WO2022122037A1 - 一种二氢异喹啉酮衍生物及其应用 - Google Patents

一种二氢异喹啉酮衍生物及其应用 Download PDF

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WO2022122037A1
WO2022122037A1 PCT/CN2021/137254 CN2021137254W WO2022122037A1 WO 2022122037 A1 WO2022122037 A1 WO 2022122037A1 CN 2021137254 W CN2021137254 W CN 2021137254W WO 2022122037 A1 WO2022122037 A1 WO 2022122037A1
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alkyl
alkoxy
substituted
optionally substituted
compound
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PCT/CN2021/137254
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English (en)
French (fr)
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郑乾刚
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上海奕拓医药科技有限责任公司
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Priority to EP21902742.2A priority Critical patent/EP4261211A1/en
Priority to CN202180083281.XA priority patent/CN116783188A/zh
Priority to US18/256,796 priority patent/US20240101535A1/en
Publication of WO2022122037A1 publication Critical patent/WO2022122037A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • 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
    • C07D487/08—Bridged systems
    • 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

Definitions

  • the present invention relates to the field of medicinal chemistry, in particular, to a novel heterocyclic compound that can be used as a WDR5 protein-protein interaction inhibitor, a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof Conformers, tautomers, solvates, isotopic substitutions, prodrugs or metabolites.
  • the present invention also relates to a preparation method of such compounds, pharmaceutical compositions containing such compounds, and use of such compounds for preparing medicines for treating diseases or conditions related to abnormal WDR5 activity.
  • WDR5 belongs to the WD40 domain repeat protein family (WD40-repeat protein).
  • WD40 is an important structural domain consisting of about 40 amino acid residues.
  • the WDR domain contains a ring-shaped seven-leaf ⁇ -propeller domain. Each contains the conserved serine-histidine (SH) and tryptophan-aspartic acid (WD) sequences.
  • the WDR5 protein contains a central cavity formed by a 7-lobed ⁇ -helix that runs up and down.
  • the WDR5 protein mainly plays a regulatory role through a deep arginine binding pocket, that is, the WIN site forms a core catalytic complex with MLL1, and forms the core catalytic complex of MWRAD (MLL1, WDR5, RbBP5, ASH2L and DYP-30) with other proteins. , catalyzes histone H3 methylation, activates gene transcription and participates in epigenetic regulation.
  • MLL family protein complex which is widespread in eukaryotes, is an important class of histone methyltransferases that catalyze the methylation of histone H3K4, either by catalyzing the methylation of H3K4 and/or by recruiting other transcription-related proteins to interact with Mediators, which activate transcription, play a crucial role during development. Mutations in these proteins, including genomic translocations where they fuse with other transcription factors, can cause a variety of diseases, such as mixed lineage leukemia (MLL), lymphoma, and Kabuki syndrome.
  • MLL mixed lineage leukemia
  • MLL1 is the 3775-3786 amino acid (MLL1 AS , activation segment) inserted into the barrel structure of WDR5. center, while MLL3 is an amino-terminal insertion of the SET domain into WDR5.
  • WDR5 as a drug target, compounds designed for the WIN pocket where WDR5 binds to histones and MLL1 can reduce the expression of genes downstream of WDR5 and treat MLL rearrangement-dependent leukemia.
  • the TP53 gene is the most frequently mutated gene in tumors, and TP53 mutations occur in 50% of human cancers.
  • the high frequency of missense mutations and the high expression level of mutant p53 (mp53) protein in cancer cells promote mp53 protein to have new functions (“gain of function” (GOF)), and also actively promote cancer development and progression.
  • GAF gain of function
  • the growth of tumor cells driven by mutations in the p53 gene depends on the binding of WDR5 to MLL. MLL, MOZ and histone modifications are all regulated by the expression of GOF p53. Therefore, WDR5 protein interaction inhibitors can also be used to treat TP53-mutated tumors.
  • MYC is a class of oncoproteins with transcription factor functions, which are overexpressed in most malignant tumors. MYC can bind to the regulatory sequences of thousands of target genes, regulate target gene expression, and affect processes such as cell growth, proliferation, metabolism, genome stability, and apoptosis. Earlier studies have found that the extensive binding of MYC to chromatin also depends on the interaction of WDR5, and that MYC binds to the hydrophobic cleft on the surface of WDR5 through its evolutionarily conserved "MYC box IIIb" sequence, which plays an important role in tumorigenesis in vivo. Therefore, by blocking the WDR5 protein-protein interaction, MYC function can be blocked and the ability of MYC to drive carcinogenesis can be inhibited.
  • the object of the present invention is to provide a compound of formula I or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, and the compound or pharmaceutical composition thereof in the prevention and treatment of and WDR5 Abnormal-related diseases or conditions.
  • a compound of formula I or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvate thereof , polymorphs, prodrugs or metabolites:
  • Ring A is a substituted or unsubstituted 3-8 membered saturated or unsaturated carbocyclic ring or a substituted or unsubstituted 3-8 membered saturated or unsaturated heterocyclic ring, the heterocyclic ring contains 1-2 independently selected from N, O and heteroatoms of S;
  • X 3 is selected from CR 5 and N;
  • X 5 is selected from N and CR 5 ;
  • L 1 is selected from bond, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkylene-O-, optionally substituted C1-C6 alkylene-NH-, optionally substituted C1 -C6 alkylene-S- and optionally substituted C2-C4 alkenylene;
  • L 2 is selected from bond, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkylene-O-, optionally substituted C1-C6 alkylene-NH-, optionally substituted C1 -C6 alkylene-S- and optionally substituted C2-C4 alkenylene;
  • R 0 is selected from H, C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkyl, -C(O)NR 3 R 4 , -CH 2 OR 3 and - NR 3 R 4 substituted C1-C6 alkyl;
  • R 1 is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino and guanidino;
  • R is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
  • R 3 and R 4 are each independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkyl, optionally substituted 4-10 membered Heterocyclyl and optionally substituted 5-10 membered heteroaryl; alternatively, R and R together with the nitrogen atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl or 5-10 membered heteroaryl ;
  • R 5 is selected from H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl and C1-C6 alkoxy;
  • R 6 is selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl and C1-C6 alkoxy.
  • ring A is C3-C8 cycloalkyl or 3-7 membered heterocyclyl.
  • Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl , piperazinyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl.
  • ring A is substituted with 1, 2 or 3 C1-C6 groups selected from halogen, hydroxy, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy Alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR a R b , -NR a R b substituted carbonyl, -NR a R b substituted C1-C6 alkyl, C1-C6 Alkylcarbonyl, C1-C6alkoxycarbonyl, optionally substituted 6-14-membered aryl, optionally substituted 5-10-membered heteroaryl, optionally substituted 4-10-membered heterocyclyl, optionally substituted 6-14-membered aryl, optionally substituted 5-10-membered heteroaryl, optionally substituted 4-10-membered heterocyclyl, optionally substituted 6-14-membered aryl, optionally substituted 5-10-
  • Ring A is cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, azetidine or tetrahydrofuranyl,
  • Ring A is optionally surrounded by 1, 2 or 3 selected from F, Cl, Br, CF3 , CH3 , -OH, -OCH3 , -NH2 , - Substituents of NHCH 3 ,-NH 2 (CH 3 ) 2 are substituted.
  • R 0 is a C1-C6 alkyl group substituted by -NR 3 R 4 ; wherein R 3 and R 4 are each independently selected from H, optionally by 1, 2, 3, 4, 5 or 6 C1-C6 alkyl substituted with substituents selected from halogen, cyano, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR a R b and hydroxy, or R 3 and R 4 together with the nitrogen atom to which it is attached forms azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2-piperazinone, morpholinyl, pyridyl, pyrrolyl, pyrazolyl , imidazo
  • R 0 is a C1-C6 alkyl substituted with -NR 3 R 4 , and wherein R 3 and R 4 together with the nitrogen atom to which they are attached form an azetidinyl group , pyrrolidinyl, piperidinyl, piperazinyl, 2-piperazinone, morpholinyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazine base, indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl,
  • R 0 is a C1-C6 alkyl substituted by -NR 3 R 4 , wherein R 3 and R 4 together with the nitrogen atom to which they are attached form an azetidinyl group, Pyrrolidinyl, piperidinyl, piperazinyl, 2-piperazinone, morpholinyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl , indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzis
  • the compounds of formula I described in the present invention or their pharmaceutically acceptable salts, or their enantiomers, diastereomers, tautomers, isotopic substitutions, solvates,
  • X 3 and/or X 5 are CR 5 .
  • R 5 is selected from H and C1-C4 alkyl.
  • X 4 is -(CH 2 ) n -, and n is 1 or 2; and wherein the -(CH 2 ) n - is optionally selected from 1 or 2 by 1 or 2 Substituents of halogen, hydroxy, amino, C1-C6 alkyl and halogenated C1-C6 alkyl are substituted.
  • L 1 is selected from C1-C6 alkylene, C1-C6 alkylene-O-, C1-C6 alkylene-NH-, C1-C6 alkylene- S- and C2-C4 alkenylene, the C1-C6 alkylene, C1-C6 alkylene-O-, C1-C6 alkylene-NH-, C1-C6 alkylene-S- and The C2-C4 alkenylene group is optionally substituted with 1, 2 or 3 substituents selected from halogen, C1-C4 alkyl and hydroxy.
  • L1 is selected from C1 -C6 alkylene or C1-alkylene optionally substituted with 1, 2 or 3 substituents selected from halogen, C1-C4 alkyl and hydroxy C6 alkylene-NH-.
  • R 1 is selected from optionally substituted C3-C8 cycloalkyl, optionally substituted 6-14-membered aryl, optionally substituted 5-10-membered heteroaryl and Optionally substituted 4-10 membered heterocyclyl, and each of said cycloalkyl, aryl, heteroaryl and heterocyclyl may be optionally Substituent substitution of -C6 alkyl, halogen, hydroxy, C1-C6 alkoxy, C1-C6 haloalkyl and cyano; wherein, the optionally substituted amino is -NR a R b , wherein R a and R b is each independently H or C1-C6 alkyl.
  • R 1 is selected from optionally substituted phenyl, naphthyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, Triazinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, pyridoimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, Pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, pyridodihydrofuranyl, pyri
  • the L 1 is C1-C4 alkylene or C1-C4 alkylene-NH-
  • R 1 is pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl or The pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl or Optionally substituted with 1 or 2 substituents selected from halogen, C1-C4 alkyl and -NR a R b , wherein R a and R b are each independently H or C1-C4 alkyl.
  • L 2 is selected from a bond and a C1-C6 alkylene group, wherein the C1-C6 alkylene group is optionally surrounded by 1, 2 or 3 selected from halogen, C1 Substituent substitution of -C3 alkyl, C3-C5 cycloalkyl and hydroxy.
  • R 2 is optionally replaced by 1, 2 or 3 selected from -NR a R b , cyano, C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy base, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl-O-, 6-14-membered aryl, 5-10-membered heteroaryl and cyano substituents; wherein, R a and R b are each independently H or C1-C6 alkyl; and wherein, the heteroaryl group is preferably a heteroaryl group containing 1 or 2 ring nitrogen atoms, preferably
  • R 2 is selected from 6-14-membered aryl, 5-10-membered heteroaryl and 4-10-membered heterocyclic group, the 6-14-membered aryl, 5- 10-membered heteroaryl and 4-10-membered heterocyclyl are optionally surrounded by 1, 2 or 3 members selected from -NR a R b , cyano, C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl-O-, 6-14-membered aryl, 5-10-membered heteroary
  • R 2 is selected from phenyl, naphthyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl, Indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, azetidine Alkyl, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, pyridodihydrofuranyl, pyr
  • L 2 is C1-C4 alkylene
  • R 2 is 1 or 2 selected from C1-C6 alkoxy, halogen, C1-C6 alkyl, cyano, 6-14-membered aryl, 5-10-membered nitrogen-containing heteroaryl or 4-10-membered heterocyclic substituted by substituents of C3-C8 cycloalkyl-O- and halogenated C1-C6 alkoxy, preferably Phenyl, pyridyl, pyrazolyl, pyrrolopyridyl, pyridodihydrofuranyl, pyrido1,3-dioxocyclopentenyl or indolyl.
  • ring A is a C3-C6 cycloalkyl or a 4-8 membered heterocyclyl, and the cycloalkyl or heterocyclyl is optionally selected from 1, 2 or 3 Substituents from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy;
  • X 3 and X 5 are both CH;
  • X 4 is CH 2 ;
  • L 1 is C1-C4 alkylene
  • R 1 is a 5- or 6-membered nitrogen-containing heteroaryl optionally substituted with 1 or 2 substituents selected from halogen, C1-C4 alkyl and -NR a R b , the 5 or 6-membered nitrogen-containing heteroaryl
  • the group is preferably pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl or wherein, R a and R b are each independently H or C1-C4 alkyl;
  • L 2 is C1-C4 alkylene
  • R 2 is phenyl, 5-10-membered nitrogen-containing heteroaryl or 4-10-membered heterocyclic group, preferably pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyrazinyl, pyrrolopyridyl , pyridodihydrofuranyl, pyrido1,3-dioxocyclopentenyl or indolyl, each of said phenyl, 5-10-membered nitrogen-containing heteroaryl and 4-10-membered heterocyclyl is optional ground is substituted with 1 or 2 substituents selected from C1-C6 alkoxy, halogen, C1-C6 alkyl, cyano, C3-C8 cycloalkyl-O- and halogenated C1-C6 alkoxy;
  • R 0 is C1-C4 alkyl substituted by -NR 3 R 4 ; wherein, R 3 and R 4 are each independently selected from H, C1 optionally substituted with 1-6 substituents selected from hydroxy, cyano and halogen -C6 alkyl and optionally 1, 2 or 3 selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR a 4-8-membered heterocyclic group substituted by substituents of R b and hydroxy, wherein R a and R b are each independently H or C1-C4 alkyl; or R 3 and R 4 together with the nitrogen atom to which they are attached form optionally by 1, 2 or 3 selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, hal
  • Ring A is a C3-C6 cycloalkyl optionally surrounded by 1, 2 or 3 selected from halogen, C1-C4 alkyl and halogenated C1 Substituent substitution of -C4 alkyl;
  • X 3 and X 5 are both CH;
  • X 4 is CH 2 ;
  • L 1 is C1-C4 alkylene
  • R 1 is a 5- or 6-membered nitrogen-containing heteroaryl substituted by 1 or 2 substituents selected from C1-C4 alkyl and -NR a R b , preferably pyridyl, pyrrolyl, pyrazolyl, imidazolyl , triazolyl, pyrimidinyl, pyrazinyl, triazinyl, or wherein, R a and R b are each independently H or C1-C4 alkyl;
  • L 2 is C1-C4 alkylene
  • R 2 is a 5-10-membered nitrogen-containing heteroaryl group or a 4-10-membered heterocyclic group, preferably pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyrazinyl, pyrrolopyridyl, pyrido Dihydrofuranyl, pyrido1,3-dioxolyl or indolyl, each of the 5-10-membered nitrogen-containing heteroaryl or 4-10-membered heterocyclic group is optionally selected from 1 or 2 Substituents from C1-C6alkoxy, C1-C6alkyl, C3-C8cycloalkyl-O-, halogenated C1-C6alkoxy, halogen and cyano;
  • R 0 is -NR 3 R 4 substituted C1-C4 alkyl, wherein R 3 and R 4 are each independently selected from H and optionally by 1, 2, 3, 4, 5 or 6 selected from hydroxyl, cyano A C1-C6 alkyl group substituted with a halogen substituent, or R3 and R4 together with the nitrogen atom to which they are attached form optionally substituted by 1 , 2 or 3 groups selected from halogen, hydroxy, C1-C4 alkoxy, C3 -C6 alkoxy and C1-C4 alkyl substituted 4-8-membered heterocyclic group, preferably, the 4-8-membered heterocyclic group is selected from azetidinyl, pyrrolidinyl, piperidinyl, Piperazinyl, Morpholinyl,
  • a compound of formula II or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvate, Polymorphs, prodrugs or metabolites:
  • Ring A is a substituted or unsubstituted 3-8 membered saturated or unsaturated carbocyclic ring or a substituted or unsubstituted 3-8 membered saturated or unsaturated heterocyclic ring, the heterocyclic ring contains 1-2 independently selected from N, O and heteroatoms of S;
  • L 2 is selected from bond, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkylene-O-, optionally substituted C1-C6 alkylene-NH-, optionally substituted C1 -C6 alkylene-S- and optionally substituted C2-C4 alkenylene;
  • R 0 is selected from H, C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkyl, -C(O)NR 3 R 4 , -CH 2 OR 3 , - NR 3 R 4 substituted C1-C6 alkyl;
  • R is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
  • R 3 and R 4 are each independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkyl, optionally substituted 4-10 membered Heterocyclyl and optionally substituted 5-10 membered heteroaryl; alternatively, R and R together with the nitrogen atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl or 5-10 membered heteroaryl ;and
  • Rc and Rd are each independently H or C1-C4 alkyl.
  • ring A is C3-C8 cycloalkyl or 3-7 membered heterocyclyl.
  • Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl , piperazinyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl.
  • ring A is substituted with 1, 2 or 3 C1-C6 groups selected from halogen, hydroxy, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy Substituent substitution of alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR a R b , C1-C6 alkylcarbonyl and C1-C6 alkoxycarbonyl, the R a and R b is each independently selected from H and C1-C6 alkyl.
  • ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexane, azetidine, oxetanyl, azetidine, tetrahydrofuran base or oxane.
  • Ring A is optionally surrounded by 1, 2 or 3 selected from F, Cl, Br, CF3 , CH3 , -OH, -OCH3 , -NH2 , - Substituents of NHCH 3 ,-NH 2 (CH 3 ) 2 are substituted.
  • R 0 is a C1-C6 alkyl group substituted by -NR 3 R 4 ; wherein R 3 and R 4 are each independently selected from H, optionally by 1, 2, 3, 4, 5 or 6 C1-C6 alkyl substituted with substituents selected from halogen, cyano, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR a R b and hydroxy, or R 3 and R 4 together with the nitrogen atom to which it is attached forms azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2-piperazinone, morpholinyl, pyridyl, pyrrolyl, pyrazolyl , imidazo
  • R 0 is a C1-C6 alkyl substituted with -NR 3 R 4 , and wherein R 3 and R 4 together with the nitrogen atom to which they are attached form an azetidinyl group , pyrrolidinyl, piperidinyl, piperazinyl, 2-piperazinone, morpholinyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazine base, indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl,
  • R 0 is a C1-C6 alkyl substituted by -NR 3 R 4 , wherein R 3 and R 4 together with the nitrogen atom to which they are attached form an azetidinyl group, Pyrrolidinyl, piperidinyl, piperazinyl, 2-piperazinone, morpholinyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl , indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzis
  • Rc and Rd are each independently H or methyl.
  • L 2 is selected from a bond and a C1-C6 alkylene group, wherein the C1-C6 alkylene group is optionally surrounded by 1, 2 or 3 selected from halogen, C1 Substituent substitution of -C3 alkyl, C3-C5 cycloalkyl and hydroxy.
  • R 2 is optionally replaced by 1, 2 or 3 selected from -NR a R b , cyano, C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy base, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl-O-, 6-14-membered aryl, 5-10-membered heteroaryl and cyano substituents; wherein, R a and R b are each independently H or C1-C6 alkyl; and wherein, the heteroaryl group is preferably a heteroaryl group containing 1 or 2 ring nitrogen atoms, preferably
  • R 2 is selected from 6-14-membered aryl, 5-10-membered heteroaryl and 4-10-membered heterocyclic group
  • the 6-14-membered aryl, 5- 10-membered heteroaryl and 4-10-membered heterocyclyl can be optionally surrounded by 1, 2 or 3 members selected from -NR a R b , cyano, C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy base, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl-O-, 6-14-membered aryl, 5-10-membered hetero
  • R 2 is selected from phenyl, naphthyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl, Indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, azetidine Alkyl, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, pyridodihydrofuranyl, pyr
  • L 2 is C1-C4 alkylene
  • R 2 is phenyl, pyridyl, pyrazolyl, pyrrolopyridyl, pyridodihydrofuranyl, pyrido1 ,3-dioxolyl or indolyl
  • the phenyl, pyridyl, pyrazolyl, pyrrolopyridyl, pyridodihydrofuranyl, pyrido1,3-dioxolyl or indolyl optionally by 1 or 2 selected from C1-C6 alkoxy, halogen, C1-C6 alkyl, cyano, C3-C8 cycloalkyl-O-
  • Ring A is a C3-C6 cycloalkyl optionally substituted with a substituent selected from F, Cl, hydroxy or C1-C4 alkyl, or contains 1 nitrogen or 1 C4-C6 heterocyclyl of O, preferably cyclopropyl, cyclobutyl, oxetanyl or azetidine optionally substituted by F or C1-C4 alkyl;
  • R 0 is a C1-C4 alkyl substituted by H or -NR 3 R 4 , wherein R 3 and R 4 are each independently selected from H, 4-6 membered heterocyclyl and optionally 1, 2, 3, 4, C1-C6 alkyl substituted with 5 or 6 substituents selected from hydroxy, cyano and halogen, or R3 and R4 taken together with the nitrogen atom to which they are attached form optionally substituted by 1, 2 or 3 substituents selected from halogen, 4-6-membered heterocyclic group substituted by hydroxyl, C1-C4 alkoxy, C3-C6 cycloalkyl and C1-C4 alkyl; wherein, the 4-6-membered heterocyclic group preferably contains oxygen and/or nitrogen
  • the heterocyclic group is preferably selected from oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-pipe
  • L 2 is C1-C4 alkylene
  • R 2 is a 6-14-membered aryl group, a 5-10-membered nitrogen-containing heteroaryl group or a 4-10-membered heterocyclic group, preferably phenyl, pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyridine oxazinyl, indolyl, pyrrolopyridyl, pyridodihydrofuranyl, pyrido1,3-dioxolyl,
  • the 6-14-membered aryl group, 5-10-membered nitrogen-containing heteroaryl group or 4-10-membered heterocyclic group are each optionally selected from 1 or 2 C1-C6 alkoxy, C1-C4 alkyl, halogen , C3-C6 cycloalkyl-oxy, halogenated C1-C4 alkoxy and cyano substituents;
  • Rc and Rd are each independently H or C1-C4 alkyl.
  • ring A is a C3-C6 cycloalkyl or a 4-8 membered heterocyclyl, and the cycloalkyl or heterocyclyl is optionally selected from 1, 2 or 3 Substituents from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy;
  • L 2 is C1-C4 alkylene
  • R 2 is phenyl, 5-10-membered nitrogen-containing heteroaryl or 4-10-membered heterocyclic group, preferably pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyrazinyl, pyrrolopyridyl , pyridodihydrofuranyl or pyrido1,3-dioxolane or indolyl, each of said phenyl, 5-10-membered nitrogen-containing heteroaryl and 4-10-membered heterocyclyl is optional ground is substituted with 1 or 2 substituents selected from C1-C6 alkoxy, halogen, C1-C6 alkyl, cyano, C3-C8 cycloalkyl-O- and halogenated C1-C6 alkoxy;
  • R 0 is C1-C4 alkyl substituted by -NR 3 R 4 ; wherein, R 3 and R 4 are each independently selected from H, C1 optionally substituted with 1-6 substituents selected from hydroxy, cyano and halogen -C6 alkyl and optionally 1, 2 or 3 selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR a 4-8-membered heterocyclic group substituted by substituents of R b and hydroxy, wherein R a and R b are each independently H or C1-C4 alkyl; or R 3 and R 4 together with the nitrogen atom to which they are attached form optionally by 1, 2 or 3 selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, hal
  • Rc and Rd are each independently H or C1-C4 alkyl.
  • Ring A is a C3-C6 cycloalkyl optionally surrounded by 1, 2 or 3 selected from halogen, C1-C4 alkyl and halogenated C1 Substituent substitution of -C4 alkyl;
  • L 2 is C1-C4 alkylene
  • R 2 is a 5-10-membered nitrogen-containing heteroaryl group or a 4-10-membered heterocyclic group, preferably pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyrazinyl, pyrrolopyridyl, pyrido Dihydrofuranyl or pyrido1,3-dioxolyl or indolyl, the 5-10-membered nitrogen-containing heteroaryl group or the 4-10-membered heterocyclic group are each optionally selected from 1 or 2 Substituents from C1-C6alkoxy, C1-C6alkyl, C3-C8cycloalkyl-O-, halogenated C1-C6alkoxy, halogen and cyano;
  • R 0 is -NR 3 R 4 substituted C1-C4 alkyl, wherein R 3 and R 4 are each independently selected from H and optionally by 1, 2, 3, 4, 5 or 6 selected from hydroxyl, cyano A C1-C6 alkyl group substituted with a halogen substituent, or R3 and R4 together with the nitrogen atom to which they are attached form optionally replaced by 1, 2 or 3 groups selected from halogen, hydroxy, C1- C4 alkoxy and C1 -C4 alkyl-substituted 4-8-membered heterocyclic group, preferably, the 4-8-membered heterocyclic group is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2-piperidine oxazinone group, morpholino group, and
  • Rc and Rd are each independently H or C1-C4 alkyl.
  • a compound of formula III or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvate thereof , polymorphs, prodrugs or metabolites, characterized in that,
  • L 2 is selected from bond, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkylene-O-, optionally substituted C1-C6 alkylene-NH-, optionally substituted C1 -C6 alkylene-S- and optionally substituted C2-C4 alkenylene;
  • R 0 is selected from H, C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkyl, -C(O)NR 3 R 4 , -CH 2 OR 3 , - NR 3 R 4 substituted C1-C6 alkyl;
  • R is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
  • R 3 and R 4 are each independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkyl, optionally substituted 4-10 membered Heterocyclyl and optionally substituted 5-10 membered heteroaryl; alternatively, R and R together with the nitrogen atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl or 5-10 membered heteroaryl ;
  • X 6 is each independently selected from C, O, N, S,
  • q is an integer of 1, 2 or 3
  • R 7 is selected from F, Cl, cyano, hydroxy, C1-C6 alkyl, fluoro or chloro C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, C1-C6 alkoxy, fluoro or chloro Substituted C1-C6 alkoxy, hydroxy-substituted C1-C6 alkyl and -NR a R b ; wherein, said R a and R b are each independently selected from H and C1-C6 alkyl,
  • n is an integer of 0, 1, 2 or 3;
  • Rc and Rd are each independently H or C1-C4 alkyl.
  • R 0 is a C1-C6 alkyl group substituted by -NR 3 R 4 ; wherein R 3 and R 4 are each independently selected from H, optionally by 1, 2, 3, 4, 5 or 6 C1-C6 alkyl substituted with substituents selected from halogen, cyano, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR a R b and hydroxy, or R 3 and R 4 together with the nitrogen atom to which it is attached forms azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2-piperazinone, morpholinyl, pyridyl, pyrrolyl, pyrazolyl , imidazoly
  • R 0 is a C1-C6 alkyl substituted with -NR 3 R 4 , and wherein R 3 and R 4 together with the nitrogen atom to which they are attached form an azetidinyl group , pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, iso Indolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, qui
  • R 0 is a C1-C6 alkyl substituted by -NR 3 R 4 , wherein R 3 and R 4 together with the nitrogen atom to which they are attached form an azetidinyl group, Pyrrolidinyl, piperidinyl, piperazinyl, 2-piperazinone, morpholinyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl , indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzis
  • Rc and Rd are each independently H or methyl.
  • L 2 is selected from a bond and a C1-C6 alkylene group, wherein the C1-C6 alkylene group is optionally surrounded by 1, 2 or 3 selected from halogen, C1 Substituent substitution of -C3 alkyl, C3-C5 cycloalkyl and hydroxy.
  • R 2 is optionally replaced by 1, 2 or 3 selected from -NR a R b , cyano, C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy base, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl-O-, 6-14-membered aryl, 5-10-membered heteroaryl and cyano substituents; wherein, R a and R b are each independently H or C1-C6 alkyl; and wherein, the heteroaryl group is preferably a heteroaryl group containing 1 or 2 ring nitrogen atoms, preferably
  • R 2 is selected from 6-14-membered aryl, 5-10-membered heteroaryl and 4-10-membered heterocyclic group, the 6-14-membered aryl, 5- 10-membered heteroaryl and 4-10-membered heterocyclyl are optionally surrounded by 1, 2 or 3 members selected from -NR a R b , cyano, C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy , halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl-O-, 6-14-membered aryl, 5-10-membered heteroary
  • R 2 is selected from phenyl, naphthyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl, Indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, azetidine Alkyl, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, pyridodihydrofuranyl, pyr
  • L 2 is C1-C4 alkylene
  • R 2 is 1 or 2 selected from C1-C6 alkoxy, halogen, C1-C6 alkyl, cyano, 6-14-membered aryl, 5-10-membered nitrogen-containing heteroaryl or 4-10-membered heterocyclic substituted by substituents of C3-C8 cycloalkyl-O- and halogenated C1-C6 alkoxy, preferably Phenyl, pyridyl, pyrazolyl, pyrrolopyridyl, pyridodihydrofuranyl, pyrido1,3-dioxocyclopentenyl or indolyl.
  • R 0 is H or -NR 3 R 4 substituted C1-C4 alkyl group, wherein R 3 and R 4 are each independently selected from H, 4-6 membered heterocyclic group and C1-C6 alkyl optionally substituted with 1, 2, 3, 4 , 5 or 6 substituents selected from hydroxy, cyano and halogen, or R and R together with the nitrogen atom to which they are attached form any 4-6-membered heterocyclic group substituted by 1, 2 or 3 members selected from halogen, hydroxyl, C1-C4 alkoxy and C1-C4 alkyl; wherein, the 4-6-membered heterocyclic group preferably contains Oxygen and/or nitrogen heterocyclyl, preferably selected from oxetanyl,
  • L 2 is C1-C4 alkylene
  • R 2 is a 6-14-membered aryl group, a 5-10-membered nitrogen-containing heteroaryl group or a 4-10-membered heterocyclic group, preferably phenyl, pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyridine oxazinyl, indolyl, pyrrolopyridyl, pyridodihydrofuranyl or pyrido1,3-dioxolyl, the 6-14-membered aryl, 5-10-membered nitrogen-containing heteroaryl or 4-10-membered heterocyclic groups are each optionally replaced by 1 or 2 groups selected from C1-C6 alkoxy, C1-C4 alkyl, halogen, C3-C6 cycloalkyl-oxy, halogenated C1-C4 alkoxy Substituent substitution of cyano group and cyano group;
  • R c and R d are each independently H or C1-C4 alkyl
  • X 6 is C or O
  • q 1 or 2;
  • R 7 is selected from F, Cl, cyano, hydroxy, C1-C6 alkyl, fluoro or chloro C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, C1-C6 alkoxy, fluoro or chloro Substituted C1-C6 alkoxy and hydroxy substituted C1-C6 alkyl.
  • L 2 is C1-C4 alkylene
  • R 2 is phenyl, 5-10-membered nitrogen-containing heteroaryl or 4-10-membered heterocyclic group, preferably pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyrazinyl, pyrrolopyridyl , pyridodihydrofuranyl or pyrido1,3-dioxolane or indolyl, each of said phenyl, 5-10-membered nitrogen-containing heteroaryl and 4-10-membered heterocyclyl is optional ground is substituted with 1 or 2 substituents selected from C1-C6 alkoxy, halogen, C1-C6 alkyl, cyano, C3-C8 cycloalkyl-O- and halogenated C1-C6 alkoxy;
  • R 0 is C1-C4 alkyl substituted by -NR 3 R 4 ; wherein, R 3 and R 4 are each independently selected from H, C1 optionally substituted with 1-6 substituents selected from hydroxy, cyano and halogen -C6 alkyl and optionally 1, 2 or 3 selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR a 4-8-membered heterocyclic group substituted by substituents of R b and hydroxy, wherein R a and R b are each independently H or C1-C4 alkyl; or R 3 and R 4 together with the nitrogen atom to which they are attached form optionally by 1, 2 or 3 selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy,
  • R c and R d are each independently H or C1-C4 alkyl
  • X 6 is C or O
  • q 1 or 2;
  • R 7 is selected from F, Cl, cyano, hydroxy, C1-C6 alkyl, fluoro or chloro C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, C1-C6 alkoxy, fluoro or chloro Substituted C1-C6 alkoxy and hydroxy substituted C1-C6 alkyl.
  • L 2 is C1-C4 alkylene
  • R 2 is a 5-10-membered nitrogen-containing heteroaryl group or a 4-10-membered heterocyclic group, preferably pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyrazinyl, pyrrolopyridyl, pyrido Dihydrofuranyl or pyrido1,3-dioxolyl or indolyl, the 5-10-membered nitrogen-containing heteroaryl group or the 4-10-membered heterocyclic group are each optionally selected from 1 or 2 Substituents from C1-C6alkoxy, C1-C6alkyl, C3-C8cycloalkyl-O-, halogenated C1-C6alkoxy, halogen and cyano;
  • R 0 is -NR 3 R 4 substituted C1-C4 alkyl, wherein R 3 and R 4 are each independently selected from H and optionally by 1, 2, 3, 4, 5 or 6 selected from hydroxyl, cyano C1-C6 alkyl substituted with a halogen substituent, or R3 and R4 together with the nitrogen atom to which they are attached form a 4 optionally substituted with 1, 2 or 3 selected from halogen, hydroxy and C1-C4 alkyl -8-membered heterocyclic group, preferably, the 4-8 membered heterocyclic group is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,
  • R c and R d are each independently H or C1-C4 alkyl
  • X 6 is C or O
  • q 1 or 2;
  • R 7 is selected from F, Cl, cyano, hydroxy, C1-C6 alkyl, fluoro or chloro C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, C1-C6 alkoxy, fluoro or chloro Substituted C1-C6 alkoxy and hydroxy substituted C1-C6 alkyl.
  • a compound of formula I or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution thereof, Solvate, Polymorph, Prodrug or Metabolite:
  • Ring A is a substituted or unsubstituted 3-8 membered saturated carbocyclic ring or a substituted or unsubstituted 3-8 membered saturated heterocyclic ring containing 1-2 heteroatoms independently selected from N, O and S;
  • X 3 is selected from CR 5 and N;
  • X 5 is selected from N and CR 5 ;
  • L 1 is selected from bond, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkylene-O-, optionally substituted C1-C6 alkylene-NH-, optionally substituted C1 -C6 alkylene-S- and optionally substituted C2-C4 alkenylene;
  • L 2 is selected from bond, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkylene-O-, optionally substituted C1-C6 alkylene-NH-, optionally substituted C1 -C6 alkylene-S- and optionally substituted C2-C4 alkenylene;
  • R 0 is selected from optionally substituted C1-C6 haloalkyl, -C(O)NR 3 R 4 , -CH 2 OR 3 and -NR 3 R 4 substituted C1-C6 alkyl;
  • R 1 is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino and guanidino;
  • R is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
  • R 3 and R 4 are each independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkyl, optionally substituted 4-10 membered Heterocyclyl and optionally substituted 5-10 membered heteroaryl; alternatively, R and R together with the nitrogen atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl or 5-10 membered heteroaryl ;
  • R 5 is selected from H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl and C1-C6 alkoxy;
  • R 6 is selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl and C1-C6 alkoxy.
  • ring A is C3-C8 cycloalkyl or 3-7 membered heterocyclyl.
  • Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl , piperazinyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl.
  • Ring A is substituted with 1, 2 or 3 C1-C6 groups selected from halogen, hydroxy, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy Substituents of alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy and -NR a R b are substituted; wherein said R a and R b are each independently selected from H and C1-C6 alkyl.
  • Ring A is cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, azetidine or tetrahydrofuranyl,
  • Ring A is optionally surrounded by 1, 2 or 3 selected from F, Cl, Br, CF3 , CH3 , -OH, -OCH3 , -NH2 , - Substituent substitution of NHCH 3, -NH 2 (CH 3 ) 2 .
  • R 0 is a C1-C6 alkyl group substituted by -NR 3 R 4 ; wherein R 3 and R 4 are each independently selected from H, optionally by 1, 2, 3, 4, 5 or 6 C1-C6 alkyl substituted with substituents selected from halogen, cyano, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR a R b and hydroxy, or R 3 and R 4 together with the nitrogen atom to which it is attached forms azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2-piperazinone, morpholinyl, pyridyl, pyrrolyl, pyrazolyl , imidazo
  • R 0 is a C1-C6 alkyl substituted with -NR 3 R 4 , and wherein R 3 and R 4 together with the nitrogen atom to which they are attached form an azetidinyl group , pyrrolidinyl, piperidinyl, piperazinyl, 2-piperazinone, morpholinyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazine base, indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl,
  • R 0 is a C1-C6 alkyl substituted by -NR 3 R 4 , wherein R 3 and R 4 together with the nitrogen atom to which they are attached form an azetidinyl group, Pyrrolidinyl, piperidinyl, piperazinyl, 2-piperazinone, morpholinyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl , indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzis
  • the compounds of formula I described in the present invention or their pharmaceutically acceptable salts, or their enantiomers, diastereomers, tautomers, isotopic substitutions, solvates,
  • X 3 and/or X 5 are CR 5 .
  • R 5 is selected from H and C1-C4 alkyl.
  • X 4 is -(CH 2 ) n -, and n is 1 or 2; and wherein the -(CH 2 ) n - is optionally selected from 1 or 2 by 1 or 2 Substituents of halogen, hydroxy, amino, C1-C6 alkyl and halogenated C1-C6 alkyl are substituted.
  • X3 and X5 are both CR5 ; and X4 is optionally substituted -( CH2 )-.
  • L 1 is selected from C1-C6 alkylene, C1-C6 alkylene-O-, C1-C6 alkylene-NH-, C1-C6 alkylene- S- and C2-C4 alkenylene, the C1-C6 alkylene, C1-C6 alkylene-O-, C1-C6 alkylene-NH-, C1-C6 alkylene-S- and The C2-C4 alkenylene group may be optionally substituted with 1, 2 or 3 substituents selected from halogen, C1-C4 alkyl and hydroxy.
  • L 1 is selected from C1-C6 alkylene and C1-C6 alkylene-NH-, said C1-C6 alkylene and C1-C6 alkylene-NH - optionally substituted with 1, 2 or 3 substituents selected from halogen, C1-C4 alkyl and hydroxy.
  • R 1 is selected from optionally substituted C3-C8 cycloalkyl, optionally substituted 6-14-membered aryl, optionally substituted 5-10-membered heteroaryl and Optionally substituted 4-10 membered heterocyclyl, and each of said cycloalkyl, aryl, heteroaryl and heterocyclyl may be optionally Substituent substitution of -C6 alkyl, halogen, hydroxy, C1-C6 alkoxy, C1-C6 haloalkyl and cyano; wherein, the optionally substituted amino is -NR a R b , wherein R a and R b is each independently H or C1-C6 alkyl.
  • R 1 is selected from optionally substituted phenyl, naphthylpyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazolyl Azinyl, pyridoimidazolyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, pyrrole Alkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, pyridodihydrofuranyl, pyr
  • the L 1 is C1-C4 alkylene or C1-C4 alkylene-NH-
  • R 1 is pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl or The pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl or Optionally substituted with 1 or 2 substituents selected from halogen, C1-C4 alkyl and -NR a R b , wherein R a and R b are each independently H or C1-C4 alkyl.
  • L 2 is selected from a bond and a C1-C6 alkylene group, wherein the C1-C6 alkylene group is optionally surrounded by 1, 2 or 3 selected from halogen, C1 Substituent substitution of -C3 alkyl, C3-C5 cycloalkyl and hydroxy.
  • R 2 is optionally replaced by 1, 2 or 3 selected from -NR a R b , cyano, C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy base, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl-O-, 6-14-membered aryl, 5-10-membered heteroaryl and cyano substituents; wherein, R a and R b are each independently H or C1-C6 alkyl; and wherein, the heteroaryl group is preferably a heteroaryl group containing 1 or 2 ring nitrogen atoms, preferably
  • R 2 is selected from 6-14-membered aryl, 5-10-membered heteroaryl and 4-10-membered heterocyclic group
  • the 6-14-membered aryl, 5- 10-membered heteroaryl and 4-10-membered heterocyclyl can be optionally surrounded by 1, 2 or 3 members selected from -NR a R b , cyano, C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy base, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl-O-, 6-14-membered aryl, 5-10-membered hetero
  • R 2 is selected from phenyl, naphthyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl, Indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, azetidine Alkyl, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, pyridodihydrofuranyl, pyr
  • L 2 is a C1-C4 alkylene group
  • R 2 is a 6-14-membered aryl group, a 5-10-membered nitrogen-containing heteroaryl group or a 4-10-membered heterocyclic group
  • the 6-14-membered aryl group, 5-10-membered nitrogen-containing heteroaryl group or 4-10-membered heterocyclic group is optionally replaced by 1 or 2 members selected from C1-C6 alkoxy, halogen, C1-C6 alkyl , cyano, C3-C8 cycloalkyl-O- and halogenated C1-C6 alkoxy substituents, preferably phenyl, pyridyl, pyrazolyl, pyrrolopyr
  • ring A is a C3-C6 cycloalkyl or a 4-8 membered heterocyclyl, and the cycloalkyl or heterocyclyl is optionally selected from 1, 2 or 3 Substituted from substituents of halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy and halogenated C1-C4 alkoxy;
  • X 3 and X 5 are both CH;
  • X 4 is CH 2 ;
  • L 1 is C1-C4 alkylene
  • L 2 is C1-C4 alkylene
  • R 2 is phenyl, 5-10-membered nitrogen-containing heteroaryl or 4-10-membered heterocyclic group, preferably pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyrazinyl, pyrrolopyridyl , pyridodihydrofuranyl or pyrido1,3-dioxolane or indolyl, each of said phenyl, 5-10-membered nitrogen-containing heteroaryl and 4-10-membered heterocyclyl is optional ground is substituted with 1 or 2 substituents selected from C1-C6 alkoxy, halogen, C1-C6 alkyl, cyano, C3-C8 cycloalkyl-O- and halogenated C1-C6 alkoxy;
  • R 0 is C1-C4 alkyl substituted by -NR 3 R 4 ; wherein, R 3 and R 4 are each independently selected from H, C1 optionally substituted with 1-6 substituents selected from hydroxy, cyano and halogen -C6 alkyl and optionally 1, 2 or 3 selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1- 4-8-membered heterocyclic group substituted by substituents of C6 alkoxy, -NR a R b and hydroxy, wherein R a and R b are each independently H or C1-C4 alkyl; or R 3 and R 4 are their The attached nitrogen atoms are taken together to form optionally 1, 2 or 3 atoms selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-
  • Ring A is a C3-C6 cycloalkyl optionally surrounded by 1, 2 or 3 selected from halogen, C1-C4 alkyl and halogenated C1 Substituent substitution of -C4 alkyl;
  • X 3 and X 5 are both CH;
  • X 4 is CH 2 ;
  • L 1 is C1-C4 alkylene
  • L 2 is C1-C4 alkylene
  • R 2 is a 5-10-membered nitrogen-containing heteroaryl group or a 4-10-membered heterocyclic group, preferably pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyrazinyl, pyrrolopyridyl, pyrido Dihydrofuranyl or pyrido1,3-dioxolyl or indolyl, the 5-10-membered nitrogen-containing heteroaryl group or the 4-10-membered heterocyclic group are each optionally selected from 1 or 2 Substituents from C1-C6alkoxy, C1-C6alkyl, C3-C8cycloalkyl-O-, halogenated C1-C6alkoxy, halogen and cyano;
  • R 0 is -NR 3 R 4 substituted C1-C4 alkyl, wherein R 3 and R 4 are each independently selected from H and optionally by 1, 2, 3, 4, 5 or 6 selected from hydroxyl, cyano A C1-C6 alkyl group substituted with a halogen substituent, or R3 and R4 together with the nitrogen atom to which they are attached form optionally replaced by 1, 2 or 3 groups selected from halogen, hydroxy, C1- C4 alkoxy and C1 -C4 alkyl substituted 4-8-membered heterocyclic group, preferably, the 4-8-membered heterocyclic group is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl ,
  • a pharmaceutical composition which contains the compound described in this application, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or isomer thereof.
  • a compound described in this application or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, or isotopic substitution thereof , solvate, polymorph, prodrug or metabolite in the manufacture of a medicament for the treatment or prevention of WDR5-mediated diseases.
  • WDR5-mediated diseases include Kabuki syndrome, and various solid and hematological tumors.
  • the WDR5-mediated diseases include Noonan syndrome, Leopard syndrome, neuroblastoma, sarcoma, melanoma, articular chondroma, cholangiomas, leukemia, breast cancer, gastrointestinal stromal tumors, histiocytes lymphoma, lung cancer, esophageal cancer, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, colon cancer, nasopharyngeal cancer, brain cancer, bone cancer, kidney cancer, oral cavity cancer cancer, head cancer, neuroblastoma, squamous cell carcinoma of the head and neck, anaplastic large cell lymphoma or glioblastoma, wherein the leukemia is preferably juvenile myelomonocytic leukemia, human myelomonocytic leukemia, Lung cancer is preferably non-small cell lung cancer, small cell lung cancer, lung squamous cell carcinoma, and lung
  • the inventors prepared a novel heterocyclic compound compound represented by formula I, which can inhibit the growth of tumor cells by blocking the WDR5 protein-protein interaction.
  • the compound of the present invention exhibits good biological activity and druggability, and has a good prospect for drug development. It can inhibit the WDR5 protein-protein interaction at a very low concentration (can be as low as ⁇ 100 nM/L).
  • the inhibitory activity is quite excellent, so it can be used to treat diseases or conditions related to WDR5, such as tumors.
  • reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention.
  • the techniques and methods described above can generally be carried out according to conventional methods well known in the art from the descriptions in the various general and more specific documents cited and discussed in this specification.
  • groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituents When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2- .
  • C1-C6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified notation does not include carbons that may be present in the substituents of the group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • Hydroxyalkyl refers to an alkyl group as defined below substituted with hydroxy (-OH).
  • Niro refers to -NO2 .
  • Cyano refers to -CN.
  • Amino refers to -NH2 .
  • Substituted amino refers to an amino group substituted with one or two alkyl, alkylcarbonyl, alkyl-substituted aminocarbonyl, aralkyl, heteroaralkyl as defined below, eg, monoalkylamino, Dialkylamino, alkylamido, aralkylamino, heteroaralkylamino, alkylaminocarbonylamino.
  • Carboxyl refers to -COOH.
  • alkyl as a group or part of another group (eg, as used in a halogen (eg, fluorine, chlorine, bromine, or iodine) substituted alkyl group, etc.), refers to fully saturated A straight or branched hydrocarbon chain radical consisting only of carbon atoms and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and is bonded to the molecule by a single bond the rest of the connection.
  • halogen eg, fluorine, chlorine, bromine, or iodine
  • Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2 - Dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl, etc. More preferred alkyl groups are C1-C4 alkyl groups.
  • alkylene refers to a divalent alkyl group such as -( CH2 ) n- , wherein n is an integer from 1-12, preferably an integer from 1-6, more preferably an integer from 1-4.
  • the divalent alkyl group can also be a straight chain or branched chain group, such as -CH( CH3 ) CH2-, -CH2CH ( CH3 ) CH2-, and the like.
  • alkenyl as a group or part of another group means consisting only of carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 20 (preferably 2 to 10) a straight or branched hydrocarbon chain group having 2 to 6, more preferably 2 to 4) carbon atoms and connected to the rest of the molecule by a single bond.
  • Alkenyl groups include, but are not limited to, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, and the like.
  • alkynyl as a group or part of another group, means consisting only of carbon and hydrogen atoms, containing at least one triple bond, having, for example, 2 to 20 (preferably 2 to 10 a straight or branched hydrocarbon chain group having 2 to 6, more preferably 2 to 4) carbon atoms and connected to the rest of the molecule by a single bond.
  • Alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.
  • alkoxy as a group or part of another group means “alkyl-O-", as defined herein.
  • Preferred alkoxy groups are C1-C6 alkoxy groups, more preferably C1-C4 alkoxy groups, including but not limited to methoxy, ethoxy and the like.
  • cyclohydrocarbyl means a stable non-aromatic monocyclic or polycyclic hydrocarbon group (eg, alkyl, alkenyl, etc.) consisting only of carbon atoms and hydrogen atoms. or alkynyl), which may include fused ring systems, bridged ring systems or spiro ring systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, such as 3 , 4, 5, 6, 7 or 8 carbon atoms, and it is saturated or unsaturated and can be linked to the rest of the molecule by a single bond through any suitable carbon atom.
  • cyclohydrocarbyl means a stable non-aromatic monocyclic or polycyclic hydrocarbon group (eg, alkyl, alkenyl, etc.) consisting only of carbon atoms and hydrogen atoms. or alkynyl), which may include fused ring systems, bridged ring systems or spiro ring systems, having
  • carbon atoms in a cyclic hydrocarbon group may be optionally oxidized.
  • cyclohydrocarbyl refers to a cycloalkyl group having 3-8 ring carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indene base, 2,3-indenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzoyl Cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, Fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl,
  • heterocyclyl as part of a group or other group means from 2 to 14 carbon atoms (eg 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13 or 14 carbon atoms) and a stable 3- to 20-membered non-aromatic cyclic group consisting of 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more ring ring system, which may include a fused ring system, a bridged ring system or a spiro ring system;
  • the nitrogen, carbon, or sulfur atoms of a can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl group can be partially or fully saturated.
  • a heterocyclyl group can be attached to the rest of the molecule via a carbon atom or a heteroatom and through a single bond.
  • heterocyclyl containing fused rings one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclyl group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur group, more preferably a stable 4- to 10-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • the number of ring atoms of a heterocyclyl group is 4-9, 4-8, or 4-7. In some embodiments, the number of ring atoms in the heterocyclyl group is 3-8, preferably 3-7, more preferably 3-6.
  • heterocyclyl groups include, but are not limited to: azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diazepine Hetero-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptane -2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, pyridodihydrofuranyl, pyrido1,3-dioxocyclopentenyl, tetrahydrofuranyl, oxa azinyl, dioxolane, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imid
  • aryl means having 6 to 18 carbon atoms, such as 6 to 14 carbon atoms (preferably having 6 to 10 carbon atoms, such as 6 , 7, 8, 9 or 10 carbon atoms) conjugated hydrocarbon ring system group.
  • an aryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by single bonds.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3(4H)-one-7-yl and the like.
  • arylalkyl refers to an alkyl group as defined above substituted with an aryl group as defined above.
  • heteroaryl as a group or part of another group means a ring having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms, eg 1, 2, 3, 4 , 5, 6, 7, 8, 9 or 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, a 5- to 16-membered, preferably 5-10 membered, conjugated ring system group.
  • a heteroaryl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and can also be fused to a cycloalkyl or heterocyclyl group as defined above, provided that the heterocyclic group
  • the aryl group is attached to the rest of the molecule by a single bond through an atom on the aromatic ring.
  • a nitrogen, carbon or sulfur atom in a heteroaryl group can optionally be oxidized; the nitrogen atom can optionally be quaternized.
  • a heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 1 to 4 selected heteroatoms.
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl , purinyl, quinolinyl, isoquinolinyl, diazanaphthyl, naphthyridinyl,
  • heteroarylalkyl refers to an alkyl group, as defined above, substituted with a heteroaryl group, as defined above.
  • substituents described in the claims and specification sections of the present invention include, but are not limited to, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloepoxy, haloalkenyl, haloalkyne , cyano, cycloalkyl-O-, nitro, amino, optionally substituted amino, alkoxy, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted One or more of cycloalkyl and optionally substituted heterocyclyl.
  • substituents include, but are not limited to, C1-C6 alkyl, haloalkyl, haloepoxy, cycloalkyl, amino, C1-C6 alkyl substituted amino, halogen, cyano, C3- One or more of C8 cycloalkyl-O-, aryl and heteroaryl.
  • the number of substituents may be 1-5, such as 1-3, depending on the structure of the substituted group.
  • phenyl may be substituted with 1-3 substituents selected from C1-C6 alkoxy, C3-C8 cycloalkyl-O-, halogen and amino.
  • WDR5 refers to WD40 domain repeat family protein 5
  • WD40 domain refers to the smallest conserved unit comprising approximately 40 amino acids (typically supported by glycine-histidine and tryptophan-aspartic acid).
  • moiety refers to a specific fragment or functional group in a molecule.
  • a chemical moiety is usually thought of as a chemical entity embedded or attached to a molecule.
  • intermediate compound functional groups may need to be protected by suitable protecting groups.
  • suitable protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc.
  • Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable thiol protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like.
  • Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymeric resin.
  • the compound of formula I of the present invention has the following formula structure:
  • Ring A is a substituted or unsubstituted 3-8 membered saturated or unsaturated carbocyclic ring, a substituted or unsubstituted 3-8 membered saturated or unsaturated heterocyclic ring, and the heterocyclic ring contains 1-2 independently selected from N, O and heteroatoms of S;
  • X 3 is selected from CR 5 and N;
  • X 5 is selected from N and CR 5 ;
  • L 1 is selected from bond, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkylene-O-, optionally substituted C1-C6 alkylene-NH-, optionally substituted C1 -C6 alkylene-S- and optionally substituted C2-C4 alkenylene;
  • L 2 is selected from bond, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkylene-O-, optionally substituted C1-C6 alkylene-NH-, optionally substituted C1 -C6 alkylene-S- and optionally substituted C2-C4 alkenylene;
  • R 0 is selected from H, C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkyl and -NR 3 R 4 substituted C1-C6 alkyl;
  • R 1 is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino and guanidino;
  • R is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
  • R 3 and R 4 are each independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkyl, optionally substituted 4-10 membered Heterocyclyl and optionally substituted 5-10 membered heteroaryl; alternatively, R and R together with the nitrogen atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl or 5-10 membered heteroaryl ;
  • R 5 is selected from H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl and C1-C6 alkoxy;
  • R 6 is selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl and C1-C6 alkoxy.
  • ring A is a C3-C8 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or, ring A is a 3-7 membered heterocyclic group, such as azacyclopropyl, nitrogen Heterocyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl and the like.
  • the groups of Ring A described herein include the C atom shared by Ring A and the ring containing X 4 .
