycloalkyl , C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfonyl or 3-8 membered heterocyclyl.
  • R g is selected from hydrogen, deuterium, C 1-6 alkyl, C 3-12 cycloalkyl, C 6
  • the R 1 is selected from cyclopropyl substituted with one or more R g , wherein the R g is selected from hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkynyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, and the C 1-6 alkyl, C 2-6 alkynyl, C 6-12 aryl , 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfonyl or 3-8 membered heterocyclyl.
  • the R g is selected from hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkynyl, C 6
  • the R 1 is selected from methyl substituted with one or more R g , wherein the R g is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, and the C 1-6 alkyl, C 3-12 cycloalkyl , C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfonyl or 3-8 membered heterocyclyl.
  • the R g is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-12 cycl
  • the R 1 is selected from ethyl substituted with one or more R g , wherein the R g is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, and the C 1-6 alkyl, C 3-12 cycloalkyl , C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfonyl or 3-8 membered heterocyclyl.
  • the R g is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 3
  • the R 1 is selected from -O(CH 2 ) p R g -, the p is selected from 0, 1, 2, 3 or 4, the R g is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, the C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfonyl, C 1-6
  • the R 1 is selected from -O(CH 2 ) p R g -, the p is selected from 0, 1, 2, 3 or 4, the R g is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, the C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfonyl or 3-8 membere
  • the R 1 is selected from -(CH 2 ) q OR g -, the q is selected from 0, 1, 2, 3 or 4, the R g is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, and the C 1-6 alkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfonyl or 3-8 membered heterocyclyl.
  • the R 1 is selected from
  • the R 1 is selected from
  • the compound of the present invention or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof is selected from the following compounds:
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), A compound represented by (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), (Vw), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg
  • the present invention provides a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn ...
  • the present invention provides compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vn
  • the present invention also provides a method for treating a disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a method of treating a disease or condition as described above, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a method of treating a disease or condition as described above, wherein the method comprises administering to a patient in need thereof a method of treating a disease or condition as described above, wherein the method comprises administering to a patient in need thereof a method of treating a disease or condition as described above, wherein the method comprises administering to a patient in need thereof a method of treating a disease or condition as described above, wherein the method comprises administering to a patient in need thereof a method of treating a disease or condition as described above, wherein the method comprises administering to a patient in need thereof a method of treating a disease or condition as described above ), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (V
  • the disease to be treated and/or prevented is selected from a disease or condition mediated by POL ⁇ and related diseases or conditions.
  • the POL ⁇ -mediated disease or condition and related diseases or conditions are selected from tumors or cancers.
  • the cancer is characterized by homologous recombination (HR) deficiency, decreased or absent expression of HR-related genes.
  • HR homologous recombination
  • the cancer is characterized by decreased or absent expression of a BRCA gene, absence of a BRAC gene, or reduced function of a BRCA protein.
  • the cancer is characterized by loss of the 53BP1/Shieldin complex.
  • the cancer is characterized by increased dependence on MMEJ DSB repair.
  • the cancer is characterized by being resistant to PARPi treatment with or without prior PARPi treatment.
  • the tumor or cancer is selected from a hematological tumor or a solid tumor, wherein the solid tumor includes but is not limited to soft tissue cancer, rhabdoid cancer, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblasts, central nervous system cancer, urinary tract cancer, upper gastrointestinal cancer, kidney cancer, skin cancer, esophageal cancer and pancreatic cancer; the hematological tumor includes but is not limited to lymphoma and leukemia.
  • the hematological tumor includes but is not limited to lymphoma and leukemia.
  • the present invention provides a compound represented by formula (M), or a stereoisomer, tautomer, deuterated compound, or pharmaceutically acceptable salt thereof:
  • RM1 is selected from iodine, biboronic acid pinacol ester group (Bpin) or ring A, wherein the definition of ring A is as described in general formula (Ia) or (Ib), and RM2 is selected from hydrogen or C1-6 alkyl.
  • the present invention provides an intermediate compound M1, the chemical name of which is 5'-iodo-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid methyl ester, and the structural formula thereof is as follows:
  • the present invention provides an intermediate compound M2, the chemical name of which is 1'-methyl-2'-oxo-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid methyl ester, and its structural formula is as follows:
  • the present invention provides an intermediate compound M3, whose structural formula is as follows:
  • ring A is as defined in formula (Ia) or (Ib).
  • the present invention provides a compound represented by the above formula (M) or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts in the preparation of the above formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (V ...
  • halogen refers to fluorine, chlorine, bromine, or iodine, unless otherwise indicated.
  • alkyl includes linear or branched monovalent saturated hydrocarbon groups.
  • alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc.
  • the " 1-6 " in " C1-6 alkyl” refers to a group containing 1, 2, 3, 4, 5, or 6 carbon atoms in a linear or branched form.
  • alkoxy refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl groups, ie, -O-alkyl.
  • haloalkyl refers to an alkyl group in which one or more H groups have been replaced by a halogen atom.
  • oxo or "oxo group” refers to an oxygen atom in the form of a divalent substituent, which forms a carbonyl group when attached to C, and forms a sulfoxide group or a sulfone group or an N-oxide group when attached to a heteroatom.
  • cycloalkyl refers to a ring system having at least one cyclized alkyl group. Preferably, it is a C3-12 cycloalkyl group, where " C3-12 " means that the cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms.
  • the cycloalkyl group can include monocyclic and polycyclic rings (e.g., having 2, 3, or 4 fused rings, spirocyclic rings, bridged rings, etc.).
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like; the cycloalkyl group can also be fused to an aryl, heterocyclyl, or heteroaryl ring, wherein the ring attached to the parent structure is the cycloalkyl group.
  • alkenyl refers to an alkyl group having one or more carbon-carbon double bonds, for example, ethenyl, propenyl, 1,3-butadiene, maleinyl, trans-butenyl, and the like.
  • alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds, for example, ethynyl, propynyl, and the like.
  • hydroxyalkyl refers to a hydroxy group further substituted with an alkyl group as defined above, i.e., -alkyl-OH, such as C1-6 hydroxyalkyl , including but not limited to -CH2OH , -C2H5OH , -CH2CH2CH2OH or -CH ( CH3 ) 2OH .
  • alkylthio refers to a straight or branched alkyl group connected by a sulfur atom, i.e., -S-alkyl, such as C1-6 alkylthio, including but not limited to methylthio, ethylthio, propylthio (including n-propylthio, isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio, tert-butylthio), pentylthio (including n-pentylthio, isopentylthio, neopentylthio), hexylthio (n-hexylthio, 2-methylpentylthio, 3-methylpentylthio, 2,3-dimethylbutylthio, 2,2-dimethylbutylthio), etc.
  • alkylsulfonyl refers to a straight-chain or branched alkyl group connected through a sulfone group, i.e., a -SO2 -alkyl group, such as a C1-6 alkylsulfonyl group, including but not limited to methylsulfonyl, ethylsulfonyl, propylsulfonyl (including n-propylsulfonyl and isopropylsulfonyl), butylsulfonyl (including n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl), pentanylsulfonyl (including n-pentylsulfonyl, isopentanylsulfonyl and neopentylsulfonyl), hex
  • alkylamino refers to an open-chain alkyl group containing a nitrogen atom, such as a C1-6 alkylamino group, including but not limited to methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, and the like.
  • alkyl ester group refers to a straight-chain or branched alkyl group connected by an ester group, that is, -alkyl- CO2- , such as C1-6 alkyl ester group, including but not limited to methyl ester group, ethyl ester group, propyl ester group (including n-propyl ester group and isopropyl ester group), butyl ester group (including n-butyl ester group, isobutyl ester group, sec-butyl ester group, tert-butyl ester group), pentyl ester group (including n-pentyl ester group, isopentyl ester group, neopentyl ester group), hexyl ester group (n-hexyl ester group, 2-methylpentyl ester group, 3-methylpentyl ester group, 2,3-dimethylbutyl ester group, 2,2-dimethylbutyl ester group),
  • alkyl acyl refers to a straight or branched alkyl group connected by an acyl group, i.e., -alkyl-CO-, such as C1-6 alkyl acyl, including but not limited to formyl, acetyl, propionyl (including n-propionyl and isopropionyl), butyryl (including n-butyryl, isobutyryl, sec-butyryl, tert-butyryl), valeryl (including n-valeryl, isovaleryl, pivaloyl), hexanoyl (n-hexanoyl, 2-methylvaleryl, 3-methylvaleryl, 2,3-dimethylbutyryl, 2,2-dimethylbutyryl), etc.
  • acyl group i.e., -alkyl-CO-, such as C1-6 alkyl acyl, including but not limited to formyl, acetyl, propionyl (including n-propiony
  • alkylamide refers to a straight or branched alkyl group connected by an amide group, i.e., -alkyl-CONH-, such as a C1-6 alkylamide, including but not limited to formamide, acetamide, propionamide (including n-propionamide and isopropionamide), butyramide (including n-butyramide, isobutyramide, sec-butyramide, tert-butyramide), valeramide (including n-valeramide, isovaleramide, pivaleramide), hexanamide (n-hexanamide, 2-methylvaleramide, 3-methylvaleramide, 2,3-dimethylbutyramide, 2,2-dimethylbutyramide), and the like.
  • amide group i.e., -alkyl-CONH-, such as a C1-6 alkylamide, including but not limited to formamide, acetamide, propionamide (including n-propionamide and isopropionamide
  • alkylsulfonyl refers to a straight or branched alkyl group connected through a sulfonyl group, i.e., -alkyl- SO2- , such as C1-6 alkylsulfonyl, including but not limited to methylsulfonyl, ethylsulfonyl, propylsulfonyl (including n-propylsulfonyl and isopropylsulfonyl), butanesulfonyl (including n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl), pentanesulfonyl (including n-pentanesulfonyl, isopentanesulfonyl and neopentanesulfonyl), hexanesulfonyl (n-hexanes
  • alkylsulfonyl refers to a straight or branched alkyl group connected through a sulfonyl group, i.e., -alkyl- SO2N- , such as C1-6 alkylsulfonyl, including but not limited to methanesulfonyl, ethylsulfonyl, propanesulfonyl (including n-propanesulfonyl and isopropylsulfonyl), butanesulfonyl (including n-butanesulfonyl, isobutylsulfonyl, sec-butanesulfonyl and tert-butanesulfonyl), pentanesulfonyl (including n-pentanesulfonyl, isopentanesulfonyl and neopentanesulfonyl), hexanesulfonyl (n-hexanesulfon
  • phosphoryl i.e. -PO 2 -, such as C 1-6 phosphoryl, includes but is not limited to methylphosphoryl, ethylphosphoryl, propylphosphoryl (including n-propylphosphoryl and isopropylphosphoryl), butylphosphoryl (including n-butylphosphoryl, isobutylphosphoryl, sec-butylphosphoryl and tert-butylphosphoryl), pentylphosphoryl (including n-pentylphosphoryl, isopentylphosphoryl and neopentylphosphoryl), hexylphosphoryl (n-hexylphosphoryl, 2-methylpentylphosphoryl, 3-methylpentylphosphoryl, 2,3-dimethylbutylphosphoryl and 2,2-dimethylbutylphosphoryl), and the like.
  • aryl refers to an unsubstituted or substituted monocyclic or fused-ring aromatic group comprising carbon ring atoms. Preferred are C 6-12 aryl groups, and more preferably, aryl groups are monocyclic or bicyclic aromatic ring groups comprising C 6-10 . Preferred are phenyl and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring.
  • Non-limiting examples include, but are not limited to, benzocyclopentyl.
  • heteroaryl in the present invention, unless otherwise specified, refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom, wherein the heteroatom is selected from N, O, and/or S, and wherein the nitrogen or sulfur heteroatom may be selectively oxidized, and the nitrogen heteroatom may be selectively quaternized.
  • it is a 5-14-membered heteroaryl, wherein the "5-14 members" in the 5-14-membered heteroaryl refers to a heteroaryl group consisting of 5-14 ring atoms of C, N, O, or S.
  • heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolyl, or isoquinolyl.
  • the heteroaryl group may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring.
  • heterocyclyl refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heterocyclic ring, wherein the heteroatom is selected from N, O and/or S.
  • the heterocyclyl group may include a monocyclic or polycyclic ring (e.g., having 2, 3 or 4 fused rings, spirocyclic rings, bridged rings, etc.).
  • the heterocyclyl group may be connected to the other parts of the compound via a ring-forming carbon atom or a ring-forming heteroatom.
  • the heterocyclyl group is a 3-14-membered group, wherein the "3-14 members" in the 3-14-membered heterocyclyl group refers to a heterocyclyl group consisting of 3-14 C, N, O or S ring atoms; more preferably a 3-8-membered heterocyclyl group, and even more preferably a 5-6-membered heterocyclyl group; wherein the nitrogen or sulfur heteroatom may be selectively oxidized, and the nitrogen heteroatom may be selectively quaternized.
  • heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridine, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl.
  • the heterocyclic group may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclic group.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc and the like. Particularly preferred are salts of ammonium, calcium, magnesium, potassium and sodium.
  • Nontoxic organic bases that can be derived into pharmaceutically acceptable salts include primary amines, secondary amines and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines.
  • non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • compound provided by the invention is a base
  • Such acid includes, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid
  • Prodrugs of the compounds of the present invention are encompassed within the scope of the present invention. Generally, such prodrugs are functional derivatives that are readily converted in vivo into the desired compound. For example, any pharmaceutically acceptable salt, ester, ester salt, or other derivative of a compound of the present invention, which upon administration to a recipient, can directly or indirectly provide a compound of the present invention or a pharmaceutically active metabolite or residue thereof.
  • the compounds of the present invention may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers.
  • the present invention includes all possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts thereof.
  • the present invention also includes all isotopes of atoms, whether in intermediates or final compounds.
  • Isotopes include atoms with the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • pharmaceutical composition refers to a mixture of one or more compounds of the present invention or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present invention to an organism.
  • pharmaceutically acceptable excipient refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound.
  • Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.
  • treat generally refers to obtaining a desired pharmacological and/or physiological effect. This effect can be therapeutic in terms of partial or complete stabilization or cure of a disease and/or side effects caused by the disease.
  • treat encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., arresting its progression; or (b) relieving the symptoms of the disease, i.e., causing regression of the disease or its symptoms.
  • the term "effective amount” means an amount of a compound of the present invention 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 as described herein.
  • the amount of a compound of the present invention 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 knowledge and this disclosure.
  • the present invention has the following beneficial effects:
  • this invention has developed a series of novel heterocyclic amide compounds. Biological experiments have demonstrated that the compounds can significantly inhibit cell proliferation and Pol ⁇ ATPase activity, exhibit excellent in vivo anti-tumor efficacy, exhibit low hERG toxicity, exhibit stable in vitro liver microsome metabolism, and exhibit favorable pharmacokinetic properties. Furthermore, the compounds provided by this invention exhibit novel, safe, environmentally friendly synthetic routes, and possess good production feasibility.
  • H 2 SO 4 sulfuric acid; HNO 3 : nitric acid; Na 2 SO 4 : sodium sulfate; EA: ethyl acetate; DMSO: dimethyl sulfoxide; K 2 CO 3 : potassium carbonate; NaCl: sodium chloride; PE: petroleum ether; DMF: N,N-dimethylformamide; AcOH: acetic acid; Fe: iron powder; NaHCO 3 : sodium bicarbonate; Pd(dppf)Cl 2 : [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; THF: tetrahydrofuran; HCl: hydrochloric acid; MeOH: methanol; N 2 : nitrogen; DCM: dichloromethane; NaH: sodium hydride; MeCN: acetonitrile; Pd/C: palladium on carbon; Pd(PPh 3 ) 4 : tetrakistriphenylpho
  • reaction raw materials, common intermediates, etc. involved in the embodiments of the present invention can be purchased commercially or obtained in-house.
  • the preparation process of the raw materials and common intermediates that need to be obtained in-house is described in detail below.
  • Step 1 Synthesis of 1-(tert-butyl) 6-methyl-2-oxoindoline-1,6-dicarboxylate (M1-2)
  • Step 2 Synthesis of 1'-(tert-butyl)6'-methyl 2'-oxospiro[cyclopropane-1,3'-indoline]-1',6'-dicarboxylate (M1-3)
  • Step 3 Synthesis of methyl 2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (M1-4)
  • Step 4 Synthesis of methyl 1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (M1-5)
  • Step 5 Synthesis of methyl 5'-iodo-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (M1)
  • Step 1 Synthesis of methyl 5'-bromo-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (M2-1)
  • Step 2 Synthesis of methyl 1'-methyl-2'-oxo-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxylate (M2)
  • the X is selected from bromine or iodine.
  • Step 1 Synthesis of methyl 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (1-1)
  • Step 2 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (1-2)
  • Step 3 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (1)
  • Step 2 Synthesis of tert-butyl 6'-bromo-2'-oxospiro[cyclopropane-1,3'-dihydroindole]-1'-carboxylate (2-3)
  • Step 5 Synthesis of 6'-bromo-5'-(2-chloroacetyl)-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one (2-6)
  • Step 6 Synthesis of 6'-bromo-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxylic acid (2-7)
  • Compound 2-6 (50 mg, 0.15 mmol) was dissolved in pyridine (3 mL), heated to 90°C with stirring for 3 hours, then cooled to 50°C and reacted for 16 hours. Filter the mixture, add the filter cake to 4N sodium hydroxide solution (5 mL), heat to 80°C and stir for 16 hours. Cool to room temperature, adjust the pH to 3-4 with 2N hydrochloric acid, and precipitate a solid. Filter the solid, wash the filter cake with water, and dry to obtain compound 2-7, which was used in the next step without purification.
  • Step 7 Synthesis of methyl 6'-bromo-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxylate (2-8)
  • Step 8 Synthesis of methyl 6'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxylate (2-9)
  • Step 9 Synthesis of 6'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxylic acid (2-10)
  • Step 10 Synthesis of 6'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxamide (2)
  • Methyl 2-bromo-4-fluorobenzoate (10.0 g, 43.10 mmol) was dissolved in H2SO4 (20 mL), and HNO3 (20 mL) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 4 hours. The reaction solution was poured into ice water (200 mL), and the pH was adjusted to above 7 with saturated aqueous sodium carbonate solution (200 mL). The mixture was extracted with EA (200 mL ⁇ 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous Na2SO4 , filtered, and the filtrate was concentrated under reduced pressure to give compound 24-1 (3.0 g) in a yield of 25.1%.
  • Step 3 Synthesis of methyl 2-bromo-4-(1-(ethoxycarbonyl)cyclopropyloxy)-5-nitrobenzoate (24-3)
  • Step 4 Synthesis of methyl 7-bromo-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylate (24-4)
  • Step 5 Synthesis of methyl 7-bromo-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylate (24-5)
  • Step 6 Synthesis of methyl 7-(2-chloro-5-methoxypyridin-4-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylate (24-6)
  • Step 7 Synthesis of 7-(2-chloro-5-methoxypyridin-4-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylic acid (24-7)
  • Step 8 Synthesis of 7-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxamide (24)
  • Step 1 Synthesis of methyl 5'-(2-methoxy-5-(trifluoromethyl)phenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (43-1)
  • Step 2 Synthesis of 5'-(2-methoxy-5-(trifluoromethyl)phenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (43-2)
  • Step 3 Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(2-methoxy-5-(trifluoromethyl)phenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (43)
  • Step 1 Synthesis of methyl 5'-(5-cyano-2-methoxyphenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (45-1)
  • Step 2 Synthesis of 5'-(5-cyano-2-methoxyphenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (45-2)
  • Step 3 Synthesis of 5'-(5-cyano-2-methoxyphenyl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (45)
  • Step 2 Synthesis of methyl 5'-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (47-2)
  • Step 3 Synthesis of 5'-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (47-3)
  • Step 4 Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (47)
  • Step 1 Synthesis of 5-((tetrahydrofuran-3-yl)methoxy)-1,3,4-thiadiazole-2-amine (81-1)
  • Step 2 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-3-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (81)
  • Step 1 Synthesis of 5-((tetrahydro-2H-pyran-4-yl)methoxy)-1,3,4-thiadiazol-2-amine (83-1)
  • Step 2 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-3-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (83)
  • 6-Chloro-5-fluoropyridin-3-ol (1.0 g, 6.80 mmol) was dissolved in MeCN (10 mL), and iodomethane (2.9 g, 20.40 mmol) and potassium carbonate (2.8 g, 20.40 mmol) were added. The mixture was allowed to react at room temperature for 3 h. After completion of the reaction, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL ⁇ 3).
  • Step 3 Synthesis of methyl 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (96-3)
  • Step 4 Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (96-4)
  • Step 5 Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (96)
  • Step 1 Synthesis of (R)-5-((1,4-dioxan-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (97-1)
  • Step 2 Synthesis of (R)-N-(5-(((1,4-dioxan-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (97)
  • Step 1 Synthesis of tert-butyl (5-(2-cyclopropylethyl)-1,3,4-thiadiazol-2-yl)carbamate (98-1)
  • Step 3 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(2-cyclopropylethyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (98)
  • Step 1 Synthesis of tert-butyl (5-(3,3-dimethylbut-1-yn-1-yl-1,3,4-thiadiazol-2-yl)carbamate (99-1)
  • Step 3 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(3,3-dimethylbut-1-yn-1-yl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (99)
  • Step 1 Synthesis of tert-butyl (5-((tetrahydro-2H-pyran-4-yl)ethynyl)-1,3,4-thiadiazol-2-yl)carbamate (100-1)
  • Step 3 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydro-2H-pyran-4-yl)ethynyl)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (100)
  • Step 1 Synthesis of (R)-5-((4-methylmorpholin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (101-1)
  • Step 2 Synthesis of (R)-5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-3-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (101)
  • Example 102 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-N-(5-(3-morpholinopropoxy)-1,3,4-thiadiazol-2-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (102)
  • Step 2 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-N-(5-(3-morpholinopropoxy)-1,3,4-thiadiazol-2-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (102)
  • Example 103 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(3-(dimethylamino)propoxy)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (103)
  • Step 1 Synthesis of 5-(3-(dimethylamino)propoxy)-1,3,4-thiadiazole-2-amine (103-1)
  • Step 2 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(3-(dimethylamino)propoxy)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (103)
  • Example 104 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (104)
  • Step 1 Synthesis of 5-((tetrahydrofuran-2-yl)methoxy)-1,3,4-thiadiazole-2-amine (104-1)
  • Step 2 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (104)
  • Example 105 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (105)
  • Step 2 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (105)
  • Example 106 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methylspiro[cyclopropane-1,3'-indoline]-6'-carboxamide (106)
  • Step 1 Synthesis of methyl 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methylspiro[cyclopropane-1,3'-indoline]-6'-carboxylate (106-1)
  • Step 3 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methylspiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (106-2)
  • Step 4 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methylspiro[cyclopropane-1,3'-indoline]-6'-carboxamide (106)
  • the crude compound 106-2 was dissolved in dichloromethane (2 mL), and 5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (30 mg, 0.18 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (50 mg, 0.18 mmol), and N-methylimidazole (29 mg, 0.36 mmol) were added sequentially. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with EA (30 mL x 3).
  • Step 1 Synthesis of methyl 5'-(3-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (107-1)
  • Step 2 Synthesis of 5'-(3-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (107-2)
  • Step 3 Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(3-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (107)
  • target compound 108 was similar to that of compound 107 in Example 107, except that the raw material (3-methoxypyridin-4-yl)boric acid was replaced with (5-methoxy-2-methylpyridin-4-yl)boric acid.
  • the other intermediate raw materials and preparation method were the same as those in Example 107 to obtain target compound 108 (4 mg) with a total yield of 0.9%.
  • target compound 109 was similar to that of compound 107 in Example 107, except that the raw material (3-methoxypyridin-4-yl)boric acid was replaced with (5-methoxy-2-cyclopropylpyridin-4-yl)boric acid.
  • the other intermediate raw materials and preparation method were the same as those in Example 107 to obtain target compound 109 (9 mg) with a total yield of 1.8%.
  • target compound 112 was similar to that of compound 110 in Example 110, except that compound 1-2 was replaced by compound 96-4. Other raw materials and preparation methods were the same as those in Example 110 to obtain target compound 112 (7 mg) with a yield of 10.8%.
  • target compound 113 was prepared similar to that of compound 112 in Example 112, except that the raw material 5-methoxy-1,3,4-thiadiazole-2-amine was replaced with 5-ethoxy-1,3,4-thiadiazole-2-amine.
  • the other raw materials and preparation method were the same as those in Example 112 to obtain target compound 113 (6 mg) with a yield of 9.0%.
  • target compound 114 was similar to that of compound 110 in Example 110, except that compound 1-2 was replaced by compound 47-2. Other raw materials and preparation methods were the same as those in Example 110 to obtain target compound 114 (15 mg) with a yield of 38.5%.
  • target compound 115 was similar to that of compound 112 in Example 112, except that 5-methoxy-1,3,4-thiadiazole-2-amine was replaced with 5-ethyl-1,3,4-thiadiazole-2-amine.
  • the other intermediate raw materials and preparation method were the same as those in Example 112, and target compound 115 (13 mg) was obtained with a yield of 25.1%.
  • Step 1 Synthesis of 5-(methoxy-d 3 )-1,3,4-thiadiazol-2-amine (116-1)
  • Step 2 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d 3 )-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (116)
  • Step 1 Synthesis of methyl 5-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (117-1)
  • Step 2 Synthesis of methyl 3,3,5-tribromo-1-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (117-2)
  • Step 3 Synthesis of methyl 5-bromo-1-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (117-3)
  • Step 4 Synthesis of methyl 5'-bromo-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-6'-carboxylate (117-4)
  • Step 5 Synthesis of methyl 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-6'-carboxylate (117-5)
  • Step 6 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-6'-carboxylic acid (117-6)
  • Step 7 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-6'-carboxamide (117)
  • Step 1 Synthesis of 2-chloro-3-fluoro-5-(methoxy-d 3 )pyridine (119-1)
  • Step 2 Synthesis of 2-chloro-3-fluoro-4-iodo-5-(methoxy-d 3 )pyridine (119-2)
  • Step 3 Synthesis of methyl 5'-(2-chloro-3-fluoro-5-(methoxy-d 3 )pyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (119-3)
  • Step 4 Synthesis of 5'-(2-chloro-3-fluoro-5-(methoxy-d 3 )pyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (119-4)
  • Step 5 Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d 3 )-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (119)
  • Step 1 Synthesis of methyl 4-bromo-1-methyl-1H-indole-6-carboxylate (120-1)
  • Step 2 Synthesis of methyl 1,4-dimethyl-1H-indole-6-carboxylate (120-2)
  • Step 3 Synthesis of methyl 1,4-dimethyl-2-oxoindole-6-carboxylate (120-3)
  • Step 4 Synthesis of methyl 1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (120-4)
  • Step 5 Synthesis of methyl 5'-bromo-1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (120-5)
  • Step 6 Synthesis of methyl 5'-(2-chloro-5-methoxypyridin-4-yl)-1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (120-6)
  • Step 7 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (120-7)
  • Step 8 Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (120)
  • Example 121 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d 3 )-1,3,4-thiadiazol-2-yl)-1'-(methyl-d 3 )-2'-oxospiro[cyclopropane-1,3'-indole]-6'-carboxamide (121)
  • the preparation method of compound 121-1 refers to the preparation method of intermediate M2, except that deuterated iodomethane is replaced by iodomethane, and the other intermediate raw materials are the same as the preparation method.
  • the preparation method of target compound 121 refers to the preparation method of compound 119 in Example 119, except that intermediate M2 is replaced by compound 121-1 and compound 119-2 is replaced by compound 96-2.
  • Other raw materials and preparation methods are the same as in Example 119 to obtain target compound 121 (15 mg) with a three-step yield of 3.6%.
  • Example 122 Synthesis of 7-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d3)-1,3,4-thiadiazol-2-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxamide (122)
  • Step 1 Synthesis of methyl 4-methyl-3-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylate (122-1)
  • Step 2 Synthesis of methyl 7-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylate (122-2)
  • Step 3 Synthesis of 7-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylic acid (122-3)
  • Step 4 Synthesis of 7-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d 3 )-1,3,4-thiadiazol-2-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxamide (122)
  • Example 127 Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-N-(5-(oxetane-3-yloxy)-1,3,4-thiadiazol-2-yl)-2'-oxospiro[cyclopropane-1,3'-indole]-6'-carboxamide (127)
  • Oxetane-3-ol (1.24 g, 16.76 mmol) was dissolved in tetrahydrofuran (10 mL) and DMF (0.5 mL). Under nitrogen, sodium hydride (900 mg, 22.34 mmol) was added under an ice-water bath. The mixture was reacted at 0°C for 1 h under nitrogen. 5-Bromo-1,3,4-thiadiazol-2-amine (2.0 g, 11.17 mmol) was then added and the reaction continued at 0°C for 2 h under nitrogen. The reaction mixture was quenched by water (20 mL) and extracted with ethyl acetate (20 mL x 3).
  • Step 2 Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-N-(5-(oxetan-3-yloxy)-1,3,4-thiadiazol-2-yl)-2'-oxospiro[cyclopropane-1,3'-indole]-6'-carboxamide (127)
  • Example 129 Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-3-yl)oxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indole]-6'-carboxamide (129)
  • the preparation method of target compound 129 refers to the preparation method of compound 127 in Example 127, except that oxetane-3-ol is replaced by 3-hydroxytetrahydrofuran.
  • the other raw materials and preparation method are the same as Example 127 to obtain target compound 129 (100 mg) with a two-step yield of 1.6%.
  • the ADP Glo assay was used to test the ability of compounds to bind to and inhibit Pol ⁇ helicase activity in vitro.
  • the ADP-Glo TM Kinase Assay kit was provided by Zhejiang Promega Biotechnology Co., Ltd., model number V9102.
  • the compound was dissolved in DMSO and then serially diluted three-fold with sterile deionized ultrapure water to create eight compound solutions.
  • a 2 ⁇ helicase domain Pol ⁇ enzyme and DNA mixture was prepared in a buffer solution (25 mM Tris-HCl pH 7.5, 6 mM NaCl, 1.5 mM MgCl 2 , 5% (v/v) glycerol, 0.01% (v/v) Triton X-100, 0.01% (w/v) Bovine ⁇ -Globulin, 1 mM dithiothreitol).
  • a substrate solution containing 2 ⁇ ATP was prepared in the buffer solution. 1 ⁇ L of each compound solution was added to a 384-well plate and centrifuged.
  • HCT116 BRCA2 -/- cells (provided by Guangzhou Yuanjing Biotechnology Co., Ltd., model YKO-H668) in the logarithmic phase were seeded in 96-well cell culture plates at 800/well. After 24 hours of incubation at 37 ° C and 5% CO 2 , compound solutions of various concentrations were added and continued to be incubated at 37 ° C and 5% CO 2 for 7 days. After 7 days, 10 ⁇ L of CCK8 solution was added to the cell culture plate and incubated in a 37 ° C incubator for 2 hours. After 2 hours, the absorbance at a wavelength of 450 nM was measured using a microplate reader and the inhibition rate of each compound was calculated. The results are shown in Table 2.
  • the compounds of the present invention have good plasma exposure and oral bioavailability after oral administration, showing excellent oral administration potential.
  • test substance and positive control testosterone were incubated with microsomes in the presence of NADPH for 120 min, and a negative control group was set up (the test substance was incubated with microsomes for 120 min without any coenzyme); samples were taken at 0 min and 120 min, and 300 ⁇ L of pre-cooled methanol solution containing the internal standard (ramelteon: 1.000 ng/mL) was added to the sample. The sample was vortexed (2500 rpm, 1 min) and centrifuged (4700 rpm, 4°C) for 10 min. 50.0 ⁇ L of the supernatant + 200 ⁇ L of pure water were taken and placed in a 96-well plate.
  • the plate was vortexed (1000 rpm, 10 min), sealed, and subjected to LC-MS/MS analysis.
  • the parent amount of the test article or probe substrate was measured by LC-MS/MS.
  • the test results are shown in Table 5 below.

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Abstract

The present invention relates to the technical field of medicine, and in particular to a Polθ inhibitor, a preparation method therefor and a use thereof in medicine. The present invention provides a Polθ inhibitor represented by formula (Ia) or (Ib), a composition comprising same and a use thereof, wherein the compound can be used for treating or preventing Polθ-mediated diseases or disorders and related diseases or disorders.

Description

一种杂环酰胺类化合物及其在医药上的应用A heterocyclic amide compound and its application in medicine 技术领域Technical Field

本发明涉及医药技术领域，具体涉及一种式(Ia)或(Ib)所示的杂环酰胺类化合物或其药学上可接受的盐，及其在制备治疗相关疾病的药物中的应用。The present invention relates to the field of medical technology, and specifically to a heterocyclic amide compound represented by formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, and use thereof in preparing a medicament for treating related diseases.

背景技术Background Art

DNA损伤常见的有单链断裂、双链断裂(double-strand breaks,DSB)和碱基损伤等多种形式，其中以DSB损伤最为严重，DSB若不能被及时修复，染色体会出现断裂、缺失、重排等异常。因此，DSB的及时修复对维持基因组的稳定性、保证细胞存活以及抑制肿瘤的发生发展均具有重要作用。双链DNA断裂的修复大致可分为三个主要途径：同源重组修复(homologous recombination,HR)，一种以受损DNA同源的双链DNA作为模板来合成DNA的修复过程，具有高保真度，错配修复率低；非同源末端链接(non-homologous end joining,NHEJ)，通过捕获断裂双链DNA的损伤末端，利用蛋白质的相互作用，直接将受损末端相连，是一种容易出错的修复过程；微同源末端链接(microhomology-mediated end joining,MMEJ)，一种更广泛且容易出错的末端连接机制，也被称为替代端连接(alternative end-joining,alt-EJ)，由DNA端侧的微同源序列退火所驱动。Common forms of DNA damage include single-strand breaks, double-strand breaks (DSBs), and base damage. DSBs are the most serious. If DSBs are not repaired promptly, chromosomes may experience abnormalities such as breakage, deletions, and rearrangements. Therefore, timely DSB repair plays an important role in maintaining genomic stability, ensuring cell survival, and inhibiting the occurrence and development of tumors. The repair of double-stranded DNA breaks can be roughly divided into three main pathways: homologous recombination (HR), a repair process that uses double-stranded DNA homologous to the damaged DNA as a template to synthesize DNA with high fidelity and low mismatch repair rate; non-homologous end joining (NHEJ), which captures the damaged ends of the broken double-stranded DNA and directly connects the damaged ends through protein interactions, which is an error-prone repair process; microhomology-mediated end joining (MMEJ), a more widespread and error-prone end joining mechanism, also known as alternative end-joining (alt-EJ), is driven by the annealing of microhomologous sequences on the DNA end sides.

在正常情况下，MMEJ作为HR的替代修复，发生的比例很低，但在HR缺陷的细胞中，MMEJ成为主要的DSB修复方式。例如BRCA基因缺陷的癌细胞中，HR修复方式受损，MMEJ成为DSB主要的修复途径。在此过程中，DNA聚合酶θ(Polθ)具有非常关键的作用。Polθ在切除的DSB处将RPA替换下来以促进微同源ssDNA的退火，随后合成DNA填补切除的缺口，完成损伤末端的连接。Polθ在正常组织中几乎不表达，但在多种肿瘤类型(如乳腺癌、卵巢癌、结直肠癌和肺癌)中高度表达，其表达上调与癌症预后不良相关。在这些肿瘤中普遍存在同源重组修复缺陷(homologous recombination deficiency,HRD)，与DNA修复相关的肿瘤抑制基因(包括BRCA1、BRCA2、ATM和FANCD2)缺失。Under normal circumstances, MMEJ, an alternative repair method to HR, occurs at a very low rate. However, in HR-deficient cells, MMEJ becomes the primary DSB repair pathway. For example, in cancer cells with BRCA gene defects, HR repair is impaired, and MMEJ becomes the primary DSB repair pathway. In this process, DNA polymerase θ (Polθ) plays a crucial role. Polθ replaces RPA at the resected DSB to promote the annealing of microhomology ssDNA, and then synthesizes DNA to fill the resected gap, completing the connection of the damaged ends. Polθ is barely expressed in normal tissues but is highly expressed in various tumor types (such as breast, ovarian, colorectal, and lung cancers), and its upregulation is associated with poor cancer prognosis. Homologous recombination deficiency (HRD) is common in these tumors, and tumor suppressor genes associated with DNA repair (including BRCA1, BRCA2, ATM, and FANCD2) are lost.

关于Polθ的研究为肿瘤治疗提供了一种新的靶向策略。在HR和NHEJ受损或失活的癌细胞中，DSB的修复高度依赖MMEJ过程，若Polθ的活性受到抑制，将使细胞丧失执行MMEJ的能力，使得DSB无法得到及时修复，长期累积导致癌细胞死亡。因此对于携带HRD例如BRCA1/2突变的肿瘤患者，Polθ抑制剂可以与PARP抑制剂联合使用达到协同杀伤肿瘤的效果；此外，接受PARP抑制剂维持治疗的患者会出现耐药性，这可能是由于发生基因突变从而部分恢复了HR通路活性，例如TP53BP1的丢失，此时HR修复方式主要为Polθ依赖性的MMEJ，因此Polθ抑制剂还可以克服对PARP抑制剂的耐药性，为更多患者带来福音。Research on Polθ provides a new targeted strategy for cancer treatment. In cancer cells with damaged or inactivated HR and NHEJ, DSB repair is highly dependent on the MMEJ process. If Polθ activity is inhibited, the cells will lose the ability to perform MMEJ, making it impossible for DSB to be repaired in a timely manner. Long-term accumulation leads to cancer cell death. Therefore, for patients with tumors carrying HRD, such as BRCA1/2 mutations, Polθ inhibitors can be used in combination with PARP inhibitors to achieve a synergistic tumor-killing effect. In addition, patients receiving maintenance treatment with PARP inhibitors will develop drug resistance, which may be due to gene mutations that partially restore HR pathway activity, such as the loss of TP53BP1. At this time, the main HR repair method is Polθ-dependent MMEJ. Therefore, Polθ inhibitors can also overcome resistance to PARP inhibitors, bringing good news to more patients.

综上所述，Polθ抑制剂可以为同源重组修复缺陷的肿瘤靶向治疗提供一种新的策略，有着巨大的未曾满足的临床需求，开发新型高效的Polθ抑制剂具有巨大的科学研究意义和临床价值。本发明旨在提供一种结构全新的杂环酰胺类衍生物及其用途，所描述的化合物具有优良的Polθ抑制活性，可作为Polθ抑制剂用于相关肿瘤或癌症的治疗。In summary, Polθ inhibitors could provide a new strategy for the targeted treatment of tumors deficient in homologous recombination repair, representing a significant unmet clinical need. The development of novel and highly effective Polθ inhibitors holds immense scientific research significance and clinical value. The present invention provides novel heterocyclic amide derivatives and their uses. These compounds possess excellent Polθ inhibitory activity and can be used as Polθ inhibitors in the treatment of related tumors or cancers.

