WO2024002379A1 - Compound used as wdr5 inhibitor or pharmaceutically acceptable salt thereof, and use of compound - Google Patents

Compound used as wdr5 inhibitor or pharmaceutically acceptable salt thereof, and use of compound Download PDF

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WO2024002379A1
WO2024002379A1 PCT/CN2023/105609 CN2023105609W WO2024002379A1 WO 2024002379 A1 WO2024002379 A1 WO 2024002379A1 CN 2023105609 W CN2023105609 W CN 2023105609W WO 2024002379 A1 WO2024002379 A1 WO 2024002379A1
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alkyl
alkylene
cycloalkyl
heterocycloalkyl
aryl
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Chinese (zh)
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徐福明
陈文敏
李晓光
周冠
王康华
赵倩倩
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甘李药业股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • 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
    • C07D401/10—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 aromatic rings
    • 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
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/10—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 two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D471/10—Spiro-condensed systems

Definitions

  • the invention belongs to the technical field of chemical drugs, and specifically relates to a compound with WDR5-inhibiting activity, its composition and application.
  • WDR5 is a common subunit of all six mammalian histone H3K4 methyltransferases. WDR5 has 334 amino acids and contains 7 typical WD40 repeat domains, each domain containing approximately 40 amino acids. Structural studies show that WD40 repeats to form a seven-blade propeller fold, with each blade consisting of four anti-parallel strands. This structural feature suggests that WDR5 has many exposed surfaces, allowing it to serve as an adapter for interaction with other proteins. In addition, pull-down assays indicate that WDR5 preferentially binds dimethylated histone H3K4 peptides.
  • Histone methylation plays a key role in many biological processes and is a major research topic in the field of epigenetic regulation.
  • Translocation and rearrangement of the histone H3K4 methyltransferase MLL1 gene can lead to leukemia.
  • Research shows that more than 70% of infants with leukemia carry a translocation involving chromosome 11, resulting in the fusion of the MLL1 gene with other genes.
  • MLL1 translocations are also found in approximately 10% of adult patients with acute myeloid leukemia (AML). After the MLL1 gene is rearranged, it fuses with other chaperone genes to form a fusion gene that expresses an oncogenic MLL fusion protein.
  • MLL1 alone has poor catalytic activity in H3K4 methylation and can only catalyze monomethylation; when MLL1 combines with WDR5, RbBP5, Ash2L and DPY30 to form a complex, the enzyme catalytic activity is greatly improved, especially Is the catalytic activity for H3K4me2.
  • MLL1 directly interacts with WDR5 through its C-terminal WIN motif portion, mediating the interaction of the MLL1 SET catalytic domain with other protein complexes.
  • the inhibitor OICR-9429 which specifically targets the Win site, has been reported and belongs to the collection of more traditional small molecule inhibitors that disrupt the WDR5-MLL1 interaction (Bolshan et al., 2013; Chen et al., 2018; Grebien et al., 2015 ; Li et al., 2016a; Li et al., 2016b; Senisterra et al., 2013).
  • OICR-9429 or its analogs effectively reduce the growth of the number of disease-associated cells, such as patient AML cells, MLL translocated cells, Li-Fraumeni syndrome (LFS) fibroblasts, pancreatic Ductal adenocarcinoma (PDAC), neuroblastoma cells, and myofiber-associated satellite cells.
  • LFS Li-Fraumeni syndrome
  • PDAC pancreatic Ductal adenocarcinoma
  • neuroblastoma cells and myofiber-associated satellite cells.
  • WDR5 inhibitors currently developed for WDR5 are still in preclinical stage. In the development stage, therefore, there is still a need and necessity for further research and development of more inhibitors targeting specific sites of WDR5.
  • the present invention designs and provides new compounds with more significant inhibitory activity against WDR5 and considerable pharmaceutical properties.
  • the present invention provides a compound having the structural formula shown in formula I0 or a pharmaceutically acceptable salt thereof,
  • R 1A is an unsubstituted or substituted 3-15-membered heterocycloalkyl group containing at least one nitrogen atom, and the 3-15-membered heterocycloalkyl group is a monocyclic heterocycloalkyl group or a fused-ring heterocycloalkyl group.