  • Ring A may be optionally substituted with 1, 2 or 3 groups selected from halogen, cyano, hydroxy, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, C1- C6 alkoxy, halogenated C1-C6 alkoxy, hydroxy substituted C1-C6 alkyl, -NR a R b , -NR a R b substituted carbonyl, -NR a R b substituted C1-C6 alkyl , C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, optionally substituted 6-14-membered aryl, optionally substituted 5-10-membered heteroaryl, optionally substituted C3-C8 cycloalkyl, Optionally substituted 4-10 membered heteroaryl, optionally substituted 6-14 membered aryl substituted C1-C6 alkyl, optionally substituted 5-10
  • the substituents may be 1, 2 or 3 selected from halogen , C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR a R b , -NR a R b substituted carbonyl, -NR a R Substituents of b -substituted C1-C6 alkyl, C1-C6 alkylcarbonyl, and C1-C6 alkoxycarbonyl.
  • the R a and R b are each independently selected from H and C1-C6 alkyl.
  • the substituent may be on C or on N.
  • Ring A is a C3-C6 cycloalkyl or 3-6 membered heterocyclyl optionally surrounded by 1, 2 or 3 groups selected from C1-C4 alkyl, halogenated C1-C4 alkyl , hydroxy-substituted C1-C4 alkyl, -NR a R b substituted carbonyl and -NR a R b substituted C1-C4 alkyl substituents, wherein, said R a and R b are each independently selected from H and C1-C4 alkyl.
  • X 3 is CR 5 .
  • R 5 is selected from H and C1-C4 alkyl.
  • X 4 is -(CH 2 ) n -, and n is 1 or 2.
  • the number of substituents may be 1 or 2, and the substituents may be selected from halogen, hydroxyl, amino, C1-C6 alkyl and halogenated C1 -C6 alkyl, preferably halogen and C1-C6 alkyl.
  • L 1 is selected from bond, C1-C6 alkylene, C1-C6 alkylene-O-, C1-C6 alkylene-NH-, C1-C6 alkylene-S- and C2-C4 alkylene Alkenyl, more preferably C1-C6 alkyl or C1-C6 alkylene-NH-.
  • L 1 may be optionally substituted, the substituents may be selected from halogen, C1-C4 alkyl and hydroxyl, and the number of substituents may be 1, 2 or 3. It is understood that when the C1-C6 alkyl and C1-C6 alkylene- are substituted with C1-C4 alkyl, a branched alkyl or branched alkylene may be formed.
  • R 1 is selected from optionally substituted C3-C8 cycloalkyl, optionally substituted 6-14 membered aryl, optionally substituted 5-10 membered heteroaryl and optionally substituted 4-10 membered heteroaryl ring base.
  • preferred 6-14 membered aryl groups include phenyl and naphthyl.
  • the preferred 5-10-membered heteroaryl group is a heteroaryl group with one or more (such as within 4 or within 3) ring nitrogen atoms, especially a 5- or 6-membered nitrogen-containing heteroaryl group, Including, but not limited to, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl (such as triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl and 1,3 , 4-triazolyl), pyrimidinyl, pyrazinyl, triazinyl.
  • Heteroaryl groups can also be fused rings including, but not limited to, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, pyrrolopyridyl, benzene And isoxazolyl, quinolyl and so on.
  • Preferred heteroaryl groups are pyridyl, pyrrolyl, imidazolyl and triazolyl, more preferably imidazolyl and pyridyl.
  • R 1 is a heteroaryl group, it is attached to L 1 through a nitrogen atom on the heteroaryl ring.
  • preferred 5-10 membered heterocyclic groups include but are not limited to pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, pyridodihydrofuranyl, pyridine 1,3-dioxolyl, tetrahydropyranyl, tetrahydrofuranyl, oxazinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolinyl , thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indoline, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidine, phthalimide Amino etc.
  • the cycloalkyl group, aryl group, heteroaryl group and heterocyclic group can each be optionally substituted by 1, 2 or 3 substituents, and the preferred substituents can be selected from optionally substituted amino, Alkyl (such as C1-C6 alkyl), halogen, hydroxyl, alkoxy (such as C1-C6 alkoxy), haloalkyl (such as C1-C6 haloalkyl) and cyano, etc.; wherein, optionally substituted amino Can be -NR a R b , wherein R a and R b are each independently H or C1-C6 alkyl; more preferably, the substituents on the cycloalkyl, aryl, heteroaryl and heterocyclyl Can be independently the optionally substituted amino, halo, alkyl and cyano.
  • R 1 is an optionally substituted amino group or a guanidino group
  • the substituent on the amino group can be an aminocarbonyl group optionally substituted by an alkyl group, that is, NR a R b -CO-, wherein R a and R b are each independently H or C1-C6 alkyl.
  • R1 is substituted amino, halogen, alkyl and/or cyano substituted 5- or 6 -membered nitrogen-containing heteroaryl, especially substituted amino, halogen, alkyl and/or cyano substituted imidazole pyrimidinyl, pyrimidinyl, triazolyl, pyridyl, pyrazinyl, pyrrolyl and pyrazolyl, etc., more preferably substituted amino, halogen, alkyl and/or cyano substituted imidazolyl and pyridyl, wherein , the substituted amino group is preferably -NR a R b , wherein R a and R b are each independently H or C1-C6 alkyl.
  • Ring A is cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, azepanyl or tetrahydrofuranyl, which is optionally substituted by 1 , 2 or 3 substituents selected from F, Cl, Br, CF 3 , CH 3 , -OH, -OCH 3 , -NH 2 , -NHCH 3 , -NH 2 (CH 3 ) 2 are substituted.
  • the L 1 is C1-C4 alkylene or C1-C4 alkylene-NH-
  • R 1 is optionally 1 or 2 selected from halogen, cyano, C1-C4 5- or 6-membered nitrogen-containing heteroaryl substituted by substituents of alkyl and -NR a R b , preferably pyridyl, pyrrolyl, pyrazolyl, imidazolyl, imidazolone, pyridopyrrolyl, oxazolone group, oxazolidinone group, triazolyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, wherein R a and R b are each independently H or C1-C4 alkyl group.
  • the alkylene group may be a straight or branched chain alkylene group.
  • L 2 may be selected from bonds, C3-C5 cycloalkyl and C1-C6 alkylene.
  • L 2 may be optionally substituted with a substituent selected from halogen, C1-C3 alkyl, C3-C5 cycloalkyl and hydroxy, and the number of substituents may be 1, 2 or 3.
  • Preferred L 2 is optionally substituted C1-C4 alkylene.
  • the alkylene group may be a straight or branched chain alkylene group.
  • R 2 is selected from optionally substituted 6-14 membered aryl, optionally substituted 5-10 membered heteroaryl and optionally substituted 4-10 membered heterocyclyl, more preferably optionally substituted mono Cyclic or bicyclic aryl, monocyclic or bicyclic heteroaromatic or monocyclic or bicyclic heterocyclyl.
  • the aryl group is preferably phenyl or naphthyl.
  • the heteroaryl group is preferably a heteroaryl group with one or more (such as within 4 or 3) ring nitrogen atoms, especially a 5-membered or 6-membered nitrogen-containing heteroaryl group, including but not limited to pyridyl, pyrrole base, pyrazolyl, imidazolyl, triazolyl (such as triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl and 1,3,4-triazolyl), Pyrimidyl, pyrazinyl, triazinyl.
  • the heteroaryl group can also be a fused ring, including but not limited to indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl , pyrrolopyridyl, benzisoxazolyl, quinolyl, etc.
  • Preferred heteroaryl groups are pyridyl, pyrazolyl, pyrrolopyridyl, or indolyl.
  • the heterocyclic group is preferably azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, pyridodihydrofuranyl, Pyrido-1,3-dioxocyclopentenyl, tetrahydropyranyl, tetrahydrofuranyl, oxazinyl, tetrahydroisoquinolinyl, chromanyl, decahydroisoquinolinyl, imidazolinyl , imidazolidinyl, 6,7-dihydro-5H-cyclopentane[c]pyridine, quinazolidinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indoline, octahydro Indolyl, octahydroisoindolyl,
  • the substituents on R 2 may be 1, 2 or 3, preferably selected from optionally substituted amino, cyano, C1-C6 alkyl, halogen, hydroxyl, C1-C6 alkoxy, halogenated C1 -C6 alkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl-O-, 6-14-membered aryl (such as phenyl), 5-10-membered heteroaryl (preferably a heteroaryl group containing 1 or 2 ring nitrogen atoms, such as pyrazolyl, imidazolyl, pyridyl, pyrazinyl, piperazinyl, etc.), 4-10 membered heterocyclic group (such as oxetane) group, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl,
  • substituents on R 2 are C1-C6 alkoxy, halogen, C1-C6 alkyl, cyano, C3-C8 cycloalkyl-O- and halogenated C1-C6 alkoxy.
  • the substituents on R 2 include at least C1-C6 alkoxy, halogenated C1-C6 alkoxy or C3-C8 cycloalkyloxy.
  • the number of substituents on R 2 is 2, preferably at least one of the substituents is C1-C6 alkoxy, halogenated C1-C6 alkoxy or C3-C8 cycloalkyloxy.
  • the C1-C6 alkoxy, halo-C1-C6 alkoxy or C3-C8 cycloalkyloxy is located in the meta position of the C to which R 2 is attached to L 2 .
  • R 2 is optionally surrounded by 1 or 2 groups selected from C1-C6 alkoxy, halogen, C1-C6 alkyl, cyano, C3-C8 cycloalkyl-O- and halogenated C1-C6 alkoxy Substituents of radicals substituted phenyl.
  • R 2 is optionally surrounded by 1 or 2 groups selected from C1-C6 alkoxy, halogen, C1-C6 alkyl, cyano, C3-C8 cycloalkyl-O- and halogenated C1-C6 alkoxy 5-10-membered nitrogen-containing heteroaryl substituted by the substituent of the base (such as pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyrazinyl, pyrrolopyridyl, or indolyl, etc.) or 4 -10-membered heterocyclic group, such as pyridodihydrofuranyl and pyrido1,3-dioxolyl, etc.
  • the base such as pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyrazinyl, pyrrolopyridyl, or ind
  • L 2 is a C1-C4 alkylene group
  • R 2 is a group consisting of 1 or 2 groups selected from C1-C6 alkoxy, halogen, C1-C6 alkyl, cyano, C3-C8 cycloalkane 6-14-membered aryl (such as phenyl) or 5-10-membered nitrogen-containing heteroaryl (such as pyridyl, pyrazolyl, pyrrolo) substituted by substituents of base-O- and halogenated C1-C6 alkoxy pyridyl, or indolyl) or 4-10 membered heterocyclyl (eg, pyridodihydrofuranyl and pyrido1,3-dioxolyl).
  • R 0 is H.
  • R 0 is -NR 3 R 4 substituted C1-C6 alkyl, wherein R 3 and R 4 are each independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted 4 -10 membered heterocyclyl and optionally substituted 5-10 membered heteroaryl.
  • the C1-C6 alkyl group may be optionally replaced by 1, 2, 3, 4, 5 or 6 selected from halogen, cyano, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR a Substituent substitution of R b and hydroxy, wherein R a and R b are each independently H or C1-C4 alkyl.
  • the 4-10 membered heterocyclic groups include but are not limited to nitrogen- and/or oxygen-containing heterocyclic groups, such as oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, Piperazinyl, tetrahydropyranyl, morpholinyl, etc.
  • the 5-10-membered heteroaryl groups include, but are not limited to, 5-10-membered nitrogen-containing and/or oxygen-containing heteroaryl groups, such as pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazine base, triazinyl, indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl and quinoline Base et al.
  • 5-10-membered nitrogen-containing and/or oxygen-containing heteroaryl groups such as pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazine base, triazinyl, indolyl, isoindolyl, indazolyl, benzopyr
  • the 4-10-membered heterocyclic group and the 5-10-membered heteroaryl group may each be optionally surrounded by 1, 2 or 3 groups selected from halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, Substituent substitution of C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR a R b and hydroxy, wherein R a and R b are each independently H or C1-C4 alkyl.
  • R3 and R4 are not both said optionally substituted 4-10 membered heterocyclyl or said optionally substituted 5-10 membered heteroaryl or both.
  • R3 and R4 together with the nitrogen atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl or 5-10 membered heteroaryl.
  • the 4-10 membered heterocyclic group includes, but is not limited to, nitrogen- and/or oxygen-containing heterocyclic groups, such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like.
  • the 5-10-membered heteroaryl groups include, but are not limited to, 5-10-membered nitrogen-containing and/or oxygen-containing heteroaryl groups, such as pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazine base, triazinyl, indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl and quinoline Base et al.
  • 5-10-membered nitrogen-containing and/or oxygen-containing heteroaryl groups such as pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazine base, triazinyl, indolyl, isoindolyl, indazolyl, benzopyr
  • the 4-10-membered heterocyclic group and the 5-10-membered heteroaryl group may each be optionally replaced by 1, 2 or 3 groups selected from halogen, cyano, sulfo, C1-C6 alkylsulfonyl, C1-C6 Alkoxysulfonyl, C1-C6 alkylcarbonyl, halogenated C1-C6 alkylcarbonyl, C1-C6 alkoxycarbonyl, halogenated C1-C6 alkoxycarbonyl, C1-C6 alkyl, halogenated C1- Substituent substitution of C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR a R b and hydroxy, wherein R a and R b are each independently H or C1-C4 alkyl.
  • R 0 is -NR 3 R 4 substituted C1-C4 alkyl, wherein R 3 and R 4 are each independently selected from H, optionally substituted C1-C6 alkyl and optionally substituted 4-8-membered heterocyclic group, or R 3 and R 4 together with the nitrogen atom to which they are attached form an optionally substituted 4-8-membered heterocyclic group; further preferably, the C1-C6 alkyl group is optionally replaced by 1 -6 substituents selected from hydroxy, cyano and halogen, each of said 4-8 membered heterocyclyl groups is optionally substituted with 1, 2 or 3 substituents selected from halogen, C1-C6 alkyl, halogenated C1- C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, sulfo, C1-C6 alkylsulfonyl, C1-C6 alkoxysulfonyl,
  • Ring A is a C3-C6 cycloalkyl or 4-8 membered heterocyclyl, which may be optionally selected from 1, 2 or 3 Halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, -NR a R b substituted carbonyl and -NR a R b substituted C1- C4 alkyl substituted; X 3 and X 5 are both CH; X 4 is CH 2 ; L 1 is C1-C4 alkylene; R 1 is optionally 1 or 2 selected from halogen, C1-C4 alkyl and -5- or 6-membered nitrogen-containing heteroaryl substituted by the substituent of NR a R b , preferably pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyra
  • Ring A is a C3-C6 cycloalkyl, which may be optionally surrounded by 1, 2, or 3 groups selected from halogen, C1-C4 alkyl, and halogenated C1- Substituents substituted for C4 alkyl; X 3 and X 5 are both CH; X 4 is CH 2 ; L 1 is C1-C4 alkylene; R 1 is 1 or 2 selected from C1-C4 alkyl and - 5 or 6-membered nitrogen-containing heteroaryl substituted by the substituent of NR a R b , preferably pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl, R a and R b are each independently H or C1-C4 alkyl; L 2 is C1-C4 alkylene; R 2 is 5-10-membered nitrogen-containing heteroaryl
  • the compound of formula I has the structure shown in formula II below:
  • Ring A, R 0 , L 2 and R 2 are each as described in any of the embodiments herein, and R c and R d are each independently H or C1-C6 alkyl.
  • ring A is a C3-C6 cycloalkyl group or a 4-10-membered heterocyclic group, and the C3-C6 cycloalkyl group or a 4-10-membered heterocyclic group can be optionally replaced by 1, 2 or 3 selected from halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, -NR a R b substituted carbonyl and -NR a R b -substituted C1-C4 alkyl substituted, wherein R a and R b are each independently H or C1-C4 alkyl; R 0 is -NR 3 R 4 substituted C
  • ring A is a C3-C6 cycloalkyl group, and the cycloalkyl group may be optionally surrounded by 1, 2 or 3 groups selected from halogen, C1-C4 alkyl and halogenated C1-C4 alkane Substituent substitution of the base;
  • L 2 is a C1-C4 alkylene group;
  • R 2 is a 5-10-membered nitrogen-containing heteroaryl group, such as pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyrazinyl or Indolyl, the 5-10-membered nitrogen-containing heteroaryl can be optionally substituted by 1 or 2 substituents selected from C1-C6 alkoxy, halogen and cyano;
  • R 0 is -NR 3 R 4 substituted C1-C4 alkyl group, wherein, R 3 and R 4 are each independently selected from H and C1-C6 alkyl group
  • ring A is C3-C optionally substituted by a substituent selected from C1-C4 alkyl, -NR a R b substituted carbonyl and -NR a R b substituted C1-C4 alkyl substituents.
  • C6 cycloalkyl or C4-C6 heterocyclic group containing 1 nitrogen or 1 O preferably cyclopropyl, cyclobutyl, oxetanyl or azetidine, the cyclopropyl, cyclobutyl Butyl, oxetanyl or azetidine, the cyclopropyl, cyclobutyl, oxetanyl or azetidine, the cyclopropyl, cyclobutyl, oxetan Butyl or azetidine is optionally substituted by C1-C4 alkyl, -NR a R b substituted carbonyl and -NR a R b substituted C1-C4 alkyl substituent; R 0 is H or - C1-C4 alkyl substituted by NR 3 R 4 , wherein R 3 and R 4 are each independently selected from H, 4-6 membered heterocyclyl and optionally by 1, 2, 3, 4, 5
  • the compound of formula I has the structure shown in formula III below:
  • Ring A, R 0 , L 2 and R 2 are each as described in any of the embodiments herein, and R c and R d are each independently H or C1-C4 alkyl.
  • X 6 is each independently selected from C, O, N, S, and q is an integer of 1, 2 or 3.
  • X 6 is C.
  • q is 1 or 2.
  • R 7 is selected from F, Cl, cyano, hydroxy, C1-C6 alkyl, fluoro or chloro C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy, fluoro substituted or chloro-substituted C1-C6 alkoxy, hydroxy substituted C1-C6 alkyl, -NR a R b , -NR a R b substituted carbonyl, -NR a R b substituted C1-C6 alkyl, C1- C6 alkylcarbonyl, C1-C6 alkoxycarbonyl; wherein, the R a and R b are each independently selected from H and C1-C6 alkyl, and m is an integer of 0, 1, 2 or 3. Preferably, m is 0 or 2.
  • a compound of formula I or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution thereof, Solvate, Polymorph, Prodrug or Metabolite:
  • Ring A is a substituted or unsubstituted 3-8 membered saturated carbocyclic ring or a substituted or unsubstituted 3-8 membered saturated heterocyclic ring containing 1-2 heteroatoms independently selected from N, O and S;
  • X 3 is selected from CR 5 and N;
  • X 5 is selected from N and CR 5 ;
  • L 1 is selected from bond, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkylene-O-, optionally substituted C1-C6 alkylene-NH-, optionally substituted C1 -C6 alkylene-S- and optionally substituted C2-C4 alkenylene;
  • L 2 is selected from bond, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkylene-O-, optionally substituted C1-C6 alkylene-NH-, optionally substituted C1 -C6 alkylene-S- and optionally substituted C2-C4 alkenylene;
  • R 0 is selected from optionally substituted C1-C6 haloalkyl, -C(O)NR 3 R 4 , -CH 2 OR 3 and -NR 3 R 4 substituted C1-C6 alkyl;
  • R 1 is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino and guanidino;
  • R is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
  • R 3 and R 4 are each independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkyl, optionally substituted 4-10-membered Heterocyclyl and optionally substituted 5-10 membered heteroaryl; alternatively, R and R together with the nitrogen atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl or 5-10 membered heteroaryl ;
  • R 5 is selected from H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl and C1-C6 alkoxy;
  • R 6 is selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl and C1-C6 alkoxy.
  • ring A is C3-C8 cycloalkyl or 3-7 membered heterocyclyl.
  • Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl , piperazinyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl.
  • ring A is substituted with 1, 2 or 3 C1-C6 groups selected from halogen, hydroxy, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy Substituents of alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy and -NR a R b are substituted; wherein said R a and R b are each independently selected from H and C1-C6 alkyl.
  • Ring A is cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, azetidine or tetrahydrofuranyl,
  • Ring A is optionally surrounded by 1, 2 or 3 selected from F, Cl, Br, CF3 , CH3 , -OH, -OCH3 , -NH2 , - Substituent substitution of NHCH 3, -NH 2 (CH 3 ) 2 .
  • R 0 is a C1-C6 alkyl group substituted by -NR 3 R 4 ; wherein R 3 and R 4 are each independently selected from H, optionally by 1, 2, 3, 4, 5 or 6 C1-C6 alkyl substituted with a substituent selected from halogen, cyano, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR a R b and hydroxy, or R 3 and R 4 together with the nitrogen atom to which it is attached forms azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 2-piperazinone, morpholinyl, pyridyl, pyrrolyl, pyrazolyl , imid
  • R 0 is a C1-C6 alkyl substituted with -NR 3 R 4 , and wherein R 3 and R 4 together with the nitrogen atom to which they are attached form an azetidinyl group , pyrrolidinyl, piperidinyl, piperazinyl, 2-piperazinone, morpholinyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazine base, indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl,
  • R 0 is a C1-C6 alkyl substituted by -NR 3 R 4 , wherein R 3 and R 4 together with the nitrogen atom to which they are attached form an azetidinyl group, Pyrrolidinyl, piperidinyl, piperazinyl, 2-piperazinone, morpholinyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl , indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzis
  • the compounds of formula I described in the present invention or their pharmaceutically acceptable salts, or their enantiomers, diastereomers, tautomers, isotopic substitutions, solvates,
  • X 3 and/or X 5 are CR 5 .
  • R 5 is selected from H and C1-C4 alkyl.
  • X 4 is -(CH 2 ) n -, and n is 1 or 2; and wherein the -(CH 2 ) n - is optionally selected from 1 or 2 by 1 or 2 Substituents of halogen, hydroxy, amino, C1-C6 alkyl and halogenated C1-C6 alkyl are substituted.
  • X3 and X5 are both CR5 ; and X4 is optionally substituted -( CH2 )-.
  • L 1 is selected from C1-C6 alkylene, C1-C6 alkylene-O-, C1-C6 alkylene-NH-, C1-C6 alkylene- S- and C2-C4 alkenylene, the C1-C6 alkylene, C1-C6 alkylene-O-, C1-C6 alkylene-NH-, C1-C6 alkylene-S- and The C2-C4 alkenylene group may be optionally substituted with 1, 2 or 3 substituents selected from halogen, C1-C4 alkyl and hydroxy.
  • L 1 is selected from C1-C6 alkylene and C1-C6 alkylene-NH-, said C1-C6 alkylene and C1-C6 alkylene-NH - optionally substituted with 1, 2 or 3 substituents selected from halogen, C1-C4 alkyl and hydroxy.
  • R 1 is selected from optionally substituted C3-C8 cycloalkyl, optionally substituted 6-14-membered aryl, optionally substituted 5-10-membered heteroaryl and Optionally substituted 4-10 membered heterocyclyl, and each of said cycloalkyl, aryl, heteroaryl and heterocyclyl may be optionally Substituent substitution of -C6 alkyl, halogen, hydroxy, C1-C6 alkoxy, C1-C6 haloalkyl and cyano; wherein, the optionally substituted amino is -NR a R b , wherein R a and R b is each independently H or C1-C6 alkyl.
  • R 1 is selected from optionally substituted phenyl, naphthylpyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazolyl Azinyl, pyridoimidazolyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, pyrrole Alkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, pyridodihydrofuranyl, pyr
  • the L 1 is C1-C4 alkylene or C1-C4 alkylene-NH-
  • R 1 is pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl or The pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl or Optionally substituted with 1 or 2 substituents selected from halogen, C1-C4 alkyl and -NR a R b , wherein R a and R b are each independently H or C1-C4 alkyl.
  • L 2 is selected from a bond and a C1-C6 alkylene group, wherein the C1-C6 alkylene group is optionally surrounded by 1, 2 or 3 selected from halogen, C1 Substituent substitution of -C3 alkyl, C3-C5 cycloalkyl and hydroxy.
  • R 2 is optionally replaced by 1, 2 or 3 selected from -NR a R b , cyano, C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy base, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl-O-, 6-14-membered aryl, 5-10-membered heteroaryl and cyano substituents; wherein, R a and R b are each independently H or C1-C6 alkyl; and wherein, the heteroaryl group is preferably a heteroaryl group containing 1 or 2 ring nitrogen atoms, preferably
  • R 2 is selected from 6-14-membered aryl, 5-10-membered heteroaryl and 4-10-membered heterocyclic group
  • the 6-14-membered aryl, 5- 10-membered heteroaryl and 4-10-membered heterocyclyl can be optionally surrounded by 1, 2 or 3 members selected from -NR a R b , cyano, C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy base, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl-O-, 6-14-membered aryl, 5-10-membered hetero
  • R 2 is selected from phenyl, naphthyl, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl, Indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, azetidine Alkyl, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, pyridodihydrofuranyl, pyr
  • L 2 is a C1-C4 alkylene group
  • R 2 is a 6-14-membered aryl group, a 5-10-membered nitrogen-containing heteroaryl group or a 4-10-membered heterocyclic group
  • the 6-14-membered aryl group, 5-10-membered nitrogen-containing heteroaryl group or 4-10-membered heterocyclic group is optionally replaced by 1 or 2 members selected from C1-C6 alkoxy, halogen, C1-C6 alkyl , cyano, C3-C8 cycloalkyl-O- and halogenated C1-C6 alkoxy substituents, preferably phenyl, pyridyl, pyrazolyl, pyrrolopyr
  • ring A is a C3-C6 cycloalkyl or a 4-8 membered heterocyclyl, and the cycloalkyl or heterocyclyl is optionally selected from 1, 2 or 3 Substituted from substituents of halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy and halogenated C1-C4 alkoxy;
  • X 3 and X 5 are both CH;
  • X 4 is CH 2 ;
  • L 1 is C1-C4 alkylene
  • L 2 is C1-C4 alkylene
  • R 2 is phenyl, 5-10-membered nitrogen-containing heteroaryl or 4-10-membered heterocyclic group, preferably pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyrazinyl, pyrrolopyridyl , pyridodihydrofuranyl or pyrido1,3-dioxolane or indolyl, each of said phenyl, 5-10-membered nitrogen-containing heteroaryl and 4-10-membered heterocyclic group is optional ground is substituted with 1 or 2 substituents selected from C1-C6 alkoxy, halogen, C1-C6 alkyl, cyano, C3-C8 cycloalkyl-O- and halogenated C1-C6 alkoxy;
  • R 0 is C1-C4 alkyl substituted by -NR 3 R 4 ; wherein, R 3 and R 4 are each independently selected from H, C1 optionally substituted with 1-6 substituents selected from hydroxy, cyano and halogen -C6 alkyl and optionally 1, 2 or 3 selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1- 4-8-membered heterocyclic group substituted by substituents of C6 alkoxy, -NR a R b and hydroxy, wherein R a and R b are each independently H or C1-C4 alkyl; or R 3 and R 4 are their The attached nitrogen atoms are taken together to form optionally 1, 2 or 3 atoms selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-
  • Ring A is a C3-C6 cycloalkyl optionally surrounded by 1, 2 or 3 selected from halogen, C1-C4 alkyl and halogenated C1 Substituent substitution of -C4 alkyl;
  • X 3 and X 5 are both CH;
  • X 4 is CH 2 ;
  • L 1 is C1-C4 alkylene
  • L 2 is C1-C4 alkylene
  • R 2 is a 5-10-membered nitrogen-containing heteroaryl group or a 4-10-membered heterocyclic group, preferably pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyrazinyl, pyrrolopyridyl, pyrido Dihydrofuranyl or pyrido1,3-dioxolyl or indolyl, the 5-10-membered nitrogen-containing heteroaryl group or the 4-10-membered heterocyclic group are each optionally selected from 1 or 2 Substituents from C1-C6alkoxy, C1-C6alkyl, C3-C8cycloalkyl-O-, halogenated C1-C6alkoxy, halogen and cyano;
  • R 0 is -NR 3 R 4 substituted C1-C4 alkyl, wherein R 3 and R 4 are each independently selected from H and optionally by 1, 2, 3, 4, 5 or 6 selected from hydroxyl, cyano A C1-C6 alkyl group substituted with a halogen substituent, or R3 and R4 together with the nitrogen atom to which they are attached form optionally replaced by 1, 2 or 3 groups selected from halogen, hydroxy, C1- C4 alkoxy and C1 -C4 alkyl substituted 4-8-membered heterocyclic group, preferably, the 4-8-membered heterocyclic group is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl ,
  • Exemplary compounds of formula I of the present invention include, but are not limited to, the following compounds and their pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, isotopic substitutions, solvates, poly Crystal form, prodrug or metabolite:
  • Embodiment 1 A compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvate, polymorph thereof Substances, prodrugs or metabolites:
  • Ring A is a substituted or unsubstituted 3-8 membered saturated or unsaturated carbocyclic ring or a substituted or unsubstituted 3-8 membered saturated or unsaturated heterocyclic ring, the heterocyclic ring contains 1-2 independently selected from N, O and heteroatoms of S;
  • X 3 is selected from CR 5 and N;
  • X 5 is selected from N and CR 5 ;
  • L 1 is selected from bond, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkylene-O-, optionally substituted C1-C6 alkylene-NH-, optionally substituted C1 -C6 alkylene-S- and optionally substituted C2-C4 alkenylene;
  • L 2 is selected from bond, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkylene-O-, optionally substituted C1-C6 alkylene-NH-, optionally substituted C1 -C6 alkylene-S- and optionally substituted C2-C4 alkenylene;
  • R 0 is selected from H, C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkyl and -NR 3 R 4 substituted C1-C6 alkyl;
  • R 1 is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted amino and guanidino;
  • R is selected from optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
  • R 3 and R 4 are each independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkyl, optionally substituted 4-10 membered Heterocyclyl and optionally substituted 5-10 membered heteroaryl; alternatively, R and R together with the nitrogen atom to which they are attached form an optionally substituted 4-10 membered heterocyclyl or 5-10 membered heteroaryl ;
  • R 5 is selected from H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl and C1-C6 alkoxy;
  • R 6 is selected from H, C1-C6 alkyl, halogenated C1-C6 alkyl and C1-C6 alkoxy.
  • Embodiment 2 The compound of formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvent thereof compound, polymorph, prodrug or metabolite, characterized in that Ring A is C3-C8 cycloalkyl or 3-7 membered heterocyclic group, preferably selected from cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, aziridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and morpholine base;
  • Ring A is optionally substituted with 1, 2 or 3 groups selected from halogen, hydroxy, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, C1-C6 alkyl Alkoxy, halogenated C1-C6 alkoxy, -NR a R b , -NR a R b substituted carbonyl, -NR a R b substituted C1-C6 alkyl, C1-C6 alkyl carbonyl, C1 -C6 alkoxycarbonyl, optionally substituted 6-14 membered aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C8 ring Alkyl, optionally substituted 6-14 membered aryl substituted C1-C6 alkyl, optionally substituted 5-10 membered heteroaryl substituted C1-C6 substituted C
  • Embodiment 3 The compound of formula I according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution thereof , solvate, polymorph, prodrug or metabolite, wherein ring A is cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, azetidine or tetrahydrofuranyl,
  • Ring A is optionally surrounded by 1, 2 or 3 rings selected from F, Cl, Br, CF3 , CH3 , -OH, -OCH3 , -NH2 , -NHCH3 , -NH2 ( CH3 ) 2 is substituted with the substituent.
  • Embodiment 4 The compound of formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvent thereof compound, polymorph, prodrug or metabolite, characterized in that,
  • X 3 is CR 5 , and R 5 is selected from H and C1-C4 alkyl; and/or
  • X 4 is -(CH 2 ) n -, and n is 1 or 2; wherein, the -(CH 2 ) n - is optionally selected from halogen, hydroxyl, amino, C1-C6 alkyl and halogen by 1 or 2 Substituents substituted for C1-C6 alkyl groups.
  • Embodiment 5 The compound of formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvent thereof compound, polymorph, prodrug or metabolite, wherein L is selected from C1 -C6 sub-substituents optionally substituted with 1, 2 or 3 substituents selected from halogen, C1-C4 alkyl and hydroxy Alkyl, C1-C6 alkylene-O-, C1-C6 alkylene-NH-, C1-C6 alkylene-S- and C2-C4 alkenylene, preferably selected from optionally 1, 2 or C1-C6 alkylene or C1-C6 alkylene-NH- substituted with 3 substituents selected from halogen, C1-C4 alkyl and hydroxy.
  • L is selected from C1 -C6 sub-substituents optionally substituted with 1, 2 or 3 substituents selected from hal
  • Embodiment 6 The compound of formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvent thereof compound, polymorph, prodrug or metabolite, characterized in that R 1 is selected from optionally substituted C3-C8 cycloalkyl, optionally substituted 6-14-membered aryl, optionally substituted 5-10 membered heteroaryl and optionally substituted 4-10 membered heterocyclyl;
  • the 6-14-membered aryl group is phenyl or naphthyl
  • the 5-10-membered heteroaryl group is selected from pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyridyl Azinyl, triazinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl and quinolinyl, preferably pyridine base, pyrrolyl, imidazolyl and triazolyl;
  • the 4-10 membered heterocyclic group is selected from pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, pyranyl, pyrido Dihydrofuranyl, pyrido1,3-dioxocyclopenten
  • each of the alkoxy, aryl, heteroaryl and heterocyclyl groups may be optionally replaced by 1, 2 or 3 groups selected from optionally substituted amino, C1-C6 alkyl, halogen, hydroxy, C1 Substituent substitution of -C6 alkoxy, C1-C6 haloalkyl and cyano; wherein, the optionally substituted amino is -NR a R b , wherein R a and R b are each independently H or C1-C6 alkyl.
  • Embodiment 7 The compound of formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvent thereof compound, polymorph, prodrug or metabolite, characterized in that L 1 is C1-C4 alkylene or C1-C4 alkylene-NH-, R 1 is optionally selected from 1 or 2 5- or 6-membered nitrogen-containing heteroaryl substituted from halogen, C1-C4 alkyl and substituents of -NR a R b , the 5- or 6-membered nitrogen-containing heteroaryl is preferably pyridyl, pyrrolyl, pyrazole group, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl or triazinyl, wherein R a and R b are each independently H or C1-C4 alkyl.
  • Embodiment 8 The compound of formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvent thereof compound, polymorph, prodrug or metabolite, wherein L is selected from a bond and a C1 - C6 alkylene group, wherein the C1-C6 alkylene group is optionally surrounded by 1, 2 or 3 Substituents selected from halogen, C1-C3 alkyl, C3-C5 cycloalkyl and hydroxy are substituted.
  • Embodiment 9 The compound of formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvent thereof compound, polymorph, prodrug or metabolite, characterized in that R 2 is selected from optionally substituted 6-14-membered aryl, optionally substituted 5-10-membered heteroaryl, and optionally substituted 4- 10-membered heterocyclic group;
  • the 6-14-membered aryl group is phenyl or naphthyl;
  • the 5-10-membered heteroaryl group is selected from pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, pyridyl Azinyl, triazinyl, indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl and quinoline Linyl, preferably pyridyl, pyrrolopyridyl, pyrazolyl or indolyl;
  • the 4-10-membered heterocyclic group is selected from azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, Homopiperazinyl, piperidinyl, pyranyl,
  • R 2 is optionally replaced by 1, 2 or 3 optionally substituted amino, cyano, C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy, halogenated C1-C6 alkyl , halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyl-O-, 6-14-membered aryl, 5-10-membered heteroaryl and cyano substituents; wherein , the optionally substituted amino group is -NR a R b , wherein R a and R b are each independently H or C1-C6 alkyl; wherein, the heteroaryl group preferably contains 1 or 2 ring nitrogen atoms
  • the heteroaryl group is preferably selected from pyrazolyl, imidazolyl, pyridyl, pyrazinyl and piperazinyl.
  • Embodiment 10 The compound of formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvent thereof
  • L 2 is a C1-C4 alkylene group
  • R 2 is 1 or 2 selected from C1-C6 alkoxy, halogen, C1-C6 alkane 6-14-membered aryl, 5-10-membered nitrogen-containing heteroaryl or 4-10-membered heteroaryl
  • the cyclic group is preferably phenyl, pyridyl, pyrazolyl, pyrrolopyridyl, pyridodihydrofuranyl, pyrido1,3-dioxolyl or indolyl.
  • Embodiment 11 The compound of formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvent thereof compound, polymorph, prodrug or metabolite, characterized in that R 0 is H or -NR 3 R 4 substituted C1-C6 alkyl; wherein, R 3 and R 4 are each independently selected from H, optionally C1-substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, cyano, C1-C6alkoxy, halogenated C1-C6alkoxy, -NR a R b and hydroxy C6 alkyl, or R3 and R4 together with the nitrogen atom to which they are attached form optionally substituted 4-10 membered heterocyclyl and optionally substituted 5-10 membered heteroaryl, wherein each of R a and R b independently H or C1-C4 alkyl;
  • the 4-10 membered heterocyclic group is preferably a nitrogen and/or oxygen-containing heterocyclic group, preferably selected from oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidine pyridyl, piperazinyl, tetrahydropyranyl and morpholinyl;
  • the 5-10-membered heteroaryl group is a 5-10-membered nitrogen-containing and/or oxa-heteroaryl group, preferably selected from pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, Pyrazinyl, triazinyl, indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl and quinolinyl;
  • the 4-10-membered heterocyclic group and the 5-10-membered heteroaryl group are each optionally replaced by 1, 2 or 3 groups selected from halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkane substituted by substituents of radicals, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR a R b and hydroxy, wherein R a and R b are each independently H or C1-C4 alkyl.
  • Embodiment 12 The compound of formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvent thereof compound, polymorph, prodrug or metabolite, characterized in that R 0 is a C1-C6 alkyl substituted with -NR 3 R 4 , wherein R 3 and R 4 together with the nitrogen atom to which they are attached form an optional Substituted 4-10 membered heterocyclyl or 5-10 membered heteroaryl;
  • the 4-10 membered heterocyclic group is a nitrogen- and/or oxygen-containing heterocyclic group, preferably selected from oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidine group, piperazinyl, tetrahydropyranyl and morpholinyl;
  • the 5-10-membered heteroaryl group is a 5-10-membered nitrogen-containing and/or oxa-heteroaryl group, preferably selected from pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, Pyrazinyl, triazinyl, indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl and quinolinyl;
  • the 4-10-membered heterocyclic group and the 5-10-membered heteroaryl group are each optionally replaced by 1, 2 or 3 groups selected from halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkane substituted by substituents of radicals, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR a R b and hydroxy, wherein R a and R b are each independently H or C1-C4 alkyl.
  • Embodiment 13 The compound of formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvent thereof compound, polymorph, prodrug or metabolite, characterized in that R 0 is a C1-C6 alkyl substituted with -NR 3 R 4 , wherein R 3 and R 4 together with the nitrogen atom to which they are attached form an optional Substituted 4-10 membered heterocyclyl or 5-10 membered heteroaryl;
  • the 4-10 membered heterocyclic group is a nitrogen- and/or oxygen-containing heterocyclic group, preferably selected from oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidine group, piperazinyl, tetrahydropyranyl and morpholinyl;
  • the 5-10-membered heteroaryl group is a 5-10-membered nitrogen-containing and/or oxa-heteroaryl group, preferably selected from pyridyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrimidinyl, Pyrazinyl, triazinyl, indolyl, isoindolyl, indazolyl, benzopyrrolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl and quinolinyl;
  • the 4-10-membered heterocyclic group and the 5-10-membered heteroaryl group are each optionally replaced by 1, 2 or 3 groups selected from halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkane base, C1-C6 alkoxy, halogenated C1-C6 alkoxy, sulfo, C1-C6 alkylsulfonyl, C1-C6 alkoxysulfonyl, C1-C6 alkylcarbonyl, halogenated C1-C6 Substituent substitution of alkylcarbonyl, C1-C6 alkoxycarbonyl, halogenated C1-C6 alkoxycarbonyl, -NR a R b and hydroxy, wherein R a and R b are each independently H or C1-C4 alkane base.
  • Embodiment 14 The compound of formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvent thereof compound, polymorph, prodrug or metabolite, characterized in that,
  • Ring A is a C3-C6 cycloalkyl group or a 4-8 membered heterocyclyl group, the cycloalkyl or heterocyclyl group is optionally surrounded by 1, 2 or 3 groups selected from halogen, C1-C4 alkyl, halogenated C1 -C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, -NR a R b substituted carbonyl and -NR a R b substituted C1-C4 alkyl substituted; wherein R a and R b is each independently H or C1-C4 alkyl;
  • X 3 and X 5 are both CH;
  • X 4 is CH 2 ;
  • L 1 is C1-C4 alkylene
  • R 1 is a 5- or 6-membered nitrogen-containing heteroaryl optionally substituted by 1 or 2 substituents selected from halogen, C1-C4 alkyl and -NR a R b , preferably pyridyl, pyrrolyl, pyrazole base, imidazolyl, triazolyl, pyrimidinyl, pyrazinyl, triazinyl; wherein, R a and R b are each independently H or C1-C4 alkyl;
  • L 2 is C1-C4 alkylene
  • R 2 is phenyl, 5-10-membered nitrogen-containing heteroaryl or 4-10-membered heterocyclic group, preferably pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyrazinyl, pyrrolopyridyl , pyridodihydrofuranyl or pyrido1,3-dioxolane or indolyl, each of said phenyl, 5-10-membered nitrogen-containing heteroaryl and 4-10-membered heterocyclyl is optional ground is substituted with 1 or 2 substituents selected from C1-C6 alkoxy, halogen, C1-C6 alkyl, cyano, C3-C8 cycloalkyl-O- and halogenated C1-C6 alkoxy;
  • R 0 is C1-C4 alkyl substituted by -NR 3 R 4 ; wherein, R 3 and R 4 are each independently selected from H, C1 optionally substituted with 1-6 substituents selected from hydroxy, cyano and halogen -C6 alkyl and optionally 1, 2 or 3 selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR a 4-8-membered heterocyclic group substituted by substituents of R b and hydroxy, wherein R a and R b are each independently H or C1-C4 alkyl; or R 3 and R 4 together with the nitrogen atom to which they are attached form optionally by 1, 2 or 3 selected from halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy,
  • Embodiment 15 The compound of formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvent thereof compound, polymorph, prodrug or metabolite, characterized in that,
  • Ring A is a C3-C6 cycloalkyl optionally substituted with 1, 2 or 3 substituents selected from halogen, C1-C4 alkyl and halo-C1-C4 alkyl;
  • X 3 and X 5 are both CH;
  • X 4 is CH 2 ;
  • L 1 is C1-C4 alkylene
  • R 1 is a 5- or 6-membered nitrogen-containing heteroaryl substituted by 1 or 2 substituents selected from C1-C4 alkyl and -NR a R b , preferably pyridyl, pyrrolyl, pyrazolyl, imidazolyl , triazolyl, pyrimidinyl, pyrazinyl, triazinyl; wherein, R a and R b are each independently H or C1-C4 alkyl;
  • L 2 is C1-C4 alkylene
  • R 2 is a 5-10-membered nitrogen-containing heteroaryl group or a 4-10-membered heterocyclic group, preferably pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyrazinyl, pyrrolopyridyl, pyrido Dihydrofuranyl or pyrido1,3-dioxolyl or indolyl, the 5-10-membered nitrogen-containing heteroaryl group or the 4-10-membered heterocyclic group are each optionally selected from 1 or 2 Substituents from C1-C6alkoxy, C1-C6alkyl, C3-C8cycloalkyl-O-, halogenated C1-C6alkoxy, halogen and cyano;
  • R 0 is -NR 3 R 4 substituted C1-C4 alkyl, wherein R 3 and R 4 are each independently selected from H and optionally by 1, 2, 3, 4, 5 or 6 selected from hydroxyl, cyano C1-C6 alkyl substituted with a halogen substituent, or R3 and R4 together with the nitrogen atom to which they are attached form a 4 optionally substituted with 1, 2 or 3 selected from halogen, hydroxy and C1-C4 alkyl -8-membered heterocyclic group, preferably, the 4-8 membered heterocyclic group is selected from oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, Tetrahydropyranyl and morpholinyl.
  • Embodiment 16 The compound of formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvent thereof compound, polymorph, prodrug or metabolite, characterized in that the compound of formula I has the structure shown in the following formula II:
  • Ring A is as described in Embodiment 1, 2, 3, 14 or 15;
  • R 0 is as described in Embodiment 11, 12, 13, 14 or 15;
  • L 2 is as described in Embodiment 8,
  • 10, 14 or 15 R is as described in Embodiment 9 , 10, 14 or 15;
  • Rc and Rd are each independently H or C1-C4 alkyl.
  • Embodiment 17 The compound of formula I according to Embodiment 16, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvent thereof compound, polymorph, prodrug or metabolite, characterized in that in formula II:
  • Ring A is a C3-C6 ring optionally substituted with a substituent selected from F, Cl, hydroxy, C1-C4 alkyl, -NR a R b substituted carbonyl, and -NR a R b substituted C1-C4 alkyl group Alkyl or C4-C6 heterocyclyl containing 1 nitrogen or 1 O, preferably C1-C4 alkyl optionally substituted by C1-C4 alkyl, -NR a R b substituted carbonyl and -NR a R b substituted C1-C4 alkane cyclopropyl, cyclobutyl, oxetanyl or azetidine substituted by the substituent of the group; wherein, R a and R b are each independently H or C1-C4 alkyl;
  • R 0 is a C1-C4 alkyl substituted by H or -NR 3 R 4 , wherein R 3 and R 4 are each independently selected from H, 4-6 membered heterocyclyl and optionally 1, 2, 3, 4, C1-C6 alkyl substituted with 5 or 6 substituents selected from hydroxy, cyano and halogen, or R3 and R4 taken together with the nitrogen atom to which they are attached form optionally substituted by 1, 2 or 3 substituents selected from halogen, 4-6-membered heterocyclic group substituted by hydroxyl and C1-C4 alkyl; wherein, the 4-6-membered heterocyclic group is preferably an oxygen- and/or nitrogen-containing heterocyclic group, preferably selected from oxetanyl , azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl and morpholinyl;
  • L 2 is C1-C4 alkylene
  • R 2 is a 6-14-membered aryl group, a 5-10-membered nitrogen-containing heteroaryl group or a 4-10-membered heterocyclic group, preferably phenyl, pyridyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, pyridine oxazinyl, indolyl, pyrrolopyridyl, pyridodihydrofuranyl or pyrido1,3-dioxolyl, the 6-14-membered aryl, 5-10-membered nitrogen-containing heteroaryl or 4-10-membered heterocyclic groups are each optionally replaced by 1 or 2 groups selected from C1-C6 alkoxy, C1-C4 alkyl, halogen, C3-C6 cycloalkyl-oxy, halogenated C1-C4 alkoxy Substituent substitution of cyano group and cyano group;
  • Rc and Rd are each independently H or C1-C4 alkyl.
  • Embodiment 18 The compound of formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvent thereof compound, polymorph, prodrug or metabolite, characterized in that the compound of formula I has the structure shown in the following formula III:
  • X 6 is each independently selected from C, O, N, S,
  • q is an integer of 1, 2 or 3
  • R 7 is selected from F, Cl, cyano, hydroxy, C1-C6 alkyl, fluoro or chloro C1-C6 alkyl, hydroxy substituted C1-C6 alkyl, C1-C6 alkoxy, fluoro or chloro Substituted C1-C6 alkoxy, hydroxy substituted C1-C6 alkyl, -NR a R b , -NR a R b substituted carbonyl, -NR a R b substituted C1-C6 alkyl, C1-C6 alkyl Carbonyl, C1-C6 alkoxycarbonyl; wherein, the R a and R b are each independently selected from H and C1-C6 alkyl,
  • n is an integer of 0, 1, 2 or 3.
  • Embodiment 19 The compound of formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution, solvent thereof compound, polymorph, prodrug or metabolite, characterized in that the compound is selected from:
  • Embodiment 20 A pharmaceutical composition comprising the compound of any one of Embodiments 1-16, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, Tautomers, isotopic substitutions, solvates, polymorphs, prodrugs or metabolites, and pharmaceutically acceptable carriers or excipients.
  • Embodiment 21 The compound of any one of Embodiments 1-19, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, isotopic substitution thereof Use of a compound, solvate, polymorph, prodrug or metabolite in the manufacture of a medicament for the treatment or prevention of WDR5-mediated diseases.
  • Embodiment 22 The use according to Embodiment 21, wherein the WDR5-mediated diseases include Kabuki syndrome, and various solid tumors and hematological tumors; preferably, the solid tumors and hematological tumors are selected from the group consisting of: Southern syndrome, Leopard syndrome, neuroblastoma, sarcoma, melanoma, articular chondroma, cholangiomas, leukemia, breast cancer, gastrointestinal stromal tumor, histiocytic lymphoma, lung cancer, esophageal cancer, pancreatic cancer, Breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, bowel cancer, nasopharyngeal cancer, brain cancer, bone cancer, kidney cancer, oral cancer, head cancer, neuroblastoma, head and neck cancer Squamous cell carcinoma, anaplastic large cell lymphoma or glioblastoma, wherein the leukemia is preferably juvenile myelomono
  • the present invention includes pharmaceutically acceptable salts of compounds of formula I.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salts” refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other adverse effects.
  • Inorganic acid salts include but are not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include but are not limited to formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, hexamethylene Acid, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-tol
  • “Pharmaceutically acceptable base addition salts” refers to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other adverse effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, the following salts: primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperazine pyridine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicycl
  • the present invention also includes isomers of the compounds of formula I, including stereoisomers, enantiomers or tautomers.
  • stereoisomers refer to compounds composed of the same atoms, bonded by the same bonds, but having different three-dimensional structures.
  • the present invention encompasses various stereoisomers and mixtures thereof.
  • “Tautomer” refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention are also intended to be included within the scope of the present invention.
  • the compounds of the present invention may contain one or more chiral carbon atoms, and thus may give rise to enantiomeric, diastereomeric, and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • the compounds of the present invention can be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as crystallization and chiral chromatography.
  • the compounds of the present invention are intended to include both E- and Z-geometric isomers.
  • the present invention also includes all suitable isotopic variations of the compounds of the present invention, pharmaceutically acceptable salts or isomers thereof.
  • Isotopic variants of the compounds of the present invention, pharmaceutically acceptable salts or isomers thereof are defined as those in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from that often found in nature .
  • Isotopes that can be incorporated into the compounds of the present invention, pharmaceutically acceptable salts or isomers thereof include, but are not limited to, isotopes of H, C, N and O, such as 2 H, 3 H, 11 C, 13 C, 14C , 15N , 17O , 18O , 35S , 18F , 36Cl and 125I .
  • Isotopic variations of the compounds of the present invention, pharmaceutically acceptable salts or isomers thereof can be prepared by conventional techniques using appropriate isotopic variations with appropriate reagents.
  • the compounds of Formula Ha of the present invention can be prepared by the methods shown in the following schemes:
  • intermediate IIa-1 is reduced to obtain intermediate IIa-2; IIa-2 is obtained by amine transesterification to obtain IIa-3; IIa-3 is obtained by acid-catalyzed cyclization to obtain IIa-4;
  • the ester compound IIa-5 is formed; the aromatic ring of IIa-5 is halogenated to obtain IIa-6; the ester group of IIa-6 is reduced to form IIa-7; the hydroxyl group of IIa-7 is further halogenated to form IIa-8;
  • IIa-8 IIa-9 is obtained after alkylation with imidazolamine; IIa-9 is obtained by catalytic coupling with boronic acid derivatives to obtain IIa-10; IIa-10 is alkylated with R 2 -L 2 -Br to form IIa-11; IIa -11 Deprotection gives compounds of formula IIa.
  • the reaction conditions for each step are shown in the reaction scheme.
  • the catalytic cyclization reaction of IIa-3 to IIa-4 is used to construct the aromatic spiro intermediate of formula IIa-4.
  • the reaction is carried out under the catalysis of an acid (preferably trifluoromethanesulfonic acid) in a halogenated alkane (preferably dichloromethane) at low temperature or room temperature.
  • an acid preferably trifluoromethanesulfonic acid
  • a halogenated alkane preferably dichloromethane
  • IIa-8 can react with imidazole compounds to introduce the imidazole group on the right to obtain IIa-9.
  • alkali and phase transfer catalyst preferably cesium carbonate, tetrabutylammonium iodide
  • Catalytic coupling reaction between IIa-9 and boronic acid compound to introduce R 0 substituent can be carried out in the presence of water and organic solvent (such as alcohol or ether solvent, preferably dioxane).
  • organic solvent such as alcohol or ether solvent, preferably dioxane
  • IIa-10 is obtained in the presence of a base (eg, sodium carbonate) and a catalyst such as a palladium-based catalyst (eg, Pd(dppf)Cl2 ) under heating conditions.
  • Reaction of IIa-10 with a halide under the condition of a base introduces the R2 - L2- group.
  • the solvent for the alkylation reaction may be an organic solvent, preferably tetrahydrofuran, DMF or NMP.
  • the above scheme also includes the step of removing the Boc protecting group.
  • the deprotection reaction can be carried out in a conventional manner.
  • the general method of the compound of the formula IIa can be adopted, and different raw materials can be changed to obtain different compounds.
  • the preparation method usually includes the above-mentioned steps of catalytic ring closure, catalytic coupling, reductive halogenation and alkylation substitution reactions.
  • WDR5 belongs to the WD40 domain repeat protein family (WD40-repeat protein).
  • WD40 is an important structural domain consisting of about 40 amino acid residues.
  • the WDR domain contains a ring-shaped seven-leaf ⁇ -propeller domain. Each contains the conserved serine-histidine (SH) and tryptophan-aspartic acid (WD) sequences.
  • the WDR5 protein contains a central cavity formed by a 7-lobed ⁇ -helix that runs up and down.
  • the WDR5 protein mainly plays a regulatory role through a deep arginine binding pocket, that is, the WIN site forms a core catalytic complex with MLL1, and forms the core catalytic complex of MWRAD (MLL1, WDR5, RbBP5, ASH2L and DYP-30) with other proteins. , catalyzes histone H3 methylation, activates gene transcription and participates in epigenetic regulation.