发明内容Summary of the Invention

本发明要解决的技术问题在于，提供一种结构全新的杂环酰胺类化合物，其可作为Polθ抑制剂，用于制备治疗Polθ介导的疾病或病症及相关疾病或病症的药物。为解决上述技术问题，本发明提供的技术方案如下：The technical problem to be solved by the present invention is to provide a novel heterocyclic amide compound that can be used as a Polθ inhibitor for the preparation of a drug for treating Polθ-mediated diseases or conditions and related diseases or conditions. To solve the above technical problem, the present invention provides the following technical solutions:

一种杂环酰胺类化合物，为具有如下结构通式(I)的化合物、同分异构体或其药学上可接受的盐：
A heterocyclic amide compound, a compound having the following structural formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof:

其中：in:

环C选自 Ring C is selected from

U’、V’、Z’、W’各自独立地选自且U’、V’、Z’、W’中至少有一个选自 U', V', Z', W' are each independently selected from And at least one of U', V', Z', W' is selected from

Ru、Rv、Rw、Rx各自独立地选自氢、氘、卤素、氰基、羟基、氨基、巯基、氧代基、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的C3-6环烷基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷砜基、取代或未取代的C1-6烷硫基、取代或未取代的C1-6烷胺基、取代或未取代的4-10元杂环基、取代或未取代的5-14元杂芳基、取代或未取代的C6-12芳基；当C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、4-10元杂环基、5-14元杂芳基、C6-12芳基存在取代基时，可被至少一个如下基团取代：氘、卤素、氰基、羟基、氨基、巯基、氧代基、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的C3-6环烷基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷砜基、取代或未取代的C1-6烷硫基、取代或未取代的C1-6烷胺基、取代或未取代的C1-6烷脂基、取代或未取代的C1-6烷基酰基、取代或未取代的C1-6烷基酰胺基、取代或未取代的C1-6烷基磺酰基、取代或未取代的C1-6烷基磺酰胺基、取代或未取代的C1-6磷酰基、取代或未取代的3-8元杂环基、取代或未取代的5-10元杂芳基、取代或未取代的C6- 14芳基；进一步，当C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷脂基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6烷基磺酰胺基、C1-6磷酰基、3-8元杂环基、5-10元杂芳基、C6-14芳基存在取代基时，可被至少如下一个基团取代：氘、卤素、氰基、硝基、羟基、氨基、巯基、氧代基、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的C3-6环烷基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷砜基、取代或未取代的C1-6烷硫基、取代或未取代的C1-6烷胺基、取代或未取代的C1-6烷脂基、取代或未取代的C1-6烷基酰基、取代或未取代的C1-6烷基酰胺基、取代或未取代的C1-6烷基磺酰基、取代或未取代的C1-6烷基磺酰胺基、取代或未取代的C1-6磷脂基、取代或未取代的3-8元杂环基、取代或未取代的5-14元杂芳基、取代或未取代的C6-12芳基；更进一步，当C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷脂基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1- 6烷基磺酰胺基、C1-6磷脂基、3-8元杂环基、5-14元杂芳基、C6-12芳基存在取代基时，可被至少如下一个基团取代：氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基；R u , R v , R w , and R x are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, or substituted or unsubstituted C 6-12 aryl; when C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C When substituents are present, C 1-6 alkylthio, C 1-6 alkylamino, 4-10 membered heterocyclyl, 5-14 membered heteroaryl, or C 6-12 aryl may be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkyl fat, substituted or unsubstituted C 1-6 alkylacyl, substituted or unsubstituted C 1-6 alkylamide, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylfatty acid, C 1-6 alkylacyl, C 1-6 alkylamide, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamido, C 1-6 phosphoryl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylfatty acid, C 1-6 alkylacyl, C 1-6 alkylamide, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamido, C 1-6 phosphoryl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C When a 6-14 aryl group has a substituent, it may be substituted by at least one of the following groups: deuterium, halogen, cyano, nitro, hydroxyl, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfone, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkyl fat, substituted or unsubstituted C 1-6 alkylacyl, substituted or unsubstituted C 1-6 alkylamide, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylsulfonamido, substituted or unsubstituted C C 1-6 phospholipid group, a substituted or unsubstituted 3-8 membered heterocyclyl, a substituted or unsubstituted 5-14 membered heteroaryl, or a substituted or unsubstituted C 6-12 aryl group; further, when a C 1-6 alkyl, a C 2-6 alkenyl, a C 2-6 alkynyl, a C 3-6 cycloalkyl, a C 1-6 alkoxy, a C 1-6 alkylsulfonyl, a C 1-6 alkylthio, a C 1-6 alkylamino, a C 1-6 alkyl fat group, a C 1-6 alkylacyl group, a C 1-6 alkylamide group, a C 1-6 alkylsulfonyl group, a C 1-6 alkylsulfonamide group, a C 1-6 phospholipid group, a 3-8 membered heterocyclyl, a 5-14 membered heteroaryl group, or a C 6-12 aryl group has a substituent, it may be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxy, amino, thiol, oxo, or C 1-6 alkyl group;

Ry和Rz相互连接与共有碳原子形成3-8元的脂肪环或杂环，前述脂肪环或杂环可被至少如下一个基团取代：氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C1- 6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、4-10元杂环基、5-14元杂芳基或C6-12芳基； Ry and Rz are linked to each other and form a 3-8 membered aliphatic or heterocyclic ring with a common carbon atom, and the aforementioned aliphatic or heterocyclic ring may be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfone, C1-6 alkylthio, C1-6 alkylamino, 4-10 membered heterocyclyl, 5-14 membered heteroaryl or C6-12 aryl ;

n1选自0、1、2或3；n 1 is selected from 0, 1, 2 or 3;

X’、Ya和Yb各自独立地选自N或CR1a；X', Ya and Yb are each independently selected from N or CR 1a ;

R1a选自氢、氘、卤素、氰基、羟基、氨基、巯基、氧代基、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的C3-6环烷基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷砜基、取代或未取代的C1-6烷硫基、取代或未取代的C1-6烷胺基、取代或未取代的C1-6烷脂基、取代或未取代的C1-6烷基酰基、取代或未取代的C1-6烷基酰胺基、取代或未取代的C1-6烷基磺酰基、取代或未取代的C1-6烷基磺酰胺基、取代或未取代的C1-6磷酰基、取代或未取代的3-8元杂环基、取代或未取代的5-10元杂芳基、取代或未取代的C6-14芳基；当C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷脂基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6烷基磺酰胺基、C1-6磷酰基、3-8元杂环基、5-10元杂芳基、C6-14芳基存在取代基时，可被至少如下一个基团取代：氘、卤素、氰基、硝基、羟基、氨基、巯基、氧代基、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的C3-6环烷基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷砜基、取代或未取代的C1-6烷硫基、取代或未取代的C1-6烷胺基、取代或未取代的C1-6烷脂基、取代或未取代的C1-6烷基酰基、取代或未取代的C1-6烷基酰胺基、取代或未取代的C1-6烷基磺酰基、取代或未取代的C1-6烷基磺酰胺基、取代或未取代的C1-6磷脂基、取代或未取代的3-8元杂环基、取代或未取代的5-14元杂芳基、取代或未取代的C6-12芳基；进一步，当C1-6烷基、C2-6烯基、C2- 6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷脂基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6烷基磺酰胺基、C1-6磷脂基、3-8元杂环基、5-14元杂芳基、C6-12芳基存在取代基时，可被至少如下一个基团取代：氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基；R 1a is selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkylfatty, substituted or unsubstituted C 1-6 alkylacyl, substituted or unsubstituted C 1-6 alkylamido, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylsulfonamido, substituted or unsubstituted C C 1-6 phosphoryl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 6-14 aryl; when C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylfatty, C 1-6 alkylacyl , C 1-6 alkylamide, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide, C 1-6 phosphoryl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C 6-14 aryl has a substituent, it may be substituted by at least one of the following groups: deuterium, halogen, cyano, nitro, hydroxy, amino, mercapto, oxo, substituted or unsubstituted C C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfone, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkylfatty, substituted or unsubstituted C 1-6 alkylacyl, substituted or unsubstituted C 1-6 alkylamido, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylsulfonamido, substituted or unsubstituted C 1-6 phospholipid group, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted C 6-12 aryl; further, when C 1-6 alkyl , C 2-6 alkenyl, C When substituents are present, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfone, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylfatty, C1-6 alkylacyl, C1-6 alkylamide, C1-6 alkylsulfonyl, C1-6 alkylsulfonamido, C1-6 phospholipid group, 3-8 membered heterocyclyl, 5-14 membered heteroaryl, or C6-12 aryl may be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxy, amino, thiol, oxo, or C1-6 alkyl;

环B为3-18元杂环基、5-10元杂芳基、C6-14芳基或4-10元环烯基；当环B存在取代基时，可被至少如下一个基团取代：氘、卤素、氰基、羟基、氨基、巯基、氧代基、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的C3-6环烷基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷砜基、取代或未取代的C1-6烷硫基、取代或未取代的C1-6烷胺基、取代或未取代的3-8元杂环基、取代或未取代的C1-6烷脂基、取代或未取代的C1-6烷基酰基、取代或未取代的C1-6烷基酰胺基、取代或未取代的C1-6烷基磺酰基、取代或未取代的C1-6烷基磺酰胺基；当C1-6烷基、C2-6烯基、C2- 6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、3-8元杂环基、C1-6烷脂基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6烷基磺酰胺基存在取代基时，可被至少如下一个基团取代：氘、卤素、氰基、硝基、羟基、氨基、巯基、氧代基、取代或未取代的C1-6烷基、取代或未取代的C2- 6烯基、取代或未取代的C2-6炔基、取代或未取代的C3-6环烷基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷砜基、取代或未取代的C1-6烷硫基、取代或未取代的C1-6烷胺基、取代或未取代的C1-6烷脂基、取代或未取代的C1-6烷基酰基、取代或未取代的C1-6烷基酰胺基、取代或未取代的C1-6烷基磺酰基、取代或未取代的C1-6烷基磺酰胺基、取代或未取代的C1-6磷脂基、取代或未取代的3-8元杂环基、取代或未取代的5-14元杂芳基、取代或未取代的C6-12芳基；进一步，当C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷脂基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6烷基磺酰胺基、C1-6磷脂基、3-8元杂环基、5-14元杂芳基、C6-12芳基存在取代基时，可被至少如下一个基团取代：氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基；Ring B is a 3-18 membered heterocyclyl, a 5-10 membered heteroaryl, a C 6-14 aryl or a 4-10 membered cycloalkenyl; when ring B has a substituent, it may be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxy, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C 1-6 alkyl aliphatic, substituted or unsubstituted C 1-6 alkylacyl, substituted or unsubstituted C 1-6 alkylamido, substituted or unsubstituted C C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylsulfonyl, C 1-6 alkylsulfonylamino; when C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylamino, 3-8 membered heterocyclyl, C 1-6 alkyl aliphatic group, C 1-6 alkylacyl, C 1-6 alkylamide, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonylamino, C 1-6 alkylsulfonylamino, when substituents are present, they may be substituted by at least one of the following groups: deuterium, halogen, cyano, nitro , hydroxyl, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkylfatty group, substituted or unsubstituted C 1-6 alkylacyl, substituted or unsubstituted C 1-6 alkylamido, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylsulfonamido, substituted or unsubstituted C 1-6 phospholipid group, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted C 6-12 aryl; further, when C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy , C 1-6 alkylsulfonyl, C 1-6 alkylthio , C 1-6 alkylamino, C When a C 1-6 alkyl group, a C 1-6 alkyl acyl group, a C 1-6 alkyl amido group, a C 1-6 alkylsulfonyl group, a C 1-6 alkylsulfonamido group, a C 1-6 phospholipid group, a 3-8 membered heterocyclic group, a 5-14 membered heteroaryl group, or a C 6-12 aryl group has a substituent, the substituent may be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, or C 1-6 alkyl group;

L为共价键，取代或未取代的C1-6亚烷基、取代或未取代的C2-6亚烯基、取代或未取代的C2-6亚炔基、取代或未取代的C3-8亚环烷基、取代或未取代的C6-10亚芳基、取代或未取代的C1-6亚烷氧基、取代或未取代的C1-6亚烷砜基、取代或未取代的C1-6亚烷硫基、取代或未取代的C1-6亚烷胺基，当C1-6亚烷基、C2-6亚烯基、C2-6亚炔基、C3-8亚环烷基、C6-10亚芳基、C1-6亚烷氧基、C1-6亚烷砜基、C1-6亚烷硫基、C1-6亚烷胺基存在取代基时，可被至少如下一个基团取代：氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、3-8元杂环基；L is a covalent bond, a substituted or unsubstituted C 1-6 alkylene group, a substituted or unsubstituted C 2-6 alkenylene group, a substituted or unsubstituted C 2-6 alkynylene group, a substituted or unsubstituted C 3-8 cycloalkylene group, a substituted or unsubstituted C 6-10 arylene group, a substituted or unsubstituted C 1-6 alkyleneoxy group, a substituted or unsubstituted C 1-6 alkylenesulfonyl group, a substituted or unsubstituted C 1-6 alkylenethio group, a substituted or unsubstituted C 1-6 alkyleneamino group, when C 1-6 alkylene group, C 2-6 alkenylene group, C 2-6 alkynylene group, C 3-8 cycloalkylene group, C 6-10 arylene group, C 1-6 alkyleneoxy group, C 1-6 alkylenesulfonyl group, C 1-6 alkylenethio group, C When the 1-6 alkyleneamino group has a substituent, it may be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfone, C 1-6 alkylthio, C 1-6 alkylamino, or a 3-8 membered heterocyclyl group;

RL选自取代或未取代的C1-6烷基，取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷砜基、取代或未取代的C1-6烷硫基、取代或未取代的C1-6烷胺基、取代或未取代的C3-8环烷基、取代或未取代的C2-9杂环基、取代或未取代的C6-10芳基、取代或未取代的C2-10杂芳基；当C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C3-8环烷基、C2-9杂环基、C6-10芳基、C2-10杂芳基存在取代基时，可被至少如下一个基团取代：氘、卤素、氰基、硝基、羟基、氨基、巯基、氧代基、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的C3-6环烷基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷砜基、取代或未取代的C1-6烷硫基、取代或未取代的C1-6烷胺基、取代或未取代的C1-6烷脂基、取代或未取代的C1-6烷基酰基、取代或未取代的C1-6烷基酰胺基、取代或未取代的C1-6烷基磺酰基、取代或未取代的C1-6烷基磺酰胺基、取代或未取代的C1-6磷脂基、取代或未取代的3-8元杂环基、取代或未取代的5-14元杂芳基、取代或未取代的C6-12芳基；进一步，当C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1- 6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷脂基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6烷基磺酰胺基、C1-6磷脂基、3-8元杂环基、5-14元杂芳基或C6-12芳基存在取代基时，可被至少如下一个基团取代：氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基；R L is selected from substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 2-9 heterocyclyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted C 2-10 heteroaryl; when C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylamino , C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl , C When substituents are present in the 2-10 heteroaryl groups, they may be substituted by at least one of the following groups: deuterium, halogen, cyano, nitro, hydroxyl, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkyl fat, substituted or unsubstituted C 1-6 alkylacyl, substituted or unsubstituted C 1-6 alkylamide, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylsulfonamido, substituted or unsubstituted C C 1-6 phospholipid group, a substituted or unsubstituted 3-8 membered heterocyclyl, a substituted or unsubstituted 5-14 membered heteroaryl, or a substituted or unsubstituted C 6-12 aryl group; further, when a C 1-6 alkyl, a C 2-6 alkenyl, a C 2-6 alkynyl, a C 3-6 cycloalkyl, a C 1-6 alkoxy, a C 1-6 alkylsulfonyl, a C 1-6 alkylthio, a C 1-6 alkylamino, a C 1-6 alkyl fat group, a C 1-6 alkylacyl group, a C 1-6 alkylamide group, a C 1-6 alkylsulfonyl group, a C 1-6 alkylsulfonamido group, a C 1-6 phospholipid group, a 3-8 membered heterocyclyl, a 5-14 membered heteroaryl group, or a C 6-12 aryl group has a substituent, it may be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxy, amino, thiol, oxo, or C 1-6 alkyl group;

杂环基、杂芳基中含有至少一个杂原子，杂原子选自N、O或S。The heterocyclic group and the heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S.

优选的，一种杂环酰胺类化合物，可为结构通式(II)所示的化合物或其药学上可接受的盐：
Preferably, a heterocyclic amide compound may be a compound represented by the general structural formula (II) or a pharmaceutically acceptable salt thereof:

其中，U’、V’、Z’、W’、环B、L和RL的定义如通式(I)中所述。wherein U', V', Z', W', Ring B, L and RL are as defined in Formula (I).

更优选的，一种杂环酰胺类化合物，可为结构通式(IIA)所示的化合物或其药学上可接受的盐：
More preferably, a heterocyclic amide compound may be a compound represented by the general structural formula (IIA) or a pharmaceutically acceptable salt thereof:

其中，环B选自 wherein ring B is selected from

RL选自取代或未取代的C3-6环烷基、取代或未取代的3-8元杂环基、取代或未取代的5-10元杂芳基、取代或未取代的C6-14芳基；当C3-6环烷基、3-8元杂环基、5-10元杂芳基、C6-14芳基存在取代基时，可被至少如下一个基团取代：卤素、羟基、氨基、氰基、氧代基、C1-6烷基； RL is selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C6-14 aryl; when C3-6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C6-14 aryl has a substituent, it may be substituted by at least one of the following groups: halogen, hydroxyl, amino, cyano, oxo, C1-6 alkyl;

Ru选自氢、氘、取代或未取代的C1-6烷基、取代或未取代的C3-6环烷基、取代或未取代的3-8元杂环基；当C1-6烷基、C3-6环烷基、3-8元杂环基存在取代基时，可被至少如下一个基团取代：羟基、氨基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷胺基、取代或未取代的C1-6烷砜基、取代或未取代的3-8元杂环基；进一步，当C1-6烷氧基、C1-6烷胺基、C1-6烷砜基、3-8元杂环基存在取代基时，可被至少如下一个基团取代：卤素、羟基、氨基、氰基、氧代基；R u is selected from hydrogen, deuterium, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl; when C 1-6 alkyl, C 3-6 cycloalkyl, or 3-8 membered heterocyclyl has a substituent, it may be substituted by at least one of the following groups: hydroxy, amino, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkylsulfone, or substituted or unsubstituted 3-8 membered heterocyclyl; further, when C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylsulfone, or 3-8 membered heterocyclyl has a substituent, it may be substituted by at least one of the following groups: halogen, hydroxy, amino, cyano, or oxo;

RB、RB’各自独立地选自氢、氘、卤素、氰基、羟基、氨基、巯基、氧代基、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的C3-6环烷基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷砜基、取代或未取代的C1-6烷硫基、取代或未取代的C1-6烷胺基、取代或未取代的C1-6烷脂基、取代或未取代的C1-6烷基酰基、取代或未取代的C1-6烷基酰胺基、取代或未取代的C1-6烷基磺酰基、取代或未取代的C1-6烷基磺酰胺基、取代或未取代的C1-6磷酰基、取代或未取代的3-8元杂环基、取代或未取代的5-10元杂芳基、取代或未取代的C6-14芳基；当C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷脂基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6烷基磺酰胺基、C1-6磷酰基、3-8元杂环基、5-10元杂芳基、C6-14芳基存在取代基时，可被至少如下一个基团取代：氘、卤素、氰基、硝基、羟基、氨基、巯基、氧代基、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的C3-6环烷基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷砜基、取代或未取代的C1-6烷硫基、取代或未取代的C1-6烷胺基、取代或未取代的C1-6烷脂基、取代或未取代的C1-6烷基酰基、取代或未取代的C1-6烷基酰胺基、取代或未取代的C1-6烷基磺酰基、取代或未取代的C1-6烷基磺酰胺基、取代或未取代的C1-6磷脂基、取代或未取代的3-8元杂环基、取代或未取代的5-14元杂芳基、取代或未取代的C6-12芳基；进一步，当C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷脂基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6烷基磺酰胺基、C1-6磷脂基、3-8元杂环基、5-14元杂芳基、C6-12芳基存在取代基时，可被至少如下一个基团取代：氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基； RB and RB ' are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, thiol, oxo, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C1-6 alkoxy, substituted or unsubstituted C1-6 alkylsulfonyl, substituted or unsubstituted C1-6 alkylthio, substituted or unsubstituted C1-6 alkylamino, substituted or unsubstituted C1-6 alkylfatty, substituted or unsubstituted C1-6 alkylacyl, substituted or unsubstituted C1-6 alkylamido, substituted or unsubstituted C1-6 alkylsulfonyl, substituted or unsubstituted C1-6 alkylsulfonamido, substituted or unsubstituted C C 1-6 phosphoryl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 6-14 aryl; when C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylfatty, C 1-6 alkylacyl , C 1-6 alkylamide, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamide, C 1-6 phosphoryl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C 6-14 aryl has a substituent, it may be substituted by at least one of the following groups: deuterium, halogen, cyano, nitro, hydroxy, amino, mercapto, oxo, substituted or unsubstituted C C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfone, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkylfatty, substituted or unsubstituted C 1-6 alkylacyl, substituted or unsubstituted C 1-6 alkylamido, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylsulfonamido, substituted or unsubstituted C 1-6 phospholipid group, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted C 6-12 aryl; further, when C 1-6 alkyl , C 2-6 alkenyl, C When substituents are present , C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfone, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylfatty, C1-6 alkylacyl, C1-6 alkylamide, C1-6 alkylsulfonyl, C1-6 alkylsulfonamido, C1-6 phospholipid group, 3-8 membered heterocyclyl, 5-14 membered heteroaryl, C6-12 aryl may be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxy, amino, thiol, oxo, C1-6 alkyl;

杂环基、杂芳基中含有至少一个杂原子，杂原子选自N、O或S；The heterocyclic group and heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S;

Ry和Rz的定义如通式(I)中所述。 Ry and Rz are as defined in the general formula (I).

更优选的，一种杂环酰胺类化合物，可为结构通式(IIB)所示的化合物或其药学上可接受的盐：
More preferably, a heterocyclic amide compound may be a compound represented by the general structural formula (IIB) or a pharmaceutically acceptable salt thereof:

其中，RL选自取代或未取代的C3-6环烷基、取代或未取代的3-8元杂环基、取代或未取代的5-10元杂芳基、取代或未取代的C6-14芳基、取代或未取代的C2-6炔基；当C3-6环烷基、3-8元杂环基、5-10元杂芳基、C6-14芳基、C2-6炔基存在取代基时，可被至少如下一个基团取代：卤素、羟基、氨基、氰基、氧代基、C1-6烷基；wherein RL is selected from substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C6-14 aryl, substituted or unsubstituted C2-6 alkynyl; when C3-6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C6-14 aryl, C2-6 alkynyl has a substituent, it may be substituted by at least one of the following groups: halogen, hydroxyl, amino, cyano, oxo, C1-6 alkyl;

杂环基、杂芳基中含有至少一个杂原子，杂原子选自N、O或S；The heterocyclic group and heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S;

Ry、Rz、环B和Ru的定义如通式(IIA)中所述。R y , R z , Ring B and Ru are as defined in the general formula (IIA).

更优选的，一种杂环酰胺类化合物，可为结构通式(IIC)所示的化合物或其药学上可接受的盐：
More preferably, a heterocyclic amide compound may be a compound represented by the general structural formula (IIC) or a pharmaceutically acceptable salt thereof:

其中，L选自-OCH2-、-CH2-；wherein L is selected from -OCH 2 -, -CH 2 -;

RL选自取代或未取代的C1-6烷基、取代或未取代的C3-6环烷基、取代或未取代的C6-14芳基、取代或未取代的C3-6环烷基、取代或未取代的3-8元杂环基、取代或未取代的5-10元杂芳基、取代或未取代的C6- 14芳基、取代或未取代的C2-6炔基；当C3-6环烷基、3-8元杂环基、5-10元杂芳基、C6-14芳基、C2-6炔基存在取代基时，可被至少如下一个基团取代：卤素、羟基、氨基、氰基、氧代基、取代或未取代的C1-6烷基；进一步，当C1-6烷基存在取代基时，可被至少如下一个基团取代：羟基； RL is selected from substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted C6-14 aryl, substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C6-14 aryl, substituted or unsubstituted C2-6 alkynyl; when C3-6 cycloalkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, C6-14 aryl, C2-6 alkynyl has substituents, they may be substituted by at least one of the following groups: halogen, hydroxyl, amino, cyano, oxo, substituted or unsubstituted C1-6 alkyl; further, when C1-6 alkyl has substituents, they may be substituted by at least one of the following groups: hydroxyl ;

杂环基、杂芳基中含有至少一个杂原子，杂原子选自N、O或S；The heterocyclic group and heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S;

Ry、Rz、环B和Ru的定义如通式(IIA)中所述。R y , R z , Ring B and Ru are as defined in the general formula (IIA).

更优选的，一种杂环酰胺类化合物，可为结构通式(IID)所示的化合物或其药学上可接受的盐：
More preferably, a heterocyclic amide compound may be a compound represented by the general structural formula (IID) or a pharmaceutically acceptable salt thereof:

其中，U’、V’、Z’、W’各自独立地选自 且U’、V’、Z’、W’中至少有一个选自 Wherein, U', V', Z', W' are each independently selected from And at least one of U', V', Z', W' is selected from

n1为1；n 1 is 1;

Ru、Rv、Rw、Rx、Ry和Rz的定义如通式(I)中所述；R u , R v , R w , R x , R y and R z are as defined in formula (I);

环B和RL的定义如通式(IIA)中所述。Ring B and RL are as defined in the general formula (IIA).

优选的，一种杂环酰胺类化合物，可为结构通式(III)所示的化合物或其药学上可接受的盐：
Preferably, a heterocyclic amide compound may be a compound represented by the general structural formula (III) or a pharmaceutically acceptable salt thereof:

其中，U’、V’、Z’、W’各自独立地选自 且U’、V’、Z’、W’中至少有一个选自 Wherein, U', V', Z', W' are each independently selected from And at least one of U', V', Z', W' is selected from

n1选自0、1、2或3；n 1 is selected from 0, 1, 2 or 3;

Ru、Rv、Rw、Rx各自独立地选自氢、氘、卤素、氰基、羟基、氨基、巯基、氧代基、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的C3-6环烷基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷砜基、取代或未取代的C1-6烷硫基、取代或未取代的C1-6烷胺基、取代或未取代的4-10元杂环基、取代或未取代的5-14元杂芳基、取代或未取代的C6-12芳基；当C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、4-10元杂环基、5-14元杂芳基、C6-12芳基存在取代基时，可被至少一个如下基团取代：氘、卤素、氰基、羟基、氨基、巯基、氧代基、取代或未取代的C1-6烷基、取代或未取代的C2-6烯基、取代或未取代的C2-6炔基、取代或未取代的C3-6环烷基、取代或未取代的C1-6烷氧基、取代或未取代的C1-6烷砜基、取代或未取代的C1-6烷硫基、取代或未取代的C1-6烷胺基、取代或未取代的C1-6烷脂基、取代或未取代的C1-6烷基酰基、取代或未取代的C1-6烷基酰胺基、取代或未取代的C1-6烷基磺酰基、取代或未取代的C1-6烷基磺酰胺基、取代或未取代的C1-6磷酰基、取代或未取代的3-8元杂环基、取代或未取代的5-10元杂芳基、取代或未取代的C6- 14芳基；R u , R v , R w , and R x are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, or substituted or unsubstituted C 6-12 aryl; when C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C When substituents are present, C 1-6 alkylthio, C 1-6 alkylamino, 4-10 membered heterocyclyl, 5-14 membered heteroaryl, or C 6-12 aryl may be substituted by at least one of the following groups: deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 1-6 alkoxy, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 alkylamino, substituted or unsubstituted C 1-6 alkyl fat, substituted or unsubstituted C 1-6 alkylacyl, substituted or unsubstituted C 1-6 alkylamide, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 phosphoryl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C 6-14 aryl ;

杂环基、杂芳基中含有至少一个杂原子，杂原子选自N、O或S；The heterocyclic group and heteroaryl group contain at least one heteroatom, and the heteroatom is selected from N, O or S;

Ry、Rz、环B和RL的定义如通式(IIA)中所述。R y , R z , Ring B and RL are as defined in the general formula (IIA).

一方面，本发明提供一种通式(Ia)或(Ib)所示的杂环酰胺类化合物，其立体异构体、互变异构体、氘代物或药用盐：
In one aspect, the present invention provides a heterocyclic amide compound represented by general formula (Ia) or (Ib), and its stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts:

其中，环A选自3-14元杂环基、5-14元杂芳基、C6-14芳基或4-10元环烯基；所述3-14元杂环基、5-14元杂芳基、C6-C14芳基或4-10元环烯基可任选进一步被一个或多个Ra所取代；wherein Ring A is selected from a 3-14 membered heterocyclyl, a 5-14 membered heteroaryl, a C 6-14 aryl or a 4-10 membered cycloalkenyl; the 3-14 membered heterocyclyl, the 5-14 membered heteroaryl, the C 6 -C 14 aryl or the 4-10 membered cycloalkenyl may be optionally further substituted with one or more Ra ;

所述X选自N或CR2；所述R2各自独立选自氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C3-6环烷基或C1-6卤代烷基；The X is selected from N or CR 2 ; the R 2 are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl;

所述Y1、Y2各自独立地选自N或CR4；所述R4各自独立选自氢、氘、卤素、氨基、氰基、羟基、C1- 6烷基、C1-6烷氧基、C3-6环烷基或C1-6卤代烷基；Said Y 1 and Y 2 are each independently selected from N or CR 4 ; said R 4 are each independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl , C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl;

所述U、V、W、Z各自独立地选自-(C＝O)-、-SO2-、-O-、-NRb-、-(CRcRd)n-或-CReRf-，且U、V、W、Z中至少有一个选自-CReRf-；U, V, W, and Z are each independently selected from -(C=O)-, -SO 2 -, -O-, -NR b -, -(CR c R d ) n -, or -CR e R f -, and at least one of U, V, W, and Z is selected from -CR e R f -;

所述n选自0、1、2或3；Said n is selected from 0, 1, 2 or 3;

所述Re、Rf及其所连接的原子共同形成C3-12环烷基或3-12元杂环基；所述C3-12环烷基或3-12元杂环基可任选进一步被一个或多个Ra所取代；The R e , R f and the atoms to which they are connected together form a C 3-12 cycloalkyl group or a 3-12 membered heterocyclic group; the C 3-12 cycloalkyl group or the 3-12 membered heterocyclic group may be optionally further substituted by one or more R a ;

所述Ra、Rb、Rc、Rd各自独立地选自氢、氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷酯基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6烷基磺酰胺基、C1-6磷酰基、3-8元杂环基、5-14元杂芳基或C6-12芳基；所述C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷酯基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6烷基磺酰胺基、C1-6磷酰基、3-8元杂环基，5-14元杂芳基或C6-12芳基可任选进一步被一个或多个氢、氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基、C1-6羟基烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷基酰基、4-10元杂环基、5-14元杂芳基或C6-12芳基所取代；Said Ra , Rb , Rc , and Rd are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylester, C1-6 alkylacyl, C1-6 alkylamide, C1-6 alkylsulfonyl, C1-6 alkylsulfonamido, C1-6 phosphoryl, 3-8 membered heterocyclyl , 5-14 membered heteroaryl or C6-12 aryl ; said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl , C1-6 C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylester, C 1-6 alkylacyl, C 1-6 alkylamido, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamido, C 1-6 phosphoryl, 3-8 membered heterocyclyl, 5-14 membered heteroaryl or C 6-12 aryl may be further optionally replaced by one or more hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylacyl, 4-10 membered heterocyclyl, 5-14 membered heteroaryl or C 6-12 aryl . 6-12 aryl substituted;

所述R1选自卤素、氰基、氨基、-ORg-、被一个或多个Rg取代的C1-6烷基、C2-6烯基、C2-6炔基、C3- 8环烷基、3-8元杂环基、5-14元杂芳基、C6-10芳基、C1-6烷氧基、C1-6羟基烷基、C1-6烷砜基、C1-6烷硫基或C1-6烷胺基；Said R 1 is selected from halogen, cyano, amino, -OR g -, C 1-6 alkyl substituted by one or more R g , C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-14 membered heteroaryl, C 6-10 aryl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylsulfone, C 1-6 alkylthio or C 1-6 alkylamino;

所述Rg选自氢、氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C3- 12环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷酯基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6磷酰基、C6-12芳基、3-8元杂环基或5-14元杂芳基；所述C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷酯基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6磷酰基、C6-12芳基、3-8元杂环基或5-14元杂芳基可任选进一步被一个或多个氢、氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基、C1-6羟基烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷基酰基、4-10元杂环基、5-14元杂芳基或C6-12芳基所取代。The Rg is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylester, C1-6 alkylacyl , C1-6 alkylamide, C1-6 alkylsulfonyl, C1-6 phosphoryl, C6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl; the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl , C1-6 alkoxy , C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylester, C1-6 alkylacyl, C1-6 alkylamide, C1-6 alkylsulfonyl, C1-6 phosphoryl, C6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl; The C 1-6 alkylacyl, C 1-6 alkylamido, C 1-6 alkylsulfonyl, C 1-6 phosphino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, cyano, hydroxy, amino, thiol, oxo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylacyl, 4-10 membered heterocyclyl, 5-14 membered heteroaryl or C 6-12 aryl.

在进一步优先方案中，通式(Ia)或(Ib)所示的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其中，所述R1选自被一个或多个Rg取代的C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、5-14元杂芳基、C6-10芳基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基或C1-6烷胺基；In a further preferred embodiment, the compound represented by general formula (Ia) or (Ib), or a stereoisomer, tautomer, deuterated form or pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-14 membered heteroaryl, C 6-10 aryl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio or C 1-6 alkylamino substituted with one or more R g ;

所述Rg选自氢、氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C3- 12环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷酯基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6磷酰基、C6-12芳基、3-8元杂环基或5-14元杂芳基；所述C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷酯基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6磷酰基、C6-12芳基、3-8元杂环基或5-14元杂芳基可任选进一步被一个或多个氢、氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基、C1-6羟基烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷基酰基、4-10元杂环基、5-14元杂芳基或C6-12芳基所取代。The Rg is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylester, C1-6 alkylacyl , C1-6 alkylamide, C1-6 alkylsulfonyl, C1-6 phosphoryl, C6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl; the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylester, C1-6 alkylacyl, C1-6 alkylamide, C1-6 alkylsulfonyl, C1-6 phosphoryl, C6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl; The C 1-6 alkylacyl, C 1-6 alkylamido, C 1-6 alkylsulfonyl, C 1-6 phosphino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, cyano, hydroxy, amino, thiol, oxo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylacyl, 4-10 membered heterocyclyl, 5-14 membered heteroaryl or C 6-12 aryl.

在一些实施方案中，所述化合物具有如下式(IIa)或(IIb)所示结构化合物，或其立体异构体、互变异构体、氘代物或药用盐：
In some embodiments, the compound has a structure represented by the following formula (IIa) or (IIb), or a stereoisomer, tautomer, deuterated compound, or pharmaceutically acceptable salt thereof:

其中，所述环A、Y1、Y2、U、V、W、Z、R1的定义如通式(Ia)或(Ib)中所述。Wherein, the definitions of the ring A, Y 1 , Y 2 , U, V, W, Z, and R 1 are the same as those in the general formula (Ia) or (Ib).

在一些实施方案中，所述化合物具有如下式(IIIa)或(IIIb)所示结构化合物，或其立体异构体、互变异构体、氘代物或药用盐：
In some embodiments, the compound has a structure represented by the following formula (IIIa) or (IIIb), or a stereoisomer, tautomer, deuterated compound, or pharmaceutically acceptable salt thereof:

其中，所述U、V、W各自独立地选自-(C＝O)-、-SO2-、-O-、-NRb-、-CRcRd-或-CReRf-，且U、V、W中至少有一个选自-CReRf-；wherein U, V, and W are each independently selected from -(C=O)-, -SO 2 -, -O-, -NR b -, -CR c R d -, or -CR e R f -, and at least one of U, V, and W is selected from -CR e R f -;

所述环A、Y1、Y2、R1、Rb、Rc、Rd、Re、Rf的定义如通式(Ia)或(Ib)中所述。The ring A, Y 1 , Y 2 , R 1 , R b , R c , R d , Re , and R f are as defined in the general formula (Ia) or (Ib).

在一些实施方案中，所述化合物具有如下式(IVa)、(IVb)、(IVc)、(IVd)、(IVe)或(IVf)所示结构化合物，或其立体异构体、互变异构体、氘代物或药用盐：
In some embodiments, the compound has a structure represented by the following formula (IVa), (IVb), (IVc), (IVd), (IVe) or (IVf), or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof:

其中，U、V、W各自独立地选自-(C＝O)-、-SO2-、-O-、-NRb-或-CRcRd-；wherein U, V, and W are each independently selected from -(C=O)-, -SO 2 -, -O-, -NR b -, or -CR c R d -;

m和t各自独立地选自0、1、2、3、4或5，m和t不同时为0；m and t are each independently selected from 0, 1, 2, 3, 4 or 5, and m and t are not 0 at the same time;

Q选自O、S、SO2、C(R3)2或NR3；所述R3各自独立选自氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C3-6环烷基或C1-6卤代烷基；Q is selected from O, S, SO 2 , C(R 3 ) 2 or NR 3 ; each of the R 3 groups is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl;

环A、Y1、Y2、R1、Rb、Rc、Rd的定义如通式(Ia)或(Ib)中所述。Ring A, Y 1 , Y 2 , R 1 , R b , R c , and R d are as defined in the general formula (Ia) or (Ib).

在一些实施方案中，所述化合物具有如下式(Va)、(Vb)、(Vc)、(Vd)、(Ve)、(Vf)、(Vg)、(Vh)、(Vi)、(Vj)、(Vk)、(Vl)、(Vm)、(Vn)、(Vo)、(Vp)、(Vq)、(Vr)、(Vs)、(Vt)、(Vu)、(Vv)或(Vw)所示结构化合物，或其立体异构体、互变异构体、氘代物或药用盐：
In some embodiments, the compound has a structure represented by Formula (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv) or (Vw), or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof:

其中，R3选自氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C3-6环烷基或C1-6卤代烷基；wherein R 3 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl;

环A、R1、Rb的定义如通式(Ia)或(Ib)中所述。Ring A, R 1 and R b are as defined in the general formula (Ia) or (Ib).

在一些实施方案中，所述化合物具有如下式式(Va)、(Vb)、(Vc)、(Vd)、(Ve)、(Vf)、(Vg)、(Vh)、(Vi)、(Vj)、(Vk)、(Vl)、(Vm)、(Vn)、(Vo)、(Vp)、(Vq)、(Vr)、(Vs)、(Vt)、(Vu)或(Vv)所示结构：
In some embodiments, the compound has a structure represented by Formula (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), or (Vv):

其中，R3选自氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C3-6环烷基或C1-6卤代烷基；wherein R 3 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl;

环A、R1、Rb的定义如通式(Ia)或(Ib)中所述。Ring A, R 1 and R b are as defined in the general formula (Ia) or (Ib).

在一些实施方案中，所述化合物具有如下式(IIIc)或(IIId)所示结构化合物，或其立体异构体、互变异构体、氘代物或药用盐：
In some embodiments, the compound has a structure represented by the following formula (IIIc) or (IIId), or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof:

其中，U、V、W、Z各自独立地选自-(C＝O)-、-SO2-、-O-、-NRb-、-CRcRd-或-CReRf-、且U、V、W、Z中至少有一个选自-CReRf-；wherein U, V, W, and Z are each independently selected from -(C=O)-, -SO 2 -, -O-, -NR b -, -CR c R d -, or -CR e R f -, and at least one of U, V, W, and Z is selected from -CR e R f -;

环A、Y1、Y2、R1、Rb、Rc、Rd、Re、Rf的定义如通式(Ia)或(Ib)中所述。Ring A, Y 1 , Y 2 , R 1 , R b , R c , R d , Re , and R f are as defined in the general formula (Ia) or (Ib).

在一些实施方案中，所述化合物具有如下式(IVg)、(IVh)、(IVi)、(IVj)或(IVk)所示结构化合物，或其立体异构体、互变异构体、氘代物或药用盐：
In some embodiments, the compound has a structure represented by the following formula (IVg), (IVh), (IVi), (IVj) or (IVk), or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof:

其中，U、V、W、Z各自独立地选自-(C＝O)-、-SO2-、-O-、-NRb-或-CRcRd-；wherein U, V, W, and Z are each independently selected from -(C=O)-, -SO 2 -, -O-, -NR b -, or -CR c R d -;

m和t各自独立地选自0、1、2、3、4或5，m和t不同时为0；m and t are each independently selected from 0, 1, 2, 3, 4 or 5, and m and t are not 0 at the same time;

Q选自O、S、SO2、C(R3)2或NR3；所述R3各自独立选自氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C3-6环烷基或C1-6卤代烷基；Q is selected from O, S, SO 2 , C(R 3 ) 2 or NR 3 ; each of the R 3 groups is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl;

环A、Y1、Y2、R1、Rb、Rc、Rd的定义如通式(Ia)或(Ib)中所述。Ring A, Y 1 , Y 2 , R 1 , R b , R c , and R d are as defined in the general formula (Ia) or (Ib).

在一些实施方案中，所述化合物具有如下式(VIa)、(VIb)、(VIc)、(VId)、(VIe)、(VIf)、(VIg)、(VIh)、(VIi)、(VIj)、(VIk)、(VIl)、(VIm)、(VIn)、(VIo)、(VIp)、(VIq)、(VIr)、(VIs)、(VIt)、(VIu)、(VIv)或(VIw)所示结构化合物，或其立体异构体、互变异构体、氘代物或药用盐：

In some embodiments, the compound has a structure represented by Formula (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), (VIn), (VIo), (VIp), (VIq), (VIr), (VIs), (VIt), (VIu), (VIv) or (VIw), or a stereoisomer, tautomer, deuterated form or pharmaceutically acceptable salt thereof:

其中，环A、R1、Rb的定义如通式(Ia)或(Ib)中所述。wherein, ring A, R 1 , and R b are as defined in the general formula (Ia) or (Ib).

在一些实施方案中，所述环A选自苯基、吡啶基、吗啉基、吡啶酮基或环己烯基；所述的苯基、吡啶基、吗啉基、吡啶酮基或环己烯基可任选进一步被一个或多个Ra取代，所述Ra各自独立选自氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基或3-8元杂环基。In some embodiments, the ring A is selected from phenyl, pyridyl, morpholinyl, pyridonyl or cyclohexenyl; the phenyl, pyridyl, morpholinyl, pyridonyl or cyclohexenyl may be optionally further substituted with one or more Ra , each of which is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl or 3-8 membered heterocyclyl.

在一些实施方案中，所述环A选自苯基，所述的苯基可任选进一步被一个或多个Ra取代，所述Ra选自氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基或3-8元杂环基。In some embodiments, the ring A is selected from phenyl, which may be optionally further substituted with one or more Ra , wherein Ra is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl or 3-8 membered heterocyclyl.

在一些实施方案中，所述环A选自吡啶基，所述的吡啶基可任选进一步被一个或多个Ra取代，所述Ra选自氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基或3-8元杂环基。In some embodiments, the ring A is selected from pyridinyl, which may be optionally further substituted with one or more Ra , wherein Ra is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl or 3-8 membered heterocyclyl.

在一些实施方案中，所述环A选自 In some embodiments, the ring A is selected from

在一些实施方式中，所述环A选自 In some embodiments, the ring A is selected from

在一些实施方案中，所述环A选自 In some embodiments, the ring A is selected from

在一些实施方案中，所述R1选自被Rg取代的乙炔基，所述Rg选自氢、氘、C1-6烷基、C3-12环烷基、C6-12芳基、3-8元杂环基或5-14元杂芳基，所述C1-6烷基、C3-12环烷基、C6-12芳基、3-8元杂环基或5-14元杂芳基可任选进一步被一个或多个氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷砜基或3-8元杂环基取代。In some embodiments, the R 1 is selected from ethynyl substituted by R g , wherein the R g is selected from hydrogen, deuterium, C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, and the C 1-6 alkyl, C 3-12 cycloalkyl , C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfonyl or 3-8 membered heterocyclyl.