  • spirocyclic heterocycloalkyl or bridged heterocycloalkyl the substituted 3-15 membered heterocycloalkyl containing at least one nitrogen atom is selected from one, two, three or more of the following Substituent substitution: halogen, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR 9 , -SR 9 , alkylene- OR 9 , alkylene-SR 9 , -NR 10 R 11 , alkylene-CR 9 R 10 R 11 and alkylene-NR 10 R 11 , wherein optionally, the alkyl, heteroalkyl, Alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylene, aryl, and heteroaryl are each independently selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy,
  • R 2A is an unsubstituted or substituted aryl, heteroaryl or heterocycloalkyl group, each of the heteroaryl or heterocycloalkyl groups independently contains 1, 2 or 3 atoms each independently selected from N, O or S optionally, the unsubstituted or substituted aryl and heteroaryl groups are each independently fused to the heterocycloalkyl or cycloalkyl group, and the substituted aryl, heteroaryl and heterocyclic
  • R 3A is an unsubstituted or substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl group
  • the unsubstituted or substituted cycloalkyl and heterocycloalkyl groups are each independently a monocyclic or condensed ring , bridged ring, or spirocyclic group group
  • the unsubstituted or substituted aryl group and heteroaryl group are each independently a monocyclic or condensed ring group
  • the unsubstituted or substituted aryl group and heteroaryl group are each independently condensed and for heterocycloalkyl or cycloalkyl
  • R 9 and R 12 is independently selected from H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, -C(O)alkyl, -C(O)haloalkyl, -C( O)O alkyl, -C(O)NH alkyl, -SO 2 alkyl, -SO 2 HN alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl and C 1-6 alkylene cycloalkyl, optionally, the alkyl, ring Alkyl, heterocycloalkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene aryl, C 1-6 alkylene heteroaryl, C 1-6 alkylene Heterocycloalkyl and C 1-6 alkylenecycloalkyl are each independently selected from halogen,
  • R 10 , R 11 , R 13 , and R 14 is independently selected from H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, -C(O)alkyl, -C(O )Haloalkyl, -C(O)O alkyl, -C(O)NH alkyl, -SO 2 alkyl, -SO 2 HN alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene aryl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl and C 1-6 alkylene cycloalkyl, optionally, the alkyl Base, cycloalkyl, heterocycloalkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene aryl, C 1-6 alkylene heteroaryl, C 1-6 Alkyleneheterocycloalkyl and C 1-6 alkylenecycloalkyl,
  • R 15 is independently selected from H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, -C(O)alkyl, -C(O)haloalkyl, -C(O)O Alkyl, -C(O)NH alkyl, -SO 2 alkyl, -SO 2 HN alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene aryl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl and C 1-6 alkylene cycloalkyl, optionally, the alkyl, cycloalkyl, heterocycloalkyl , C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene aryl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl and C 1 -6 alkylenecycloalkyl groups are each independently selected from halogen, alkyl,
  • R 16 and R 17 are each independently selected from H, alkyl, haloalkyl, -C(O)alkyl, -C(O)haloalkyl, -C(O)aryl, -C(O)cycloalkyl , -C(O)heteroaryl, -C(O)heterocycloalkyl, -C(O)Oalkyl, -C(O)Ohaloalkyl, -C(O)Oaryl, -C( O)O cycloalkyl, -C(O)O heteroaryl, -C(O)O heterocycloalkyl, -C(O)NH alkyl, -C(O)NHC 1-6 haloalkyl, - C(O)NH aryl, -C(O)NH cycloalkyl, -C(O)NH heteroaryl, -C(O)NH heterocycloalkyl, -SO 2 alkyl,
  • Cycloalkyl or cycloalkyl, the 3-10 membered heterocycloalkyl and cycloalkyl are unsubstituted or independently selected from one or more halogen, -CN, nitro, -OR 18 , -SR 18 , -NR 19 R 20 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 hydroxyalkyl, -C(O)R 18 , -C(O)OR 18 , -C( O)N R 19 R 20 , -S(O)C 1-6 alkyl, -SO 2 C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl base, 3-15 membered heterocycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene heteroaryl , C 1-6 alkylene R 18 , C 1-6 alkylene OR