  • the MLL family protein complex which is widespread in eukaryotes, is an important class of histone methyltransferases that catalyze the methylation of histone H3K4, either by catalyzing the methylation of H3K4 and/or by recruiting other transcription-related proteins to interact with Mediators, which activate transcription, play a crucial role during development. Mutations in these proteins, including genomic translocations where they fuse with other transcription factors, can cause a variety of diseases, such as mixed lineage leukemia (MLL), lymphoma, and Kabuki syndrome.
  • MLL mixed lineage leukemia
  • Using WDR5 as a drug target compounds designed for the WIN pocket where WDR5 binds to histones and MLL1 can reduce the expression of genes downstream of WDR5 and treat MLL rearrangement-dependent leukemia.
  • the TP53 gene is the most frequently mutated gene in tumors, and TP53 mutations occur in 50% of human cancers.
  • the high frequency of missense mutations and the high expression level of mutant p53 (mp53) protein in cancer cells promote mp53 protein to have new functions (“gain of function” (GOF)), and also actively promote cancer development and progression.
  • GAF gain of function
  • the growth of tumor cells driven by mutations in the p53 gene depends on the binding of WDR5 to MLL. MLL, MOZ and histone modifications are all regulated by the expression of GOF p53.
  • Inhibitors at the WDR5WIN locus can effectively block the growth of breast cancer cell lines and leukemia cells driven by mutations in the p53 gene.
  • MYC is a class of oncoproteins with transcription factor functions, which are overexpressed in most malignant tumors. MYC can bind to the regulatory sequences of thousands of target genes, regulate target gene expression, and affect processes such as cell growth, proliferation, metabolism, genome stability, and apoptosis. Earlier studies have found that the extensive binding of MYC to chromatin also depends on the interaction of WDR5, and that MYC binds to the hydrophobic cleft on the surface of WDR5 through its evolutionarily conserved "MYC box IIIb" sequence, which plays an important role in tumorigenesis in vivo. Blocking the interaction of MYC with WDR5 inhibits the ability of MYC to drive carcinogenesis. Inhibitors targeting the WDR5WIN site can be used as targeted therapies for MYC-driven tumors.
  • WDR5 is highly expressed in a variety of solid tumors, and there is a certain correlation with poor tumor prognosis. On the one hand, it is due to the regulatory effect of WDR5 on EMT.
  • Epithelial-mesenchymal transition refers to the biological process by which epithelial cells are transformed into cells with a mesenchymal phenotype through a specific program. EMT is an important biological process for epithelial cell-derived malignant tumor cells to acquire the ability to migrate and invade. WDR5 can directly regulate the TGF ⁇ 1 signaling pathway, thereby participating in tumor cell ETM and migration.
  • WDR5 inhibitor does not have obvious killing effect, but can enhance the sensitivity of cells to PTX by reducing the level of TGF ⁇ 1 and inhibit the ability of tumor metastasis. This also suggests the potential of WDR5 inhibitors in combination therapy. WDR5 can also mediate the expression of multiple EMT signature molecules such as N-cadherin, ZNF407, HOXA9, SNAIL1 and VIMENTIN.
  • EMT signature molecules such as N-cadherin, ZNF407, HOXA9, SNAIL1 and VIMENTIN.
  • the researchers also found that while WDR5 regulates the expression of tumor-related signaling molecules, it is also regulated by multiple upstream signaling pathways or molecules.
  • PI3K/AKT-mediated upregulation of WDR5 promotes colorectal cancer metastasis, while in gastric cancer, inducible expression of cyclin D1 upregulates WDR5 and promotes tumorigenesis.
  • WDR5 protein-protein interaction inhibitors can be used to treat a variety of diseases, including Kabuki syndrome, and various solid and hematological tumors, including but not limited to Noonan syndrome, Leopard syndrome, neuroblastoma, Sarcoma, melanoma, articular chondroma, cholangiomas, leukemia (such as juvenile myelomonocytic leukemia, human myelomonocytic leukemia, etc.), breast cancer, gastrointestinal stromal tumor, histiocytic lymphoma, lung cancer (such as non-small cell lung cancer, small cell lung cancer, lung squamous cell carcinoma, lung adenocarcinoma, etc.), esophageal cancer, pancreatic cancer,
  • the compounds of formula I, pharmaceutically acceptable salts and isomers thereof of the present invention are inhibitors of WDR5, which can inhibit the binding of WDR5 to MLL1 or MYC, and can also inhibit the activity of WDR5 itself. Therefore, the compounds of formula I, pharmaceutically acceptable salts and isomers thereof of the present invention can be used for the treatment or prevention of WDR5-mediated diseases.
  • WDR5-mediated disease refers to a disease in which WDR5 is involved in the occurrence and/or development of the disease, and the purpose of alleviation, treatment and/or prevention can be achieved by inhibiting the expression and/or activity of WDR5.
  • WDR5-mediated diseases include but are not limited to the Kabuki syndrome described above, as well as various solid tumors and hematological tumors, especially including MLL rearrangement-dependent leukemia (such as human myelomonocytic leukemia), MYC driven tumors and breast cancer, etc.
  • MYC-driven tumors refer to tumors caused by MYC activity.
  • the compounds of formula I, pharmaceutically acceptable salts and isomers thereof of the present invention can also be used to inhibit epithelial-mesenchymal transition (EMT), thereby inhibiting the metastasis of epithelial-derived malignant tumor cells. Therefore, "WDR5-mediated disease" as described in this application also includes the metastasis of cancer, especially the metastasis of malignant tumor of epithelial cell origin.
  • the present invention provides a method of treating or preventing the WDR5-mediated diseases described herein, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, pharmaceutically acceptable salts and isomers thereof of the present invention Or a pharmaceutical composition containing the compound of formula I of the present invention, its pharmaceutically acceptable salts and isomers.
  • Subject or “individual” as used herein refers to mammals, particularly primates, and more particularly humans.
  • preventing and preventing include reducing the likelihood of the occurrence or exacerbation of a disease or disorder in a patient; the terms also include: preventing the occurrence of a disease or disorder in mammals, particularly when such mammals are susceptible to When you have the disease or condition, but have not been diagnosed with the disease or condition.
  • "Treat” and other similar synonyms include the following meanings: (i) inhibiting a disease or disorder, ie, arresting its progression; (ii) alleviating a disease or disorder, ie, causing regression of the state of the disease or disorder; or (iii) alleviating the Symptoms caused by a disease or condition.
  • an “effective amount” for use in therapy is the amount of a composition comprising a compound of Formula I disclosed herein, a pharmaceutically acceptable salt or isomer thereof, required to provide clinically significant relief of the condition.
  • the dosage can be determined according to factors such as the subject's age, sex, disease and its severity. An effective amount appropriate in any individual case can be determined using techniques such as dose escalation assays.
  • administering refers to methods capable of delivering a compound or composition to the desired site of biological action.
  • Administration methods well known in the art can be used in the present invention. These methods include, but are not limited to, the oral route, the duodenal route, parenteral injection (including intrapulmonary, intranasal, intrathecal, intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), Topical and rectal administration.
  • a compound of formula I of the present invention, a pharmaceutically acceptable salt or isomer thereof, or a medicament containing a compound of formula I of the present invention, a pharmaceutically acceptable salt or isomer thereof, is administered orally combination.
  • the compound of formula I of the present invention, its pharmaceutically acceptable salts and isomers or the pharmaceutical composition containing the compound of formula I of the present invention, its pharmaceutically acceptable salts and isomers can be combined with other pharmacologically active compounds
  • the compounds are used in combination, especially in the treatment of cancer.
  • the compounds of formula I, pharmaceutically acceptable salts and isomers thereof of the present invention or pharmaceutical compositions containing the compounds of formula I, pharmaceutically acceptable salts and isomers thereof of the present invention may be combined with one or more Simultaneous, sequential or separate administration of a combination of multiple drugs selected from the group consisting of chemotherapeutic agents, such as mitotic inhibitors, such as taxanes, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine, Vinorelbine or vinorelbine, other anticancer agents such as cisplatin, 5-fluorouracil or 5-fluoro-2-4(1H,3H)-pyrimidinedione (5FU), flutamide or gemcitabine, etc.
  • chemotherapeutic agents such as mitotic inhibitors, such as taxanes, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine, Vinorelbine or vinorelbine
  • other anticancer agents
  • the inventive compounds of formula I, pharmaceutically acceptable salts and isomers thereof of the present invention or pharmaceutical compositions comprising the inventive compounds of formula I, pharmaceutically acceptable salts and isomers thereof also It can be used for cancer treatment together with tumor immunotherapy drugs known in the art, such as anti-PD1 antibodies.
  • tumor immunotherapy drugs known in the art, such as anti-PD1 antibodies.
  • the compound of formula I of the present invention, its pharmaceutically acceptable salts and isomers or the pharmaceutical composition containing the compound of formula I of the present invention, its pharmaceutically acceptable salts and isomers can also be combined with conventional radiotherapy use.
  • combination refers to drug therapy obtained by mixing or combining more than one active ingredient, which includes fixed and non-fixed active ingredients Combination, or the combination of two or more different treatments.
  • fixed combination refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or single dosage form.
  • unfixed combination refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation at variable intervals to a patient as separate entities. These also apply to cocktail therapy, eg the administration of three or more active ingredients.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I of the present invention, a pharmaceutically acceptable salt or isomer thereof, and a pharmaceutically acceptable carrier or excipient.
  • pharmaceutical composition refers to a compound of formula I of the present invention, a pharmaceutically acceptable salt or isomer thereof, and a compound generally accepted in the art for the delivery of biologically active compounds to mammals (eg, humans) preparation of the medium.
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • pharmaceutically acceptable refers to a substance (eg, a carrier or diluent) that does not affect the biological activity or properties of a compound of formula I of the present invention, a pharmaceutically acceptable salt or isomer thereof, and is relatively non-toxic , that is, the substance can be administered to an individual without causing an adverse biological response or interacting in an undesired manner with any of the components contained in the composition.
  • “Pharmaceutically acceptable carrier or excipient” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, Diluents, preservatives, dyes/colorants, flavors, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • the active ingredient of the pharmaceutical composition of the present invention may contain, in addition to the compound of formula I of the present invention, a pharmaceutically acceptable salt or isomer thereof, other known anticancer agents, including but not Limited to taxanes, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, vinflunine, cisplatin, 5-fluorouracil, 5-fluoro-2-4(1H , 3H)-pyrimidinedione (5FU), flutamide and gemcitabine, etc.
  • other known anticancer agents including but not Limited to taxanes, vinca alkaloids, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, vinflunine, cisplatin, 5-fluorouracil, 5-fluoro-2-4(1H , 3H)-pyrimidinedione (5FU), flutamide and gemcitabine, etc.
  • the present invention relates to compounds of formula I of the present invention, pharmaceutically acceptable salts and isomers thereof, or pharmaceutical compositions comprising compounds of formula I of the present invention, pharmaceutically acceptable salts and isomers thereof, in the treatment or prophylaxis herein
  • the present invention also provides compounds of formula I according to the present invention, pharmaceutically acceptable salts and isomers thereof or containing compounds of formula I according to the present invention, for use in the treatment or prevention of WDR5-mediated diseases described herein Pharmaceutical compositions of the above acceptable salts and isomers.
  • the starting materials used in the following examples can be purchased from chemical vendors such as Aldrich, TCI, Alfa Aesar, Bidder, Anegi, etc., or can be synthesized by known methods.
  • the ice bath refers to -5°C to 0°C
  • the room temperature refers to 10°C to 30°C
  • the reflux temperature generally refers to the reflux temperature of the solvent under normal pressure.
  • the reaction overnight generally refers to a time of 8-15 hours.
  • the specific operating temperature is not limited, and all are carried out at room temperature.
  • the separation and purification of intermediates and final products are carried out by normal-phase or reversed-phase chromatographic column separation or other suitable methods.
  • the normal phase flash chromatography column uses ethyl acetate and n-hexane or methanol and dichloromethane as mobile phases.
  • Reversed-phase preparative high pressure liquid chromatography (HPLC) was performed on a C18 column with UV detection at 214 nm and 254 nm with mobile phases A (water and 0.1% formic acid), B (acetonitrile) or mobile phase A (water and 0.1% carbonic acid) ammonium hydrogen), B (acetonitrile).
  • LCMS instrument pump: Agilent 1260;
  • UV detector Agilent 1260 DAD Mass Spectrometer API 3000;
  • Step 1 -78°C, under argon protection, to a solution of 2-bromo-5-fluoropyridine (A1-1, 102 g, 580.0 mmol) in tetrahydrofuran (1.0 L) was added dropwise LDA (2M, tetrahydrofuran solution, 434 mL, 868.0 mmol). After reacting at this temperature for 1 hour, triisopropyl borate (163 g, 870.0 mmol) was added, and the mixture was reacted at this temperature for 30 minutes, and then the temperature was raised to room temperature and reacted for 16 hours.
  • reaction solution was cooled to 0°C, an aqueous solution of sodium hydroxide (4M, 2.5L) was added, and the temperature was warmed to room temperature and stirred for 1 hour.
  • the aqueous phase was separated and the pH was adjusted to 3 with 6M aqueous hydrochloric acid. Extract with ethyl acetate (3*1.5L), wash the organic phase with saturated brine, dry, filter, and concentrate to dryness to give crude (2-bromo-5-fluoropyridin-4-yl)boronic acid (A1-2, 114.5 g, yield : 89.9%).
  • Step 2 To the suspension of (2-bromo-5-fluoropyridin-4-yl)boronic acid (A1-2, 114.5 g, 520.9 mmol) in dichloromethane (1.5 L) was added hydrogen peroxide (30%) at 0°C aq., 177.1 g, 1562.7 mmol). After the addition was completed, the temperature was raised to room temperature for 16 hours.
  • reaction solution was concentrated to remove the solvent, water (500 mL) and ethyl acetate (1.0 L) were added, the layers were separated, the aqueous phase was extracted with ethyl acetate (2*1.0 L), the organic phases were combined, and concentrated to dryness to obtain crude 2-bromo -5-Fluoropyridin-4-ol (A1-3, 96 g, yield: 96.0%).
  • Step 3 To a solution of 2-bromo-5-fluoropyridin-4-ol (A1-3, 96g, 500mmol) in DMF (600mL) was added potassium carbonate (138.1g, 1000mmol) and iodoethane (234g, 1500mmol) . The reaction was carried out at room temperature for 16 hours. The reaction solution was poured into saturated brine, extracted with ethyl acetate (2*1000mL), the organic phase was washed with water (3*1500mL) and saturated brine (2*1500mL) successively, dried, filtered, concentrated to dryness under reduced pressure, and the mixture was filtered through a column. Purification by chromatography gave 2-bromo-4-ethoxy-5-fluoropyridine (A1-4, 85 g, yield: 77.3%) as a colorless liquid.
  • Step 4 Under argon protection, 2-bromo-4-ethoxy-5-fluoropyridine (A1-4, 42 g, 190.9 mmol) and tributyl(1-ethoxyvinyl)stannane (103.4 g , 286.4 mmol) in 1,4-dioxane (1,4-dioxane) was added tetrakistriphenylphosphine palladium (7.3 g, 0.03 mmol). The temperature was raised to 100°C for 16 hours. The solvent was removed by concentration under reduced pressure, diluted with ethyl acetate (800 mL), saturated aqueous potassium fluoride solution was added, and the mixture was stirred at room temperature for 1 hour.
  • reaction solution was separated into layers, the aqueous phase was extracted with dichloromethane (2*1000 mL), the organic phases were combined, washed with saturated brine, dried, filtered, concentrated to dryness under reduced pressure, and purified by column chromatography to obtain A1-5 (32.5 g, collected rate: 93.0%).
  • Step 5 Dissolve 1-(5-fluoro-4-ethoxypyridin-2-yl)ethan-1-one (A1-5, 28.4 g, 155.0 mmol) in ethanol (560 mL), cool to 0°C , sodium borohydride (5.85 g, 155.0 mmol) was added in three portions. After the addition was completed, the reaction was kept at 0°C for 10 minutes, and then the temperature was raised to room temperature for overnight reaction.
  • reaction solution was poured into ice water, extracted with dichloromethane (4*1000 mL), the organic phases were combined, washed with saturated brine, dried, filtered, concentrated to dryness under reduced pressure, and purified by column chromatography to obtain a pale yellow oil 1-( 5-Fluoro-4-ethoxypyridin-2-yl)ethan-1-ol (A1-6, 25 g, yield: 87.1%).
  • Step 6 1-(5-Fluoro-4-ethoxypyridin-2-yl)ethane-1-ol (A1-6, 24.2 g, 130.7 mmol) and triphenyl
  • a solution of phosphorus (61.7 g, 235.2 mmol) in tetrahydrofuran (500 mL) was added dropwise a solution of carbon tetrabromide (65.0 g, 196.0 mmol) in tetrahydrofuran (100 mL).
  • the reaction was kept at 0°C for 10 minutes, and the temperature was raised to room temperature for overnight reaction.
  • the reaction solution was filtered, the filter cake was washed with tetrahydrofuran, the filtrate was concentrated to dryness under reduced pressure, and purified by column chromatography to obtain light yellow oil A1 (24 g, yield: 74.1%).
  • Step 1 Add sodium methoxide (5.5 g, 101.7 mmol) to a methanol (200 mL) solution of 4,6-dichloronicotinonitrile (A2-1, 16.0 g, 92.5 mmol) at 0°C under argon protection. After adding 0°C and reacting for 20 minutes, the temperature was raised to room temperature for 3 hours.
  • Step 2 under argon protection, 6-chloro-4-methoxynicotinonitrile (A2-2, 11 g, 65.2 mmol) and tributyl(1-ethoxyvinyl)stannane (35.3 g, 97.8 mmol) were added ) in 1,4-dioxane was added tetrakistriphenylphosphine palladium (3.78 g, 3.26 mmol). The temperature was raised to 100°C for 16 hours. The solvent was removed by concentration under reduced pressure, diluted with ethyl acetate (300 mL), saturated aqueous potassium fluoride solution was added, and the mixture was stirred at room temperature for 1 hour.
  • Step 3 Dissolve 6-(1-ethoxyvinyl)-4-methoxynicotinonitrile (A2-3, 14g, 65.2mmol) in tetrahydrofuran (200mL) and add aqueous hydrochloric acid (2M, 130mL, 260mmol), The reaction was carried out at room temperature for 60 minutes.
  • Step 4 To a solution of 6-acetyl-4-methoxynicotinonitrile (A2-4, 8.5 g, 47.75 mmol) in methanol (50 mL) was added sodium borohydride (2.7 g, 71.63 mmol) in an ice-water bath. The reaction was carried out at 0°C for 60 minutes. The reaction was quenched with ice water. Concentrate under reduced pressure to remove most of the methanol solvent.
  • Step 5 6-(1-hydroxyethyl)-4-methoxynicotinonitrile (A2-5, 5.6 g, 31.46 mmol) and carbon tetrabromide (15.63 g, 47.19 mmol) were added under argon protection at 0°C ) in dichloromethane (120 mL) was added a solution of triphenylphosphine (12.36 g, 47.19 mmol) in dichloromethane (30 mL). The reaction was stirred at 0°C for 60 minutes.
  • Step 1 To a solution of 4,6-dichloronicotinonitrile (A2-1, 20.0 g, 115.6 mmol) in tetrahydrofuran (400 mL) was added sodium ethoxide ethanol solution (20%, 101.3 g) at 0°C under argon protection. , 121.4 mmol). After adding 0°C and reacting for 10 minutes, the temperature was raised to room temperature for 2 hours.
  • Step 2 Under argon protection, 6-chloro-4-ethylnicotinonitrile (A3-2, 16.5 g, 90.36 mmol) and tributyl(1-ethoxyethylene) tin (49.0 g, 135.54 mmol) were added ) in 1,4-dioxane (300 mL) was added tetrakistriphenylphosphine palladium (5.2 g, 4.52 mmol). The temperature was raised to 100°C for 16 hours. Concentrate under reduced pressure to remove the solvent, dilute with ethyl acetate (150 mL), add saturated potassium fluoride aqueous solution, stir at room temperature for 1 hour, and separate the layers.
  • aqueous phase is extracted with ethyl acetate (200 mL), the organic phases are combined, washed with saturated brine, and dried. , filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in tetrahydrofuran (100 mL) and aqueous hydrochloric acid (2M, 120 mL, 240 mmol) was added. The reaction was carried out at room temperature for 1 hour.
  • Step 3 To a methanol (400 mL) solution of 6-acetyl-4-ethoxynicotinonitrile (A3-3, 16.6 g, 87.28 mmol) was added sodium borohydride (3.3 g, 87.28 mmol) at 0°C. The reaction was carried out at 0°C for 1 hour. The reaction was quenched with ice water. Concentrate under reduced pressure to remove most of the methanol solvent.
  • Step 4 To 4-ethoxy-6-(1-hydroxyethyl)nicotinonitrile (A3-4, 12.3 g, 63.99 mmol) and triphenylphosphine (33.6 g, 127.98 mmol) at 0°C under argon mmol) in tetrahydrofuran (400 mL) was added carbon tetrabromide (31.8 g, 95.98 mmol). After 5 minutes of reaction at 0°C, the reaction was stirred at room temperature for 16 hours.
  • Step 1 Add 1-(6-fluoro-5-methoxypyridin-3-yl)ethan-1-one (A4-1, 3.0 g, 17.73 mmol) in methanol (30 mL) solution under ice-water bath Sodium borohydride (671 mg, 17.73 mmol). The reaction was stirred at room temperature for 60 minutes. The reaction solution was quenched by adding ice water.
  • Step 2 1-(6-Fluoro-5-methoxypyridin-3-yl)ethan-1-ol (A4-2, 2.6 g, 15.19 mmol) in dichloromethane ( 40 mL) solution was added triphenylphosphine (6.0 g, 22.78 mmol) and NBS (4.1 g, 22.78 mmol). The reaction was stirred at room temperature for 5 hours.
  • reaction solution was diluted with dichloromethane (100 mL), washed with saturated brine (3*100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (0 to 20% gradient of ethyl acetate: Petroleum ether) was purified to obtain solid A4 (2.5 g, yield: 70%).
  • Step 1 To a solution of 2-bromo-5-fluoropyridin-4-ol (A5-1, 6.0 g, 31.3 mmol) in DMF (50 mL) was added potassium carbonate (10.8 g, 78.2 mmol) and methyl iodide (11.0 g) , 77.5 mmol). The reaction was carried out at room temperature for 16 hours. The reaction solution was diluted with water (50mL), extracted with ethyl acetate (2*150mL), the organic phase was washed with water (3*200mL) and saturated brine (2*200mL), dried, filtered, the filtrate was concentrated to dryness under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. Chromatographic purification gave white solid A5-2 (2.6 g, yield: 40.4%).
  • Step 2 Under argon protection, 2-bromo-5-fluoro-4-methoxypyridine (A5-2, 2.6 g, 12.6 mmol) and tributyl(1-ethoxyvinyl)stannane (6.8 g, 18.9 mmol) in dioxane solution was added tetrakistriphenylphosphine palladium (1.0 g, 0.87 mmol), the temperature was raised to 100°C, and the reaction was carried out for 16 hours. The solvent was removed by concentration under reduced pressure, diluted with ethyl acetate (100 mL), saturated aqueous potassium fluoride solution was added, and the mixture was stirred at room temperature for 1 hour.
  • reaction solution was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate and saturated brine successively, dried, filtered, concentrated to dryness under reduced pressure, and purified by column chromatography to obtain white solid A5-3 (1.8 g, yield: 84.3%).
  • Step 3 1-(5-fluoro-4-methoxypyridin-2-yl)ethanone (A5-3, 12.9 g, 76.3 mmol) in methanol (100 mL) solution was divided into methanol (100 mL) at 0°C under argon protection. Sodium borohydride (5.75 g, 152.5 mmol) was added in batches. The reaction was stirred at room temperature for 1 hour.
  • Step 4 Triphenylphosphine (2.14g, 8.18mmol), NBS (1.25g, 7.01 g) were successively added to a solution of A5-4 (1.0g, 5.84mmol) in dichloromethane (10mL) at 0°C under argon protection mmol). The reaction was stirred at room temperature for 18 hours.
  • Step 1 To A8-1 (1.0 g, 6.40 mmol) and potassium carbonate (2.66 g, 19.21 mmol) in DMF (10 mL) was added iodoethane (5.0 g, 32.02 mmol) dropwise. Heat to 50°C and stir the reaction for 5 hours. The reaction solution was diluted with ethyl acetate (30 mL), washed with saturated brine (3*50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and chromatographed on silica gel (0 to 30% gradient of ethyl acetate: petroleum ether) Purification gave white solid A8-2 (1.1 g, yield: 93.2%).
  • Step 2 To A8-2 (1.0 g, 5.43 mmol) in tetrahydrofuran (15 mL) was added dropwise lithium borohydride (2.0 M in THF, 5.4 mL, 10.86 mmol). Heat to 40°C and stir the reaction overnight. The reaction was quenched by adding sodium sulfate decahydrate (3.0 g), filtered, and the filtrate was concentrated under reduced pressure, and purified by silica gel chromatography (0 to 50% gradient of ethyl acetate: petroleum ether) to give A8-3 (580 mg, obtained as a colorless oil). rate: 68.4%).
  • Step 1 [1,1'-bis(diphenylphosphino)ferrocene]di Palladium chloride (321 mg, 0.44 mmol) and DIPEA (1.69 g, 13.17 mmol). After replacing the air with carbon monoxide, the mixture was heated to 100°C and reacted for 12 hours. It was diluted with ethyl acetate (400 mL), saturated brine was added, and the mixture was stirred at room temperature for 1 hour.
  • Step 2 To a solution of A13-1 (206 mg, 1 mmol) in methanol (10 mL) was added sodium borohydride (75.6 mg, 2 mmol) under an ice-water bath. The reaction was carried out at 0°C for 60 minutes. The reaction was quenched with ice water. Concentrate under reduced pressure to remove most of the methanol solvent.
  • Step 3 To a solution of A13-2 (80 mg, 0.45 mmol) in dichloromethane (10 mL) was added thionyl chloride (107 mg, 0.9 mmol) under an ice-water bath. The reaction was carried out at 0°C for 60 minutes.
  • Step 1 -75°C, under argon protection, to A1-4 (2.70g, 12.27mmol) in anhydrous tetrahydrofuran (40mL) was added dropwise n-BuLi (1.6M in hexane, 11.5ml, 18.41mmol), -75 The reaction was carried out at °C for 15 minutes. Anhydrous DMF (1.42 ml, 2.05 mmol) was added. React at -75°C for 15 minutes. Add water to quench, extract with ethyl acetate (3*60 mL), combine the organic phases, wash with water, dry, filter, concentrate, and purified by column chromatography to obtain A14-1 (915 mg, yield: 44.1%).
  • Step 2 To a solution of A14-1 (1.0 g, 5.91 mmol) in ethanol (20 mL) was added sodium borohydride (671 mg, 17.74 mmol) at 0°C under argon protection. The reaction was carried out at room temperature for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride solution, water was added, extracted with ethyl acetate, dried, concentrated, and purified by column chromatography to obtain A14-2 (690 mg, yield: 68.2%).
  • Step 3 To a solution of A14-2 (250 mg, 1.46 mmol) in acetonitrile (10 mL) was added thionyl chloride (0.32 ml, 4.39 mmol) dropwise. The reaction was carried out at room temperature for 1 hour. Distilled under reduced pressure, added dichloromethane, washed with sodium bicarbonate, dried, concentrated, and purified by column chromatography to obtain Intermediate A14 (240 mg, yield: 86.6%).
  • Step 3 A15-3 (1.0 g, 5.61 mmol) was mixed with trimethylsilyl chloride (10 mL) and stirred at room temperature for 60 minutes. The reaction solution was poured into ice water. Extracted with ethyl acetate (2*50 mL), the organic phases were combined, washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and concentrated to obtain Intermediate A15 (1.1 g, yield: 100%). used directly in the next step.
  • Step 1 To a solution of A16-1 (600 mg, 4.0 mmol) in ethanol (60 mL) was added sodium borohydride (453 mg, 12.0 mmol) at 0°C. The reaction was stirred at room temperature for 12 hours. The reaction solution was poured into ice water (50 mL), extracted with dichloromethane (2*50 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and subjected to column chromatography Purification gave A16-2 as a colorless oil (450 mg, yield: 74.0%).
  • Step 1 under argon protection, to A1-3 (4.59g, 23.91mmol) in N,N-dimethylformamide (135mL) solution under ice-water bath was slowly added sodium hydrogen (60% dispersed in oil, 2.87 g) g, 71.75 mmol). Continue stirring for 10 minutes after the addition is complete. Chlorodifluoroacetic acid (4.66 g, 35.85 mmol) was then added dropwise. React overnight at 70°C.
  • Step 2 Compound A17-1 (622mg, 2.57mmol), tributyl(1-ethoxyethylene)tin (1.39g, 3.85mmol), and tetrakis(triphenylphosphorus)palladium (149mg) were added to the dry flask in turn , 0.13 mmol), 1,4-dioxane (40 mL). After the addition, the reaction was carried out at 100°C overnight under nitrogen protection. The reaction solution was concentrated, dissolved in ethyl acetate (20 mL), a saturated aqueous potassium fluoride solution (15 mL) was added, and the mixture was stirred at room temperature for 1 hour.
  • Step 3 Trifluoroacetic acid (6 mL) was added dropwise to a solution of A17-2 (590 mg, 2.53 mmol) in dichloromethane (20 mL) under an ice-water bath. React overnight at room temperature. The reaction solution was placed in an ice bath and stirred, and sodium bicarbonate solution was added to adjust to weakly alkaline, water (15 mL) was added for layering, and extraction was performed. The aqueous phase was washed with dichloromethane (2*15 mL). (2*15mL) washed, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel chromatography to obtain colorless liquid A17-3 (308 mg, yield: 59.3%).
  • Step 4 To a solution of A17-3 (308 mg, 1.50 mmol) in methanol (10 mL) was slowly added sodium borohydride (114 mg, 3.0 mmol) under an ice-water bath. After the addition, the reaction was carried out at room temperature overnight. The reaction solution was quenched by adding water (20mL), extracted with ethyl acetate (3*20mL), the organic phases were combined, washed with saturated brine (2*15mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, Prep-TLC Purification gave A17-4 as a colorless oil (295 mg, yield: 94.8%).
  • Step 5 Under nitrogen protection, a solution of carbon tetrabromide (180 mg, 0.54 mmol) was added dropwise to a solution of A17-4 (75 mg, 0.36 mmol) and triphenylphosphorus (171 mg, 0.65 mmol) in tetrahydrofuran (4 mL) under an ice-water bath. A solution in tetrahydrofuran (1 mL). React overnight at room temperature.
  • Step 1 The synthetic method of reference Tetrahedron Letters (2008), 49(44), 6368-6370 generates A18-1 from A1-3 in one step.
  • Step 2 Referring to the synthetic route of intermediate A17, intermediate A18 is generated from intermediate A18-1 through a four-step reaction.
  • Step 1 To a solution of A19-1 (2.0 g, 13.14 mmol) in acetonitrile/acetone (40 mL/10 mL) was added phosphorus pentoxide (9.3 g, 65.72 mmol). Heated to 75°C and reacted for 3 hours. Phosphorus pentoxide (4.67 g*4, 131.50 mmol) was added in batches every 4 hours. The reaction was continued for 48 hours.
  • Step 3 A19-3 (490 mg, 2.52 mmol) was mixed with trimethylchlorosilane (5 mL) and stirred at room temperature for 1 hour. The reaction solution was poured into ice water, extracted with ethyl acetate (2*20 mL), the organic phases were combined, washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate and concentrated to obtain A19 (500 mg, yield: 93.2%).
  • Step 4 Trifluoromethanesulfonic acid (30.4 mL, 344.91 mmol) was slowly added dropwise to a solution of B1-5 (27.8 g, 68.77 mmol) in dichloromethane (500 mL) at 0°C under argon protection. The reaction was stirred at 0°C for 1 hour.
  • Step 5 To 7'-bromo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-1'-one (B1-6, 10.72g, 42.52 mmol) in methanol (20 mL) and DMSO (20 mL) was added Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 (3.32 g, 4.07 mmol) and N,N-diisopropylethylamine (21.1 mL, 128.13 mmol). After replacing the air with CO three times, the temperature was raised to 90° C. and reacted for 16 hours.
  • Step 6 Add 1'-ketoketo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4 to the mixed solution of concentrated sulfuric acid (20 mL) and glacial acetic acid (20 mL) at 0°C '-Isoquinoline]-7'-carboxylate methyl ester (B1-7, 4.0 g, 17.3 mmol). After stirring for 20 minutes, a solution of 1,3-dibromo-5,5-dimethylhydantoin (4.9 g, 17.3 mmol) in glacial acetic acid (20 mL) was added dropwise to the reaction solution. The reaction was carried out at room temperature for 5 hours.
  • Step 7 To 5'-bromo-1'-keto-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-carboxylic acid methyl ester ( To a solution of B1-8, 3.1 g, 10 mmol) in tetrahydrofuran (50 mL) and water (50 mL) was added lithium hydroxide monohydrate (800 mg, 20 mmol). The reaction was carried out at room temperature for 14 hours. LCMS showed 80% product. The solvent tetrahydrofuran was removed under reduced pressure.
  • Step 8 To 5'-bromo-1'-keto-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-carboxylic acid at 0°C To a solution of (B1-9, 2.2 g, 7.4 mmol) and triethylamine (2.24 g, 22.2 mmol) in dichloromethane (30 mL) was added isobutyl chloroformate (2.02 g, 14.8 mmol). The reaction was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and stirred at room temperature for 1 hour.
  • Step 9 To a solution of B1-10 (1.65 g, 4.2 mmol) in tetrahydrofuran (30 mL) was added sodium borohydride (472 mg, 12.5 mmol) at 0°C. The reaction was carried out at room temperature for 2 hours. The reaction was quenched by the addition of methanol (10 mL). The reaction solution was poured into ice water and stirred at room temperature for 0.5 hour.
  • Step 10 Add thionyl chloride (127 mg, 1.068 mmol) to a solution of B1-11 (100 mg, 0.356 mmol) in acetonitrile (20 mL) at 0°C, and react at room temperature for 6 hours. The reaction solution was spin-dried to obtain the crude product 5'-bromo-7'-(chloromethyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-1 ⁇ -ketone (B1, 110 mg, yield: 100%).
  • Step 1 To a solution of B2-1 (25 g, 127.52 mmol) in DMF (500 mL) was added sodium hydride (60% in mineral oil, 20.4 g, 510.07 mmol) in portions at 0°C under argon. The reaction was carried out at 0°C for 30 minutes. A solution of 1,3-dibromopropane (19.42 mL, 191.28 mmol) in DMF (50 mL) was added dropwise. The reaction was carried out at room temperature for 1 hour. Quench with ice water.
  • Step 5 To a solution of B2-5 (1.8 g, 6.77 mmol) in methanol (10 mL) and DMSO (30 mL) was added N,N-diisopropylethylamine (3.3 mL, 20.30 mmol) and [1,1' - Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (552 mg, 0.677 mmol). After replacing the air with CO three times, the temperature was raised to 90° C. and reacted for 16 hours.
  • Step 6 To the mixed solution of B2-6 (1.3g, 5.3mmol) in concentrated sulfuric acid (10mL) and glacial acetic acid (10mL) at 0°C, 1,3-dibromo-5,5-dimethyl was slowly added dropwise Hydantoin (3.0 g, 10.6 mmol) in glacial acetic acid (10 mL). The reaction was carried out at room temperature for 16 hours. The reaction was quenched with ice water, extracted with ethyl acetate (3*50 mL), the organic phases were combined, dried, filtered, concentrated, and purified by column chromatography to obtain B2-7 (1.2 g, yield: 69.8%).
  • Step 7 Lithium borohydride (2M in THF, 9.3 mL, 18.51 mmol) was added dropwise to a mixed solution of B2-7 (1.2 g, 3.70 mmol) in THF (10 mL) and ethanol (2 mL) at 0°C. The reaction was carried out at room temperature for 10 minutes and then heated to 45°C for 2 hours. The reaction was quenched with ice water. Extracted with ethyl acetate (3*50 mL), combined the organic phases, dried, filtered, concentrated, and purified by column chromatography to obtain B2-8 (580 mg, yield: 52.7%).
  • Step 8 To a solution of B2-8 (200 mg, 0.675 mmol) in acetonitrile (10 mL) was added dropwise thionyl chloride (0.15 mL, 2.03 mmol) at 0°C. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain B2 (215 mg, 0.675 mmol), and the crude product was directly used in the next step.
  • Step 2 To a solution of B10-2 (21 g, 82.32 mmol) in tetrahydrofuran (300 mL) was added (trifluoromethyl)trimethylsilane (93.6 g, 658.54 mmol) and sodium iodide (7.4 g, 49.39 mmol). The reaction was carried out in a stuffy tank at 110°C for 14 hours.
  • Step 4 To a solution of B10-4 (31.8 g, 114.78 mmol) in DMA (600 mL) was added DIPEA (89.0 g, 688.66 mmol) and HATU (52.37 g, 137.73 mmol). Stir at room temperature for 30 minutes. Ammonium chloride (18.42 g, 344.33 mmol) was added. After stirring at room temperature for 30 minutes, the reaction solution was heated to 60°C for 16 hours. After cooling to room temperature, add ethyl acetate (1.5L) to dilute, wash with water (3*1L), and wash with saturated aqueous sodium chloride solution (1L).
  • Step 8 To a solution of B10-8 (7.8 g, 27.07 mmol) in methanol (80 mL) and dimethyl sulfoxide (160 mL) was added DIPEA (10.5 g, 81.22 mmol) and [1,1'-bis(diphenylene)] phosphino)ferrocene]palladium dichloride (1.98 g, 2.71 mmol). After replacing the air with carbon monoxide, the reaction was carried out at 90°C for 8 hours.
  • Step 9 Add 1,3-dibromo-1,3,5-triazine-2,4,6-triazine to a solution of B10-9 (3 g, 11.23 mmol) in acetic acid (30 mL) and concentrated sulfuric acid (60 mL) Ketone (8 g, 28.07 mmol). The reaction was carried out at room temperature for 3 hours.
  • Step eleven To a solution of B10-11 in dichloromethane (6 mL) was added thionyl chloride (375 mg, 3.14 mmol) dropwise. The reaction was carried out at room temperature for 5 hours. After monitoring that the reaction was not completed, thionyl chloride (750 mg, 6.28 mmol) was added, and the reaction was continued for 16 hours.
  • Step 1 To a solution of B11-1 (50 g, 255.03 mmol) in DMF (1 L) was added sodium hydride (60% in oil, 22.4 g, 561.08 mmol) in portions under ice-water bath. Stir at room temperature for 1 hour. 1,3-Dibromo-2,2-dimethoxypropane (73.5 g, 280.54 mmol) was added dropwise. Heated to 60°C for 16 hours.
  • reaction solution was cooled to room temperature, poured into ice water, extracted with ethyl acetate (2*700mL), the organic phases were combined, washed with water (3*500mL), washed with saturated aqueous sodium chloride solution (2*700mL), and dried over anhydrous sodium sulfate After concentration. The residue was dissolved in petroleum ether and filtered to obtain B11-2 (55 g, yield: 72.8%).
  • Step 3 B11-3 (30 g, 120.0 mmol) was dissolved in dichloromethane (300 mL) and methanol (0.3 mL). After stirring for 10 minutes, DAST (92 mL, 319.8 mmol) was added dropwise under an ice-water bath. The reaction was carried out at room temperature for 3 hours.
  • Step 6 Trifluoromethanesulfonic acid (32.7 mL, 369.82 mmol) was added dropwise to a solution of B11-7 (24.0 g, 52.83 mmol) in dichloromethane (300 mL) under an ice-water bath. The reaction was carried out at room temperature for 3 hours. The reaction solution was poured into ice water, dichloromethane (500 mL) was added, the organic phase was washed with water (2*500 mL), washed with saturated aqueous sodium chloride solution (2*500 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was dissolved in petroleum ether/dichloromethane (10/1), and filtered to obtain B11-8 (8.3 g, yield: 51.9%).
  • Step 7 To B11-8 (7.5 g, 24.82 mmol) in methanol (25 mL) and dimethyl sulfoxide (100 mL) was added DIPEA (9.6 g, 74.47 mmol) and [1,1'-bis(diphenyl) phosphine)ferrocene]palladium dichloride (1.27 g, 1.74 mmol). The carbon monoxide environment was reacted at 90°C for 4 hours.
  • Step 1 2-nitro-1H-imidazole (C1-1, 9000 mg, 79.8 mmol) was added to anhydrous tetrahydrofuran (270 mL), and sodium hydrogen (60%, 3.5 g, 87.5 mmol) was added under ice bath. The reaction was carried out at 0°C for 0.5 hours under argon protection. After dropwise addition of (2-(chloromethoxy)ethyl)trimethylsilicon (14.6 g, 87.6 mmol), the mixture was reacted at 0°C for 2 hours.
  • Step 2 Add 2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole 14-2 (C1-2, 14.3 g, 58.8 mmol) to in absolute ethanol (420 mL). The hydrogen was replaced three times, and the reaction was carried out at room temperature for 16 hours under the protection of hydrogen. The reaction solution was filtered, and the filtrate was concentrated to obtain crude 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-amine. The crude 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-amine was dissolved in dichloromethane (300 mL).
  • Step 3 (1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)carbamic acid tert-butyl ester (C1-3, 9.6g, 30.7 mmol) was added to anhydrous tetrahydrofuran (300 mL). Cool to 0 °C, add sodium hydrogen (60%, 1.5 g, 37.5 mmol). Under argon protection, react at 0 °C for 15 minutes, and dropwise add iodomethane (6.5 g, 45.8 mmol). mmol). Reaction at 0 °C for 3 hours.
  • Step 4 tert-butylmethyl (1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)carbamate (C1-4, 8.2g , 25.0 mmol) was added to anhydrous tetrahydrofuran (200 mL), and a solution of tetrabutylamine fluoride in tetrahydrofuran (1 M, 125 mL, 125 mmol) was added. The reaction was carried out at 80° C. for 1 hour under argon protection. The reaction solution was concentrated, and the crude product was subjected to column chromatography.
  • Step 1 To a solution (4 mL) of 1-ethylpiperazine (460 mg, 4 mmol) in tetrahydrofuran (20 mL) was added potassium bromomethyl trifluoroborate (200 mg, 1 mmol). After replacing the air with nitrogen, the reaction was carried out at 80°C for 3 hours. The reaction solution was spin-dried to obtain crude product. The obtained crude product was dissolved in acetone (20 mL), potassium bicarbonate (100 mg, 1 mmol) was added, and the suspension was stirred at room temperature for 1 hour. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain a white solid ((4-ethylpiperazin-1-yl)methyl)potassium trifluoroborate (D57, 250 mg, yield: 100%).
  • Step 1 To tert-butyl (1H-imidazol-2-yl)(methyl)carbamate (C1, 197 mg, 1 mmol), tetrabutylammonium iodide (369 mg, 1 mmol) and cesium carbonate (650 mg) at 0°C , 2mmol) in DMF (45mL) was added 5'-bromo-7'-(chloromethyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline Lino]-1'-one (B1, 302 mg, 1 mmol). The reaction was carried out at 80°C for 5 hours.
  • Step 2 To tert-butyl(1-(((5'-bromo-1'-one-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline] -7'-yl)methyl)-1H-imidazol-2-yl)(methyl)carbamate (1-1, 230 mg, 0.5 mmol) and N,N-dimethylaminomethyltrifluoroboronic acid To a mixed solution of potassium (1-2, 165 mg, 1 mmol) in dioxane (dioxane, 6 mL) and water (2 mL) was added Pd(dppf)Cl 2 (37 mg, 0.05 mmol), K 2 CO 3 (138 mg, 1 mmol).
  • Step 3 Add tert-butyl(1-((5'-(((dimethylamino)methyl)-1'-keto-2',3'-dihydro-1'H-spiro at 0°C [Cyclopropane-1,4'-isoquinoline]-7'-(methyl)-1H-imidazol-2-yl)(methyl)carbamate (1-3, 100 mg, 0.228 mmol) in DMF To the solution (15 mL) was added NaH (60% in mineral oil, 30 mg, 0.72 mmol). Stir at 0°C for 20 min. Add 2-(1-bromoethyl)-4-ethoxy-5-fluoropyridine ( A1, 90 mg, 0.363 mmol).
  • reaction was stirred at room temperature for 2 hours.
  • the reaction solution was poured into ice water (20 mL), extracted with dichloromethane (2*50 mL), the organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate.
  • Step 4 To tert-butyl(1-((5'-((dimethylamino)methyl)-2'-(1-(4-ethoxy-5-fluoropyridin-2-yl) at 0°C )ethyl)-1'-one-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)methyl)-1H-imidazole To a solution of -2-yl)(methyl)carbamate (1-4, 90 mg, 0.148 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (4 mL). The reaction was stirred at room temperature for 2 hours.
  • reaction solution was poured into ice water (30 mL) and neutralized to pH 7 with saturated aqueous sodium bicarbonate solution.
  • Dichloromethane (2*100mL) was extracted, the organic phases were combined, washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and separated and purified by high performance liquid chromatography (SunFire Prep C18OBD 10um, acetonitrile/water system) to give a white solid, which was then passed through SFC (column type: Mobile phase: redistilled grade EtOH and Supercritical CO 2 ; wavelength: 214 nm) to separate compound 1 (formate, 16 mg, yield: 19.5%) and compound 1' (formate, 18 mg, yield: 22%).
  • SFC columnumn type: Mobile phase: redistilled grade EtOH and Supercritical CO 2 ; wavelength: 214 nm
  • the following compounds can be synthesized by the same method or an improved method by referring to the synthesis method of compound 1 in Example 1, using the corresponding intermediate.
  • Step 1 Under argon protection, tert-butyl(1-((5'-(((dimethylamino)methyl)-1'-one-2',3'-dihydro-1 'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-(methyl)-1H-imidazol-2-yl)(methyl)carbamate (1-3, 80 mg, 0.18 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 21 mg, 0.55 mmol). Stir at 0°C for 20 min.
  • Step 2 To tert-butyl(1-((2'-(1-(5-cyano-4-methoxypyridin-2-yl)ethyl)-5'-((dimethyl Amino)methyl)-1'-one 2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-7'-yl)methyl)-1H-imidazole To a solution of -2-yl)(methyl)carbamate (2-1, 30 mg, 0.05 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred at room temperature for 2 hours.
  • Step 1 0°C, under argon protection, to tert-butyl(1-((5'-(((dimethylamino)methyl)-1'-one-2',3'-dihydro-1' H-spiro[cyclopropane-1,4'-isoquinoline]-7'-(methyl)-1H-imidazol-2-yl)(methyl)carbamate (1-3, 80 mg, 0.18 mmol ) in DMF (10 mL) was added NaH (60% in mineral oil, 21 mg, 0.55 mmol). Stir at 0°C for 20 min.
  • Step 2 To tert-butyl(1-((2'-(1-(5-cyano-4-ethoxypyridin-2-yl)ethyl)-5)-((dimethyl) at 0°C (ylamino)methyl)-1'-one 2',3'-dihydro-1'H-spiro[cyclopropan-1,4'-isoquinolin]-7'-yl)methyl)-1H- To a solution of imidazol-2-yl)(methyl)carbamate (3-1, 45 mg, 0.073 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred at room temperature for 2 hours.
  • Step 1 To tert-butyl(1-(((5'-bromo-1'-one-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline] -7'-yl)methyl]-1H-imidazol-2-yl)(methyl)carbamate (1-1, 46 mg, 0.1 mmol) and 1-((trifluoroboranyl)methyl) To a solution of pyrrolidine potassium salt (D75, 38.4 mg, 0.2 mmol) in water (1 mL) and dioxane (4 mL) was added 1,1-bis(diphenylphosphino)pyridinium palladium dichloride (7.3 mg) , 0.01 mmol) and potassium carbonate (26.8 mg, 0.2 mmol).
  • Step 2 To tert-butylmethyl (1-((1'-keto-5'-(pyrrolidin-1-ylmethyl)-2',3'-dihydro-1'H-spiro at 0°C [Cyclopropan-1,4'-isoquinolin]-7'-yl)methyl)-1H-imidazol-2-yl)carbamate (6-2, 30 mg, 0.064 mmol) in N,N- To a solution of dimethylformamide (10 mL) was added sodium hydride (60% in mineral oil, 10 mg, 0.204 mmol). Stir at 0°C for 20 minutes.
  • Step 3 To tert-butyl(1-((2'-(1-(4-ethoxy-5-fluoropyridin-2-yl)ethyl)-1)-one 5'-( Pyrrolidin-1-ylmethyl)-2',3'-dihydro-1'H-spiro[cyclopropan-1,4'-isoquinolin]-7'-yl)methyl)-1H-imidazole To a solution of -2-yl)(methyl)carbamate (6-3, 20 mg, 0.0316 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred at room temperature for 2 hours.
  • Step 1 To a solution of B2 (215 mg, 0.675 mmol) in DMF (10 mL) at 0°C was added cesium carbonate (445 mg, 1.369 mmol) and tetrabutylamine iodide (253 mg, 0.685 mmol). After 20 minutes of reaction at 0°C, a solution of (1H-imidazol-2-yl)(methyl)carbamate C1 (270 mg, 1.369 mmol) in DMF (2 mL) was added. The reaction was carried out at 80°C for 3 hours. The reaction was complete as monitored by LCMS.
  • Step 2 under argon protection, 23-1 (180 mg, 0.379 mmol) and N,N-dimethyl-1-(trifluoro-14-boranyl)methanamine potassium salt 1-2 (125 mg, 0.757 mmol), potassium carbonate (105 mg, 0.757 mmol) in dioxane (6 mL) and water (2 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride Dichloromethane complex (62 mg, 0.076 mmol). The reaction was microwaved at 115°C for 1.5 hours under argon protection. The reaction was complete as monitored by LCMS.
  • Step 3 To a solution of 23-2 (33 mg, 0.072 mmol) in dry DMF (8 mL) was added sodium hydride (60% in oil, 13 mg, 0.325 mmol) at 0°C under nitrogen protection. After stirring was continued for 30 minutes at 0°C, a solution of A3 (30 mg, 0.118 mmol) in DMF (2 mL) was added dropwise. The reaction solution was kept at 0°C for 20 minutes.
  • Step 4 To a solution of 23-3 (25 mg, 0.040 mmol) in dichloromethane (10 mL) was added dropwise trifluoroacetic acid (2.5 mL). The reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated to remove trifluoroacetic acid, the residue was diluted with dichloromethane (50 mL), the organic phase was washed successively with saturated sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated To dryness, the residue was purified by high performance liquid chromatography (SunFire Prep C18OBD 10um, acetonitrile/water system) to obtain the racemic product, and then passed through SFC (column type: Mobile phase: redistilled grade EtOH and Supercritical CO 2 ; wavelength: 214 nm; system: Waters SFC 150) was purified to obtain chiral compounds 23 (9 mg, yield: 42.9%) and 23' (8.8
  • the following compounds can be synthesized by the same method or an improved method by referring to the synthesis method of compound 23 in Example 5, using the corresponding intermediate.
  • Step 2 To a solution of 70-1 (513 mg, 1.13 mmol) in dry DMF (15 mL) was added sodium hydride (60% in oil, 200 mg, 5 mmol) at 0°C under nitrogen protection. The reaction was kept at 0°C for 30 minutes. A solution of Al (330 mg, 1.33 mmol) in DMF (5 mL) was added dropwise. The reaction was kept at 0°C for 30 minutes.
  • Step 3 Lithium borohydride (2M in tetrahydrofuran, 1.2 mL, 2.4 mmol) was added dropwise to a solution of compound 70-2 (500 mg, 0.80 mmol) in dry tetrahydrofuran (30 mL) at 0°C under nitrogen protection. After keeping the temperature at 0°C for 5 minutes, the temperature was raised to 25°C, and the reaction was incubated overnight. The reaction solution was poured into water, extracted with dichloromethane (3*80 mL), the organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and the residue was dissolved in methanol (50 mL).
  • Step 4 Triethylamine (104 mg, 1.03 mmol) was added to a solution of compound 70-3 (50 mg, 0.086 mmol) in dichloromethane (5 mL) at 0°C under nitrogen protection, followed by dropwise addition of methanesulfonyl chloride (80 mg, 0.70 mmol). ) in dichloromethane (4 mL). After the addition was completed, the temperature was raised to 25°C after the reaction was kept at 0°C for 5 minutes, and the reaction was maintained for 1 hour.
  • reaction solution was poured into water, extracted with dichloromethane (2*50 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a colorless oil 70-4 (crude, 60 mg).
  • Step 6 To a solution of 70-6 (50 mg, 0.074 mmol) in dichloromethane (10 mL) was added dropwise trifluoroacetic acid (2.5 mL). The reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated to remove trifluoroacetic acid, the residue was diluted with dichloromethane (50 mL), washed successively with saturated sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness , the residue was separated and purified by high performance liquid chromatography to obtain a light yellow solid, which was separated and purified by SFC to obtain 2'-((S)-1-(4-ethoxy-5-fluoropyridin-2-yl)ethyl )-5'-((3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)-7'-((2-(methylamino)- 1
  • Step 1 Dess-Martin oxidant (190 mg, 0.45 mmol) was added to a solution of 70-3 (200 mg, 0.35 mmol) in dichloromethane (10 mL) at 0°C under nitrogen protection. After the addition was completed, the reaction was kept at 0°C for 2 hours. The reaction solution was poured into water, extracted with dichloromethane (2*60 mL), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and purified by column chromatography to obtain white Solid 41-1 (200 mg, yield: 100%).
  • Step 2 To a solution of 41-1 (50 mg, 0.086 mmol) in dichloroethane (10 mL) was added methylamine tetrahydrofuran solution (2 mL, 4 mmol) under nitrogen protection. React overnight at room temperature. The reaction solution was cooled to 0°C. Sodium cyanoborohydride (10 mg, 0.17 mmol) was added. The temperature was raised to room temperature for 2 hours.