在一些实施方案中，所述R1选自被一个或多个Rg取代的环丙基，所述Rg选自氢、氘、C1-6烷基、C2- 6炔基、C6-12芳基、3-8元杂环基或5-14元杂芳基，所述C1-6烷基、C2-6炔基、C6-12芳基、3-8元杂环基或5-14元杂芳基可任选进一步被一个或多个氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷砜基或3-8元杂环基取代。In some embodiments, the R 1 is selected from cyclopropyl substituted with one or more R g , wherein the R g is selected from hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkynyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, and the C 1-6 alkyl, C 2-6 alkynyl, C 6-12 aryl , 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfonyl or 3-8 membered heterocyclyl.

在一些实施方案中，所述R1选自被一个或多个Rg取代的甲基，所述Rg选自氢、氘、卤素、C1-6烷基、C3-12环烷基、C6-12芳基、3-8元杂环基或5-14元杂芳基，所述C1-6烷基、C3-12环烷基、C6-12芳基、3-8元杂环基或5-14元杂芳基可任选进一步被一个或多个氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷砜基或3-8元杂环基取代。In some embodiments, the R 1 is selected from methyl substituted with one or more R g , wherein the R g is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, and the C 1-6 alkyl, C 3-12 cycloalkyl , C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfonyl or 3-8 membered heterocyclyl.

在一些实施方案中，所述R1选自被一个或多个Rg取代的乙基，所述Rg选自氢、氘、卤素、C1-6烷基、C3-12环烷基、C6-12芳基、3-8元杂环基或5-14元杂芳基，所述C1-6烷基、C3-12环烷基、C6-12芳基、3-8元杂环基或5-14元杂芳基可任选进一步被一个或多个氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷砜基或3-8元杂环基取代。In some embodiments, the R 1 is selected from ethyl substituted with one or more R g , wherein the R g is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, and the C 1-6 alkyl, C 3-12 cycloalkyl , C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfonyl or 3-8 membered heterocyclyl.

在一些实施方案中，所述R1选自-O(CH2)pRg-，所述p选自0、1、2、3或4，所述Rg选自氢、氘、卤素、羟基、C1-6烷基、C3-12环烷基、C1-6烷胺基、C6-12芳基、3-8元杂环基或5-14元杂芳基，所述C1-6烷基、C3-12环烷基、C1-6烷胺基、C6-12芳基、3-8元杂环基或5-14元杂芳基可任选进一步被一个或多个氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷砜基、C1-6羟基烷基或3-8元杂环基取代。In some embodiments, the R 1 is selected from -O(CH 2 ) p R g -, the p is selected from 0, 1, 2, 3 or 4, the R g is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, the C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfonyl, C 1-6 hydroxyalkyl or 3-8 membered heterocyclyl.

在一些实施方案中，所述R1选自-O(CH2)pRg-，所述p选自0、1、2、3或4，所述Rg选自氢、氘、卤素、羟基、C1-6烷基、C3-12环烷基、C1-6烷胺基、C6-12芳基、3-8元杂环基或5-14元杂芳基，所述C1-6烷基、C3-12环烷基、C1-6烷胺基、C6-12芳基、3-8元杂环基或5-14元杂芳基可任选进一步被一个或多个氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷砜基或3-8元杂环基取代。In some embodiments, the R 1 is selected from -O(CH 2 ) p R g -, the p is selected from 0, 1, 2, 3 or 4, the R g is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, the C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfonyl or 3-8 membered heterocyclyl.

在一些实施方案中，所述R1选自-(CH2)qORg-，所述q选自0、1、2、3或4，所述Rg选自氢、氘、卤素、羟基、C1-6烷基、C6-12芳基、3-8元杂环基或5-14元杂芳基，所述C1-6烷基、C6-12芳基、3-8元杂环基或5-14元杂芳基可任选进一步被一个或多个氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷砜基或3-8元杂环基取代。In some embodiments, the R 1 is selected from -(CH 2 ) q OR g -, the q is selected from 0, 1, 2, 3 or 4, the R g is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, and the C 1-6 alkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfonyl or 3-8 membered heterocyclyl.

在一些实施方案中，所述R1选自 In some embodiments, the R 1 is selected from

在一些实施方案中，所述R1选自 In some embodiments, the R 1 is selected from

在一些实施方案中，本发明所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐选自以下化合物：




In some embodiments, the compound of the present invention, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof is selected from the following compounds:




另一方面，本发明提供了一种药物组合物，所述药物组合物含有治疗有效量的式(I)、(II)、(IIA)、(IIB)、(IIC)、(IID)、(III)、(Ia)、(Ib)、(IIa)、(IIb)、(IIIa)、(IIIb)、(IIIc)、(IIId)、(IVa)、(IVb)、(IVc)、(IVd)、(IVe)、(IVf)、(IVg)、(IVh)、(IVi)、(IVj)、(IVk)、(Va)、(Vb)、(Vc)、(Vd)、(Ve)、(Vf)、(Vg)、(Vh)、(Vi)、(Vj)、(Vk)、(Vl)、(Vm)、(Vn)、(Vo)、(Vp)、(Vq)、(Vr)、(Vs)、(Vt)、(Vu)、(Vv)、(Vw)、(VIa)、(VIb)、(VIc)、(VId)、(VIe)、(VIf)、(VIg)、(VIh)、(VIi)、(VIj)、(VIk)、(VIl)、(VIm)、(VIn)、(VIo)、(VIp)、(VIq)、(VIr)、(VIs)、(VIt)、(VIu)、(VIv)或(VIw)所示的化合物或其立体异构体、互变异构体、氘代物或药用盐。In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), A compound represented by (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), (Vw), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), (VIn), (VIo), (VIp), (VIq), (VIr), (VIs), (VIt), (VIu), (VIv) or (VIw), or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof.

再一方面，本发明提供了如上述的式(I)、(II)、(IIA)、(IIB)、(IIC)、(IID)、(III)、(Ia)、(Ib)、(IIa)、(IIb)、(IIIa)、(IIIb)、(IIIc)、(IIId)、(IVa)、(IVb)、(IVc)、(IVd)、(IVe)、(IVf)、(IVg)、(IVh)、(IVi)、(IVj)、(IVk)、(Va)、(Vb)、(Vc)、(Vd)、(Ve)、(Vf)、(Vg)、(Vh)、(Vi)、(Vj)、(Vk)、(Vl)、(Vm)、(Vn)、(Vo)、(Vp)、(Vq)、(Vr)、(Vs)、(Vt)、(Vu)、(Vv)、(Vw)、(VIa)、(VIb)、(VIc)、(VId)、(VIe)、(VIf)、(VIg)、(VIh)、(VIi)、(VIj)、(VIk)、(VIl)、(VIm)、(VIn)、(VIo)、(VIp)、(VIq)、(VIr)、(VIs)、(VIt)、(VIu)、(VIv)或(VIw)所示化合物或其立体异构体、互变异构体、氘代物或药用盐在制备用于治疗POLθ介导的疾病或病症及相关疾病或病症的药物中的应用。In another aspect, the present invention provides a compound of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn ... Use of a compound represented by (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), (Vw), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), (VIn), (VIo), (VIp), (VIq), (VIr), (VIs), (VIt), (VIu), (VIv) or (VIw), or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating diseases or conditions mediated by POLθ and related diseases or conditions.

再一方面，本发明提供了如上述的式(I)、(II)、(IIA)、(IIB)、(IIC)、(IID)、(III)、(Ia)、(Ib)、(IIa)、(IIb)、(IIIa)、(IIIb)、(IIIc)、(IIId)、(IVa)、(IVb)、(IVc)、(IVd)、(IVe)、(IVf)、(IVg)、(IVh)、(IVi)、(IVj)、(IVk)、(Va)、(Vb)、(Vc)、(Vd)、(Ve)、(Vf)、(Vg)、(Vh)、(Vi)、(Vj)、(Vk)、(Vl)、(Vm)、(Vn)、(Vo)、(Vp)、(Vq)、(Vr)、(Vs)、(Vt)、(Vu)、(Vv)、(Vw)、(VIa)、(VIb)、(VIc)、(VId)、(VIe)、(VIf)、(VIg)、(VIh)、(VIi)、(VIj)、(VIk)、(VIl)、(VIm)、(VIn)、(VIo)、(VIp)、(VIq)、(VIr)、(VIs)、(VIt)、(VIu)、(VIv)或(VIw)所示化合物或其立体异构体、互变异构体、氘代物或药用盐用于治疗和/或预防POLθ介导的疾病或病症及相关疾病或病症。In another aspect, the present invention provides compounds of formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vn The compounds represented by (V), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), (Vw), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), (VIn), (VIo), (VIp), (VIq), (VIr), (VIs), (VIt), (VIu), (VIv) or (VIw), or their stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, are used to treat and/or prevent diseases or conditions mediated by POLθ and related diseases or conditions.

本发明还提供一种疾病或病症的治疗方法，所述方法包括向有需要的患者施用治疗有效量的如上文所述的式(I)、(II)、(IIA)、(IIB)、(IIC)、(IID)、(III)、(Ia)、(Ib)、(IIa)、(IIb)、(IIIa)、(IIIb)、(IIIc)、(IIId)、(IVa)、(IVb)、(IVc)、(IVd)、(IVe)、(IVf)、(IVg)、(IVh)、(IVi)、(IVj)、(IVk)、(Va)、(Vb)、(Vc)、(Vd)、(Ve)、(Vf)、(Vg)、(Vh)、(Vi)、(Vj)、(Vk)、(Vl)、(Vm)、(Vn)、(Vo)、(Vp)、(Vq)、(Vr)、(Vs)、(Vt)、(Vu)、(Vv)、(Vw)、(VIa)、(VIb)、(VIc)、(VId)、(VIe)、(VIf)、(VIg)、(VIh)、(VIi)、(VIj)、(VIk)、(VIl)、(VIm)、(VIn)、(VIo)、(VIp)、(VIq)、(VIr)、(VIs)、(VIt)、(VIu)、(VIv)或(VIw)所示化合物或其立体异构体、互变异构体、氘代物或药用盐。The present invention also provides a method for treating a disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a method of treating a disease or condition as described above, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a method of treating a disease or condition as described above, wherein the method comprises administering to a patient in need thereof a method of treating a disease or condition as described above, wherein the method comprises administering to a patient in need thereof a method of treating a disease or condition as described above, wherein the method comprises administering to a patient in need thereof a method of treating a disease or condition as described above, wherein the method comprises administering to a patient in need thereof a method of treating a disease or condition as described above, wherein the method comprises administering to a patient in need thereof a method of treating a disease or condition as described above ), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), (Vw), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), (VIn), (VIo), (VIp), (VIq), (VIr), (VIs), (VIt), (VIu), (VIv) or (VIw), or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof.

在一些实施方案中，所述治疗和/或预防的疾病选自POLθ介导的疾病或病症及相关疾病或病症。In some embodiments, the disease to be treated and/or prevented is selected from a disease or condition mediated by POLθ and related diseases or conditions.

在一些实施方案中，所述POLθ介导的疾病或病症及相关疾病或病症选自肿瘤或癌症。In some embodiments, the POLθ-mediated disease or condition and related diseases or conditions are selected from tumors or cancers.

在一些实施方案中，所述癌症的特征为同源重组(HR)缺陷、HR相关基因表达的减少或缺失。In some embodiments, the cancer is characterized by homologous recombination (HR) deficiency, decreased or absent expression of HR-related genes.

在一些实施方案中，所述癌症的特征为BRCA基因表达的减少或缺失、BRAC基因的缺失或BRCA蛋白的功能降低。In some embodiments, the cancer is characterized by decreased or absent expression of a BRCA gene, absence of a BRAC gene, or reduced function of a BRCA protein.

在一些实施方案中，所述癌症的特征为缺失53BP1/Shieldin复合物。In some embodiments, the cancer is characterized by loss of the 53BP1/Shieldin complex.

在一些实施方案中，所述癌症的特征为对MMEJ DSB修复的依赖性增加。In some embodiments, the cancer is characterized by increased dependence on MMEJ DSB repair.

在一些实施方案中，所述癌症的特征为接受或未接受PARPi药物治疗，对PARPi治疗具有耐药性。In some embodiments, the cancer is characterized by being resistant to PARPi treatment with or without prior PARPi treatment.

在一些实施方案中，所述的肿瘤或癌症选自血液瘤或实体瘤，所述实体瘤包括但不限于软组织癌、横纹肌样癌、多发性骨髓瘤、子宫癌、胃癌、周围神经系统癌、横纹肌肉瘤、骨癌、结直肠癌、间皮瘤、乳腺癌、卵巢癌、肺癌、成纤维细胞、中枢神经系统癌、泌尿道癌、上消化道癌、肾脏癌、皮肤癌、食道癌和胰腺癌；所述血液瘤包括但不限于淋巴瘤和白血病。In some embodiments, the tumor or cancer is selected from a hematological tumor or a solid tumor, wherein the solid tumor includes but is not limited to soft tissue cancer, rhabdoid cancer, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblasts, central nervous system cancer, urinary tract cancer, upper gastrointestinal cancer, kidney cancer, skin cancer, esophageal cancer and pancreatic cancer; the hematological tumor includes but is not limited to lymphoma and leukemia.

另一方面，本发明提供式(M)所示的化合物，或其立体异构体、互变异构体、氘代物或药用盐：
In another aspect, the present invention provides a compound represented by formula (M), or a stereoisomer, tautomer, deuterated compound, or pharmaceutically acceptable salt thereof:

其中，RM1选自碘、联硼酸频那醇酯基团(Bpin)或环A，所述环A的定义如通式(Ia)或(Ib)中所述，RM2选自氢或C1-6烷基。wherein RM1 is selected from iodine, biboronic acid pinacol ester group (Bpin) or ring A, wherein the definition of ring A is as described in general formula (Ia) or (Ib), and RM2 is selected from hydrogen or C1-6 alkyl.

在一些实施方案中，本发明提供中间体化合物M1，所述的化学名为5'-碘代-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯，其结构式如下：
In some embodiments, the present invention provides an intermediate compound M1, the chemical name of which is 5'-iodo-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid methyl ester, and the structural formula thereof is as follows:

在一些实施方案中，本发明提供中间体化合物M2，所述的化学名为1'-甲基-2'-氧代-5'-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯，其结构式如下：
In some embodiments, the present invention provides an intermediate compound M2, the chemical name of which is 1'-methyl-2'-oxo-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid methyl ester, and its structural formula is as follows:

在一些实施方案中，本发明提供中间体化合物M3，其结构式如下：
In some embodiments, the present invention provides an intermediate compound M3, whose structural formula is as follows:

其中，环A的定义如通式(Ia)或(Ib)中所述。wherein, ring A is as defined in formula (Ia) or (Ib).

另一方面，本发明提供了如上述的式(M)所示化合物或其立体异构体、互变异构体、氘代物或药用盐在制备如上文所述的式(I)、(II)、(IIA)、(IIB)、(IIC)、(IID)、(III)、(Ia)、(Ib)、(IIa)、(IIb)、(IIIa)、(IIIb)、(IIIc)、(IIId)、(IVa)、(IVb)、(IVc)、(IVd)、(IVe)、(IVf)、(IVg)、(IVh)、(IVi)、(IVj)、(IVk)、(Va)、(Vb)、(Vc)、(Vd)、(Ve)、(Vf)、(Vg)、(Vh)、(Vi)、(Vj)、(Vk)、(Vl)、(Vm)、(Vn)、(Vo)、(Vp)、(Vq)、(Vr)、(Vs)、(Vt)、(Vu)、(Vv)、(Vw)、(VIa)、(VIb)、(VIc)、(VId)、(VIe)、(VIf)、(VIg)、(VIh)、(VIi)、(VIj)、(VIk)、(VIl)、(VIm)、(VIn)、(VIo)、(VIp)、(VIq)、(VIr)、(VIs)、(VIt)、(VIu)、(VIv)或(VIw)所示化合物或其立体异构体、互变异构体、氘代物或药用盐中的用途。On the other hand, the present invention provides a compound represented by the above formula (M) or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts in the preparation of the above formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (V ... Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), (Vw), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), (VIn), (VIo), (VIp), (VIq), (VIr), (VIs), (VIt), (VIu), (VIv) or (VIw), or their stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts.

除非另有说明，所述结构通式中使用的一般化学术语具有通常的含义。Unless otherwise indicated, general chemical terms used in the structural formulae have their usual meanings.

例如，除非另有说明，本发明所用的术语“卤素”是指氟、氯、溴或碘。For example, the term "halogen," as used herein, refers to fluorine, chlorine, bromine, or iodine, unless otherwise indicated.

在本发明中，除非另有说明，“烷基”包括直链或支链的一价饱和烃基。例如，烷基包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、正己基、2-己基、2-甲基戊基等。类似的，“C1-6烷基”中的“1-6”是指包含有1、2、3、4、5或6个碳原子的直链或支链形式排列的基团。In the present invention, unless otherwise specified, "alkyl" includes linear or branched monovalent saturated hydrocarbon groups. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, the " 1-6 " in " C1-6 alkyl" refers to a group containing 1, 2, 3, 4, 5, or 6 carbon atoms in a linear or branched form.

术语“烷氧基”是指前述的直链或支链烷基的氧醚形式，即-O-烷基。The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl groups, ie, -O-alkyl.

术语“卤代烷基”是指一个或多个H已经被卤素原子置换的烷基。The term "haloalkyl" refers to an alkyl group in which one or more H groups have been replaced by a halogen atom.

术语“氧代”或“氧代基”是指呈二价取代基形式的氧原子，其与C连接时形成羰基，其与杂原子连接时形成亚砜基或砜基或N-氧化物基团。The term "oxo" or "oxo group" refers to an oxygen atom in the form of a divalent substituent, which forms a carbonyl group when attached to C, and forms a sulfoxide group or a sulfone group or an N-oxide group when attached to a heteroatom.

术语“环烷基”是指具有至少一个环化烷基的环系统。优选C3-12环烷基，其中的“C3-12”是指环烷基可以具有3、4、5、6、7、8、9、10、11或12个成环原子。所述环烷基可以包括单环和多环(例如具有2、3或4个稠合环、螺环、桥环等)。一些实施例中环烷基包括但不限于环丙基、环丁基、环戊基等；所述环烷基还可以稠合于芳基、杂环基或杂芳基环上，其中与母体结构连接在一起的环为环烷基。The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. Preferably, it is a C3-12 cycloalkyl group, where " C3-12 " means that the cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms. The cycloalkyl group can include monocyclic and polycyclic rings (e.g., having 2, 3, or 4 fused rings, spirocyclic rings, bridged rings, etc.). In some embodiments, cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like; the cycloalkyl group can also be fused to an aryl, heterocyclyl, or heteroaryl ring, wherein the ring attached to the parent structure is the cycloalkyl group.

术语“烯基”是指具有一个或多个碳碳双键的烷基，例如乙烯基、丙烯基、1,3-丁二烯、顺丁烯基、反丁烯基等。The term "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds, for example, ethenyl, propenyl, 1,3-butadiene, maleinyl, trans-butenyl, and the like.

术语“炔基”是指具有一个或多个碳碳三键的烷基，例如乙炔基、丙炔基等。The term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds, for example, ethynyl, propynyl, and the like.

术语“羟基烷基”，指进一步取代有如上定义烷基的羟基，即-烷基-OH，如C1-6羟基烷基，包括但不限于-CH2OH、-C2H5OH、-CH2CH2CH2OH或-CH(CH3)2OH等。The term "hydroxyalkyl" refers to a hydroxy group further substituted with an alkyl group as defined above, i.e., -alkyl-OH, such as C1-6 hydroxyalkyl , including but not limited to -CH2OH , -C2H5OH , -CH2CH2CH2OH or -CH ( CH3 ) 2OH .

术语“烷硫基”，指通过硫原子相连的直链或支链烷基，即-S-烷基，如C1-6烷硫基，包括但不限于甲硫基、乙硫基、丙硫基(含正丙硫基、异丙硫基)、丁硫基(含正丁硫基、异丁硫基、仲丁硫基、叔丁硫基)、戊硫基(含正戊硫基、异戊硫基、新戊硫基)、己硫基(正己硫基、2-甲基戊硫基、3-甲基戊硫基、2,3-二甲基丁硫基、2,2-二甲基丁硫基)等。The term "alkylthio" refers to a straight or branched alkyl group connected by a sulfur atom, i.e., -S-alkyl, such as C1-6 alkylthio, including but not limited to methylthio, ethylthio, propylthio (including n-propylthio, isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio, tert-butylthio), pentylthio (including n-pentylthio, isopentylthio, neopentylthio), hexylthio (n-hexylthio, 2-methylpentylthio, 3-methylpentylthio, 2,3-dimethylbutylthio, 2,2-dimethylbutylthio), etc.

术语“烷砜基”，指通过砜基相连的直链或支链烷基，即-SO2-烷基，如C1-6烷砜基，包括但不限于甲砜基、乙砜基、丙砜基(含正丙砜基、异丙砜基)、丁硫基(含正丁砜基、异丁砜基、仲丁砜基、叔丁砜基)、戊砜基(含正戊砜基、异戊砜基、新戊砜基)、己砜基(正己砜基、2-甲基戊砜基、3-甲基戊砜基、2,3-二甲基丁砜基、2,2-二甲基丁砜基)等。The term "alkylsulfonyl" refers to a straight-chain or branched alkyl group connected through a sulfone group, i.e., a -SO2 -alkyl group, such as a C1-6 alkylsulfonyl group, including but not limited to methylsulfonyl, ethylsulfonyl, propylsulfonyl (including n-propylsulfonyl and isopropylsulfonyl), butylsulfonyl (including n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl), pentanylsulfonyl (including n-pentylsulfonyl, isopentanylsulfonyl and neopentylsulfonyl), hexylsulfonyl (n-hexylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl, 2,3-dimethylbutylsulfonyl and 2,2-dimethylbutylsulfonyl), and the like.

术语“烷胺基”，指含有氮原子的开链烷基，如C1-6烷胺基，包括但不限于甲胺基、乙胺基、异丙胺基、二甲基胺基、甲基乙基胺基、二乙基胺基等。The term "alkylamino" refers to an open-chain alkyl group containing a nitrogen atom, such as a C1-6 alkylamino group, including but not limited to methylamino, ethylamino, isopropylamino, dimethylamino, methylethylamino, diethylamino, and the like.

术语“烷酯基”，指通过酯基相连的直链或支链烷基，即-烷基-CO2-，如C1-6烷酯基，包括但不限于甲酯基、乙酯基、丙酯基(含正丙酯基、异丙酯基)、丁酯基(含正丁酯基、异丁酯基、仲丁酯基、叔丁酯基)、戊酯基(含正戊酯基、异戊酯基、新戊酯基)、己酯基(正己酯基、2-甲基戊酯基、3-甲基戊酯基、2,3-二甲基丁酯基、2,2-二甲基丁酯基)等。The term "alkyl ester group" refers to a straight-chain or branched alkyl group connected by an ester group, that is, -alkyl- CO2- , such as C1-6 alkyl ester group, including but not limited to methyl ester group, ethyl ester group, propyl ester group (including n-propyl ester group and isopropyl ester group), butyl ester group (including n-butyl ester group, isobutyl ester group, sec-butyl ester group, tert-butyl ester group), pentyl ester group (including n-pentyl ester group, isopentyl ester group, neopentyl ester group), hexyl ester group (n-hexyl ester group, 2-methylpentyl ester group, 3-methylpentyl ester group, 2,3-dimethylbutyl ester group, 2,2-dimethylbutyl ester group), etc.

术语“烷基酰基”，指通过酰基相连的直链或支链烷基，即-烷基-CO-，如C1-6烷基酰基，包括但不限于甲酰基、乙酰基、丙酰基(含正丙酰基、异丙酰基)、丁酰基(含正丁酰基、异丁酰基、仲丁酰基、叔丁酰基)、戊酰基(含正戊酰基、异戊酰基、新戊酰基)、己酰基(正己酰基、2-甲基戊酰基、3-甲基戊酰基、2,3-二甲基丁酰基、2,2-二甲基丁酰基)等。The term "alkyl acyl" refers to a straight or branched alkyl group connected by an acyl group, i.e., -alkyl-CO-, such as C1-6 alkyl acyl, including but not limited to formyl, acetyl, propionyl (including n-propionyl and isopropionyl), butyryl (including n-butyryl, isobutyryl, sec-butyryl, tert-butyryl), valeryl (including n-valeryl, isovaleryl, pivaloyl), hexanoyl (n-hexanoyl, 2-methylvaleryl, 3-methylvaleryl, 2,3-dimethylbutyryl, 2,2-dimethylbutyryl), etc.

术语“烷基酰胺基”，指通过酰胺基相连的直链或支链烷基，即-烷基-CONH-，如C1-6烷基酰胺基，包括但不限于甲酰胺基、乙酰胺基、丙酰胺基(含正丙酰胺基、异丙酰胺基)、丁酰胺基(含正丁酰胺基、异丁酰胺基、仲丁酰胺基、叔丁酰胺基)、戊酰胺基(含正戊酰胺基、异戊酰胺基、新戊酰胺基)、己酰胺基(正己酰胺基、2-甲基戊酰胺基、3-甲基戊酰胺基、2,3-二甲基丁酰胺基、2,2-二甲基丁酰胺基)等。The term "alkylamide" refers to a straight or branched alkyl group connected by an amide group, i.e., -alkyl-CONH-, such as a C1-6 alkylamide, including but not limited to formamide, acetamide, propionamide (including n-propionamide and isopropionamide), butyramide (including n-butyramide, isobutyramide, sec-butyramide, tert-butyramide), valeramide (including n-valeramide, isovaleramide, pivaleramide), hexanamide (n-hexanamide, 2-methylvaleramide, 3-methylvaleramide, 2,3-dimethylbutyramide, 2,2-dimethylbutyramide), and the like.

术语“烷基磺酰基”，指通过磺酰基相连的直链或支链烷基，即-烷基-SO2-，如C1-6烷基磺酰基，包括但不限于甲磺酰基、乙磺酰基、丙磺酰基(含正丙磺酰基、异丙磺酰基)、丁磺酰基(含正丁磺酰基、异丁磺酰基、仲丁磺酰基、叔丁磺酰基)、戊磺酰基(含正戊磺酰基、异戊磺酰基、新戊磺酰基)、己磺酰基(正己磺酰基、2-甲基戊磺酰基、3-甲基戊磺酰基、2,3-二甲基丁磺酰基、2,2-二甲基丁磺酰基)等。The term "alkylsulfonyl" refers to a straight or branched alkyl group connected through a sulfonyl group, i.e., -alkyl- SO2- , such as C1-6 alkylsulfonyl, including but not limited to methylsulfonyl, ethylsulfonyl, propylsulfonyl (including n-propylsulfonyl and isopropylsulfonyl), butanesulfonyl (including n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl), pentanesulfonyl (including n-pentanesulfonyl, isopentanesulfonyl and neopentanesulfonyl), hexanesulfonyl (n-hexanesulfonyl, 2-methylpentanesulfonyl, 3-methylpentanesulfonyl, 2,3-dimethylbutanesulfonyl and 2,2-dimethylbutanesulfonyl), and the like.

术语“烷基磺酰胺基”，指通过磺酰胺基相连的直链或支链烷基，即-烷基-SO2N-，如C1-6烷基磺酰胺基，包括但不限于甲磺酰胺基、乙磺酰胺基、丙磺酰胺基(含正丙磺酰胺基、异丙磺酰胺基)、丁磺酰胺基(含正丁磺酰胺基、异丁磺酰胺基、仲丁磺酰胺基、叔丁磺酰胺基)、戊磺酰胺基(含正戊磺酰胺基、异戊磺酰胺基、新戊磺酰胺基)、己磺酰胺基(正己磺酰胺基、2-甲基戊磺酰胺基、3-甲基戊磺酰胺基、2,3-二甲基丁磺酰胺基、2,2-二甲基丁磺酰胺基)等。The term "alkylsulfonyl" refers to a straight or branched alkyl group connected through a sulfonyl group, i.e., -alkyl- SO2N- , such as C1-6 alkylsulfonyl, including but not limited to methanesulfonyl, ethylsulfonyl, propanesulfonyl (including n-propanesulfonyl and isopropylsulfonyl), butanesulfonyl (including n-butanesulfonyl, isobutylsulfonyl, sec-butanesulfonyl and tert-butanesulfonyl), pentanesulfonyl (including n-pentanesulfonyl, isopentanesulfonyl and neopentanesulfonyl), hexanesulfonyl (n-hexanesulfonyl, 2-methylpentanesulfonyl, 3-methylpentanesulfonyl, 2,3-dimethylbutanesulfonyl and 2,2-dimethylbutanesulfonyl), and the like.

术语“磷酰基”，即-PO2-，如C1-6磷酰基，包括但不限于甲磷酰基、乙磷酰基、丙磷酰基(含正丙磷酰基、异丙磷酰基)、丁磷酰基(含正丁磷酰基、异丁磷酰基、仲丁磷酰基、叔丁磷酰基)、戊磷酰基(含正戊磷酰基、异戊磷酰基、新戊磷酰基)、己磷酰基(正己磷酰基、2-甲基戊磷酰基、3-甲基戊磷酰基、2,3-二甲基丁磷酰基、2,2-二甲基丁磷酰基)等。The term "phosphoryl", i.e. -PO 2 -, such as C 1-6 phosphoryl, includes but is not limited to methylphosphoryl, ethylphosphoryl, propylphosphoryl (including n-propylphosphoryl and isopropylphosphoryl), butylphosphoryl (including n-butylphosphoryl, isobutylphosphoryl, sec-butylphosphoryl and tert-butylphosphoryl), pentylphosphoryl (including n-pentylphosphoryl, isopentylphosphoryl and neopentylphosphoryl), hexylphosphoryl (n-hexylphosphoryl, 2-methylpentylphosphoryl, 3-methylpentylphosphoryl, 2,3-dimethylbutylphosphoryl and 2,2-dimethylbutylphosphoryl), and the like.

术语“芳基”，在本发明中，除非另有说明，是指未取代或取代的包括碳环的原子的单环或稠环芳香基团。优选C6-12芳基，更优选芳基为C6-10的单环或双环的芳香环基团。优选为苯基、萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基上，其中与母体结构连接在一起的环为芳基环，非限制性实例包括但不限于苯并环戊基。The term "aryl," as used herein, unless otherwise indicated, refers to an unsubstituted or substituted monocyclic or fused-ring aromatic group comprising carbon ring atoms. Preferred are C 6-12 aryl groups, and more preferably, aryl groups are monocyclic or bicyclic aromatic ring groups comprising C 6-10 . Preferred are phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring. Non-limiting examples include, but are not limited to, benzocyclopentyl.

术语“杂芳基”，在本发明中，除非另有说明，是指具有至少一个杂原子的单环或多环(例如稠合双环)芳香族杂环，所述杂原子选自N、O和/或S，并且其中所述氮或硫杂原子可以选择性地被氧化，所述氮杂原子可以选择性地被季铵化。优选5-14元杂芳基，其中5-14元杂芳基中的“5-14元”是指含有5-14个C、N、O或S的成环原子组成的杂芳基。更优选的是5-10元杂芳基，更更优选的是5-6元杂芳基。杂芳基的实例包括但不限于噻吩基、呋喃基、咪唑基、异恶唑基、恶唑基、吡唑基、吡咯基、噻唑基、噻二唑基、三唑基、吡啶基、哒嗪基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并异恶唑基、苯并噻唑基、苯并噻唑基、苯并噻二唑基、苯并三唑基腺嘌呤、喹啉基或异喹啉基。所述杂芳基可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。The term "heteroaryl" in the present invention, unless otherwise specified, refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom, wherein the heteroatom is selected from N, O, and/or S, and wherein the nitrogen or sulfur heteroatom may be selectively oxidized, and the nitrogen heteroatom may be selectively quaternized. Preferably, it is a 5-14-membered heteroaryl, wherein the "5-14 members" in the 5-14-membered heteroaryl refers to a heteroaryl group consisting of 5-14 ring atoms of C, N, O, or S. More preferred is a 5-10-membered heteroaryl, and even more preferred is a 5-6-membered heteroaryl. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolyl, or isoquinolyl. The heteroaryl group may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring.

术语“杂环基”是指具有至少一个含有杂环子的环化烷基或环化烯基的环系统，所述杂原子选自N、O和/或S。所述杂环基可以包括单环或多环(例如具有2、3或4个稠合环、螺环、桥环等)。杂环基可以经由成环碳原子或成环杂原子与化合物其他部分相连接。优选3-14元杂环基，3-14元杂环基中的“3-14元”是指含有3-14个C、N、O或S的成环原子组成的杂环基；更优选3-8元杂环基，更更优选5-6元杂环基；其中氮或硫杂原子可以选择性地被氧化，并且氮杂原子可以选择性地被季铵化。这些杂环基的实例包括但不限于氮杂环丁烷基、吡咯烷基、哌啶基、1,2,3,6-四氢吡啶、哌嗪基、氧代哌嗪基、氧代哌啶基、四氢呋喃基、二氧戊环基、四氢咪唑基、四氢噻唑基、四氢恶唑基、四氢吡喃基、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜基和四氢恶二唑基。所述杂环基可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基。The term "heterocyclyl" refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heterocyclic ring, wherein the heteroatom is selected from N, O and/or S. The heterocyclyl group may include a monocyclic or polycyclic ring (e.g., having 2, 3 or 4 fused rings, spirocyclic rings, bridged rings, etc.). The heterocyclyl group may be connected to the other parts of the compound via a ring-forming carbon atom or a ring-forming heteroatom. Preferably, the heterocyclyl group is a 3-14-membered group, wherein the "3-14 members" in the 3-14-membered heterocyclyl group refers to a heterocyclyl group consisting of 3-14 C, N, O or S ring atoms; more preferably a 3-8-membered heterocyclyl group, and even more preferably a 5-6-membered heterocyclyl group; wherein the nitrogen or sulfur heteroatom may be selectively oxidized, and the nitrogen heteroatom may be selectively quaternized. Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridine, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. The heterocyclic group may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocyclic group.

术语“药用盐”是指从药学上可接受的无毒的碱或酸制备的盐。The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.

当本发明提供的化合物是酸时，可以从药学上可接受的无毒的碱，包括无机碱和有机碱，方便地制得其相应的盐。从无机碱衍生的盐包括铝、铵、钙、铜(高价和低价)、三价铁、亚铁、锂、镁、锰(高价和低价)、钾、钠、锌之类的盐。特别优选铵、钙、镁、钾和钠的盐。能够衍生成药学上可接受的盐的无毒有机碱包括伯胺、仲胺和叔胺，也包括环胺及含有取代基的胺，如天然存在的和合成的含取代基的胺。能够成盐的其他药学上可接受的无毒有机碱，包括离子交换树脂以及精氨酸、甜菜碱、咖啡因、胆碱、N',N'-二苄乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡萄糖胺、氨基葡萄糖、组氨酸、异丙胺、赖氨酸，甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、氯普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。When the compound provided by the present invention is an acid, its corresponding salt can be easily prepared from pharmaceutically acceptable nontoxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc and the like. Particularly preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Nontoxic organic bases that can be derived into pharmaceutically acceptable salts include primary amines, secondary amines and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

当本发明提供的化合物是碱时，可以从药学上可接受的无毒的酸，包括无机酸和有机酸，方便制得其相应的盐。这样的酸包括，如，醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、甲酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、黏酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、草酸、丙酸、乙醇酸、氢碘酸、高氯酸、环己氨磺酸、水杨酸、2-萘磺酸、糖精酸、三氟乙酸、酒石酸和对甲苯磺酸等。When compound provided by the invention is a base, it is possible to conveniently prepare its corresponding salt from pharmaceutically acceptable nontoxic acids, including inorganic and organic acids. Such acid includes, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid etc.

本发明化合物的药物前体包含在本发明的保护范围内。通常，所述药物前体是指很容易在体内转化成所需化合物的功能性衍生物。例如，本发明化合物的任何药学上可接受的盐、酯、酯的盐或其它衍生物，其在向受体施用后能够直接或间接地提供本发明化合物或其具有药学活性的代谢物或残基。Prodrugs of the compounds of the present invention are encompassed within the scope of the present invention. Generally, such prodrugs are functional derivatives that are readily converted in vivo into the desired compound. For example, any pharmaceutically acceptable salt, ester, ester salt, or other derivative of a compound of the present invention, which upon administration to a recipient, can directly or indirectly provide a compound of the present invention or a pharmaceutically active metabolite or residue thereof.

本发明所述化合物可能含有一个或多个不对称中心，并可能由此产生非对映异构体和光学异构体。本发明包括所有可能的非对映异构体及其外消旋混合物、其基本上纯的拆分对映异构体、所有可能的几何异构体及其药用盐。The compounds of the present invention may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts thereof.

当式(I)、(II)、(IIA)、(IIB)、(IIC)、(IID)、(III)、(Ia)(Ib)、(IIa)、(IIb)、(IIIa)、(IIIb)、(IIIc)、(IIId)、(IVa)、(IVb)、(IVc)、(IVd)、(IVe)、(IVf)、(IVg)、(IVh)、(IVi)、(IVj)、(IVk)、(Va)、(Vb)、(Vc)、(Vd)、(Ve)、(Vf)、(Vg)、(Vh)、(Vi)、(Vj)、(Vk)、(Vl)、(Vm)、(Vn)、(Vo)、(Vp)、(Vq)、(Vr)、(Vs)、(Vt)、(Vu)、(Vv)、(Vw)、(VIa)、(VIb)、(VIc)、(VId)、(VIe)、(VIf)、(VIg)、(VIh)、(VIi)、(VIj)、(VIk)、(VIl)、(VIm)、(VIn)、(VIo)、(VIp)、(VIq)、(VIr)、(VIs)、(VIt)、(VIu)、(VIv)或(VIw)所示化合物存在互变异构体时，除非特别声明，本发明包括任何可能的互变异构体和其药用盐，及它们的混合物。When formula (I), (II), (IIA), (IIB), (IIC), (IID), (III), (Ia) (Ib), (IIa), (IIb), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), (IVh), (IVi), (IVj), (IVk), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo When the compound represented by (Va), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv), (Vw), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), (VIn), (VIo), (VIp), (VIq), (VIr), (VIs), (VIt), (VIu), (VIv) or (VIw) exists in tautomer form, unless otherwise stated, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

本发明还包括所有同位素的原子，无论是在中间体或最后的化合物。同位素的原子包括具有相同的原子数，但不同质量数。例如，氢的同位素包括氚和氘。The present invention also includes all isotopes of atoms, whether in intermediates or final compounds. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

术语“药物组合物”是指一种或多种本发明化合物或其药用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发明化合物。The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present invention to an organism.

在本发明中，“一”、“一个”、“该”、“至少一个”和“一个或多个”可互换使用。因此，例如，包含“一种”药学上可接受的辅料组成的混合物可以被解释为表示该药物组合物包括“一种或多种”药学上可接受的辅料。In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient composition can be interpreted as indicating that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

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 excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

本发明的药物组合物可通过将本发明化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

给予本发明化合物或其药用盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。The term "treat" generally refers to obtaining a desired pharmacological and/or physiological effect. This effect can be therapeutic in terms of partial or complete stabilization or cure of a disease and/or side effects caused by the disease. As used herein, "treat" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., arresting its progression; or (b) relieving the symptoms of the disease, i.e., causing regression of the disease or its symptoms.

术语“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发明化合物的用量。构成“治疗有效量”的本发明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 "effective amount" means an amount of a compound of the present invention 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 as described herein. The amount of a compound of the present invention 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 knowledge and this disclosure.

与现有技术相比，本发明的有益效果如下：Compared with the prior art, the present invention has the following beneficial effects:

本发明基于Polθ抑制剂的靶标设计，开发了一系列结构新颖的杂环酰胺类化合物，相关的生物学试验表明：本发明的化合物能显著抑制细胞增殖和PolθATP酶活、具有优良的抗肿瘤体内药效，且化合物的hERG毒性低、体外肝微粒体代谢稳定、药代动力学性质良好。此外，本发明提供的化合物合成路线新颖，安全、环保，生产可行性好。Based on target design for Polθ inhibitors, this invention has developed a series of novel heterocyclic amide compounds. Biological experiments have demonstrated that the compounds can significantly inhibit cell proliferation and Polθ ATPase activity, exhibit excellent in vivo anti-tumor efficacy, exhibit low hERG toxicity, exhibit stable in vitro liver microsome metabolism, and exhibit favorable pharmacokinetic properties. Furthermore, the compounds provided by this invention exhibit novel, safe, environmentally friendly synthetic routes, and possess good production feasibility.

具体实施方式DETAILED DESCRIPTION

为使上述内容更清楚、明确，本发明将用以下实施例来进一步阐述本发明的技术方案。以下实施例仅用于说明本发明的具体实施方式，以使本领域的技术人员能够理解本发明，但不用于限制本发明的保护范围。本发明的具体实施方式中，未作特别说明的技术手段或方法等为本领域的常规技术手段或方法等。To make the above content clearer and more specific, the present invention will further illustrate the technical solutions of the present invention with the following examples. The following examples are only used to illustrate the specific embodiments of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific embodiments of the present invention, technical means or methods not specifically described are conventional technical means or methods in the art.

除非另有说明，本发明所有温度均指摄氏度。Unless otherwise stated, all temperatures herein are in degrees Celsius.