  • R 18 is selected from H, alkyl, C 1-6 haloalkyl, -C(O) alkyl, -C(O) haloalkyl, cycloalkyl, 3-heterocycloalkyl, aryl, heteroaryl, ylidene Alkylaryl, alkyleneheteroaryl, alkylenecycloalkyl and alkyleneheterocycloalkyl, optionally, the alkyl, C 1-6 haloalkyl, -C(O)alkyl , -C(O)haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylenearyl, alkyleneheteroaryl, alkylenecycloalkyl and alkyleneheterocycle
  • Each alkyl group is independently selected from one or more halogen, -CN, alkyl, haloalkyl, -OH, -SH, alkoxy, -O halo
  • R 19 and R 20 are each independently selected from H, alkyl, haloalkyl, -C(O)alkyl, -C(O)fluoroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl , alkylene aryl, alkylenecycloalkyl, alkyleneheteroaryl, alkyleneheterocycloalkyl, -C(O)aryl, -C(O)cycloalkyl, -C(O )Heteroaryl, -C(O)heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)OC 1-6 haloalkyl, -C(O)OC 6-10 aryl , -C(O)OC 3-10 cycloalkyl, -C(O)OC 4-10 heteroaryl, -C(O)OC 3-15 heterocycloalkyl, -C(O)NH alkyl,
  • R 21 is selected from H, hydroxyl, amino, alkyl, alkoxy and halogen.
  • R 1A is an unsubstituted or substituted 3-15-membered heterocycloalkyl group containing at least one nitrogen atom
  • the 3-15-membered heterocycloalkyl group is a monoheterocycloalkyl group, a fused ring heterocycloalkyl group, or a spiro ring Heterocycloalkyl or bridged heterocycloalkyl
  • the substituted 3-15 membered heterocycloalkyl containing at least one nitrogen atom is substituted with one, two, three or more substituents selected from the following : Halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, C 3- 10 heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OR 9 , -SR 9 , C 1-6 alkylene -OR 9
  • R 3A is an unsubstituted or substituted 6- to 14-membered aryl group, a 5- to 14-membered heteroaryl group, a 3- to 15-membered cycloalkyl group, or a 3 to 15-membered heterocycloalkyl group, and the unsubstituted or substituted 3A
  • To 15-membered cycloalkyl and 3 to 15-membered heterocycloalkyl are each independently a monocyclic, fused ring, bridged ring, or spirocyclic group
  • the unsubstituted or substituted 6 to 14-membered aryl and 5 to 14-membered heteroaryl groups are each independently a monocyclic or fused ring group, optionally, the unsubstituted or substituted 6- to 14-membered aryl groups and 5- to 14-membered heteroaryl groups are each independently fused to 3-6 membered heterocycloalkyl or 3-6 membered cyclo
  • R 10 , R 11 , R 13 , and R 14 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered hetero Cycloalkyl, -C(O)C 1-6 alkyl, -C(O)C 1-6 haloalkyl, -C(O)OC 1-6 alkyl, -C(O)NHC 1-6 alkyl base, -SO 2 C 1-6 alkyl, -SO 2 HNC 1-6 alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene heterocycloalkyl and C 1-6 alkylene C 3- cycloalkyl, optionally, the C 1- 6 alkyl, C 3-10 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkylene OC 1-6 alky
  • the nitrogen atoms or C atoms together form a 3-6 membered heterocycloalkyl or cycloalkyl group that is unsubstituted or is one or more independently selected from halogen, -CN, nitro, -OR 18 , -SR 18 , -NR 19 R 20 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 hydroxyalkyl, -C(O)R 18 , -C(O)OR 18 , -C(O)N R 19 R 20 , -S(O)C 1-6 alkyl, -SO 2 C 1-6 alkyl, C 6-10 aryl, 5- 10-membered heteroaryl, C 3-10 cycloalkyl, 3-10-membered heterocycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 3-10 cycloalkyl group, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene R 18 , C
  • R 19 and R 20 are each independently selected from H, C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O)C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl Base, C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkylene, C 6-10 aryl, C 1 -6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene C 3-15 heterocycloalkyl, -C(O)C 6-10 aryl, -C(O)C 3-10 cycloalkyl, -C(O)C 4-10 heteroaryl, -C(O)C 3-15 heterocycloalkyl, -C(O )OC 1-6 alkyl, -C(O)OC 1-6 fluoroalkyl, -C(O)OC 6-10
  • R 1A is an unsubstituted or substituted 4-10-membered heterocycloalkyl group containing at least one nitrogen atom, and the 4-10-membered heterocycloalkyl group is a monocyclic heterocycloalkyl group, a condensed ring heterocycloalkyl group, or a spiro group.