  • Step 4 To a solution of 41-3 (5 mg, 0.007 mmol) in dichloromethane (5 mL) was added dropwise trifluoroacetic acid (1 mL). The reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated to remove trifluoroacetic acid. The residue was diluted with dichloromethane (50 mL), washed successively with saturated sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was subjected to HPLC Chromatographic separation and purification gave the diformate salt of white compound 41 (0.26 mg, yield: 5.3%).
  • Step 1 Referring to the synthesis process of 1-1, the intermediate 88-1 was synthesized in one step using B10 as the starting compound.
  • Step 2 Add sodium hydride (60% in oil, 40 mg, 1.01 mmol) to a solution of 88-1 (125 mg, 0.25 mmol) in DMF (5 mL) at 0°C under argon. Stir at 0°C for 0.5 hours. A solution of Al (187 mg, 0.75 mmol) in DMF (2 mL) was added dropwise. After the addition, the reaction was continued for 3 minutes. TLC showed the reaction was complete.
  • Step 4 To a solution of 88-3 (65 mg, 0.10 mmol) in dichloromethane (4 mL) was added dropwise trifluoroacetic acid (1 mL). The reaction was carried out at room temperature for 3 hours. The reaction solution was poured into ice water, extracted with dichloromethane (20 mL), concentrated and separated and purified by high performance liquid chromatography to obtain two diastereomers 5'-((dimethylamino)methyl)-2'-( 1-(4-Ethoxy-5-fluoropyridin-2-yl)ethyl)-2,2-difluoro-7'-((2-(methylamino)-1H)imidazol-1-yl)methyl base)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinolin]-1'-one (compound 88: 6 mg, yield: 10.9% and compound 89: 7 mg, yield: 12.8%).
  • Compound 88 (300 mg) was separated and purified by SFC to obtain two white solid compounds 90 (75.11 mg, yield: 25.0%) and compound 91 (78.88 mg, yield: 26.3%).
  • the absolute configuration of compound 90 and compound 91 can be obtained from XRD single crystal diffraction data, or can be obtained from the co-crystal structure analysis of compound and WDR5 protein.

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Abstract

提供二氢异喹啉酮衍生物及其应用。二氢异喹啉酮衍生物如下式I所示，包括其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、多晶型物、前药或代谢产物。式I化合物对WDR5具有较高的蛋白-蛋白相互作用抑制活性，因此可以用于预防或治疗与WDR5相关的疾病。

Description

一种二氢异喹啉酮衍生物及其应用 技术领域
本发明涉及药物化学领域，具体地说，涉及一种可用于WDR5蛋白-蛋白相互作用抑制剂的新型杂环化合物、其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、同位素取代物、前药或代谢产物。另外，本发明还涉及该类化合物的制备方法、含有该类化合物的药物组合物以及该类化合物用于制备治疗与WDR5活性异常相关疾病或病症的药物的用途。
背景技术
WDR5属于WD40域重复蛋白家族(WD40-repeat protein)，WD40是一个重要的结构域，由40个左右的氨基酸残基组成，WDR域含有圆环形状的七叶β-螺旋桨结构域，每个叶片各含有保守的丝氨酸-组氨酸(SH)和色氨酸-天冬氨酸(WD)序列。WDR5蛋白含有一个7叶β-螺旋形成的中心空腔，贯穿上下。WDR5蛋白主要通过一个深的精氨酸结合口袋，即WIN位点与MLL1组成核心催化复合物发挥调控作用，与其他蛋白构成MWRAD(MLL1，WDR5，RbBP5，ASH2L及DYP-30)核心催化复合物，催化组蛋白H3甲基化，激活基因转录参与表观调控。
在真核生物中广泛存在的MLL家族蛋白复合体，是一类重要的组蛋白甲基转移酶，催化组蛋白H3K4的甲基化，通过催化H3K4甲基化/或通过招募其它转录相关蛋白与中介因子，激活转录，在发育过程中扮演了至关重要的角色。而这些蛋白的突变，包括基因组易位使它与其它转录因子融合，则会造成多种疾病，如混合谱系白血病(MLL)，淋巴瘤，Kabuki综合征等。研究人员通过解析人源MLL1与MLL3复合物催化中心与核小体结合时的多个高分辨率电镜结构，发现MLL1是3775-3786位氨基酸(MLL1 AS,activation segment)插入到了WDR5的桶装结构中心，而MLL3是SET结构域氨基端插入WDR5中。以WDR5作为药物靶点，针对WDR5与组蛋白和MLL1结合的WIN口袋而设计的化合物，可以降低WDR5下游的基因表达，治疗MLL重排依赖的白血病。
TP53基因是肿瘤中最常见的变异基因，在人类癌症中有50％发生TP53突变。 错义突变的高频率和突变p53(mp53)蛋白在癌细胞中的高表达水平促使mp53蛋白具有新的功能(“功能获得”(GOF))，同时也积极促进了癌症的发展和进展。p53基因突变驱动的肿瘤细胞的生长依赖于WDR5与MLL的结合。MLL、MOZ及组蛋白修饰，都受GOF p53的表达调控。因此，WDR5蛋白相互作用抑制剂也可用于治疗TP53突变的肿瘤。
WDR5的WIN位点抑制剂还能够抑制MYC和WDR5共结合的基因座。MYC是一类具有转录因子功能的癌蛋白，在大部分恶性肿瘤中均存在过表达现象。MYC能与数千个靶基因的调控序列结合，调节靶基因表达，影响细胞生长、增殖、代谢、基因组稳定和凋亡等过程。早期研究已发现MYC与染色质的广泛结合也依赖于WDR5的相互作用，MYC通过其进化保守的“MYC box IIIb”序列结合在WDR5表面的疏水裂隙，在体内肿瘤发生过程中发挥了重要作用。因此，通过阻断WDR5蛋白-蛋白相互作用可以阻断MYC功能，抑制MYC驱动癌症发生的能力。
因此，本领域急需开发结构新颖、生物活性好，成药性高的WDR5蛋白-蛋白相互作用抑制剂。
发明内容
本发明的目的在于提供一种式I化合物或其药学上可接受的盐，含有该化合物或其药学上可接受的盐的药物组合物，以及该化合物或其药物组合物在预防和治疗与WDR5异常相关的疾病或病症中的应用。
在本发明的一个方面，提供一种式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物：
Figure PCTCN2021137254-appb-000001
式中，
环A为取代或未取代的3-8元饱和或不饱和碳环或取代或未取代的3-8元饱和 或不饱和杂环，所述杂环含有1-2个独立选自N、O和S的杂原子；
X 3选自CR 5和N；
X 4选自任选取代的-(CH 2) n-、-C(＝O)-和NR 6，其中，n为1、2或3；
X 5选自N和CR 5；
L 1选自键、任选取代的C1-C6亚烷基、任选取代的C1-C6亚烷基-O-、任选取代的C1-C6亚烷基-NH-、任选取代的C1-C6亚烷基-S-和任选取代的C2-C4亚链烯基；
L 2选自键、任选取代的C1-C6亚烷基、任选取代的C1-C6亚烷基-O-、任选取代的C1-C6亚烷基-NH-、任选取代的C1-C6亚烷基-S-和任选取代的C2-C4亚链烯基；
R 0选自H、C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6卤代烷基、-C(O)NR 3R 4、-CH 2OR 3和-NR 3R 4取代的C1-C6烷基；
R 1选自任选取代的环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、任选取代的氨基和胍基；
R 2选自任选取代的环烷基、任选取代的芳基、任选取代的杂芳基和任选取代的杂环基；
R 3和R 4各自独立选自H、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6卤代烷基、任选取代的4-10元杂环基和任选取代的5-10元杂芳基；或者，R 3和R 4与其所连接的氮原子一起形成任选取代的4-10元杂环基或5-10元杂芳基；
R 5选自H、卤素、C1-C6烷基、卤代C1-C6烷基和C1-C6烷氧基；
R 6选自H、C1-C6烷基、卤代C1-C6烷基和C1-C6烷氧基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A为C3-C8环烷基或3-7元杂环基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A选自环丙基、环丁基、环戊基、环己基、氮杂环丙基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、氧杂环丙基、氧杂环丁基、四氢呋喃基、四氢吡喃基和吗啉基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A被1、2或3个选自卤素、羟基、氰基、C1-C6烷基、卤代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b、-NR aR b取代的羰基、-NR aR b取代的C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基羰基、任选取代的6-14元芳基、任选取代的5-10元杂芳基、任选取代的4-10元杂环基、任选取代的C3-C8环烷基、任选取代的6-14元芳基取代的C1-C6烷基、任选取代的5-10元杂芳基取代的C1-C6烷基、任选取代的4-10元杂环基取代的C1-C6烷基、和任选取代的C3-C8环烷基取代的C1-C6烷基的取代基取代；其中，所述6-14元芳基、5-10元杂芳基、4-10元杂环基和C3-C8环烷基被取代时，取代基为1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b、-NR aR b取代的羰基、-NR aR b取代的C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基羰基的取代基；并且其中，所述R a和R b各自独立选自H和C1-C6烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A为环丙基、环丁基、环戊基、氮杂环丁基、氧杂环丁基、氮杂环戊基或四氢呋喃基，
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A任选地被1、2或3个选自F、Cl、Br、CF 3、CH 3、-OH、-OCH 3、-NH 2、-NHCH 3,-NH 2(CH 3) 2的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 0为-NR 3R 4取代的C1-C6烷基；其中，R 3和R 4各自独立选自H，任选被1、2、3、4、5或6个选自卤素、氰基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的C1-C6烷基，或者R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000002
所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌 嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000003
各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、羟基和卤代C1-C6烷基羰基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 0为-NR 3R 4取代的C1-C6烷基，并且其中，R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000004
所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000005
各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、-NR aR b和羟基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 0为-NR 3R 4取代的C1-C6烷基，其中，R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000006
所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯 并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000007
各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代；其中，R a和R b各自独立为H或C1-C4烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，X 3和/或X 5为CR 5。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 5选自H和C1-C4烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，X 4为-(CH 2) n-，n为1或2；并且其中，所述-(CH 2) n-任选被1或2个选自卤素、羟基、氨基、C1-C6烷基和卤代C1-C6烷基的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，L 1选自C1-C6亚烷基、C1-C6亚烷基-O-、C1-C6亚烷基-NH-、C1-C6亚烷基-S-和C2-C4亚链烯基，所述C1-C6亚烷基、C1-C6亚烷基-O-、C1-C6亚烷基-NH-、C1-C6亚烷基-S-和C2-C4亚链烯基任选被1、2或3个选自卤素、C1-C4烷基和羟基的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，L 1选自任选被1、2或3个选自卤素、C1-C4烷基和羟基的取代基取代的C1-C6亚烷基或C1-C6亚烷基-NH-。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 1选自任选取代的C3-C8环烷基、任选取代的6-14元芳基、任选取代的5-10元杂芳基和任选取代的4-10元杂环基，并且所述环烷基、芳基、杂芳基和杂环基各自可任选地被1、2或3个选自任选取代的氨基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、C1-C6卤代烷基和氰基的取代基取代；其中，所述任选取代的 氨基是-NR aR b，其中，R a和R b各自独立为H或C1-C6烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 1选自任选取代的苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并咪唑基、吡啶并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基、
Figure PCTCN2021137254-appb-000008
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，所述L 1为C1-C4亚烷基或C1-C4亚烷基-NH-，R 1为吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基或
Figure PCTCN2021137254-appb-000009
所述吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基或
Figure PCTCN2021137254-appb-000010
任选被1或2个选自卤素、C1-C4烷基和-NR aR b的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，L 2选自键和C1-C6亚烷基，其中，所述C1-C6亚烷基任选地被1、2或3个选自卤素、C1-C3烷基、C3-C5环烷基和羟基的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 2任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷 基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代；其中，R a和R b各自独立为H或C1-C6烷基；并且其中，所述杂芳基优选为含有1或2个环氮原子的杂芳基，优选选自吡唑基、咪唑基、吡啶基、吡嗪基和哌嗪基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 2选自6-14元芳基、5-10元杂芳基和4-10元杂环基，所述6-14元芳基、5-10元杂芳基和4-10元杂环基任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 2选自苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、
Figure PCTCN2021137254-appb-000011
所述苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、
Figure PCTCN2021137254-appb-000012
任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的其取 代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，L 2为C1-C4亚烷基，R 2为被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代的6-14元芳基、5-10元含氮杂芳基或4-10元杂环基，优选为苯基、吡啶基、吡唑基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基或吲哚基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A为C3-C6环烷基或4-8元杂环基，所述环烷基或杂环基任选地被1、2或3个选自卤素、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基的取代基取代；
X 3和X 5均为CH；
X 4为CH 2；
L 1为C1-C4亚烷基；
R 1为任选被1或2个选自卤素、C1-C4烷基和-NR aR b的取代基取代的5或6元含氮杂芳基，所述5或6元含氮杂芳基优选为吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基或
Figure PCTCN2021137254-appb-000013
其中，R a和R b各自独立为H或C1-C4烷基；
L 2为C1-C4亚烷基；
R 2为苯基、5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基或吲哚基，所述苯基、5-10元含氮杂芳基和4-10元杂环基各自任选地被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代；
R 0为-NR 3R 4取代的C1-C4烷基；其中，R 3和R 4各自独立选自H，任选被1-6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基和任选被1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和 羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；优选地，所述4-8元杂环基各自独立选自氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基、吗啉基、
Figure PCTCN2021137254-appb-000014
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A为C3-C6环烷基，所述环烷基任选地被1、2或3个选自卤素、C1-C4烷基和卤代C1-C4烷基的取代基取代；
X 3和X 5均为CH；
X 4为CH 2；
L 1为C1-C4亚烷基；
R 1为被1或2个选自C1-C4烷基和-NR aR b的取代基取代的5或6元含氮杂芳基，优选为吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、或
Figure PCTCN2021137254-appb-000015
其中，R a和R b各自独立为H或C1-C4烷基；
L 2为C1-C4亚烷基；
R 2为5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基或吲哚基，所述5-10元含氮杂芳基或4-10元杂环基各自任选被1或2个选自C1-C6烷氧基、C1-C6烷基、C3-C8环烷基-O-、卤代C1-C6烷氧基、卤素和氰基的取代基取代；
R 0为-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H和任选被1、2、3、4、5或6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基，或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、羟基、C1-C4烷氧基、C3-C6烷氧基和C1-C4烷基取代的4-8元杂环基，优选地，所述4-8元杂环基选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、
Figure PCTCN2021137254-appb-000016
在本发明的一个方面，提供了式II化合物，或其药学上可接受的盐，或其对映 异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物：
Figure PCTCN2021137254-appb-000017
其中，
环A为取代或未取代的3-8元饱和或不饱和碳环或取代或未取代的3-8元饱和或不饱和杂环，所述杂环含有1-2个独立选自N、O和S的杂原子；
L 2选自键、任选取代的C1-C6亚烷基、任选取代的C1-C6亚烷基-O-、任选取代的C1-C6亚烷基-NH-、任选取代的C1-C6亚烷基-S-和任选取代的C2-C4亚链烯基；
R 0选自H、C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6卤代烷基、-C(O)NR 3R 4、-CH 2OR 3、-NR 3R 4取代的C1-C6烷基；
R 2选自任选取代的环烷基、任选取代的芳基、任选取代的杂芳基和任选取代的杂环基；
R 3和R 4各自独立选自H、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6卤代烷基、任选取代的4-10元杂环基和任选取代的5-10元杂芳基；或者，R 3和R 4与其所连接的氮原子一起形成任选取代的4-10元杂环基或5-10元杂芳基；并且
R c和R d各自独立为H或C1-C4烷基。
特别地，在本发明所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A为C3-C8环烷基或3-7元杂环基。
特别地，在本发明所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A选自环丙基、环丁基、环戊基、环己基、氮杂环丙基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、氧杂环丙基、氧杂环丁基、四氢呋喃基、四氢吡喃基 和吗啉基。
特别地，在本发明所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A被1、2或3个选自卤素、羟基、氰基、C1-C6烷基、卤代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b、C1-C6烷基羰基和C1-C6烷氧基羰基的取代基取代，所述R a和R b各自独立选自H和C1-C6烷基。
特别地，在本发明所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A为环丙基、环丁基、环戊基、环己烷、氮杂环丁基、氧杂环丁基、氮杂环戊基、四氢呋喃基或氧杂环己烷。
特别地，在本发明所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A任选地被1、2或3个选自F、Cl、Br、CF 3、CH 3、-OH、-OCH 3、-NH 2、-NHCH 3,-NH 2(CH 3) 2的取代基取代。
特别地，在本发明所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 0为-NR 3R 4取代的C1-C6烷基；其中，R 3和R 4各自独立选自H，任选被1、2、3、4、5或6个选自卤素、氰基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的C1-C6烷基，或者R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000018
所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000019
各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、-NR aR b和 羟基的取代基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
特别地，在本发明所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 0为-NR 3R 4取代的C1-C6烷基，并且其中，R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000020
其中，各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、-NR aR b和羟基的取代基取代；其中，R a和R b各自独立为H或C1-C4烷基。
特别地，在本发明所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 0为-NR 3R 4取代的C1-C6烷基，其中，R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000021
所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000022
各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代；其中，R a和R b各自独立为H或C1-C4烷基。
特别地，在本发明所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R c和R d各自独立为H或甲基。
特别地，在本发明所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代 谢产物中，L 2选自键和C1-C6亚烷基，其中，所述C1-C6亚烷基任选地被1、2或3个选自卤素、C1-C3烷基、C3-C5环烷基和羟基的取代基取代。
特别地，在本发明所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 2任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代；其中，R a和R b各自独立为H或C1-C6烷基；并且其中，所述杂芳基优选为含有1或2个环氮原子的杂芳基，优选选自吡唑基、咪唑基、吡啶基、吡嗪基和哌嗪基。
特别地，在本发明所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 2选自6-14元芳基、5-10元杂芳基和4-10元杂环基，所述6-14元芳基、5-10元杂芳基和4-10元杂环基可任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代。
特别地，在本发明所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 2选自苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、
Figure PCTCN2021137254-appb-000023
所述苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯 并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、
Figure PCTCN2021137254-appb-000024
任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代。
特别地，在本发明所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，L 2为C1-C4亚烷基，R 2为苯基、吡啶基、吡唑基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基或吲哚基，所述苯基、吡啶基、吡唑基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基或吲哚基任选地被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代。
特别地，在本发明所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A为任选被选自F、Cl、羟基或C1-C4烷基的取代基取代的C3-C6环烷基或含1个氮或1个O的C4-C6杂环基，优选为任选被F或C1-C4烷基取代的环丙基、环丁基、氧杂环丁基或氮杂环丁基；
R 0为H或-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H、4-6元杂环基和任选被1、2、3、4、5或6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基，或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、羟基、C1-C4烷氧基、C3-C6环烷基和C1-C4烷基取代的4-6元杂环基；其中，所述4-6元杂环基优选为含氧和/或氮的杂环基，优选选自氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、2-哌嗪酮基、四氢吡喃基、吗啉基、
Figure PCTCN2021137254-appb-000025
L 2为C1-C4亚烷基；
R 2为6-14元芳基、5-10元含氮杂芳基或4-10元杂环基，优选为苯基、吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吲哚基、吡咯并吡啶基、吡啶并二氢 呋喃基、吡啶并1,3-二氧环戊烯基、
Figure PCTCN2021137254-appb-000026
所述6-14元芳基、5-10元含氮杂芳基或4-10元杂环基各自任选被1或2个选自C1-C6烷氧基、C1-C4烷基、卤素、C3-C6环烷基-氧基、卤代C1-C4烷氧基和氰基的取代基取代；
R c和R d各自独立为H或C1-C4烷基。
特别地，在本发明所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A为C3-C6环烷基或4-8元杂环基，所述环烷基或杂环基任选地被1、2或3个选自卤素、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基的取代基取代；
L 2为C1-C4亚烷基；
R 2为苯基、5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基或吲哚基，所述苯基、5-10元含氮杂芳基和4-10元杂环基各自任选地被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代；
R 0为-NR 3R 4取代的C1-C4烷基；其中，R 3和R 4各自独立选自H，任选被1-6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基和任选被1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；优选地，所述4-8元杂环基各自独立选自氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、2-哌嗪酮基、四氢吡喃基、吗啉基、
Figure PCTCN2021137254-appb-000027
并且
R c和R d各自独立为H或C1-C4烷基。
特别地，在本发明所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A为C3-C6环烷基，所述环烷基任选地被1、2或3个选自卤素、C1- C4烷基和卤代C1-C4烷基的取代基取代；
L 2为C1-C4亚烷基；
R 2为5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基或吲哚基，所述5-10元含氮杂芳基或4-10元杂环基各自任选被1或2个选自C1-C6烷氧基、C1-C6烷基、C3-C8环烷基-O-、卤代C1-C6烷氧基、卤素和氰基的取代基取代；
R 0为-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H和任选被1、2、3、4、5或6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基，或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、羟基、C1-C4烷氧基和C1-C4烷基取代的4-8元杂环基，优选地，所述4-8元杂环基选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、
Figure PCTCN2021137254-appb-000028
并且
R c和R d各自独立为H或C1-C4烷基。
在本发明的另一方面.提供了式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，
Figure PCTCN2021137254-appb-000029
其中，
L 2选自键、任选取代的C1-C6亚烷基、任选取代的C1-C6亚烷基-O-、任选取代的C1-C6亚烷基-NH-、任选取代的C1-C6亚烷基-S-和任选取代的C2-C4亚链烯基；
R 0选自H、C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6卤代烷基、-C(O)NR 3R 4、-CH 2OR 3、-NR 3R 4取代的C1-C6烷基；
R 2选自任选取代的环烷基、任选取代的芳基、任选取代的杂芳基和任选取代的 杂环基；
R 3和R 4各自独立选自H、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6卤代烷基、任选取代的4-10元杂环基和任选取代的5-10元杂芳基；或者，R 3和R 4与其所连接的氮原子一起形成任选取代的4-10元杂环基或5-10元杂芳基；
X 6各自独立选自C、O、N、S，
q为1、2或3的整数，
R 7选自F、Cl、氰基、羟基、C1-C6烷基、氟代或氯代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、氟代或氯代C1-C6烷氧基、羟基取代的C1-C6烷基和-NR aR b；其中，所述R a和R b各自独立选自H和C1-C6烷基，
m为0、1、2或3的整数；并且
R c和R d各自独立为H或C1-C4烷基。
特别地，在本发明所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 0为-NR 3R 4取代的C1-C6烷基；其中，R 3和R 4各自独立选自H，任选被1、2、3、4、5或6个选自卤素、氰基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的C1-C6烷基，或者R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000030
所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000031
各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、-NR aR b和羟基的取代基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
特别地，在本发明所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或 代谢产物中，R 0为-NR 3R 4取代的C1-C6烷基，并且其中，R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000032
所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000033
各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、-NR aR b和羟基取代；其中，R a和R b各自独立为H或C1-C4烷基。
特别地，在本发明所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 0为-NR 3R 4取代的C1-C6烷基，其中，R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000034
所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000035
各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代；其中，R a和R b各自独立为H或C1-C4烷基。
特别地，在本发明所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R c和R d各自独立为H或甲基。
特别地，在本发明所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或 代谢产物中，L 2选自键和C1-C6亚烷基，其中，所述C1-C6亚烷基任选地被1、2或3个选自卤素、C1-C3烷基、C3-C5环烷基和羟基的取代基取代。
特别地，在本发明所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 2任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代；其中，R a和R b各自独立为H或C1-C6烷基；并且其中，所述杂芳基优选为含有1或2个环氮原子的杂芳基，优选选自吡唑基、咪唑基、吡啶基、吡嗪基和哌嗪基。
特别地，在本发明所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 2选自6-14元芳基、5-10元杂芳基和4-10元杂环基，所述6-14元芳基、5-10元杂芳基和4-10元杂环基任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代。
特别地，在本发明所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 2选自苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、2-哌嗪酮基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、
Figure PCTCN2021137254-appb-000036
所述苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、2-哌嗪酮基、四氢吡喃基、四氢呋喃基、噁 嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、
Figure PCTCN2021137254-appb-000037
任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代。
特别地，在本发明所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，L 2为C1-C4亚烷基，R 2为被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代的6-14元芳基、5-10元含氮杂芳基或4-10元杂环基，优选为苯基、吡啶基、吡唑基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基或吲哚基。
特别地，在本发明所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 0为H或-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H、4-6元杂环基和任选被1、2、3、4、5或6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基，或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、羟基、C1-C4烷氧基和C1-C4烷基取代的4-6元杂环基；其中，所述4-6元杂环基优选为含氧和/或氮的杂环基，优选选自氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、2-哌嗪酮基、四氢吡喃基、吗啉基、
Figure PCTCN2021137254-appb-000038
Figure PCTCN2021137254-appb-000039
L 2为C1-C4亚烷基；
R 2为6-14元芳基、5-10元含氮杂芳基或4-10元杂环基，优选为苯基、吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吲哚基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基，所述6-14元芳基、5-10元含氮杂芳基或4-10元杂环基各自任选被1或2个选自C1-C6烷氧基、C1-C4烷基、卤素、C3-C6环烷基-氧基、卤代C1-C4烷氧基和氰基的取代基取代；
R c和R d各自独立为H或C1-C4烷基；
X 6为C或O；
q为1或2；并且
R 7选自F、Cl、氰基、羟基、C1-C6烷基、氟代或氯代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、氟代或氯代C1-C6烷氧基以及羟基取代的C1-C6烷基。
特别地，在本发明所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，L 2为C1-C4亚烷基；
R 2为苯基、5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基或吲哚基，所述苯基、5-10元含氮杂芳基和4-10元杂环基各自任选地被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代；
R 0为-NR 3R 4取代的C1-C4烷基；其中，R 3和R 4各自独立选自H，任选被1-6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基和任选被1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；优选地，所述4-8元杂环基各自独立选自氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、2-哌嗪酮基、四氢吡喃基、吗啉基、
Figure PCTCN2021137254-appb-000040
R c和R d各自独立为H或C1-C4烷基；
X 6为C或O；
q为1或2；并且
R 7选自F、Cl、氰基、羟基、C1-C6烷基、氟代或氯代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、氟代或氯代C1-C6烷氧基以及羟基取代的C1-C6烷基。
特别地，在本发明所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，L 2为C1-C4亚烷基；
R 2为5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基或吲哚基，所述5-10元含氮杂芳基或4-10元杂环基各自任选被1或2个选自C1-C6烷氧基、C1-C6烷基、C3-C8环烷基-O-、卤代C1-C6烷氧基、卤素和氰基的取代基取代；
R 0为-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H和任选被1、2、3、4、5或6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基，或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、羟基和C1-C4烷基取代的4-8元杂环基，优选地，所述4-8元杂环基选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、
Figure PCTCN2021137254-appb-000041
R c和R d各自独立为H或C1-C4烷基；
X 6为C或O；
q为1或2；并且
R 7选自F、Cl、氰基、羟基、C1-C6烷基、氟代或氯代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、氟代或氯代C1-C6烷氧基以及羟基取代的C1-C6烷基。
在本发明的另一方面.提供了一种式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物：
Figure PCTCN2021137254-appb-000042
式中，
环A为取代或未取代的3-8元饱和碳环或取代或未取代的3-8元饱和杂环，所述杂环含有1-2个独立选自N、O和S的杂原子；
X 3选自CR 5和N；
X 4选自任选取代的-(CH 2) n-、-C(＝O)-和NR 6，其中，n为1、2或3；
X 5选自N和CR 5；
L 1选自键、任选取代的C1-C6亚烷基、任选取代的C1-C6亚烷基-O-、任选取代的C1-C6亚烷基-NH-、任选取代的C1-C6亚烷基-S-和任选取代的C2-C4亚链烯基；
L 2选自键、任选取代的C1-C6亚烷基、任选取代的C1-C6亚烷基-O-、任选取代的C1-C6亚烷基-NH-、任选取代的C1-C6亚烷基-S-和任选取代的C2-C4亚链烯基；
R 0选自任选取代的C1-C6卤代烷基、-C(O)NR 3R 4、-CH 2OR 3和-NR 3R 4取代的C1-C6烷基；
R 1选自任选取代的环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、任选取代的氨基和胍基；
R 2选自任选取代的环烷基、任选取代的芳基、任选取代的杂芳基和任选取代的杂环基；
R 3和R 4各自独立选自H、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6卤代烷基、任选取代的4-10元杂环基和任选取代的5-10元杂芳基；或者，R 3和R 4与其所连接的氮原子一起形成任选取代的4-10元杂环基或5-10元杂芳基；
R 5选自H、卤素、C1-C6烷基、卤代C1-C6烷基和C1-C6烷氧基；并且
R 6选自H、C1-C6烷基、卤代C1-C6烷基和C1-C6烷氧基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A为C3-C8环烷基或3-7元杂环基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A选自环丙基、环丁基、环戊基、环己基、氮杂环丙基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、氧杂环丙基、氧杂环丁基、四氢呋喃基、四氢吡喃基和吗啉基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A被1、2或3个选自卤素、羟基、氰基、C1-C6烷基、卤代C1-C6 烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基和-NR aR b的取代基取代；其中，所述R a和R b各自独立选自H和C1-C6烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A为环丙基、环丁基、环戊基、氮杂环丁基、氧杂环丁基、氮杂环戊基或四氢呋喃基，
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A任选地被1、2或3个选自F、Cl、Br、CF 3、CH 3、-OH、-OCH 3、-NH 2、-NHCH 3,-NH 2(CH 3) 2的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 0为-NR 3R 4取代的C1-C6烷基；其中，R 3和R 4各自独立选自H，任选被1、2、3、4、5或6个选自卤素、氰基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的C1-C6烷基，或者R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000043
所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000044
各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、-NR aR b和羟基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 0为-NR 3R 4取代的C1-C6烷基，并且其中，R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡 啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000045
所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000046
各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、-NR aR b和羟基的取代基取代；其中，R a和R b各自独立为H或C1-C4烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 0为-NR 3R 4取代的C1-C6烷基，其中，R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000047
所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000048
各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代；其中，R a和R b各自独立为H或C1-C4烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，X 3和/或X 5为CR 5。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 5选自H和C1-C4烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构 体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，X 4为-(CH 2) n-，n为1或2；并且其中，所述-(CH 2) n-任选被1或2个选自卤素、羟基、氨基、C1-C6烷基和卤代C1-C6烷基的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，X 3和X 5均为CR 5；并且X 4为任选取代的-(CH 2)-。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，L 1选自C1-C6亚烷基、C1-C6亚烷基-O-、C1-C6亚烷基-NH-、C1-C6亚烷基-S-和C2-C4亚链烯基，所述C1-C6亚烷基、C1-C6亚烷基-O-、C1-C6亚烷基-NH-、C1-C6亚烷基-S-和C2-C4亚链烯基可任选被1、2或3个选自卤素、C1-C4烷基和羟基的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，L 1选自C1-C6亚烷基和C1-C6亚烷基-NH-，所述C1-C6亚烷基和C1-C6亚烷基-NH-任选被1、2或3个选自卤素、C1-C4烷基和羟基的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 1选自任选取代的C3-C8环烷基、任选取代的6-14元芳基、任选取代的5-10元杂芳基和任选取代的4-10元杂环基，并且所述环烷基、芳基、杂芳基和杂环基各自可任选地被1、2或3个选自任选取代的氨基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、C1-C6卤代烷基和氰基的取代基取代；其中，所述任选取代的氨基是-NR aR b，其中，R a和R b各自独立为H或C1-C6烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 1选自任选取代的苯基、萘基吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吡啶并咪唑基、吲哚基、异吲哚基、吲唑基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、 咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基、
Figure PCTCN2021137254-appb-000049
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，所述L 1为C1-C4亚烷基或C1-C4亚烷基-NH-，R 1为吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基或
Figure PCTCN2021137254-appb-000050
所述吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基或
Figure PCTCN2021137254-appb-000051
任选被1或2个选自卤素、C1-C4烷基和-NR aR b的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，L 2选自键和C1-C6亚烷基，其中，所述C1-C6亚烷基任选地被1、2或3个选自卤素、C1-C3烷基、C3-C5环烷基和羟基的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 2任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代；其中，R a和R b各自独立为H或C1-C6烷基；并且其中，所述杂芳基优选为含有1或2个环氮原子的杂芳基，优选选自吡唑基、咪唑基、吡啶基、吡嗪基和哌嗪基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 2选自6-14元芳基、5-10元杂芳基和4-10元杂环基，所述6-14元芳基、5-10元杂芳基和4-10元杂环基可任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 2选自苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、
Figure PCTCN2021137254-appb-000052
所述苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、
Figure PCTCN2021137254-appb-000053
任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，L 2为C1-C4亚烷基，R 2为6-14元芳基、5-10元含氮杂芳基或4-10元杂环基，所述6-14元芳基、5-10元含氮杂芳基或4-10元杂环基任选地被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代，优选为苯基、吡啶基、吡唑基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基或吲哚基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A为C3-C6环烷基或4-8元杂环基，所述环烷基或杂环基任选地被1、2或3个选自卤素、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基和卤代C1-C4烷氧基的取代基取代；
X 3和X 5均为CH；
X 4为CH 2；
L 1为C1-C4亚烷基；
R 1为
Figure PCTCN2021137254-appb-000054
L 2为C1-C4亚烷基；
R 2为苯基、5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基或吲哚基，所述苯基、5-10元含氮杂芳基和4-10元杂环基各自任选地被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代；
R 0为-NR 3R 4取代的C1-C4烷基；其中，R 3和R 4各自独立选自H，任选被1-6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基和任选被1、2或3个选自卤素、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；优选地，所述4-8元杂环基各自独立选自氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基、吗啉基、
Figure PCTCN2021137254-appb-000055
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A为C3-C6环烷基，所述环烷基任选地被1、2或3个选自卤素、C1-C4烷基和卤代C1-C4烷基的取代基取代；
X 3和X 5均为CH；
X 4为CH 2；
L 1为C1-C4亚烷基；
R 1为
Figure PCTCN2021137254-appb-000056
L 2为C1-C4亚烷基；
R 2为5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基或吲哚基，所述5-10元含氮杂芳基或4-10元杂环基各自任选被1或2个选自C1-C6烷氧基、C1-C6烷基、C3-C8环烷基-O-、卤代C1-C6烷氧基、卤素和氰基的取代基取代；
R 0为-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H和任选被1、2、3、4、5或6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基，或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、羟基、C1-C4烷氧基和C1-C4烷基取代的4-8元杂环基，优选地，所述4-8元杂环基选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、
Figure PCTCN2021137254-appb-000057
在本发明的另一方面.提供了以下化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，所述化合物选自：
Figure PCTCN2021137254-appb-000058
Figure PCTCN2021137254-appb-000059
Figure PCTCN2021137254-appb-000060
Figure PCTCN2021137254-appb-000061
Figure PCTCN2021137254-appb-000062
Figure PCTCN2021137254-appb-000063
以及
Figure PCTCN2021137254-appb-000064
在本发明的另一方面.提供了一种药物组合物，其含有本申请所述的化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，以及药学上可接受的载体或赋形剂。
在本发明的另一方面.提供了本申请所述的化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物在制备用于治疗或预防WDR5介导的疾病的药物中的应用。特别地，所述WDR5介导的疾病包括Kabuki综合征、以及各种实体瘤和血液肿瘤。特别地，所述WDR5介导的疾病包括努南综合症、豹综合症、成神经细胞瘤、肉瘤、黑色素瘤、关节软骨瘤、胆管瘤、白血病、乳腺癌、胃肠间质瘤、组织细胞性淋巴瘤、肺癌、食道癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、肾癌、口腔癌、头癌、成神经细胞瘤、头颈的鳞状细胞癌、间变性大细胞淋巴瘤或成胶质细胞瘤，其中，白血病优选为青少年髓单核细胞白血病、人髓性单核细胞白血病，肺癌优选为非小细胞肺癌、小细胞肺癌、肺鳞癌、和肺腺癌。
具体实施方式
本发明人经过长期而深入的研究，制备了一类具有式I所示的新颖的杂环化合物化合物，其能够通过阻断WDR5蛋白-蛋白相互作用，从而达到抑制肿瘤细胞生长的目的。本发明的化合物表现出很好的生物活性及可成药性，具有很好的药物开发前景，其在极低浓度(可低至≤100nM/L)下，即对WDR5蛋白-蛋白相互作用产生抑制作用，抑制活性相当优异，因而可以用于治疗与WDR5相关的疾病或病症，如肿瘤。基于上述发现，发明人完成了本发明。
术语
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性，其可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”之义。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4TH ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH 2O-等同于-OCH 2-。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C1-C6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。
在本申请中，术语“卤素”是指氟、氯、溴或碘。
“羟基”是指-OH基团。
“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基。
“羰基”是指-C(＝O)-基团。
“硝基”是指-NO 2。
“氰基”是指-CN。
“氨基”是指-NH 2。
“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、烷基取代的氨基羰基、芳烷基、杂芳烷基取代的氨基，例如，单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基、烷基氨基羰基氨基。
“羧基”是指-COOH。
在本申请中，作为基团或是其它基团的一部分(例如用在卤素(例如氟、氯、溴或碘)取代的烷基等基团中)，术语“烷基”是指完全饱和的直链或支链的烃链基，仅由碳原子和氢原子组成、具有例如1至12个(优选为1至8个，更优选为1至6个)碳原子，且通过单键与分子的其余部分连接。烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。更优选的烷基是C1-C4烷基。术语“亚烷基”指二价烷基基团，如-(CH 2) n-，其中，n为1-12的整数，优选为1-6的整数，更优选为1-4的整数。该二价烷基基团也可以是直链或支链基团，如-CH(CH 3)CH 2-、-CH 2CH(CH 3)CH 2-等。
在本申请中，作为基团或是其它基团的一部分，术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至20个(优选为2至10个，更优选为2至6个，更优选2至4个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烯基包括但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。术语“亚烯基”或“亚链烯基”指二价的烯基或链烯基，如-CH＝CH-、-CH 2-CH＝CH-等。
在本申请中，作为基团或是其它基团的一部分，术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个三键、具有例如2至20个(优选为2至10个，更优选为2至6个，更优选2至4个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。炔基包括但不限于乙炔基、丙炔基等。
在本申请中，作为基团或是其它基团的一部分，术语“烷氧基”意指“烷基-O-”，所述烷基如本文所定义。优选的烷氧基为C1-C6烷氧基，更优选为C1-C4烷氧基，包括但不限于甲氧基、乙氧基等。
在本申请中，作为基团或是其它基团的一部分，术语“环烃基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基(例如烷基、烯基或炔基)，其可包括稠合环体系、桥环体系或螺环体系，具有3至15个碳原子，优选具有3至10个碳原子，更优选具有3至8个碳原子，例如3、4、5、6、7或8个碳原子，且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明，环烃基中的碳原子可以任选地被氧化。优选地，术语“环烃基”指环碳原子数为3-8个的环烷基。环烃基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯并基等。环烃基也包括二价基团，即通过两个键与分子的其余部分连接；连接可发生在同一个环碳原子上，也可发生在不同环碳原子上。
在本申请中，作为基团或是其它基团的一部分，术语“杂环基”意指由2至14个碳原子(例如2、3、4、5、6、7、8、9、10、11、12、13或14个碳原子)以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；其杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至10元非芳香性单环、双环、桥环或螺环基团。在一些实施方案中，杂环基的环原子数为4-9个、4-8个或4-7个。在一些实施方案中，杂环基的环原子数为3-8个，优选为3-7个，更优选为3-6个。杂环基的实例包括但不限于：杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6- 氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、邻苯二甲酰亚氨基等。
在本申请中，作为基团或是其它基团的一部分，术语“芳基”意指具有6至18个碳原子，如6至14个碳原子(优选具有6至10个碳原子，例如6、7、8、9或10个碳原子)的共轭烃环体系基团。就本发明的目的而言，芳基可以为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。
在本申请中，术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子，例如1、2、3、4、5、6、7、8、9或10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元、优选5-10元共轭环系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团，更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、吡咯并吡啶基、苯并吡咯基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁 唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]三唑并[4,3-b]哒嗪、[1,2,4]三唑并[4,3-a]吡嗪、[1,2,4]三唑并[4,3-c]嘧啶、[1,2,4]三唑并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。
在本申请中，术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。
在本申请中，“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。本发明权利要求书和说明书部分所述的“任选”的取代基包括但不限于烷基、烯基、炔基、卤素、卤代烷基、卤代环氧基、卤代烯基、卤代炔基、氰基、环烷基-O-、硝基、氨基、任选取代的氨基、烷氧基、环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的环烃基和任选取代的杂环基中的一个或多个。在优选的实施方案中，取代基包括但不限于C1-C6烷基、卤代烷基、卤代环氧基、环烷基、氨基、C1-C6烷基取代的氨基、卤素、氰基、C3-C8环烷基-O-、芳基和杂芳基中的一个或多个。在本申请中，当被取代时，视被取代的基团的结构，取代基的数量可以是1-5个，如1-3个。例如，苯基可被1-3个选自C1-C6烷氧基、C3-C8环烷基-O-、卤素和氨基的取代基取代。
本文中，“WDR5”指WD40域重复家族蛋白5，WD40域指的是包含大约40个氨基酸(典型由甘氨酸-组氨酸和色氨酸-天冬氨酸)支撑的最小保守单元。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi  Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
式I化合物
本发明的式I化合物具有下式结构：
Figure PCTCN2021137254-appb-000065
式中：
环A为取代或未取代的3-8元饱和或不饱和碳环、取代或未取代的3-8元饱和或不饱和杂环，所述杂环含有1-2个独立选自N、O和S的杂原子；
X 3选自CR 5和N；
X 4选自任选取代的-(CH 2) n-、-C(＝O)-和NR 6，其中，n为1、2或3；
X 5选自N和CR 5；
L 1选自键、任选取代的C1-C6亚烷基、任选取代的C1-C6亚烷基-O-、任选取代的C1-C6亚烷基-NH-、任选取代的C1-C6亚烷基-S-和任选取代的C2-C4亚链烯基；
L 2选自键、任选取代的C1-C6亚烷基、任选取代的C1-C6亚烷基-O-、任选取代的C1-C6亚烷基-NH-、任选取代的C1-C6亚烷基-S-和任选取代的C2-C4亚链烯基；
R 0选自H、C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6卤代烷基和-NR 3R 4取代的C1-C6烷基；
R 1选自任选取代的环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、任选取代的氨基和胍基；
R 2选自任选取代的环烷基、任选取代的芳基、任选取代的杂芳基和任选取代的杂环基；
R 3和R 4各自独立选自H、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6卤代烷基、任选取代的4-10元杂环基和任选取代的5-10元杂芳基；或者，R 3和R 4与其所连接的氮原子一起形成任选取代的4-10元杂环基或5-10 元杂芳基；
R 5选自H、卤素、C1-C6烷基、卤代C1-C6烷基和C1-C6烷氧基；
R 6选自H、C1-C6烷基、卤代C1-C6烷基和C1-C6烷氧基。
优选地，环A为C3-C8环烷基，如环丙基、环丁基、环戊基或环己基；或者，环A为3-7元杂环基，如氮杂环丙基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、氧杂环丙基、氧杂环丁基、四氢呋喃基、四氢吡喃基和吗啉基等。应理解，本文所述的环A的基团包括环A与含X 4的环共用的C原子。
优选地，环A可任选地被1、2或3个选自卤素、氰基、羟基、C1-C6烷基、卤代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、羟基取代的C1-C6烷基、-NR aR b、-NR aR b取代的羰基、-NR aR b取代的C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基羰基、任选取代的6-14元芳基、任选取代的5-10元杂芳基、任选取代的C3-C8环烷基、任选取代的4-10元杂芳基、任选取代的6-14元芳基取代的C1-C6烷基、任选取代的5-10元杂芳基取代的C1-C6烷基、任选取代的4-10元杂芳基取代的C1-C6烷基和任选取代的C3-C8环烷基取代的C1-C6烷基的取代基取代；优选的取代基为卤素、C1-C6烷基、卤代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、羟基取代的C1-C6烷基、-NR aR b、-NR aR b取代的羰基、-NR aR b取代的C1-C6烷基、C1-C6烷基羰基和C1-C6烷氧基羰基中的一个或多个。其中，所述6-14元芳基、5-10元杂芳基、4-10元杂芳基和C3-C8环烷基被取代时，取代基可为1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b、-NR aR b取代的羰基、-NR aR b取代的C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基羰基的取代基。其中，所述R a和R b各自独立选自H和C1-C6烷基。环A被取代时，取代基可在C上，也可在N上。
在优选的实施方案中，环A为C3-C6环烷基或3-6元杂环基，其任选被1、2或3个选自C1-C4烷基、卤代C1-C4烷基、羟基取代的C1-C4烷基、-NR aR b取代的羰基和-NR aR b取代的C1-C4烷基的取代基取代，其中，所述R a和R b各自独立选自H和C1-C4烷基。
优选地，X 3为CR 5。
优选地，R 5选自H和C1-C4烷基。
优选地，X 4为-(CH 2) n-，n为1或2。
优选地，当X 4为-(CH 2) n-且被取代时，取代基的数量可以是1或2个，取代基可选自卤素、羟基、氨基、C1-C6烷基和卤代C1-C6烷基，优选为卤素和C1-C6烷基。
优选地，L 1选自键、C1-C6亚烷基、C1-C6亚烷基-O-、C1-C6亚烷基-NH-、C1-C6亚烷基-S-和C2-C4亚链烯基，更优选为C1-C6烷基或C1-C6亚烷基-NH-。L 1可任选地被取代，取代基可选自卤素、C1-C4烷基和羟基，取代基的数量可以是1、2或3个。应理解，当所述C1-C6烷基和C1-C6亚烷基-被C1-C4烷基取代时，可形成支链烷基或支链亚烷基。