实施例中使用了下列缩略语：The following abbreviations are used in the examples:

H2SO4：硫酸；HNO3：硝酸；Na2SO4：硫酸钠；EA：乙酸乙酯；DMSO：二甲基亚砜；K2CO3：碳酸钾；NaCl：氯化钠；PE：石油醚；DMF：N,N-二甲基甲酰胺；AcOH：醋酸；Fe：铁粉；NaHCO3：碳酸氢钠；Pd(dppf)Cl2：[1,1'-双(二苯基膦)二茂铁]二氯化钯；THF：四氢呋喃；HCl：盐酸；MeOH：甲醇；N2：氮气；DCM：二氯甲烷；NaH：氢化钠；MeCN：乙腈；Pd/C：钯/碳；Pd(PPh3)4：四三苯基膦钯；TEA：三乙胺；TCFH：N,N,N',N'-四甲基氯甲脒六氟磷酸盐；NMI：N-甲基咪唑；HATU：2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；H2O：水；Cs2CO3：碳酸铯；dioxane：二氧六环；NBS：N-溴代丁二酰亚胺；Pd2(dpa)3：三(二亚苄基丙酮)二钯；BIDIME：(S)-3-(叔丁基)-4-(2,6-二甲氧基苯基)-2,3-二氢苯并[d][1,3]氧磷杂环戊二烯；K3PO4：磷酸钾；xylene：二甲苯；LiOH：氢氧化锂；Bpin：联硼酸频那醇酯基团；Boc：叔丁氧基羰基保护基；LC-MS：液相色谱-质谱联用仪；本发明实施例中x mL×y：表示重复y次，每次xmL，如用二氯甲烷萃取三次(20mL×3)，表示用每次用20mL的二氯甲烷萃取，重复3次；本发明实施例中洗脱剂用量为体积比，如含有10％乙酸乙酯的石油醚溶液，表示石油醚和乙酸乙酯用量的体积比为9:1，PE:EA＝5:1表示石油醚和乙酸乙酯用量的体积比为5:1。H 2 SO 4 : sulfuric acid; HNO 3 : nitric acid; Na 2 SO 4 : sodium sulfate; EA: ethyl acetate; DMSO: dimethyl sulfoxide; K 2 CO 3 : potassium carbonate; NaCl: sodium chloride; PE: petroleum ether; DMF: N,N-dimethylformamide; AcOH: acetic acid; Fe: iron powder; NaHCO 3 : sodium bicarbonate; Pd(dppf)Cl 2 : [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; THF: tetrahydrofuran; HCl: hydrochloric acid; MeOH: methanol; N 2 : nitrogen; DCM: dichloromethane; NaH: sodium hydride; MeCN: acetonitrile; Pd/C: palladium on carbon; Pd(PPh 3 ) 4 : tetrakistriphenylphosphine palladium; TEA: triethylamine; TCFH: N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate; NMI: N-methylimidazole; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; H 2 O: water; Cs 2 CO 3 : cesium carbonate; dioxane: dioxane; NBS: N-bromosuccinimide; Pd 2 (dpa) 3 : tris(dibenzylideneacetone)dipalladium; BIDIME: (S)-3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxaphosphole; K 3 PO 4 : potassium phosphate; xylene: xylene; LiOH: lithium hydroxide; Bpin: biboronic acid pinacol ester group; Boc: tert-butoxycarbonyl protecting group; LC-MS: liquid chromatography-mass spectrometry; in the embodiments of the present invention, x mL×y means repeated y times, x mL each time, such as three extractions with dichloromethane (20 mL×3), which means extraction with 20 mL of dichloromethane each time, repeated 3 times; the amount of eluent in the embodiments of the present invention is a volume ratio, such as a petroleum ether solution containing 10% ethyl acetate, which means that the volume ratio of petroleum ether and ethyl acetate is 9:1, and PE:EA=5:1 means that the volume ratio of petroleum ether and ethyl acetate is 5:1.

此外，凡涉及易氧化或易水解的原料的所有操作都在氮气保护下进行。除非另有说明，本发明使用的原料都是市售原料、无需进一步纯化可以直接使用。In addition, all operations involving raw materials that are easily oxidized or hydrolyzed were carried out under nitrogen protection. Unless otherwise specified, the raw materials used in the present invention were commercially available and could be used directly without further purification.

本发明实施例中涉及的各反应原料、共用中间体等均可通过市售购得或自制获得，其中需要自制获得的原料和共用中间体，制备过程详述如下。The reaction raw materials, common intermediates, etc. involved in the embodiments of the present invention can be purchased commercially or obtained in-house. The preparation process of the raw materials and common intermediates that need to be obtained in-house is described in detail below.

制备路线：关键中间体M1的制备
Preparation route: Preparation of key intermediate M1

步骤1：1-(叔丁基)6-甲基-2-氧代吲哚啉-1,6-二羧酸酯(M1-2)的合成Step 1: Synthesis of 1-(tert-butyl) 6-methyl-2-oxoindoline-1,6-dicarboxylate (M1-2)

将M1-1(500mg,2.62mmol)溶于四氢呋喃(10mL)中，加入碳酸氢钠(1.3g,15.71mmol)和二碳酸二叔丁酯(860mg,3.93mmol)，升温至70℃搅拌3小时。体系冷却至室温，加水(20mL)淬灭，用二氯甲烷萃取三次(20mL×3)，合并有机相，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤。滤液减压浓缩。残留物经柱层析纯化，洗脱剂为10％乙酸乙酯的石油醚溶液，得到化合物M1-2(400mg)，产率52.5％。M1-1 (500 mg, 2.62 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium bicarbonate (1.3 g, 15.71 mmol) and di-tert-butyl dicarbonate (860 mg, 3.93 mmol) were added. The mixture was heated to 70°C and stirred for 3 hours. The system was cooled to room temperature, quenched with water (20 mL), and extracted three times with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 10% ethyl acetate in petroleum ether as the eluent to obtain compound M1-2 (400 mg) in a 52.5% yield.

LC-MS(m/z):292.0[M+H]+。LC-MS (m/z): 292.0 [M+H] + .

步骤2：1'-(叔丁基)6'-甲基2'-氧代螺[环丙烷-1,3'-吲哚啉]-1',6'-二羧酸酯(M1-3)的合成Step 2: Synthesis of 1'-(tert-butyl)6'-methyl 2'-oxospiro[cyclopropane-1,3'-indoline]-1',6'-dicarboxylate (M1-3)

将化合物M1-2(1.40g,4.81mmol)溶于DMSO(10mL)中，加入碳酸钾(1.70g,1.23mmol)和二溴乙烷(500μL,5.77mmol)，室温搅拌16小时。体系加水(20mL)淬灭，用乙酸乙酯萃取三次(20mL×3)，合并有机相，有机相水洗三次(20mL×3)，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤。滤液减压浓缩。残留物经柱层析纯化，洗脱剂为6％乙酸乙酯的石油醚溶液，得到化合物M1-3(400mg)，产率26.3％。Compound M1-2 (1.40 g, 4.81 mmol) was dissolved in DMSO (10 mL), potassium carbonate (1.70 g, 1.23 mmol) and dibromoethane (500 μL, 5.77 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The mixture was quenched with water (20 mL) and extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed three times with water (20 mL x 3), then with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 6% ethyl acetate in petroleum ether as the eluent to obtain compound M1-3 (400 mg) in a 26.3% yield.

LC-MS(m/z):318.0[M+H]+。LC-MS (m/z): 318.0 [M+H] + .

步骤3：2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯(M1-4)的合成Step 3: Synthesis of methyl 2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (M1-4)

将化合物M1-3(400mg,1.26mmol)溶于二氯甲烷(10mL)中，滴加三氟乙酸(2mL)，体系室温下搅拌2小时。体系加入饱和碳酸氢钠溶液调节pH至中性，用乙酸乙酯萃取三次(20mL×3)，合并有机相，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤。滤液减压浓缩后得到脱Boc产物(粗品)，直接用于下一步反应。Compound M1-3 (400 mg, 1.26 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate solution was added to adjust the pH to neutral, and the mixture was extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the de-Boc product (crude), which was used directly in the next reaction.

LC-MS(m/z):218.0[M+H]+。LC-MS (m/z): 218.0 [M+H] + .

步骤4：1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯(M1-5)的合成Step 4: Synthesis of methyl 1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (M1-5)

将上一步得到的粗品溶于DMF(5mL)中，加入碳酸铯(760mg，2.33mmol)和碘甲烷(200μL,3.21mmol)，体系室温下搅拌16小时。加水淬灭，用乙酸乙酯萃取三次(20mL×3)，合并有机相，有机相水洗三次(20mL×3)，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤。滤液减压浓缩。残留物经柱层析纯化，洗脱剂为20％乙酸乙酯的石油醚溶液，得到化合物M1-5(130mg)，步骤3和步骤4两步反应总产率为44.6％。The crude product obtained in the previous step was dissolved in DMF (5 mL), and cesium carbonate (760 mg, 2.33 mmol) and iodomethane (200 μL, 3.21 mmol) were added. The system was stirred at room temperature for 16 hours. The mixture was quenched with water and extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed three times with water (20 mL x 3), then with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 20% ethyl acetate in petroleum ether as the eluent to obtain compound M1-5 (130 mg). The total yield of Steps 3 and 4 was 44.6%.

LC-MS(m/z):232.0[M+H]+。LC-MS (m/z): 232.0 [M+H] + .

步骤5：5'-碘代-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯(M1)的合成Step 5: Synthesis of methyl 5'-iodo-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (M1)

将化合物M1-5(100mg,0.43mmol)溶于乙腈(5mL)中，加入三滴三氟乙酸和N-碘代丁二酰亚胺(166mg,0.73mmol)，体系升温至70℃搅拌16小时。体系冷却至室温，加水(20mL)淬灭，减压浓缩，用乙酸乙酯萃取三次(20mL×3)，合并有机相，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤。滤液减压浓缩。残留物经柱层析纯化，洗脱剂为5％乙酸乙酯的石油醚溶液，得到化合物M1-6(133mg)，产率86.1％。Compound M1-5 (100 mg, 0.43 mmol) was dissolved in acetonitrile (5 mL), and three drops of trifluoroacetic acid and N-iodosuccinimide (166 mg, 0.73 mmol) were added. The system was heated to 70°C and stirred for 16 hours. The system was cooled to room temperature, quenched with water (20 mL), concentrated under reduced pressure, and extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 5% ethyl acetate in petroleum ether as the eluent to obtain compound M1-6 (133 mg) in an 86.1% yield.

LC-MS(m/z):358.0[M+H]+。LC-MS (m/z): 358.0 [M+H] + .

关键中间体M2的制备
Preparation of key intermediate M2

步骤1：5'-溴-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯(M2-1)的合成Step 1: Synthesis of methyl 5'-bromo-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (M2-1)

将1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯(1.7g，7.34mmol)溶于DMF(10mL)中，降至0℃，加入N-溴代丁二酰亚胺(1.6g，8.83mmol)，室温下反应16h。反应结束后，加水(20mL)，用乙酸乙酯萃取(10mL×3)，合并有机相用饱和食盐水洗涤(20mL×3)，无水Na2SO4干燥，过滤，减压浓缩。残留物经柱层析纯化(PE:EA＝5:1)，得到化合物M2-1(1.7g)，产率74.9％。Methyl 1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (1.7 g, 7.34 mmol) was dissolved in DMF (10 mL), cooled to 0°C, and N-bromosuccinimide (1.6 g, 8.83 mmol) was added. The reaction was allowed to react at room temperature for 16 h. After completion of the reaction, water (20 mL) was added and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous Na₂SO₄ , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to obtain compound M2-1 (1.7 g) in a 74.9% yield.

LC-MS(m/z):310.0[M+H]+。LC-MS (m/z): 310.0 [M+H] + .

步骤2：1'-甲基-2'-氧代-5'-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯(M2)的合成Step 2: Synthesis of methyl 1'-methyl-2'-oxo-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxylate (M2)

将化合物M2-1(1.7g，5.50mmol)、联硼酸频那醇酯(2.8g，11.00mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(402mg，0.55mmol)和醋酸钾(1.35g，13.75mmol)加入到反应瓶中，随后加入二氧六环(20mL)，体系置换为N2氛围，90℃下反应2h。反应结束后，降至室温，反应液减压浓缩，残留物经柱层析纯化(PE:EA＝5:1)，得到化合物M2(700mg)，产率39.6％。Compound M2-1 (1.7 g, 5.50 mmol), pinacol diboron (2.8 g, 11.00 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (402 mg, 0.55 mmol), and potassium acetate (1.35 g, 13.75 mmol) were added to a reaction flask. Dioxane (20 mL) was then added, and the atmosphere was replaced with nitrogen . The reaction was continued at 90°C for 2 h. After completion of the reaction, the temperature was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to obtain compound M2 (700 mg) in a 39.6% yield.

LC-MS(m/z):358.0[M+H]+。LC-MS (m/z): 358.0 [M+H] + .

关键中间体M3的制备
Preparation of key intermediate M3

化合物M1与取代硼酸(或化合物M2与取代卤素)在钯催化剂存在下，发生Suziki偶联得到化合物M3-1，化合物M3-1发生碱性水解得到化合物M3。Compound M1 and substituted boronic acid (or compound M2 and substituted halogen) undergo Suziki coupling in the presence of a palladium catalyst to obtain compound M3-1, and compound M3-1 undergoes alkaline hydrolysis to obtain compound M3.

其中，所述X选自溴或碘。Wherein, the X is selected from bromine or iodine.

实施例1：5'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(1)的合成
Example 1: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (1)

步骤1：5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯(1-1)的合成Step 1: Synthesis of methyl 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (1-1)

将中间体M1(50mg,0.14mmol)溶于二氧六环/水(5mL/1mL)中，依次加入(2-氯-5-甲氧基吡啶-4-基)硼酸(26mg,0.14mmol)、1,1'-二(二苯膦基)二茂铁二氯化钯(10mg,0.01mmol)和碳酸钾(40mg,0.28mmol)，体系置换为氮气氛围，升温至80℃搅拌2小时。冷却至室温，减压浓缩，加水淬灭，用乙酸乙酯萃取三次(20mL×3)，合并有机相，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤。滤液减压浓缩。残留物经柱层析纯化，洗脱剂为20％乙酸乙酯的石油醚溶液，得到化合物1-1(21mg)，产率40.3％。Intermediate M1 (50 mg, 0.14 mmol) was dissolved in dioxane/water (5 mL/1 mL). (2-Chloro-5-methoxypyridin-4-yl)boronic acid (26 mg, 0.14 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (10 mg, 0.01 mmol), and potassium carbonate (40 mg, 0.28 mmol) were added sequentially. The system was replaced with a nitrogen atmosphere, heated to 80°C, and stirred for 2 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, quenched with water, and extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 20% ethyl acetate in petroleum ether as the eluent to afford compound 1-1 (21 mg) in a 40.3% yield.

LC-MS(m/z):373.0[M+H]+。LC-MS (m/z): 373.0 [M+H] + .

步骤2：5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸(1-2)的合成Step 2: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (1-2)

将化合物1-1(500mg,1.34mmol)溶于四氢呋喃/水(5mL/5mL)中，加入氢氧化锂一水合物(200mg,4.03mmol)，体系室温搅拌16小时。减压浓缩，用2N盐酸调节pH至5，过滤，滤饼干燥，得到化合物1-2(460mg)，产率95.6％。Compound 1-1 (500 mg, 1.34 mmol) was dissolved in tetrahydrofuran/water (5 mL/5 mL), and lithium hydroxide monohydrate (200 mg, 4.03 mmol) was added. The system was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, the pH was adjusted to 5 with 2N hydrochloric acid, and the filter cake was dried to obtain compound 1-2 (460 mg) in a yield of 95.6%.

LC-MS(m/z):357.0[M-H]-。LC-MS (m/z): 357.0 [MH] - .

步骤3：5'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(1)的合成Step 3: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (1)

将化合物1-2(200mg,0.56mmol)溶于DMF(10mL)中，依次加入5-(环丙基乙炔基)-1,3,4-噻二唑-2-胺(100mg,0.61mmol)、HATU(200mg,0.53mmol)和三乙胺(200mg,1.98mmol)，体系室温搅拌4小时后加入碳酸铯(398mg,1.22mmol)，室温继续搅拌2小时。加水(20mL)淬灭，用乙酸乙酯萃取三次(20mL×3)，合并有机相，有机相水洗三次(20mL×3)，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤。滤液减压浓缩。残留物经柱层析纯化，洗脱剂为2.5％甲醇的二氯甲烷溶液，再经过全制备液相色谱仪纯化，得到目标化合物1(10mg)，产率3.5％。Compound 1-2 (200 mg, 0.56 mmol) was dissolved in DMF (10 mL). 5-(Cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (100 mg, 0.61 mmol), HATU (200 mg, 0.53 mmol), and triethylamine (200 mg, 1.98 mmol) were added sequentially. After stirring at room temperature for 4 hours, cesium carbonate (398 mg, 1.22 mmol) was added and stirring continued at room temperature for 2 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate three times (20 mL x 3). The organic phases were combined, washed with water three times (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 2.5% methanol in dichloromethane as the eluent and then by preparative liquid chromatography to obtain the target compound 1 (10 mg) in a 3.5% yield.

LC-MS(m/z):506.0[M+H]+。LC-MS (m/z): 506.0 [M+H] + .

1H NMR(400MHz,DMSO-d6):δ13.17(s,1H),8.02(s,1H),7.57(s,1H),7.45(s,1H),7.17(s,1H),3.51(s,3H),3.31(s,3H),1.83(s,2H),1.71-1.66(m,1H),1.61(d,J＝4.4Hz,2H),1.01-0.96(m,2H),0.88-0.84(m,2H). 1 H NMR (400MHz, DMSO-d 6 ): δ13.17(s,1H),8.02(s,1H),7.57(s,1H),7.45(s,1H),7.17(s,1H),3.51(s,3H),3.31(s,3H ),1.83(s,2H),1.71-1.66(m,1H),1.61(d,J＝4.4Hz,2H),1.01-0.96(m,2H),0.88-0.84(m,2H).

实施例2：6'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-5'-甲酰胺(2)的合成
Example 2: Synthesis of 6'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxamide (2)

步骤1：6-溴-2-氧代吲哚啉-1-羧酸叔丁酯(2-2)的合成Step 1: Synthesis of tert-butyl 6-bromo-2-oxoindoline-1-carboxylate (2-2)

将化合物2-1(414mg,2.00mmol)溶于四氢呋喃(10mL)中，加入碳酸氢钠(1.01g,12.00mmol)和二碳酸二叔丁酯(532mg,2.40mmol)，升温至70℃搅拌3小时。冷却至室温，加水淬灭，用二氯甲烷萃取三次(20mL×3)，合并有机相，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤。滤液减压浓缩。残留物经柱层析纯化，洗脱剂为10％乙酸乙酯的石油醚溶液，得到化合物2-2(422mg)，收率80.7％。Compound 2-1 (414 mg, 2.00 mmol) was dissolved in tetrahydrofuran (10 mL), and sodium bicarbonate (1.01 g, 12.00 mmol) and di-tert-butyl dicarbonate (532 mg, 2.40 mmol) were added. The mixture was heated to 70°C and stirred for 3 hours. The mixture was cooled to room temperature, quenched with water, and extracted three times with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 10% ethyl acetate in petroleum ether as the eluent to obtain compound 2-2 (422 mg) in an 80.7% yield.

LC-MS(m/z):312.0,314.0[M+H]+。LC-MS(m/z):312.0,314.0[M+H] + .

步骤2：6’-溴-2’-氧代螺[环丙烷-1,3’-二氢吲哚]-1’-羧酸叔丁酯(2-3)的合成Step 2: Synthesis of tert-butyl 6'-bromo-2'-oxospiro[cyclopropane-1,3'-dihydroindole]-1'-carboxylate (2-3)

将化合物2-2(100mg,0.32mmol)溶于DMSO(3mL)中，加入碳酸钾(110mg,0.80mmol)和二溴乙烷(40μL,0.39mmol)，室温搅拌16小时。加水淬灭，用乙酸乙酯萃取三次(20mL×3)，合并有机相，有机相水洗三次(20mL×3)，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤。滤液减压浓缩。残留物经柱层析纯化，洗脱剂为6％乙酸乙酯的石油醚溶液，得到化合物2-3(85mg)，收率78.4％。Compound 2-2 (100 mg, 0.32 mmol) was dissolved in DMSO (3 mL), potassium carbonate (110 mg, 0.80 mmol) and dibromoethane (40 μL, 0.39 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The mixture was quenched with water and extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed three times with water (20 mL x 3), then with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 6% ethyl acetate in petroleum ether as the eluent to obtain compound 2-3 (85 mg) in a yield of 78.4%.

LC-MS(m/z):338.0,340.0[M+H]+。LC-MS(m/z):338.0,340.0[M+H] + .

步骤3：6’-溴螺[环丙烷-1,3’-吲哚啉]-2’-酮(2-4)的合成Step 3: Synthesis of 6'-bromospiro[cyclopropane-1,3'-indolin]-2'-one (2-4)

将化合物2-3(400mg,1.19mmol)溶于二氯甲烷(10mL)中，滴加三氟乙酸(2mL)，体系室温下搅拌2小时。加入饱和碳酸氢钠调节pH至中性，用乙酸乙酯萃取三次(20mL×3)，合并有机相，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤。滤液减压浓缩后得到脱Boc产物，直接用于下一步反应。Compound 2-3 (400 mg, 1.19 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added dropwise. The system was stirred at room temperature for 2 hours. Saturated sodium bicarbonate was added to adjust the pH to neutral, and the mixture was extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the de-Boc product, which was used directly in the next reaction.

LC-MS(m/z):238.0,240.0[M+H]+。LC-MS(m/z):238.0,240.0[M+H] + .

步骤4：6'-溴-1'-甲基螺[环丙烷-1,3'-吲哚啉]-2'-酮(2-5)的合成Step 4: Synthesis of 6'-bromo-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one (2-5)

将上一步得到的粗品溶于DMF(5mL)中，加入碳酸铯(760mg,2.33mmol)和碘甲烷(200μL,3.21mmol)，体系室温下搅拌16小时。加水淬灭，用乙酸乙酯萃取三次(20mL×3)，合并有机相，有机相水洗三次(20mL×3)，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤。滤液减压浓缩。残留物经柱层析纯化，洗脱剂为20％乙酸乙酯的石油醚溶液，得到化合物2-5(147mg)，两步反应总收率为49.2％。The crude product obtained in the previous step was dissolved in DMF (5 mL), and cesium carbonate (760 mg, 2.33 mmol) and iodomethane (200 μL, 3.21 mmol) were added. The system was stirred at room temperature for 16 hours. The mixture was quenched with water and extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed three times with water (20 mL x 3), then with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 20% ethyl acetate in petroleum ether as the eluent to obtain compound 2-5 (147 mg). The total yield of the two-step reaction was 49.2%.

LC-MS(m/z):252.0,254.0[M+H]+。LC-MS(m/z):252.0,254.0[M+H] + .

步骤5：6'-溴-5'-(2-氯乙酰基)-1'-甲基螺[环丙烷-1,3'-吲哚啉]-2'-酮(2-6)的合成Step 5: Synthesis of 6'-bromo-5'-(2-chloroacetyl)-1'-methylspiro[cyclopropane-1,3'-indolin]-2'-one (2-6)

将化合物2-5(100mg,0.40mmol)溶于1,2-二氯乙烷(3mL)中，冰浴下依次加入氯乙酰氯(70μL,0.80mmol)和三氯化铝(210mg,1.60mmol)，随后升温搅拌3小时。加水淬灭，用二氯甲烷萃取三次(20mL×3)，合并有机相，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤。滤液减压浓缩。残留物经柱层析纯化，洗脱剂为25％乙酸乙酯的石油醚溶液，得到化合物2-6(57mg)，收率43.6％。Compound 2-5 (100 mg, 0.40 mmol) was dissolved in 1,2-dichloroethane (3 mL). Chloroacetyl chloride (70 μL, 0.80 mmol) and aluminum chloride (210 mg, 1.60 mmol) were added sequentially under ice-cooling, and the mixture was stirred at elevated temperature for 3 hours. The mixture was quenched with water and extracted three times with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 25% ethyl acetate in petroleum ether as the eluent to obtain compound 2-6 (57 mg) in a 43.6% yield.

LC-MS(m/z):328.0,330.0[M+H]+。LC-MS(m/z):328.0,330.0[M+H] + .

步骤6：6'-溴-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-5'-羧酸(2-7)的合成Step 6: Synthesis of 6'-bromo-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxylic acid (2-7)

将化合物2-6(50mg,0.15mmol)溶于吡啶(3mL)中，升温至90℃搅拌3小时，后降温至50℃反应16小时。过滤，滤饼加入到4N氢氧化钠溶液(5mL)中，升温至80℃搅拌16小时。冷却至室温，体系用2N盐酸调节pH至3～4，析出固体，抽滤，滤饼水洗，干燥后得到化合物2-7，无需纯化即可用于下一步反应。Compound 2-6 (50 mg, 0.15 mmol) was dissolved in pyridine (3 mL), heated to 90°C with stirring for 3 hours, then cooled to 50°C and reacted for 16 hours. Filter the mixture, add the filter cake to 4N sodium hydroxide solution (5 mL), heat to 80°C and stir for 16 hours. Cool to room temperature, adjust the pH to 3-4 with 2N hydrochloric acid, and precipitate a solid. Filter the solid, wash the filter cake with water, and dry to obtain compound 2-7, which was used in the next step without purification.

LC-MS(m/z):294.0,296.0[M-H]-。LC-MS(m/z):294.0,296.0[MH] - .

步骤7：6'-溴-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-5'-羧酸甲酯(2-8)的合成Step 7: Synthesis of methyl 6'-bromo-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxylate (2-8)

将上步得到的化合物2-7溶于干燥二氯甲烷(3mL)中，冰浴下加入草酰氯(22μL,0.17mmol)和一滴DMF，室温搅拌3小时后滴加1mL甲醇，继续搅拌1小时。加水淬灭，用二氯甲烷萃取三次(20mL×3)，合并有机相，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤。滤液减压浓缩得到化合物2-8(27mg)，两步反应总收率57.2％。Compound 2-7 obtained in the previous step was dissolved in dry dichloromethane (3 mL). Oxalyl chloride (22 μL, 0.17 mmol) and one drop of DMF were added under ice-cooling. After stirring at room temperature for 3 hours, 1 mL of methanol was added dropwise and stirring continued for 1 hour. The mixture was quenched with water and extracted three times with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 2-8 (27 mg). The total yield of the two-step reaction was 57.2%.

LC-MS(m/z):310.0,312.0[M+H]+。LC-MS(m/z):310.0,312.0[M+H] + .

步骤8：6'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-5'-羧酸甲酯(2-9)的合成Step 8: Synthesis of methyl 6'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxylate (2-9)

将化合物2-8(310mg,1.00mmol)溶于二氧六环/水(5mL/1mL)中，依次加入化合物(2-氯-5-甲氧基吡啶-4-基)硼酸(200mg,1.10mmol)、1,1'-二(二苯膦基)二茂铁二氯化钯(73mg,0.10mmol)和碳酸钾(276g,2.00mmol)，体系升温至100℃搅拌2小时。冷却至室温，减压浓缩，加水淬灭，用乙酸乙酯萃取三次(20mL×3)，合并有机相，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤。滤液减压浓缩。残留物经柱层析纯化，洗脱剂为20％乙酸乙酯的石油醚溶液，得到化合物2-9(340mg)，收率91.4％。Compound 2-8 (310 mg, 1.00 mmol) was dissolved in dioxane/water (5 mL/1 mL). (2-chloro-5-methoxypyridin-4-yl)boronic acid (200 mg, 1.10 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (73 mg, 0.10 mmol), and potassium carbonate (276 g, 2.00 mmol) were added sequentially. The system was heated to 100°C and stirred for 2 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, quenched with water, and extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 20% ethyl acetate in petroleum ether as the eluent to obtain compound 2-9 (340 mg) in a 91.4% yield.

LC-MS(m/z):373.0[M+H]+。LC-MS (m/z): 373.0 [M+H] + .

步骤9：6'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-5'-羧酸(2-10)的合成Step 9: Synthesis of 6'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxylic acid (2-10)

将化合物2-9(340mg,0.91mmol)溶于四氢呋喃/水(5mL/5mL)中，加入氢氧化锂一水合物(154mg,3.66mmol)，体系室温搅拌16小时。减压浓缩，用2N盐酸调节pH至5，过滤，滤饼干燥，得到化合物2-10(320mg)，收率97.9％。Compound 2-9 (340 mg, 0.91 mmol) was dissolved in tetrahydrofuran/water (5 mL/5 mL), and lithium hydroxide monohydrate (154 mg, 3.66 mmol) was added. The system was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, the pH was adjusted to 5 with 2N hydrochloric acid, and the filter cake was dried to obtain compound 2-10 (320 mg) in a yield of 97.9%.

LC-MS(m/z):m/z＝357.0[M-H]-。LC-MS (m/z): m/z=357.0 [MH] - .

步骤10：6'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-5'-甲酰胺(2)的合成Step 10: Synthesis of 6'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxamide (2)

将化合物2-10(150mg,0.42mmol)溶于DMF(5mL)中，依次加入5-(环丙基乙炔基)-1,3,4-噻二唑-2-胺(80mg,0.46mmol)、HATU(145mg,0.38mmol)和三乙胺(85mg,0.84mmol)，体系室温搅拌4小时后加入碳酸铯(145mg,0.44mmol)，室温继续搅拌2小时。加水淬灭，用乙酸乙酯萃取三次(20mL×3)，合并有机相，有机相水洗三次(20mL×3)，饱和食盐水洗(20mL)，无水硫酸钠干燥，过滤。滤液减压浓缩。残留物经柱层析纯化，洗脱剂为3％甲醇的二氯甲烷溶液，再经过全制备液相色谱仪纯化，得到目标化合物2(20mg)，收率9.4％。Compound 2-10 (150 mg, 0.42 mmol) was dissolved in DMF (5 mL). 5-(Cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (80 mg, 0.46 mmol), HATU (145 mg, 0.38 mmol), and triethylamine (85 mg, 0.84 mmol) were added sequentially. The system was stirred at room temperature for 4 hours before the addition of cesium carbonate (145 mg, 0.44 mmol). Stirring was continued at room temperature for 2 hours. The mixture was quenched with water and extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed three times with water (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 3% methanol in dichloromethane as the eluent and then by preparative liquid chromatography to obtain the target compound 2 (20 mg) in a 9.4% yield.

LC-MS(m/z):506.0[M+H]+。LC-MS (m/z): 506.0 [M+H] + .

1H NMR(400MHz,DMSO-d6):δ12.97(s,1H),8.07(s,1H),7.57(s,1H),7.48(s,1H),7.17(s,1H),3.54(s,3H),3.28(s,3H),1.80-1.79(m,2H),1.71-1.65(m,1H),1.64-1.62(m,2H),1.00-0.96(m,2H),0.86-0.82(m,2H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.97(s,1H),8.07(s,1H),7.57(s,1H),7.48(s,1H),7.17(s,1H),3.54(s,3H),3.28(s,3H) ,1.80-1.79(m,2H),1.71-1.65(m,1H),1.64-1.62(m,2H),1.00-0.96(m,2H),0.86-0.82(m,2H).

实施例24：7-(2-氯-5-甲氧基吡啶-4-基)-N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-4-甲基-3-氧代-3,4-二氢螺环[苯并[b][1,4]恶嗪-2,1'-环丙烷]-6-甲酰胺(24)的合成
Example 24: Synthesis of 7-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxamide (24)

步骤1：2-溴-4-氟-5-硝基苯甲酸甲酯(24-1)的合成Step 1: Synthesis of methyl 2-bromo-4-fluoro-5-nitrobenzoate (24-1)

将2-溴-4-氟苯甲酸甲酯(10.0g，43.10mmol)溶于H2SO4(20mL)，冰浴条件下滴加HNO3(20mL)，室温反应4小时。将反应液倒入到冰水(200mL)中，用饱和碳酸钠水溶液(200mL)调节pH至7以上，并用EA(200mL×3)萃取，合并有机相用饱和食盐水洗涤(200mL)，无水Na2SO4干燥，过滤，滤液减压浓缩得到化合物24-1(3.0g)，产率25.1％。Methyl 2-bromo-4-fluorobenzoate (10.0 g, 43.10 mmol) was dissolved in H₂SO₄ (20 mL), and HNO₃ (20 mL) was added dropwise in an ice bath. The mixture was allowed to react at room temperature for 4 hours. The reaction solution was poured into ice water (200 mL), and the pH was adjusted to above 7 with saturated aqueous sodium carbonate solution (200 mL). The mixture was extracted with EA (200 mL × 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to give compound 24-1 (3.0 g) in a yield of 25.1%.

LC-MS(m/z):278.0[M+H]+。LC-MS (m/z): 278.0 [M+H] + .

步骤2：2-溴-4-羟基-5-硝基苯甲酸甲酯(24-2)的合成Step 2: Synthesis of methyl 2-bromo-4-hydroxy-5-nitrobenzoate (24-2)

将化合物24-1(2.5g，9.09mmol)溶于DMSO(20mL)，依次加入乙酰氧肟酸(2.8g，10.18mmol)和K2CO3(2.51g，18.18mmol)，80℃反应2小时。加水(10mL)淬灭，用EA萃取(30mL×3)，合并有机相用饱和食盐水洗涤(30mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(PE:EA＝10:1)得到化合物24-2(2.5g)，产率93.3％。Compound 24-1 (2.5 g, 9.09 mmol) was dissolved in DMSO (20 mL), and acetohydroxamic acid (2.8 g, 10.18 mmol) and K 2 CO 3 (2.51 g, 18.18 mmol) were added sequentially. The reaction was allowed to proceed at 80°C for 2 hours. Water (10 mL) was added to quench the reaction, and the mixture was extracted with EA (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to afford compound 24-2 (2.5 g) in a 93.3% yield.

LC-MS(m/z):276.0[M+H]+。LC-MS (m/z): 276.0 [M+H] + .

步骤3：2-溴-4-(1-(乙氧羰基)环丙氧基)-5-硝基苯甲酸甲酯(24-3)的合成Step 3: Synthesis of methyl 2-bromo-4-(1-(ethoxycarbonyl)cyclopropyloxy)-5-nitrobenzoate (24-3)

将化合物24-2(2.5g，9.02mmol)溶于DMF(20mL)，依次加入2,4-二溴丁酸乙酯(3.0g，10.82mmol)和K2CO3(3.8g，27.14mmol)，80℃反应10小时。反应液加水(10mL)淬灭，用EA萃取(30mL×3)，合并有机相用饱和食盐水洗涤(30mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(PE:EA＝5:1)得到化合物24-3(0.7g)，产率19.8％。Compound 24-2 (2.5 g, 9.02 mmol) was dissolved in DMF (20 mL), and ethyl 2,4-dibromobutyrate (3.0 g, 10.82 mmol) and K₂CO₃ (3.8 g, 27.14 mmol) were added sequentially. The reaction was allowed to react at 80°C for 10 hours. The reaction solution was quenched with water (10 mL) and extracted with EA (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to afford compound 24-3 (0.7 g) in a 19.8% yield.

LC-MS(m/z):388.1[M+H]+。LC-MS (m/z): 388.1 [M+H] + .

步骤4：7-溴-3-氧代-3,4-二氢螺环[苯并[b][1,4]恶嗪-2,1'-环丙烷]-6-羧酸甲酯(24-4)的合成Step 4: Synthesis of methyl 7-bromo-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylate (24-4)

将化合物24-3(0.7g，1.80mmol)溶于AcOH(10mL)，冰浴条件下加入还原铁粉(304mg，5.42mmol)，90℃反应0.5小时。反应液减压浓缩，加入水(10mL)，用饱和NaHCO3水溶液(100mL)调节pH至7以上，用EA(100mL×3)萃取，合并有机相，饱和食盐水洗涤(200mL)，无水Na2SO4干燥，过滤，滤液减压浓缩得到化合物24-4(0.3g)，产率53.3％。Compound 24-3 (0.7 g, 1.80 mmol) was dissolved in AcOH (10 mL), and reduced iron powder (304 mg, 5.42 mmol) was added in an ice bath. The reaction was carried out at 90°C for 0.5 h. The reaction solution was concentrated under reduced pressure, and water (10 mL) was added. The pH was adjusted to above 7 with saturated aqueous NaHCO₃ (100 mL). The solution was extracted with EA (100 mL × 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure to obtain compound 24-4 (0.3 g) in a yield of 53.3%.

LC-MS(m/z):312.1[M+H]+。LC-MS (m/z): 312.1 [M+H] + .

步骤5：7-溴-4-甲基-3-氧代-3,4-二氢螺环[苯并[b][1,4]恶嗪-2,1'-环丙烷]-6-羧酸甲酯(24-5)的合成Step 5: Synthesis of methyl 7-bromo-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylate (24-5)

将化合物24-4(300mg，0.96mmol)溶于DMF(5mL)，依次加入碘甲烷(980mg，6.50mmol)和碳酸铯(656mg，1.92mmol)，室温反应16小时。反应混合物加入水(10mL)稀释，用EA萃取(30mL×3)，合并有机相用饱和食盐水洗涤(30mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(PE:EA＝5:1)得到化合物24-5(300mg)，产率95.6％。Compound 24-4 (300 mg, 0.96 mmol) was dissolved in DMF (5 mL), and iodomethane (980 mg, 6.50 mmol) and cesium carbonate (656 mg, 1.92 mmol) were added sequentially. The reaction mixture was allowed to react at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to afford compound 24-5 (300 mg) in a 95.6% yield.

LC-MS(m/z):326.1[M+H]+。LC-MS (m/z): 326.1 [M+H] + .

步骤6：7-(2-氯-5-甲氧基吡啶-4-基)-4-甲基-3-氧代-3,4-二氢螺环[苯并[b][1,4]恶嗪-2,1'-环丙烷]-6-羧酸甲酯(24-6)的合成Step 6: Synthesis of methyl 7-(2-chloro-5-methoxypyridin-4-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylate (24-6)

向瓶中依次加入化合物24-5(300mg，0.92mmol)、(2-氯-5-甲氧基吡啶-4-基)硼酸(206mg，1.10mmol)、K2CO3(381mg，2.76mmol)和Pd(dppf)Cl2(68mg，0.09mmol)，加入二氧六环(5mL)和水(5mL)溶解，体系在氮气保护下80℃反应1小时。反应结束后，加水(10mL)稀释，用EA萃取(30mL×3)，合并有机相用饱和食盐水洗涤(40mL)，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝20:1)，得到化合物24-6(240mg)，产率87.6％。Compound 24-5 (300 mg, 0.92 mmol), (2-chloro-5-methoxypyridin-4-yl)boronic acid (206 mg, 1.10 mmol), K₂CO₃ ( 381 mg, 2.76 mmol), and Pd(dppf) Cl₂ (68 mg, 0.09 mmol) were added to a vial in sequence. Dioxane (5 mL) and water (5 mL) were added for dissolution. The system was reacted at 80°C under nitrogen for 1 hour. After completion of the reaction, the mixture was diluted with water (10 mL) and extracted with EA (30 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to afford compound 24-6 (240 mg) in an 87.6% yield.

LC-MS(m/z):389.0[M+H]+。LC-MS (m/z): 389.0 [M+H] + .

步骤7：7-(2-氯-5-甲氧基吡啶-4-基)-4-甲基-3-氧代-3,4-二氢螺环[苯并[b][1,4]恶嗪-2,1'-环丙烷]-6-羧酸(24-7)的合成Step 7: Synthesis of 7-(2-chloro-5-methoxypyridin-4-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylic acid (24-7)

将化合物24-6(240mg，1.80mmol)溶于甲醇(2mL)、水(2mL)和THF(2mL)的混合溶液中，加入氢氧化锂(432mg，18.0mmol)，室温反应16小时。减压蒸馏除去溶剂，加入水(10mL)，用1mol/LHCl溶液调节pH至7以下，并用EA(100mL×3)萃取，合并有机相用饱和食盐水洗涤(200mL)，无水Na2SO4干燥，过滤，滤液减压浓缩得到化合物24-7(180mg)，产率77.9％。Compound 24-6 (240 mg, 1.80 mmol) was dissolved in a mixture of methanol (2 mL), water (2 mL), and THF (2 mL). Lithium hydroxide (432 mg, 18.0 mmol) was added and the mixture was allowed to react at room temperature for 16 hours. The solvent was removed by distillation under reduced pressure, and water (10 mL) was added. The pH was adjusted to below 7 with 1 mol/L HCl solution, and the mixture was extracted with EA (100 mL × 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to afford compound 24-7 (180 mg) in a yield of 77.9%.

LC-MS(m/z):375.0[M+H]+。LC-MS (m/z): 375.0 [M+H] + .

步骤8：7-(2-氯-5-甲氧基吡啶-4-基)-N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-4-甲基-3-氧代-3,4-二氢螺环[苯并[b][1,4]恶嗪-2,1'-环丙烷]-6-甲酰胺(24)的合成Step 8: Synthesis of 7-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxamide (24)

将化合物24-7(180mg，0.48mmol)溶于DMF(5mL)，依次加入5-(环丙基乙炔基)-1,3,4-噻二唑-2-胺(119mg，0.72mmol)、N,N,N',N'-四甲基氯甲脒六氟磷酸盐(202mg，0.72mmol)和N-甲基咪唑(118mg，1.44mmol)，室温反应16小时。反应混合物加入水(10mL)淬灭，用EA萃取(30mL×3)，合并有机相用饱和食盐水洗涤(30mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝20:1)得到目标化合物24(25mg)，产率10.1％。Compound 24-7 (180 mg, 0.48 mmol) was dissolved in DMF (5 mL), and 5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (119 mg, 0.72 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (202 mg, 0.72 mmol), and N-methylimidazole (118 mg, 1.44 mmol) were added sequentially. The mixture was allowed to react at room temperature for 16 hours. The reaction mixture was quenched by adding water (10 mL) and extracted with EA (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to afford the target compound 24 (25 mg) in a 10.1% yield.