优选地，R 1选自任选取代的C3-C8环烷基、任选取代的6-14元芳基、任选取代的5-10元杂芳基和任选取代的4-10元杂环基。R 1中，优选的6-14元芳基包括苯基和萘基。R 1中，优选的5-10元杂芳基是具有一个或多个(如4个以内或3个以内)环氮原子的杂芳基，尤其是5元或6元含氮杂芳基，包括但不限于吡啶基、吡咯基、吡唑基、咪唑基、三唑基(如连三唑基、1,2,4-三唑基、1,2,5-三唑基和1,3,4-三唑基)、嘧啶基、吡嗪基、三嗪基。杂芳基还可以是稠合环，包括但不限于吲哚基、异吲哚基、吲唑基、苯并咪唑基、苯并三唑基、苯并噁唑基、吡咯并吡啶基、苯并异噁唑基、喹啉基等。优选的杂芳基是吡啶基、吡咯基、咪唑基和三唑基，更优选为咪唑基和吡啶基。优选地，当R 1为杂芳基时，其通过杂芳环上的氮原子与L 1连接。R 1中，优选的5-10元杂环基包括但不限于吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。R 1中，所述的环烷基、芳基、杂芳基和杂环基各自可任选地被1、2或3个取代基取代，优选的取代基可选自任选取代的氨基、烷基(如C1-C6烷基)、卤素、羟基、烷氧基(如C1-C6烷氧基)、卤代烷基(如C1-C6卤代烷基)和氰基等；其中，任选取代的氨基可以是-NR aR b，其中，R a和R b各自独立为H或C1-C6烷基；更优选地，所述环烷基、芳基、杂芳基和杂环基上的取代基可独立为所述任选取代的氨基、卤素、烷基和氰基。R 1为任选取代的氨基或胍基时，该氨基上的取代基可以是任选被烷基取代的氨基羰基，即NR aR b-CO-，其中，R a和R b各自独立为H或C1-C6烷基。特别优选的R 1是取代的氨基、卤素、烷基和/或氰基取代的5元或6元含氮杂芳基，尤其是取代的氨基、卤 素、烷基和/或氰基取代的咪唑基、嘧啶基、三唑基、吡啶基、吡嗪基、吡咯基和吡唑基等，更优选的是取代的氨基、卤素、烷基和/或氰基取代的咪唑基和吡啶基，其中，取代的氨基优选是-NR aR b，其中，R a和R b各自独立为H或C1-C6烷基。
在特别优选的实施方案中，环A为环丙基、环丁基、环戊基、氮杂环丁基、氧杂环丁基、氮杂环戊基或四氢呋喃基，其任选地被1、2或3个选自F、Cl、Br、CF 3、CH 3、-OH、-OCH 3、-NH 2、-NHCH 3,-NH 2(CH 3) 2的取代基取代。
在特别优选的实施方案中，所述L 1为C1-C4亚烷基或C1-C4亚烷基-NH-，R 1为任选被1或2个选自卤素、氰基、C1-C4烷基和-NR aR b的取代基取代的5或6元含氮杂芳基，优选为吡啶基、吡咯基、吡唑基、咪唑基、咪唑酮基、吡啶并吡咯基、噁唑酮基、噁唑烷酮基、三唑基、嘧啶基、吡嗪基、三嗪基，其中，R a和R b各自独立为H或C1-C4烷基。所述亚烷基可以是直链或支链亚烷基。
优选地，L 2可选自键、C3-C5环烷基和C1-C6亚烷基。L 2可任选地被选自卤素、C1-C3烷基、C3-C5环烷基和羟基的取代基取代，取代基的数量可以是1、2或3个。优选的L 2为任选取代的C1-C4亚烷基。该亚烷基可以是直链或支链亚烷基。
优选地，R 2选自任选取代的6-14元芳基、任选取代的5-10元杂芳基和任选取代的4-10元杂环基，更优选为任选取代的单环或双环芳基、单环或双环杂芳环或单环或双环杂环基。R 2中，所述芳基优选为苯基或萘基。所述杂芳基优选是一个或多个(如4个以内或3个以内)环氮原子的杂芳基，尤其是5元或6元含氮杂芳基，包括但不限于吡啶基、吡咯基、吡唑基、咪唑基、三唑基(如连三唑基、1,2,4-三唑基、1,2,5-三唑基和1,3,4-三唑基)、嘧啶基、吡嗪基、三嗪基。所述杂芳基还可以是稠合环，包括但不限于吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、吡咯并吡啶基、苯并异噁唑基、喹啉基等。优选的杂芳基是吡啶基、吡唑基、吡咯并吡啶基、或吲哚基。R 2中，所述杂环基优选为杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基等。
优选地，R 2上的取代基可为1、2或3个，优选选自任选取代的氨基、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、 C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基(如苯基)、5-10元杂芳基(优选含有1或2个环氮原子的杂芳基，如吡唑基、咪唑基、吡啶基、吡嗪基、哌嗪基等)、4-10元杂环基(如氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基、吗啉基等)和氰基等；其中，任选取代的氨基可以是-NR aR b，其中，R a和R b各自独立为H或C1-C6烷基。R 2上特别优选的取代基为C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基。优选地，R 2上的取代基至少包括C1-C6烷氧基、卤代C1-C6烷氧基或C3-C8环烷基氧基。优选地，R 2上的取代基数量为2个，优选地其中至少一个取代基为C1-C6烷氧基、卤代C1-C6烷氧基或C3-C8环烷基氧基。在一些实施方案中，优选地，所述C1-C6烷氧基、卤代C1-C6烷氧基或C3-C8环烷基氧基位于R 2与L 2连接的C的间位。
优选地，R 2为任选被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代的苯基。
优选地，R 2为任选被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代的5-10元含氮杂芳基(如吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、或吲哚基等)或4-10元杂环基，如吡啶并二氢呋喃基和吡啶并1,3-二氧环戊烯基等。
优选地，式I中，L 2为C1-C4亚烷基，R 2为被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代的6-14元芳基(如苯基)或5-10元含氮杂芳基(如吡啶基、吡唑基、吡咯并吡啶基、或吲哚基)或4-10元杂环基(如吡啶并二氢呋喃基和吡啶并1,3-二氧环戊烯基)。
优选地，在一些实施方案中，R 0为H。在一些实施方案中，R 0为-NR 3R 4取代的C1-C6烷基，其中，R 3和R 4各自独立选自H、任选取代的C1-C6烷基、任选取代的4-10元杂环基和任选取代的5-10元杂芳基。所述C1-C6烷基可任选地被1、2、3、4、5或6个选自卤素、氰基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。所述4-10元杂环基包括但不限于含氮和/或氧的杂环基，如氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基、吗啉基等。所述5-10元杂芳基包括但不限于5-10元含氮和/或氧杂芳基，如吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基和喹啉基等。所述4-10元杂环基和5-10 元杂芳基各自可任选地被1、2或3个选自卤素、氰基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。优选地，R 3和R 4不同时为所述任选取代的4-10元杂环基或所述任选取代的5-10元杂芳基或两者。
优选地，在一些实施方案中，R 3和R 4与其所连接的氮原子一起形成任选取代的4-10元杂环基或5-10元杂芳基。所述4-10元杂环基包括但不限于含氮和/或氧的杂环基，如氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基等。所述5-10元杂芳基包括但不限于5-10元含氮和/或氧杂芳基，如吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基和喹啉基等。所述4-10元杂环基和5-10元杂芳基各自可任选地被1、2或3个选自卤素、氰基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
优选地，式I中，R 0为-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H、任选取代的C1-C6烷基和任选取代的4-8元杂环基，或R 3和R 4与其所连接的氮原子一起形成任选取代的4-8元杂环基；进一步优选地，所述C1-C6烷基任选地被1-6个选自羟基、氰基和卤素的取代基取代，所述4-8元杂环基各自任选地被1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、-NR aR b和羟基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基；进一步优选地，所述4-8元杂环基各自独立选自氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基和吗啉基。
在式I的一些优选实施方案中，环A为C3-C6环烷基或4-8元杂环基，所述环烷基或杂环基可任选地被1、2或3个选自卤素、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、-NR aR b取代的羰基和-NR aR b取代的C1-C4烷基取代；X 3和X 5均为CH；X 4为CH 2；L 1为C1-C4亚烷基；R 1为任选被1或2个选自卤素、C1-C4烷基和-NR aR b的取代基取代的5或6元含氮杂芳基，优选为吡啶 基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基；L 2为C1-C4亚烷基；R 2为苯基、5-10元含氮杂芳基或4-9元杂环基，如吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基或吲哚基，所述苯基、5-10元含氮杂芳基或4-9元杂环基可任选被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代；R 0为-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H、任选取代的C1-C6烷基和任选取代的4-8元杂环基，或R 3和R 4与其所连接的氮原子一起形成任选取代的4-8元杂环基，优选地，所述C1-C6烷基任选地被1-6个选自羟基、氰基和卤素的取代基取代，所述4-8元杂环基各自任选地被1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基，所述4-8元杂环基各自独立选自氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基和吗啉基。
在式I的一些优选实施方案中，环A为C3-C6环烷基，所述环烷基可任选地被1、2或3个选自卤素、C1-C4烷基和卤代C1-C4烷基的取代基取代；X 3和X 5均为CH；X 4为CH 2；L 1为C1-C4亚烷基；R 1为被1或2个选自C1-C4烷基和-NR aR b的取代基取代的5或6元含氮杂芳基，优选为吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基，R a和R b各自独立为H或C1-C4烷基；L 2为C1-C4亚烷基；R 2为5-10元含氮杂芳基，如吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基或吲哚基，所述5-10元含氮杂芳基可任选被1或2个选自C1-C6烷氧基、C1-C6烷基、C3-C8环烷基-氧基、卤代C1-C6烷氧基、卤素和氰基的取代基取代；R 0为-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H和任选被1、2、3、4、5或6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基，或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、羟基和C1-C4烷基取代的4-8元杂环基，优选地，所述4-8元杂环基选自氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基和吗啉基。
在式I的一些优选实施方案中，所述式I化合物具有下式II所示的结构：
Figure PCTCN2021137254-appb-000066
式中，环A、R 0、L 2和R 2各自如本文任一实施方案所述，R c和R d各自独立为H或C1-C6烷基。优选的是，式II中，环A为C3-C6环烷基或4-10元杂环基，所述C3-C6环烷基或4-10元杂环基可任选地被1、2或3个选自卤素、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、-NR aR b取代的羰基和-NR aR b取代的C1-C4烷基取代，其中，R a和R b各自独立为H或C1-C4烷基；R 0为-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H、任选取代的C1-C6烷基和任选取代的4-8元杂环基，或R 3和R 4与其所连接的氮原子一起形成任选取代的4-8元杂环基，优选地，所述C1-C6烷基任选地被1-6个选自羟基、氰基和卤素的取代基取代，所述4-8元杂环基各自任选地被1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基，所述4-8元杂环基各自独立选自氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基和吗啉基；L 2为C1-C4亚烷基；R 2为苯基、5-10元含氮杂芳基或4-10元杂环基，如吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基或吲哚基，所述苯基或5-10元含氮杂芳基可任选被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代；以及所述R c和R d各自独立为H或C1-C4烷基。
进一步优选地，式II中，环A为C3-C6环烷基，所述环烷基可任选地被1、2或3个选自卤素、C1-C4烷基和卤代C1-C4烷基的取代基取代；L 2为C1-C4亚烷基；R 2为5-10元含氮杂芳基，如吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基或吲哚基，所述5-10元含氮杂芳基可任选被1或2个选自C1-C6烷氧基、卤素和氰基的取代基取代；R 0为-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H和C1-C6烷基，或R 3和R 4与其所连接的氮原子一起形成4-8元杂环基，优选地，所述4-8元杂环基选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基和吗啉基； R c和R d各自独立为H或C1-C4烷基。
进一步优选地，式II中，环A为任选被选自C1-C4烷基、-NR aR b取代的羰基和-NR aR b取代的C1-C4烷基的取代基取代的C3-C6环烷基或含1个氮或1个O的C4-C6杂环基，优选为环丙基、环丁基、氧杂环丁基或氮杂环丁基，所述环丙基、环丁基、氧杂环丁基或氮杂环丁基，所述环丙基、环丁基、氧杂环丁基或氮杂环丁基，所述环丙基、环丁基、氧杂环丁基或氮杂环丁基任选被C1-C4烷基、-NR aR b取代的羰基和-NR aR b取代的C1-C4烷基的取代基取代的；R 0为H或-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H、4-6元杂环基和任选被1、2、3、4、5或6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基，或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、羟基和C1-C4烷基取代的4-6元杂环基，优选地，所述4-6元杂环基各自独立为含氧和/或氮的4-6元杂环基，优选各自独立选自氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基和吗啉基；L 2为C1-C4亚烷基；R 2为6-14元芳基、5-10元含氮杂芳基或4-10元杂环基，如苯基、吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吲哚基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基，所述6-14元芳基、5-10元含氮杂芳基或4-10元杂环基任选被1或2个选自C1-C6烷氧基、C1-C4烷基、卤素、C3-C6环烷基-氧基、卤代C1-C4烷氧基和氰基的取代基取代；R c和R d各自独立为H或C1-C4烷基。
在式I的一些优选实施方案中，所述式I化合物具有下式III所示的结构：
Figure PCTCN2021137254-appb-000067
式中，环A、R 0、L 2和R 2各自如本文任一实施方案所述，R c和R d各自独立为H或C1-C4烷基。X 6各自独立选自C、O、N、S，q为1、2或3的整数。优选地，X 6为C。优选地，q为1或2。优选地，R 7选自F、Cl、氰基、羟基、C1-C6烷基、氟代或氯代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、氟代或氯代C1-C6烷氧基、羟基取代的C1-C6烷基、-NR aR b、-NR aR b取代的羰基、-NR aR b取代的 C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基羰基；其中，所述R a和R b各自独立选自H和C1-C6烷基，m为0、1、2或3的整数。优选地，m为0或2。
在本发明的另一方面.提供了一种式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物：
Figure PCTCN2021137254-appb-000068
式中，
环A为取代或未取代的3-8元饱和碳环或取代或未取代的3-8元饱和杂环，所述杂环含有1-2个独立选自N、O和S的杂原子；
X 3选自CR 5和N；
X 4选自任选取代的-(CH 2) n-、-C(＝O)-和NR 6，其中，n为1、2或3；
X 5选自N和CR 5；
L 1选自键、任选取代的C1-C6亚烷基、任选取代的C1-C6亚烷基-O-、任选取代的C1-C6亚烷基-NH-、任选取代的C1-C6亚烷基-S-和任选取代的C2-C4亚链烯基；
L 2选自键、任选取代的C1-C6亚烷基、任选取代的C1-C6亚烷基-O-、任选取代的C1-C6亚烷基-NH-、任选取代的C1-C6亚烷基-S-和任选取代的C2-C4亚链烯基；
R 0选自任选取代的C1-C6卤代烷基、-C(O)NR 3R 4、-CH 2OR 3和-NR 3R 4取代的C1-C6烷基；
R 1选自任选取代的环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、任选取代的氨基和胍基；
R 2选自任选取代的环烷基、任选取代的芳基、任选取代的杂芳基和任选取代的杂环基；
R 3和R 4各自独立选自H、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、 任选取代的C1-C6卤代烷基、任选取代的4-10元杂环基和任选取代的5-10元杂芳基；或者，R 3和R 4与其所连接的氮原子一起形成任选取代的4-10元杂环基或5-10元杂芳基；
R 5选自H、卤素、C1-C6烷基、卤代C1-C6烷基和C1-C6烷氧基；并且
R 6选自H、C1-C6烷基、卤代C1-C6烷基和C1-C6烷氧基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A为C3-C8环烷基或3-7元杂环基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A选自环丙基、环丁基、环戊基、环己基、氮杂环丙基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、氧杂环丙基、氧杂环丁基、四氢呋喃基、四氢吡喃基和吗啉基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A被1、2或3个选自卤素、羟基、氰基、C1-C6烷基、卤代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基和-NR aR b的取代基取代；其中，所述R a和R b各自独立选自H和C1-C6烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A为环丙基、环丁基、环戊基、氮杂环丁基、氧杂环丁基、氮杂环戊基或四氢呋喃基，
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A任选地被1、2或3个选自F、Cl、Br、CF 3、CH 3、-OH、-OCH 3、-NH 2、-NHCH 3,-NH 2(CH 3) 2的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 0为-NR 3R 4取代的C1-C6烷基；其中，R 3和R 4各自独立选自H，任选被1、2、3、4、5或6个选自卤素、氰基、C1-C6烷氧基、卤代C1-C6烷氧基、- NR aR b和羟基的取代基取代的C1-C6烷基，或者R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000069
所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000070
各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、-NR aR b和羟基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 0为-NR 3R 4取代的C1-C6烷基，并且其中，R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000071
所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000072
各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、-NR aR b和羟基的取代基取代；其中，R a和R b各自独立为H或C1-C4烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 0为-NR 3R 4取代的C1-C6烷基，其中，R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、 吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000073
所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
Figure PCTCN2021137254-appb-000074
各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代；其中，R a和R b各自独立为H或C1-C4烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，X 3和/或X 5为CR 5。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 5选自H和C1-C4烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，X 4为-(CH 2) n-，n为1或2；并且其中，所述-(CH 2) n-任选被1或2个选自卤素、羟基、氨基、C1-C6烷基和卤代C1-C6烷基的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，X 3和X 5均为CR 5；并且X 4为任选取代的-(CH 2)-。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，L 1选自C1-C6亚烷基、C1-C6亚烷基-O-、C1-C6亚烷基-NH-、C1-C6亚烷基-S-和C2-C4亚链烯基，所述C1-C6亚烷基、C1-C6亚烷基-O-、C1-C6亚烷基-NH-、C1-C6亚烷基-S-和C2-C4亚链烯基可任选被1、2或3个选自卤素、C1-C4烷基和羟基的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代 谢产物中，L 1选自C1-C6亚烷基和C1-C6亚烷基-NH-，所述C1-C6亚烷基和C1-C6亚烷基-NH-任选被1、2或3个选自卤素、C1-C4烷基和羟基的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 1选自任选取代的C3-C8环烷基、任选取代的6-14元芳基、任选取代的5-10元杂芳基和任选取代的4-10元杂环基，并且所述环烷基、芳基、杂芳基和杂环基各自可任选地被1、2或3个选自任选取代的氨基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、C1-C6卤代烷基和氰基的取代基取代；其中，所述任选取代的氨基是-NR aR b，其中，R a和R b各自独立为H或C1-C6烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 1选自任选取代的苯基、萘基吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吡啶并咪唑基、吲哚基、异吲哚基、吲唑基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基、
Figure PCTCN2021137254-appb-000075
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，所述L 1为C1-C4亚烷基或C1-C4亚烷基-NH-，R 1为吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基或
Figure PCTCN2021137254-appb-000076
所述吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基或
Figure PCTCN2021137254-appb-000077
任选被1或2个选自卤素、C1-C4烷基和-NR aR b的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，L 2选自键和C1-C6亚烷基，其中，所述C1-C6亚烷基任选地被1、2或3个选自卤素、C1-C3烷基、C3-C5环烷基和羟基的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 2任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代；其中，R a和R b各自独立为H或C1-C6烷基；并且其中，所述杂芳基优选为含有1或2个环氮原子的杂芳基，优选选自吡唑基、咪唑基、吡啶基、吡嗪基和哌嗪基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 2选自6-14元芳基、5-10元杂芳基和4-10元杂环基，所述6-14元芳基、5-10元杂芳基和4-10元杂环基可任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，R 2选自苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、
Figure PCTCN2021137254-appb-000078
所述苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、杂氮环丁烷 基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、
Figure PCTCN2021137254-appb-000079
任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，L 2为C1-C4亚烷基，R 2为6-14元芳基、5-10元含氮杂芳基或4-10元杂环基，所述6-14元芳基、5-10元含氮杂芳基或4-10元杂环基任选地被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代，优选为苯基、吡啶基、吡唑基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基或吲哚基。
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A为C3-C6环烷基或4-8元杂环基，所述环烷基或杂环基任选地被1、2或3个选自卤素、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基和卤代C1-C4烷氧基的取代基取代；
X 3和X 5均为CH；
X 4为CH 2；
L 1为C1-C4亚烷基；
R 1为
Figure PCTCN2021137254-appb-000080
L 2为C1-C4亚烷基；
R 2为苯基、5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3- 二氧环戊烯基或吲哚基，所述苯基、5-10元含氮杂芳基和4-10元杂环基各自任选地被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代；
R 0为-NR 3R 4取代的C1-C4烷基；其中，R 3和R 4各自独立选自H，任选被1-6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基和任选被1、2或3个选自卤素、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；优选地，所述4-8元杂环基各自独立选自氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基、吗啉基、
Figure PCTCN2021137254-appb-000081
特别地，在本发明所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物中，环A为C3-C6环烷基，所述环烷基任选地被1、2或3个选自卤素、C1-C4烷基和卤代C1-C4烷基的取代基取代；
X 3和X 5均为CH；
X 4为CH 2；
L 1为C1-C4亚烷基；
R 1为
Figure PCTCN2021137254-appb-000082
L 2为C1-C4亚烷基；
R 2为5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基或吲哚基，所述5-10元含氮杂芳基或4-10元杂环基各自任选被1或2个选自C1-C6烷氧基、C1-C6烷基、C3-C8环烷基-O-、卤代C1-C6烷氧基、卤素和氰基的取代基取代；
R 0为-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H和任选被1、2、3、4、5或6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基，或R 3和R 4 与其所连接的氮原子一起形成任选被1、2或3个选自卤素、羟基、C1-C4烷氧基和C1-C4烷基取代的4-8元杂环基，优选地，所述4-8元杂环基选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、
Figure PCTCN2021137254-appb-000083
示例性的本发明式I化合物包括但不限于以下化合物及其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物：
Figure PCTCN2021137254-appb-000084
Figure PCTCN2021137254-appb-000085
Figure PCTCN2021137254-appb-000086
Figure PCTCN2021137254-appb-000087
Figure PCTCN2021137254-appb-000088
Figure PCTCN2021137254-appb-000089
以及
Figure PCTCN2021137254-appb-000090
本领域技术人员将理解，在本申请中所提供的将包括但不限于以下所列出的实施方案：
实施方案1.一种式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物：
Figure PCTCN2021137254-appb-000091
式中，
环A为取代或未取代的3-8元饱和或不饱和碳环或取代或未取代的3-8元饱和或不饱和杂环，所述杂环含有1-2个独立选自N、O和S的杂原子；
X 3选自CR 5和N；
X 4选自任选取代的-(CH 2) n-、-C(＝O)-和NR 6，其中，n为1、2或3；
X 5选自N和CR 5；
L 1选自键、任选取代的C1-C6亚烷基、任选取代的C1-C6亚烷基-O-、任选取代的C1-C6亚烷基-NH-、任选取代的C1-C6亚烷基-S-和任选取代的C2-C4亚链烯基；
L 2选自键、任选取代的C1-C6亚烷基、任选取代的C1-C6亚烷基-O-、任选取代的C1-C6亚烷基-NH-、任选取代的C1-C6亚烷基-S-和任选取代的C2-C4亚链烯基；
R 0选自H、C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6卤代烷基和-NR 3R 4取代的C1-C6烷基；
R 1选自任选取代的环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、任选取代的氨基和胍基；
R 2选自任选取代的环烷基、任选取代的芳基、任选取代的杂芳基和任选取代的杂环基；
R 3和R 4各自独立选自H、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6卤代烷基、任选取代的4-10元杂环基和任选取代的5-10元杂芳基；或者，R 3和R 4与其所连接的氮原子一起形成任选取代的4-10元杂环基或5-10元杂芳基；
R 5选自H、卤素、C1-C6烷基、卤代C1-C6烷基和C1-C6烷氧基；
R 6选自H、C1-C6烷基、卤代C1-C6烷基和C1-C6烷氧基。
实施方案2.如实施方案1所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，环A为C3-C8环烷基或3-7元杂环基，优选选自环丙基、环丁基、环戊基、环己基、氮杂环丙基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、氧杂环丙基、氧杂环丁基、四氢呋喃基、四氢吡喃基和吗啉基；
优选地，环A任选地被1、2或3个选自卤素、羟基、氰基、C1-C6烷基、卤代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、、-NR aR b、-NR aR b取代的羰基、-NR aR b取代的C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基羰基、任选取代的6-14元芳基、任选取代的5-10元杂芳基、任选取代的4-10元杂环基、任选取代的C3-C8环烷基、任选取代的6-14元芳基取代的C1-C6烷基、任选取代的5-10元杂芳基取代的C1-C6烷基、任选取代的4-10元杂环基取代的C1-C6烷基、和任选取代的C3-C8环烷基取代的C1-C6烷基的取代基取代；其中，所述6-14元芳基、5-10元杂芳基、4-10元杂环基和C3-C8环烷基被取代时，取代基为1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b、-NR aR b取代的羰基、-NR aR b取代的C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基羰基的取代基；其中，所述R a和R b各自独立选自H和C1-C6烷基。
实施方案3.如实施方案1或2所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，环A为环丙基、环丁基、环戊基、氮杂环丁基、氧杂环丁基、氮杂环戊基或四氢呋喃基，
优选地，环A任选地被1、2或3个选自F、Cl、Br、CF 3、CH 3、-OH、-OCH 3、-NH 2、-NHCH 3,-NH 2(CH 3) 2的取代基取代。
实施方案4.如实施方案1所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，
X 3为CR 5，R 5选自H和C1-C4烷基；和/或
X 4为-(CH 2) n-，n为1或2；其中，所述-(CH 2) n-任选被1或2个选自卤素、羟基、氨基、C1-C6烷基和卤代C1-C6烷基的取代基取代。
实施方案5.如实施方案1所述的式I化合物，或其药学上可接受的盐，或其 对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，L 1选自任选被1、2或3个选自卤素、C1-C4烷基和羟基的取代基取代的C1-C6亚烷基、C1-C6亚烷基-O-、C1-C6亚烷基-NH-、C1-C6亚烷基-S-和C2-C4亚链烯基，优选选自任选被1、2或3个选自卤素、C1-C4烷基和羟基的取代基取代的C1-C6亚烷基或C1-C6亚烷基-NH-。
实施方案6.如实施方案1所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 1选自任选取代的C3-C8环烷基、任选取代的6-14元芳基、任选取代的5-10元杂芳基和任选取代的4-10元杂环基；
优选地，所述6-14元芳基为苯基或萘基；所述5-10元杂芳基选自吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基和喹啉基，优选吡啶基、吡咯基、咪唑基和三唑基；所述4-10元杂环基选自吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基和邻苯二甲酰亚氨基；
优选地，所述烷氧基、芳基、杂芳基和杂环基各自可任选地被1、2或3个选自任选取代的氨基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、C1-C6卤代烷基和氰基的取代基取代；其中，所述任选取代的氨基是-NR aR b，其中，R a和R b各自独立为H或C1-C6烷基。
实施方案7.如实施方案1所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，所述L 1为C1-C4亚烷基或C1-C4亚烷基-NH-，R 1为任选被1或2个选自卤素、C1-C4烷基和-NR aR b的取代基取代的5或6元含氮杂芳基，所述5或6元含氮杂芳基优选为吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基或三嗪基，其中，R a和R b各自独立为H或C1-C4烷基。
实施方案8.如实施方案1所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，L 2选自键和C1-C6亚烷基，其中，所述C1-C6亚烷 基任选地被1、2或3个选自卤素、C1-C3烷基、C3-C5环烷基和羟基的取代基取代。
实施方案9.如实施方案1所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 2选自任选取代的6-14元芳基、任选取代的5-10元杂芳基和任选取代的4-10元杂环基；
优选地，所述6-14元芳基为苯基或萘基；所述5-10元杂芳基选自吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基和喹啉基，优选吡啶基、吡咯并吡啶基、吡唑基或吲哚基；所述4-10元杂环基选自杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基和吡唑烷基；
优选地，R 2任选地被1、2或3个选自任选取代的氨基、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代；其中，所述任选取代的氨基为-NR aR b，其中，R a和R b各自独立为H或C1-C6烷基；其中，所述杂芳基优选为含有1或2个环氮原子的杂芳基，优选选自吡唑基、咪唑基、吡啶基、吡嗪基和哌嗪基。
实施方案10.如实施方案1所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，L 2为C1-C4亚烷基，R 2为被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代的6-14元芳基、5-10元含氮杂芳基或4-10元杂环基，优选为苯基、吡啶基、吡唑基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基或吲哚基。
实施方案11.如实施方案1所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 0为H或-NR 3R 4取代的C1-C6烷基；其中，R 3和 R 4各自独立选自H，任选被1、2、3、4、5或6个选自卤素、氰基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的C1-C6烷基，或者R 3和R 4与其所连接的氮原子一起形成任选取代的4-10元杂环基和任选取代的5-10元杂芳基，其中，R a和R b各自独立为H或C1-C4烷基；
优选地，所述4-10元杂环基优选为含氮和/或氧的杂环基，优选选自氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基和吗啉基；
优选地，所述5-10元杂芳基为5-10元含氮和/或氧杂芳基，优选选自吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基和喹啉基；
优选地，所述4-10元杂环基和5-10元杂芳基各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
实施方案12.如实施方案1所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 0为-NR 3R 4取代的C1-C6烷基，其中，R 3和R 4与其所连接的氮原子一起形成任选取代的4-10元杂环基或5-10元杂芳基；
优选地，所述4-10元杂环基为含氮和/或氧的杂环基，优选选自氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基和吗啉基；
优选地，所述5-10元杂芳基为5-10元含氮和/或氧杂芳基，优选选自吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基和喹啉基；
优选地，所述4-10元杂环基和5-10元杂芳基各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
实施方案13.如实施方案1所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 0为-NR 3R 4取代的C1-C6烷基，其中，R 3和R 4与 其所连接的氮原子一起形成任选取代的4-10元杂环基或5-10元杂芳基；
优选地，所述4-10元杂环基为含氮和/或氧的杂环基，优选选自氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基和吗啉基；
优选地，所述5-10元杂芳基为5-10元含氮和/或氧杂芳基，优选选自吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基和喹啉基；
优选地，所述4-10元杂环基和5-10元杂芳基各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、-NR aR b和羟基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
实施方案14.如实施方案1所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，
环A为C3-C6环烷基或4-8元杂环基，所述环烷基或杂环基任选地被1、2或3个选自卤素、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基、-NR aR b取代的羰基和-NR aR b取代的C1-C4烷基取代；其中，R a和R b各自独立为H或C1-C4烷基；
X 3和X 5均为CH；
X 4为CH 2；
L 1为C1-C4亚烷基；
R 1为任选被1或2个选自卤素、C1-C4烷基和-NR aR b的取代基取代的5或6元含氮杂芳基，优选为吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基；其中，R a和R b各自独立为H或C1-C4烷基；
L 2为C1-C4亚烷基；
R 2为苯基、5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基或吲哚基，所述苯基、5-10元含氮杂芳基和4-10元杂环基各自任选地被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和 卤代C1-C6烷氧基的取代基取代；
R 0为-NR 3R 4取代的C1-C4烷基；其中，R 3和R 4各自独立选自H，任选被1-6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基和任选被1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；优选地，所述4-8元杂环基各自独立选自氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基和吗啉基。
实施方案15.如实施方案1所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，
环A为C3-C6环烷基，所述环烷基任选地被1、2或3个选自卤素、C1-C4烷基和卤代C1-C4烷基的取代基取代；
X 3和X 5均为CH；
X 4为CH 2；
L 1为C1-C4亚烷基；
R 1为被1或2个选自C1-C4烷基和-NR aR b的取代基取代的5或6元含氮杂芳基，优选为吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基；其中，R a和R b各自独立为H或C1-C4烷基；
L 2为C1-C4亚烷基；
R 2为5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基或吲哚基，所述5-10元含氮杂芳基或4-10元杂环基各自任选被1或2个选自C1-C6烷氧基、C1-C6烷基、C3-C8环烷基-O-、卤代C1-C6烷氧基、卤素和氰基的取代基取代；
R 0为-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H和任选被1、2、3、4、5或6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基，或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、羟基和C1-C4烷基取 代的4-8元杂环基，优选地，所述4-8元杂环基选自氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基和吗啉基。
实施方案16.如实施方案1所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，所述式I化合物具有下式II所示的结构：
Figure PCTCN2021137254-appb-000092
式中，环A如实施方案1、2、3、14或15所述；R 0如实施方案11、12、13、14或15所述；L 2如实施方案8、10、14或15所述；R 2如实施方案9、10、14或15所述；
R c和R d各自独立为H或C1-C4烷基。
实施方案17.如实施方案16所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，式II中：
环A为任选被选自F、Cl、羟基、C1-C4烷基、-NR aR b取代的羰基和-NR aR b取代的C1-C4烷基的取代基取代的C3-C6环烷基或含1个氮或1个O的C4-C6杂环基，优选为任选被C1-C4烷基、-NR aR b取代的羰基和-NR aR b取代的C1-C4烷基的取代基取代的环丙基、环丁基、氧杂环丁基或氮杂环丁基；其中，R a和R b各自独立为H或C1-C4烷基；
R 0为H或-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H、4-6元杂环基和任选被1、2、3、4、5或6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基，或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、羟基和C1-C4烷基取代的4-6元杂环基；其中，所述4-6元杂环基优选为含氧和/或氮的杂环基，优选选自氧杂环丁烷基、氮杂环丁烷基、吡咯烷基、四氢呋喃基、哌啶基、哌嗪基、四氢吡喃基和吗啉基；
L 2为C1-C4亚烷基；
R 2为6-14元芳基、5-10元含氮杂芳基或4-10元杂环基，优选为苯基、吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吲哚基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基，所述6-14元芳基、5-10元含氮杂芳基或4-10元杂环基各自任选被1或2个选自C1-C6烷氧基、C1-C4烷基、卤素、C3-C6环烷基-氧基、卤代C1-C4烷氧基和氰基的取代基取代；
R c和R d各自独立为H或C1-C4烷基。
实施方案18.如实施方案1所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，所述式I化合物具有下式III所示的结构：
Figure PCTCN2021137254-appb-000093
式中，R 0如实施方案11、12、13、14、15或17所述；L 2如实施方案8、10、14、15或17所述；R 2如实施方案9、10、14、15或17所述；R c和R d如实施方案16或17所述，
X 6各自独立选自C、O、N、S，
q为1、2或3的整数，
R 7选自F、Cl、氰基、羟基、C1-C6烷基、氟代或氯代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、氟代或氯代C1-C6烷氧基、羟基取代的C1-C6烷基、-NR aR b、-NR aR b取代的羰基、-NR aR b取代的C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基羰基；其中，所述R a和R b各自独立选自H和C1-C6烷基，
m为0、1、2或3的整数。
实施方案19.如实施方案1所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，所述化合物选自：
Figure PCTCN2021137254-appb-000094
Figure PCTCN2021137254-appb-000095
Figure PCTCN2021137254-appb-000096
Figure PCTCN2021137254-appb-000097
Figure PCTCN2021137254-appb-000098
实施方案20.一种药物组合物，其含有实施方案1-16中任一项所述的化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，以及药学上可接受的载体或赋形剂。
实施方案21.实施方案1-19中任一项所述的化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物在制备治疗或预防WDR5介导的疾病的药物中的应用。
实施方案22.如实施方案21所述的应用，其特征在于，所述WDR5介导的疾病包括Kabuki综合征、以及各种实体瘤和血液肿瘤；优选地，实体瘤和血液肿瘤选自：努南综合症、豹综合症、成神经细胞瘤、肉瘤、黑色素瘤、关节软骨瘤、胆管瘤、白血病、乳腺癌、胃肠间质瘤、组织细胞性淋巴瘤、肺癌、食道癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、肾癌、口腔癌、头癌、成神经细胞瘤、头颈的鳞状细胞癌、间变性大细胞淋巴瘤或成胶质细胞瘤，其中，白血病优选为青少年髓单核细胞白血病、人髓性单核细胞白血病，肺癌优选为非小细胞肺癌、小细胞肺癌、肺鳞癌、肺腺癌。
本发明包括式I化合物的药学上可接受的盐。在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”指能够保留游离碱的生物有效性而无其它副作用的、与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫 酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本领域已知的方法制备。
“药学上可接受的碱加成盐”指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本领域已知的方法制备。
本发明还包括式I化合物的异构体，包括立体异构体、对映异构体或互变异构体。本文中，“立体异构体”指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本发明涵盖各种立体异构体及其混合物。“互变异构体”指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使 用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。
当本发明的化合物中含有烯双键时，除非另有说明，否则本发明的化合物旨在包含E-和Z-几何异构体。
本发明还包括本发明的化合物、其药学上可接受的盐或异构体的所有适宜的同位素变体。本发明的化合物、其药学上可接受的盐或异构体的同位素变体被定义为其中至少一个原子被具有相同原子数、但原子质量与自然界经常发现的原子质量不同的原子所替换的那些。可以掺入到本发明的化合物、其药学上可接受的盐或异构体中的同位素包括但不限于H、C、N和O的同位素，例如 2H、 3H、 11C、 13C、 14C、 15N、 17O、 18O、 35S、 18F、 36Cl和 125I。本发明所述化合物、其药学上可接受的盐或异构体的同位素变体可以通过常规技术、采用适宜试剂的适当同位素变体来制备。
式I化合物的制备
在一些实施方案中，本发明式IIa化合物可通过如下方案所示的方法制备：
Figure PCTCN2021137254-appb-000099
方案中，中间体IIa-1经还原反应得中间体IIa-2；IIa-2经胺酯交换得到IIa-3；IIa-3经酸催化环化得到IIa-4；IIa-4经催化插羰反应后生成酯类化合物IIa-5；IIa-5芳香环卤代得IIa-6；IIa-6酯基还原后生成IIa-7；IIa-7的羟基进一步卤交换生成IIa-8；IIa-8和咪唑胺进行烷基化反应后得到IIa-9；IIa-9与硼酸衍生物催化偶联得到IIa-10；IIa-10与R 2-L 2-Br烷基化反应生成IIa-11；IIa-11脱保护基得到式IIa化合物。各步骤的反应条件如反应流程所示。
上述反应流程的各式中，各基团的定义如上文中所述。
本发明的制备方法中，IIa-3到IIa-4的催化环化反应用于构建式IIa-4的芳香螺环中间体。反应在酸的催化下(优选三氟甲磺酸)，在卤代烷烃(优选二氯甲烷)中在低温或室温下进行。
在碱和相转移催化剂(优选碳酸铯，四丁基碘化铵)的条件下，IIa-8可以和咪唑类化合物反应引入右边的咪唑类基团,得到IIa-9。
IIa-9和硼酸类化合物进行催化偶联反应引入R 0取代基，可在水与有机溶剂(如醇类或醚类溶剂，优选二氧六环)的存在下进行。在碱(如碳酸钠)和催化剂如钯类催化剂(如Pd(dppf)Cl 2)的条件在加热的条件下进行，得到IIa-10。
在碱(优选钠氢)的条件下，IIa-10和卤代物反应引入R 2-L 2-基团。烷基化反 应的溶剂可以是有机溶剂，优选四氢呋喃，DMF或NMP。
上述方案中还包括脱Boc保护基步骤。可采用常规的方式进行所述脱保护基反应。
上述方案中，如终产物有手性中心且需要手性拆分时，可采用本领域常规的方法，比如SFC或者手性HPLC进行手性拆分。
反应中，当需要纯化时，可采用本领域常规的方法进行纯化，例如可先进行萃取，然后再进行柱层析。
本发明的式I和式II化合物的合成，可采用式IIa化合物的通用方法，变换不同的原料，得到不同的化合物。其制备方法通常包括上文所述的催化关环、催化偶联、还原卤代和烷基化取代反应等步骤。
药理学、用途、方法和药物组合物
WDR5属于WD40域重复蛋白家族(WD40-repeat protein)，WD40是一个重要的结构域，由40个左右的氨基酸残基组成，WDR域含有圆环形状的七叶β-螺旋桨结构域，每个叶片各含有保守的丝氨酸-组氨酸(SH)和色氨酸-天冬氨酸(WD)序列。WDR5蛋白含有一个7叶β-螺旋形成的中心空腔，贯穿上下。WDR5蛋白主要通过一个深的精氨酸结合口袋，即WIN位点与MLL1组成核心催化复合物发挥调控作用，与其他蛋白构成MWRAD(MLL1，WDR5，RbBP5，ASH2L及DYP-30)核心催化复合物，催化组蛋白H3甲基化，激活基因转录参与表观调控。
在真核生物中广泛存在的MLL家族蛋白复合体，是一类重要的组蛋白甲基转移酶，催化组蛋白H3K4的甲基化，通过催化H3K4甲基化/或通过招募其它转录相关蛋白与中介因子，激活转录，在发育过程中扮演了至关重要的角色。而这些蛋白的突变，包括基因组易位使它与其它转录因子融合，则会造成多种疾病，如混合谱系白血病(MLL)，淋巴瘤，Kabuki综合征等。以WDR5作为药物靶点，针对WDR5与组蛋白和MLL1结合的WIN口袋而设计的化合物，可以降低WDR5下游的基因表达，治疗MLL重排依赖的白血病。
TP53基因是肿瘤中最常见的变异基因，在人类癌症中有50％发生TP53突变。错义突变的高频率和突变p53(mp53)蛋白在癌细胞中的高表达水平促使mp53蛋白具有新的功能(“功能获得”(GOF))，同时也积极促进了癌症的发展和进展。p53基因突变驱动的肿瘤细胞的生长依赖于WDR5与MLL的结合。MLL、MOZ及组 蛋白修饰，都受GOF p53的表达调控。WDR5WIN位点抑制剂能够有效阻断由p53基因突变驱动的乳腺癌细胞系的生长以及白血病细胞的生长。
WDR5的WIN位点抑制剂还能够抑制MYC和WDR5共结合的基因座。MYC是一类具有转录因子功能的癌蛋白，在大部分恶性肿瘤中均存在过表达现象。MYC能与数千个靶基因的调控序列结合，调节靶基因表达，影响细胞生长、增殖、代谢、基因组稳定和凋亡等过程。早期研究已发现MYC与染色质的广泛结合也依赖于WDR5的相互作用，MYC通过其进化保守的“MYC box IIIb”序列结合在WDR5表面的疏水裂隙，在体内肿瘤发生过程中发挥了重要作用，阻断MYC与WDR5相互作用会抑制MYC驱动癌症发生的能力。针对WDR5WIN位点的抑制剂可作为治疗MYC驱动肿瘤的靶向治疗药物。
在临床研究中发现，WDR5在多种实体瘤中高表达，与肿瘤预后差存在一定的相关性。一方面是由于WDR5对EMT的调控作用。上皮细胞-间充质转化(EMT)，是指上皮细胞通过特定程序转化为具有间质表型细胞的生物学过程。EMT是上皮细胞来源的恶性肿瘤细胞获得迁移和侵袭能力的重要生物学过程。WDR5可以直接调控TGFβ1信号通路，从而参与到肿瘤细胞ETM和迁移过程。对于有耐药性产生的乳腺癌细胞，WDR5的抑制剂并没有明显的杀伤，但可以通过降低TGFβ1的水平来增强细胞对PTX的敏感性，抑制肿瘤转移能力。这也提示WDR5抑制剂在联合用药上的应用潜力。WDR5也能介导N-cadherin、ZNF407、HOXA9、SNAIL1和VIMENTIN等多个EMT特征分子的表达。另一方面，研究人员也发现WDR5调控肿瘤相关信号分子表达的同时，也受多条上游信号通路或分子的调控。PI3K/AKT介导的WDR5表达上调促进了结直肠癌的转移，而在胃癌中，诱导表达的细胞周期蛋白D1能上调WDR5，促进肿瘤形成。
综上所述，在癌细胞里面，WDR5蛋白广泛参与了MLL1、TP53、MYC、TGFβ1以及PI3K/AKT等信号通路的激活，促进了癌细胞的生长、增殖、分化及迁移。因此，WDR5蛋白-蛋白相互作用抑制剂可以用于治疗多种疾病，包括Kabuki综合征、以及各种实体瘤和血液肿瘤，包括但不限于努南综合症、豹综合症、成神经细胞瘤、肉瘤、黑色素瘤、关节软骨瘤、胆管瘤、白血病(如青少年髓单核细胞白血病、人髓性单核细胞白血病等)、乳腺癌、胃肠间质瘤、组织细胞性淋巴瘤、肺癌(如非小细胞肺癌、小细胞肺癌、肺鳞癌、肺腺癌、等)、食道癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、 鼻咽癌、脑癌、骨癌、肾癌、口腔癌、头癌、成神经细胞瘤、头颈的鳞状细胞癌、间变性大细胞淋巴瘤或成胶质细胞瘤等疾病。
本发明式I化合物、其药学上可接受的盐及异构体是WDR5的抑制剂，可以抑制WDR5与MLL1或MYC的结合，也可抑制WDR5自身的活性。因此，本发明的式I化合物、其药学上可接受的盐及异构体可用于治疗或预防WDR5介导的疾病。本文中，“WDR5介导的疾病”指WDR5参与了疾病的发生和/或发展、通过抑制WDR5的表达和/或活性可实现缓解、治疗和/或预防目的的疾病。本发明中，WDR5介导的疾病包括但不限于前文所述的Kabuki综合征、以及各种实体瘤和血液肿瘤，尤其包括MLL重排依赖的白血病(如人髓性单核细胞白血病)、MYC驱动的肿瘤和乳腺癌等。本文中，MYC驱动的肿瘤指MYC活性引起的肿瘤。本发明的式I化合物、其药学上可接受的盐及异构体还可用于抑制上皮细胞-间充质转化(EMT)，从而抑制上皮细胞来源的恶性肿瘤细胞的转移。因此，本申请所述的“WDR5介导的疾病”也包括癌症的转移，尤其是上皮细胞来源的恶性肿瘤的转移。
因此，本发明提供一种治疗或预防本文所述的WDR5介导的疾病的方法，该方法包括给予需要的对象治疗有效量的本发明式I化合物、其药学上可接受的盐及异构体或含有本发明的式I化合物、其药学上可接受的盐及异构体的药物组合物。
本文所述的“对象”或“个体”指哺乳动物，尤其是灵长类动物，更具体是人。
本文所用术语“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性；该术语也包括：预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时。“治疗”和其它类似的同义词包括以下含义：(i)抑制疾病或病症，即遏制其发展；(ii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者(iii)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”、“给药量”、“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开的式I化合物、其药学上可接受的盐或异构体的组合物的量。可根据对象的年龄、性别、所患疾病及其严重程度等因素确定给药量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进 行生物作用的所需位点的方法。本领域周知的给药方法均可用于本发明。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括肺内、鼻内、鞘内、静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington’s,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，通过口服施用本发明的式I化合物、其药学上可接受的盐或异构体或含有本发明的式I化合物、其药学上可接受的盐或异构体的药物组合物。
本发明的发明式I化合物、其药学上可接受的盐及异构体或含有本发明的式I化合物、其药学上可接受的盐及异构体的药物组合物可以与其它具有药理活性的化合物联用，尤其可联用于治疗癌症。例如，本发明的发明式I化合物、其药学上可接受的盐及异构体或含有本发明的式I化合物、其药学上可接受的盐及异构体的药物组合物可以与一种或多种选自如下的药物组合地同时、依次或分别施用：化疗剂，比如有丝分裂抑制剂，如紫杉烷、长春花生物碱、紫杉醇、多西他赛、长春花新碱、长春花碱、长春瑞滨或长春氟宁，其它抗癌剂如顺铂、5-氟尿嘧啶或5-氟-2-4(1H，3H)-嘧啶二酮(5FU)、氟他胺或吉西他滨等。在一些实施方案中，本发明的发明式I化合物、其药学上可接受的盐及异构体或含有本发明的式I化合物、其药学上可接受的盐及异构体的药物组合物还可与本领域周知的肿瘤免疫治疗药物，如抗PD1抗体等一起用于癌症的治疗。或者，本发明式I化合物、其药学上可接受的盐及异构体或含有本发明的式I化合物、其药学上可接受的盐及异构体的药物组合物也可与常规的放疗联用。
本文中，“联用”、“药物联用”、“联合用药”或“联合治疗”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合，或者指两种或两种以上不同的治疗手段的组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。
本发明也提供一种药物组合物，其含有本发明的式I化合物、其药学上可接受 的盐或异构体，以及药学上可接受的载体或赋形剂。
在本申请中，“药物组合物”是指含有本发明式I化合物、其药学上可接受的盐或异构体与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。本文所用术语“药学上可接受的”是指不影响本发明式I化合物、其药学上可接受的盐或异构体的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。“药学上可接受的载体或赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
在一些实施方案中，本发明的药物组合物的活性成分中，除本发明式I化合物、其药学上可接受的盐或异构体外，还可含有其它的已知抗癌剂，包括但不限于紫杉烷、长春花生物碱、紫杉醇、多西他赛、长春花新碱、长春花碱、长春瑞滨、长春氟宁、顺铂、5-氟尿嘧啶、5-氟-2-4(1H，3H)-嘧啶二酮(5FU)、氟他胺和吉西他滨等。
本发明涉及本发明的式I化合物、其药学上可接受的盐及异构体或含有本发明的式I化合物、其药学上可接受的盐及异构体的药物组合物在治疗或预防本文所述的WDR5介导的疾病中的应用，或在制备用于治疗或预防本文所述的WDR5介导的疾病的药物中的应用。本发明也提供用于治疗或预防本文所述的WDR5介导的疾病的本发明所述的式I化合物、其药学上可接受的盐及异构体或含有本发明的式I化合物、其药学上可接受的盐及异构体的药物组合物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
下述实施例中所用的起始物可由化学品销售商如Aldrich、TCI、Alfa Aesar、毕得、安耐吉等处购得，或者可通过已知的方法来合成。
下述实施例中所涉及的英文简称所代表的意思如下表所述。
Figure PCTCN2021137254-appb-000100
下述实施例中，冰浴是指-5℃至0℃，室温是指10℃至30℃，回流温度一般是指溶剂在常压下的回流温度。反应过夜一般是指时间为8-15小时。下述实施例中， 未限定具体操作温度的，均在室温下进行。
下述实施例中，中间体和最终产物的分离提纯是通过正相或反相色谱柱分离或者其它合适的方法。正相快速色谱柱是用乙酸乙酯和正己烷或甲醇和二氯甲烷等作为流动相。反相制备性高压液相色谱(HPLC)是用C18柱并用UV 214nm和254nm来检测，其流动相为A(水和0.1％甲酸)、B(乙腈)或者流动相A(水和0.1％碳酸氢铵)、B(乙腈)。
各实施例中：LCMS仪器：泵：Agilent 1260；
UV检测器：Agilent 1260 DAD Mass Spectrometer API 3000；
层析柱：Waters sunfire C18,4.6×50mm,5um；
流动相：A-H2O(0.1％HCOOH)；B-乙腈NMR；
仪器：Bruker Ascend 400M(1H NMR：400MHz；13C NMR：100MHz)。
中间体A1的合成：2-(1-溴乙基)-5-氟-4-乙氧基吡啶的合成
Figure PCTCN2021137254-appb-000101
步骤一：-78℃，氩气保护下，向2-溴-5-氟吡啶(A1-1，102g，580.0mmol)的四氢呋喃(1.0L)溶液中滴加LDA(2M，四氢呋喃溶液，434mL，868.0mmol)。在该温度下反应1小时之后加入硼酸三异丙酯(163g，870.0mmol)，在该温度下反应30分钟后升温到室温反应16小时。将反应液冷却到0℃，加入氢氧化钠(4M，2.5L)水溶液，加完升温到室温搅拌1小时。分出水相，用6M盐酸水溶液调pH到3。乙酸乙酯(3*1.5L)萃取，有机相饱和盐水洗，干燥，过滤，浓缩干得粗品(2-溴-5-氟吡啶-4-基)硼酸(A1-2，114.5g，收率：89.9％)。
LCMS:m/z 222.0[M+H] +.
步骤二：0℃下向(2-溴-5-氟吡啶-4-基)硼酸(A1-2，114.5g，520.9mmol)的 二氯甲烷(1.5L)悬浊液中加入双氧水(30％aq.，177.1g，1562.7mmol)。加完升温到室温反应16小时。将反应液浓缩除去溶剂，加入水(500mL)和乙酸乙酯(1.0L)，分液，水相用乙酸乙酯(2*1.0L)萃取，合并有机相，浓缩至干得粗品2-溴-5-氟吡啶-4-醇(A1-3，96g，收率：96.0％)。
LCMS:m/z 192.1[M+H] +.
步骤三：向2-溴-5-氟吡啶-4-醇(A1-3，96g，500mmol)的DMF(600mL)溶液中加入碳酸钾(138.1g，1000mmol)和碘乙烷(234g，1500mmol)。室温反应16小时。将反应液倒入饱和盐水中，乙酸乙酯萃取(2*1000mL)，有机相依次用水(3*1500mL)和饱和盐水(2*1500mL)洗，干燥，过滤，减压浓缩至干，经柱层析纯化得无色液体2-溴-4-乙氧基-5-氟吡啶(A1-4，85g，收率：77.3％)。
LCMS:m/z 222.0[M+H] +.
步骤四：氩气保护下向2-溴-4-乙氧基-5-氟吡啶(A1-4，42g，190.9mmol)和三丁基(1-乙氧基乙烯基)锡烷(103.4g，286.4mmol)的1,4-二氧六环(1,4-dioxane)溶液中加入四三苯基膦钯(7.3g，0.03mmol)。升温到100℃反应16小时。减压浓缩除去溶剂，用乙酸乙酯(800mL)稀释，加入饱和氟化钾水溶液，室温搅拌1小时。分液，水相用乙酸乙酯(500mL)萃取，合并有机相，饱和盐水洗，干燥，过滤，减压浓缩至干。将残余物溶于四氢呋喃(500mL)，加入2M盐酸水溶液(382mL，764.0mmol)。室温反应2小时。反应液分层，水相用二氯甲烷(2*1000mL)萃取，合并有机相，饱和盐水洗，干燥，过滤，减压浓缩至干，经柱层析纯化得A1-5(32.5g，收率：93.0％)。
LCMS:m/z 184.1[M+H] +.
步骤五：将1-(5-氟-4-乙氧基吡啶-2-基)乙烷-1-酮(A1-5，28.4g，155.0mmol)溶于乙醇(560mL)，冷却到0℃，分三批加入硼氢化钠(5.85g，155.0mmol)。加毕，保持0℃反应10分钟后升温到室温反应过夜。将反应液倒入冰水中，用二氯甲烷(4*1000mL)萃取，合并有机相，饱和盐水洗，干燥，过滤，减压浓缩至干，经柱层析纯化得浅黄色油状物1-(5-氟-4-乙氧基吡啶-2-基)乙烷-1-醇(A1-6，25g，收率：87.1％)。
LCMS:m/z 186.2[M+H] +.
步骤六：0℃，氩气保护下向1-(5-氟-4-乙氧基吡啶-2-基)乙烷-1-醇(A1-6，24.2g，130.7mmol)和三苯基磷(61.7g，235.2mmol)的四氢呋喃(500mL)溶 液中滴加四溴化碳(65.0g，196.0mmol)的四氢呋喃(100mL)溶液。加毕，保持0℃反应10分钟，升温到室温反应过夜。将反应液过滤，滤饼用四氢呋喃洗涤，滤液减压浓缩至干，经柱层析纯化得浅黄色油状物A1(24g，收率：74.1％)。
LCMS:m/z 247.9[M+H] +.
1H NMR(400MHz,氯仿-d),δppm 8.26(d,J＝2.8Hz,1H),7.06(d,J＝6.4Hz,1H),5.19～5.14(m,1H),4.23～4.18(m,2H),2.05(d,J＝7.2Hz,3H),1.50(t,J＝6.8Hz,3H).
中间体A2的合成：6-(1-溴乙基)-4-甲氧基烟腈的合成
Figure PCTCN2021137254-appb-000102
步骤一：0℃，氩气保护下向4,6-二氯烟腈(A2-1，16.0g，92.5mmol)的甲醇(200mL)溶液中加入甲醇钠(5.5g，101.7mmol)。加完0℃反应20分钟后升温到室温反应3小时。将反应液倒入饱和氯化铵水溶液中，乙酸乙酯(3*200mL)萃取，有机相饱和盐水洗，干燥，过滤，浓缩至干，经柱层析纯化(石油醚：乙酸乙酯＝10:1)得白色固体6-氯-4-甲氧基烟腈(A2-2，9.8g，收率：62.8％)。
1H NMR(400MHz,氯仿-d)：δppm 8.47(s,1H),6.96(s,1H),4.02(s,3H).
步骤二：氩气保护下向6-氯-4-甲氧基烟腈(A2-2，11g，65.2mmol)和三丁基(1-乙氧基乙烯基)锡烷(35.3g，97.8mmol)的1,4-二氧六环溶液中加入四三苯基膦钯(3.78g，3.26mmol)。升温到100℃反应16小时。减压浓缩除去溶剂，用乙酸乙酯(300mL)稀释，加入饱和氟化钾水溶液，室温搅拌1小时。分液，水相用乙酸乙酯(300mL)萃取，合并有机相，饱和盐水洗，干燥，过滤，减压浓缩至干得粗品6-(1-乙氧基乙烯基)-4-甲氧基烟腈(A2-3，14g)。
LCMS:m/z 205.1[M+H] +.
步骤三：将6-(1-乙氧基乙烯基)-4-甲氧基烟腈(A2-3，14g，65.2mmol)溶于四氢呋喃(200mL)加入盐酸水溶液(2M，130mL，260mmol)，室温反应 60分钟。反应液用乙酸乙酯(300mL)稀释后依次用饱和碳酸氢钠和饱和盐水洗，干燥，过滤，减压浓缩至干，经柱层析纯化(石油醚：乙酸乙酯＝8:1)得白色固体6-乙酰基-4-甲氧基烟腈(A2-4，8.5g,两步收率：73.9％)。
LCMS:m/z 177.0[M+H] +.
步骤四：冰水浴下向6-乙酰基-4-甲氧基烟腈(A2-4，8.5g，47.75mmol)的甲醇(50mL)溶液中加入硼氢化钠(2.7g，71.63mmol)。0℃反应60分钟。反应加冰水淬灭。减压浓缩除去大部分甲醇溶剂。加乙酸乙酯(80mL)稀释，饱和盐水(3*80mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩至干，柱层析纯化(石油醚：乙酸乙酯＝1:1)纯化得淡黄色固体6-(1-羟乙基)-4-甲氧基烟腈(A2-5，6.8g，收率：79.1％)。
LCMS:m/z 179.1[M+H] +.
步骤五：0℃，氩气保护下向6-(1-羟乙基)-4-甲氧基烟腈(A2-5，5.6g，31.46mmol)和四溴化碳(15.63g，47.19mmol)的二氯甲烷(120mL)溶液中加入三苯基膦(12.36g，47.19mmol)的二氯甲烷(30mL)溶液。0℃下搅拌反应60分钟。反应液浓缩至干，柱层析纯化(石油醚：乙酸乙酯＝5:1)得白色固体6-(1-溴乙基)-4-甲氧基烟腈(A2，3.5g，收率：46.2％)。
1H NMR(400MHz,氯仿-d)：δppm 8.62(s,1H),7.06(s,1H),5.17-5.15(m,1H),4.04(s,3H),2.07(d,J＝7.2Hz,3H).
中间体A3的合成：6-(1-溴乙基)-4-乙氧基烟腈的合成
Figure PCTCN2021137254-appb-000103
步骤一：在0℃，氩气保护条件下向4,6-二氯烟腈(A2-1，20.0g，115.6mmol)的四氢呋喃(400mL)溶液中加入乙醇钠乙醇溶液(20％，101.3g，121.4mmol)。加完0℃反应10分钟后升温到室温反应2小时。将反应液倒入饱和氯化铵水溶液中， 乙酸乙酯(3*200mL)萃取，合并有机相，饱和盐水洗，干燥，过滤，滤液减压浓缩至干，经柱层析纯化(乙酸乙酯/石油醚＝1/20)得白色固体6-氯-4-乙基烟腈(A3-2，16.5g，收率：78.2％)。
LCMS:m/z 183.0[M+H] +.
1H NMR(400MHz,氯仿-d):δppm 8.47(s,1H),6.93(s,1H),4.27(q,J＝6.8Hz,2H),1.54(t,J＝7.2Hz,3H).
步骤二：在氩气保护条件下向6-氯-4-乙基烟腈(A3-2，16.5g，90.36mmol)和三丁基(1-乙氧基乙烯)锡(49.0g，135.54mmol)的1,4-二氧六环溶液(300mL)中加入四三苯基膦钯(5.2g，4.52mmol)。升温到100℃反应16小时。减压浓缩除去溶剂，用乙酸乙酯(150mL)稀释，加入饱和氟化钾水溶液，室温搅拌1小时后分液，水相用乙酸乙酯(200mL)萃取，合并有机相，饱和盐水洗，干燥，过滤，滤液减压浓缩至干。将残余物溶于四氢呋喃(100mL)中，加入盐酸水溶液(2M，120mL，240mmol)。室温反应1小时。反应液用乙酸乙酯(300mL)稀释，依次用饱和碳酸氢钠和饱和盐水洗，干燥，过滤，减压浓缩至干，经柱层析(乙酸乙酯/石油醚＝1/30)纯化得白色固体6-乙酰基-4-乙氧基烟腈(A3-3，16.6g，收率：96.6％)。
LCMS:m/z 191.1[M+H] +
1H NMR(400MHz,氯仿-d):δppm 8.72(s,1H),7.61(s,1H),4.35～4.30(q,J＝7.2Hz,2H),2.72(s,3H),1.54(t,J＝7.2Hz,3H).
步骤三：0℃下向6-乙酰基-4-乙氧基烟腈(A3-3，16.6g，87.28mmol)的甲醇(400mL)溶液中加入硼氢化钠(3.3g，87.28mmol)。0℃反应1小时。反应加冰水淬灭。减压浓缩除去大部分甲醇溶剂。加乙酸乙酯(150mL)稀释，饱和盐水(3*50mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩至干，硅胶色谱法(乙酸乙酯/石油醚＝1/10)纯化得淡黄色固体4-乙氧基-6-(1-羟乙基)烟腈(A3-4，12.3g，收率：73.3％)。
LCMS:m/z 193.0[M+H] +.
1H NMR(400MHz,DMSO-d6):δppm 8.71(s,1H),7.31(s,1H),5.63(d,J＝4.4Hz,1H),4.76～4.69(m,1H),4.36～4.28(m,2H),1.41～1.36(m,6H).
步骤四：在0℃，氩气保护下向4-乙氧基-6-(1-羟乙基)烟腈(A3-4，12.3g，63.99mmol)和三苯基膦(33.6g，127.98mmol)的四氢呋喃(400mL)溶液中加入四溴化碳(31.8g，95.98mmol)。0℃反应5分钟后升至室温搅拌反应16小时。反 应液过滤，滤液减压浓缩至干，硅胶色谱法(乙酸乙酯：石油醚＝1/20)纯化得淡黄色固体6-(1-溴乙基)-4-乙氧基烟腈(A3，14.2g，收率：86.9％)。
LCMS:m/z 255.0[M+H] +.
1H NMR(400MHz,DMSO-d6):δppm 8.81(s,1H),7.47(s,1H),5.46(q,J＝6.8Hz,1H),4.39～4.28(m,2H),1.99(d,J＝6.8Hz,3H),1.39(t,J＝7.2Hz,3H).
中间体A4的合成：5-(1-溴乙基)-2-氟-3-甲氧基吡啶的合成
Figure PCTCN2021137254-appb-000104
步骤一：冰水浴下向1-(6-氟-5-甲氧基吡啶-3-基)乙烷-1-酮(A4-1，3.0g，17.73mmol)的甲醇(30mL)溶液中加入硼氢化钠(671mg，17.73mmol)。反应室温搅拌60分钟。反应液加冰水淬灭。加乙酸乙酯(100mL)稀释，饱和盐水(3*100mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩，硅胶色谱法(0至50％梯度的乙酸乙酯：石油醚)纯化得无色油状物A4-2(2.9g，收率：96％)。
步骤二：0℃，氩气保护下向1-(6-氟-5-甲氧基吡啶-3-基)乙-1-醇(A4-2，2.6g，15.19mmol)的二氯甲烷(40mL)溶液中加入三苯基膦(6.0g，22.78mmol)和NBS(4.1g，22.78mmol)。室温搅拌反应5小时。反应液加二氯甲烷(100mL)稀释，饱和食盐水洗(3*100mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物通过硅胶色谱法(0至20％梯度的乙酸乙酯：石油醚)纯化得固体A4(2.5g，收率：70％)。
1H NMR(400MHz,氯仿-d):δppm 7.74(s,1H),7.39(dd,J＝9.6,2.0Hz,1H),5.18(q,J＝7.2Hz,1H),3.94(s,3H),2.06(d,J＝7.2Hz,3H).
19F NMR(376MHz,DMSO-d6):δppm-84.25.
中间体A5的合成：2-(1-溴乙基)-5-氟-4-甲氧基吡啶的合成
Figure PCTCN2021137254-appb-000105
步骤一：向2-溴-5-氟吡啶-4-醇(A5-1，6.0g，31.3mmol)的DMF(50mL)溶液中加入碳酸钾(10.8g，78.2mmol)和碘甲烷(11.0g，77.5mmol)。室温反应16小时。将反应液用水(50mL)稀释，乙酸乙酯(2*150mL)萃取，有机相用水(3*200mL)和饱和盐水(2*200mL)洗，干燥，过滤，滤液减压浓缩至干，经柱层析纯化得白色固体A5-2(2.6g，收率：40.4％)。
LCMS:m/z 206.1[M+H] +.
步骤二：氩气保护下向2-溴-5-氟-4-甲氧基吡啶(A5-2，2.6g，12.6mmol)和三丁基(1-乙氧基乙烯基)锡烷(6.8g，18.9mmol)的二氧六环溶液中加入四三苯基膦钯(1.0g，0.87mmol)，升温到100℃，反应16小时。减压浓缩除去溶剂，用乙酸乙酯(100mL)稀释，加入饱和氟化钾水溶液，室温搅拌1小时。分液，水相用乙酸乙酯(100mL)萃取，合并有机相，用食盐水洗涤，干燥，过滤，减压浓缩至干，将残余物溶于四氢呋喃(50mL)加入盐酸水溶液(2M，25.5mL，51.0mmol)，室温反应1小时。反应液用乙酸乙酯(100mL)稀释后依次用饱和碳酸氢钠和饱和盐水洗，干燥，过滤，减压浓缩至干，经柱层析纯化得到白色固体A5-3(1.8g，收率：84.3％)。
LCMS:m/z 170.1[M+H] +.
1H NMR(400MHz,氯仿-d),δppm 8.37(d,J＝2.8Hz,1H),7.72(d,J＝6.8Hz,1H),4.00(s,3H),2.69(s,3H).
步骤三：0℃，氩气保护下向1-(5-氟-4-甲氧基吡啶-2-基)乙酮(A5-3，12.9g，76.3mmol)的甲醇(100mL)溶液中分批加入硼氢化钠(5.75g，152.5mmol)。室温搅拌反应1小时。反应冰水淬灭，乙酸乙酯萃取(3*100mL)，饱和盐水洗(100mL)，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析(二氯甲烷：甲醇＝40：1)得黄色固体1-(5-氟-4-甲氧基吡啶-2-基)乙烷-1-醇(A5-4，6.1g，收率：46.7％)。
LCMS:m/z 172.1[M+H] +.
步骤四：0℃，氩气保护下向A5-4(1.0g，5.84mmol)的二氯甲烷(10mL)溶液中依次加入三苯基膦(2.14g，8.18mmol)，NBS(1.25g,7.01mmol)。室温搅拌反应18小时。反应冰水淬灭，乙酸乙酯萃取(3*50mL)，饱和盐水洗(50mL)，无水硫酸钠干燥，过滤，浓缩，硅胶柱层析(石油醚：乙酸乙酯＝30：1)得白色固体A5(770mg，收率：56.3％)。
LCMS:m/z 234.0[M+H] +.
中间体A6的合成：4-(1-溴甲基)-1-氟-2-甲氧基苯的合成
Figure PCTCN2021137254-appb-000106
参考A4的合成路线，用A6-1代替A4-1，经过两步合成A6：
LCMS:m/z 232.99[M+H] +.
中间体A7的合成:3-(氯甲基)-5-甲氧基-1-甲基-1H-吡唑
Figure PCTCN2021137254-appb-000107
参考中间体A8的合成，经过四步合成A7。
LCMS:m/z 161.04[M+H] +.
中间体A8的合成:3-(氯甲基)-5-乙氧基-1-甲基-1H-吡唑
Figure PCTCN2021137254-appb-000108
步骤一：向A8-1(1.0g，6.40mmol)和碳酸钾(2.66g，19.21mmol)的DMF(10mL)中滴加碘乙烷(5.0g，32.02mmol)。加热至50℃搅拌反应5小时。反应液加乙酸乙酯(30mL)稀释，饱和盐水(3*50mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩，硅胶色谱法(0至30％梯度的乙酸乙酯：石油醚)纯化得白色固体A8-2(1.1g，收率：93.2％)。
1H NMR(400MHz,氯仿-d):δppm 6.05(s,1H),4.16(q,J＝7.2Hz,2H),3.90(s,3H),3.72(s,3H),1.44(t,J＝7.2Hz,3H).
步骤二：向A8-2(1.0g，5.43mmol)的四氢呋喃(15mL)中滴加硼氢化锂(2.0M in THF，5.4mL，10.86mmol)。加热至40℃搅拌反应过夜。反应加十水硫酸钠(3.0g)淬灭，过滤，滤液减压浓缩，硅胶色谱法(0至50％梯度的乙酸乙酯：石油醚)纯化得无色油状物A8-3(580mg，收率：68.4％)。
1H NMR(400MHz,氯仿-d):δppm 5.51(s,1H),4.56(s,2H),4.12(q,J＝7.2Hz,2H),3.61(s,3H),1.42(t,J＝7.2Hz,3H).
步骤三：向A8-3(312mg，2mmol)的乙腈(10mL)溶液中加入氯化亚砜(714mg，6mmol)。氮气置换后室温反应3h。旋干反应液得到粗品，饱和碳酸氢钠水溶液中和至pH＝7。二氯甲烷(2×100mL)萃取，合并有机相，饱和盐水洗(100mL)，无水硫酸钠干燥，过滤，滤液减压浓缩至干,经硅胶柱层析纯化得到白色固体3-(氯甲基)-5-乙氧基-1-甲基-1H-吡唑(260mg，收率：74.1％)。
LCMS:m/z:175.5[M+H]+.
中间体A9的合成：2-(1-溴乙基)-4-环丙氧基-5-氟吡啶的合成
Figure PCTCN2021137254-appb-000109
步骤一：向A1-3(200mg，1.04mmol)的DMA(10mL)溶液中加入碳酸铯(848mg，2.60mmol)、碘化钾(190mg，1.15mmol)和溴代环丙烷(1.76g，14.58mmol)。180℃微波反应4小时。平行投放16次。合并用乙酸乙酯(200mL)和水稀释，分液，有机相用水洗(4*200mL)，饱和盐水洗(2*200mL)，无水硫酸钠干燥后浓缩，经柱层析纯化(石油醚：乙酸乙酯＝50：1)得黄色液体A9-1(1.6g，收率：41.3％)。
LCMS:m/z:232.3[M+H] +.
1H NMR(400Hz,氯仿-d)δppm 8.09(d,J＝2.4Hz,1H),7.38(d,J＝6.0Hz,1H),3.89～3.85(m,1H),0.92～0.90(m,4H).
19F NMR(376Hz,氯仿-d)δppm-151.47.
参照中间体A1的合成，从中间体A9-1经过三步反应得到A9。
LCMS:m/z 260.0[M+H] +.
中间体A13的合成：6-(氯甲基)-4-乙氧基烟腈的合成
Figure PCTCN2021137254-appb-000110
步骤一：向A3-2(800mg，4.38mmol)的甲醇(15mL)和二甲亚砜(50mL)的混合溶液中加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(321mg，0.44mmol)和DIPEA(1.69g，13.17mmol)。一氧化碳置换空气后加热至100℃反应12小时。用乙酸乙酯(400mL)稀释，加入饱和盐水，室温搅拌1小时。分液，水相用乙酸乙酯(300 mL)萃取，合并有机相，用饱和盐水洗涤，干燥，过滤，滤液减压浓缩至干，经柱层析纯化得A13-1(180mg，收率：19.9％)。
LCMS:m/z:207.1[M+H] +.
步骤二：冰水浴下向A13-1(206mg，1mmol)的甲醇(10mL)溶液中加入硼氢化钠(75.6mg，2mmol)。0℃反应60分钟。反应加冰水淬灭。减压浓缩除去大部分甲醇溶剂。加乙酸乙酯(80mL)稀释，饱和盐水(3*80mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩至干，硅胶色谱法(0至50％梯度的乙酸乙酯：石油醚)纯化得淡黄色油状产物A13-2(78mg，收率：43.8％)。
LCMS:m/z:179.1[M+H] +.
步骤三：冰水浴下向A13-2(80mg，0.45mmol)的二氯甲烷(10mL)溶液中加入氯化亚砜(107mg，0.9mmol)。0℃反应60分钟。减压浓缩除去大部分溶剂，饱和碳酸氢钠水溶液中和至pH＝7，加乙酸乙酯(80mL)稀释，饱和盐水(3*80mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩至干，硅胶色谱法(0至50％梯度的乙酸乙酯：石油醚)纯化得淡黄色固体A13(60mg，收率:68.0％)。
LCMS:m/z:197.1[M+H] +。
中间体A14的合成：2-(氯甲基)-4-乙氧基-5-氟吡啶
Figure PCTCN2021137254-appb-000111
步骤一：-75℃，氩气保护下向A1-4(2.70g，12.27mmol)的无水四氢呋喃(40mL)中滴加n-BuLi(1.6M in hexane，11.5ml，18.41mmol)，-75℃下反应15分钟。加入无水DMF(1.42ml，2.05mmol)。-75℃下反应15分钟。加水淬灭，乙酸乙酯(3*60mL)萃取，合并有机相，水洗，干燥，过滤，浓缩，经柱层析纯化得A14-1(915mg，收率：44.1％)。
LCMS:m/z:170.0[M+H] +
步骤二：0℃，氩气保护下向A14-1(1.0g，5.91mmol)的乙醇(20mL)溶液中加入硼氢化钠(671mg，17.74mmol)。室温下反应3小时。反应加饱和氯化铵水溶液淬灭，加水，乙酸乙酯萃取，干燥，浓缩，经柱层析纯化得A14-2(690mg，收率：68.2％)。
LCMS:m/z:172.0[M+H] +.
步骤三：向A14-2(250mg，1.46mmol)的乙腈(10mL)溶液中逐滴加入二氯亚砜(0.32ml，4.39mmol)。室温下反应1小时。减压蒸馏，加二氯甲烷，碳酸氢钠洗，干燥，浓缩，经柱层析纯化得中间体A14(240mg，收率：86.6％)。
LCMS:m/z:190.0[M+H] +.
中间体A15的合成：1-氯-4-乙氧基-2,3-二氢-1H-茚
Figure PCTCN2021137254-appb-000112
步骤一：向A15-1(2.6g，17.55mmol)的丙酮(100mL)溶液中先后加入碳酸钾(12.1g，87.74mmol)和碘乙烷(27.4g，175.49mmol)。60℃反应5小时。反应液冷却至室温后过滤，滤液减压浓缩后经柱层析纯化(石油醚：乙酸乙酯＝20:1)得A15-2(2.9g，收率：93.8％)。
1H NMR(400Hz,氯仿-d)δppm:7.34～7.27(m,2H),7.02～7.00(m,1H),4.15(q,J＝6.8Hz,2H),3.05～3.02(m,2H),2.68～2.66(m,2H),1.46(t,J＝7.2Hz,3H).
步骤二：冰水浴下向A15-2(3.2g，18.16mmol)的甲醇(50mL)溶液中分批加入硼氢化钠(690mg，18.16mmol)。室温反应3小时。反应液浓缩后经柱层析纯化(石油醚：乙酸乙酯＝10:1)得A15-3(3.0g，收率：92.7％)。
1H NMR(400Hz,氯仿-d)δppm:7.21～7.17(m,1H),7.01～6.99(m,1H),6.75～6.73(m,1H),5.23～5.20(m,1H),4.08～4.03(m,2H),3.04～2.97(m,1H),2.77～2.69(m,1H),2.50～2.44(m,1H),1.95～1.87(m,1H),1.42(t,J＝7.2Hz,3H).
步骤三：将A15-3(1.0g，5.61mmol)与三甲基氯硅烷(10mL)混合室温搅拌60分钟。反应液倒入冰水中。乙酸乙酯萃取(2*50mL)，有机相合并，饱和氯化钠水溶液(100mL)洗，无水硫酸钠干燥后浓缩得中间体A15(1.1g，收率：100％ 计)。直接用于下一步。
中间体A16的合成：5-(氯甲基)苯并[d][1,3]二氧六环
Figure PCTCN2021137254-appb-000113
步骤一：在0℃下向A16-1(600mg，4.0mmol)的乙醇(60mL)溶液中加入硼氢化钠(453mg，12.0mmol)。室温搅拌反应12小时。反应液倒入冰水中(50mL)，二氯甲烷(2*50mL)萃取，合并有机相，饱和盐水(100mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩至干，经柱层析纯化得无色油状物A16-2(450mg，收率：74.0％)。
步骤二：向A16-2(304mg，2.0mmol)的二氯甲烷(50mL)溶液中滴加氯化亚砜(714mg，3.0mmol)。室温反应4小时。反应液减压浓缩至干。得到得粗品用二氯甲烷(100mL)稀释，饱和碳酸氢钠水溶液中和至pH＝7。二氯甲烷(2*100mL)萃取，合并有机相，饱和盐水(100mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩至干，经柱层析纯化得无色油状物A16(280mg，收率：82.3％)。
中间体A17的合成：2-(1-溴乙基)-4-(二氟甲氧基)-5-氟吡啶
Figure PCTCN2021137254-appb-000114
步骤一：氩气保护，冰水浴下向A1-3(4.59g，23.91mmol)的N,N-二甲基甲酰胺(135mL)溶液中慢慢加入钠氢(60％分散于油中，2.87g，71.75mmol)。加 完后继续搅拌10分钟。随后滴加氯二氟乙酸(4.66g，35.85mmol)。70℃下反应过夜。反应冷却至室温，加水(80mL)淬灭，加乙酸乙酯(3*30mL)萃取，合并有机相，饱和食盐水(2*20mL)洗，无水硫酸钠干燥，过滤后减压浓缩，硅胶色谱纯化得淡黄色液体A17-1(622mg，收率：10.8％)。
LCMS:m/z:242.0[M+H] +.
步骤二：干燥的烧瓶中依次加入化合物A17-1(622mg，2.57mmol)、三丁基(1-乙氧基乙烯)锡(1.39g，3.85mmol)、四(三苯基磷)钯(149mg，0.13mmol)、1,4-二氧六环(40mL)。加完后氮气保护下100℃下反应过夜。反应液浓缩，乙酸乙酯(20mL)溶解，加氟化钾饱和水溶液(15mL)，室温下搅拌1小时。过滤，加水(30mL)分层后萃取，水相用乙酸乙酯(2*15mL)萃取，合并有机相，用饱和食盐水(15mL)洗，无水硫酸钠干燥，过滤后减压浓缩，硅胶色谱纯化得淡黄色液体A17-2(590mg，收率：98.6％)。
LCMS:m/z:234.0[M+H] +.
步骤三：冰水浴下向A17-2(590mg，2.53mmol)的二氯甲烷(20mL)溶液中滴加三氟乙酸(6mL)。室温下反应过夜。反应液置于冰浴中搅拌，加碳酸氢钠溶液调节至弱碱性，加水(15mL)分层后萃取，水相用二氯甲烷(2*15mL)洗，合并有机相，用饱和食盐水(2*15mL)洗，无水硫酸钠干燥，过滤后减压浓缩，硅胶色谱纯化得无色液体A17-3(308mg，收率：59.3％)。
LCMS:m/z:206.0[M+H] +.
步骤四：冰水浴下向A17-3(308mg，1.50mmol)的甲醇(10mL)溶液中慢慢加入硼氢化钠(114mg，3.0mmol)。加完后室温反应过夜。反应液加水(20mL)淬灭，用乙酸乙酯(3*20mL)萃取，合并有机相，用饱和食盐水(2*15mL)洗，无水硫酸钠干燥，过滤后减压浓缩，Prep-TLC纯化得无色油状物A17-4(295mg，收率：94.8％)。
LCMS:m/z:208.0[M+H] +.
步骤五：氮气保护，冰水浴下向A17-4(75mg，0.36mmol)和三苯基磷(171mg，0.65mmol)的四氢呋喃(4mL)溶液中滴加四溴化碳(180mg，0.54mmol)的四氢呋喃(1mL)溶液。室温下反应过夜。反应液加水(15mL)，用乙酸乙酯(20mL*3)萃取，合并有机相，用饱和食盐水(2*15mL)洗，无水硫酸钠干燥，过滤后减压浓缩，Prep-TLC纯化得淡黄色固物A17(72mg，收率：73.6％)。
LCMS:m/z:269.9[M+H] +.
中间体A18的合成：2-(1-溴乙基)-4-(三氟甲氧基)-5-氟吡啶
Figure PCTCN2021137254-appb-000115
步骤一：参考文献Tetrahedron Letters(2008),49(44),6368-6370的合成方法从A1-3一步生成A18-1.
步骤二：参考中间体A17的合成路线，经过四步反应从中间体A18-1生成中间体A18.
LCMS:m/z:287.9[M+H] +.
中间体A19的合成：5-(1-氯乙基)-2,2-二甲基苯并[d][1,3]二氧环戊烯
Figure PCTCN2021137254-appb-000116
步骤一：向A19-1(2.0g，13.14mmol)的乙腈/丙酮(40mL/10mL)溶液中加入五氧化二磷(9.3g，65.72mmol)。加热至75℃反应3小时。每4小时分批次添加五氧化二磷(4.67g*4，131.50mmol)。继续反应48小时。反应冷却至室温后倒入冰水(100mL)中，乙酸乙酯(3*30mL)萃取，合并有机相，饱和氯化钠水溶液 (100mL)洗，无水硫酸钠干燥后浓缩，经柱层析(石油醚：乙酸乙酯＝10:1)纯化得A19-2(900mg，收率：35.6％)。
1H NMR(400Hz,氯仿-d):δppm 7.53(dd,J＝1.6Hz,8.0Hz,1H),7.36(d,J＝1.6Hz,1H),6.77(d,J＝4.4Hz,1H),2.53(s,3H),1.70(s,6H).
步骤二：冰水浴下向A19-2(900mg，4.68mmol)的甲醇(10mL)溶液中分批加入硼氢化钠(355mg，9.36mmol)。室温反应3小时。反应液浓缩后经过柱层析纯化(石油醚：乙酸乙酯＝10:1～5:1)得A19-3(580mg，收率：63.8％)。
1H NMR(400Hz,氯仿-d):δppm 6.80～6.79(m,1H),6.77～6.75(m,1H),6.68～6.66(m,1H),4.80～4.78(m,1H),1.82(s,1H),1.67(d,J＝1.2Hz,6H),1.46(d,J＝2.4Hz,3H).
步骤三：将A19-3(490mg，2.52mmol)与三甲基氯硅烷(5mL)混合室温搅拌1小时。反应液倒入冰水中，乙酸乙酯(2*20mL)萃取，有机相合并，饱和氯化钠水溶液(30mL)洗，无水硫酸钠干燥后浓缩得A19(500mg，收率：93.2％)。
中间体B1的合成：5'-溴-7'-(氯甲基)-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮
Figure PCTCN2021137254-appb-000117
步骤一：向2-羟基苯甲酸甲酯(B1-1,25g，164.31mmol)的二氯甲烷(300mL)溶液中加入三乙胺(34mL，246.47mmol)。在氩气保护下，0℃时，缓慢滴加三光气(36.6g，123.23mmol)的二氯甲烷(100mL)溶液。室温下反应3小时。反应液浓缩，经柱层析纯化(乙酸乙酯/石油醚＝1/10)得B1-2(26g，收率：47.9％)。
1H NMR(400MHz,DMSO-d6):δ8.02-7.99(m,2H),7.80-7.66(m,2H),7.53-7.44(m,4H),3.90(s,6H).
步骤二：在氩气保护下，0℃下向1-(4-溴苯基)环丙烷腈(B1-3,50g，228.13mmol)的四氢呋喃(500mL)溶液中逐滴加入BH 3·THF(1M，四氢呋喃溶液，566mL，566mmol)。然后升至70℃反应4小时。LCMS监测反应完全。反应加甲醇淬灭，浓缩，经柱层析纯化(二氯甲烷/甲醇＝35/1)得(1-(4-溴苯基)环丙基)甲胺(B1-4,48g，收率：94.3％)。
LCMS:m/z 226.1[M+H] +.
步骤三：在氩气保护下向(1-(4-溴苯基)环丙基)甲胺(B1-4,17.73g，78.41mmol)的四氢呋喃(400mL)溶液中分批次加入2,2'-(羰基双(氧基))二苯甲酸二甲酯(B1-2,26g，78.79mmol)。室温下反应5小时。反应液浓缩，经柱层析纯化(乙酸乙酯/石油醚＝1/20)得B1-5(27.8g，收率：87.2％)。
LCMS:m/z 404.0[M+H] +.
步骤四：在0℃，氩气保护下向B1-5(27.8g，68.77mmol)的二氯甲烷(500mL)溶液中缓慢滴加三氟甲磺酸(30.4mL，344.91mmol)。0℃下搅拌反应1小时。用饱和碳酸氢钠水溶液淬灭，二氯甲烷萃取，合并萃取液，无水硫酸钠干燥，过滤，浓缩，经柱层析纯化得7'-溴-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮(B1-6,10.72g，收率：61.9％)。
LCMS:m/z:252.0[M+H] +.
步骤五：向7'-溴-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮(B1-6,10.72g，42.52mmol)的甲醇(20mL)和DMSO(20mL)的溶液中，加入Pd(dppf)Cl 2·CH 2Cl 2(3.32g，4.07mmol)和N,N-二异丙基乙胺(21.1mL，128.13mmol)。CO置换空气三次后升温至90℃反应16小时。反应液倒入水中，二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，旋干，经柱层析纯化(乙酸乙酯/石油醚＝1/10)得1'-酮-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-羧酸甲酯(B1-7,6.13g，收率：62.3％)。
LCMS:m/z:232.1[M+H] +.
步骤六：0℃下向浓硫酸(20mL)和冰醋酸(20mL)的混合溶液中加入1'-酮酮-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-羧酸甲酯(B1-7,4.0g，17.3mmol)。搅拌20分钟后向反应液中滴加1,3-二溴-5,5-二甲基海因(4.9g,17.3mmol)的冰醋酸(20mL)溶液。室温反应5小时。加乙酸乙酯(200mL)稀释，将反应液倒入冰水中，室温搅拌1小时。分液，水相用乙酸乙酯(300mL)萃取，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩至干，经柱层析纯化(乙酸乙酯/石油醚＝1/10)得白色固体5'-溴-1'-酮-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-羧酸甲酯(B1-8,2.0g，收率：37.3％)。
LCMS:m/z 310.0/312.0[M+H] +.
1H NMR(400MHz,DMSO-d6):δppm 8.46(d,J＝2.0Hz,2H),8.11(d,J＝2.0Hz,1H),3.88(s,3H),3.16(d,J＝2.8Hz,2H),1.90～1.87(m,2H),1.07～1.05(m,2H).
步骤七：向5'-溴-1'-酮-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-羧酸甲酯(B1-8,3.1g，10mmol)的四氢呋喃(50mL)和水(50mL)溶液中加入一水合氢氧化锂(800mg,20mmol)。室温反应14小时。LCMS检测显示有80％的产物。减压除去溶剂四氢呋喃。用1M aq.HCl水溶液调pH至7，有大量白色固体析出，过滤得5'-溴-1'-酮-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-羧酸(B1-9,2.2g，收率：74.3％)。
LCMS:m/z 295.7/297.7[M+H] +.
步骤八：0℃下向5'-溴-1'-酮-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-羧酸(B1-9,2.2g,7.4mmol)和三乙胺(2.24g，22.2mmol)的二氯甲烷(30mL)溶液中加入氯甲酸异丁脂(2.02g,14.8mmol)。室温搅拌反应2小时。将反应液倒入冰水中，室温搅拌1小时。分液，水相用二氯甲烷(300mL)萃取，合并有机相，饱和盐水洗，无水硫酸钠干燥，过滤，减压浓缩至干得粗品B1-10(1.68g，收率:57.3％)。
LCMS:m/z 396.1/398.1[M+H] +.
步骤九：0℃下向B1-10(1.65g,4.2mmol)的四氢呋喃(30mL)溶液中加入硼氢化钠(472mg,12.5mmol)。室温反应2小时。加入甲醇(10mL)淬灭反应。将反应液倒入冰水中，室温搅拌0.5小时。分液，水相用二氯甲烷(200mL)萃取，合并有机相，饱和盐水洗，无水硫酸钠干燥，过滤，减压浓缩至干，经过柱层析纯化(乙酸乙酯/石油醚＝1/3)得到油状B1-11(460mg，收率:39.2％)。
LCMS:m/z:282.2/284.2[M+H] +.
步骤十：0℃下,向B1-11(100mg,0.356mmol)的乙腈(20mL)溶液中加入氯化亚砜(127mg,1.068mmol)，室温反应6小时。将反应液旋干得粗品5'-溴-7'-(氯甲基)-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1`-酮(B1,110mg，收率：100％)。
LCMS:m/z:299.97[M+H] +.
中间体B2的合成：5'-溴-7'-(氯甲基)-2',3'-二氢-1'H-螺[环丁烷-1,4'-异喹啉]-1'-酮
Figure PCTCN2021137254-appb-000118
步骤一：在0℃，氩气保护下向B2-1(25g，127.52mmol)的DMF(500mL)溶液中分批次加入氢化钠(60％分散在矿物油中，20.4g，510.07mmol)。0℃下反应30分钟。滴加1,3-二溴丙烷(19.42mL，191.28mmol)的DMF(50mL)溶液。室温反应1小时。冰水淬灭。乙酸乙酯(3*300mL)萃取，合并有机相，用饱和盐水洗，干燥，过滤，浓缩，经柱层析纯化(石油醚：乙酸乙酯＝20:1)得B2-2(20g，收率：66.4％)。
1H NMR(400MHz,DMSO-d6):δppm 7.64(d,J＝8.8Hz,2H),7.43(d,J＝8.4Hz,2H),2.77-2.71(m,2H),2.64-2.56(m,2H),2.33-2.22(m,1H),2.05-1.96(m,1H).
步骤二：在0℃，氩气保护下向B2-2(20g，84.71mmol)的THF(200mL)溶液中逐滴加入BH 3·THF(1M in THF，212mL，212mmol)。70℃下反应4小时。LCMS监测反应完全。反应用甲醇淬灭，减压浓缩，经柱层析纯化(二氯甲烷：甲醇＝20:1)得B2-3(5.5g，收率：27.0％)。
LCMS:m/z:242.1[M+H]+.
步骤三:在氩气保护下向B2-3(4.5g，18.75mmol)的THF(40mL)溶液中分批次加入B1-2(6.2g，18.75mmol)。室温下反应6小时。反应液减压浓缩，经柱层析纯化(石油醚：乙酸乙酯＝1:1)得B2-4(7.2g，收率：91.9％)。
1H NMR(400MHz,DMSO-d6):δppm 7.86(t,J＝6.4Hz,1H),7.82-7.80(m,1H),7.61-7.57(m,1H),7.51-7.49(m,2H),7.32(t,J＝7.2Hz,1H),7.15-7.13(m,2H),7.86(d,J＝8.0Hz,1H),3.73(s,3H),3.36(s,1H),3.34(s,1H),2.36-2.29(m,2H),2.23-2.16(m,2H),2.10-2.03(m,1H),1.81-1.72(m,1H).
步骤四：在0℃，氩气保护下向B2-4(7.2g，17.21mmol)的二氯甲烷(100mL)溶液中逐滴加入三氟甲磺酸(7.6mL，86.06mmol)。室温下反应2小时。反应用饱和碳酸氢钠水溶液淬灭。二氯甲烷(3*100mL)萃取，合并有机相，干燥，过滤，浓缩，经柱层析纯化(石油醚：乙酸乙酯＝1:1)得B2-5(1.8g，收率：39.3％)。
LCMS:m/z:266.0[M+H]+.
步骤五：向B2-5(1.8g，6.77mmol)的甲醇(10mL)和DMSO(30mL)溶液中加入N,N-二异丙基乙胺(3.3mL，20.30mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(552mg，0.677mmol)。CO置换空气三次后升温至90℃反应16小时。加水(50mL)稀释，乙酸乙酯(3*50mL)萃取，合并有机相，干燥，过滤，浓缩，经柱层析纯化(石油醚：乙酸乙酯＝1:3)得B2-6(1.3g，收率：78.4％)。
LCMS:m/z:246.1[M+H]+.
步骤六：0℃下向B2-6(1.3g，5.3mmol)的浓硫酸(10mL)和冰醋酸(10mL)的混合溶液中缓慢滴加1,3-二溴-5,5-二甲基海因(3.0g，10.6mmol)的冰醋酸(10mL)溶液。室温反应16小时。反应用冰水淬灭，用乙酸乙酯(3*50mL)萃取，合并有机相，干燥，过滤，浓缩，经柱层析纯化得B2-7(1.2g，收率：69.8％)。
LCMS:m/z:326.0[M+H]+.
步骤七：在0℃下向B2-7(1.2g，3.70mmol)的THF(10mL)和乙醇(2mL)的混合溶液中滴加硼氢化锂(2M in THF，9.3mL，18.51mmol)。室温下反应10分钟后加热至45℃下反应2小时。反应用冰水淬灭。乙酸乙酯(3*50mL)萃取，合并有机相，干燥，过滤，浓缩，经柱层析纯化得B2-8(580mg，收率：52.7％)。
LCMS:m/z:296.0[M+H]+.
步骤八：在0℃下向B2-8(200mg，0.675mmol)的乙腈(10mL)溶液中滴加氯化亚砜(0.15mL，2.03mmol)。室温搅拌反应1小时。反应液减压浓缩得B2(215mg，0.675mmol)，粗品直接用于下一步。
LCMS:m/z:316.0[M+H]+.
中间体B3的合成：5'-溴-7'-(氯甲基)-2',3'-二氢-1'H-螺[环戊烷-1,4'-异喹啉]-1'-酮
Figure PCTCN2021137254-appb-000119
参考B1的合成路线，用B3-1代替B1-3，经过九步反应得到中间体B3。
LCMS:m/z:328.0[M+H] +.
中间体B10的合成：5'-溴-7'-(氯甲基)-2,2-二氟-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮
Figure PCTCN2021137254-appb-000120
步骤一：向B10-1(100g，411.35mmol)的甲苯(1.5L)溶液中加入多聚甲醛(18.51g，617.03mmol)，四丁基碘化胺(7.60g，20.57mmol)和碳酸钾(85.28g，617.03mmol)。加热至85℃反应16小时。冷却至室温后过滤，滤液减压浓缩后经柱层析纯化(石油醚：乙酸乙酯＝50：1)得到B10-2(61g，收率：58.1％)。
1H NMR(400Hz,氯仿-d)δppm:7.50～7.47(m,2H),7.31～7.28(m,2H),6.38(d,J＝1.2Hz,1H),5.89(d,J＝0.8Hz,1H),4.31～4.26(m,2H),1.33(t,J＝7.2Hz,3H).
步骤二：向B10-2(21g，82.32mmol)的四氢呋喃(300mL)溶液中加入(三氟甲基)三甲基硅烷(93.6g，658.54mmol)和碘化钠(7.4g，49.39mmol)。闷罐110℃反应14小时。反应液用乙酸乙酯稀释(700mL)，水洗(2*700mL)，饱和氯化钠水溶液洗涤(700mL)，无水硫酸钠干燥后浓缩，经柱层析分离纯化(石油醚：乙酸乙酯＝50：1)得B10-3(21g，收率：83.7％)。
1H NMR(400Hz,氯仿-d)δppm:7.44～7.40(m,2H),7.24～7.18(m,2H),4.15～4.05(m,2H),2.59～2.53(m,1H),1.84～1.78(m,1H),1.13(t,J＝7.2Hz,3H).
步骤三：将B10-3(73.5g，240.89mmol)溶解于甲醇(600mL)中。加入水(300mL)和四氢呋喃(150mL)后再加入氢氧化锂(28.91g，1.20mol)。室温搅拌反应3小时。反应液浓缩减压浓缩除去溶剂甲醇和四氢呋喃。残留物加水稀释(700mL)，稀盐酸(3M)调pH＝3～4。乙酸乙酯萃取(3*600mL)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化(石油醚：乙酸乙酯：乙酸＝10：1：0.001)得B10-4(31.8g，收率：47.6％)。
1H NMR(400Hz,DMSO-d 6)δppm:13.45(s,1H),7.59～7.57(m,2H),7.37～7.35(m,2H),2.58～2.53(m,1H),2.30～2.24(m,1H).
步骤四：B10-4(31.8g，114.78mmol)的DMA(600mL)溶液中加入DIPEA(89.0g，688.66mmol)和HATU(52.37g，137.73mmol)。室温搅拌30分钟。加入氯化铵(18.42g，344.33mmol)。室温搅拌30分钟后加热至60℃反应液16小时。冷却至室温后加乙酸乙酯(1.5L)稀释，水洗(3*1L)，饱和氯化钠水溶液洗(1L)。无水硫酸钠干燥，过滤，滤液减压浓缩，经过柱层析纯化(石油醚：乙酸乙酯＝2：1)得B10-5(17g，收率：53.6％)。
LCMS:m/z:275.9[M+H] +.
步骤五：冰水浴下向B10-5(15.8g，57.23mmol)的四氢呋喃(300mL)溶液中滴加BH 3·THF(1M in四氢呋喃，143mL，143.0mmol)。加毕，逐渐升温至75℃反应16小时。反应液冷却至0℃后滴加甲醇(100mL)淬灭。减压浓缩出去溶剂。残留物用甲醇溶解稀释，并于75℃搅拌10小时。浓缩，经柱层析分离纯化(二氯甲烷：甲醇＝50：1～20：1)得B10-6(11g，收率：73.3％)。
LCMS:m/z:263.9[M+H] +.
步骤六：向B10-6(12g，45.78mmol)的四氢呋喃(150mL)溶液中加入2,2'-(羰基双(氧))二苯甲酸二甲酯(15.1g，45.78mmol)。室温搅拌48小时。反应液直接浓缩，经过柱层析纯化(石油醚：乙酸乙酯＝10：1～5：1)得B10-7(17g，收率：84.6％)。
LCMS:m/z 464.0[M+Na] +.
步骤七：冰水浴下向B10-7(17g，38.61mmol)的1,2-二氯乙烷(400mL)溶液中滴加三氟甲磺酸(200mL)。室温搅拌3.5小时。反应液倒入冰水中，二氯甲烷萃取(2*300mL)，合并有机相，饱和氯化钠水溶液洗(300mL)，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化(二氯甲烷:甲醇＝100:1)得B10-8(6.5g， 收率：58.5％)。
LCMS:m/z 289.9[M+H] +.
步骤八：向B10-8(7.8g，27.07mmol)的甲醇(80mL)和二甲基亚砜(160mL)溶液中加入DIPEA(10.5g，81.22mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(1.98g，2.71mmol)。一氧化碳置换空气后于90℃反应8小时。冷却至室温后加二氯甲烷(400mL)稀释，水洗(3*400mL)，饱和氯化钠水溶液洗(400mL)，无水硫酸钠干燥，过滤，滤液减压浓缩后经过柱层析纯化(二氯甲烷：甲醇＝50：1)得B10-9(6.4g，收率：88.9％)。
LCMS:m/z 268.0[M+H] +.
步骤九：向B10-9(3g，11.23mmol)的醋酸(30mL)和浓硫酸(60mL)溶液中加入1,3-二溴-1,3,5-三嗪-2,4,6-三酮(8g，28.07mmol)。室温反应3小时。反应液倒入冰水中，乙酸乙酯萃取(2*150mL)，合并有机相，饱和亚硫酸钠水溶液洗(100mL)，饱和氯化钠水溶液洗(150mL)，无水硫酸钠干燥，过滤，滤液减压浓缩后经过柱层析纯化(二氯甲烷：甲醇＝200：1)得B10-10(900mg，收率：23.2％)。
LCMS:m/z 348.0[M+H] +.
步骤十：0℃，氩气保护下向B10-10(500mg，1.44mmol)的四氢呋喃(20mL)中滴加LiAlH 4(1M in四氢呋喃，2.9mL，2.89mmol)。保温反应10分钟。反应液倒入冰水中。二氯甲烷萃取(2*50mL)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化(二氯甲烷：甲醇＝20：1)得B10-11(350mg，收率：76.2％)。
LCMS:m/z 317.9[M+H] +.
步骤十一：向B10-11的二氯甲烷(6mL)溶液中滴加氯化亚砜(375mg，3.14mmol)。室温反应5小时。监测未反应完全，补加氯化亚砜(750mg，6.28mmol)，继续反应16小时。反应液倒入冰水中(20mL)，二氯甲烷(50mL)萃取2次，合并有机相，饱和盐水洗(200mL)，无水硫酸钠干燥，浓缩，经柱层析纯化(二氯甲烷：甲醇＝50：1)得B10(200mg，收率：94.8％)。
LCMS:m/z:337.9[M+H] +.
中间体B11的合成：5'-溴-7'-(氯甲基)-3,3-二氟-2',3'-二氢-1'H-螺[环丁烷-1,4'-异喹啉]-1'-酮
Figure PCTCN2021137254-appb-000121
步骤一：冰水浴下向B11-1(50g，255.03mmol)的DMF(1L)溶液中分批加入氢化钠(60％分散于油中，22.4g，561.08mmol)。室温搅拌1小时。滴加1,3-二溴-2,2-二甲氧基丙烷(73.5g，280.54mmol)。加热至60℃反应16小时。反应液冷却至室温后倒入冰水中，乙酸乙酯(2*700mL)萃取，合并有机相，水(3*500mL)洗，饱和氯化钠水溶液(2*700mL)洗，无水硫酸钠干燥后浓缩。残留物加石油醚溶解后过滤得B11-2(55g，收率：72.8％)。
1H NMR(400Hz,氯仿-d)δppm:7.54～7.51(m,2H),7.38～7.34(m,2H),3.27(s,3H),3.17(s,3H),3.12～3.11(m,1H),3.09～3.08(m,1H),2.71～2.69(m,1H),2.67～2.66(m,1H).
步骤二：向B11-2(59g，199.2mmol)的丙酮(700mL)溶液中滴加盐酸(6M，180mL)。加毕，升温至60℃反应3小时。反应液冷却至室温后加乙酸乙酯(1L)稀释，水(700mL)洗，饱和氯化钠水溶液(700mL)洗，无水硫酸钠干燥后浓缩，经柱层析分离纯化(石油醚：乙酸乙酯＝15：1)得B11-3(47g，收率：94.4％)。
1H NMR(400Hz,氯仿-d)δppm:7.61～7.58(m,2H),7.39～7.36(m,2H),4.09～4.03(m,2H),3.72～3.65(m,2H).
步骤三：B11-3(30g，120.0mmol)溶解到二氯甲烷(300mL)和甲醇(0.3mL) 中。搅拌10分钟后于冰水浴下滴加DAST(92mL，319.8mmol)。室温反应3小时。反应液倒入冰水中，二氯甲烷(2*400mL)萃取，有机相合并，饱和氯化钠水溶液(500mL)洗，无水硫酸钠干燥，过滤，浓缩后经柱层析纯化(石油醚：乙酸乙酯＝100：1～60：1)得B11-4(18g，收率：55.2％)。
1H NMR(400Hz,氯仿-d)δppm:7.60～7.56(m,2H),7.36～7.32(m,2H),3.56～3.47(m,2H),3.23～3.12(m,2H).
19F NMR(376Hz,氯仿-d)δppm:-85.72,-86.25,-92.02,-92.55
步骤四：冰水浴下向B11-4(19.3g，70.93mmol)的四氢呋喃(150mL)溶液中滴加BH 3·THF的溶液(1M，213mL，213.00mmoL)。加热回流反应16小时。冰水浴下向反应液中滴加甲醇(30mL)淬灭。浓缩，残留物用甲醇(300mL)稀释，加热回流5小时。浓缩，柱层析纯化(二氯甲烷/甲醇＝50：1)得B11-5(13.0g，收率：66.4％)。
LCMS:m/z:278.0[M+H] +.
步骤五：将B11-5(13.6g，49.25mmol)和B1-2(16.3g，49.25mmol)溶解于四氢呋喃(150mL)中。室温搅拌16小时。反应液直接浓缩，经过柱层析纯化(石油醚：乙酸乙酯＝10：1～5：1)得B11-7(22.0g，收率：98.3％)。
LCMS:m/z:477.9[M+H] +.
步骤六：冰水浴下向B11-7(24.0g，52.83mmol)的二氯甲烷(300mL)溶液中滴加三氟甲磺酸(32.7mL，369.82mmoL)。室温反应3小时。反应液倒入冰水中，加二氯甲烷(500mL)，有机相水(2*500mL)洗，饱和氯化钠水溶液(2*500mL)洗，无水硫酸钠干燥，浓缩。粗品加石油醚/二氯甲烷(10/1)溶解，过滤得B11-8(8.3g，收率：51.9％)。
LCMS:m/z 301.7(M+H) +.
1H NMR(400Hz,DMSO-d6)δppm:8.28(s,1H),7.97(d,J＝2.0Hz,1H),7.81～7.79(m,1H),7.60～7.58(m,1H),3.46(d,J＝2.0Hz,2H),2.99～2.89(m,2H),2.84～2.75(m,2H).
19F NMR(400Hz,DMSO-d6)δppm:-84.92,-84.44,-87.73,-88.25.
步骤七：向B11-8(7.5g，24.82mmol)的甲醇(25mL)和二甲基亚砜(100mL)中加入DIPEA(9.6g，74.47mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(1.27g，1.74mmol)。一氧化碳环境90℃反应4小时。冷却至室温后加二氯甲烷(40mL)稀 释，水(3*500mL)洗，饱和氯化钠水溶液(300mL)洗，浓缩后经过柱层析纯化(二氯甲烷：甲醇＝100:1～50：1)得B11-9(6.1g，收率：87.4％)。
LCMS:m/z 282.1[M+H] +.
步骤八：向B11-9(700mg，2.49mmol)的醋酸(6mL)和浓硫酸(3mL)中溶液中加入1,3-二溴-1,3,5-三嗪-2,4,6-三酮(785mg，2.74mmol)。加毕室温反应1小时。反应液倒入冰水中，乙酸乙酯(2*500mL)萃取，有机相合并，饱和亚硫酸钠水溶液(50mL)洗，饱和氯化钠水溶液(50mL)洗，浓缩后经柱层析纯化(二氯甲烷：乙酸乙酯＝20：1～5：1)得B11-10(600mg，收率：66.9％)。
LCMS:m/z 360.0[M+H] +.
1H NMR(400Hz,DMSO-d6)δppm:8.51～8.48(m,2H),8.27(d,J＝2.0Hz,1H),3.90(s,3H),3.87～3.74(m,2H),3.49(s,2H),2.72～2.63(m,2H).
19F NMR(400Hz,DMSO-d6)δppm:-81.54,-82.06,-87.19,-87.71.
步骤九：0℃，氩气保护下向B11-10(800mg，2.22mmol)的四氢呋喃(20mL)溶液中滴加硼氢化锂的四氢呋喃溶液(2M，2.8mL，5.60mmol)。保温反应2小时。反应液倒入冰水中，二氯甲烷(3*100mL)萃取，有机相浓缩后经柱层析纯化(二氯甲烷：甲醇＝25：1)得B11-11(500mg，收率：67.8％)。
LCMS:m/z 332.0[M+H] +.
步骤十：0℃下向B11-11(610mg，1.85mmol)的乙腈溶液中加入氯化亚砜(970mg，6.47mmol)。常温反应1小时。反应液加入二氯甲烷(50mL)稀释，加入饱和碳酸氢钠，二氯甲烷萃取，有机相用食盐水洗涤，干燥，过滤，浓缩至干，经柱层析(石油醚/乙酸乙酯＝2/1)纯化得黄色固体B11(600mg，收率：93.2％)。
LCMS:m/z:350[M+H] +.
中间体C1的合成：(1H-咪唑-2-基)(甲基)氨基甲酸叔丁酯
Figure PCTCN2021137254-appb-000122
步骤一：将2-硝基-1H-咪唑(C1-1，9000mg，79.8mmol)加入到无水四氢呋喃(270mL)中，冰浴下加入钠氢(60％,3.5g,87.5mmol)。氩气保护下0℃反应0.5小时。滴加(2-(氯甲氧基)乙基)三甲基硅(14.6g，87.6mmol)后0℃反应2小时。将反应液缓慢倒入冰水(200mL)中，乙酸乙酯(3*200mL)萃取，有机相合并用饱和食盐水(200mL)洗，无水硫酸钠干燥，过滤，浓缩，粗品通过柱层析(乙酸乙酯/石油醚＝1/5)得黄色固体2-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑(C1-2,14.3g，收率：73.8％)。
步骤二：将2-硝基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑14-2(C1-2,14.3g，58.8mmol)加入到无水乙醇(420mL)中。氢气置换三次，氢气保护下室温反应16小时。反应液过滤，滤液浓缩，得到粗品1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-2-胺。将粗品1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-2-胺用二氯甲烷(300mL)溶解。加入碳酸钾(35.0g,253.3mmol)，滴加二碳酸二叔丁酯(44.0g,201.6mmol)，室温反应16小时。反应液过滤，滤液浓缩干，加入甲醇(600mL)溶解，加入碳酸钾(35.0g,253.3mmol)，室温搅拌16小时，反应液过滤，滤液浓缩干，柱层析(乙酸乙酯/石油醚＝1/20)得(1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-2-基)氨基甲酸叔丁酯(C1-3,9.6g，收率：58.1％)。
LCMS：m/z 314.5[M+H] +.
步骤三：将(1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-2-基)氨基甲酸叔丁酯(C1-3,9.6g，30.7mmol)加入到无水四氢呋喃(300mL)中。冷却至0℃，加入钠氢(60％，1.5g，37.5mmol)。氩气保护下0℃反应15分钟，滴加碘甲烷(6.5g，45.8mmol)。0℃反应3小时。将反应液缓慢倒入冰水中，乙酸乙酯(3*200mL)萃取，有机相合并用饱和食盐水(200mL)洗涤，浓缩，粗品 通过柱层析(乙酸乙酯/石油醚＝1/20)得到黄色固体叔丁基甲基(1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-2-基)氨基甲酸酯(C1-4,8.2g，收率：81.4％)。
LCMS：m/z 328.5[M+H] +.
步骤四：将叔丁基甲基(1-(((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-咪唑-2-基)氨基甲酸酯(C1-4,8.2g，25.0mmol)加入到无水四氢呋喃(200mL)中，加入四丁基氟化胺的四氢呋喃溶液(1M，125mL，125mmol)。氩气保护下80℃反应1小时。反应液浓缩，粗品柱层析(乙酸乙酯:石油醚＝1:10)得黄色固体(1H-咪唑-2-基)(甲基)氨基甲酸叔丁酯(C1,2.3g，收率：48.0％)。
LCMS：m/z 198.5[M+H] +.
下列中间体商业可得：
Figure PCTCN2021137254-appb-000123
中间体D57的合成：((4-乙基哌嗪-1-基)甲基)三氟硼酸钾
Figure PCTCN2021137254-appb-000124
步骤一：向1-乙基哌嗪(460mg，4mmol)的四氢呋喃(20mL)溶液中(4mL)加入溴甲基三氟硼酸钾(200mg，1mmol)。氮气置换空气后80℃反应3小时。旋干反应液得到粗品。将得到的粗产物溶于丙酮(20mL)中，并加入碳酸氢钾(100mg,1mmol)，将该悬浮液室温搅拌1小时。过滤，滤液减压浓缩至干得到白色固体((4-乙基哌嗪-1-基)甲基)三氟硼酸钾(D57，250mg，收率：100％)。
按照如上方法合成如下中间体：
Figure PCTCN2021137254-appb-000125
Figure PCTCN2021137254-appb-000126
实施例一：化合物1和1’的合成
(S)-5'-((二甲基胺基)甲基)-2'-(1-(4-乙氧基-5-氟吡啶-2-基)乙基)-7'- ((2-(甲基氨基)-1H-咪唑-1-基)甲基)-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1`-酮
(R)-5'-((二甲基胺基)甲基)-2'-(1-(4-乙氧基-5-氟吡啶-2-基)乙基)-7'-((2-(甲基氨基)-1H-咪唑-1-基)甲基)-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1`-酮
Figure PCTCN2021137254-appb-000127
步骤一：在0℃下向(1H-咪唑-2-基)(甲基)氨基甲酸叔丁酯(C1，197mg,1mmol)，四丁基碘化铵(369mg,1mmol)和碳酸铯(650mg,2mmol)的DMF(45mL)溶液中加入5'-溴-7'-(氯甲基)-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1`-酮(B1，302mg，1mmol)。80℃反应5小时。反应液倒入冰水中(20mL)，二氯甲烷(2*150mL)萃取，合并有机相，饱和盐水洗(200mL)，无水硫酸钠干燥，过滤，滤液减压浓缩至干，经柱层析纯化(乙酸乙酯:石油醚＝1:3)得到黄色固体叔丁基(1-(((5'-溴-1'-酮-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-基)甲基)-1H-咪唑-2-基)(甲基)氨基甲酸酯(1-1，350mg，收率：75.9％)。
LCMS:m/z:461.1/463.1[M+H] +.
步骤二：向叔丁基(1-(((5'-溴-1'-酮-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-基)甲基)-1H-咪唑-2-基)(甲基)氨基甲酸酯(1-1，230mg，0.5mmol)和N,N-二甲基氨基甲基三氟硼酸钾(1-2，165mg,1mmol)的二氧六环(dioxane，6mL)和水(2mL)的混合溶液中加入Pd(dppf)Cl 2(37mg,0.05mmol)，K 2CO 3(138mg,1mmol)。氮气置换后115℃微波反应2小时。LCMS显示50％是产物。乙酸乙酯(200mL)稀释，加入饱和盐水溶液，分液，水相用乙酸乙酯(100mL)萃取，合并有机相，饱和盐水洗，无水硫酸钠干燥，过滤，减压浓缩至干，经柱层析纯化(乙酸乙酯:石油醚＝1:2)得到黄色固体叔丁基(1-((5'-(((二甲基胺基)甲基)-1'-酮-2'， 3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-(甲基)-1H-咪唑-2-基)(甲基)氨基甲酸酯(1-3，105mg，收率：47.8％)。
LCMS:m/z:440.5[M+H] +.
步骤三：0℃下向叔丁基(1-((5'-(((二甲基胺基)甲基)-1'-酮-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-(甲基)-1H-咪唑-2-基)(甲基)氨基甲酸酯(1-3，100mg，0.228mmol)的DMF(15mL)溶液中加入NaH(60％分散在矿物油中，30mg，0.72mmol)。0℃搅拌20分钟。加入2-(1-溴乙基)-4-乙氧基-5-氟吡啶(A1，90mg，0.363mmol)。室温搅拌反应2小时。反应液倒入冰水中(20mL)，二氯甲烷(2*50mL)萃取，合并有机相，饱和盐水洗(100mL)，无水硫酸钠干燥，过滤，滤液减压浓缩至干,经柱层析纯化(乙酸乙酯:石油醚＝2:1)得到黄色固体叔丁基(1-((5'-((二甲基氨基)甲基)-2'-(1-(4-乙氧基-5-氟吡啶-2-基)乙基)-1'-酮-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-基)甲基)-1H-咪唑-2-基)(甲基)氨基甲酸酯(1-4，90mg，收率：65.2％)。
LCMS:m/z:607.8[M+H] +.
步骤四：0℃下向叔丁基(1-((5'-((二甲基氨基)甲基)-2'-(1-(4-乙氧基-5-氟吡啶-2-基)乙基)-1'-酮-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-基)甲基)-1H-咪唑-2-基)(甲基)氨基甲酸酯(1-4，90mg，0.148mmol)的二氯甲烷(10mL)溶液中加入三氟乙酸(4mL)。室温搅拌反应2小时。反应液倒入冰水中(30mL)，饱和碳酸氢钠水溶液中和pH至7。二氯甲烷(2*100mL)萃取，合并有机相，饱和食盐水(100mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩至干,经高效液相色谱分离纯化(SunFire Prep C18OBD 10um，乙腈/水体系)得白色固体，然后通过SFC(柱子型号:
Figure PCTCN2021137254-appb-000128
流动相:redistilled grade EtOH和Supercritical CO 2；波长：214nm)分离得到化合物1(甲酸盐，16mg，收率：19.5％)和化合物1’(甲酸盐，18mg，收率：22％)。
化合物1：(S)-5'-((二甲基胺基)甲基)-2'-(1-(4-乙氧基-5-氟吡啶-2-基)乙基)-7'-((2-(甲基氨基)-1H-咪唑-1-基)甲基)-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1`-酮
LCMS:m/z 507.4[M+H] +.