LC-MS(m/z):522.0[M+H]+。LC-MS (m/z): 522.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ13.21(s,1H),8.06(s,1H),7.64(s,1H),7.45(s,1H),7.06(s,1H),3.54(s,3H),3.42(s,3H),1.71-1.68(m,1H),1.35(s,2H),1.28(s,2H),1.01-0.98(m,2H),0.87(s,2H). 1 H NMR (600MHz, DMSO-d 6 ): δ13.21(s,1H),8.06(s,1H),7.64(s,1H),7.45(s,1H),7.06(s,1H),3.54(s,3H),3.4 2(s,3H),1.71-1.68(m,1H),1.35(s,2H),1.28(s,2H),1.01-0.98(m,2H),0.87(s,2H).

实施例43：N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-5'-(2-甲氧基-5-(三氟甲基)苯基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(43)的合成
Example 43: Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(2-methoxy-5-(trifluoromethyl)phenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (43)

步骤1：5'-(2-甲氧基-5-(三氟甲基)苯基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯(43-1)的合成Step 1: Synthesis of methyl 5'-(2-methoxy-5-(trifluoromethyl)phenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (43-1)

向瓶中依次加入中间体M1(100mg，0.28mmol)、2-甲氧基-5-三氟甲基苯硼酸(123mg，0.56mmol)、K2CO3(77mg，0.56mmol)和Pd(dppf)Cl2(22mg，0.03mmol)，加入二氧六环(2mL)和水(1mL)，氮气保护下80℃反应2小时。反应结束后，体系加入水(10mL)稀释，用EA萃取(30mL×3)，合并有机相用饱和食盐水洗涤(40mL)，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(PE:EA＝5:1)，得到化合物43-1(90mg)，产率79.3％。To a vial were added intermediate M1 (100 mg, 0.28 mmol), 2-methoxy-5-trifluoromethylphenylboronic acid (123 mg, 0.56 mmol), K₂CO₃ (77 mg, 0.56 mmol), and Pd(dppf) Cl₂ (22 mg, 0.03 mmol). Dioxane (2 mL) and water (1 mL) were added, and the mixture was reacted at 80°C under nitrogen for 2 hours. After completion of the reaction, the system was diluted with water (10 mL) and extracted with EA (30 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1) to afford compound 43-1 (90 mg) in a 79.3% yield.

LC-MS(m/z):406.0[M+H]+。LC-MS (m/z): 406.0 [M+H] + .

步骤2：5'-(2-甲氧基-5-(三氟甲基)苯基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸(43-2)的合成Step 2: Synthesis of 5'-(2-methoxy-5-(trifluoromethyl)phenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (43-2)

将化合物43-1(90mg，0.22mmol)溶于甲醇(2mL)、水(2mL)和THF(2mL)的混合溶液中，室温条件下加入氢氧化锂(91mg，2.22mmol)，室温反应16小时。将反应液减压浓缩，加入水(5mL)，用1mol/L HCl溶液(30mL)调节pH至7以下，并用EA(50mL×3)萃取，合并有机相用饱和食盐水洗涤(100mL)，无水Na2SO4干燥，过滤，滤液减压浓缩，得到化合物43-2(80mg)，产率92.0％。Compound 43-1 (90 mg, 0.22 mmol) was dissolved in a mixture of methanol (2 mL), water (2 mL), and THF (2 mL). Lithium hydroxide (91 mg, 2.22 mmol) was added at room temperature and allowed to react for 16 hours. The reaction solution was concentrated under reduced pressure, water (5 mL) was added, and the pH was adjusted to below 7 with 1 mol/L HCl solution (30 mL). The mixture was extracted with EA (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to obtain compound 43-2 (80 mg) with a yield of 92.0%.

LC-MS(m/z):392.0[M+H]+。LC-MS (m/z): 392.0 [M+H] + .

步骤3：N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-5'-(2-甲氧基-5-(三氟甲基)苯基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(43)的合成Step 3: Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(2-methoxy-5-(trifluoromethyl)phenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (43)

将化合物43-2(80mg，0.20mmol)溶于DMF(2mL)，依次加入5-(环丙基乙炔基)-1,3,4-噻二唑-2-胺(50mg，0.30mmol)、N,N,N',N'-四甲基氯甲脒六氟磷酸盐(84mg，0.30mmol)和N-甲基咪唑(49mg，0.60mmol)，室温反应16小时。体系加入水(10mL)稀释，用EA萃取(30mL×3)，合并有机相用饱和食盐水洗涤(30mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝20:1)得到化合物43(6mg)，产率5.4％。Compound 43-2 (80 mg, 0.20 mmol) was dissolved in DMF (2 mL), and 5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (50 mg, 0.30 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (84 mg, 0.30 mmol), and N-methylimidazole (49 mg, 0.60 mmol) were added sequentially. The mixture was allowed to react at room temperature for 16 hours. The mixture was diluted with water (10 mL) and extracted with EA (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to afford compound 43 (6 mg) in a 5.4% yield.

LC-MS(m/z):539.0[M+H]+。LC-MS (m/z): 539.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ13.03(s,1H),7.65(dd,J1＝9.0Hz,J2＝2.4Hz,1H),7.58(s,1H),7.51(s,1H),7.11(s,1H),7.07(d,J＝8.4Hz,1H),3.49(s,3H),3.29(s,3H),1.69-1.66(m,1H),1.58(d,J＝4.8Hz,2H),1.26-1.23(m,2H),1.00-0.96(m,2H),0.86-0.83(m,2H). 1 H NMR (600MHz, DMSO-d 6 ): δ13.03 (s, 1H), 7.65 (dd, J 1 = 9.0 Hz, J 2 ＝2.4Hz,1H),7.58(s,1H),7.51(s,1H),7.11(s,1H),7.07(d,J＝8.4Hz,1H),3.49(s,3H),3.29(s,3H) ,1.69-1.66(m,1H),1.58(d,J＝4.8Hz,2H),1.26-1.23(m,2H),1.00-0.96(m,2H),0.86-0.83(m,2H).

实施例45：5'-(5-氰基-2-甲氧基苯基)-N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(45)的合成
Example 45: Synthesis of 5'-(5-cyano-2-methoxyphenyl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (45)

步骤1：5'-(5-氰基-2-甲氧基苯基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯(45-1)的合成Step 1: Synthesis of methyl 5'-(5-cyano-2-methoxyphenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (45-1)

将中间体M1(100mg，0.60mmol)溶于二氧六环(6mL)和水(1mL)，依次加入(5-氰基-2-甲氧基苯基)硼酸(200mg，1.20mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(40mg，0.06mmol)和碳酸钾(160mg，1.20mmol)，体系氮气保护下80℃反应2小时。反应液减压浓缩，残留物经柱层析纯化(PE:EA＝3:1)，得到化合物45-1(190mg)，产率87.4％。Intermediate M1 (100 mg, 0.60 mmol) was dissolved in dioxane (6 mL) and water (1 mL). (5-Cyano-2-methoxyphenyl)boronic acid (200 mg, 1.20 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (40 mg, 0.06 mmol), and potassium carbonate (160 mg, 1.20 mmol) were added sequentially. The mixture was reacted at 80°C under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 3:1) to obtain compound 45-1 (190 mg) in an 87.4% yield.

LC-MS(m/z):363.0[M+H]+。LC-MS (m/z): 363.0 [M+H] + .

步骤2：5'-(5-氰基-2-甲氧基苯基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸(45-2)的合成Step 2: Synthesis of 5'-(5-cyano-2-methoxyphenyl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (45-2)

向瓶中依次加入化合物45-1(190mg，0.52mmol)、氢氧化锂一水合物(110mg，0.60mmol)，加入THF(6mL)、MeOH(3mL)和H2O(1.8mL)，室温反应16h。反应结束后，反应液减压浓缩，所得残留物加水(1.8mL)，1N HCl调pH至弱酸性，抽滤，得到化合物45-2(80mg)，产率44.2％。Compound 45-1 (190 mg, 0.52 mmol), lithium hydroxide monohydrate (110 mg, 0.60 mmol), THF (6 mL), MeOH (3 mL), and H 2 O (1.8 mL) were added to the flask in sequence, and the mixture was allowed to react at room temperature for 16 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was added with water (1.8 mL). The pH was adjusted to weak acidity with 1N HCl, and filtered to obtain compound 45-2 (80 mg) with a yield of 44.2%.

LC-MS(m/z):349.0[M+H]+。LC-MS (m/z): 349.0 [M+H] + .

步骤3：5'-(5-氰基-2-甲氧基苯基)-N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(45)的合成Step 3: Synthesis of 5'-(5-cyano-2-methoxyphenyl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (45)

将化合物45-2(80mg，0.23mmol)溶于超干二氯甲烷(3mL)，依次加入5-(环丙基乙炔基)-1,3,4-噻二唑-2-胺(45mg，0.27mmol)、N,N,N',N'-四甲基氯甲脒六氟磷酸盐(193mg，0.69mmol)和N-甲基咪唑(94mg，1.15mmol)，室温反应2小时。反应结束后，反应液减压浓缩，残余物经柱层析纯化(DCM:MeOH＝50:1)，再经反相色谱纯化，得到目标化合物45(7mg)，产率6.1％。Compound 45-2 (80 mg, 0.23 mmol) was dissolved in ultra-dry dichloromethane (3 mL). 5-(Cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (45 mg, 0.27 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (193 mg, 0.69 mmol), and N-methylimidazole (94 mg, 1.15 mmol) were added sequentially. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 50:1) and then by reverse-phase chromatography to obtain the target compound 45 (7 mg) in a 6.1% yield.

LC-MS(m/z):496.0[M+H]+。LC-MS (m/z): 496.0 [M+H] + .

实施例47：N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-5'-(2-(二氟甲基)-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(47)的合成
Example 47: Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (47)

步骤1：4-溴-2-(二氟甲基)-5-甲氧基吡啶(47-1)的合成Step 1: Synthesis of 4-bromo-2-(difluoromethyl)-5-methoxypyridine (47-1)

将4-溴-5-甲氧基吡啶甲醛(950mg，4.37mmol)溶于二氯甲烷(10mL)，氮气保护，冰水浴下缓慢加入二乙胺基三氟化硫(915mg，5.68mmol)，升至室温反应16h。反应结束后，降至0℃，缓慢加入甲醇淬灭反应。过滤，滤液减压浓缩，残留物经柱层析纯化(PE:EA＝10:1)，得到化合物47-1(700mg)，产率67.3％。4-Bromo-5-methoxypicolinaldehyde (950 mg, 4.37 mmol) was dissolved in dichloromethane (10 mL). Under nitrogen, diethylaminosulfur trifluoride (915 mg, 5.68 mmol) was slowly added under an ice-water bath. The mixture was allowed to warm to room temperature and allowed to react for 16 h. After completion of the reaction, the temperature was lowered to 0°C and methanol was slowly added to quench the reaction. The filtrate was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 10:1) to afford compound 47-1 (700 mg) in a 67.3% yield.

LC-MS(m/z):238.0[M+H]+。LC-MS (m/z): 238.0 [M+H] + .

步骤2：5'-(2-(二氟甲基)-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯(47-2)的合成Step 2: Synthesis of methyl 5'-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (47-2)

将中间体M2(250mg，0.7mmol)、化合物47-1(166mg，0.70mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(51mg，0.07mmol)和碳酸钾(290mg，2.10mmol)加入到反应瓶中，加入二氧六环(10mL)和水(2mL)，N2氛围下100℃反应2h。反应结束后，加水(10mL)稀释，用乙酸乙酯萃取(10mL×3)，合并有机相用饱和食盐水洗涤(20mL)，无水Na2SO4干燥，过滤，滤液减压浓缩，残留物经柱层析纯化(PE:EA＝3:1)，得到化合物47-2(130mg)，产率48.0％。Intermediate M2 (250 mg, 0.7 mmol), compound 47-1 (166 mg, 0.70 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (51 mg, 0.07 mmol), and potassium carbonate (290 mg, 2.10 mmol) were added to a reaction flask. Dioxane (10 mL) and water (2 mL) were added, and the mixture was reacted at 100°C under a nitrogen atmosphere for 2 h. After completion of the reaction, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to obtain compound 47-2 (130 mg) in a yield of 48.0%.

LC-MS(m/z):389.0[M+H]+。LC-MS (m/z): 389.0 [M+H] + .

步骤3：5'-(2-(二氟甲基)-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸(47-3)的合成Step 3: Synthesis of 5'-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (47-3)

将化合物47-2(130mg，0.34mmol)溶于10mL混合溶剂中(甲醇：四氢呋喃：水＝2:2:1)，加入氢氧化锂水合物(140mg，3.35mmol)，室温下反应16h。反应结束后，浓缩去除有机溶剂，向体系中加入4N盐酸调节pH至5-6，过滤，滤渣充分干燥，得到化合物47-3(100mg)，产率80.0％。Compound 47-2 (130 mg, 0.34 mmol) was dissolved in 10 mL of a mixed solvent (methanol:tetrahydrofuran:water = 2:2:1), and lithium hydroxide hydrate (140 mg, 3.35 mmol) was added. The mixture was allowed to react at room temperature for 16 h. After completion of the reaction, the organic solvent was removed by concentration, and the pH of the mixture was adjusted to 5-6 by adding 4N hydrochloric acid. The mixture was filtered, and the filter residue was thoroughly dried to obtain compound 47-3 (100 mg) in an 80.0% yield.

LC-MS(m/z):375.0[M+H]+。LC-MS (m/z): 375.0 [M+H] + .

步骤4：N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-5'-(2-(二氟甲基)-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(47)的合成Step 4: Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (47)

将化合物47-3(50mg，0.14mmol)、5-(环丙基乙炔基)-1,3,4-噻二唑-2-胺(30mg，0.16mmol)、N,N,N',N'-四甲基氯甲脒六氟磷酸盐(77mg，0.27mmol)和N-甲基咪唑(33mg，0.41mmol)加入到DCM(5mL)中，室温下搅拌2h。反应结束后，反应液浓缩，残余物经柱层析纯化(DCM:MeOH＝20:1)，得到目标化合物47(38mg)，产率53.5％。Compound 47-3 (50 mg, 0.14 mmol), 5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (30 mg, 0.16 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (77 mg, 0.27 mmol), and N-methylimidazole (33 mg, 0.41 mmol) were added to DCM (5 mL) and stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain the target compound 47 (38 mg) in a 53.5% yield.

LC-MS(m/z):522.0[M+H]+。LC-MS (m/z): 522.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ13.20(s,1H),8.32(s,1H),7.64(s,1H),7.56(s,1H),7.20(s,1H),7.04(t,J＝55.2Hz,1H),3.59(s,3H),3.30(s,3H),1.86(d,J＝4.8Hz,2H),1.72-1.67(m,1H),1.61(d,J＝4.8Hz,2H),1.01-0.98(m,2H),0.88-0.85(m,2H). 1 H NMR (600MHz, DMSO-d 6 ): δ13.20(s,1H),8.32(s,1H),7.64(s,1H),7.56(s,1H),7.20(s,1H),7.04(t,J＝55.2Hz,1H),3.59(s,3H),3.3 0(s,3H),1.86(d,J＝4.8Hz,2H),1.72-1.67(m,1H),1.61(d,J＝4.8Hz,2H),1.01-0.98(m,2H),0.88-0.85(m,2H).

实施例81：5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代-N-(5-((四氢呋喃-3-基)甲氧基)-1,3,4-噻二唑-2-基)螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(81)的合成
Example 81: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-3-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (81)

步骤1：5-((四氢呋喃-3-基)甲氧基)-1,3,4-噻二唑-2-胺(81-1)的合成Step 1: Synthesis of 5-((tetrahydrofuran-3-yl)methoxy)-1,3,4-thiadiazole-2-amine (81-1)

向瓶中加入(四氢呋喃-3-基)甲醇(245mg，2.40mmol)，再加入四氢呋喃(4mL)，氮气保护下降至0℃，向体系里加入NaH(120mg，3.00mmol)，0℃下反应1h。再向体系里加入5-溴-1,3,4-噻二唑-2-胺(360mg，2.00mmol)，0℃下反应1小时。反应结束后，反应混合物加入饱和氯化铵水溶液(10mL)淬灭，用EA萃取(30mL×3)，合并有机相用饱和食盐水洗涤(40mL)，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝10:1)，得到化合物81-1(40mg)，产率9.8％。To the flask, (tetrahydrofuran-3-yl)methanol (245 mg, 2.40 mmol) was added, followed by tetrahydrofuran (4 mL). The temperature was lowered to 0°C under nitrogen atmosphere, and NaH (120 mg, 3.00 mmol) was added. The reaction was allowed to react at 0°C for 1 hour. 5-Bromo-1,3,4-thiadiazol-2-amine (360 mg, 2.00 mmol) was then added, and the reaction was allowed to react at 0°C for 1 hour. After the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with EA (30 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to afford compound 81-1 (40 mg) in a 9.8% yield.

LC-MS(m/z):202.0[M+H]+。LC-MS (m/z): 202.0 [M+H] + .

步骤2：5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代-N-(5-((四氢呋喃-3-基)甲氧基)-1,3,4-噻二唑-2-基)螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(81)的合成Step 2: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-3-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (81)

将化合物1-2(72mg，0.20mmol)溶于DMF(2mL)，依次加入化合物81-1(40mg，0.20mmol)、N,N,N',N'-四甲基氯甲脒六氟磷酸盐(56mg，0.30mmol)和N-甲基咪唑(49mg，0.60mmol)，室温反应16小时。体系加入水(10mL)稀释，用EA萃取(30mL×3)，合并有机相用饱和食盐水洗涤(30mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝20:1)得到目标化合物81(6mg)，产率5.7％。Compound 1-2 (72 mg, 0.20 mmol) was dissolved in DMF (2 mL), and compound 81-1 (40 mg, 0.20 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (56 mg, 0.30 mmol), and N-methylimidazole (49 mg, 0.60 mmol) were added sequentially. The mixture was allowed to react at room temperature for 16 hours. The mixture was diluted with water (10 mL) and extracted with EA (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to afford the target compound 81 (6 mg) in a 5.7% yield.

LC-MS(m/z):542.0[M+H]+。LC-MS (m/z): 542.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ12.64(s,1H),8.05(s,1H),7.52(s,1H),7.44(s,1H),7.17(s,1H),4.40-4.31(m,2H),3.78-3.74(m,2H),3.67(q,J＝7.8Hz,1H),3.58(s,3H),3.54-3.51(m,1H),3.29(s,3H),2.03-1.96(m,1H),1.83(s,2H),1.61(d,J＝4.8Hz,2H),1.26-1.23(m,2H). 1 H NMR (600MHz, DMSO-d 6 ): δ12.64(s,1H),8.05(s,1H),7.52(s,1H),7.44(s,1H),7.17(s,1H),4.40-4.31(m,2H),3.78-3.74(m,2H),3.67(q,J＝7.8Hz ,1H),3.58(s,3H),3.54-3.51(m,1H),3.29(s,3H),2.03-1.96(m,1H),1.83(s,2H),1.61(d,J=4.8Hz,2H),1.26-1.23(m,2H).

实施例83：5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代-N-(5-((四氢呋喃-3-基)甲氧基)-1,3,4-噻二唑-2-基)螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(83)的合成
Example 83: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-3-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (83)

步骤1：5-((四氢-2H-吡喃-4-基)甲氧基)-1,3,4-噻二唑-2-胺(83-1)的合成Step 1: Synthesis of 5-((tetrahydro-2H-pyran-4-yl)methoxy)-1,3,4-thiadiazol-2-amine (83-1)

向瓶中加入(四氢-2H-吡喃-4-基)甲醇(348.0mg，3.00mmol)，再加入四氢呋喃(10mL)，体系氮气保护，冷却至0℃，加入NaH(120mg，3.00mmol)，0℃下反应1h。再向体系里加入5-溴-1,3,4-噻二唑-2-胺(360mg，2.00mmol)，0℃下反应1h。反应结束后，反应混合物加入饱和氯化铵溶液(10mL)淬灭，用EA萃取(30mL×3)，合并有机相用饱和食盐水洗涤(40mL)，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝10:1)，得到化合物83-1(40mg)，产率5.8％。To the vial, (tetrahydro-2H-pyran-4-yl)methanol (348.0 mg, 3.00 mmol) was added, followed by tetrahydrofuran (10 mL). The system was protected with nitrogen and cooled to 0°C. NaH (120 mg, 3.00 mmol) was added, and the reaction was continued at 0°C for 1 h. 5-Bromo-1,3,4-thiadiazol-2-amine (360 mg, 2.00 mmol) was then added, and the reaction was continued at 0°C for 1 h. After the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with EA (30 mL x 3 ). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to afford compound 83-1 (40 mg) in a 5.8% yield.

LC-MS(m/z):216.0[M+H]+。LC-MS (m/z): 216.0 [M+H] + .

步骤2：5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代-N-(5-((四氢呋喃-3-基)甲氧基)-1,3,4-噻二唑-2-基)螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(83)的合成Step 2: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-3-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (83)

将化合物1-2(68mg，0.19mmol)溶于二氯甲烷(2mL)，依次加入化合物83-1(40mg，0.19mmol)、N,N,N',N'-四甲基氯甲脒六氟磷酸盐(56mg，0.30mmol)和NMI(37mg，0.45mmol)，室温反应2h。反应结束后，反应液减压浓缩，残留物经柱层析纯化(DCM:MeOH＝20:1)，得到目标化合物83(6mg)，产率5.7％。Compound 1-2 (68 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL). Compound 83-1 (40 mg, 0.19 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (56 mg, 0.30 mmol), and NMI (37 mg, 0.45 mmol) were added sequentially. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain the target compound 83 (6 mg) in a 5.7% yield.

LC-MS(m/z):556.0[M+H]+。LC-MS (m/z): 556.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ12.64(s,1H),8.05(s,1H),7.51(s,1H),7.45(s,1H),7.17(s,1H),4.28(d,J＝6.6Hz,2H),3.88(dd,J1＝11.6Hz,J2＝4.2Hz,2H),3.58(s,3H),3.31(s,3H),3.33(m,2H),2.09-2.05(m,1H),1.83(s,2H),1.65-1.60(m,4H),1.35-1.28(m,2H). 1 H NMR (600MHz, DMSO-d 6 ): δ 12.64 (s, 1H), 8.05 (s, 1H), 7.51 (s, 1H), 7.45 (s, 1H), 7.17 (s, 1H), 4.28 (d, J = 6.6Hz, 2H), 3.88 (dd, J 1 = 11.6Hz, J 2 =4.2Hz,2H),3.58(s,3H),3.31(s,3H),3.33(m,2H),2.09-2.05(m,1H),1.83(s,2H),1.65-1.60(m,4H),1.35-1.28(m,2H).

实施例96：5'-(2-氯-3-氟-5-甲氧基吡啶-4-基)-N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(96)的合成
Example 96: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (96)

步骤1：2-氯-3-氟-5-甲氧基吡啶(96-1)的合成Step 1: Synthesis of 2-chloro-3-fluoro-5-methoxypyridine (96-1)

将6-氯-5-氟吡啶-3-醇(1.0g，6.80mmol)溶于MeCN(10mL)中，加入碘甲烷(2.9g，20.40mmol)和碳酸钾(2.8g，20.40mmol)，室温下反应3h。反应结束后，混合物加入水(20mL)稀释，用乙酸乙酯萃取(20mL×3)，合并有机相用饱和NaCl水溶液洗涤(10mL×3)，无水Na2SO4干燥，过滤，滤液减压浓缩得化合物96-1(800mg)，产率72.7％。6-Chloro-5-fluoropyridin-3-ol (1.0 g, 6.80 mmol) was dissolved in MeCN (10 mL), and iodomethane (2.9 g, 20.40 mmol) and potassium carbonate (2.8 g, 20.40 mmol) were added. The mixture was allowed to react at room temperature for 3 h. After completion of the reaction, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated aqueous NaCl solution ( 10 mL × 3), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to obtain compound 96-1 (800 mg) in a yield of 72.7%.

LC-MS(m/z):162.0[M+H]+。LC-MS (m/z): 162.0 [M+H] + .

步骤2：2-氯-3-氟-4-碘-5-甲氧基吡啶(96-2)的合成Step 2: Synthesis of 2-chloro-3-fluoro-4-iodo-5-methoxypyridine (96-2)

将化合物96-1(800mg，4.94mmol)溶于THF(10mL)，N2氛围，降至-78℃，缓慢滴入正丁基锂(37mL，7.41mmol)溶液，-78℃搅拌30min，随后加入I2(1.25g，4.94mmol)，回至室温反应2h。反应结束后，向反应液中加入饱和氯化铵水溶液淬灭(15mL)，硫代硫酸钠水溶液洗涤(20mL)，乙酸乙酯萃取(20mL×3)，合并有机相，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析(PE:EA＝10:1)得化合物96-2(370mg)，产率26.5％。Compound 96-1 (800 mg, 4.94 mmol) was dissolved in THF (10 mL) under an N₂ atmosphere and the temperature was lowered to -78°C. A solution of n-butyllithium (37 mL, 7.41 mmol) was slowly added dropwise. The mixture was stirred at -78°C for 30 min, followed by the addition of I₂ (1.25 g, 4.94 mmol). The mixture was allowed to return to room temperature and allowed to react for 2 h. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL), washed with aqueous sodium thiosulfate (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous Na₂SO₄ , filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to afford compound 96-2 (370 mg) in a 26.5% yield.

LC-MS(m/z):288.0[M+H]+。LC-MS (m/z): 288.0 [M+H] + .

步骤3：5'-(2-氯-3-氟-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯(96-3)的合成Step 3: Synthesis of methyl 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (96-3)

将中间体M2(150mg，0.56mmol)、化合物96-2(144mg，0.50mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(40mg，0.06mmol)、碳酸钾(200mg，1.40mmol)溶于二氧六环(10mL)和水(2mL)，N2氛围下80℃反应2h。反应结束后，用乙酸乙酯萃取(10mL×3)，合并有机相用饱和食盐水洗涤(20mL×3)，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(PE:EA＝3:1)得化合物96-3(48mg)，产率24.6％。Intermediate M2 (150 mg, 0.56 mmol), compound 96-2 (144 mg, 0.50 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (40 mg, 0.06 mmol), and potassium carbonate (200 mg, 1.40 mmol) were dissolved in dioxane (10 mL) and water (2 mL) and reacted at 80°C under a nitrogen atmosphere for 2 h. After completion of the reaction, the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to afford compound 96-3 (48 mg) in a 24.6% yield.

LC-MS(m/z):391.0[M+H]+。LC-MS (m/z): 391.0 [M+H] + .

步骤4：5'-(2-氯-3-氟-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸(96-4)的合成Step 4: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (96-4)

将化合物96-3(48mg，0.12mmol)溶于10mL混合溶剂中(甲醇：四氢呋喃：水＝2:2:1)，加入氢氧化锂水合物(52mg，1.23mmol)，室温反应16h。反应结束后，浓缩去除有机溶剂，向体系中加入4M盐酸水溶液调至pH至5-6，过滤，滤渣充分干燥得化合物96-4(28mg)，产率60.8％。Compound 96-3 (48 mg, 0.12 mmol) was dissolved in 10 mL of a mixed solvent (methanol:tetrahydrofuran:water = 2:2:1), and lithium hydroxide hydrate (52 mg, 1.23 mmol) was added. The mixture was allowed to react at room temperature for 16 h. After completion of the reaction, the organic solvent was removed by concentration, and the solution was adjusted to pH 5-6 by addition of 4 M aqueous hydrochloric acid. The solution was filtered, and the filter residue was thoroughly dried to afford compound 96-4 (28 mg) in a yield of 60.8%.

LC-MS(m/z):377.0[M+H]+。LC-MS (m/z): 377.0 [M+H] + .

步骤5：5'-(2-氯-3-氟-5-甲氧基吡啶-4-基)-N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(96)的合成Step 5: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (96)

将化合物96-4(20mg，0.05mmol)、5-(环丙基乙炔基)-1,3,4-噻二唑-2-胺(12mg，0.06mmol)、N,N,N',N'-四甲基氯甲脒六氟磷酸盐(30mg，0.11mmol)和N-甲基咪唑(13mg，0.16mmol)溶于DCM(10mL)，室温搅拌2h。反应结束后，反应液浓缩，残余物经柱层析纯化(DCM:MeOH＝20:1)，得到目标化合物96(6mg)，产率22.2％。Compound 96-4 (20 mg, 0.05 mmol), 5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (12 mg, 0.06 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (30 mg, 0.11 mmol), and N-methylimidazole (13 mg, 0.16 mmol) were dissolved in DCM (10 mL) and stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain the target compound 96 (6 mg) in a 22.2% yield.

LC-MS(m/z):524.0[M+H]+。LC-MS (m/z): 524.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ13.31(s,1H),8.06(s,1H),7.71(s,1H),7.22(s,1H),3.64(s,3H),3.30(s,3H),1.76–1.72(m,2H),1.69(m,1H),1.63(m,2H),0.99(m,2H),0.86(m,2H). 1 H NMR (600MHz, DMSO-d 6 ): δ13.31(s,1H),8.06(s,1H),7.71(s,1H),7.22(s,1H),3.64(s,3H),3.30(s ,3H),1.76–1.72(m,2H),1.69(m,1H),1.63(m,2H),0.99(m,2H),0.86(m,2H).

实施例97：(R)-N-(5-((1,4-二恶烷-2-基)甲氧基)-1,3,4-噻二唑-2-基)-5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(97)的合成
Example 97: Synthesis of (R)-N-(5-((1,4-dioxan-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (97)

步骤1：(R)-5-((1,4-二恶烷-2-基)甲氧基)-1,3,4-噻二唑-2-胺(97-1)的合成Step 1: Synthesis of (R)-5-((1,4-dioxan-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (97-1)

将(S)-(1,4-二恶烷-2-基)甲醇(200mg，1.68mmol)溶于四氢呋喃(10mL)，氮气保护，冰水浴下加入氢化钠(70mg，2.25mmol)，氮气保护下0℃反应1h，然后加入5-溴-1,3,4-噻二唑-2-胺(200mg，1.12mmol)，氮气保护下0℃继续反应2h。反应混合物加入水(20mL)淬灭，用乙酸乙酯萃取(20mL×3)，合并有机相用饱和食盐水洗涤(30mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝10:1)，得到化合物97-1(50mg)，产率20.5％。(S)-(1,4-Dioxan-2-yl)methanol (200 mg, 1.68 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen, sodium hydride (70 mg, 2.25 mmol) was added under an ice-water bath. The mixture was allowed to react at 0°C for 1 h under nitrogen. 5-Bromo-1,3,4-thiadiazol- 2 -amine (200 mg, 1.12 mmol) was then added and the reaction continued at 0°C for 2 h under nitrogen. The reaction mixture was quenched by water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to afford compound 97-1 (50 mg) in a 20.5% yield.

LC-MS(m/z):218.0[M+H]+。LC-MS (m/z): 218.0 [M+H] + .

步骤2：(R)-N-(5-(((1,4-二恶烷-2-基)甲氧基)-1,3,4-噻二唑-2-基)-5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(97)的合成Step 2: Synthesis of (R)-N-(5-(((1,4-dioxan-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (97)

将化合物1-2(110mg，0.3mmol)溶解于超干二氯甲烷(10mL)，加入化合物97-1(50mg，0.23mmol)、HATU(110mg，0.25mmol)和三乙胺(70mg，0.69mmol)，室温反应16小时。反应结束后，反应混合物加入水(10mL)淬灭，用二氯甲烷萃取(10mL×3)，合并有机相用饱和食盐水洗涤(20mL×3)，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝20:1)，得到目标化合物97(20mg)，产率15.7％。Compound 1-2 (110 mg, 0.3 mmol) was dissolved in ultra-dry dichloromethane (10 mL), and compound 97-1 (50 mg, 0.23 mmol), HATU (110 mg, 0.25 mmol), and triethylamine (70 mg, 0.69 mmol) were added. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain the target compound 97 (20 mg) in a 15.7% yield.

LC-MS(m/z):558.0[M+H]+。LC-MS (m/z): 558.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ12.65(s,1H),8.05(s,1H),7.51(s,1H),7.45(s,1H),7.17(s,1H),4.42-4.37(m,2H),3.93-3.89(m,1H),3.80-3.75(m,2H),3.67-3.58(m,2H),3.58(s,3H),3.51-3.47(m,1H),3.39-3.36(m,1H),3.31(m,3H),1.83(s,2H),1.61(d,J＝4.8Hz,2H). 1 H NMR (600MHz, DMSO-d 6 ): δ12.65(s,1H),8.05(s,1H),7.51(s,1H),7.45(s,1H),7.17(s,1H),4.42-4.37(m,2H),3.93-3.89(m,1H),3.80-3.75(m, 2H),3.67-3.58(m,2H),3.58(s,3H),3.51-3.47(m,1H),3.39-3.36(m,1H),3.31(m,3H),1.83(s,2H),1.61(d,J＝4.8Hz,2H).

实施例98：5'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-(2-环丙基乙基)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(98)的合成
Example 98: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(2-cyclopropylethyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (98)

步骤1：(5-(2-环丙基乙基)-1,3,4-噻二唑-2-基)氨基甲酸叔丁酯(98-1)的合成Step 1: Synthesis of tert-butyl (5-(2-cyclopropylethyl)-1,3,4-thiadiazol-2-yl)carbamate (98-1)

将(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)氨基甲酸叔丁酯(100mg，0.38mmol)溶于乙醇(10mL)中，室温条件下加入10％ Pd/C(60mg)，室温反应24小时。过滤，滤液减压浓缩得到化合物98-1(40mg)，产率39.4％。Tert-butyl (5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)carbamate (100 mg, 0.38 mmol) was dissolved in ethanol (10 mL). 10% Pd/C (60 mg) was added at room temperature and allowed to react for 24 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford compound 98-1 (40 mg) in a 39.4% yield.

LC-MS(m/z):270.0[M+H]+。LC-MS (m/z): 270.0 [M+H] + .

步骤2：5-(2-环丙基乙基)-1,3,4-噻二唑-2-胺(98-2)的合成Step 2: Synthesis of 5-(2-cyclopropylethyl)-1,3,4-thiadiazole-2-amine (98-2)

将化合物98-1(80mg，0.30mmol)溶于DCM(2mL)，加入三氟乙酸(0.5mL)，室温反应2小时。将体系减压浓缩，得到化合物98-2(20mg)，产率39.8％。Compound 98-1 (80 mg, 0.30 mmol) was dissolved in DCM (2 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was reacted at room temperature for 2 hours. The system was concentrated under reduced pressure to obtain compound 98-2 (20 mg) with a yield of 39.8%.

LC-MS(m/z):170.0[M+H]+。LC-MS (m/z): 170.0 [M+H] + .

步骤3：5'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-(2-环丙基乙基)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(98)的合成Step 3: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(2-cyclopropylethyl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (98)

将化合物1-2(43mg，0.12mmol)溶于DMF(2mL)，依次加入化合物98-2(20mg，0.12mmol)、N,N,N',N'-四甲基氯甲脒六氟磷酸盐(67mg，0.24mmol)和N-甲基咪唑(29mg，0.36mmol)，室温反应16小时。反应混合物加入水(10mL)稀释，用EA萃取(30mL×3)，合并有机相用饱和食盐水洗涤(30mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝20:1)，得到目标化合物98(6mg)，产率10.1％。Compound 1-2 (43 mg, 0.12 mmol) was dissolved in DMF (2 mL), and compound 98-2 (20 mg, 0.12 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (67 mg, 0.24 mmol), and N-methylimidazole (29 mg, 0.36 mmol) were added sequentially. The mixture was allowed to react at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain the target compound 98 (6 mg) in a 10.1% yield.

LC-MS(m/z):510.0[M+H]+。LC-MS (m/z): 510.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ12.74(s,1H),8.04(s,1H),7.54(s,1H),7.45(s,1H),7.18(s,1H),3.53(s,3H),3.29(s,3H),3.07(t,J＝7.2Hz,2H),1.83(s,2H),1.63-1.60(m,2H),1.26-1.23(m,2H),0.78-0.72(m,1H),0.42-0.39(m,2H),0.08-0.05(m,2H). 1 H NMR (600MHz, DMSO-d 6 ): δ12.74(s,1H),8.04(s,1H),7.54(s,1H),7.45(s,1H),7.18(s,1H),3.53(s,3H),3.29(s,3H),3.07(t,J＝7.2Hz ,2H),1.83(s,2H),1.63-1.60(m,2H),1.26-1.23(m,2H),0.78-0.72(m,1H),0.42-0.39(m,2H),0.08-0.05(m,2H).

实施例99：5'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-(3,3-二甲基丁-1-炔-1-基)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(99)的合成
Example 99: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(3,3-dimethylbut-1-yn-1-yl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (99)

步骤1：(5-(3,3-二甲基丁-1-炔-1-基-1,3,4-噻二唑-2-基)氨基甲酸叔丁酯(99-1)的合成Step 1: Synthesis of tert-butyl (5-(3,3-dimethylbut-1-yn-1-yl-1,3,4-thiadiazol-2-yl)carbamate (99-1)

将叔丁基(5-溴-1,3,4-噻二唑-2-基)氨基甲酸酯(1.0g，3.60mmol)溶于DMF(20mL)，依次加入Pd(PPh3)4(200mg，1.20mmol)、碘化亚铜(40mg，0.06mmol)和三乙胺(160mg，1.20mmol)，氮气保护下60℃反应6小时。反应结束后，反应液加水(40mL)，用乙酸乙酯萃取(40mL×3)，合步有机相，水洗后再用饱和食盐水洗(20mL)，减压浓缩，残留物经柱层析纯化(PE:EA＝3:1)，得到化合物99-1(400mg)，产率39.5％。Tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl) carbamate (1.0 g, 3.60 mmol) was dissolved in DMF (20 mL). Pd(PPh 3 ) 4 (200 mg, 1.20 mmol), cuprous iodide (40 mg, 0.06 mmol), and triethylamine (160 mg, 1.20 mmol) were added sequentially. The mixture was reacted at 60°C under nitrogen for 6 hours. After completion of the reaction, water (40 mL) was added to the reaction solution, which was then extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with water and then with saturated brine (20 mL), and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to obtain compound 99-1 (400 mg) in a yield of 39.5%.

LC-MS(m/z):282.0[M+H]+。LC-MS (m/z): 282.0 [M+H] + .

步骤2：5-(3,3-二甲基丁-1-烯-1-基)-1,3,4-噻二唑-2-胺(99-2)的合成Step 2: Synthesis of 5-(3,3-dimethylbut-1-en-1-yl)-1,3,4-thiadiazol-2-amine (99-2)

向瓶中加入化合物99-1(250mg，0.89mmol)，用DCM(10mL)溶解，加入三氟乙酸(3mL)，室温反应16h。反应结束后，反应液减压浓缩，所得残留物经柱层析纯化(DCM:MeOH＝20:1)，得到化合物99-2(120mg)，产率74.5％。Compound 99-1 (250 mg, 0.89 mmol) was added to the vial and dissolved in DCM (10 mL). Trifluoroacetic acid (3 mL) was added and the mixture was allowed to react at room temperature for 16 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (DCM:MeOH = 20:1) to afford compound 99-2 (120 mg) in a 74.5% yield.

LC-MS(m/z):182.0[M+H]+。LC-MS (m/z): 182.0 [M+H] + .

步骤3：5'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-(3,3-二甲基丁-1-炔-1-基)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(99)的合成Step 3: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(3,3-dimethylbut-1-yn-1-yl)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (99)

将化合物1-2(72mg，0.20mmol)溶于超干DCM(3mL)，依次加入化合物99-2(43mg，0.24mmol)、N,N,N',N'-四甲基氯甲脒六氟磷酸盐(84mg，0.30mmol)和N-甲基咪唑(50mg，0.60mmol)，室温反应2小时。反应结束后，反应液减压浓缩，残余物经柱层析纯化(DCM:MeOH＝50:1)，再经反相色谱纯化，得到目标化合物99(7mg)，产率6.7％。Compound 1-2 (72 mg, 0.20 mmol) was dissolved in ultra-dry DCM (3 mL). Compound 99-2 (43 mg, 0.24 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (84 mg, 0.30 mmol), and N-methylimidazole (50 mg, 0.60 mmol) were added sequentially. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 50:1) and then by reverse-phase chromatography to obtain the target compound 99 (7 mg) in a 6.7% yield.

LC-MS(m/z):522.0[M+H]+。LC-MS (m/z): 522.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ13.19(s,1H),8.02(s,1H),7.57(s,1H),7.47(s,1H),7.20(s,1H),3.51(s,3H),3.31(s,3H),1.84(s,2H),1.61(d,J＝4.2Hz,2H),1.32(s,9H). 1 H NMR (600MHz, DMSO-d 6 ): δ13.19(s,1H),8.02(s,1H),7.57(s,1H),7.47(s,1H),7.20(s,1H),3. 51(s,3H),3.31(s,3H),1.84(s,2H),1.61(d,J=4.2Hz,2H),1.32(s,9H).

实施例100：5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代-N-(5-((四氢-2H-吡喃-4-基)乙炔基)-1,3,4-噻二唑-2-基)螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(100)的合成
Example 100: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydro-2H-pyran-4-yl)ethynyl)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (100)

步骤1：(5-((四氢-2H-吡喃-4-基)乙炔基)-1,3,4-噻二唑-2-基)氨基甲酸叔丁酯(100-1)的合成Step 1: Synthesis of tert-butyl (5-((tetrahydro-2H-pyran-4-yl)ethynyl)-1,3,4-thiadiazol-2-yl)carbamate (100-1)

将(5-溴-1,3,4-噻二唑-2-基)氨基甲酸叔丁酯(500mg，1.78mmol)溶于DMF(5mL)，依次加入4-乙炔基四氢-2H-吡喃(589mg，5.35mmol)、四三苯基膦钯(206mg,0.18mmol)、碘化亚铜(17mg，0.09mmol)和三乙胺(542mg，5.35mmol)，氮气保护下60℃反应12h。体系加水(20mL)淬灭，用EA萃取(15mL×3)，合并有机相用饱和食盐水洗涤(30mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(PE:EA＝2:1)，得到化合物100-1(180mg)，产率32.6％。Tert-butyl (5-bromo-1,3,4-thiadiazol-2-yl)carbamate (500 mg, 1.78 mmol) was dissolved in DMF (5 mL). 4-Ethynyltetrahydro-2H-pyran (589 mg, 5.35 mmol), tetrakistriphenylphosphine palladium (206 mg, 0.18 mmol), cuprous iodide (17 mg, 0.09 mmol), and triethylamine (542 mg, 5.35 mmol ) were added sequentially. The mixture was reacted at 60°C under nitrogen for 12 h. The mixture was quenched with water (20 mL) and extracted with EA (15 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 2:1) to afford compound 100-1 (180 mg) in a 32.6% yield.

LC-MS(m/z):310.0[M+H]+。LC-MS (m/z): 310.0 [M+H] + .

步骤2：5-(四氢-2H-吡喃-4-基)乙基)-1,3,4-噻二唑-2-胺(100-2)的合成Step 2: Synthesis of 5-(tetrahydro-2H-pyran-4-yl)ethyl)-1,3,4-thiadiazol-2-amine (100-2)

将化合物100-1(180mg，0.58mmol)溶于二氯甲烷(2mL)，加入三氟乙酸(0.5mL)和室温下反应3小时。反应结束后，浓缩，残留物加入饱和碳酸氢钠溶液(15mL)，用二氯甲烷(10mL×3)萃取，合并有机相，用饱和食盐水洗涤(40mL)，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(100％ EA)，得到化合物100-2(92mg)，产率75.6％。Compound 100-1 (180 mg, 0.58 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the mixture was concentrated, and the residue was added with saturated sodium bicarbonate solution (15 mL). The mixture was extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (100% EA) to afford compound 100-2 (92 mg) in a 75.6% yield.

LC-MS(m/z):210.0[M+H]+。LC-MS (m/z): 210.0 [M+H] + .

步骤3：5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代-N-(5-((四氢-2H-吡喃-4-基)乙炔基)-1,3,4-噻二唑-2-基)螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(100)的合成Step 3: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydro-2H-pyran-4-yl)ethynyl)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (100)

将化合物1-2(120mg，0.33mmol)溶解于二氯甲烷(10mL)，加入化合物100-2(84mg，0.40mmol)、N-甲基咪唑(82mg,1.0mmol)和N,N,N',N'-四甲基氯甲脒六氟磷酸盐(140.0mg，0.50mmol)，室温反应12小时。反应结束后，体系加水(10mL)淬灭，用二氯甲烷萃取(10mL×3)，合并有机相用饱和食盐水洗涤(20mL×3)，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝50:1)，得到目标化合物100(20mg)，产率10.9％。Compound 1-2 (120 mg, 0.33 mmol) was dissolved in dichloromethane (10 mL), and compound 100-2 (84 mg, 0.40 mmol), N-methylimidazole (82 mg, 1.0 mmol), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (140.0 mg, 0.50 mmol) were added. The reaction was allowed to react at room temperature for 12 hours. After completion, the system was quenched with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 50:1) to obtain the target compound 100 (20 mg) in a 10.9% yield.

LC-MS(m/z):550.0[M+H]+。LC-MS (m/z): 550.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ13.22(s,1H),8.03(s,1H),7.57(s,1H),7.48(s,1H),7.20(s,1H),3.82-3.78(m,2H),3.52(s,3H),3.48-3.44(m,2H),3.31(s,3H),3.06-3.03(m,1H),1.91-1.82(m,4H),1.67-1.61(m,4H). 1 H NMR (600MHz, DMSO-d 6 ): δ13.22(s,1H),8.03(s,1H),7.57(s,1H),7.48(s,1H),7.20(s,1H),3.82-3.78(m,2H),3.52( s,3H),3.48-3.44(m,2H),3.31(s,3H),3.06-3.03(m,1H),1.91-1.82(m,4H),1.67-1.61(m,4H).

实施例101：(R)-5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-N-(5-((4-甲基吗啉-2-基)甲氧基)-1,3,4-噻二唑-2-基)-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(101)的合成
Example 101: Synthesis of (R)-5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-N-(5-((4-methylmorpholin-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (101)

步骤1：(R)-5-((4-甲基吗啉-2-基)甲氧基)-1,3,4-噻二唑-2-胺(101-1)的合成Step 1: Synthesis of (R)-5-((4-methylmorpholin-2-yl)methoxy)-1,3,4-thiadiazol-2-amine (101-1)

向瓶中加入(R)-(4-甲基吗啉-2-基)甲醇(393mg，3.00mmol)，再加入四氢呋喃(10mL)，氮气保护下降至0℃，向体系里加入NaH(120mg，3.00mmol)，0℃下反应一个小时。再向体系里加入5-溴-1,3,4-噻二唑-2-胺(360mg，2.00mmol)，继续反应一个小时。加入饱和氯化铵水溶液(10mL)淬灭，用EA萃取(30mL×3)，合并有机相用饱和食盐水洗涤(40mL)，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝10:1)，得到化合物101-1(40mg)，产率9.8％。To the flask, (R)-(4-methylmorpholin-2-yl)methanol (393 mg, 3.00 mmol) was added, followed by tetrahydrofuran (10 mL). The temperature was lowered to 0°C under nitrogen. NaH (120 mg, 3.00 mmol) was added and the reaction was continued at 0°C for one hour. 5-Bromo-1,3,4-thiadiazol-2-amine (360 mg, 2.00 mmol) was then added and the reaction continued for one hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride (10 mL), and the mixture was extracted with EA (30 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to afford compound 101-1 (40 mg) in a 9.8% yield.

LC-MS(m/z):231.0[M+H]+。LC-MS (m/z): 231.0 [M+H] + .

步骤2：(R)-5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代-N-(5-((四氢呋喃-3-基)甲氧基)-1,3,4-噻二唑-2-基)螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(101)的合成Step 2: Synthesis of (R)-5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-3-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (101)

将化合物1-2(54mg，0.15mmol)溶于DCM(2mL)，依次加入化合物101-1(35mg，0.15mmol)、TCFH(56mg，0.30mmol)和NMI(37mg，0.45mmol)，室温反应16小时。反应混合物加入水(10mL)稀释，用EA萃取(30mL×3)，合并有机相用饱和食盐水洗涤(30mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝20:1)得到目标化合物101(12mg)，产率13.3％。Compound 1-2 (54 mg, 0.15 mmol) was dissolved in DCM (2 mL), and compound 101-1 (35 mg, 0.15 mmol), TCFH (56 mg, 0.30 mmol), and NMI (37 mg, 0.45 mmol) were added sequentially. The mixture was allowed to react at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with EA (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to afford the target compound 101 (12 mg) in a 13.3% yield.

LC-MS(m/z):571.0[M+H]+。LC-MS (m/z): 571.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ12.72(s,1H),8.05(s,1H),7.51(s,1H),7.46(s,1H),7.19(s,1H),4.56-4.47(m,2H),4.12-4.02(m,2H),3.79(t,J＝12.6Hz,1H),3.58(s,3H),3.53-3.51(m,1H),3.31(s,3H),3.05(s,2H),2.83(s,3H),2.02-1.96(m,1H),1.84(s,2H),1.61(d,J＝4.8Hz,2H). 1 H NMR (600MHz, DMSO-d 6 ): δ12.72(s,1H),8.05(s,1H),7.51(s,1H),7.46(s,1H),7.19(s,1H),4.56-4.47(m,2H),4.12-4.02(m,2H),3.79(t,J＝12.6Hz,1 H),3.58(s,3H),3.53-3.51(m,1H),3.31(s,3H),3.05(s,2H),2.83(s,3H),2.02-1.96(m,1H),1.84(s,2H),1.61(d,J＝4.8Hz,2H).

实施例102：5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-N-(5-(3-吗啉基丙氧基)-1,3,4-噻二唑-2-基)-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(102)的合成
Example 102: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-N-(5-(3-morpholinopropoxy)-1,3,4-thiadiazol-2-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (102)

步骤1：5-(3-吗啉基丙氧基)-1,3,4-噻二唑-2-胺(102-1)的合成Step 1: Synthesis of 5-(3-morpholinopropoxy)-1,3,4-thiadiazol-2-amine (102-1)

将3-吗啉基丙烷-1-醇5-溴-1,3,4-噻二唑-2-胺(725mg，5.00mmol)溶于THF(20mL)，0℃下加入NaH(200mg，5.00mmol)，0℃搅拌30分钟，向反应液中加入5-溴-1,3,4-噻二唑-2-胺(597g，3.33mmol)，室温反应1小时。反应结束后，加入MeOH(5mL)淬灭，减压浓缩，残余物经柱层析纯化(DCM:MeOH＝10:1)，得到化合物102-1(110mg)，产率13.5％。3-Morpholinylpropane-1-ol 5-bromo-1,3,4-thiadiazol-2-amine (725 mg, 5.00 mmol) was dissolved in THF (20 mL). NaH (200 mg, 5.00 mmol) was added at 0°C and stirred at 0°C for 30 minutes. 5-Bromo-1,3,4-thiadiazol-2-amine (597 g, 3.33 mmol) was added to the reaction solution and allowed to react at room temperature for 1 hour. After completion of the reaction, MeOH (5 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 102-1 (110 mg) in a 13.5% yield.

LC-MS(m/z):245.0[M+H]+。LC-MS (m/z): 245.0 [M+H] + .

步骤2：5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-N-(5-(3-吗啉基丙氧基)-1,3,4-噻二唑-2-基)-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(102)的合成Step 2: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-N-(5-(3-morpholinopropoxy)-1,3,4-thiadiazol-2-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (102)

向瓶中加入化合物1-2(143mg，0.20mmol)，用DCM(3mL)溶解，依次加入化合物102-1(110mg，0.43mmol)、N,N,N',N'-四甲基氯甲脒六氟磷酸盐(182mg，0.48mmol)和N-甲基咪唑(88mg，0.80mmol)，室温反应2小时。反应结束后，反应液减压浓缩，残余物经柱层析纯化(DCM:MeOH＝50:1)，再经反相色谱纯化，得到目标化合物102(8mg)，产率3.4％。Compound 1-2 (143 mg, 0.20 mmol) was added to a vial and dissolved in DCM (3 mL). Compound 102-1 (110 mg, 0.43 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (182 mg, 0.48 mmol), and N-methylimidazole (88 mg, 0.80 mmol) were then added sequentially. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 50:1) and then by reverse-phase chromatography to obtain the target compound 102 (8 mg) in a 3.4% yield.

LC-MS(m/z):585.0[M+H]+。LC-MS (m/z): 585.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ12.64(s,1H),8.04(s,1H),7.53(s,1H),7.42(s,1H),7.14(s,1H),4.44(t,J＝6.6Hz,2H),3.58(s,3H),3.57(t,J＝4.8Hz,4H),3.30(s,3H),2.41(t,J＝7.2Hz,2H),2.35(s,4H),1.94(p,J＝6.6Hz,2H),1.82(s,2H),1.60(d,J＝4.2Hz,2H). 1 H NMR (600MHz, DMSO-d 6 ): δ12.64(s,1H),8.04(s,1H),7.53(s,1H),7.42(s,1H),7.14(s,1H),4.44(t,J＝6.6Hz,2H),3.58(s,3H),3.57(t,J＝4 .8Hz,4H),3.30(s,3H),2.41(t,J＝7.2Hz,2H),2.35(s,4H),1.94(p,J＝6.6Hz,2H),1.82(s,2H),1.60(d,J＝4.2Hz,2H).

实施例103：5'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-(3-(二甲基氨基)丙氧基)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(103)的合成
Example 103: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(3-(dimethylamino)propoxy)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (103)

步骤1：5-(3-(二甲基氨基)丙氧基)-1,3,4-噻二唑-2-胺(103-1)的合成Step 1: Synthesis of 5-(3-(dimethylamino)propoxy)-1,3,4-thiadiazole-2-amine (103-1)

将3-(二甲基氨基)丙-1-醇(2.9g，27.77mmol)溶于THF(20mL)，氮气保护冰水浴下加入NaH(1.7g，41.66mmol)，氮气保护下0℃反应1h，然后加入5-溴-1,3,4-噻二唑-2-胺(5.0g，27.77mmol)，氮气保护下0℃继续反应3h。反应混合物加入水(20mL)稀释，用EA萃取(20mL×3)，合并有机相用饱和食盐水洗涤(30mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝10:1)，得到化合物103-1(180mg)，产率32.6％。3-(Dimethylamino)propan-1-ol (2.9 g, 27.77 mmol) was dissolved in THF (20 mL). NaH (1.7 g, 41.66 mmol) was added under nitrogen protection in an ice-water bath. The reaction was continued at 0°C under nitrogen protection for 1 h. 5-Bromo-1,3,4-thiadiazol-2-amine (5.0 g, 27.77 mmol) was then added and the reaction was continued at 0°C under nitrogen protection for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 103-1 (180 mg) in a 32.6% yield.

LC-MS(m/z):203.0[M+H]+。LC-MS (m/z): 203.0 [M+H] + .

步骤2：5'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-(3-(二甲基氨基)丙氧基)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(103)的合成Step 2: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(3-(dimethylamino)propoxy)-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (103)

将化合物1-2(100mg，0.27mmol)溶解于超干二氯甲烷(10mL)，加入化合物103-1(55mg，0.27mmol)、HATU(102mg，0.27mmol)和三乙胺(55mg，0.54mmol)，室温反应12小时。反应结束后，反应混合物加入水(10mL)稀释，用二氯甲烷萃取(10mL×3)，合并有机相用饱和食盐水洗涤(20mL×3)，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝10:1)，得到目标化合物103(2mg)，产率1.3％。Compound 1-2 (100 mg, 0.27 mmol) was dissolved in ultra-dry dichloromethane (10 mL), and compound 103-1 (55 mg, 0.27 mmol), HATU (102 mg, 0.27 mmol), and triethylamine (55 mg, 0.54 mmol) were added. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to obtain the target compound 103 (2 mg) in a 1.3% yield.

LC-MS(m/z):543.0[M+H]+。LC-MS (m/z): 543.0 [M+H] + .

实施例104：5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代-N-(5-((四氢呋喃-2-基)甲氧基)-1,3,4-噻二唑-2-基)螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(104)的合成
Example 104: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (104)

步骤1：5-((四氢呋喃-2-基)甲氧基)-1,3,4-噻二唑-2-胺(104-1)的合成Step 1: Synthesis of 5-((tetrahydrofuran-2-yl)methoxy)-1,3,4-thiadiazole-2-amine (104-1)

将(四氢呋喃-2-基)甲醇(750mg，7.26mmol)溶于四氢呋喃(10mL)，氮气保护，冰水浴下加入氢化钠(340mg，8.39mmol)，氮气保护下0℃反应1h，然后加入5-溴-1,3,4-噻二唑-2-胺(1.0g，5.59mmol)，氮气保护下0℃继续反应2h。反应混合物加入水(20mL)稀释，用乙酸乙酯萃取(20mL×3)，合并有机相用饱和食盐水洗涤(30mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝10:1)，得到化合物104-1(300mg)，产率26.7％。(Tetrahydrofuran-2-yl)methanol (750 mg, 7.26 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen protection, sodium hydride (340 mg, 8.39 mmol) was added under an ice-water bath. The mixture was allowed to react at 0°C for 1 h under nitrogen protection. 5-Bromo-1,3,4-thiadiazol-2-amine ( 1.0 g, 5.59 mmol) was then added and the reaction continued at 0°C for 2 h under nitrogen protection. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to afford compound 104-1 (300 mg) in a 26.7% yield.

LC-MS(m/z):202.0[M+H]+。LC-MS (m/z): 202.0 [M+H] + .

步骤2：5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代-N-(5-((四氢呋喃-2-基)甲氧基)-1,3,4-噻二唑-2-基)螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(104)的合成Step 2: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-2-yl)methoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (104)

将化合物1-2(400mg，1.50mmol)溶解于超干二氯甲烷(10mL)，加入化合物104-1(300mg，1.50mmol)、HATU(570mg，1.50mmol)和三乙胺(454mg，4.50mmol)，室温反应16小时。反应结束后，反应混合物加入水(10mL)稀释，用二氯甲烷萃取(10mL×3)，合并有机相用饱和食盐水洗涤(20mL×3)，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝20:1)，得到目标化合物104(30mg)，产率3.7％。Compound 1-2 (400 mg, 1.50 mmol) was dissolved in ultra-dry dichloromethane (10 mL), and compound 104-1 (300 mg, 1.50 mmol), HATU (570 mg, 1.50 mmol), and triethylamine (454 mg, 4.50 mmol) were added. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain the target compound 104 (30 mg) in a 3.7% yield.

LC-MS(m/z):542.0[M+H]+。LC-MS (m/z): 542.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ12.97(s,1H),8.07(s,1H),7.57(s,1H),7.48(s,1H),7.17(s,1H),3.54(s,3H),3.33(s,5H),3.28(s,3H),1.80(d,J＝4.8Hz,2H),1.63(d,J＝4.8Hz,2H),1.00-0.96(m,2H),0.86-0.82(m,2H). 1 H NMR (600MHz, DMSO-d 6 ): δ12.97(s,1H),8.07(s,1H),7.57(s,1H),7.48(s,1H),7.17(s,1H),3.54(s,3H),3.33(s,5H), 3.28(s,3H),1.80(d,J＝4.8Hz,2H),1.63(d,J＝4.8Hz,2H),1.00-0.96(m,2H),0.86-0.82(m,2H).

实施例105：5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代-N-(5-(2-(四氢-2H-吡喃-4-基)乙氧基)-1,3,4-噻二唑-2-基)螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(105)的合成
Example 105: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (105)

步骤1：5-(2-(四氢-2H-吡喃-4-基)乙氧基)-1,3,4-噻二唑-2-胺(105-1)的合成Step 1: Synthesis of 5-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)-1,3,4-thiadiazol-2-amine (105-1)

将2-(四氢-2H-吡喃-4-基)乙-1-醇(1.3g，10.00mmol)溶于THF(20mL)，0℃下加入NaH(480mg，12.00mmol)，0℃搅拌30分钟，向反应液中加入5-溴-1,3,4-噻二唑-2-胺(1.4g，7.82mmol)，室温反应1小时。反应结束后，反应液加入MeOH(5mL)淬灭，减压浓缩，残余物经柱层析纯化(DCM:MeOH＝10:1)，得到化合物105-1(115mg)，产率4.9％。2-(Tetrahydro-2H-pyran-4-yl)ethan-1-ol (1.3 g, 10.00 mmol) was dissolved in THF (20 mL). NaH (480 mg, 12.00 mmol) was added at 0°C and stirred at 0°C for 30 minutes. 5-Bromo-1,3,4-thiadiazol-2-amine (1.4 g, 7.82 mmol) was added to the reaction solution and allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction solution was quenched with MeOH (5 mL) and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 105-1 (115 mg) in a 4.9% yield.

LC-MS(m/z):230.0[M+H]+。LC-MS (m/z): 230.0 [M+H] + .

步骤2：5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代-N-(5-(2-(四氢-2H-吡喃-4-基)乙氧基)-1,3,4-噻二唑-2-基)螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(105)的合成Step 2: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxamide (105)

向瓶中加入化合物1-2(143mg，0.40mmol)，用DCM(3mL)溶解，依次加入化合物105-1(115mg，0.49mmol)、N,N,N',N'-四甲基氯甲脒六氟磷酸盐(182mg，0.48mmol)和N-甲基咪唑(88mg，0.80mmol)，室温反应2小时。反应结束后，反应液减压浓缩，残余物经柱层析纯化(DCM:MeOH＝50:1)，再经反相色谱纯化，冻干，得到目标化合物105(8mg)，产率3.5％。Compound 1-2 (143 mg, 0.40 mmol) was added to a vial and dissolved in DCM (3 mL). Compound 105-1 (115 mg, 0.49 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (182 mg, 0.48 mmol), and N-methylimidazole (88 mg, 0.80 mmol) were then added sequentially. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 50:1), followed by reverse-phase chromatography, and lyophilized to obtain the target compound 105 (8 mg) in a 3.5% yield.

LC-MS(m/z):570.0[M+H]+。LC-MS (m/z): 570.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ12.65(s,1H),8.05(s,1H),7.52(s,1H),7.43(s,1H),7.16(s,1H),4.47(t,J＝6.0Hz,2H),3.84-3.81(m,2H),3.58(s,3H),3.31(s,3H),3.28(dd,J1＝11.4Hz,J2＝2.4Hz,2H),1.82(s,2H),1.73-1.70(m,3H),1.62-1.59(m,4H),1.24-1.18(m,2H). 1 H NMR (600MHz, DMSO-d 6 ): δ12.65(s,1H),8.05(s,1H),7.52(s,1H),7.43(s,1H),7.16(s,1H),4.4 7(t,J＝6.0Hz,2H),3.84-3.81(m,2H),3.58(s,3H),3.31(s,3H),3.28(dd,J 1 = 11.4Hz, J 2 = 2.4Hz, 2H), 1.82 (s, 2H), 1.73-1.70 (m, 3H), 1.62-1.59 (m, 4H), 1.24-1.18 (m, 2H).

实施例106：5'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-1'-甲基螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(106)的合成
Example 106: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methylspiro[cyclopropane-1,3'-indoline]-6'-carboxamide (106)

步骤1：5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯(106-1)的合成Step 1: Synthesis of methyl 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methylspiro[cyclopropane-1,3'-indoline]-6'-carboxylate (106-1)

向瓶中加入化合物1-7(200mg，0.54mmol)，再加入四氢呋喃(5mL)，氮气保护下降至0℃，向体系里加入硼烷二甲硫醚(5.4mL，5.40mmol)，60℃下反应6h。反应结束后，反应混合物加入饱和氯化铵溶液(10mL)淬灭，用EA萃取(30mL×3)，合并有机相用饱和食盐水洗涤(40mL)，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝20:1)，得到化合物106-1(40mg)，产率20.8％。Compound 1-7 (200 mg, 0.54 mmol) was added to the vial, followed by tetrahydrofuran (5 mL). The temperature was lowered to 0°C under nitrogen. Borane dimethyl sulfide (5.4 mL, 5.40 mmol) was added to the system, and the reaction was continued at 60°C for 6 h. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with EA (30 mL x 3). The combined organic phases were washed with saturated brine (40 mL), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to afford compound 106-1 (40 mg) in a 20.8% yield.

LC-MS(m/z):359.0[M+H]+。LC-MS (m/z): 359.0 [M+H] + .

步骤3：5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基螺[环丙烷-1,3'-吲哚啉]-6'-羧酸(106-2)的合成Step 3: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methylspiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (106-2)

将化合物106-1(40mg，0.11mmol)溶于甲醇(2mL)、水(2mL)和THF(2mL)的混合溶液中，室温条件下加入LiOH(26mg，1.10mmol)，室温反应16h。反应结束后，体系减压浓缩，加入水(10mL)，用1mol/L HCl溶液(15mL)调节pH至7以下，并用EA(30mL×3)萃取，合并有机相用饱和食盐水洗涤(20mL)，无水Na2SO4干燥，过滤，滤液减压浓缩，得到化合物106-2(40mg)粗品。Compound 106-1 (40 mg, 0.11 mmol) was dissolved in a mixture of methanol (2 mL), water (2 mL), and THF (2 mL). LiOH (26 mg, 1.10 mmol) was added at room temperature and allowed to react for 16 h. After completion of the reaction, the system was concentrated under reduced pressure, water (10 mL) was added, and the pH was adjusted to below 7 with 1 mol/L HCl solution (15 mL). The mixture was extracted with EA (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 106-2 (40 mg).

LC-MS(m/z):345.0[M+H]+。LC-MS (m/z): 345.0 [M+H] + .

步骤4：5'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-1'-甲基螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(106)的合成Step 4: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-1'-methylspiro[cyclopropane-1,3'-indoline]-6'-carboxamide (106)

将化合物106-2粗品溶于二氯甲烷(2mL)，依次加入5-(环丙基乙炔基)-1,3,4-噻二唑-2-胺(30mg，0.18mmol)、N,N,N',N'-四甲基氯甲脒六氟磷酸盐(50mg，0.18mmol)和N-甲基咪唑(29mg，0.36mmol)，室温反应2h。反应结束后，反应混合物加入水(10mL)稀释，用EA萃取(30mL×3)，合并有机相用饱和食盐水洗涤(30mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝20:1)得到目标化合物106(1.2mg)，两步产率2.2％。The crude compound 106-2 was dissolved in dichloromethane (2 mL), and 5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (30 mg, 0.18 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (50 mg, 0.18 mmol), and N-methylimidazole (29 mg, 0.36 mmol) were added sequentially. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with EA (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to afford the target compound 106 (1.2 mg) in a two-step yield of 2.2%.

LC-MS(m/z):492.0[M+H]+。LC-MS (m/z): 492.0 [M+H] + .

实施例107：N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-5'-(3-甲氧基吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(107)的合成
Example 107: Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(3-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (107)

步骤1：5'-(3-甲氧基吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯(107-1)的合成Step 1: Synthesis of methyl 5'-(3-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (107-1)

将中间体M1(180mg，0.50mmol)溶于二氧六环(6mL)和水(1mL)，依次加入(3-甲氧基吡啶-4-基)硼酸(92mg，0.60mmol)、Pd(dppf)Cl2(36mg，0.05mmol)和K2CO3(138mg，1.00mmol)，氮气保护下80℃反应2小时。反应液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝50:1)，得到化合物107-1(80mg)，产率47.3％。Intermediate M1 (180 mg, 0.50 mmol) was dissolved in dioxane (6 mL) and water (1 mL). (3-Methoxypyridin-4-yl)boronic acid (92 mg, 0.60 mmol), Pd(dppf) Cl₂ (36 mg, 0.05 mmol), and K₂CO₃ (138 mg, 1.00 mmol) were added sequentially. The mixture was reacted at 80°C under nitrogen for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 50:1) to afford compound 107-1 (80 mg) in a 47.3% yield.

LC-MS(m/z):339.0[M+H]+。LC-MS (m/z): 339.0 [M+H] + .

步骤2：5'-(3-甲氧基吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸(107-2)的合成Step 2: Synthesis of 5'-(3-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (107-2)

向瓶中依次加入化合物107-1(80mg，0.24mmol)、氢氧化锂一水合物(110mg，2.40mmol)，加入THF(5mL)、MeOH(1.5mL)和H2O(1mL)，室温反应16h。反应结束后，反应液减压浓缩，所得残留物加H2O(2mL)，1N HCl调pH至弱酸性，减压浓缩得到化合物107-2(45mg)，产率57.9％。Compound 107-1 (80 mg, 0.24 mmol) and lithium hydroxide monohydrate (110 mg, 2.40 mmol) were added to the vial in sequence, followed by THF (5 mL), MeOH (1.5 mL), and H 2 O (1 mL). The mixture was allowed to react at room temperature for 16 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was added with H 2 O (2 mL). The pH was adjusted to weakly acidic with 1N HCl, and the mixture was concentrated under reduced pressure to afford compound 107-2 (45 mg) in a yield of 57.9%.

LC-MS(m/z):325.0[M+H]+。LC-MS (m/z): 325.0 [M+H] + .

步骤3：N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-5'-(3-甲氧基吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(107)的合成Step 3: Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(3-methoxypyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (107)

将化合物107-2(45mg，0.12mmol)溶于超干DCM(3mL)，依次加入5-(环丙基乙炔基)-1,3,4-噻二唑-2-胺(23mg，0.14mmol)、N,N,N',N'-四甲基氯甲脒六氟磷酸盐(50mg，0.18mmol)和N-甲基咪唑(30mg，0.36mmol)，室温反应2小时。反应结束后，反应液减压浓缩，残余物经柱层析纯化(DCM:MeOH＝50:1)，得到目标化合物107(53mg)，产率93.7％。Compound 107-2 (45 mg, 0.12 mmol) was dissolved in ultra-dry DCM (3 mL). 5-(Cyclopropylethynyl)-1,3,4-thiadiazol-2-amine (23 mg, 0.14 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (50 mg, 0.18 mmol), and N-methylimidazole (30 mg, 0.36 mmol) were added sequentially. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 50:1) to obtain the target compound 107 (53 mg) in a 93.7% yield.

LC-MS(m/z):472.0[M+H]+。LC-MS (m/z): 472.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ13.15(s,1H),8.28(d,J＝4.8Hz,1H),8.23(s,1H),7.53(s,1H),7.34(d,J＝4.8Hz,1H),7.14(s,1H),3.53(s,3H),3.32(s,3H),1.82-1.80(m,2H),1.71-1.67(m,1H),1.62(q,J＝3.6Hz,2H),1.01-0.98(m,2H),0.88-0.86(m,2H). 1 H NMR (600MHz, DMSO-d 6 ): δ13.15(s,1H),8.28(d,J＝4.8Hz,1H),8.23(s,1H),7.53(s,1H),7.34(d,J＝4.8Hz,1H),7.14(s,1H),3.53(s,3H ),3.32(s,3H),1.82-1.80(m,2H),1.71-1.67(m,1H),1.62(q,J＝3.6Hz,2H),1.01-0.98(m,2H),0.88-0.86(m,2H).

实施例108：N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-5'-(5-甲氧基-2-甲基吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(108)的合成
Example 108: Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(5-methoxy-2-methylpyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (108)

目标化合物108的制备方法参考实施例107中化合物107的制备方法，仅将原料(3-甲氧基吡啶-4-基)硼酸替换为(5-甲氧基-2-甲基吡啶-4-基)硼酸，其他中间体原料与制备方法同实施例107，得到目标化合物108(4mg)，总产率0.9％。The preparation method of target compound 108 was similar to that of compound 107 in Example 107, except that the raw material (3-methoxypyridin-4-yl)boric acid was replaced with (5-methoxy-2-methylpyridin-4-yl)boric acid. The other intermediate raw materials and preparation method were the same as those in Example 107 to obtain target compound 108 (4 mg) with a total yield of 0.9%.

LC-MS(m/z):486.0[M+H]+。LC-MS (m/z): 486.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ13.13(s,1H),8.07(s,1H),7.52(s,1H),7.25(s,1H),7.14(s,1H),3.48(s,3H),3.31(s,3H),2.47(s,3H),1.82-1.80(m,2H),1.71-1.68(m,1H),1.62-1.60(m,2H),1.01-0.98(m,2H),0.88-0.85(m,2H). 1 H NMR (600MHz, DMSO-d 6 ): δ13.13(s,1H),8.07(s,1H),7.52(s,1H),7.25(s,1H),7.14(s,1H),3.48(s,3H),3.31(s,3H),2.47( s,3H),1.82-1.80(m,2H),1.71-1.68(m,1H),1.62-1.60(m,2H),1.01-0.98(m,2H),0.88-0.85(m,2H).

实施例109：N-(5-(环丙基乙炔基)-1,3,4-噻二唑-2-基)-5'-(5-甲氧基-2-环丙基吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(109)的合成
Example 109: Synthesis of N-(5-(cyclopropylethynyl)-1,3,4-thiadiazol-2-yl)-5'-(5-methoxy-2-cyclopropylpyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (109)

目标化合物109的制备方法参考实施例107中化合物107的制备方法，仅将原料(3-甲氧基吡啶-4-基)硼酸替换为(5-甲氧基-2-环丙基吡啶-4-基)硼酸，其他中间体原料与制备方法同实施例107，得到目标化合物109(9mg)，总产率1.8％。The preparation method of target compound 109 was similar to that of compound 107 in Example 107, except that the raw material (3-methoxypyridin-4-yl)boric acid was replaced with (5-methoxy-2-cyclopropylpyridin-4-yl)boric acid. The other intermediate raw materials and preparation method were the same as those in Example 107 to obtain target compound 109 (9 mg) with a total yield of 1.8%.

LC-MS(m/z):512.0[M+H]+。LC-MS (m/z): 512.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ13.11(s,1H),8.01(s,1H),7.51(s,1H),7.23(s,1H),7.15(s,1H),3.45(s,3H),3.31(s,3H),2.10-2.06(m,1H),1.82-1.80(m,2H),1.71-1.67(m,1H),1.61(d,J＝4.8Hz,2H),1.00-0.97(m,2H),0.91-0.89(m,2H),0.88-0.84(m,4H). 1 H NMR (600MHz, DMSO-d 6 ): δ13.11(s,1H),8.01(s,1H),7.51(s,1H),7.23(s,1H),7.15(s,1H),3.45(s,3H),3.31(s,3H),2.10-2.06(m,1H),1 .82-1.80(m,2H),1.71-1.67(m,1H),1.61(d,J＝4.8Hz,2H),1.00-0.97(m,2H),0.91-0.89(m,2H),0.88-0.84(m,4H).

实施例110：5'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-甲氧基-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(110)的合成
Example 110: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (110)

将化合物1-2(120mg，0.34mmol)、5-甲氧基-1,3,4-噻二唑-2-胺(45mg，0.34mmol)、N,N,N',N'-四甲基氯甲脒六氟磷酸盐(280mg，1.0mmol)和N-甲基咪唑(135mg，1.65mmol)溶于DCM，室温下搅拌2h。反应结束后，反应液减压浓缩，残余物经柱层析纯化(DCM:MeOH＝20:1)，得到目标化合物110(8mg)，产率5.1％。Compound 1-2 (120 mg, 0.34 mmol), 5-methoxy-1,3,4-thiadiazol-2-amine (45 mg, 0.34 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (280 mg, 1.0 mmol), and N-methylimidazole (135 mg, 1.65 mmol) were dissolved in DCM and stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain the target compound 110 (8 mg) in a 5.1% yield.

LC-MS(m/z):472.0[M+H]+。LC-MS (m/z): 472.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ12.65(s,1H),8.05(s,1H),7.52(s,1H),7.45(s,1H),7.17(s,1H),4.07(s,3H),3.58(s,3H),3.31(s,3H),1.83(s,2H),1.61(d,J＝4.8Hz,2H). 1 H NMR (600MHz, DMSO-d 6 ): δ12.65(s,1H),8.05(s,1H),7.52(s,1H),7.45(s,1H),7.17(s,1H),4. 07(s,3H),3.58(s,3H),3.31(s,3H),1.83(s,2H),1.61(d,J＝4.8Hz,2H).

实施例112:5'-(2-氯-3-氟-5-甲氧基吡啶-4-基)-N-(5-甲氧基-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(112)的合成
Example 112: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (112)

目标化合物112的制备方法参考实施例110中化合物110的制备方法，仅将化合物1-2替换为化合物96-4，其他原料与制备方法同实施例110，得到目标化合物112(7mg)，产率10.8％。The preparation method of target compound 112 was similar to that of compound 110 in Example 110, except that compound 1-2 was replaced by compound 96-4. Other raw materials and preparation methods were the same as those in Example 110 to obtain target compound 112 (7 mg) with a yield of 10.8%.

LC-MS(m/z):490.0[M+H]+。LC-MS (m/z): 490.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ12.79(s,1H),8.07(s,1H),7.68(s,1H),7.17(s,1H),4.06(s,3H),3.68(s,3H),3.31(s,3H),1.72(s,2H),1.62(s,2H). 1 H NMR (600MHz, DMSO-d 6 ): δ12.79(s,1H),8.07(s,1H),7.68(s,1H),7.17(s,1H),4.06(s,3H),3.68(s,3H),3.31(s,3H),1.72(s,2H),1.62(s,2H).

实施例113:5'-(2-氯-3-氟-5-甲氧基吡啶-4-基)-N-(5-乙氧基-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(113)的合成
Example 113: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-ethoxy-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (113)

目标化合物113的制备方法参考实施例112中化合物112的制备方法，仅将原料5-甲氧基-1,3,4-噻二唑-2-胺替换为5-乙氧基-1,3,4-噻二唑-2-胺，其他原料与制备方法同实施例112，得到目标化合物113(6mg)，产率9.0％。The preparation method of target compound 113 was similar to that of compound 112 in Example 112, except that the raw material 5-methoxy-1,3,4-thiadiazole-2-amine was replaced with 5-ethoxy-1,3,4-thiadiazole-2-amine. The other raw materials and preparation method were the same as those in Example 112 to obtain target compound 113 (6 mg) with a yield of 9.0%.

LC-MS(m/z):504.0[M+H]+。LC-MS (m/z): 504.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ12.77(s,1H),8.07(s,1H),7.69(s,1H),7.15(s,1H),4.44-4.42(m,2H),3.68(s,3H),3.30(s,3H),1.72(s,2H),1.61(s,2H),1.37(t,J＝7.2Hz,3H). 1 H NMR (600MHz, DMSO-d 6 ): δ12.77(s,1H),8.07(s,1H),7.69(s,1H),7.15(s,1H),4.44-4.42(m,2H) ,3.68(s,3H),3.30(s,3H),1.72(s,2H),1.61(s,2H),1.37(t,J=7.2Hz,3H).

实施例114:5'-(2-(二氟甲基)-5-甲氧基吡啶-4-基)-N-(5-甲氧基-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(114)的合成
Example 114: Synthesis of 5'-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (114)

目标化合物114的制备方法参考实施例110中化合物110的制备方法，仅将化合物1-2替换为化合物47-2，其他原料与制备方法同实施例110，得到目标化合物114(15mg)，产率38.5％。The preparation method of target compound 114 was similar to that of compound 110 in Example 110, except that compound 1-2 was replaced by compound 47-2. Other raw materials and preparation methods were the same as those in Example 110 to obtain target compound 114 (15 mg) with a yield of 38.5%.

LC-MS(m/z):488.0[M+H]+。LC-MS (m/z): 488.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ12.69(s,1H),8.33(s,1H),7.61(s,1H),7.53(s,1H),7.15(s,1H),7.03(t,J＝55.2Hz,1H),4.06(s,3H),3.65(s,3H),3.30(s,3H),1.85-1.81(m,2H),1.60(d,J＝4.8Hz,2H). 1 H NMR (600MHz, DMSO-d 6 ): δ12.69(s,1H),8.33(s,1H),7.61(s,1H),7.53(s,1H),7.15(s,1H),7.03(t,J＝55.2H z,1H),4.06(s,3H),3.65(s,3H),3.30(s,3H),1.85-1.81(m,2H),1.60(d,J＝4.8Hz,2H).

实施例115:5'-(2-氯-3-氟-5-甲氧基吡啶-4-基)-N-(5-乙基-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(115)的合成
Example 115: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (115)

目标化合物115的制备方法参考实施例112中化合物112的制备方法，仅将5-甲氧基-1,3,4-噻二唑-2-胺替换为5-乙基-1,3,4-噻二唑-2-胺，其他中间体原料与制备方法与实施例112相同，得到目标化合物115(13mg)，产率25.1％。The preparation method of target compound 115 was similar to that of compound 112 in Example 112, except that 5-methoxy-1,3,4-thiadiazole-2-amine was replaced with 5-ethyl-1,3,4-thiadiazole-2-amine. The other intermediate raw materials and preparation method were the same as those in Example 112, and target compound 115 (13 mg) was obtained with a yield of 25.1%.

LC-MS(m/z):488.0[M+H]+。LC-MS (m/z): 488.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ12.90(s,1H),8.08(s,1H),7.70(s,1H),7.19(s,1H),3.66(s,3H),3.33(s,3H),2.98(q,J＝7.2Hz,2H),1.76-1.71(m,2H),1.65-1.60(m,2H),1.30(t,J＝7.8Hz,3H). 1 H NMR (600MHz, DMSO-d 6 ): δ12.90(s,1H),8.08(s,1H),7.70(s,1H),7.19(s,1H),3.66(s,3H),3.33(s,3H), 2.98(q,J＝7.2Hz,2H),1.76-1.71(m,2H),1.65-1.60(m,2H),1.30(t,J＝7.8Hz,3H).

实施例116:5'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-(甲氧基-d3)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(116)的合成
Example 116: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d 3 )-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (116)

步骤1：5-(甲氧基-d3)-1,3,4-噻二唑-2-胺(116-1)的合成Step 1: Synthesis of 5-(methoxy-d 3 )-1,3,4-thiadiazol-2-amine (116-1)

反应瓶中加入氘代甲醇(0.5mL)，氮气保护，冰水浴下加入氢化钠(40mg，1.20mmol)，0℃反应0.5h，然后加入5-溴-1,3,4-噻二唑-2-胺(179mg，1.00mmol)，继续反应2h。反应液减压浓缩，残留物经柱层析纯化(DCM:MeOH＝20:1)，得到化合物116-1(80mg)，产率59.7％。Deuterated methanol (0.5 mL) was added to the reaction flask. Under nitrogen protection, sodium hydride (40 mg, 1.20 mmol) was added under an ice-water bath. The reaction was allowed to proceed at 0°C for 0.5 h. 5-Bromo-1,3,4-thiadiazol-2-amine (179 mg, 1.00 mmol) was then added and the reaction continued for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to afford compound 116-1 (80 mg) in a 59.7% yield.

LC-MS(m/z):135.0[M+H]+。LC-MS (m/z): 135.0 [M+H] + .