1H NMR(400MHz,甲醇-d 4):δppm 8.48(s,1H),8.23(d,J＝3.2Hz,1H),7.84(s,1H),7.29(s,1H),7.17(d,J＝6.8Hz,1H),6.95(d,J＝2.0Hz,1H),6.91(d,J＝2.4Hz,1H), 5.96～5.90(m,1H),5.08(s,2H),4.24～4.16(m,2H),3.60～3.47(m,2H),3.37-3.34(m,1H),3.01-2.98(m,1H),2.98(s,3H),2.24(s,6H),1.56～1.51(m,4H),1.43(t,J＝7.2Hz,3H),1.08～1.05(m,1H),0.95～0.90(m,1H),0.53～0.48(m,1H).
19F NMR(376MHz,甲醇-d 4):δppm-153.96.
化合物1’：(R)-5'-((二甲基胺基)甲基)-2'-(1-(4-乙氧基-5-氟吡啶-2-基)乙基)-7'-((2-(甲基氨基)-1H-咪唑-1-基)甲基)-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1`-酮
分析数据：
LCMS:m/z 507.1[M+H] +.
1H NMR(400MHz,DMSO-d 6):δppm 8.37(d,J＝2.8Hz,1H),7.74(d,J＝1.6Hz,1H),7.18(d,J＝1.6Hz,1H),7.13(d,J＝6.8Hz,1H),6.74(s,1H),6.59(s,1H),6.23-6.21(m,1H),5.89-5.83(m,1H),4.96(s,2H),4.25-4.11(m,2H),3.34-3.17(m,3H),2.91(d,J＝12.8Hz,1H),2.76(d,J＝4.8Hz,3H),2.06(s,6H),1.47(d,J＝7.2Hz,3H),1.43-1.39(m,1H),1.35(t,J＝6.8Hz,3H),1.16-1.12(m,1H),0.83-0.78(m,1H),0.52-0.47(m,1H).
1F NMR(376MHz,DMSO-d 6):δppm-153.19.
如下化合物可参照实施例一化合物1的合成方法，使用相应的中间体，用相同的方法或改进的方法来合成的。
如下实施例是游离的化合物，或者药学上可以接受的盐。
Figure PCTCN2021137254-appb-000129
Figure PCTCN2021137254-appb-000130
Figure PCTCN2021137254-appb-000131
Figure PCTCN2021137254-appb-000132
Figure PCTCN2021137254-appb-000133
Figure PCTCN2021137254-appb-000134
Figure PCTCN2021137254-appb-000135
Figure PCTCN2021137254-appb-000136
Figure PCTCN2021137254-appb-000137
Figure PCTCN2021137254-appb-000138
Figure PCTCN2021137254-appb-000139
Figure PCTCN2021137254-appb-000140
Figure PCTCN2021137254-appb-000141
Figure PCTCN2021137254-appb-000142
Figure PCTCN2021137254-appb-000143
Figure PCTCN2021137254-appb-000144
实施例二：化合物2和2’的合成
(S)-6-(1-(5'-(((二甲基氨基)甲基)-7'-((2-(甲基胺基)-1H-咪唑-1-基)甲基)-1'-酮-1'H-螺[环丙烷-1,4'-异喹啉]-2'(3'H)-基)乙基)-4-甲氧基烟腈
(R)-6-(1-(5'-(((二甲基氨基)甲基)-7'-((2-(甲基胺基)-1H-咪唑-1-基)甲基)-1'-氧代-1'H-螺[环丙烷-1,4'-异喹啉]-2'(3'H)-基)乙基)-4-甲氧基烟腈
Figure PCTCN2021137254-appb-000145
步骤一：0℃，氩气保护下向叔丁基(1-((5'-(((二甲基胺基)甲基)-1'-酮-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-(甲基)-1H-咪唑-2-基)(甲基)氨基甲酸酯(1-3，80mg,0.18mmol)的DMF(10mL)溶液中加入NaH(60％分散在矿物油中，21mg，0.55mmol)。0℃搅拌20分钟。加入6-(1-溴乙基)-4-甲氧基烟腈(A2，65mg,0.27mmol)，室温搅拌反应2小时。反应液倒入冰水中(20mL)，二氯甲烷(2*50mL)萃取，合并有机相，饱和盐水洗(100mL)，无水硫酸钠干燥，过滤，滤液减压浓缩至干,经柱层析纯化(二氯甲烷：甲醇＝15:1)得到黄色固体叔丁基(1-((2'-(1-(5-氰基-4-甲氧基吡啶-2-基)乙基)-5'-((二甲基胺基)甲基)-1'-酮2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-基)甲基)-1H-咪唑-2-基)(甲基)氨基甲酸酯(2-1，30mg，收率:27.5％)。
LCMS:m/z:600.4[M+H] +.
步骤二：0℃下向叔丁基(1-((2'-(1-(5-氰基-4-甲氧基吡啶-2-基)乙基)-5'-((二甲基氨基)甲基)-1'-酮2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-基)甲 基)-1H-咪唑-2-基)(甲基)氨基甲酸酯(2-1，30mg,0.05mmol)的二氯甲烷(5mL)溶液中加入三氟醋酸(2mL)。室温搅拌反应2小时。反应液倒入冰水中(20mL)，饱和碳酸氢钠水溶液中和pH至7，二氯甲烷(2*100mL)萃取，合并有机相，饱和盐水洗(100mL)，无水硫酸钠干燥，过滤，滤液减压浓缩至干，经柱层析(二氯甲烷：甲醇＝10:1)得白色固体，然后通过SFC(柱子型号:
Figure PCTCN2021137254-appb-000146
流动相:redistilled grade EtOH和Supercritical CO 2；波长：214nm)分离得到(S)-6-(1-(5'-(((二甲基氨基)甲基)-7'-((2-(甲基胺基)-1H-咪唑-1-基)甲基)-1'-酮-1'H-螺[环丙烷-1,4'-异喹啉]-2'(3'H)-基)乙基)-4-甲氧基烟腈(化合物2，6mg，收率:24.0％)和(R)-6-(1-(5'-(((二甲基氨基)甲基)-7'-((2-(甲基胺基)-1H-咪唑-1-基)甲基)-1'-酮-1'H-螺[环丙烷-1,4'-异喹啉]-2'(3'H)-基)乙基)-4-甲氧基烟腈(化合物2’，5mg，收率:20.0％)。
化合物2：(S)-6-(1-(5'-(((二甲基氨基)甲基)-7'-((2-(甲基胺基)-1H-咪唑-1-基)甲基)-1'-酮-1'H-螺[环丙烷-1,4'-异喹啉]-2'(3'H)-基)乙基)-4-甲氧基烟腈
LCMS:m/z:500.4[M+H] +.
1H NMR(400MHz,DMSO-d 6):δppm 8.75(s,1H),7.76(s,1H),7.65(brs,1H),7.29(s,1H),7.21(s,1H),7.02(s,1H),6.94(s,1H),5.88-5.83(m,1H),5.08(s,2H),3.99(s,3H),3.33～3.21(m.2H),3.20(d,J＝13.6Hz,1H),3.06(d,J＝14.4Hz,1H),2.85(s,3H),2.09(s,6H),1.51(d,J＝7.2Hz,3H),1.41-1.35(m,1H),1.29-1.23(m,1H),0.89-0.82(m,1H),0.72-0.69(m,1H).
化合物2’：(R)-6-(1-(5'-(((二甲基氨基)甲基)-7'-((2-(甲基胺基)-1H-咪唑-1-基)甲基)-1'-酮-1'H-螺[环丙烷-1,4'-异喹啉]-2'(3'H)-基)乙基)-4-甲氧基烟腈
LCMS:m/z:500.4[M+H] +.
实施例三：化合物3和3’的合成
(S)-6-(1-(5'-(((二甲基胺基)甲基)-7'-((2-(甲基胺基)-1H-咪唑-1-基)甲基)-1'-酮-1'H-螺[环丙烷-1,4'-异喹啉]-2'(3'H)-基)乙基)-4-乙氧基烟腈
(R)-6-(1-(5'-(((二甲基胺基)甲基)-7'-((2-(甲基胺基)-1H-咪唑-1-基)甲基)-1'-酮-1'H-螺[环丙烷-1,4'-异喹啉]-2'(3'H)-基)乙基)-4-乙氧基烟腈
Figure PCTCN2021137254-appb-000147
步骤一：0℃，氩气保护下向叔丁基(1-((5'-(((二甲基氨基)甲基)-1'-酮-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-(甲基)-1H-咪唑-2-基)(甲基)氨基甲酸酯(1-3，80mg,0.18mmol)的DMF(10mL)溶液中加入NaH(60％分散在矿物油中，21mg，0.55mmol)。0℃搅拌20分钟。加入6-(1-溴乙基)-4-乙氧基烟腈(A3，70mg,0.27mmol)，室温搅拌反应2小时。反应液倒入冰水中(20mL)，二氯甲烷(2*50mL)萃取，合并有机相，饱和盐水洗(100mL)，无水硫酸钠干燥，过滤，滤液减压浓缩至干，经柱层析纯化(二氯甲烷：甲醇＝15:1)得到黄色固体叔丁基(1-((2'-(1-(5-氰基-4-乙氧基吡啶-2-基)乙基)-5)-((二甲基胺基)甲基)-1'-酮2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-基)甲基)-1H-咪唑-2-基)(甲基)氨基甲酸酯(3-1，50mg，收率：44.8％)。
LCMS:m/z:614.9[M+H] +.
步骤二：在0℃下向叔丁基(1-((2'-(1-(5-氰基-4-乙氧基吡啶-2-基)乙基)-5)-((二甲基氨基)甲基)-1'-酮2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-基)甲基)-1H-咪唑-2-基)(甲基)氨基甲酸酯(3-1，45mg,0.073mmol)的二氯甲烷(5mL)溶液中加入三氟醋酸(1mL)。室温搅拌反应2小时。反应液倒入冰水中(20mL)，饱和碳酸氢钠水溶液中和pH至7，二氯甲烷(100mL)萃取，合并有机相，饱和盐水洗(100mL)，无水硫酸钠干燥，过滤，滤液减压浓缩至干,经硅胶柱层析(二氯甲烷：甲醇＝10:1)得到白色固体，然后通过手性柱分离得到(S)-6-(1-(5'-(((二甲基胺基)甲基)-7'-((2-(甲基胺基)-1H-咪唑-1-基)甲基)-1'-酮-1'H-螺[环丙烷-1,4'-异喹啉]-2'(3'H)-基)乙基)-4-乙氧基烟腈(化合物3，10mg，收率：26.5％)和(R)-6-(1-(5'-(((二甲基胺基)甲基)-7'-((2-(甲基胺基)-1H-咪唑-1-基)甲基)-1'-酮-1'H-螺[环丙烷-1,4'-异喹啉]-2'(3'H)-基)乙基)-4-乙氧基烟腈(化合物3’，12mg，收率：32％)。
化合物3：(S)-6-(1-(5'-(((二甲基胺基)甲基)-7'-((2-(甲基胺基)-1H-咪唑-1-基)甲基)-1'-酮-1'H-螺[环丙烷-1,4'-异喹啉]-2'(3'H)-基)乙基)-4-乙氧基烟腈
LCMS:m/z:514.9[M+H] +.
1H NMR(400MHz,DMSO-d 6):δppm 8.75(s,1H),7.75(s,1H),7.25(s,2H),7.18(s,1H),6.94(s,1H),6.85(s,1H),5.86-5.81(m,1H),5.04(s,2H),4.33-4.25(m,2H),3.33-3.30(m,2H),3.23-3.17(m,1H),3.05-3.03(m,1H),2.81(d,J＝4.4Hz,3H),2.08(s,6H),1.50(d,J＝7.2Hz,3H),1.43(t,J＝6.8Hz,4H),1.28-1.25(m,1H),0.89-0.82(m,1H),0.69-0.63(m,1H).
化合物3’：(R)-6-(1-(5'-(((二甲基胺基)甲基)-7'-((2-(甲基胺基)-1H-咪唑-1-基)甲基)-1'-酮-1'H-螺[环丙烷-1,4'-异喹啉]-2'(3'H)-基)乙基)-4-乙氧基烟腈
LCMS:m/z:514.9[M+H] +.
实施例四：化合物6的合成
(S)-2'-(1-(4-乙氧基-5-氟吡啶-2-基)乙基)-7'-((2-(甲胺基)-1H-咪唑-1-基)甲基)-5'-(吡咯-1-基甲基)-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮
Figure PCTCN2021137254-appb-000148
步骤一：向叔丁基(1-(((5'-溴-1'-酮-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-基)甲基]-1H-咪唑-2-基)(甲基)氨基甲酸酯(1-1，46mg，0.1mmol)和1-((三氟硼烷基)甲基)吡咯烷钾盐(D75，38.4mg，0.2mmol)的水(1mL)和二氧六环(4mL)溶液中加入1,1-双(二苯基膦)二荗铁二氯化钯(7.3mg，0.01mmol)和碳酸钾(26.8mg，0.2mmol)。氮气置换后115℃微波反应2小时。乙酸乙酯(100mL) 稀释，加入饱和食盐水，分液，水相用乙酸乙酯(150mL)萃取，合并有机相，用饱和盐水洗，干燥，过滤，减压浓缩至干，经柱层析(二氯甲烷:甲醇＝10:1)纯化得黄色固体叔丁基甲基(1-((1'-酮-5'-(吡咯烷基-1-基甲基)-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-基)甲基)-1H-咪唑-2-基)氨基甲酸酯(6-2，12mg，收率：25.8％)。
LCMS:m/z:466.6[M+H] +.
步骤二：在0℃下向叔丁基甲基(1-((1'-酮-5'-(吡咯烷基-1-基甲基)-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-基)甲基)-1H-咪唑-2-基)氨基甲酸酯(6-2，30mg，0.064mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入氢化钠(60％分散在矿物油中，10mg，0.204mmol)。0℃搅拌20分钟。加入2-(1-溴乙基)-4-乙氧基-5-氟吡啶(A1，25.3mg，0.103mmol)，室温搅拌反应2小时。反应液倒入冰水中(20mL)，二氯甲烷(2*50mL)萃取，合并有机相，饱和食盐水洗(100mL)，无水硫酸钠干燥，过滤，滤液减压浓缩至干,经柱层析纯化(二氯甲烷:甲醇＝10:1)得到黄色固体叔丁基(1-((2'-(1-(4-乙氧基-5-氟吡啶-2-基)乙基)-1)-酮5'-(吡咯烷-1-基甲基)-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-基)甲基)-1H-咪唑-2-基)(甲基)氨基甲酸酯(6-3，25mg，收率：61.3％)。
LCMS:m/z:633.9[M+H] +.
步骤三：在0℃下向叔丁基(1-((2'-(1-(4-乙氧基-5-氟吡啶-2-基)乙基)-1)-酮5'-(吡咯烷-1-基甲基)-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-7'-基)甲基)-1H-咪唑-2-基)(甲基)氨基甲酸酯(6-3，20mg，0.0316mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。室温搅拌反应2小时。反应液倒入冰水中(20mL)，饱和碳酸氢钠水溶液中和至pH＝7。二氯甲烷(2*50mL)萃取，合并有机相，饱和盐水洗(100mL)，无水硫酸钠干燥，过滤，滤液减压浓缩至干，经柱层析(二氯甲烷:甲醇＝10:1)得到白色固体，然后通过手性柱分离得到化合物6(6mg，收率：35％)。
LCMS:m/z:533.3[M+H] +.
1H NMR(400MHz,甲醇-d 4):δppm 8.23(d,J＝3.6Hz,1H),7.87(s,1H),7.48(s,1H),7.16(d,J＝7.2Hz,1H),6.95(s,2H),5.95-5.90(m,1H),5.12(s,2H),4.60(s,1H),4.25-4.16(m,2H),4.03(s,2H),3.42-3.34(m,1H),3.06-3.03(m,1H),2.99(s,3H),2.86(s,3H),1.91(s,4H),1.56(d,J＝7.2Hz,3H),1.51-1.47(m,1H),1.43(t,J＝7.2Hz,3H), 1.09-0.99(m,2H),0.61-0.56(m,1H).
19F NMR(376MHz,甲醇-d 4):-153.93.
实施例五：化合物23和23’的合成
化合物23:(S)-6-(1-(5'-((二甲胺基)甲基)-7'-((2-(甲胺基)-1H-咪唑-1-基)甲基)-1'-酮-1'H-螺[环丁烷-1,4'-异喹啉]-2'(3'H)-基)乙基)-4-乙氧基烟腈
化合物23’:(R)-6-(1-(5'-((二甲胺基)甲基)-7'-((2-(甲胺基)-1H-咪唑-1-基)甲基)-1'-酮-1'H-螺[环丁烷-1,4'-异喹啉]-2'(3'H)-基)乙基)-4-乙氧基烟腈
Figure PCTCN2021137254-appb-000149
步骤一：在0℃下向B2(215mg，0.675mmol)的DMF(10mL)溶液中加入碳酸铯(445mg，1.369mmol)和四丁基碘化胺(253mg，0.685mmol)。0℃下反应20分钟后加入(1H-咪唑-2-基)(甲基)氨基甲酸叔丁酯C1(270mg，1.369mmol)的DMF(2mL)溶液。80℃反应3小时。LCMS监测反应完全。加水(60mL)稀释，乙酸乙酯(3*30mL)萃取，合并有机相，干燥，过滤，浓缩，经柱层析纯化(二氯甲烷：甲醇＝10:1)得23-1(280mg)。
LCMS:m/z:477.1[M+H]+.
步骤二：在氩气保护下向23-1(180mg，0.379mmol)和N，N-二甲基-1-(三 氟-14-硼烷基)甲胺钾盐1-2(125mg，0.757mmol)，碳酸钾(105mg，0.757mmol)的二氧六环(6mL)和水(2mL)的混合溶液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(62mg，0.076mmol)。氩气保护下115℃微波反应1.5小时。LCMS监测反应完全。加水(30mL)稀释，用乙酸乙酯(3*30mL)萃取，合并有机相，干燥，过滤，浓缩，经柱层析纯化(二氯甲烷：甲醇＝10:1)得23-2(90mg，收率：52.3％)。
LCMS:m/z:454.3[M+H]+.
步骤三：0℃与氮气保护下向23-2(33mg，0.072mmol)的干燥DMF(8mL)溶液中加入氢化钠(60％分散于油中，13mg，0.325mmol)。0℃继续搅拌30分钟后，滴加A3(30mg，0.118mmol)的DMF(2mL)溶液。反应液保持0℃反应20分钟。然后将反应液倒入饱和氯化铵水溶液中，用乙酸乙酯(3*30mL)萃取，合并有机相，依次用水(3*50mL)和饱和食盐水(2*50mL)洗涤，无水硫酸钠干燥，过滤，浓缩至干，残余物经柱层析(二氯甲烷/甲醇＝30/1)纯化得到23-3(25mg，收率：54.7％)。
LCMS:m/z 628.3[M+H] +
步骤四：向23-3(25mg，0.040mmol)的二氯甲烷(10mL)溶液中滴加三氟醋酸(2.5mL)。室温反应1小时。将反应液浓缩除去三氟醋酸，将残余物用二氯甲烷(50mL)稀释，有机相依次用饱和碳酸氢钠(50mL)和饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩至干，残余物经高效液相色谱分离(SunFire Prep C18OBD 10um，乙腈/水体系)纯化后得到消旋产物，再通过SFC(柱子型号:
Figure PCTCN2021137254-appb-000150
流动相:redistilled grade EtOH和Supercritical CO 2；波长：214nm；系统：Waters SFC 150)纯化得到手性化合物23(9mg，收率：42.9％)和23’(8.8mg,40％)。
LCMS:m/z 528.2[M+H] +
1H NMR(400MHZ-甲醇-d4)δ:8.66(s,1H),7.78(d,J＝1.6Hz,1H),7.46(d,J＝2.0Hz,1H),7.22(s,1H),6.97(d,J＝2.4Hz,1H),6.91(d,J＝2.4Hz,1H),5.98～5.93(m,1H),5.08(s,2H),4.35～4.27(m,2H),3.87～3.79(m,2H),3.74～3.62(m,2H),2.98(s,3H),2.87～2.84(m,1H),2.54～2.51(m,1H),2.31(s,6H),2.01～2.00(m,3H),1.70(d,J＝6.4Hz,3H),1.61～1.57(m,1H),1.49(t,J＝7.2Hz,3H).
如下化合物可参照实施例五化合物23的合成方法，使用相应的中间体，用相同的方法或改进的方法来合成的。
如下实施例是游离的化合物，或者药学上可以接受的盐。
Figure PCTCN2021137254-appb-000151
Figure PCTCN2021137254-appb-000152
Figure PCTCN2021137254-appb-000153
Figure PCTCN2021137254-appb-000154
Figure PCTCN2021137254-appb-000155
Figure PCTCN2021137254-appb-000156
Figure PCTCN2021137254-appb-000157
Figure PCTCN2021137254-appb-000158
Figure PCTCN2021137254-appb-000159
Figure PCTCN2021137254-appb-000160
Figure PCTCN2021137254-appb-000161
Figure PCTCN2021137254-appb-000162
实施例六：化合物70的合成
2'-((S)-1-(4-乙氧基-5-氟吡啶-2-基)乙基)-5'-((3-甲基-3,6-二氮杂二环[3.1.1]庚烷-6-基)甲基)-7'-((2-(甲基氨基)-1H-咪唑-1-基)甲基)-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮
Figure PCTCN2021137254-appb-000163
步骤一：1-1(1.1g，2.38mmol)的无水乙醇(25mL)中加入N,N-二异丙基乙胺(3.0g，23.8mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(389mg，0.48mmol)。一氧化碳置换空气三次后在一氧化碳3兆帕压力下升温到100℃反应过夜。将反应液浓缩至干，残余物经柱层析(二氯甲烷/甲醇＝30/1)纯化得到浅黄色固体70-1(725mg，收率：66.9％)
LCMS:m/z 455.1[M+H] +
步骤二：0℃，氮气保护下向70-1(513mg，1.13mmol)的干燥DMF(15mL)溶液中加入氢化钠(60％分散于油中，200mg，5mmol)。保持0℃反应30分钟。滴加A1(330mg，1.33mmol)的DMF(5mL)溶液。保持0℃反应30分钟。将反应液倒入饱和氯化铵水溶液中，用乙酸乙酯(3*100mL)萃取，合并有机相，依次用水(3*200mL)和饱和食盐水(2*200mL)洗涤，无水硫酸钠干燥，过滤，浓缩至干，残余物经柱层析(二氯甲烷/甲醇＝30/1)纯化得到浅黄色固体70-2(550mg，收率：78.4％)。
LCMS:m/z 622.2[M+H] +
步骤三：0℃，氮气保护下向化合物70-2(500mg，0.80mmol)的干燥四氢呋喃(30mL)溶液中滴加硼氢化锂(2M in四氢呋喃，1.2mL，2.4mmol)。保持0℃反应5分钟后升温到25℃，保温反应过夜。将反应液倒入水中，用二氯甲烷(3*80mL)萃取，合并有机相，饱和食盐水(150mL)洗涤，无水硫酸钠干燥，过滤，浓缩至干，残余物用甲醇(50mL)溶解，升温到85℃搅拌过夜。将反应液减压浓缩，残余物经柱层析(二氯甲烷/甲醇＝40/1)纯化得到白色固体70-3(360mg，收率：77.3％)。
LCMS:m/z 580.3[M+H] +
步骤四：0℃，氮气保护下向化合物70-3(50mg，0.086mmol)的二氯甲烷(5mL)溶液中加入三乙胺(104mg，1.03mmol)后滴加甲烷磺酰氯(80mg，0.70mmol)的二氯甲烷(4mL)溶液。加毕，保持0℃反应5分钟后升温到25℃，保温反应1小时。将反应液倒入水中，用二氯甲烷(2*50mL)萃取，合并有机相，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩至干，得到无色油状物70-4(粗品，60mg)。
步骤五：氮气保护下向化合物70-4(60mg，0.086mmol)和中间体70-5的盐酸盐(50mg，0.27mmol)的DMF(10mL)溶液中加入碳酸铯(295mg，0.91mmol)。升温到50℃反应过夜。将反应液倒入水中，用乙酸乙酯(3*50mL)萃取，合并有机相，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩至干，残余物经柱层析(二氯甲烷/甲醇＝10/1)纯化得到浅黄色固体70-6(50mg，两步收率：86.0％)。
LCMS:m/z 674.3[M+H] +
步骤六：向70-6(50mg，0.074mmol)的二氯甲烷(10mL)溶液中滴加三氟乙酸(2.5mL)。室温反应1小时。将反应液浓缩除去三氟乙酸，将残余物用二氯甲 烷(50mL)稀释，依次用饱和碳酸氢钠(50mL)和饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，浓缩至干，残余物经高效液相色谱分离纯化得到浅黄色固体，该化合物经SFC分离纯化得到2'-((S)-1-(4-乙氧基-5-氟吡啶-2-基)乙基)-5'-((3-甲基-3,6-二氮杂二环[3.1.1]庚烷-6-基)甲基)-7'-((2-(甲基氨基)-1H-咪唑-1-基)甲基)-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮(化合物70，4mg，收率：9.4％)。
LCMS:m/z 574.2[M+H] +
1H NMR(400MHz,甲醇-d4)δppm:8.23(d,J＝3.2Hz,1H),7.81(d,J＝1.6Hz,1H),7.17(d,J＝6.8Hz,1H),7.10(d,J＝1.6Hz,1H),6.64～6.61(m,2H),5.97～5.92(m,1H),4.95(s,2H),4.24～4.16(m,2H),3.60(s,2H),3.48～3.31(m,3H),2.97(d,J＝12.8Hz,1H),2.87(s,4H),2.84(s,3H),2.44(s,3H),2.40～2.39(m,1H),1.94(d,J＝8.0Hz,1H),1.56～1.51(m,4H),1.45(t,J＝6.8Hz,3H),1.12～1.07(m,1H),0.93～0.87(m,1H),0.49～0.46(m,1H).
19F NMR(376MHz,甲醇-d4)δppm:-154.04
实施例七：化合物41的合成
2'-(1-(4-乙氧基-5-氟吡啶-2-基)乙基)-5'-((甲基(2,2,2-三氟乙基)胺基)甲基)-7'-((2-(甲基胺基)-1H-咪唑-1-基)甲基)-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮
Figure PCTCN2021137254-appb-000164
步骤一：0℃，氮气保护下向70-3(200mg，0.35mmol)的二氯甲烷(10mL) 溶液中加入戴斯-马丁氧化剂(190mg，0.45mmol)。加毕，保持0℃反应2小时。将反应液倒入水中，用二氯甲烷(2*60mL)萃取，合并有机相，饱和盐水(100mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩至干，柱层析纯化得白色固体41-1(200mg，收率：100％)。
LCMS:m/z 578.3[M+H] +
步骤二：氮气保护下向41-1(50mg，0.086mmol)的二氯乙烷(10mL)溶液中加入甲胺四氢呋喃溶液(2mL，4mmol)。室温反应过夜。将反应液冷却到0℃。加入氰基硼氢化钠(10mg，0.17mmol)。升温到室温反应2小时。将反应液倒入水中，用二氯甲烷(3*100mL)萃取，合并有机相，饱和盐水(200mL)洗，无水硫酸钠干燥，过滤，浓缩后残余物经柱层析(二氯甲烷/甲醇＝30/1)纯化得浅黄色固体41-2(50mg，收率：97.5％)。
LCMS:m/z 593.3[M+H] +
步骤三：氮气保护下向41-2(30mg，0.051mmol)和2,2,2-三氟乙基三氟甲磺酸酯(35mg，0.15mmol)的DMF(10mL)溶液中加入碳酸钾(28mg，0.2mmol)。升温到50℃反应4小时。将反应液倒入水中，用二氯甲烷(3*50mL)萃取，合并有机相，饱和盐水(200mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩至干，柱层析(二氯甲烷/甲醇＝20/1)纯化得浅黄色固体41-3(5mg，收率：14.7％)。
LCMS:m/z 675.4[M+H] +
步骤四：向41-3(5mg，0.007mmol)的二氯甲烷(5mL)溶液中滴加三氟醋酸(1mL)。室温反应1小时。将反应液浓缩除去三氟醋酸。将残余物用二氯甲烷(50mL)稀释，依次用饱和碳酸氢钠(50mL)和饱和盐水(50mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩至干，残余物经高效液相色谱分离纯化得白色化合物41的二甲酸盐(0.26mg，收率：5.3％)。
LCMS:m/z 575.3[M+H] +
1H NMR(400MHz,甲醇-d4)δppm:8.52(br,2H),8.25(d,J＝3.2Hz,1H),7.86(d,J＝2.4Hz,1H),7.31(s,1H),7.19(d,J＝6.8Hz,1H),6.90～6.86(m,2H),5.97～5.95(m,1H),4.96(s,2H),4.60(s,2H),4.24～4.21(m,2H),3.77～3.67(m,2H),3.08～2.99(m,2H),2.97(s,3H),2.36(s,3H),1.59～1.53(m,4H),1.47(t,J＝6.8Hz,3H),1.11～1.10(m,1H),0.93～0.91(m,1H),0.51～0.49(m,1H).
19F NMR(376MHz,甲醇-d4)δppm:-70.21,-153.98.
如下化合物可参照实施例七化合物41的合成方法，使用相应的中间体，使用以上的合成步骤以及合成方法或改进的方法来合成的。
如下实施例是游离的化合物，或者药学上可以接受的盐。
Figure PCTCN2021137254-appb-000165
Figure PCTCN2021137254-appb-000166
Figure PCTCN2021137254-appb-000167
实施例八：化合物88和化合物89的合成
5'-((二甲氨基)甲基)-2'-(-1-(4-乙氧基-5-氟吡啶-2-基)乙基)-2,2-二氟-7'-((2-(甲氨基)-1H咪唑-1-基)甲基)-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮
Figure PCTCN2021137254-appb-000168
步骤一：参考1-1的合成过程，以B10为起始化合物经过一步合成中间体88-1。
LCMS:m/z:497.1[M+H] +.
步骤二：0℃，氩气保护下向88-1(125mg，0.25mmol)的DMF(5mL)溶液中加入氢化钠(60％分散于油中，40mg，1.01mmol)。0℃搅拌0.5小时。滴加A1(187mg，0.75mmol)的DMF(2mL)溶液。加毕，继续反应3分钟。TLC显 示反应完全。反应液倒入冰水中，乙酸乙酯(20mL)萃取2次，合并有机相，水洗(30mL)，饱和氯化钠水溶液洗(30mL)，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析纯化得中间体88-2(120mg，收率：71.8％)。
LCMS:m/z:666.0[M+H] +.
步骤三：向88-2(120mg，0.18mmol)的1,4-二氧六环/水(10mL/2.5mL)溶液中加入二甲基氨基甲基三氟硼酸钾(147mg，0.89mmol)，碳酸钾(74mg，0.54mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(26mg，0.04mmol)。115℃微波反应0.5小时。反应液直接浓缩，柱层析纯化(二氯甲烷：甲醇＝40：1)得88-3(65mg，收率：56.0％)。
LCMS:m/z 643.2[M+H] +.
步骤四：向88-3(65mg，0.10mmol)的二氯甲烷(4mL)溶液中滴加三氟醋酸(1mL)。室温反应3小时。反应液倒入冰水中，二氯甲烷萃取(20mL)，浓缩后经高效液相色谱分离纯化得两个非对映异构体5'-((二甲氨基)甲基)-2'-(1-(4-乙氧基-5-氟吡啶-2-基)乙基)-2,2-二氟-7'-((2-(甲氨基)-1H)咪唑-1-基)甲基)-2',3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮(化合物88：6mg，收率：10.9％和化合物89：7mg，收率：12.8％)。
化合物88：
LCMS:m/z 543.2[M+H] +.
1H NMR(400MHz,甲醇-d4):δppm 8.21(d,J＝3.6Hz,1H),7.89(d,J＝1.6Hz,1H),7.19～7.17(m,2H),6.65～6.62(m,2H),5.95～5.93(m,1H),4.99(s,2H),4.22～4.13(m,2H),3.99～3.94(m,1H),3.45～3.42(m,1H),3.31-3.26(m,1H),3.17～3.08(m,2H),2.85(s,3H),2.12(s,6H),1.74～1.67(m,1H),1.56(d,J＝7.2Hz,3H),1.41(t,J＝7.2Hz,3H).
19F NMR(376MHz,甲醇-d4):δppm-137.71,-138.11,-142.16,-142.57,-154.24.
化合物89：
LCMS:m/z 543.2[M+H] +.
1H NMR(400MHz,甲醇-d4):δppm 8.19(d,J＝3.2Hz,1H),7.87(d,J＝2.0Hz,1H),7.15～7.08(m,2H),6.63～6.61(m,2H),5.95～5.90(m,1H),4.98(d,J＝2.0Hz,2H),4.22～4.15(m,2H),3.65～3.61(m,1H),3.46～3.43(m,1H),3.31-3.12(m,3H),2.84(s,3H),2.12(s,6H),1.90～1.85(m,1H),1.63(d,J＝7.2Hz,3H),1.42(t,J＝7.2Hz,3H).
19F NMR(376MHz,甲醇-d4):δppm-137.52,-137.93,-140.86,-141.27,-154.27.
实施例九：化合物90和化合物91的合成
化合物90:(R)-5'-((二甲氨基)甲基)-2'-((R)-1-(4-乙氧基-5-氟吡啶-2-基)乙基)-2,2-二氟-7'-((2-(甲氨基)-1H咪唑-1-基)甲基)-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮
化合物91:(S)-5'-((二甲氨基)甲基)-2'-((S)-1-(4-乙氧基-5-氟吡啶-2-基)乙基)-2,2-二氟-7'-((2-(甲氨基)-1H咪唑-1-基)甲基)-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮
Figure PCTCN2021137254-appb-000169
化合物88(300mg)经SFC分离纯化得两个白色固体化合物90(75.11mg，收率：25.0％)和化合物91(78.88mg，收率：26.3％)。化合物90和化合物91的绝对构型可由XRD单晶衍射数据得到，或者可由化合物与WDR5蛋白的共晶结构解析得到。
化合物90：(R)-5'-((二甲氨基)甲基)-2'-((R)-1-(4-乙氧基-5-氟吡啶-2-基)乙基)-2,2-二氟-7'-((2-(甲氨基)-1H咪唑-1-基)甲基)-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮
LCMS:m/z 543.15[M+H] +.
1H NMR(400MHz,DMSO-d 6):δppm 8.36(d,J＝2.8Hz,1H),7.80(d,J＝1.6Hz,1H),7.35～7.31(m,2H),7.13(d,J＝6.8Hz,1H),6.97(d,J＝2.0Hz,1H),6.86(d,J＝1.2Hz,1H),5.90～5.84(m,1H),5.11(s,2H),4.23～4.04(m,2H),3.92～3.88(m,1H),3.48～3.18(m,2H),3.08-3.02(m,2H),2.84(d,J＝4.4Hz,3H),2.08(s,6H),1.96～1.91(m,1H),1.48(d,J＝7.2Hz,3H),1.33(t,J＝6.8Hz,3H).
19F NMR(376MHz,DMSO-d 6):δppm-134.96,-135.35,-140.52,-140.91,-153.14.
化合物91：(S)-5'-((二甲氨基)甲基)-2'-((S)-1-(4-乙氧基-5-氟吡啶-2-基)乙基)-2,2-二氟-7'-((2-(甲氨基)-1H咪唑-1-基)甲基)-2'，3'-二氢-1'H-螺[环丙烷-1,4'-异喹啉]-1'-酮
LCMS:m/z 543.15[M+H] +.
1H NMR(400MHz,DMSO-d 6):δppm 8.36(d,J＝3.2Hz,1H),7.80(d,J＝1.6Hz, 1H),7.35～7.28(m,2H),7.13(d,J＝6.8Hz,1H),6.96(d,J＝1.6Hz,1H),6.84(d,J＝1.6Hz,1H),5.90～5.84(m,1H),5.12(s,2H),4.21～4.06(m,2H),3.92～3.88(m,1H),3.48～3.42(m,1H),3.21～3.17(m,1H),3.08-3.02(m,2H),2.84(d,J＝4.8Hz,3H),2.08(s,6H),1.95～1.91(m,1H),1.48(d,J＝7.2Hz,3H),1.33(t,J＝6.8Hz,3H).
19F NMR(376MHz,DMSO-d 6):δppm-134.96,-135.35,-140.52,-140.91,-153.15.
参照前述实施例八化合物88，89的方法合成下表所示的化合物或其盐。
Figure PCTCN2021137254-appb-000170
Figure PCTCN2021137254-appb-000171
Figure PCTCN2021137254-appb-000172
Figure PCTCN2021137254-appb-000173
Figure PCTCN2021137254-appb-000174
实施例十：化合物100的合成：
6-(1-(5'-((双(甲基-d3)氨基)甲基)-7'-((2-(甲基氨基)-1H-咪唑-1-基)甲基)-1'-氧-1'H-螺环[环丁烷-1,4'-异喹啉]-2'(3'H)-基)乙基)-4-乙氧基烟腈
Figure PCTCN2021137254-appb-000175
步骤一：向二甲基-d6-胺盐酸盐100-1(100mg，1.14mmol)的四氢呋喃(40mL)溶液中加入(溴甲基)三氟硼酸钾(229mg，1.14mmol)和碳酸氢钾(342mg，3.42mmol)，碘化钾(18mg，0.11mmol)。70℃下反应4小时。反应液减压浓缩，加丙酮(200mL)。加热至40℃搅拌15分钟。过滤，滤液减压浓缩得100-2(180mg，收率：92.3％)。
步骤二：参考中间体23-1的合成一步合成中间体100-3。
步骤三：向100-3(200mg，0.31mmol)的二氧六环(3mL)和水(1mL)溶液中加入100-2(96mg，0.62mmol)，碳酸钾(129mg，0.93mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(49mg，0.06mmol)。氩气保护下115℃微波反应70分钟。加水淬灭。乙酸乙酯(3*20mL)萃取，合并有机相，干燥，过滤，浓缩，经柱层析纯化得100-4(170mg，收率：86.7％)。
LCMS:m/z:634.3[M+H]+
步骤四：0℃下向100-4(170mg，0.27mmol)的二氯甲烷(10mL)溶液中滴 加三氟乙酸(2mL)。室温下反应60分钟。减压浓缩，加饱和碳酸氢钠水溶液，二氯甲烷(3*20mL)萃取，合并有机相，干燥，过滤，浓缩，经高效液相色谱分离纯化得化合物100的二甲酸盐(40.5mg，收率：24.1％)。
LCMS:m/z:534.3[M+H] +
1H NMR(400MHz,甲醇-d4)δppm:8.66(s,1H),8.44(s,2H),7.84(s,1H),7.54(s,1H),7.23(s,1H),6.97(d,J＝2.4Hz,1H),6.92(d,J＝2.4Hz,1H),5.95(q,J＝7.2Hz,1H),5.10(s,2H),4.36～4.27(m,2H),4.07(s,2H),3.76～3.64(m,2H),2.99(s,3H),2.82～2.77(m,1H),2.50～2.43(m,1H),2.10～2.02(m,3H),1.71～1.61(m,4H),1.47(t,J＝6.8Hz,3H).
实施例十一：化合物101的合成
6-(1-(5'-((二甲氨基)甲基)-7'-((2-(甲氨基)-1H-咪唑-1-基)甲基)-1'-氧代-1'H-螺[环丁烷)-1,4'-异喹啉]-2'(3'H)-基)乙基-1-d)-4-乙氧基烟腈
Figure PCTCN2021137254-appb-000176
步骤一：0℃下向A3-3(485mg，2.55mmol)的氘甲醇(5mL)溶液中加入硼氘化钠(107mg，2.55mmol)。0℃反应1小时，反应加冰水淬灭。加乙酸乙酯(100mL)稀释，饱和盐水(3*20mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩至干，经柱层析(石油醚/乙酸乙酯＝1/1)纯化得淡白色固体101-1(350mg，收率：71.1％)
LCMS:m/z:194[M+H] +.
步骤二：在0℃，氩气保护下向101-1(180mg，0.93mmol)和三苯基膦(486mg，1.87mmol)的四氢呋喃(10mL)溶液中加入四溴化碳(463mg，1.40mmol)。0℃反应5分钟后升至室温搅拌反应16小时。反应液过滤，滤液减压浓缩至干，经柱层析(石油醚/乙酸乙酯＝10/1)纯化得淡黄色固体101-2(160mg，收率：67.1％)。
LCMS:m/z:256[M+H] +.
步骤三：0℃向中间体18-1(100mg，0.22mmol)的DMF(10mL)溶液中加入(氢化钠，60％分散于油中，25mg，0.66mmol)。加完0℃反应20分钟。滴加101-2(84mg，0.33mmol)的DMF溶液。0℃搅拌5分钟。将反应液加入冰水，乙酸乙酯(3*30mL)萃取，有机相用饱和盐水洗，干燥，过滤，浓缩至干，经柱层析(二氯甲烷/甲醇＝20/1)纯化得白色固体101-3(100mg，收率：72.4％)。
LCMS:m/z:629[M+H] +.
步骤四：0℃向101-3(100mg，0.16mmol)的二氯甲烷(4mL)溶液中滴加三氟醋酸(2mL)。室温反应1.5小时。反应液用二氯甲烷(10mL)稀释。加入饱和碳酸氢钠水溶液，室温搅拌后分液。水相用二氯甲烷(3*20mL)萃取，合并有机相，饱和盐水洗，干燥，过滤，减压浓缩至干，经高效液相色谱分离纯化得到化合物101的二甲酸盐(30.91mg，收率：31.3％)。
LCMS:m/z:529[M+H] +.
1H NMR(400MHz,甲醇-d4)δppm:8.67(s,1H),8.36(s,2H),7.79(d,J＝2.0Hz,1H),7.46(d,J＝2.0Hz,1H),7.22(s,1H),6.96(d,J＝2.4Hz,1H),6.91(d,J＝2.4Hz,1H),5.07(s,2H),4.35～4.27(m,2H),3.86～3.62(m,4H),2.98(s,3H),2.87～2.81(m,1H),2.56～2.46(m,1H),2.30(s,6H),2.05～1.99(m,3H),1.68(s,3H),1.60～1.56(m,1H),1.47(t,J＝6.8Hz,3H).
实施例十二：化合物111的合成
6-(1-(5'-((二甲氨基)甲基)-7'-((2-(甲氨基)-1H-咪唑-1-基)甲基)-1'-氧基-1'H-螺环[环丁烷-1,4'-异喹啉]-2'(3'H)-基)乙基)-4-(乙氧基-d5)烟腈
Figure PCTCN2021137254-appb-000177
步骤一：0℃下向111-1(5mL)溶液中加入金属钠(210mg，9.13mmol)。加完0℃反应30min后加热至80℃反应3小时。金属钠完全消失。反应液冷却至室温得111-2溶液(4mL，9.13mmol)。
步骤二：0℃下向A3-1(1.5g，8.72mmol)的四氢呋喃溶液中加入111-2的CD 3CD 2OD溶液(4mL，9.13mmol)。加完0℃反应30分钟后室温反应2小时。将反应液加入水，乙酸乙酯(3*100mL)萃取，有机相用饱和盐水洗，干燥，过滤，浓缩至干，经柱层析(石油醚/乙酸乙酯＝2/1)纯化得白色固体111-3(1.1g，收率：67.6％)。
LCMS:m/z:188[M+H] +.
步骤三：在氩气保护下向111-3(600mg，3.20mmol)和三丁基(1-乙氧基乙烯)锡(1.7g，4.79mmol)的1,4-二氧六环溶液(30mL)中加入四三苯基膦钯(0.73g，0.64mmol)。升温到100℃反应16小时。减压浓缩除去溶剂，用乙酸乙酯(50mL)稀释，加入饱和氟化钾水溶液，室温搅拌1小时后分液，水相用乙酸乙酯(50mL)萃取，合并有机相，饱和盐水洗，干燥，过滤，滤液减压浓缩至干。将残余物溶于四氢呋喃(50mL)中，加入盐酸水溶液(2M，5mL)。室温反应1小时。反应液用乙酸乙酯(100mL)稀释，依次用饱和碳酸氢钠和饱和盐水洗，干燥，过滤，减压浓缩至干，经柱层析(石油醚/乙酸乙酯＝10/1)纯化得白色固体111-4(580mg，收率：92.9％)。
LCMS:m/z:196[M+H] +.
步骤四：0℃下向111-4(580mg，2.97mmol)的甲醇(5mL)溶液中加入硼氢化钠(110mg，2.97mmol)。0℃反应1小时。LCMS监测反应完全。反应加冰水淬灭。加乙酸乙酯(50mL)稀释，饱和盐水(3*20mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩至干，经柱层析(石油醚/乙酸乙酯＝1/1)纯化得淡黄色固体111-5(540mg，收率：92.3％)
LCMS:m/z:198[M+H] +.
步骤五：0℃下向111-5(100mg，0.51mmol)和三乙胺(255mg，2.52mmol)的二氯甲烷(10mL)溶液中加入甲烷磺酰氯(174mg，1.52mmol)。室温反应60分钟。加乙酸乙酯(50mL)稀释，饱和盐水(20mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩至干，经柱层析(石油醚/乙酸乙酯＝2/1)纯化得淡黄色固体111-6(130mg，收率：93.5％)
LCMS:m/z:276.1[M+H] +.
步骤六：-70℃，氩气保护下向中间体18-2(80mg，0.18mmol)的无水四氢呋喃(10mL)溶液中滴加KHMDS(1M，0.26mL，0.26mmol)的四氢呋喃溶液。加毕升温到-30℃～-20℃保温反应60分钟。冷却到-70℃，滴加111-6(130mg，0.47mmol)的无水四氢呋喃(5mL)溶液。加毕升温到30℃保温反应20分钟。将反应液倒入冰水中，乙酸乙酯(3*50mL)萃取，合并有机相，饱和盐水(100mL)洗，干燥，过滤，浓缩，残余物经柱层析(二氯甲烷/甲醇＝40/1)纯化得浅黄色固体111-7(30mg，收率：26.9％)。
LCMS:m/z:633.5[M+H] +
步骤六：向111-7(30mg，0.05mmol)的二氯甲烷(7.5mL)溶液中滴加三氟乙酸(1.5mL)。室温反应60分钟。将反应液缓慢倒至饱和碳酸氢钠溶液(20mL)中，二氯甲烷(3*30mL)萃取，有机相合并，饱和盐水(100mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经高效液相色谱分离纯化得化合物111(10mg，收率：40.0％)。
LCMS:m/z:533.5[M+H] +
1H NMR(400MHz,甲醇-d4):δppm 8.67(s,1H),7.80(d,J＝2.0Hz,1H),7.26(d,J＝2.0Hz,1H),7.20(s,1H),6.60(d,J＝1.6Hz,1H),6.58(d,J＝1.6Hz,1H),5.99～5.94 (m,1H),4.93(s,2H),3.70～3.59(m,4H),2.91～2.89(m,1H),2.83(s,3H),2.55～2.52(m,1H),2.20(s,6H),2.00～1.95(m,3H),1.69(d,J＝7.2Hz,3H),1.51～1.54(m,1H).
实施例十三：化合物50的合成
(S)-5'-((二甲基氨基)甲基)-2'-(1-(4-乙氧基-5-氟吡啶-2-基)乙基)-7'-((2-甲基-1H-咪唑-1-基)甲基)-2’,3’-二氢-1’H-螺环[环丙烷-1,4’-异喹啉]-酮
Figure PCTCN2021137254-appb-000178
步骤一：A1-6经SFC纯化得淡黄色固体(R)-1-(5-氟-4-乙氧基吡啶-2-基)乙烷-1-醇(50-2A，24.3g，收率：47.6％，ee％：100％)。
1H NMR(400MHz,氯仿-d):δppm 8.29(d,J＝3.2Hz,1H),7.26(d,J＝7.2Hz,1H),5.41(d,J＝4.4Hz,1H),4.69～4.63(m,1H),4.25～4.17(m,2H),1.39～1.33(m,6H).
步骤二：0℃，氩气保护下向50-2A(15.0g，81.0mmol)和三乙胺(24.6g，243.0mmol)的二氯甲烷(150mL)溶液中滴加甲基磺酰氯(13.9g，121.5mmol)。室温反应2小时。反应液倒入冰水中(500mL)，二氯甲烷萃取(3*300mL)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩至干，硅胶色谱法(0至40％梯度的乙酸乙酯：石油醚)纯化得黄色油状物50-2(16.8g，收率：78.8％)。
1H NMR(400MHz,氯仿-d):δppm 8.29(d,J＝2.8Hz,1H),7.07(d,J＝6.8Hz,1H),5.73(q,J＝6.8Hz,1H),4.24(q,J＝6.8Hz,2H),2.96(s,3H),1.74(d,J＝6.8Hz,3H), 1.50(t,J＝7.2Hz,3H).
19F NMR(376MHz,氯仿-d):δppm-150.27.
步骤三：氩气保护下向B1-11(3.3g，11.7mmol)和咪唑(3.2g，46.8mmol)的DMF(60mL)溶液中滴加TBSCl(5.3g，35.1mmol)的DMF(10mL)溶液。室温反应2小时。将反应液倒入水中，乙酸乙酯(3*150mL)萃取，合并有机相，依次用水(3*250mL)，饱和食盐水(2*250mL)洗，干燥，过滤，浓缩。将残余物经柱层析(石油醚/乙酸乙酯＝15/1)纯化得白色固体50-1(4.5g，收率：97.8％)。
1H NMR(400MHz,氯仿-d):δppm 8.01(d,J＝1.6Hz,1H),7.66～7.65(m,1H),6.36(s,1H),4.70(s,2H),3.22(d,J＝2.8Hz,2H),1.97～1.94(m,2H),0.94(s,9H),0.93～0.91(m,2H),0.10(s,6H).
LCMS:m/z:398.0[M+H] +
步骤四：0℃，氩气保护下向50-1(1.2g，3.03mmol)的无水DMF(35mL)溶液中加入氢化钠(60％分散于油中，925mg，23.2mmol)。保温反应30分钟。滴加(R)-1-(4-乙氧基-5-氟吡啶-2-基)乙基甲磺酸酯50-2(1.53g，5.81mmol)的DMF(5mL)溶液。保温反应1小时。将反应液倒入冰水中。乙酸乙酯(3*80mL)萃取，合并有机相，依次用水(3*150mL)和饱和食盐水(2*150mL)洗涤，干燥，过滤，浓缩，残余物柱层析(二氯甲烷/甲醇＝40/1)纯化得浅黄色固体50-3(734mg，收率：43.5％)。
LCMS:m/z＝563.2[M+H] +
步骤五：将50-3(900mg，1.6mmol)和二甲基氨基甲基三氟硼酸钾(527mg，3.2mmol)溶于二氧六环(9mL)和水(3mL)中。加入碳酸钾(663mg，4.8mmol)。氩气吹气后加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(117mg，0.16mmol)。再氩气吹气后微波120℃反应2小时。反应液浓缩。残余物经柱层析(二氯甲烷/甲醇＝40/1)纯化得浅黄色油状物50-4(594mg，收率：68.7％)。
LCMS:m/z＝542.7[M+H] +
步骤六：0℃，氩气保护下向50-4(660mg，1.22mmol)的四氢呋喃(30mL)溶液中加入TBAF(1M in四氢呋喃，2.5mL，2.50mmol)。室温反应1小时。反应液用乙酸乙酯(500mL)稀释，有机相用水(5*300mL)和饱和盐水(250mL)洗，干燥，过滤，浓缩。残余物经柱层析(二氯甲烷/甲醇＝10/1)纯化得浅黄色固体 50-5(450mg，收率：86.3％)。
LCMS:m/z＝428.2[M+H] +
步骤七:0℃下向50-5(53mg，0.12mmol)的二氯甲烷(20mL)溶液中加入氯化亚砜(104mg，0.87mmol)。真空氩气置换3次。加毕，升温到40℃反应2小时。将反应液浓缩至干得50-6(54mg，收率：97.7％)。
LCMS:m/z＝446.1[M+H] +
步骤八：0℃下向2-甲基咪唑(C2，12mg，0.15mmol)的DMF(10mL)溶液中加入50-6(54mg，0.12mmol)的DMF(5mL)溶液和碳酸铯(119mg，0.36mmol)。真空氩气置换3次。室温反应2小时。将反应液缓慢倒至冰水(10mL)中。乙酸乙酯(3*30mL)萃取，有机相合并，饱和盐水(2*30mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经高效液相色谱分离纯化得白色化合物50(12mg，收率：20.3％)。
LCMS:m/z:492.2[M+H] +
1H NMR(400MHz,甲醇-d4):δppm 8.23(d,J＝3.2Hz,1H),7.80(d,J＝2.0Hz,1H),7.16(d,J＝6.8Hz,1H),7.12(d,J＝2.0Hz,1H),7.06(d,J＝1.2Hz,1H),6.86(d,J＝1.2Hz,1H),5.96～5.91(m,1H),5.19(s,2H),4.23～4.15(m,2H),3.44(d,J＝12.4Hz,1H),3.36(d,J＝13.2Hz,1H),3.44(d,J＝12.4Hz,1H),2.96(d,J＝13.2Hz,1H),2.30(s,3H),2.11(s,6H),1.60～1.54(m,4H),1.42(t,J＝7.2Hz,3H),1.10～1.05(m,1H),0.88～0.83(m,1H),0.44～0.40(m,1H).
19F NMR(376MHz,甲醇-d4):δppm-154.04.