步骤2：5'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-(甲氧基-d3)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(116)的合成Step 2: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d 3 )-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (116)

将化合物1-2(220mg，0.60mmol)溶解于超干乙腈(10mL)，加入化合物116-1(80mg，0.60mmol)、N,N,N',N'-四甲基氯甲脒六氟磷酸盐(252mg，0.90mmol)和N-甲基咪唑(160mg，1.80mmol)，室温反应2小时。反应结束后，反应液减压浓缩，残留物经柱层析纯化(DCM:MeOH＝20:1)，得到目标化合物116(45mg)，产率15.8％。Compound 1-2 (220 mg, 0.60 mmol) was dissolved in ultra-dry acetonitrile (10 mL), and compound 116-1 (80 mg, 0.60 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (252 mg, 0.90 mmol), and N-methylimidazole (160 mg, 1.80 mmol) were added. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain the target compound 116 (45 mg) in a 15.8% yield.

LC-MS(m/z):475.0[M+H]+。LC-MS (m/z): 475.0 [M+H] + .

实施例117:5'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-甲氧基-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代-1',2'-二氢螺[环丙烷-1,3'-吡咯并[2,3-b]吡啶]-6'-甲酰胺(117)的合成
Example 117: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-6'-carboxamide (117)

步骤1：5-溴-1-甲基-1H-吡咯并[2,3-b]吡啶-6-甲酸甲酯(117-1)的合成Step 1: Synthesis of methyl 5-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (117-1)

向瓶中加入5-溴-1H-吡咯并[2,3-b]吡啶-6-甲酸甲酯(1.0g，3.94mmol)，加入DMF(13mL)，氮气保护下将体系降温至0℃，加入NaH(192mg，4.80mmol)，反应0.5小时。再加入碘甲烷(740mg，5.21mmol)，缓慢恢复至室温，反应1h。反应结束后，加入饱和氯化铵溶液(10mL)淬灭，用EA萃取(30mL×3)，合并有机相用饱和食盐水(10mL)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(PE:EA＝10:1)，得到化合物117-1(800mg)，产率75.8％。To the flask, methyl 5-bromo-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (1.0 g, 3.94 mmol) and DMF (13 mL) were added. The system was cooled to 0°C under nitrogen, and NaH (192 mg, 4.80 mmol) was added. The reaction was allowed to react for 0.5 hours. Methyl iodide (740 mg, 5.21 mmol) was then added, and the temperature was slowly returned to room temperature. The reaction was allowed to react for 1 hour. After completion of the reaction, saturated ammonium chloride solution (10 mL) was added to quench the reaction. The mixture was extracted with EA (30 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to afford compound 117-1 (800 mg) in a 75.8% yield.

LC-MS(m/z):269.0,271.0[M+H]+。LC-MS(m/z):269.0,271.0[M+H] + .

步骤2：3,3,5-三溴-1-甲基-2-氧代-2,3-二氢-1H-吡咯并[2,3-b]吡啶-6-羧酸甲酯(117-2)的合成Step 2: Synthesis of methyl 3,3,5-tribromo-1-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (117-2)

向瓶中化合物117-1(700mg，2.61mmol)，加入叔丁醇(8mL)和水(2mL)，氮气保护下加入三溴化吡啶鎓(2.5g，7.81mmol)，40℃反应4h。反应结束后，体系减压浓缩，加入水(10mL)，用EA萃取(20mL×3)，合并有机相用饱和食盐水洗涤(20mL)，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(PE:EA＝20:1)，得到化合物117-2(700mg)，产率60.8％。To compound 117-1 (700 mg, 2.61 mmol) in a vial, tert-butanol (8 mL) and water (2 mL) were added. Pyridinium tribromide (2.5 g, 7.81 mmol) was added under nitrogen and allowed to react at 40°C for 4 h. After completion of the reaction, the system was concentrated under reduced pressure, water (10 mL) was added, and extraction was performed with EA (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL ), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 20:1) to afford compound 117-2 (700 mg) in a 60.8% yield.

LC-MS(m/z):441.0[M+H]+。LC-MS (m/z): 441.0 [M+H] + .

步骤3：5-溴-1-甲基-2-氧代-2,3-二氢-1H-吡咯并[2,3-b]吡啶-6-甲酸甲酯(117-3)的合成Step 3: Synthesis of methyl 5-bromo-1-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (117-3)

将化合物117-2(700mg，1.59mmol)溶于ACN(9mL)和AcOH(6mL)的混合溶液中，室温条件下加入锌粉(104mg，1.86mmol)，室温反应16h。反应结束后，体系减压浓缩，加入水(5mL)稀释，并加入饱和NaHCO3溶液(5mL)调节pH至7，并用EA(20mL×3)萃取，合并有机相用饱和食盐水洗涤(10mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(PE:EA＝3:1)，得到化合物117-3(350mg)，产率77.4％。Compound 117-2 (700 mg, 1.59 mmol) was dissolved in a mixture of ACN (9 mL) and AcOH (6 mL). Zinc powder (104 mg, 1.86 mmol) was added at room temperature and allowed to react for 16 h. After completion of the reaction, the system was concentrated under reduced pressure, diluted with water (5 mL), and the pH was adjusted to 7 with saturated NaHCO₃ solution (5 mL). The mixture was extracted with EA (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to afford compound 117-3 (350 mg) in a 77.4% yield.

LC-MS(m/z):285.0,287.0[M+H]+。LC-MS(m/z):285.0,287.0[M+H] + .

步骤4：5'-溴-1'-甲基-2'-氧代-1',2'-二氢螺[环丙烷-1,3'-吡咯并[2,3-b]吡啶]-6'-羧酸甲酯(117-4)的合成Step 4: Synthesis of methyl 5'-bromo-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-6'-carboxylate (117-4)

将化合物117-3(100mg，0.35mmol)溶于DMSO(2mL)，依次加入K2CO3(97mg，0.7mmol)、1,2-二溴乙烷(79mg，0.42mmol)，室温反应16h。反应结束后，反应混合物加入水(10mL)稀释，用EA萃取(20mL×3)，合并有机相用饱和食盐水洗涤(10mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(PE:EA＝10:1)，得到化合物117-4(50mg)，产率45.8％。Compound 117-3 (100 mg, 0.35 mmol) was dissolved in DMSO (2 mL), and K₂CO₃ (97 mg, 0.7 mmol) and 1,2-dibromoethane (79 mg, 0.42 mmol) were added sequentially. The mixture was allowed to react at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with EA (20 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to afford compound 117-4 (50 mg) in a 45.8% yield.

LC-MS(m/z):311.0,313.0[M+H]+。LC-MS(m/z):311.0,313.0[M+H] + .

步骤5：5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代-1',2'-二氢螺[环丙烷-1,3'-吡咯并[2,3-b]吡啶]-6'-羧酸甲酯(117-5)的合成Step 5: Synthesis of methyl 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-6'-carboxylate (117-5)

向瓶中依次加入化合物117-4(31mg，0.10mmol)、(2-氯-5-甲氧基吡啶-4-基)硼酸(20mg，0.12mmol)、K2CO3(27mg，0.20mmol)和Pd(dppf)Cl2(8mg，0.01mmol)，加入二氧六环(5mL)和水(1mL)，氮气保护下80℃反应1小时。反应结束后，反应混合物加入水(5mL)稀释，用EA萃取(10mL×3)，合并有机相用饱和食盐水洗涤(5mL)，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(PE:EA＝10:1)，得到化合物117-5(30mg)，产率80.4％。Compound 117-4 (31 mg, 0.10 mmol), (2-chloro-5-methoxypyridin-4-yl)boronic acid (20 mg, 0.12 mmol), K₂CO₃ ( 27 mg, 0.20 mmol), and Pd(dppf) Cl₂ (8 mg, 0.01 mmol) were added to a vial in sequence. Dioxane (5 mL) and water (1 mL) were then added, and the mixture was reacted at 80°C under nitrogen for 1 hour. After completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to afford compound 117-5 (30 mg) in an 80.4% yield.

LC-MS(m/z):374.0[M+H]+。LC-MS (m/z): 374.0 [M+H] + .

步骤6：5'-(2-氯-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代-1',2'-二氢螺[环丙烷-1,3'-吡咯并[2,3-b]吡啶]-6'-羧酸(117-6)的合成Step 6: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-6'-carboxylic acid (117-6)

将化合物117-5(30.0mg，0.08mmol)溶于甲醇(1mL)、水(1mL)和THF(1mL)的混合溶液中，室温条件下加入LiOH(34.4mg，0.80mmol)，室温反应16h。反应结束后，体系减压浓缩，加入水(5mL)，用1mol/L HCl溶液(8mL)调节pH至7以下，并用EA(10mL×3)萃取，合并有机相用饱和食盐水洗涤(10mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。得到化合物117-6(25mg)粗品。Compound 117-5 (30.0 mg, 0.08 mmol) was dissolved in a mixture of methanol (1 mL), water (1 mL), and THF (1 mL). LiOH (34.4 mg, 0.80 mmol) was added at room temperature and allowed to react for 16 h. After completion of the reaction, the system was concentrated under reduced pressure, water (5 mL) was added, and the pH was adjusted to below 7 with 1 mol/L HCl solution (8 mL). The mixture was extracted with EA (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 117-6 (25 mg).

LC-MS(m/z):360.0[M+H]+。LC-MS (m/z): 360.0 [M+H] + .

步骤7：5'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-甲氧基-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代-1',2'-二氢螺[环丙烷-1,3'-吡咯并[2,3-b]吡啶]-6'-甲酰胺(117)的合成Step 7: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxo-1',2'-dihydrospiro[cyclopropane-1,3'-pyrrolo[2,3-b]pyridine]-6'-carboxamide (117)

将化合物117-6(25mg，0.07mmol)溶于DMF(2mL)，依次加入5-甲氧基-1,3,4-噻二唑-2-胺(9.2mg，0.07mmol)、HATU(26.6mg，0.07mmol)和DIPEA(25mg，0.21mmol)，室温反应16h。反应结束后，反应混合物加入水(5mL)稀释，用EA萃取(10mL×3)，合并有机相用饱和食盐水洗涤(10mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝20:1)，得到目标化合物117(7mg)，产率21.9％。Compound 117-6 (25 mg, 0.07 mmol) was dissolved in DMF (2 mL), and 5-methoxy-1,3,4-thiadiazol-2-amine (9.2 mg, 0.07 mmol), HATU (26.6 mg, 0.07 mmol), and DIPEA (25 mg, 0.21 mmol) were added sequentially. The mixture was allowed to react at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain the target compound 117 (7 mg) in a 21.9% yield.

LC-MS(m/z):473.0[M+H]+。LC-MS (m/z): 473.0 [M+H] + .

1H-NMR(600MHz,DMSO-d6):δ12.70(s,1H),8.14(s,1H),7.58(s,1H),7.46(s,1H),4.08(s,3H),3.65(s,3H),3.42(s,3H),1.91(q,J＝4.2Hz,2H),1.70(d,J＝4.8Hz,2H). 1 H-NMR (600MHz, DMSO-d 6 ): δ12.70(s,1H),8.14(s,1H),7.58(s,1H),7.46(s,1H),4.08(s,3H),3.65(s,3H),3.42(s,3H),1.91(q,J＝4.2Hz,2H),1.70(d,J＝4.8Hz,2H).

实施例118:5'-(2-氯-3-氟-5-甲氧基吡啶-4-基)-N-(5-(甲氧基-d3)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(118)的合成
Example 118: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d 3 )-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (118)

将化合物96-4(100mg，0.27mmol)、5-(甲氧基-d3)-1,3,4-噻二唑-2-胺(37mg，0.27mmo)、N,N,N',N'-四甲基氯甲脒六氟磷酸盐(91mg，0.32mmol)和N-甲基咪唑(66mg，0.81mmol)溶于DCM(5mL)，室温下搅拌2h。反应结束后，反应液减压浓缩，残余物经柱层析纯化(DCM:MeOH＝20:1)，得到目标化合物118(50mg)，产率38.3％。Compound 96-4 (100 mg, 0.27 mmol), 5-(methoxy-d 3 )-1,3,4-thiadiazol-2-amine (37 mg, 0.27 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (91 mg, 0.32 mmol), and N-methylimidazole (66 mg, 0.81 mmol) were dissolved in DCM (5 mL) and stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain the target compound 118 (50 mg) in a 38.3% yield.

LC-MS(m/z):493.0[M+H]+。LC-MS (m/z): 493.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ12.80(s,1H),8.08(s,1H),7.67(s,1H),7.19(s,1H),3.68(s,3H),3.30(s,3H),1.76-1.71(m,2H),1.64-1.61(m,2H). 1 H NMR (600MHz, DMSO-d 6 ): δ12.80(s,1H),8.08(s,1H),7.67(s,1H),7.19(s,1H),3.68(s,3H),3.30(s,3H),1.76-1.71(m,2H),1.64-1.61(m,2H).

实施例119：5'-(2-氯-3-氟-5-(甲氧基-d3)吡啶-4-基)-N-(5-(甲氧基-d3)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(119)的合成
Example 119: Synthesis of 5'-(2-chloro-3-fluoro-5-(methoxy-d 3 )pyridin-4-yl)-N-(5-(methoxy-d 3 )-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (119)

步骤1：2-氯-3-氟-5-(甲氧基-d3)吡啶(119-1)的合成Step 1: Synthesis of 2-chloro-3-fluoro-5-(methoxy-d 3 )pyridine (119-1)

将6-氯-5-氟吡啶-3-醇(1.0g，6.80mmol)溶于乙腈(20mL)中，室温条件下依次加入K2CO3(1.5g，13.60mmol)和氘代碘甲烷(1.5g，10.20mmol)，室温反应16小时。反应结束后，过滤，滤液减压浓缩。残留物经柱层析纯化(PE:EA＝10:1)，得到化合物119-1(1.1g)，产率98.6％。6-Chloro-5-fluoropyridin-3-ol (1.0 g, 6.80 mmol) was dissolved in acetonitrile (20 mL). K₂CO₃ (1.5 g, 13.60 mmol) and deuterated iodomethane (1.5 g, 10.20 mmol) were added sequentially at room temperature. The mixture was allowed to react for 16 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to afford compound 119-1 (1.1 g) in a 98.6% yield.

LC-MS(m/z):165.0[M+H]+。LC-MS (m/z): 165.0 [M+H] + .

步骤2：2-氯-3-氟-4-碘-5-(甲氧基-d3)吡啶(119-2)的合成Step 2: Synthesis of 2-chloro-3-fluoro-4-iodo-5-(methoxy-d 3 )pyridine (119-2)

将化合物119-1(1.14g，6.95mmol)溶于THF(30mL)，氮气保护下冷却至-78℃，向体系缓慢滴加正丁基锂(3.5mL，8.34mmol)，体系保持-78℃搅拌0.5小时。加入碘(267.0mg，10.43mmol)，随后缓慢恢复至室温，反应2小时。反应结束后，加入饱和氯化铵溶液(20mL)淬灭，用EA萃取(20mL×3)，合并有机相用饱和食盐水洗涤(20mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(PE:EA＝10:1)得到化合物119-2(1.2g)，产率59.7％。Compound 119-1 (1.14 g, 6.95 mmol) was dissolved in THF (30 mL) and cooled to -78°C under nitrogen. n-Butyl lithium (3.5 mL, 8.34 mmol) was slowly added dropwise to the mixture, and the mixture was stirred at -78°C for 0.5 hours. Iodine (267.0 mg, 10.43 mmol) was added, and the mixture was slowly allowed to return to room temperature and allowed to react for 2 hours. After completion of the reaction, saturated ammonium chloride solution (20 mL) was added to quench the reaction, and the mixture was extracted with EA (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to afford compound 119-2 (1.2 g) in a 59.7% yield.

LC-MS(m/z):291.0[M+H]+。LC-MS (m/z): 291.0 [M+H] + .

步骤3：5'-(2-氯-3-氟-5-(甲氧基-d3)吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯(119-3)的合成Step 3: Synthesis of methyl 5'-(2-chloro-3-fluoro-5-(methoxy-d 3 )pyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (119-3)

向瓶中依次加入化合物119-2(400mg，1.37mmol)、1'-甲基-2'-氧代-5'-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯(587mg，1.64mmol)、K2CO3(378mg，2.74mmol)和Pd(dppf)Cl2(102mg，0.14mmol)，加入二氧六环(10mL)和水(2mL)，氮气保护下100℃反应4小时。反应结束后，过滤，滤液减压浓缩。残留物经柱层析纯化(PE:EA＝2:1)，得到化合物119-3(80mg)，产率14.9％Compound 119-2 (400 mg, 1.37 mmol), methyl 1'-methyl-2'-oxo-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[cyclopropane-1,3'-indoline]-6'-carboxylate (587 mg, 1.64 mmol), K2CO3 (378 mg, 2.74 mmol), and Pd(dppf) Cl2 (102 mg, 0.14 mmol) were added to the vial in sequence. Dioxane (10 mL) and water (2 mL ) were added, and the mixture was reacted at 100°C under nitrogen for 4 hours. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 2:1) to obtain compound 119-3 (80 mg) in a yield of 14.9%.

LC-MS(m/z):394.0[M+H]+。LC-MS (m/z): 394.0 [M+H] + .

步骤4：5'-(2-氯-3-氟-5-(甲氧基-d3)吡啶-4-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸(119-4)的合成Step 4: Synthesis of 5'-(2-chloro-3-fluoro-5-(methoxy-d 3 )pyridin-4-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (119-4)

将化合物119-3(80mg，0.20mmol)溶于甲醇(1mL)，水(1mL)和THF(2mL)的混合溶液中，室温条件下加入LiOH(90mg，2.10mmol)，室温反应16小时。反应结束后，反应混合物减压浓缩，向体系中加入水(5mL)，用1mol/L HCl溶液(10mL)调节pH至7以下，过滤，滤饼干燥，得到化合物119-4(80mg)粗品。Compound 119-3 (80 mg, 0.20 mmol) was dissolved in a mixture of methanol (1 mL), water (1 mL), and THF (2 mL). LiOH (90 mg, 2.10 mmol) was added at room temperature and allowed to react for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, water (5 mL) was added, and the pH was adjusted to below 7 with 1 mol/L HCl solution (10 mL). The mixture was filtered and the filter cake was dried to afford crude compound 119-4 (80 mg).

LC-MS(m/z):380.0[M+H]+。LC-MS (m/z): 380.0 [M+H] + .

步骤5：5'-(2-氯-3-氟-5-甲氧基吡啶-4-基)-N-(5-(甲氧基-d3)-1,3,4-噻二唑-2-基)-1'-甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(119)的合成Step 5: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d 3 )-1,3,4-thiadiazol-2-yl)-1'-methyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (119)

将化合物119-4(80mg，0.21mmol)溶于DMF(2mL)，依次加入5-(甲氧基-d3)-1,3,4-噻二唑-2-胺(28mg，0.21mmol)、HATU(80mg，0.21mmol)和DIPEA(75mg，0.63mmol),室温反应16小时。反应结束后，加入水(10mL)，用EA萃取(10mL×3)，合并有机相用饱和食盐水洗涤(10mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝20:1)得到目标化合物119(7mg)，两步产率7.1％。Compound 119-4 (80 mg, 0.21 mmol) was dissolved in DMF (2 mL), and 5-(methoxy-d 3 )-1,3,4-thiadiazol-2-amine (28 mg, 0.21 mmol), HATU (80 mg, 0.21 mmol), and DIPEA (75 mg, 0.63 mmol) were added sequentially. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, water (10 mL) was added, and the mixture was extracted with EA (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to afford the target compound 119 (7 mg) in a two-step yield of 7.1%.

LC-MS(m/z):496.0[M+H]+。LC-MS (m/z): 496.0 [M+H] + .

1H-NMR(600MHz,DMSO-d6):δ12.80(s,1H),8.07(s,1H),7.68(s,1H),7.17(s,1H),3.31(s,3H),1.75-1.70(m,2H),1.64-1.59(m,2H). 1 H-NMR (600MHz, DMSO-d 6 ): δ12.80(s,1H),8.07(s,1H),7.68(s,1H),7.17(s,1H),3.31(s,3H),1.75-1.70(m,2H),1.64-1.59(m,2H).

实施例120：5'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-甲氧基-1,3,4-噻二唑-2-基)-1',4'-二甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(120)的合成
Example 120: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (120)

步骤1：4-溴-1-甲基-1H-吲哚-6-甲酸甲酯(120-1)的合成Step 1: Synthesis of methyl 4-bromo-1-methyl-1H-indole-6-carboxylate (120-1)

向瓶中加入4-溴-1H-吲哚-6-甲酸甲酯(5.06g，20.00mmol)，加入DMF(50mL)，依次加入碳酸铯(13.04g，40.00mmol)和碘甲烷(5.68g，40.00mmol)，反应16h。反应结束后，用EA萃取(30mL×3)，合并有机相用饱和NaCl(10mL)洗涤，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(PE:EA＝10:1)，得到化合物120-1(5.0g)，产率93.6％。To the flask, methyl 4-bromo-1H-indole-6-carboxylate (5.06 g, 20.00 mmol) was added, followed by DMF (50 mL), cesium carbonate (13.04 g, 40.00 mmol), and iodomethane (5.68 g, 40.00 mmol). The reaction was allowed to react for 16 h. After completion of the reaction, the mixture was extracted with EA (30 mL x 3). The combined organic phases were washed with saturated NaCl (10 mL), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to afford compound 120-1 (5.0 g) in a 93.6% yield.

LC-MS(m/z):268.0,270.0[M+H]+。LC-MS(m/z):268.0,270.0[M+H] + .

步骤2：1,4-二甲基-1H-吲哚-6-甲酸甲酯(120-2)的合成Step 2: Synthesis of methyl 1,4-dimethyl-1H-indole-6-carboxylate (120-2)

向瓶中依次加入化合物120-1(5.32g，20.00mmol)、甲基硼酸(3.6g，60.00mmol)、K2CO3(5.52g，40.00mmol)和Pd(dppf)Cl2(1.56g，2.00mmol)，加入二氧六环(50mL)和水(10mL)，氮气保护下90℃反应8小时。反应结束后，反应混合物加入水(50mL)稀释，用EA萃取(100mL×3)，合并有机相用饱和NaCl洗涤(50mL)，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(PE:EA＝10:1)，得到化合物120-2(2.84g)，产率70.0％。Compound 120-1 (5.32 g, 20.00 mmol), methylboronic acid (3.6 g, 60.00 mmol), K₂CO₃ (5.52 g, 40.00 mmol), and Pd(dppf) Cl₂ (1.56 g, 2.00 mmol) were added to a vial in sequence. Dioxane (50 mL) and water (10 mL) were then added, and the mixture was reacted at 90°C under nitrogen for 8 hours. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EA (100 mL x 3). The combined organic phases were washed with saturated NaCl (50 mL), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to afford compound 120-2 (2.84 g) in a 70.0% yield.

LC-MS(m/z):204.0[M+H]+。LC-MS (m/z): 204.0 [M+H] + .

步骤3：1,4-二甲基-2-氧代吲哚-6-羧酸甲酯(120-3)的合成Step 3: Synthesis of methyl 1,4-dimethyl-2-oxoindole-6-carboxylate (120-3)

将化合物120-2(2.03g，10.00mmol)溶于叔丁醇(40mL)，室温条件下加入NBS(1.98g，11.00mmol)，氮气保护下85℃反应24小时。反应结束后，将反应混合物减压浓缩。残留物经柱层析纯化(PE:EA＝3:1)，得到化合物120-3(1.16g)，产率52.3％。Compound 120-2 (2.03 g, 10.00 mmol) was dissolved in tert-butanol (40 mL), and NBS (1.98 g, 11.00 mmol) was added at room temperature. The mixture was reacted at 85°C under nitrogen for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 3:1) to obtain compound 120-3 (1.16 g) in a 52.3% yield.

LC-MS(m/z):220.0[M+H]+。LC-MS (m/z): 220.0 [M+H] + .

步骤4：1',4'-二甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯(120-4)的合成Step 4: Synthesis of methyl 1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (120-4)

将化合物120-3(5.0g，22.83mmol)溶于DMSO(70mL)，依次加入K2CO3(7.6g，55.07mmol)和1,2-二溴乙烷(4.91g，26.40mmol)，室温反应16h。反应结束后，反应混合物加入水(50mL)稀释，用EA萃取(100mL×3)，合并有机相用饱和NaCl洗涤(100mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(PE:EA＝10:1)得到化合物120-4(4.0g)，产率71.5％。Compound 120-3 (5.0 g, 22.83 mmol) was dissolved in DMSO (70 mL), and K₂CO₃ (7.6 g, 55.07 mmol) and 1,2-dibromoethane (4.91 g, 26.40 mmol) were added sequentially. The mixture was allowed to react at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EA (100 mL x 3). The combined organic phases were washed with saturated NaCl (100 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to afford compound 120-4 (4.0 g) in a yield of 71.5%.

LC-MS(m/z):246.0[M+H]+。LC-MS (m/z): 246.0 [M+H] + .

步骤5：5'-溴-1',4'-二甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯(120-5)的合成Step 5: Synthesis of methyl 5'-bromo-1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (120-5)

将化合物120-4(500mg，2.04mmol)溶于DMF(10mL)，室温条件下加入NBS(542mg，3.04mmol)，室温反应16h。反应结束后，反应混合物加入水(10mL)稀释，用EA萃取(10mL×3)，合并有机相用饱和NaCl洗涤(10mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(PE:EA＝10:1)，得到化合物120-5(400mg)，产率60.7％。Compound 120-4 (500 mg, 2.04 mmol) was dissolved in DMF (10 mL), and NBS (542 mg, 3.04 mmol) was added at room temperature. The reaction mixture was allowed to react for 16 h. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with saturated NaCl (10 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to afford compound 120-5 (400 mg) in a 60.7% yield.

LC-MS(m/z):324.0,326.0[M+H]+。LC-MS(m/z):324.0,326.0[M+H] + .

步骤6：5'-(2-氯-5-甲氧基吡啶-4-基)-1',4'-二甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸甲酯(120-6)的合成Step 6: Synthesis of methyl 5'-(2-chloro-5-methoxypyridin-4-yl)-1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylate (120-6)

向瓶中依次加入化合物120-5(1.0g，3.10mmol)、(2-氯-5-甲氧基吡啶-4-基)硼酸(870mg，4.65mmol)、K3PO4(1.32g，6.23mmol)、Pd2(dba)3(284mg，0.31mmol)和BIDIME(205mg，0.62mmol)，加入二甲苯(20mL)，体系氮气保护下升温至95℃反应8小时。反应结束后，反应混合物加入水(20mL)稀释，用EA萃取(40mL×3)，合并有机相，用饱和NaCl洗涤(50mL)，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(PE:EA＝10:1)，得到化合物120-6(80mg)，产率6.7％。To a vial were added compound 120-5 (1.0 g, 3.10 mmol), (2-chloro-5-methoxypyridin-4-yl)boronic acid (870 mg, 4.65 mmol), K 3 PO 4 (1.32 g, 6.23 mmol), Pd 2 (dba) 3 (284 mg, 0.31 mmol), and BIDIME (205 mg, 0.62 mmol). Xylene (20 mL) was added, and the system was heated to 95°C under nitrogen for 8 hours. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EA (40 mL x 3). The organic phases were combined, washed with saturated NaCl (50 mL), dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 10:1) to afford compound 120-6 (80 mg) in a 6.7% yield.

LC-MS(m/z):387.0[M+H]+。LC-MS (m/z): 387.0 [M+H] + .

步骤7：5'-(2-氯-5-甲氧基吡啶-4-基)-1',4'-二甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-羧酸(120-7)的合成Step 7: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxylic acid (120-7)

将化合物120-6(80mg，0.21mmol)溶于甲醇(1mL)、水(1mL)和THF(3mL)的混合溶液中，室温条件下加入LiOH(50mg，2.08mmol)，室温反应16h。反应结束后，将反应混合物减压浓缩，向体系中加入水(5mL)，用1mol/L HCl溶液(8mL)调节pH至7以下，EA(10mL×3)萃取，合并有机相，用饱和NaCl洗涤(10mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。得到化合物120-7(70mg)粗品。Compound 120-6 (80 mg, 0.21 mmol) was dissolved in a mixture of methanol (1 mL), water (1 mL), and THF (3 mL). LiOH (50 mg, 2.08 mmol) was added at room temperature and allowed to react for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, water (5 mL) was added, and the pH was adjusted to below 7 with 1 mol/L HCl solution (8 mL). The mixture was extracted with EA (10 mL x 3). The organic phases were combined, washed with saturated NaCl (10 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 120-7 (70 mg).

LC-MS(m/z):373.0[M+H]+。LC-MS (m/z): 373.0 [M+H] + .

步骤8：5'-(2-氯-5-甲氧基吡啶-4-基)-N-(5-甲氧基-1,3,4-噻二唑-2-基)-1',4'-二甲基-2'-氧代螺[环丙烷-1,3'-吲哚啉]-6'-甲酰胺(120)的合成Step 8: Synthesis of 5'-(2-chloro-5-methoxypyridin-4-yl)-N-(5-methoxy-1,3,4-thiadiazol-2-yl)-1',4'-dimethyl-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (120)

将化合物120-7(70mg，0.19mmol)溶于DMF(2mL)，依次加入5-甲氧基-1,3,4-噻二唑-2-胺(25mg，0.19mmol)、HATU(72mg，0.19mmol)和DIPEA(74mg，0.57mmol)，室温反应16h。反应结束后，反应混合物加入水(5mL)稀释，用EA萃取(10mL×3)，合并有机相用饱和NaCl洗涤(10mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝20:1)得到目标化合物120(7mg)，产率21.9％。Compound 120-7 (70 mg, 0.19 mmol) was dissolved in DMF (2 mL), and 5-methoxy-1,3,4-thiadiazol-2-amine (25 mg, 0.19 mmol), HATU (72 mg, 0.19 mmol), and DIPEA (74 mg, 0.57 mmol) were added sequentially. The reaction mixture was allowed to react at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with water (5 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with saturated NaCl (10 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to afford the target compound 120 (7 mg) in a 21.9% yield.

LC-MS(m/z):486.0[M+H]+。LC-MS (m/z): 486.0 [M+H] + .

1H-NMR(600MHz,DMSO-d6):δ8.09(s,1H),7.34(s,1H),7.23(s,1H),3.87(s,3H),3.85(s,3H),3.20(s,3H),2.18(s,3H),2.10-2.07(m,2H),1.47-1.45(m,2H). 1 H-NMR (600MHz, DMSO-d 6 ): δ8.09(s,1H),7.34(s,1H),7.23(s,1H),3.87(s,3H),3.85(s,3H),3.20(s,3H),2.18(s,3H),2.10-2.07(m,2H),1.47-1.45(m,2H).

实施例121：5'-(2-氯-3-氟-5-甲氧基吡啶-4-基)-N-(5-(甲氧基-d3)-1,3,4-噻二唑-2-基)-1'-(甲基-d3)-2'-氧代螺[环丙烷-1,3'-吲哚]-6'-甲酰胺(121)
Example 121: 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d 3 )-1,3,4-thiadiazol-2-yl)-1'-(methyl-d 3 )-2'-oxospiro[cyclopropane-1,3'-indole]-6'-carboxamide (121)

化合物121-1的制备方法参考中间体M2的制备方法，仅将碘甲烷替换氘代碘甲烷，其他中间体原料与制备方法相同。The preparation method of compound 121-1 refers to the preparation method of intermediate M2, except that deuterated iodomethane is replaced by iodomethane, and the other intermediate raw materials are the same as the preparation method.

目标化合物121的制备方法参考实施例119中化合物119的制备方法，仅将中间体M2替换为化合物121-1、化合物119-2替换为化合物96-2，其他原料与制备方法与实施例119相同，得到目标化合物121(15mg)，三步产率3.6％。The preparation method of target compound 121 refers to the preparation method of compound 119 in Example 119, except that intermediate M2 is replaced by compound 121-1 and compound 119-2 is replaced by compound 96-2. Other raw materials and preparation methods are the same as in Example 119 to obtain target compound 121 (15 mg) with a three-step yield of 3.6%.

LC-MS(m/z):496.0[M+H]+。LC-MS (m/z): 496.0 [M+H] + .

1H-NMR(600MHz,DMSO-d6):δ12.81(s,1H),8.08(s,1H),7.67(s,1H),7.19(s,1H),3.68(s,3H),1.75-1.71(m,2H),1.64-1.60(m,2H). 1 H-NMR (600MHz, DMSO-d 6 ): δ12.81(s,1H),8.08(s,1H),7.67(s,1H),7.19(s,1H),3.68(s,3H),1.75-1.71(m,2H),1.64-1.60(m,2H).

实施例122：7-(2-氯-3-氟-5-甲氧基吡啶-4-基)-N-(5-(甲氧基-d3)-1,3,4-噻二唑-2-基)-4-甲基-3-氧代-3,4-二氢螺[苯并[b][1,4]恶嗪-2,1'-环丙烷]-6-甲酰胺(122)的合成
Example 122: Synthesis of 7-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d3)-1,3,4-thiadiazol-2-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxamide (122)

步骤1：4-甲基-3-氧代-7-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-3,4-二氢螺[苯并[b][1,4]恶嗪-2,1'-环丙烷]-6-羧酸甲酯(122-1)的合成Step 1: Synthesis of methyl 4-methyl-3-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylate (122-1)

将化合物24-5(622mg，1.91mmol)溶于二氧六环(5mL)中，加入联硼酸频那醇酯(533mg，2.1mmol)、醋酸钾(374mg，2.81mmol)和Pd(dppf)Cl2(139mg,0.19mmol)，体系置换N2，升温至100℃反应2h。反应结束后，滤液减压浓缩，残留物经硅胶柱层析纯化(PE:EA＝4:1)，得化合物122-1(520mg)，产率73.1％。Compound 24-5 (622 mg, 1.91 mmol) was dissolved in dioxane (5 mL), and pinacol diboronate (533 mg, 2.1 mmol), potassium acetate (374 mg, 2.81 mmol), and Pd(dppf) Cl₂ (139 mg, 0.19 mmol) were added. The atmosphere was replaced with nitrogen , and the temperature was raised to 100°C for 2 h. After completion of the reaction, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA = 4:1) to obtain compound 122-1 (520 mg) in a yield of 73.1%.

LC-MS(m/z):374.0[M+H]+。LC-MS (m/z): 374.0 [M+H] + .

步骤2：7-(2-氯-3-氟-5-甲氧基吡啶-4-基)-4-甲基-3-氧代-3,4-二氢螺[苯并[b][1,4]恶嗪-2,1'-环丙烷]-6-羧酸甲酯(122-2)的合成Step 2: Synthesis of methyl 7-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylate (122-2)

将化合物122-1(520mg，1.39mmol)溶于二氧六环(5mL)和水(1mL)中，加入2-氯-3-氟-4-碘-5-甲氧基吡啶(320mg，1.11mmol)、碳酸铯(1.36g，4.18mmol)和Pd(dppf)Cl2(102mg，0.14mmol)，体系置换N2，升温至100℃反应3h。反应结束后，滤液减压浓缩，残留物经硅胶柱层析纯化(DCM:MeOH＝50:1)，得化合物122-2(300mg)，产率52.9％。Compound 122-1 (520 mg, 1.39 mmol) was dissolved in dioxane (5 mL) and water (1 mL). 2-Chloro-3-fluoro-4-iodo-5-methoxypyridine (320 mg, 1.11 mmol), cesium carbonate (1.36 g, 4.18 mmol), and Pd(dppf) Cl₂ (102 mg, 0.14 mmol) were added. The atmosphere was replaced with nitrogen , and the temperature was raised to 100°C for 3 h. After completion of the reaction, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 50:1) to obtain compound 122-2 (300 mg) in a yield of 52.9%.

LC-MS(m/z):407.0[M+H]+。LC-MS (m/z): 407.0 [M+H] + .

步骤3：7-(2-氯-3-氟-5-甲氧基吡啶-4-基)-4-甲基-3-氧代-3,4-二氢螺[苯并[b][1,4]恶嗪-2,1'-环丙烷]-6-羧酸(122-3)的合成Step 3: Synthesis of 7-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxylic acid (122-3)

将化合物122-2(300mg，1.39mmol)溶于甲醇(2mL)和水(2mL)中，加入LiOH(88mg，3.69mmol)，室温反应24h。反应结束后，滤液减压浓缩，残留物用2N盐酸调节pH至5，过滤，固体干燥，得化合物122-3(280mg)，产率96.7％。Compound 122-2 (300 mg, 1.39 mmol) was dissolved in methanol (2 mL) and water (2 mL), and LiOH (88 mg, 3.69 mmol) was added. The mixture was allowed to react at room temperature for 24 h. After completion of the reaction, the filtrate was concentrated under reduced pressure, and the residue was adjusted to pH 5 with 2N hydrochloric acid. The residue was filtered and the solid was dried to obtain compound 122-3 (280 mg) in a 96.7% yield.

LC-MS(m/z):393.0[M+H]+。LC-MS (m/z): 393.0 [M+H] + .

步骤4：7-(2-氯-3-氟-5-甲氧基吡啶-4-基)-N-(5-(甲氧基-d3)-1,3,4-噻二唑-2-基)-4-甲基-3-氧代-3,4-二氢螺[苯并[b][1,4]恶嗪-2,1'-环丙烷]-6-甲酰胺(122)的合成Step 4: Synthesis of 7-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-N-(5-(methoxy-d 3 )-1,3,4-thiadiazol-2-yl)-4-methyl-3-oxo-3,4-dihydrospiro[benzo[b][1,4]oxazine-2,1'-cyclopropane]-6-carboxamide (122)

将化合物122-3(100mg，0.25mmol)溶于DMF(2mL)，加入HATU(95mg，0.25mmol)、三乙胺(51mg，0.51mmol)和5-(甲氧基-d3)-1,3,4-噻二唑-2-胺(34mg，0.25mmol)，室温下反应12h。反应结束后，滤液减压浓缩，残留物经硅胶柱层析纯化(DCM:MeOH＝20:1)，得目标化合物122(100mg)，产率77.2％。Compound 122-3 (100 mg, 0.25 mmol) was dissolved in DMF (2 mL), and HATU (95 mg, 0.25 mmol), triethylamine (51 mg, 0.51 mmol), and 5-(methoxy-d 3 )-1,3,4-thiadiazol-2-amine (34 mg, 0.25 mmol) were added. The mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain the target compound 122 (100 mg) in a yield of 77.2%.

LC-MS(m/z):509.0[M+H]+。LC-MS (m/z): 509.0 [M+H] + .

1H NMR(600MHz,DMSO-d6):δ12.83(s,1H),8.10(s,1H),7.72(s,1H),7.09(s,1H),3.71(s,3H),3.44(s,3H),1.39-1.37(m,1H),1.35-1.32(m,1H),1.28-1.26(m,2H). 1 H NMR (600MHz, DMSO-d 6 ;

实施例127：5'-(2-氯-3-氟-5-甲氧基吡啶-4-基)-1'-甲基-N-(5-(氧杂环丁烷-3-基氧基)-1,3,4-噻二唑-2-基)-2'-氧代螺[环丙烷-1,3'-吲哚]-6'-甲酰胺(127)的合成
Example 127: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-N-(5-(oxetane-3-yloxy)-1,3,4-thiadiazol-2-yl)-2'-oxospiro[cyclopropane-1,3'-indole]-6'-carboxamide (127)

步骤1：5-(氧杂环丁烷-3-基氧基)-1,3,4-噻二唑-2-胺(127-1)的合成Step 1: Synthesis of 5-(oxetane-3-yloxy)-1,3,4-thiadiazole-2-amine (127-1)

将氧杂环丁烷-3-醇(1.24g，16.76mmol)溶于四氢呋喃(10mL)和DMF(0.5mL)，氮气保护，冰水浴下加入氢化钠(900mg，22.34mmol)，氮气保护下0℃反应1h，然后加入5-溴-1,3,4-噻二唑-2-胺(2.0g，11.17mmol)，氮气保护下0℃继续反应2h。反应混合物加入水(20mL)淬灭，用乙酸乙酯萃取(20mL×3)，合并有机相用饱和食盐水洗涤(30mL)，无水Na2SO4干燥，过滤，滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝10:1)，得到化合物127-1(400mg)，产率20.7％。Oxetane-3-ol (1.24 g, 16.76 mmol) was dissolved in tetrahydrofuran (10 mL) and DMF (0.5 mL). Under nitrogen, sodium hydride (900 mg, 22.34 mmol) was added under an ice-water bath. The mixture was reacted at 0°C for 1 h under nitrogen. 5-Bromo-1,3,4-thiadiazol-2-amine (2.0 g, 11.17 mmol) was then added and the reaction continued at 0°C for 2 h under nitrogen. The reaction mixture was quenched by water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to afford compound 127-1 (400 mg) in a 20.7% yield.

LC-MS(m/z):174.0[M+H]+。LC-MS (m/z): 174.0 [M+H] + .

步骤2：5'-(2-氯-3-氟-5-甲氧基吡啶-4-基)-1'-甲基-N-(5-(氧杂环丁烷-3-基氧基)-1,3,4-噻二唑-2-基)-2'-氧代螺[环丙烷-1,3'-吲哚]-6'-甲酰胺(127)的合成Step 2: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-N-(5-(oxetan-3-yloxy)-1,3,4-thiadiazol-2-yl)-2'-oxospiro[cyclopropane-1,3'-indole]-6'-carboxamide (127)

将化合物127-1(50mg，0.29mmol)溶解于超干二氯甲烷(10mL)，加入化合物96-4(109mg，0.29mmol)、HATU(110mg,0.29mmol)和三乙胺(59mg，0.58mmol)，室温反应12小时。反应结束后，反应混合物加入水(10mL)稀释，用二氯甲烷萃取(10mL×3)，合并有机相用饱和食盐水洗涤(20mL×3)，无水Na2SO4干燥，过滤。滤液减压浓缩。残留物经柱层析纯化(DCM:MeOH＝20:1)，得到目标化合物127(60mg)，产率39.0％。Compound 127-1 (50 mg, 0.29 mmol) was dissolved in ultra-dry dichloromethane (10 mL), and compound 96-4 (109 mg, 0.29 mmol), HATU (110 mg, 0.29 mmol), and triethylamine (59 mg, 0.58 mmol) were added. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous Na₂SO₄ , and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to obtain the target compound 127 (60 mg) in a 39.0% yield.