如下化合物可参照实施例十三化合物50的合成方法，使用相应的中间体和合成路线，用相同的方法或改进的方法来合成的。如终产物需脱除N-Boc保护基团，可任选如下条件进行脱除：1)4N HCl/1,4-二氧六环/甲醇(1/1)液，室温或加热搅拌直至反应完成，反应液浓缩后用制备HPLC分离得到目标产物；2)三氟乙酸/二氯甲烷(1/10)溶液室温反应直至反应完成，反应液浓缩后用制备HPLC分离得到目标产物。
如下实施例是游离的化合物，或者药学上可以接受的盐。
Figure PCTCN2021137254-appb-000179
Figure PCTCN2021137254-appb-000180
Figure PCTCN2021137254-appb-000181
Figure PCTCN2021137254-appb-000182
实施例十四：化合物118的合成
4-乙氧基-6-(1-(7'-((2-(甲基胺基)-1H-咪唑-1-基)甲基)-5'-((甲基氨基)甲基)-1'-氧代-1'H-螺[环丁烷-1,4'-异喹啉]-2'(3'H)-基)乙基)烟腈
Figure PCTCN2021137254-appb-000183
步骤一：-60℃，氩气保护下向甲基氨基甲酸叔丁酯(700mg，5.34mmol)的四氢呋喃(10mL)溶液中滴加双(三甲基硅烷基)氨基钾(1mol/L，5.4mL，5.40mmol)的四氢呋喃溶液。-60℃搅拌30min。-60℃下滴加118-1(1.43g，5.34mmol)的四氢呋喃溶液。搅拌10分钟后室温搅拌过夜。反应加饱和氯化铵水溶液淬灭。乙酸乙酯萃取，浓缩得红色油状物118-2(700mg，收率：48.4％)。
LCMS:m/z:272[M+H] +.
步骤二：0℃下向118-2(700mg，2.58mmol)和碳酸钾(0.37g，2.68mmol)的丙酮/水溶液(15mL/5mL)中加入氟氢酸钾(1.04g，13.41mmol)。室温反应2小时。减压浓缩除去溶剂。残余物用丙酮(50mL)溶解，过滤，浓缩滤液。粗品加入乙醚，搅拌10分钟。过滤，滤饼乙醚洗得白色固体118-3(650mg，收率：100％)。
步骤三：118-3(290mg，1.16mmol)，100-3(150mg，0.23mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(170mg，0.23mmol)和碳酸钾(320mg，2.31mmol)在二氧六环/水(6mL/2mL)溶液中微波125℃反应70分钟。反应加乙酸乙酯和水，有机相饱和盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩至干，经柱层析(二氯甲烷/甲醇＝50/1)纯化后用C18(水/甲醇＝7/3)纯化得黄色固体118-4(65mg，收率：39.6％)。
LCMS:m/z:714[M+H] +.
步骤四：0℃下向118-4(65mg，0.09mmol)的二氯甲烷(2mL)溶液中加入三氟乙酸(1mL)。常温反应1小时。用二氯甲烷(10mL)稀释，加入饱和碳酸氢钠水溶液，室温搅拌10分钟。分液，水相用二氯甲烷(3*20mL)萃取，合并有机 相，饱和盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩至干，经高效液相色谱纯化得白色化合物118的甲酸盐(4.65mg，收率：9.1％)。
LCMS:m/z:514[M+H] +.
1H NMR(400MHz,甲醇-d4):δppm 8.67(s,1H),8.49(br,1H),7.79(d,J＝2.0Hz,1H),7.39(d,J＝1.6Hz,1H),7.20(s,1H),6.66(s,1H),6.64(s,1H),5.95(q,J＝6.8Hz,1H),4.96(s,2H),4.34～4.26(m,2H),4.03～3.96(m,2H),3.71～3.60(m,2H),2.86(s,3H),2.70～2.66(m,1H),2.48(s,3H),2.44～2.36(m,1H),2.11～2.02(m,3H),1.70～1.61(m,4H),1.46(t,J＝6.8Hz,3H).
实施例十五：化合物110的合成
(S)-2'-(1-(4-乙氧基-5-氟吡啶-2-基)乙基)-N，N-二甲基-7'-(2-(甲基氨基)-1H-咪唑-1-基)甲基)-1'-氧代-2'，3'-二氢-1'H-螺[环丙烷-1，4'-异喹啉]-5'-甲酰胺
Figure PCTCN2021137254-appb-000184
步骤一：向70-1的甲醇(10mL)和水(10mL)溶液中加入氢氧化锂(22mg，0.91mmol)。升温到65℃反应过夜。将反应液浓缩除去甲醇，残余物用硫酸氢钾调pH至5～6。减压浓缩除去水。残余物用二氯甲烷/甲醇(10/1，100mL)溶解，过滤，浓缩，残余物经柱层析(二氯甲烷/甲醇＝5/1)纯化得类白色固体110-1(120mg，收率：62.2％)。
步骤二：向110-1(110mg，0.26mmol)和N,N-二异丙基乙胺(100mg，0.78mmol)的DMF(10mL)溶液中加入二甲胺的四氢呋喃溶液(2M，2mL，4mmol)和HATU(200mg，0.52mmol)。室温反应2小时。反应液浓缩。残余物经柱层析(二氯甲烷/甲醇＝20/1)纯化得浅黄色固体110-2(50mg，收率：42.4％)。
LCMS:m/z:454.2[M+H] +
步骤三：0℃，氩气保护下向110-2(50mg，0.11mmol)的无水DMF(10mL)中加入氢化钠(60％分散于油中，18mg，0.45mmol)。加毕保温反应30分钟。滴加50-2(56mg，0.22mmol)的无水DMF(3mL)溶液。加毕保温反应1小时。反应液用饱和氯化铵水溶液淬灭。乙酸乙酯(3*50mL)萃取，合并有机相，水(3*100mL)和饱和盐水(2*100mL)洗，干燥，过滤，浓缩。残余物经柱层析(二氯甲烷/甲醇＝10/1)纯化得浅黄色固体110-3(30mg，收率：44.1％)。
LCMS:m/z:621.5[M+H] +
步骤四:向110-3(30mg，0.05mmol)的二氯甲烷(10mL)溶液中加入三氟乙酸(2mL)。加毕，室温反应1小时。将反应液倒入饱和碳酸氢钠水溶中。二氯甲烷/甲醇(20/1，3*50mL)萃取，合并有机相，饱和盐水(100mL)洗，干燥，过滤，浓缩，残余物经高效液相色谱纯化得化合物110(16mg，收率：64.0％)。
LCMS:m/z:521.3[M+H] +
1H NMR(400MHz,甲醇-d4):δppm 8.24～8.21(m,1H),7.95～7.94(m,1H),7.16(d,J＝6.8Hz,1H),7.01～7.00(m,1H),6.65(d,J＝1.6Hz,1H),6.60(d,J＝1.6Hz,1H),5.99～5.94(m,1H),4.99(s,2H),4.24～4.15(m,2H),3.66(d,J＝12.4Hz,0.5H),3.30(d,J＝16.8Hz,0.5H),3.15(d,J＝13.2Hz,0.5H),3.06(d,J＝2.0Hz,3H),2.90(d,J＝12.8Hz,0.5H),2.84(d,J＝1.2Hz,4.5H),2.78(s,1.5H),1.56(t,J＝6.8Hz,3H),1.45～1.40(m,3H),1.25～1.20(m,0.6H),1.03～0.98(m,1H),0.94～0.91(m,0.4H),0.84～0.79(m,0.5H),0.76～0.72(m,0.5H),0.65～0.62(m,0.5H),0.42～0.37(m,0.5H).
19F NMR(376MHz,甲醇-d4):δppm-153.96,-154.14.
实施例十六：化合物120，121的合成
化合物120：(S)-4-乙氧基-6-(1-(5'-(甲氧基甲基)-7'-((2-(甲氨基)-1H-咪唑-1-基)甲基)-1'-氧代-1'H-螺[环丁烷-1,4'-异喹啉]-2'(3'H)-基)乙基)烟腈
化合物121：(R)-4-乙氧基-6-(1-(5'-(甲氧基甲基)-7'-((2-(甲氨基)-1H-咪唑-1-基)甲基)-1'-氧代-1'H-螺[环丁烷-1,4'-异喹啉]-2'(3'H)-基)乙基)烟腈
Figure PCTCN2021137254-appb-000185
步骤一：-60℃，氩气保护下向甲醇(0.3g，9.38mmol)的四氢呋喃(10mL)溶液中加入KHMDS(1mol/L，9.4mL，9.40mmol)的四氢呋喃溶液。-60℃搅拌30分钟。-60℃下滴加118-1(2.5g，9.38mmol)的四氢呋喃溶液。-60℃搅拌10分钟后室温过夜。反应饱和氯化铵水溶液淬灭。乙酸乙酯萃取(50mL*2)，无水硫酸钠干燥，过滤，滤液减压浓缩得无色油状物120-1(1.6g，收率：99.7％)。
步骤二：0℃下向120-1(1.6g，9.30mmol)和碳酸钾(1.3g，9.30mmol)的丙酮/水溶液(30/10mL)中加入氟氢酸钾(3.6g，46.51mmol)。室温反应2小时。减压浓缩除去溶剂，残余物用丙酮(50mL)溶解，过滤，浓缩滤液。粗品加乙醚搅拌10分钟，过滤，滤饼乙醚洗得白色固体120-2(600mg，收率：42.5％)。
步骤三：120-2(93mg，0.62mmol)，100-3(80mg，0.12mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(27mg，0.04mmol)和碳酸钾(85mg，0.62mmol)在二氧六环/水(6mL/2mL)溶液中微波115℃反应70分钟。反应液加乙酸乙酯(50mL)和水(20mL)，有机相饱和盐水洗，无水硫酸钠干燥，经柱层析(二氯甲烷/甲醇＝50/1)纯化后再用C18(水/甲醇＝65/35)纯化得黄色固体120-3(70mg，收率：92.5％)。
LCMS:m/z:615[M+H] +.
步骤四：0℃下向120-3(70mg，0.11mmol)的二氯甲烷(2mL)溶液中加入TFA(1mL)。常温反应1小时。反应液用二氯甲烷(10mL)稀释，加入饱和碳酸氢钠水溶液，室温搅拌10分钟。分液，水相用二氯甲烷(3*20mL)萃取。合并有机 相，饱和盐水洗，无水硫酸钠干燥，过滤，滤液减压浓缩至干。残留物经高效液相色谱纯化后再用SFC纯化得化合物120(2mg，收率：3.4％)和化合物121(4mg，收率：6.8％)。
化合物120：
LCMS:m/z:515.1[M+H] +.
1H NMR(400MHz,甲醇-d4):δppm 8.67(s,1H),7.82(d,J＝1.6Hz,1H),7.35(d,J＝2.0Hz,1H),7.21(s,1H),6.64～6.62(m,2H),5.96(q,J＝7.2Hz,1H),4.96(s,2H),4.70～4.64(m,2H),4.33～4.27(m,2H),3.72～3.60(m,2H),3.41(s,3H),2.86(s,3H),2.79～2.74(m,1H),2.47～2.39(m,1H),2.04～1.98(m,3H),1.69(d,J＝7.2Hz,3H),1.59～1.56(m,1H),1.46(t,J＝6.8Hz,3H).
化合物121：
LCMS:m/z:515.1[M+H] +.
1H NMR(400MHz,甲醇-d 4):δppm 8.67(s,1H),7.82(d,J＝2.0Hz,1H),7.35(d,J＝2.0Hz,1H),7.21(s,1H),6.63～6.61(m,2H),5.96(q,J＝7.2Hz,1H),4.95(s,2H),4.70～4.64(m,2H),4.35～4.24(m,2H),3.72～3.60(m,2H),3.41(s,3H),2.85(s,3H),2.80～2.73(m,1H),2.47～2.39(m,1H),2.05～1.98(m,3H),1.69(d,J＝7.2Hz,3H),1.60～1.57(m,1H),1.46(t,J＝7.2Hz,3H).
本发明公开化合物的生物学功能在WDR5-MLL PPI活性以及细胞水平的测试中得到了证明。比如在WDR5-MLL PPI活性抑制试验中，本发明公开的化合物能够达到很强的抑制活性(IC 50＜100nM，可达10nM以内)。在细胞水平上，本发明公开化合物也表现出很好的抑制癌细胞的增殖的活性，在MV4-11细胞株上增殖抑制活性好(IC 50<200nM,可达10nM以内)。并且本方面化合物对Jurkat细胞上抑制活性弱，表明其有着良好的选择性(可超过300倍)。更进一步地，本方面化合物有着良好的药代动力学性质，在组织分布、半衰期、体内清除率和口服生物利用度等性质上效果良好。
测试例一：WDR5-MLL PPI抑制活性测试
化合物在分子水平对WDR5(WD Repeat Domain 5)与MLL1(mixed-lineage leukemia 1)多肽相互作用的影响。
利用HTRF(均相时间分辨荧光，Homogeneous Time-Resolved Fluorescence)技术来检测化合物对WDR5蛋白(22-334aa)与MLL1多肽(3672-3773aa)相互作用 的影响。Anti-6His-Eu cryptate供体识别的N端带有His标签的WDR5与链霉亲和素-APC受体识别的带有生物素标签的MLL1多肽相互作用时，供体和受体被拉到足够近的距离，产生荧光共振能量转移(FRET)。当化合物抑制WDR5和MLL1多肽相互作用时，供体和受体不再发生FRET。因此，FRET信号的降低可以反映化合物对WDR5和MLL1多肽相互作用的抑制。
待测化合物用DMSO进行3倍稀释，共设置10个浓度梯度，每个浓度设置2个重复，再用反应缓冲液(25mM HEPES pH＝7.5,100mM NaCl,0.05％Tween 20)进行稀释，使DMSO的终浓度控制在0.5％。在384孔板中，加入1μL化合物和3μL42nM WDR5蛋白，1000rpm离心1分钟，室温孵育60min，加入3μL 333nM MLL1多肽，室温孵育10min,再加入3μL Anti-6His-Eu cryptate和链霉亲和素-APC混合液，1000rpm离心1分钟，室温避光孵育60min，使用多功能酶标仪(
Figure PCTCN2021137254-appb-000186
2105)读取信号。每块板设置以下对照：对照组(1μL含5％DMSO反应缓冲液、3μL 42nM WDR5、3μL MLL1多肽、3μL Anti-6His-Eu cryptate和链霉亲和素-APC)。空白组(1μL含5％DMSO反应缓冲液、3μL反应缓冲液、3μL MLL1多肽、3μL Anti-6His-Eu cryptate和链霉亲和素-APC)。测试数据根据两束不同波长荧光的信号比计算得到：(665nm的信号/620nm的信号)*10000。抑制率的计算公式为：抑制率(％)＝100-(实验组-空白组)/(对照组-空白组)*100。IC50值采用XLfit软件计算求得。结果如表1所示。
表1
Figure PCTCN2021137254-appb-000187
Figure PCTCN2021137254-appb-000188
其中，字母A代表IC 50小于20nM；字母B代表IC 50为20nM至100nM；字母C代表IC 50大于100nM。
测试例二：MV4-11细胞(ATCC:CRL-9591)增殖抑制实验
通过CellTiter-Glo(Promega-G7573)发光法细胞活力检测试剂盒对活细胞内ATP进行定量测定，来检测待测化合物对细胞增殖的影响。
第一步：在96孔板(Greiner-655098)种接种MV4-11细胞，以每孔1,500个细胞密度接种细胞到96孔板，每孔体积140μL；细胞培养基成分:RPMI1640(Gibco-A10491-01)+10％FBS(Gibco-10099-141C)+1％Penicillin-Streptomycin(5,000U/mL,Gibco-15070-063)。
第二步：细胞接种当天，加入待测化合物处理细胞。待测化合物进行3倍梯度稀释，共设置9个浓度梯度；每孔分别加入终浓度0.5％的DMSO(Sigma,D2650)或者含待测浓度化合物的DMSO溶液，每个浓度点设置2或3个重复孔。置于37℃， 5％二氧化碳培养箱(Thermo Scientific Steri-Cycle 371)培养6天。
第三步：CellTiter-Glo Luminescent Cell Viability Assay试剂盒检测对照组和处理组细胞活力。每孔加入50μL CellTiter-Glo，混匀，室温避光孵育15min。根据试剂盒说明书，使用多功能酶标仪(EnVision,PerkinElmer)读取化学发光信号。
每个浓度点的化合物抑制百分率(％)通过以下公式计算获得：
抑制百分率(％)＝(1-化合物处理组信号值/DMSO处理组信号值)*100。
细胞增殖半抑制浓度IC 50值采用GraphPad Prism软件计算求得，结果如表2所示。
表2
Figure PCTCN2021137254-appb-000189
其中，字母A代表IC 50小于50nM；字母B代表IC 50为50nM至200nM；字母C代表IC 50大于200nM。
测试例三：Jurkat(ATCC:TIB-152)细胞增殖抑制实验
通过CellTiter-Glo(Promega-G7573)发光法细胞活力检测试剂盒对活细胞内ATP进行定量测定，来检测待测化合物对细胞增殖的影响。
第一步：在96孔板(Greiner-655098)种接种Jurkat细胞，以每孔1,500个细胞密度接种细胞到96孔板，每孔体积140μL；细胞培养基成分:RPMI1640(Gibco-A10491-01)+10％FBS(Gibco-10099-141C)+1％Penicillin-Streptomycin(5,000U/mL,Gibco-15070-063)。
第二步：细胞接种当天，加入待测化合物处理细胞。待测化合物进行3倍梯度稀释，共设置9个浓度梯度；每孔分别加入终浓度0.5％的DMSO(Sigma,D2650)或者含待测浓度化合物的DMSO溶液，每个浓度点设置2或3个重复孔。置于37℃，5％二氧化碳培养箱(Thermo Scientific Steri-Cycle 371)培养6天。
第三步：CellTiter-Glo Luminescent Cell Viability Assay试剂盒检测对照组和处理组细胞活力。每孔加入50μL CellTiter-Glo，混匀，室温避光孵育15min。根据试剂盒说明书，使用多功能酶标仪(EnVision,PerkinElmer)读取化学发光信号。
每个浓度点的化合物抑制百分率(％)通过以下公式计算获得：
抑制百分率(％)＝(1-化合物处理组信号值/DMSO处理组信号值)*100。
细胞增殖半抑制浓度IC 50值采用GraphPad Prism软件计算求得，结果如表3所示,并可进一步地计算Jurkat细胞增殖抑制活性IC 50与MV4-11细胞增殖抑制活性IC 50的比值，由此可得选择性。本发明化合物对Jurkat细胞抑制活性弱，选择性在300倍以上，表明化合物有着良好的选择性。
Figure PCTCN2021137254-appb-000190
Figure PCTCN2021137254-appb-000191
测试例四：化合物药代动力学实验
对本发明化合物进行药代动力学测定。本申请采用以下方法测定本申请的化合物药代动力学参数。
研究使用的健康雄性成年小鼠，每组动物单次灌胃给药5-100mg/Kg。禁食从给药前10小时至给药后4小时。给药后不同时间点后采血，并测定化合物血浆含量(LC-MS/MS)。血浆浓度----时间关系用专业软件分析(winnonlin)，计算化合物的药代动力学参数。本发明化合物在生物利用度、组织分布、半衰期和体内清除率等方面有着良好的性质。
在本发明中提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种简单变型，这些简单变型均属于本发明的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。此外，本发明的各种不同的实施方式之间也可以进行任意组合，只要其不违背本发明的思想，其同样应当视为本发明所公开的内容。

Claims (85)

  1. 一种式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物：
    Figure PCTCN2021137254-appb-100001
    式中，
    环A为取代或未取代的3-8元饱和或不饱和碳环或取代或未取代的3-8元饱和或不饱和杂环，所述杂环含有1-2个独立选自N、O和S的杂原子；
    X 3选自CR 5和N；
    X 4选自任选取代的-(CH 2) n-、-C(＝O)-和NR 6，其中，n为1、2或3；
    X 5选自N和CR 5；
    L 1选自键、任选取代的C1-C6亚烷基、任选取代的C1-C6亚烷基-O-、任选取代的C1-C6亚烷基-NH-、任选取代的C1-C6亚烷基-S-和任选取代的C2-C4亚链烯基；
    L 2选自键、任选取代的C1-C6亚烷基、任选取代的C1-C6亚烷基-O-、任选取代的C1-C6亚烷基-NH-、任选取代的C1-C6亚烷基-S-和任选取代的C2-C4亚链烯基；
    R 0选自H、C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6卤代烷基、-C(O)NR 3R 4、-CH 2OR 3和-NR 3R 4取代的C1-C6烷基；
    R 1选自任选取代的环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、任选取代的氨基和胍基；
    R 2选自任选取代的环烷基、任选取代的芳基、任选取代的杂芳基和任选取代的杂环基；
    R 3和R 4各自独立选自H、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6卤代烷基、任选取代的4-10元杂环基和任选取代的5-10元杂芳 基；或者，R 3和R 4与其所连接的氮原子一起形成任选取代的4-10元杂环基或5-10元杂芳基；
    R 5选自H、卤素、C1-C6烷基、卤代C1-C6烷基和C1-C6烷氧基；
    R 6选自H、C1-C6烷基、卤代C1-C6烷基和C1-C6烷氧基。
  2. 如权利要求1所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，环A为C3-C8环烷基或3-7元杂环基。
  3. 如权利要求1或2所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，环A选自环丙基、环丁基、环戊基、环己基、氮杂环丙基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、氧杂环丙基、氧杂环丁基、四氢呋喃基、四氢吡喃基和吗啉基。
  4. 如权利要求1至3之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，环A被1、2或3个选自卤素、羟基、氰基、C1-C6烷基、卤代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b、-NR aR b取代的羰基、-NR aR b取代的C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基羰基、任选取代的6-14元芳基、任选取代的5-10元杂芳基、任选取代的4-10元杂环基、任选取代的C3-C8环烷基、任选取代的6-14元芳基取代的C1-C6烷基、任选取代的5-10元杂芳基取代的C1-C6烷基、任选取代的4-10元杂环基取代的C1-C6烷基、和任选取代的C3-C8环烷基取代的C1-C6烷基的取代基取代；其中，所述6-14元芳基、5-10元杂芳基、4-10元杂环基和C3-C8环烷基被取代时，取代基为1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b、-NR aR b取代的羰基、-NR aR b取代的C1-C6烷基、C1-C6烷基羰基、C1-C6烷氧基羰基的取代基；并且其中，所述R a和R b各自独立选自H和C1-C6烷基。
  5. 如权利要求1至4之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，环A为环丙基、环丁基、环戊基、氮杂环丁基、氧杂环丁基、氮杂环戊基或四氢呋喃基。
  6. 如权利要求1至5之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，环A任选地被1、2或3个选自F、Cl、Br、CF 3、CH 3、-OH、-OCH 3、-NH 2、-NHCH 3,-NH 2(CH 3) 2的取代基取代。
  7. 如权利要求1至6之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 0为-NR 3R 4取代的C1-C6烷基；其中，R 3和R 4各自独立选自H，任选被1、2、3、4、5或6个选自卤素、氰基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的C1-C6烷基，或者R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100002
    所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100003
    各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、羟基和卤代C1-C6烷基羰基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
  8. 如权利要求1至7之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 0为-NR 3R 4取代的C1-C6烷基，并且其中，R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100004
    所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100005
    各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、-NR aR b和羟基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
  9. 如权利要求1至8之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 0为-NR 3R 4取代的C1-C6烷基，其中，R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100006
    所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100007
    各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代；其中，R a和R b各自独立为H或C1-C4烷基。
  10. 如权利要求1至9之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，
    X 3和/或X 5为CR 5。
  11. 如权利要求1至10之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 5选自H和C1-C4烷基。
  12. 如权利要求1至11之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，X 4为-(CH 2) n-，n为1或2；并且其中，所述-(CH 2) n-任选被1或2个选自卤素、羟基、氨基、C1-C6烷基和卤代C1-C6烷基的取代基取代。
  13. 如权利要求1至12之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，L 1选自C1-C6亚烷基、C1-C6亚烷基-O-、C1-C6亚烷基-NH-、C1-C6亚烷基-S-和C2-C4亚链烯基，所述C1-C6亚烷基、C1-C6亚烷基-O-、C1-C6亚烷基-NH-、C1-C6亚烷基-S-和C2-C4亚链烯基任选被1、2或3个选自卤素、C1-C4烷基和羟基的取代基取代。
  14. 如权利要求1至13之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，L 1选自C1-C6亚烷基或C1-C6亚烷基-NH-，所述C1-C6亚烷基或C1-C6亚烷基-NH-任选被1、2或3个选自卤素、C1-C4烷基和羟基的取代基取代。
  15. 如权利要求1至14之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 1选自任选取代的C3-C8环烷基、任选取代的6-14元芳基、任选取代的5-10元杂芳基和任选取代的4-10元杂环基，并且所述环烷基、芳基、杂芳基和杂环基各自可任选地被1、2或3个选自任选取代的氨基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、C1-C6卤代烷基和氰基的取代基取代；其中，所述任选取代的氨基是-NR aR b，其中，R a和R b各自独立为H或C1-C6烷基。
  16. 如权利要求1至15之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 1选自任选取代的苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、咪唑酮基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并咪唑基、吡啶并吡咯基、吡啶并咪唑基、苯并三唑基、噁唑酮基、噁唑烷酮基、苯并噁唑基、苯并异噁唑基、喹啉基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基、
    Figure PCTCN2021137254-appb-100008
  17. 如权利要求1至16之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，所述L 1为C1-C4亚烷基或C1-C4亚烷基-NH-，R 1为吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、
    Figure PCTCN2021137254-appb-100009
    Figure PCTCN2021137254-appb-100010
    所述吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、
    Figure PCTCN2021137254-appb-100011
    任选被1或2个选自卤素、C1-C4烷基、氰基和-NR aR b的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
  18. 如权利要求1至17之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，L 2选自键、C3-C5环烷基和C1-C6亚烷基，其中，所述C3-C5环烷基、C1-C6亚烷基任选地被1、2或3个选自卤素、C1-C3烷基、C3-C5环烷基和羟基的取代基取代。
  19. 如权利要求1至18之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 2任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基和5-10元杂芳基的取代基取代；其中，R a和R b各自独立为H或C1-C6烷基；并且其中，所述杂芳基优选为含有1或2个环氮原子的杂芳基，优选选自吡唑基、咪唑基、吡啶基、吡嗪基和哌嗪基。
  20. 如权利要求1至19之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 2选自6-14元芳基、5-10元杂芳基和4-10元杂环基，所述的6-14元芳基、5-10元杂芳基和4-10元杂环基可任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基和5-10元杂芳基的取代基取代。
  21. 如权利要求1至20之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 2选自苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、
    Figure PCTCN2021137254-appb-100012
    所述苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、
    Figure PCTCN2021137254-appb-100013
    任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基和5-10元杂芳基的其取代基取代。
  22. 如权利要求1至21之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，L 2为C1-C4亚烷基，R 2为6-14元芳基、5-10元含氮杂芳基或4-10元杂环基，所述6-14元芳基、5-10元含氮杂芳基或4-10元杂环基任选被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代；R 2优选为苯基、吡啶基、吡唑基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、吲哚基、
    Figure PCTCN2021137254-appb-100014
    所 述苯基、吡啶基、吡唑基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、
    Figure PCTCN2021137254-appb-100015
    任选被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代。
  23. 如权利要求1所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，
    环A为C3-C6环烷基或4-8元杂环基，所述环烷基或杂环基任选地被1、2或3个选自卤素、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基的取代基取代；
    X 3和X 5均为CH；
    X 4为CH 2；
    L 1为C1-C4亚烷基；
    R 1为任选被1或2个选自卤素、C1-C4烷基和-NR aR b的取代基取代的5或6元含氮杂芳基，所述5或6元含氮杂芳基优选为吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基或
    Figure PCTCN2021137254-appb-100016
    其中，R a和R b各自独立为H或C1-C4烷基；
    L 2为C1-C4亚烷基；
    R 2为苯基、5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基或吲哚基，所述苯基、5-10元含氮杂芳基和4-10元杂环基各自任选地被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代；
    R 0为-NR 3R 4取代的C1-C4烷基；其中，R 3和R 4各自独立选自H，任选被1-6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基和任选被1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、C1-C6烷 基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；优选地，所述4-8元杂环基各自独立选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、
    Figure PCTCN2021137254-appb-100017
  24. 如权利要求1所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，
    环A为C3-C6环烷基，所述环烷基任选地被1、2或3个选自卤素、C1-C4烷基和卤代C1-C4烷基的取代基取代；
    X 3和X 5均为CH；
    X 4为CH 2；
    L 1为C1-C4亚烷基；
    R 1为任选被1或2个选自C1-C4烷基和-NR aR b的取代基取代的5或6元含氮杂芳基，优选为吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基或
    Figure PCTCN2021137254-appb-100018
    其中，R a和R b各自独立为H或C1-C4烷基；
    L 2为C1-C4亚烷基；
    R 2为5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基或吲哚基，所述5-10元含氮杂芳基或4-10元杂环基各自任选被1或2个选自C1-C6烷氧基、C1-C6烷基、C3-C8环烷基-O-、卤代C1-C6烷氧基、卤素和氰基的取代基取代；
    R 0为-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H和任选被1、2、3、4、5或6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基，或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、羟基、C1-C4烷氧基、C3-C6烷氧基和C1-C4烷基取代的4-8元杂环基，优选地，所述4-8元杂环基选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、
    Figure PCTCN2021137254-appb-100019
  25. 式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物：
    Figure PCTCN2021137254-appb-100020
    其中，
    环A为取代或未取代的3-8元饱和或不饱和碳环或取代或未取代的3-8元饱和或不饱和杂环，所述杂环含有1-2个独立选自N、O和S的杂原子；
    L 2选自键、任选取代的C1-C6亚烷基、任选取代的C1-C6亚烷基-O-、任选取代的C1-C6亚烷基-NH-、任选取代的C1-C6亚烷基-S-和任选取代的C2-C4亚链烯基；
    R 0选自H、C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6卤代烷基、-C(O)NR 3R 4、-CH 2OR 3、-NR 3R 4取代的C1-C6烷基；
    R 2选自任选取代的环烷基、任选取代的芳基、任选取代的杂芳基和任选取代的杂环基；
    R 3和R 4各自独立选自H、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6卤代烷基、任选取代的4-10元杂环基和任选取代的5-10元杂芳基；或者，R 3和R 4与其所连接的氮原子一起形成任选取代的4-10元杂环基或5-10元杂芳基；并且
    R c和R d各自独立为H或C1-C4烷基。
  26. 如权利要求25所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，环A为C3-C8环烷基或3-7元杂环基。
  27. 如权利要求25或26所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，环A选自环丙基、环丁基、环戊基、环己基、氮杂环丙基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、氧杂环丙基、氧杂环丁基、四氢呋喃基、四氢吡喃基和吗啉基。
  28. 如权利要求25至27之一所述的式II化合物，或其药学上可接受的盐，或 其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，环A被1、2或3个选自卤素、羟基、氰基、C1-C6烷基、卤代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b、C1-C6烷基羰基和C1-C6烷氧基羰基的取代基取代，所述R a和R b各自独立选自H和C1-C6烷基。
  29. 如权利要求25至28之一所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，环A为环丙基、环丁基、环戊基、环己烷、氮杂环丁基、氧杂环丁基、氮杂环戊基、四氢呋喃基或氧杂环己烷。
  30. 如权利要求25至29之一所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，环A任选地被1、2或3个选自F、Cl、Br、CF 3、CH 3、-OH、-OCH 3、-NH 2、-NHCH 3,-NH 2(CH 3) 2的取代基取代。
  31. 如权利要求25至30之一所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 0为-NR 3R 4取代的C1-C6烷基；其中，R 3和R 4各自独立选自H，任选被1、2、3、4、5或6个选自卤素、氰基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的C1-C6烷基，或者R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100021
    所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100022
    各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、-NR aR b和羟基的取代基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
  32. 如权利要求25至31之一所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 0为-NR 3R 4取代的C1-C6烷基，并且其中，R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100023
    所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100024
    各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、-NR aR b和羟基的取代基取代；其中，R a和R b各自独立为H或C1-C4烷基。
  33. 如权利要求25至32之一所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 0为-NR 3R 4取代的C1-C6烷基，其中，R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100025
    所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100026
    各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代；其中，R a和R b各自独立为H或C1-C4烷基。
  34. 如权利要求25至33之一所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、 前药或代谢产物，其特征在于，R c和R d各自独立为H或甲基。
  35. 如权利要求25至34所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，L 2选自键和C1-C6亚烷基，其中，所述C1-C6亚烷基任选地被1、2或3个选自卤素、C1-C3烷基、C3-C5环烷基和羟基的取代基取代。
  36. 如权利要求25至35之一所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 2任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代；其中，R a和R b各自独立为H或C1-C6烷基；并且其中，所述杂芳基优选为含有1或2个环氮原子的杂芳基，优选选自吡唑基、咪唑基、吡啶基、吡嗪基和哌嗪基。
  37. 如权利要求25至36之一所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 2选自6-14元芳基、5-10元杂芳基和4-10元杂环基，所述6-14元芳基、5-10元杂芳基和4-10元杂环基任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代。
  38. 如权利要求25至37之一所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 2选自苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、
    Figure PCTCN2021137254-appb-100027
    所述苯基、萘基、吡啶基、吡咯 基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、
    Figure PCTCN2021137254-appb-100028
    任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代。
  39. 如权利要求25至38所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，L 2为C1-C4亚烷基，R 2为苯基、吡啶基、吡唑基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基或吲哚基，所述苯基、吡啶基、吡唑基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基或吲哚基被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代。
  40. 如权利要求25所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于：
    环A为任选被选自F、Cl、羟基或C1-C4烷基的取代基取代的C3-C6环烷基或含1个氮或1个O的C4-C6杂环基，优选为任选被F或C1-C4烷基取代的环丙基、环丁基、氧杂环丁基或氮杂环丁基；
    R 0为H或-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H、4-6元杂环基和任选被1、2、3、4、5或6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基，或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、羟基、C1-C4烷氧基、C3-C6环烷基和C1-C4烷基取代的4-6元杂环基；其中，所述4-6元杂环基优选为仅含氮的杂环基或含氧和氮的杂环基，优选选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、
    Figure PCTCN2021137254-appb-100029
    L 2为C1-C4亚烷基；
    R 2为6-14元芳基、5-10元含氮杂芳基或4-10元杂环基，优选为苯基、吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吲哚基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、
    Figure PCTCN2021137254-appb-100030
    所述6-14元芳基、5-10元含氮杂芳基或4-10元杂环基各自任选被1或2个选自C1-C6烷氧基、C1-C4烷基、卤素、C3-C6环烷基-氧基、卤代C1-C4烷氧基和氰基的取代基取代；
    R c和R d各自独立为H或C1-C4烷基。
  41. 如权利要求25所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，
    环A为C3-C6环烷基或4-8元杂环基，所述环烷基或杂环基任选地被1、2或3个选自卤素、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基、卤代C1-C4烷氧基的取代基取代；
    L 2为C1-C4亚烷基；
    R 2为苯基、5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基或吲哚基，所述苯基、5-10元含氮杂芳基和4-10元杂环基各自任选地被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代；
    R 0为-NR 3R 4取代的C1-C4烷基；其中，R 3和R 4各自独立选自H，任选被1-6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基和任选被1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；优选地，所述4-8元杂环基各自独立选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、
    Figure PCTCN2021137254-appb-100031
    并且
    R c和R d各自独立为H或C1-C4烷基。
  42. 如权利要求25所述的式II化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，
    环A为C3-C6环烷基，所述环烷基任选地被1、2或3个选自卤素、C1-C4烷基和卤代C1-C4烷基的取代基取代；
    L 2为C1-C4亚烷基；
    R 2为5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基或吲哚基，所述5-10元含氮杂芳基或4-10元杂环基各自任选被1或2个选自C1-C6烷氧基、C1-C6烷基、C3-C8环烷基-O-、卤代C1-C6烷氧基、卤素和氰基的取代基取代；
    R 0为-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H和任选被1、2、3、4、5或6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基，或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、羟基、C1-C4烷氧基和C1-C4烷基取代的4-8元杂环基，优选地，所述4-8元杂环基选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、
    Figure PCTCN2021137254-appb-100032
    并且
    R c和R d各自独立为H或C1-C4烷基。
  43. 式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，
    Figure PCTCN2021137254-appb-100033
    其中，
    L 2选自键、任选取代的C1-C6亚烷基、任选取代的C1-C6亚烷基-O-、任选取代的C1-C6亚烷基-NH-、任选取代的C1-C6亚烷基-S-和任选取代的C2-C4亚链烯基；
    R 0选自H、C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6卤代烷基、-C(O)NR 3R 4、-CH 2OR 3和-NR 3R 4取代的C1-C6烷基；
    R 2选自任选取代的环烷基、任选取代的芳基、任选取代的杂芳基和任选取代的杂环基；
    R 3和R 4各自独立选自H、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6卤代烷基、任选取代的4-10元杂环基和任选取代的5-10元杂芳基；或者，R 3和R 4与其所连接的氮原子一起形成任选取代的4-10元杂环基或5-10元杂芳基；
    X 6各自独立选自C、O、N、S，
    q为1、2或3的整数，
    R 7选自F、Cl、氰基、羟基、C1-C6烷基、氟代或氯代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、氟代或氯代C1-C6烷氧基、羟基取代的C1-C6烷基和-NR aR b；其中，所述R a和R b各自独立选自H和C1-C6烷基，
    m为0、1、2或3的整数；并且
    R c和R d各自独立为H或C1-C4烷基。
  44. 如权利要求43所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 0为-NR 3R 4取代的C1-C6烷基；其中，R 3和R 4各自独立选自H，任选被1、2、3、4、5或6个选自卤素、氰基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的C1-C6烷基，或者R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100034
    所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100035
    各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰 基、-NR aR b和羟基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
  45. 如权利要求43至44之一所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 0为-NR 3R 4取代的C1-C6烷基，并且其中，R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100036
    所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100037
    各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、-NR aR b和羟基的取代基取代；其中，R a和R b各自独立为H或C1-C4烷基。
  46. 如权利要求43至45之一所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 0为-NR 3R 4取代的C1-C6烷基，其中，R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100038
    所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100039
    各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代；其中，R a和R b各自独立为H或C1-C4烷基。
  47. 如权利要求43至46之一所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型 物、前药或代谢产物，其特征在于，R c和R d各自独立为H或甲基。
  48. 如权利要求43至47所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，L 2选自键和C1-C6亚烷基，其中，所述C1-C6亚烷基任选地被1、2或3个选自卤素、C1-C3烷基、C3-C5环烷基和羟基的取代基取代。
  49. 如权利要求43至48之一所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 2任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代；其中，R a和R b各自独立为H或C1-C6烷基；并且其中，所述杂芳基优选为含有1或2个环氮原子的杂芳基，优选选自吡唑基、咪唑基、吡啶基、吡嗪基和哌嗪基。
  50. 如权利要求43至49之一所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 2选自6-14元芳基、5-10元杂芳基和4-10元杂环基，所述6-14元芳基、5-10元杂芳基和4-10元杂环基任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代。
  51. 如权利要求43至50之一所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 2选自苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、2-哌嗪酮基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八 氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、
    Figure PCTCN2021137254-appb-100040
    所述苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、2-哌嗪酮基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、
    Figure PCTCN2021137254-appb-100041
    任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代。
  52. 如权利要求43至51所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，L 2为C1-C4亚烷基，R 2为6-14元芳基、5-10元含氮杂芳基或4-10元杂环基，优选为苯基、吡啶基、吡唑基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基或吲哚基，所述6-14元芳基、5-10元含氮杂芳基或4-10元杂环基可任选地被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代。
  53. 如权利要求43所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于：
    R 0为H或-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H、4-6元杂环基和任选被1、2、3、4、5或6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基，或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、羟基、C1-C4烷氧基和C1-C4烷基取代的4-6元杂环基；其中，所述4-6元杂环基优选为含氧和/或氮的杂环基，优选选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、
    Figure PCTCN2021137254-appb-100042
    L 2为C1-C4亚烷基；
    R 2为6-14元芳基、5-10元含氮杂芳基或4-10元杂环基，优选为苯基、吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吲哚基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基，所述6-14元芳基、5-10元含氮杂芳基或4-10元杂环基各自任选被1或2个选自C1-C6烷氧基、C1-C4烷基、卤素、C3-C6环烷基-氧基、卤代C1-C4烷氧基和氰基的取代基取代；
    R c和R d各自独立为H或C1-C4烷基；
    X 6为C或O；
    q为1或2；并且
    R 7选自F、Cl、氰基、羟基、C1-C6烷基、氟代或氯代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、氟代或氯代C1-C6烷氧基以及羟基取代的C1-C6烷基。
  54. 如权利要求43所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，
    L 2为C1-C4亚烷基；
    R 2为苯基、5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基或吲哚基，所述苯基、5-10元含氮杂芳基和4-10元杂环基各自任选地被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代；
    R 0为-NR 3R 4取代的C1-C4烷基；其中，R 3和R 4各自独立选自H，任选被1-6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基和任选被1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；优选地，所述4-8元杂环基各自独立选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、
    Figure PCTCN2021137254-appb-100043
    R c和R d各自独立为H或C1-C4烷基；
    X 6为C或O；
    q为1或2；并且
    R 7选自F、Cl、氰基、羟基、C1-C6烷基、氟代或氯代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、氟代或氯代C1-C6烷氧基以及羟基取代的C1-C6烷基。
  55. 如权利要求43所述的式III化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，
    L 2为C1-C4亚烷基；
    R 2为5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基或吲哚基，所述5-10元含氮杂芳基或4-10元杂环基各自任选被1或2个选自C1-C6烷氧基、C1-C6烷基、C3-C8环烷基-O-、卤代C1-C6烷氧基、卤素和氰基的取代基取代；
    R 0为-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H和任选被1、2、3、4、5或6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基，或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、羟基和C1-C4烷基取代的4-8元杂环基，优选地，所述4-8元杂环基选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、
    Figure PCTCN2021137254-appb-100044
    R c和R d各自独立为H或C1-C4烷基；
    X 6为C或O；
    q为1或2；并且
    R 7选自F、Cl、氰基、羟基、C1-C6烷基、氟代或氯代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、氟代或氯代C1-C6烷氧基以及羟基取代的C1-C6烷基。
  56. 一种式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物：
    Figure PCTCN2021137254-appb-100045
    式中，
    环A为取代或未取代的3-8元饱和碳环或取代或未取代的3-8元饱和杂环，所述杂环含有1-2个独立选自N、O和S的杂原子；
    X 3选自CR 5和N；
    X 4选自任选取代的-(CH 2) n-、-C(＝O)-和NR 6，其中，n为1、2或3；
    X 5选自N和CR 5；
    L 1选自键、任选取代的C1-C6亚烷基、任选取代的C1-C6亚烷基-O-、任选取代的C1-C6亚烷基-NH-、任选取代的C1-C6亚烷基-S-和任选取代的C2-C4亚链烯基；
    L 2选自键、任选取代的C1-C6亚烷基、任选取代的C1-C6亚烷基-O-、任选取代的C1-C6亚烷基-NH-、任选取代的C1-C6亚烷基-S-和任选取代的C2-C4亚链烯基；
    R 0选自任选取代的C1-C6卤代烷基、-C(O)NR 3R 4、-CH 2OR 3和-NR 3R 4取代的C1-C6烷基；
    R 1选自任选取代的环烷基、任选取代的芳基、任选取代的杂芳基、任选取代的杂环基、任选取代的氨基和胍基；
    R 2选自任选取代的环烷基、任选取代的芳基、任选取代的杂芳基和任选取代的杂环基；
    R 3和R 4各自独立选自H、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6卤代烷基、任选取代的4-10元杂环基和任选取代的5-10元杂芳基；或者，R 3和R 4与其所连接的氮原子一起形成任选取代的4-10元杂环基或5-10元杂芳基；
    R 5选自H、卤素、C1-C6烷基、卤代C1-C6烷基和C1-C6烷氧基；并且
    R 6选自H、C1-C6烷基、卤代C1-C6烷基和C1-C6烷氧基。
  57. 如权利要求56所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，环A为C3-C8环烷基或3-7元杂环基。
  58. 如权利要求56或57所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，环A选自环丙基、环丁基、环戊基、环己基、氮杂环丙基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、氧杂环丙基、氧杂环丁基、四氢呋喃基、四氢吡喃基和吗啉基。
  59. 如权利要求56至58之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，环A被1、2或3个选自卤素、羟基、氰基、C1-C6烷基、卤代C1-C6烷基、羟基取代的C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基和-NR aR b的取代基取代；其中，所述R a和R b各自独立选自H和C1-C6烷基。
  60. 如权利要求56至59之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，环A为环丙基、环丁基、环戊基、氮杂环丁基、氧杂环丁基、氮杂环戊基或四氢呋喃基，
  61. 如权利要求56至60之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，环A任选地被1、2或3个选自F、Cl、Br、CF 3、CH 3、-OH、-OCH 3、-NH 2、-NHCH 3,-NH 2(CH 3) 2的取代基取代。
  62. 如权利要求56至61之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 0为-NR 3R 4取代的C1-C6烷基；其中，R 3和R 4各自独立选自H，任选被1、2、3、4、5或6个选自卤素、氰基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的C1-C6烷基，或者R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100046
    所述氮杂环丁烷基、吡咯烷基、哌啶 基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100047
    各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、-NR aR b和羟基的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
  63. 如权利要求56至62之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 0为-NR 3R 4取代的C1-C6烷基，并且其中，R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100048
    所述氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100049
    各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、磺基、C1-C6烷基磺酰基、C1-C6烷氧基磺酰基、C1-C6烷基羰基、卤代C1-C6烷基羰基、C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、-NR aR b和羟基的取代基取代；其中，R a和R b各自独立为H或C1-C4烷基。
  64. 如权利要求56至63之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 0为-NR 3R 4取代的C1-C6烷基，其中，R 3和R 4与其所连接的氮原子一起形成氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100050
    所述氮杂环丁烷基、吡咯烷基、 哌啶基、哌嗪基、2-哌嗪酮基、吗啉基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、
    Figure PCTCN2021137254-appb-100051
    各自任选地被1、2或3个选自卤素、氰基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代；其中，R a和R b各自独立为H或C1-C4烷基。
  65. 如权利要求56至64之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，
    X 3和/或X 5为CR 5。
  66. 如权利要求56至65之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 5选自H和C1-C4烷基。
  67. 如权利要求56至66之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，X 4为-(CH 2) n-，n为1或2；并且其中，所述-(CH 2) n-任选被1或2个选自卤素、羟基、氨基、C1-C6烷基和卤代C1-C6烷基的取代基取代。
  68. 如权利要求56至67之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，X 3和X 5均为CR 5；并且X 4为任选取代的-(CH 2)-。
  69. 如权利要求56至68之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，L 1选自C1-C6亚烷基、C1-C6亚烷基-O-、C1-C6亚烷基-NH-、C1-C6亚烷基-S-和C2-C4亚链烯基，所述C1-C6亚烷基、C1-C6亚烷基-O-、C1-C6亚烷基-NH-、C1-C6亚烷基-S-和C2-C4亚链烯基任选被1、2或3个选自卤素、C1-C4烷基和羟基的取代基取代。
  70. 如权利要求56至69之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，L 1选自C1-C6亚烷基和C1-C6亚烷基-NH-，所述 C1-C6亚烷基和C1-C6亚烷基-NH-任选被1、2或3个选自卤素、C1-C4烷基和羟基的取代基取代。
  71. 如权利要求56至70之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 1选自任选取代的C3-C8环烷基、任选取代的6-14元芳基、任选取代的5-10元杂芳基和任选取代的4-10元杂环基，并且所述环烷基、芳基、杂芳基和杂环基各自可任选地被1、2或3个选自任选取代的氨基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、C1-C6卤代烷基和氰基的取代基取代；其中，所述任选取代的氨基是-NR aR b，其中，R a和R b各自独立为H或C1-C6烷基。
  72. 如权利要求56至71之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 1选自任选取代的苯基、萘基吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吡啶并咪唑基、吲哚基、异吲哚基、吲唑基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基、
    Figure PCTCN2021137254-appb-100052
  73. 如权利要求56至72之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，所述L 1为C1-C4亚烷基或C1-C4亚烷基-NH-，R 1为吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基或
    Figure PCTCN2021137254-appb-100053
    所述吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基或
    Figure PCTCN2021137254-appb-100054
    任选被1或2个选自卤素、C1-C4烷基和-NR aR b的取代基取代，其中，R a和R b各自独立为H或C1-C4烷基。
  74. 如权利要求56至73所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，L 2选自键和C1-C6亚烷基，其中，所述C1-C6亚烷基任选地被1、2或3个选自卤素、C1-C3烷基、C3-C5环烷基和羟基的取代基取代。
  75. 如权利要求56至74之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 2任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代；其中，R a和R b各自独立为H或C1-C6烷基；并且其中，所述杂芳基优选为含有1或2个环氮原子的杂芳基，优选选自吡唑基、咪唑基、吡啶基、吡嗪基和哌嗪基。
  76. 如权利要求56至75之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 2选自6-14元芳基、5-10元杂芳基和4-10元杂环基，所述6-14元芳基、5-10元杂芳基和4-10元杂环基可任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代。
  77. 如权利要求56至76之一所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，R 2选自苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、
    Figure PCTCN2021137254-appb-100055
    所述苯基、萘基、吡啶基、吡咯基、吡唑基、咪唑基、三唑基、嘧啶基、吡嗪基、三嗪基、吲哚基、异吲哚基、吲 唑基、苯并吡咯基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并异噁唑基、喹啉基、杂氮环丁烷基、吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、吡喃基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基、四氢吡喃基、四氢呋喃基、噁嗪基、四氢异喹啉基、苯并二氢呋喃基、十氢异喹啉基、咪唑啉基、咪唑烷基、6,7-二氢-5H-环戊烷[c]吡啶、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、
    Figure PCTCN2021137254-appb-100056
    任选地被1、2或3个选自-NR aR b、氰基、C1-C6烷基、卤素、羟基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C3-C8环烷基、C3-C8环烷基-O-、6-14元芳基、5-10元杂芳基和氰基的取代基取代。
  78. 如权利要求56至77所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，L 2为C1-C4亚烷基，R 2为6-14元芳基、5-10元含氮杂芳基或4-10元杂环基，优选为苯基、吡啶基、吡唑基、吡咯并吡啶基、吡啶并二氢呋喃基、吡啶并1,3-二氧环戊烯基或吲哚基，所述6-14元芳基、5-10元含氮杂芳基或4-10元杂环基可任选地被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代。
  79. 如权利要求56所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，
    环A为C3-C6环烷基或4-8元杂环基，所述环烷基或杂环基任选地被1、2或3个选自卤素、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基和卤代C1-C4烷氧基的取代基取代；
    X 3和X 5均为CH；
    X 4为CH 2；
    L 1为C1-C4亚烷基；
    R 1为
    Figure PCTCN2021137254-appb-100057
    L 2为C1-C4亚烷基；
    R 2为苯基、5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基或吲哚基，所述苯基、5-10元含氮杂芳基和4-10元杂环基各自任选地被1或2个选自C1-C6烷氧基、卤素、C1-C6烷基、氰基、C3-C8环烷基-O-和卤代C1-C6烷氧基的取代基取代；
    R 0为-NR 3R 4取代的C1-C4烷基；其中，R 3和R 4各自独立选自H，任选被1-6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基和任选被1、2或3个选自卤素、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、-NR aR b和羟基的取代基取代的4-8元杂环基，其中，R a和R b各自独立为H或C1-C4烷基；优选地，所述4-8元杂环基各自独立选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、
    Figure PCTCN2021137254-appb-100058
  80. 如权利要求56所述的式I化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，
    环A为C3-C6环烷基，所述环烷基任选地被1、2或3个选自卤素、C1-C4烷基和卤代C1-C4烷基的取代基取代；
    X 3和X 5均为CH；
    X 4为CH 2；
    L 1为C1-C4亚烷基；
    R 1为
    Figure PCTCN2021137254-appb-100059
    L 2为C1-C4亚烷基；
    R 2为5-10元含氮杂芳基或4-10元杂环基，优选为吡啶基、嘧啶基、吡唑基、吡咯基、咪唑基、吡嗪基、吡咯并吡啶基、吡啶并二氢呋喃基或吡啶并1,3-二氧环戊烯基或吲哚基，所述5-10元含氮杂芳基或4-10元杂环基各自任选被1或2个选自C1-C6烷氧基、C1-C6烷基、C3-C8环烷基-O-、卤代C1-C6烷氧基、卤素和氰基的取代基取代；
    R 0为-NR 3R 4取代的C1-C4烷基，其中，R 3和R 4各自独立选自H和任选被1、2、3、4、5或6个选自羟基、氰基和卤素的取代基取代的C1-C6烷基，或R 3和R 4与其所连接的氮原子一起形成任选被1、2或3个选自卤素、羟基、C1-C4烷氧基和C1-C4烷基取代的4-8元杂环基，优选地，所述4-8元杂环基选自氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、
    Figure PCTCN2021137254-appb-100060
  81. 以下化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，其特征在于，所述化合物选自：
    Figure PCTCN2021137254-appb-100061
    Figure PCTCN2021137254-appb-100062
    Figure PCTCN2021137254-appb-100063
    Figure PCTCN2021137254-appb-100064
    Figure PCTCN2021137254-appb-100065
    Figure PCTCN2021137254-appb-100066
    以及
    Figure PCTCN2021137254-appb-100067
  82. 一种药物组合物，其含有权利要求1-81中任一项所述的化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物，以及药学上可接受的载体或赋形剂。
  83. 权利要求1-81中任一项所述的化合物，或其药学上可接受的盐，或其对映异构体、非对映异构体、互变异构体、同位素取代物、溶剂化物、多晶型物、前药或代谢产物在制备用于治疗或预防WDR5介导的疾病的药物中的应用。
  84. 如权利要求83所述的应用，其特征在于，所述WDR5介导的疾病包括Kabuki综合征、以及各种实体瘤和血液肿瘤。
  85. 如权利要求83所述的应用，其特征在于，所述WDR5介导的疾病包括努南综合症、豹综合症、成神经细胞瘤、肉瘤、黑色素瘤、关节软骨瘤、胆管瘤、白血病、乳腺癌、胃肠间质瘤、组织细胞性淋巴瘤、肺癌、食道癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、肾癌、口腔癌、头癌、成神经细胞瘤、头颈的鳞状细胞癌、间变性大细胞淋巴瘤或成胶质细胞瘤，其中，白血病优选为青少年髓单核细胞白血病、人髓性单核细胞白血病，肺癌优选为非小细胞肺癌、小细胞肺癌、肺鳞癌和肺腺癌。
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