LC-MS(m/z):532.0[M+H]+。LC-MS (m/z): 532.0 [M+H] + .

1H-NMR(600MHz,DMSO-d6):δ12.89(s,1H),8.09(s,1H),7.66(s,1H),7.20(s,1H),5.68-5.64(m,1H),4.90(t,J＝7.2Hz,2H),4.65(dd,J1＝8.4Hz,J2＝4.8Hz,2H),3.68(s,3H),3.32(s,3H),1.76-1.71(m,2H),1.65-1.60(m,2H). 1 H-NMR (600MHz, DMSO-d 6 ): δ12.89 (s, 1H), 8.09 (s, 1H), 7.66 (s, 1H), 7.20 (s, 1H), 5.68-5.64 (m, 1H), 4.90 (t, J = 7.2Hz, 2H), 4.65 (dd, J 1 =8.4Hz, J 2 =4.8Hz,2H),3.68(s,3H),3.32(s,3H),1.76-1.71(m,2H),1.65-1.60(m,2H).

实施例129：5'-(2-氯-3-氟-5-甲氧基吡啶-4-基)-1'-甲基-2'-氧代-N-(5-((四氢呋喃-3-基)氧基)-1,3,4-噻二唑-2-基)螺[环丙烷-1,3'-吲哚]-6'-甲酰胺(129)的合成
Example 129: Synthesis of 5'-(2-chloro-3-fluoro-5-methoxypyridin-4-yl)-1'-methyl-2'-oxo-N-(5-((tetrahydrofuran-3-yl)oxy)-1,3,4-thiadiazol-2-yl)spiro[cyclopropane-1,3'-indole]-6'-carboxamide (129)

目标化合物129的制备方法参考实施例127中化合物127的制备方法，仅将氧杂环丁烷-3-醇替换为3-羟基四氢呋喃，其他原料和制备方法与实施例127相同，得到目标化合物129(100mg)，两步产率1.6％。The preparation method of target compound 129 refers to the preparation method of compound 127 in Example 127, except that oxetane-3-ol is replaced by 3-hydroxytetrahydrofuran. The other raw materials and preparation method are the same as Example 127 to obtain target compound 129 (100 mg) with a two-step yield of 1.6%.

LC-MS(m/z):546.0[M+H]+。LC-MS (m/z): 546.0 [M+H] + .

1H-NMR(600MHz,DMSO-d6):δ12.82(s,1H),8.08(s,1H),7.67(s,1H),7.20(s,1H),5.51(t,J＝4.8Hz,1H),3.93(d,J＝10.8Hz,1H),3.88-3.83(m,2H),3.77-3.69(m,1H),3.69(s,3H),3.33(s,3H),2.30-2.23(m,1H),2.14-2.09(m,1H),1.75-1.71(m,2H),1.65-1.60(m,2H). 1 H-NMR (600MHz, DMSO-d 6 ): δ12.82(s,1H),8.08(s,1H),7.67(s,1H),7.20(s,1H),5.51(t,J＝4.8Hz,1H),3.93(d,J＝10.8Hz,1H),3.88-3.83(m,2H) ,3.77-3.69(m,1H),3.69(s,3H),3.33(s,3H),2.30-2.23(m,1H),2.14-2.09(m,1H),1.75-1.71(m,2H),1.65-1.60(m,2H).

生物学测试Biological tests

实施例1Polθ体外ATP酶抑制活性评价Example 1 Evaluation of Polθ ATPase Inhibitory Activity in Vitro

采用ADP Glo assay测试化合物在体外结合和抑制Polθ解旋酶活性的能力。The ADP Glo assay was used to test the ability of compounds to bind to and inhibit Pol θ helicase activity in vitro.

ADP-GloTM Kinase Assay试剂盒由浙江普麦格生物科技有限公司提供，型号为V9102。The ADP-Glo ™ Kinase Assay kit was provided by Zhejiang Promega Biotechnology Co., Ltd., model number V9102.

先用DMSO将化合物溶解，再用无菌去离子超纯水将待测化合物依次3倍梯度稀释得到8个浓度的化合物溶液。在缓冲液(25mM Tris-HCl pH 7.5,6mM NaCl,1.5mM MgCl2,5％(v/v)glycerol,0.01％(v/v)Triton x-100，0.01％(w/v)Bovineγ-Globulin，1mM dithiothreitol)中配置2×helicase domain Polθ酶及DNA混合溶液，在缓冲液中配置含2×ATP的底物溶液。向384孔板中加入1μL各梯度浓度的化合物溶液，离心，再加入2μL的2×helicase domain Polθ酶及DNA混合溶液以及无酶含DNA的缓冲液，离心，预孵育30分钟。随后每孔中加入2μL 2×ATP溶液，混匀离心后室温孵育60分钟，向每孔加入5μL ADP-Glo reagent以停止反应，混匀离心，室温孵育60分钟后再向每孔加入10μL ADP-Glo Kinase Detection Reagent，离心，平衡60分钟后在酶标仪上读数并测定每个化合物的抑制率。The compound was dissolved in DMSO and then serially diluted three-fold with sterile deionized ultrapure water to create eight compound solutions. A 2× helicase domain Pol θ enzyme and DNA mixture was prepared in a buffer solution (25 mM Tris-HCl pH 7.5, 6 mM NaCl, 1.5 mM MgCl 2 , 5% (v/v) glycerol, 0.01% (v/v) Triton X-100, 0.01% (w/v) Bovine γ-Globulin, 1 mM dithiothreitol). A substrate solution containing 2× ATP was prepared in the buffer solution. 1 μL of each compound solution was added to a 384-well plate and centrifuged. Then, 2 μL of the 2× helicase domain Pol θ enzyme and DNA mixture and enzyme-free DNA-containing buffer were added, centrifuged, and pre-incubated for 30 minutes. Then, 2 μL of 2× ATP solution was added to each well, mixed and centrifuged, and incubated at room temperature for 60 minutes. 5 μL of ADP-Glo reagent was added to each well to stop the reaction, mixed and centrifuged, and incubated at room temperature for 60 minutes. 10 μL of ADP-Glo Kinase Detection Reagent was added to each well, centrifuged, and balanced for 60 minutes before reading on a microplate reader to determine the inhibition rate of each compound.

表1化合物对Polθ ATP酶的抑制活性
Table 1 Inhibitory activity of compounds on Polθ ATPase

由表1中的数据可知，本发明化合物对Polθ具有优异的体外抑制活性。The data in Table 1 show that the compounds of the present invention have excellent in vitro inhibitory activity against Polθ.

实施例2 HCT116 BRCA2-/-细胞活性的抑制作用评价Example 2 Evaluation of the inhibitory effect on HCT116 BRCA2 −/− cell activity

先用DMSO将化合物溶解，再用培养液将待测化合物依次3倍梯度稀释得到8个浓度的化合物溶液。将对数期生长的HCT116 BRCA2-/-细胞(广州源井生物科技有限公司提供，型号YKO-H668)以800/孔接种于96孔细胞培养板中，于37℃、5％CO2培养箱培养24小时后，加入各梯度浓度的化合物溶液，继续37℃、5％CO2培养箱孵育培养，共7天。7天后在细胞培养板内加入10μL CCK8溶液后放入37℃培养箱孵育2小时，2小时后用酶标仪测定450nM波长下的吸光度并计算每个化合物的抑制率，结果见表2。First, dissolve the compound in DMSO, and then dilute the test compound 3-fold in sequence with culture medium to obtain 8 concentrations of compound solution. HCT116 BRCA2 -/- cells (provided by Guangzhou Yuanjing Biotechnology Co., Ltd., model YKO-H668) in the logarithmic phase were seeded in 96-well cell culture plates at 800/well. After 24 hours of incubation at 37 ° C and 5% CO 2 , compound solutions of various concentrations were added and continued to be incubated at 37 ° C and 5% CO 2 for 7 days. After 7 days, 10 μL of CCK8 solution was added to the cell culture plate and incubated in a 37 ° C incubator for 2 hours. After 2 hours, the absorbance at a wavelength of 450 nM was measured using a microplate reader and the inhibition rate of each compound was calculated. The results are shown in Table 2.

表2化合物对HCT116 BRCA2-/-细胞的抑制活性
Table 2 Inhibitory activity of compounds against HCT116 BRCA2 -/- cells

实施例3小鼠药代特征考察Example 3 Investigation of Pharmacokinetic Characteristics in Mice

SPF级雌性Balb/c小鼠，每组3只，单次灌胃给药10mg/kg化合物，分别在规定时间点采血，分离血浆，放入-80℃冰箱保存备用。取待测血浆样品室温融化，涡旋(2500rpm，1min)，取30.0μL血浆样品于1.5mL离心管中，加入6.00μL内部标准品(雷美替胺，500.0ng/mL)，加入1000μL甲醇，涡旋(2500rpm，1min)，离心(17000g，4℃)10min，取上清液180μL于96孔板，封膜，进行LC-MS/MS分析，进样量为1.00μL。实验数据如下表所示：SPF female Balb/c mice, 3 per group, were given a single oral gavage of 10 mg/kg of the compound. Blood was collected at the specified time points, plasma was separated, and stored in a -80°C refrigerator for later use. The plasma sample to be tested was thawed at room temperature and vortexed (2500 rpm, 1 min). 30.0 μL of plasma sample was taken into a 1.5 mL centrifuge tube, 6.00 μL of internal standard (ramelteon, 500.0 ng/mL) was added, and 1000 μL of methanol was added. The tube was vortexed (2500 rpm, 1 min) and centrifuged (17000 g, 4°C) for 10 min. 180 μL of the supernatant was taken and placed in a 96-well plate, sealed, and subjected to LC-MS/MS analysis with an injection volume of 1.00 μL. The experimental data are shown in the following table:

表3化合物体内药代动力学参数(p.o.)
Table 3 Pharmacokinetic parameters of compounds in vivo (po)

由表3数据可知，本发明化合物在口服给药后具有良好的血浆暴露量和口服生物利用度，显示出优异的口服给药潜力。As can be seen from the data in Table 3, the compounds of the present invention have good plasma exposure and oral bioavailability after oral administration, showing excellent oral administration potential.

实施例4 hERG毒性Example 4 hERG toxicity

用传统膜片钳测试化合物对稳定表达于HEK293细胞(德清奥丽芙生物科技有限公司提供)的人类hERG离子通道的抑制作用。将化合物配制成10μM浓度。每个细胞都以自身为对照。化合物均采用利用自身重力的灌流系统进行灌流。每个细胞在电流稳定后，比较加入化合物前后hERG电流大小，计算化合物对hERG电流的阻断作用，结果见下表4。Compounds were tested using conventional patch clamp techniques to investigate their inhibitory effects on human hERG ion channels stably expressed in HEK293 cells (provided by Deqing Olive Biotechnology Co., Ltd.). Compounds were prepared at a concentration of 10 μM. Each cell served as its own control. Compounds were perfused using a gravity-based perfusion system. After the current stabilized, the hERG current in each cell was compared before and after compound addition, and the blocking effect of the compound on the hERG current was calculated. The results are shown in Table 4 below.

表4化合物对hERG电流的阻断作用(10μM)
Table 4 Blocking effect of compounds on hERG current (10 μM)

实施例5体外代谢稳定性Example 5 In vitro metabolic stability

主要试剂材料:
Main reagent materials:

孵育系统:
Incubation system:

实验方法：Experimental methods:

将1μM的测试物和阳性对照睾酮在有NADPH的条件下与微粒体孵育120min，并设置阴性对照组(试物在无任何辅酶的条件下与微粒体孵育120min)；分别在0min和120min时取样，加入300μL预冷的含内部标准品(雷美替胺：1.000ng/mL)的甲醇溶液的样品，涡旋(2500rpm，1min)，离心(4700rpm，4℃)10min，取上清液50.0μL+200μL纯水于96孔板，涡旋(1000rpm，10min)，封膜，进行LC-MS/MS分析。通过LC-MS/MS检测测试物或探针底物的母体剩余量，测试物的代谢稳定性用测试物在各时间点的母体剩余量相对于孵育前的母体量(0分钟)的百分比表示，数据根据以下公式计算：母体剩余百分率(Parent remaining，％)＝Tx母体量/T0母体量×100；Tx：任一孵育时间点；T0：0分钟孵育时间点。测试结果如下表5所示。1 μM test substance and positive control testosterone were incubated with microsomes in the presence of NADPH for 120 min, and a negative control group was set up (the test substance was incubated with microsomes for 120 min without any coenzyme); samples were taken at 0 min and 120 min, and 300 μL of pre-cooled methanol solution containing the internal standard (ramelteon: 1.000 ng/mL) was added to the sample. The sample was vortexed (2500 rpm, 1 min) and centrifuged (4700 rpm, 4°C) for 10 min. 50.0 μL of the supernatant + 200 μL of pure water were taken and placed in a 96-well plate. The plate was vortexed (1000 rpm, 10 min), sealed, and subjected to LC-MS/MS analysis. The parent amount of the test article or probe substrate was measured by LC-MS/MS. The metabolic stability of the test article was expressed as the percentage of the parent amount remaining at each time point relative to the parent amount before incubation (0 minutes). Data were calculated according to the following formula: Parent remaining (%) = T x parent amount / T0 parent amount × 100; Tx : any incubation time point; T0 : 0-minute incubation time point. The test results are shown in Table 5 below.

表5化合物的体外代谢稳定性结果
Table 5 In vitro metabolic stability results of the compounds

从表5数据可知，本发明化合物具有良好的体外代谢稳定性，且种属差异较小。From the data in Table 5, it can be seen that the compounds of the present invention have good in vitro metabolic stability and little species difference.

本发明所提供的前述实施方案和实施例仅用于说明，而无意限制本发明的范围。基于本公开，对所公开的实施方案的各种改变和修饰对本领域技术人员来说将是显而易见的，并且可以在不脱离本发明的精神和范围的情况下进行这种改变和修饰。The foregoing embodiments and examples provided by the present invention are for illustration only and are not intended to limit the scope of the present invention. Based on this disclosure, various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications may be made without departing from the spirit and scope of the present invention.

Claims (35)

一种通式(Ia)或(Ib)所示的杂环酰胺类化合物，其立体异构体、互变异构体、氘代物或药用盐：
A heterocyclic amide compound represented by general formula (Ia) or (Ib), and its stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts:
其中，环A选自3-14元杂环基、5-14元杂芳基、C6-14芳基或4-10元环烯基；所述3-14元杂环基、5-14元杂芳基、C6-14芳基或4-10元环烯基可任选进一步被一个或多个Ra所取代；wherein Ring A is selected from a 3-14 membered heterocyclyl, a 5-14 membered heteroaryl, a C 6-14 aryl or a 4-10 membered cycloalkenyl; the 3-14 membered heterocyclyl, the 5-14 membered heteroaryl, the C 6-14 aryl or the 4-10 membered cycloalkenyl may be optionally further substituted with one or more Ra ; 所述X选自N或CR2；所述R2选自氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C3-6环烷基或C1-6卤代烷基；The X is selected from N or CR 2 ; the R 2 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl; 所述Y1、Y2各自独立地选自N或CR4；所述R4选自氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C3-6环烷基或C1-6卤代烷基；Y 1 and Y 2 are each independently selected from N or CR 4 ; R 4 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl; 所述U、V、W、Z各自独立地选自-(C＝O)-、-SO2-、-O-、-NRb-、-(CRcRd)n-或-CReRf-，且U、V、W、Z中至少有一个选自-CReRf-；U, V, W, and Z are each independently selected from -(C=O)-, -SO 2 -, -O-, -NR b -, -(CR c R d ) n -, or -CR e R f -, and at least one of U, V, W, and Z is selected from -CR e R f -; 所述n选自0、1、2或3；Said n is selected from 0, 1, 2 or 3; 所述Re、Rf及其所连接的原子共同形成C3-12环烷基或3-12元杂环基；所述C3-12环烷基或3-12元杂环基可任选进一步被一个或多个Ra所取代；The R e , R f and the atoms to which they are connected together form a C 3-12 cycloalkyl group or a 3-12 membered heterocyclic group; the C 3-12 cycloalkyl group or the 3-12 membered heterocyclic group may be optionally further substituted by one or more R a ; 所述Ra、Rb、Rc、Rd各自独立地选自氢、氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷酯基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6烷基磺酰胺基、C1-6磷酰基、3-8元杂环基、5-14元杂芳基或C6-12芳基；所述C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷酯基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6烷基磺酰胺基、C1-6磷酰基、3-8元杂环基，5-14元杂芳基或C6-12芳基可任选进一步被一个或多个氢、氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基、C1-6羟基烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷基酰基、4-10元杂环基、5-14元杂芳基或C6-12芳基所取代；Said Ra , Rb , Rc , and Rd are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylester, C1-6 alkylacyl, C1-6 alkylamide, C1-6 alkylsulfonyl, C1-6 alkylsulfonamido, C1-6 phosphoryl, 3-8 membered heterocyclyl , 5-14 membered heteroaryl or C6-12 aryl ; said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl , C1-6 C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylester, C 1-6 alkylacyl, C 1-6 alkylamido, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonamido, C 1-6 phosphoryl, 3-8 membered heterocyclyl, 5-14 membered heteroaryl or C 6-12 aryl may be further optionally replaced by one or more hydrogen, deuterium, halogen, cyano, hydroxyl, amino, mercapto, oxo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylacyl, 4-10 membered heterocyclyl, 5-14 membered heteroaryl or C 6-12 aryl . 6-12 aryl substituted; 所述R1选自卤素、氰基、氨基、-ORg-、被一个或多个Rg取代的C1-6烷基、C2-6烯基、C2-6炔基、C3- 8环烷基、3-8元杂环基、5-14元杂芳基、C6-10芳基、C1-6烷氧基、C1-6羟基烷基、C1-6烷砜基、C1-6烷硫基或C1-6烷胺基；Said R 1 is selected from halogen, cyano, amino, -OR g -, C 1-6 alkyl substituted by one or more R g , C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, 5-14 membered heteroaryl, C 6-10 aryl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkylsulfone, C 1-6 alkylthio or C 1-6 alkylamino; 所述Rg选自氢、氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C3- 12环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷酯基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6磷酰基、C6-12芳基、3-8元杂环基或5-14元杂芳基；所述C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷酯基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6磷酰基、C6-12芳基、3-8元杂环基或5-14元杂芳基可任选进一步被一个或多个氢、氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基、C1-6羟基烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷基酰基、4-10元杂环基、5-14元杂芳基或C6-12芳基所取代。The Rg is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylester, C1-6 alkylacyl , C1-6 alkylamide, C1-6 alkylsulfonyl, C1-6 phosphoryl, C6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl; the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl , C1-6 alkoxy , C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylester, C1-6 alkylacyl, C1-6 alkylamide, C1-6 alkylsulfonyl, C1-6 phosphoryl, C6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl; The C 1-6 alkylacyl, C 1-6 alkylamido, C 1-6 alkylsulfonyl, C 1-6 phosphino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, cyano, hydroxy, amino, thiol, oxo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylacyl, 4-10 membered heterocyclyl, 5-14 membered heteroaryl or C 6-12 aryl. 如权利要求1所述的通式(Ia)或(Ib)所示的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R1选自被一个或多个Rg取代的C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、3-8元杂环基、5-14元杂芳基、C6-10芳基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基或C1-6烷胺基；The compound represented by the general formula (Ia) or (Ib) according to claim 1, or a stereoisomer, tautomer, deuterated form or pharmaceutically acceptable salt thereof, wherein R is selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a 3-8 membered heterocyclyl group, a 5-14 membered heteroaryl group, a C6-10 aryl group, a C1-6 alkoxy group, a C1-6 alkylsulfonyl group, a C1-6 alkylthio group or a C1-6 alkylamino group substituted with one or more Rg; 所述Rg选自氢、氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C3- 12环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷酯基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6磷酰基、C6-12芳基、3-8元杂环基或5-14元杂芳基；所述C1-6烷基、C2-6烯基、C2-6炔基、C3-12环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷酯基、C1-6烷基酰基、C1-6烷基酰胺基、C1-6烷基磺酰基、C1-6磷酰基、C6-12芳基、3-8元杂环基或5-14元杂芳基可任选进一步被一个或多个氢、氘、卤素、氰基、羟基、氨基、巯基、氧代基、C1-6烷基、C1-6羟基烷基、C1-6卤代烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C1-6烷氧基、C1-6烷砜基、C1-6烷硫基、C1-6烷胺基、C1-6烷基酰基、4-10元杂环基、5-14元杂芳基或C6-12芳基所取代；The Rg is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, thiol, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylester, C1-6 alkylacyl , C1-6 alkylamide, C1-6 alkylsulfonyl, C1-6 phosphoryl, C6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl; the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 cycloalkyl , C1-6 alkoxy , C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylamino, C1-6 alkylester, C1-6 alkylacyl, C1-6 alkylamide, C1-6 alkylsulfonyl, C1-6 phosphoryl, C6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl; C 1-6 alkylacyl, C 1-6 alkylamido, C 1-6 alkylsulfonyl, C 1-6 phosphino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, cyano, hydroxy, amino, thiol, oxo, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 alkylacyl, 4-10 membered heterocyclyl, 5-14 membered heteroaryl or C 6-12 aryl; 环A、X、Y1、Y2、U、V、W、Z、n、Re、Rf、Ra、Rb、Rc、Rd的定义如权利要求1中所述。Ring A, X, Y 1 , Y 2 , U, V, W, Z, n, Re, R f , Ra , R b , R c , and R d are as defined in claim 1. 如权利要求1或2所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述化合物具有如下式(IIa)或(IIb)所示结构：
The compound according to claim 1 or 2, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by the following formula (IIa) or (IIb):
其中，所述环A、Y1、Y2、U、V、W、Z、R1的定义如权利要求1或2中所述。wherein the ring A, Y 1 , Y 2 , U, V, W, Z, and R 1 are as defined in claim 1 or 2. 如权利要求3所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述化合物具有如下式(IIIa)或(IIIb)所示结构：
The compound according to claim 3, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by the following formula (IIIa) or (IIIb):
其中，所述U、V、W各自独立地选自-(C＝O)-、-SO2-、-O-、-NRb-、-CRcRd-或-CReRf-，且U、V、W中至少有一个选自-CReRf-；wherein U, V, and W are each independently selected from -(C=O)-, -SO 2 -, -O-, -NR b -, -CR c R d -, or -CR e R f -, and at least one of U, V, and W is selected from -CR e R f -; 所述环A、Y1、Y2、R1、Rb、Rc、Rd、Re、Rf的定义如权利要求1或2中所述。The definitions of ring A, Y 1 , Y 2 , R 1 , R b , R c , R d , Re and R f are as described in claim 1 or 2. 如权利要求4所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述化合物具有如下式(IVa)、(IVb)、(IVc)、(IVd)、(IVe)或(IVf)所示结构：
The compound according to claim 4, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that the compound has a structure represented by the following formula (IVa), (IVb), (IVc), (IVd), (IVe) or (IVf):
其中，U、V、W各自独立地选自-(C＝O)-、-SO2-、-O-、-NRb-或-CRcRd-；wherein U, V, and W are each independently selected from -(C=O)-, -SO 2 -, -O-, -NR b -, or -CR c R d -; m和t各自独立地选自0、1、2、3、4或5，m和t不同时为0；m and t are each independently selected from 0, 1, 2, 3, 4 or 5, and m and t are not 0 at the same time; Q选自O、S、SO2、C(R3)2或NR3；所述R3各自独立选自氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C3-6环烷基或C1-6卤代烷基；Q is selected from O, S, SO 2 , C(R 3 ) 2 or NR 3 ; each of the R 3 groups is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl; 环A、Y1、Y2、R1、Rb、Rc、Rd的定义如权利要求1或2中所述。Ring A, Y 1 , Y 2 , R 1 , R b , R c , and R d are as defined in claim 1 or 2. 如权利要求5所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述化合物具有如下式(Va)、(Vb)、(Vc)、(Vd)、(Ve)、(Vf)、(Vg)、(Vh)、(Vi)、(Vj)、(Vk)、(Vl)、(Vm)、(Vn)、(Vo)、(Vp)、(Vq)、(Vr)、(Vs)、(Vt)、(Vu)、(Vv)或(Vw)所示结构：

The compound according to claim 5, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that the compound has a structure represented by the following formula (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu), (Vv) or (Vw):

其中，R3选自氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C3-6环烷基或C1-6卤代烷基；wherein R 3 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl; 环A、R1、Rb的定义如权利要求1或2中所述。Ring A, R 1 and R b are as defined in claim 1 or 2. 如权利要求5所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述化合物具有如下式(Va)、(Vb)、(Vc)、(Vd)、(Ve)、(Vf)、(Vg)、(Vh)、(Vi)、(Vj)、(Vk)、(Vl)、(Vm)、(Vn)、(Vo)、(Vp)、(Vq)、(Vr)、(Vs)、(Vt)、(Vu)或(Vv)所示结构：

The compound according to claim 5, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, characterized in that the compound has a structure represented by the following formula (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg), (Vh), (Vi), (Vj), (Vk), (Vl), (Vm), (Vn), (Vo), (Vp), (Vq), (Vr), (Vs), (Vt), (Vu) or (Vv):

其中，R3选自氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C3-6环烷基或C1-6卤代烷基；wherein R 3 is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl; 环A、R1、Rb的定义如权利要求1或2中所述。Ring A, R 1 and R b are as defined in claim 1 or 2. 如权利要求3所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述化合物具有如下式(IIIc)或(IIId)所示结构：
The compound according to claim 3, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by the following formula (IIIc) or (IIId):
其中，U、V、W、Z各自独立地选自-(C＝O)-、-SO2-、-O-、-NRb-、-CRcRd-或-CReRf-、且U、V、W、Z中至少有一个选自-CReRf-；wherein U, V, W, and Z are each independently selected from -(C=O)-, -SO 2 -, -O-, -NR b -, -CR c R d -, or -CR e R f -, and at least one of U, V, W, and Z is selected from -CR e R f -; 环A、Y1、Y2、R1、Rb、Rc、Rd、Re、Rf的定义如权利要求1或2中所述。Ring A, Y 1 , Y 2 , R 1 , R b , R c , R d , Re , and R f are as defined in claim 1 or 2. 如权利要求8所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述化合物具有如下式(IVg)、(IVh)、(IVi)、(IVj)或(IVk)所示结构：

The compound according to claim 8, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by the following formula (IVg), (IVh), (IVi), (IVj) or (IVk):

其中，U、V、W、Z各自独立地选自-(C＝O)-、-SO2-、-O-、-NRb-或-CRcRd-；wherein U, V, W, and Z are each independently selected from -(C=O)-, -SO 2 -, -O-, -NR b -, or -CR c R d -; m和t各自独立地选自0、1、2、3、4或5，m和t不同时为0；m and t are each independently selected from 0, 1, 2, 3, 4 or 5, and m and t are not 0 at the same time; Q选自O、S、SO2、C(R3)2或NR3；所述R3各自独立选自氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C3-6环烷基或C1-6卤代烷基；Q is selected from O, S, SO 2 , C(R 3 ) 2 or NR 3 ; each of the R 3 groups is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or C 1-6 haloalkyl; 环A、Y1、Y2、R1、Rb、Rc、Rd的定义如权利要求1或2中所述。Ring A, Y 1 , Y 2 , R 1 , R b , R c , and R d are as defined in claim 1 or 2. 如权利要求9所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述化合物具有如下式(VIa)、(VIb)、(VIc)、(VId)、(VIe)、(VIf)、(VIg)、(VIh)、(VIi)、(VIj)、(VIk)、(VIl)、(VIm)、(VIn)、(VIo)、(VIp)、(VIq)、(VIr)、(VIs)、(VIt)、(VIu)、(VIv)或(VIw)所示结构：

The compound according to claim 9, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by the following formula (VIa), (VIb), (VIc), (VId), (VIe), (VIf), (VIg), (VIh), (VIi), (VIj), (VIk), (VIl), (VIm), (VIn), (VIo), (VIp), (VIq), (VIr), (VIs), (VIt), (VIu), (VIv) or (VIw):

其中，环A、R1、Rb的定义如权利要求1或2中所述。wherein, ring A, R 1 , and R b are as defined in claim 1 or 2. 如权利要求1-10中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述环A选自苯基、吡啶基、吗啉基、吡啶酮基或环己烯基；所述的苯基、吡啶基、吗啉基、吡啶酮基或环己烯基可任选进一步被一个或多个Ra取代，所述Ra各自独立选自氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基或3-8元杂环基。The compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, deuterated form or pharmaceutically acceptable salt thereof, wherein the ring A is selected from phenyl, pyridyl, morpholinyl, pyridonyl or cyclohexenyl; the phenyl, pyridyl, morpholinyl, pyridonyl or cyclohexenyl group may be optionally further substituted with one or more Ra , each of which is independently selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfone or 3-8 membered heterocyclyl. 如权利要求11所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述环A选自苯基，所述的苯基可任选进一步被一个或多个Ra取代，所述Ra选自氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基或3-8元杂环基。The compound according to claim 11, or a stereoisomer, tautomer, deuterated form or pharmaceutically acceptable salt thereof, wherein the ring A is selected from a phenyl group, the phenyl group may be optionally further substituted with one or more Ra , wherein Ra is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl or a 3-8 membered heterocyclic group. 如权利要求11所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述环A选自吡啶基，所述的吡啶基可任选进一步被一个或多个Ra取代，所述Ra选自氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷氧基、C1-6烷砜基或3-8元杂环基。The compound according to claim 11, or a stereoisomer, tautomer, deuterated form or pharmaceutically acceptable salt thereof, wherein the ring A is selected from pyridyl, and the pyridyl may be optionally further substituted with one or more Ra , wherein Ra is selected from hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 alkylsulfonyl or 3-8 membered heterocyclic group. 如权利要求11-13中任一项所述化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述环A选自 The compound according to any one of claims 11 to 13, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein the ring A is selected from 如权利要求11-13中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述环A选自 The compound according to any one of claims 11 to 13, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein the ring A is selected from 如权利要求11-13中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述环A选自 The compound according to any one of claims 11 to 13, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein the ring A is selected from 如权利要求1-16中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R1选自被Rg取代的乙炔基，所述Rg选自氢、氘、C1-6烷基、C3-12环烷基、C6-12芳基、3-8元杂环基或5-14元杂芳基，所述C1-6烷基、C3-12环烷基、C6-12芳基、3-8元杂环基或5-14元杂芳基可任选进一步被一个或多个氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷砜基或3-8元杂环基取代。The compound according to any one of claims 1 to 16, or a stereoisomer, tautomer, deuterated form or pharmaceutically acceptable salt thereof, wherein R 1 is selected from ethynyl substituted by R g , wherein R g is selected from hydrogen, deuterium, C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, and the C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be further optionally substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfonyl or 3-8 membered heterocyclyl. 如权利要求1-16中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R1选自被一个或多个Rg取代的环丙基，所述Rg选自氢、氘、C1-6烷基、C2-6炔基、C6-12芳基、3-8元杂环基或5-14元杂芳基，所述C1-6烷基、C2-6炔基、C6-12芳基、3-8元杂环基或5-14元杂芳基可任选进一步被一个或多个氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C2- 6炔基、C3-6环烷基、C1-6烷砜基或3-8元杂环基取代。The compound according to any one of claims 1 to 16, or a stereoisomer, tautomer, deuterated form or pharmaceutically acceptable salt thereof, wherein R 1 is selected from cyclopropyl substituted by one or more R g , wherein R g is selected from hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkynyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, and the C 1-6 alkyl, C 2-6 alkynyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl , C 1-6 alkylsulfone or 3-8 membered heterocyclyl. 如权利要求1-16中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R1选自被一个或多个Rg取代的甲基，所述Rg选自氢、氘、卤素、C1-6烷基、C3-12环烷基、C6-12芳基、3-8元杂环基或5-14元杂芳基，所述C1-6烷基、C3-12环烷基、C6-12芳基、3-8元杂环基或5-14元杂芳基可任选进一步被一个或多个氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷砜基或3-8元杂环基取代。The compound according to any one of claims 1 to 16, or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, wherein R 1 is selected from methyl substituted by one or more R g , wherein R g is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, and the C 1-6 alkyl, C 3-12 cycloalkyl , C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfonyl or 3-8 membered heterocyclyl. 如权利要求1-16中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R1选自被一个或多个Rg取代的乙基，所述Rg选自氢、氘、卤素、C1-6烷基、C3-12环烷基、C6-12芳基、3-8元杂环基或5-14元杂芳基，所述C1-6烷基、C3-12环烷基、C6-12芳基、3-8元杂环基或5-14元杂芳基可任选进一步被一个或多个氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷砜基或3-8元杂环基取代。The compound according to any one of claims 1 to 16, or a stereoisomer, tautomer, deuterated form or pharmaceutically acceptable salt thereof, wherein R 1 is selected from ethyl substituted with one or more R g , wherein R g is selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, and the C 1-6 alkyl, C 3-12 cycloalkyl , C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfonyl or 3-8 membered heterocyclyl. 如权利要求1-16中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R1选自-O(CH2)pRg-，所述p选自0、1、2、3或4，所述Rg选自氢、氘、卤素、羟基、C1-6烷基、C3-12环烷基、C1-6烷胺基、C6-12芳基、3-8元杂环基或5-14元杂芳基，所述C1-6烷基、C3-12环烷基、C1-6烷胺基、C6-12芳基、3-8元杂环基或5-14元杂芳基可任选进一步被一个或多个氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷砜基、C1-6羟基烷基或3-8元杂环基取代。The compound according to any one of claims 1 to 16, or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, characterized in that R 1 is selected from -O(CH 2 ) p R g -, p is selected from 0, 1, 2, 3 or 4, and R g is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, and the C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C The alkyl group is substituted with a C 1-6 alkylsulfonyl group, a C 1-6 hydroxyalkyl group or a 3-8 membered heterocyclic group. 如权利要求1-16中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R1选自-O(CH2)pRg-，所述p选自0、1、2、3或4，所述Rg选自氢、氘、卤素、羟基、C1-6烷基、C3-12环烷基、C1-6烷胺基、C6-12芳基、3-8元杂环基或5-14元杂芳基，所述C1-6烷基、C3-12环烷基、C1-6烷胺基、C6-12芳基、3-8元杂环基或5-14元杂芳基可任选进一步被一个或多个氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷砜基或3-8元杂环基取代。The compound according to any one of claims 1 to 16, or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, characterized in that R 1 is selected from -O(CH 2 ) p R g -, p is selected from 0, 1, 2, 3 or 4, and R g is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, and the C 1-6 alkyl, C 3-12 cycloalkyl, C 1-6 alkylamino, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C substituted with a 1-6- membered alkylsulfone or a 3-8-membered heterocyclic group. 如权利要求1-16中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R1选自-(CH2)qORg-，所述q选自0、1、2、3或4，所述Rg选自氢、氘、卤素、羟基、C1-6烷基、C6-12芳基、3-8元杂环基或5-14元杂芳基，所述C1-6烷基、C6-12芳基、3-8元杂环基或5-14元杂芳基可任选进一步被一个或多个氢、氘、卤素、氨基、氰基、羟基、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C2-6炔基、C3-6环烷基、C1-6烷砜基或3-8元杂环基取代。The compound according to any one of claims 1 to 16, or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof, wherein R 1 is selected from -(CH 2 ) q OR g -, q is selected from 0, 1, 2, 3 or 4, and R g is selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl, and the C 1-6 alkyl, C 6-12 aryl, 3-8 membered heterocyclyl or 5-14 membered heteroaryl may be optionally further substituted with one or more hydrogen, deuterium, halogen, amino, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 1-6 alkylsulfone or 3-8 membered heterocyclyl. 如权利要求17-23中任一项所述化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R1选自 The compound according to any one of claims 17 to 23, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein R 1 is selected from 如权利要求17-23中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R1选自 The compound according to any one of claims 17 to 23, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein R 1 is selected from 如权利要求1-25中任一项所述的化合物，或其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述化合物选自以下化合物：




The compound according to any one of claims 1 to 25, or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:




一种药物组合物，其特征在于，所述药物组合物含有治疗有效量的权利要求1-26中任一项所述的化合物或其立体异构体、互变异构体、氘代物或药用盐。A pharmaceutical composition, characterized in that the pharmaceutical composition contains a therapeutically effective amount of the compound according to any one of claims 1 to 26 or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts. 权利要求1-26中任一项所述的化合物或其立体异构体、互变异构体、氘代物或药用盐或权利要求27所述的药物组合物在制备用于治疗POLθ介导的疾病或病症及相关疾病或病症的药物中的应用。Use of the compound according to any one of claims 1 to 26 or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 27 in the preparation of a medicament for treating diseases or conditions mediated by POLθ and related diseases or conditions. 权利要求1-26中任一项所述的化合物或其立体异构体、互变异构体、氘代物或药用盐或权利要求27所述的药物组合物用于治疗POLθ介导的疾病或病症及相关疾病或病症。The compound according to any one of claims 1 to 26 or its stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 27 is used to treat diseases or conditions mediated by POLθ and related diseases or conditions. 一种治疗和/或预防疾病的方法，包括向治疗对象施用治疗有效量的权利要求1-26中任一项所述的化合物或其立体异构体、互变异构体、氘代物或药用盐或权利要求27所述的药物组合物；所述治疗和/或预防的疾病选自POLθ介导的疾病或病症及相关疾病或病症。A method for treating and/or preventing a disease, comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 26, or a stereoisomer, tautomer, deuterated form, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27; the disease to be treated and/or prevented is selected from a disease or condition mediated by POLθ and related diseases or conditions. 如权利要求28或29所述的应用，或权利要求30所述的方法，其特征在于，所述POLθ介导的疾病或病症及相关疾病或病症选自肿瘤或癌症。The use according to claim 28 or 29, or the method according to claim 30, wherein the POLθ-mediated disease or condition and related diseases or conditions are selected from tumors or cancers. 如权利要求31所述的应用或方法，其特征在于，所述癌症的特征为以下任意一种或多种的组合：The use or method according to claim 31, wherein the cancer is characterized by any one or more combinations of the following: 1)所述癌症的特征为同源重组(HR)缺陷、HR相关基因表达的减少或缺失；1) The cancer is characterized by homologous recombination (HR) deficiency or decreased or absent expression of HR-related genes; 2)所述癌症的特征为BRCA基因表达的减少或缺失、BRAC基因的缺失或BRCA蛋白的功能降低；2) The cancer is characterized by decreased or absent BRCA gene expression, BRAC gene deletion, or reduced BRCA protein function; 3)所述癌症的特征为缺失53BP1/Shieldin复合物；4)所述癌症的特征为对MMEJ DSB修复的依赖性增加；5)所述癌症的特征为接受或未接受PARPi药物治疗，对PARPi治疗具有耐药性。3) The cancer is characterized by the absence of the 53BP1/Shieldin complex; 4) The cancer is characterized by an increased dependence on MMEJ DSB repair; 5) The cancer is characterized by receiving or not receiving PARPi drug treatment and being resistant to PARPi treatment. 如权利要求31或32所述的应用或方法，其特征在于，所述的肿瘤或癌症选自血液瘤或实体瘤，所述实体瘤包括但不限于软组织癌、横纹肌样癌、多发性骨髓瘤、子宫癌、胃癌、周围神经系统癌、横纹肌肉瘤、骨癌、结直肠癌、间皮瘤、乳腺癌、卵巢癌、肺癌、成纤维细胞、中枢神经系统癌、泌尿道癌、上消化道癌、肾脏癌、皮肤癌、食道癌和胰腺癌；所述血液瘤包括但不限于淋巴瘤和白血病。The use or method according to claim 31 or 32, characterized in that the tumor or cancer is selected from a hematological tumor or a solid tumor, the solid tumor including but not limited to soft tissue cancer, rhabdoid cancer, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblasts, central nervous system cancer, urinary tract cancer, upper gastrointestinal cancer, kidney cancer, skin cancer, esophageal cancer and pancreatic cancer; the hematological tumor includes but not limited to lymphoma and leukemia. 一种式(M)所示的化合物，或其立体异构体、互变异构体、氘代物或药用盐：
A compound represented by formula (M), or a stereoisomer, tautomer, deuterated compound or pharmaceutically acceptable salt thereof:
其中，RM1选自碘、联硼酸频那醇酯基团(Bpin)或环A，所述环A的定义如权利要求1中所述；wherein RM1 is selected from iodine, a pinacol borate ester group (Bpin) or ring A, wherein the definition of ring A is as described in claim 1; RM2选自氢或C1-6烷基；R M2 is selected from hydrogen or C 1-6 alkyl; 所述式(M)所示的化合物，优选为所述环A的定义如权利要求1中所述。The compound represented by formula (M) is preferably The definition of the ring A is as described in claim 1. 权利要求34所述的化合物或其立体异构体、互变异构体、氘代物或药用盐在制备权利要求1-26中任一项所述的化合物或其立体异构体、互变异构体、氘代物或药用盐中的用途。Use of the compound of claim 34 or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts in the preparation of the compound of any one of claims 1 to 26 or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts.
PCT/CN2025/088697 2024-04-15 2025-04-14 Heterocyclic amide compound and use thereof in medicine Pending WO2025218615A1 (en)

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