  • Cyclic heterocycloalkyl or bridged cyclic heterocycloalkyl the substituted 4-10 membered heterocycloalkyl containing at least one nitrogen atom is selected from one, two, three or more substituents below Substitution: F, Cl, Br, I,, C 1-3 alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, OR 9 , -SR 9 , C 1-3 alkylene OH, C 1-3 alkylene -CR 9 R 10 R 11 , -NR 10 R 11 , and C 1-3 alkylene NR 10 R 11 , wherein, optionally, The C 1-3 alkyl group, C 1-3 fluoroalkyl group, C 3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C 1-3 alkylene OH, C 1-3 alkylene group -CR 9 R 10 R 11 and C 1-3 alkylene NR 10 R 11 , each
  • the substituted 4-10-membered heterocycloalkyl group containing at least one nitrogen atom is selected from one, two, three or More substituents: F, Cl, Br, I, methyl, ethyl, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclobutylmethylene, cyclopentyl, cyclopentylmethylene, cyclohexyl, cyclohexylmethylene, methoxy, amino , and hydroxyl; preferably, the R 1A is selected from the following groups that are unsubstituted or substituted by one or more substituents:
  • the substituent is selected from F, Cl, Br, I, C 1-3 alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, OR 9 , - SR 9 , C 1-3 alkylene OH, C 1-3 alkylene -CR 9 R 10 R 11 , -NR 10 R 11 , and C 1-3 alkylene NR 10 R 11 , wherein optionally Ground, the C 1-3 alkyl group, C 1-3 fluoroalkyl group, C 3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C 1-3 alkylene OH, C 1-3 alkylene group Alkyl-CR 9 R 10 R 11 and C 1-3 alkylene NR 10 R 11 , each independently selected from F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy , C 1-3 halogenated Alkyl, hydroxyl, C 1-3 hydroxyalkyl, cyan
  • the substituent is selected from: F, Cl, Br, I, methyl, ethyl, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclobutylmethylene, cyclopentyl, cyclopentylmethylene, cyclohexyl, cyclohexylmethylene, methoxy, amino , and hydroxyl; wherein, R 9 , R 10 , and R 11 are as defined in claim 1 or 2.
  • R 9 is independently selected from H, C 1-3 alkyl, C 1- 3- fluoroalkyl, -C(O)C 1-3 alkyl, C(O)C 1-3 fluoroalkyl, C 3-6 cycloalkyl, and 3-6 membered heterocycloalkyl;
  • R 10 and Each occurrence of R 11 is independently selected from H, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C(O)C 1-3 alkyl, -C(O)C 1-3 haloalkyl, -C(O)OC 1-3 alkyl, -C(O)NHC 1-3 alkyl, C 1-6 alkylene C 3-6 heterocycloalkyl and C 1-6 alkylene C 3-6 cycloalkyl, or R 10 and R 11 together with the C or N atom to which they are attached independently form unsubstituted or substituted by one or more
  • each occurrence of R 5A is independently selected from F, Cl, Br, I, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-3 alkoxy and Amino groups are preferably each independently selected from F, Cl, Br, I, methyl, difluoromethyl, trifluoromethyl, fluoromethyl, methoxy and amino; each occurrence of n is independently 0 , 1, 2 or 3; and/or
  • R 15 , R 16 , R 17 , and R 4A are as defined in claim 1 or 2.
  • R 15 is selected from H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O) C 1-6 alkyl, and C(O)C 1-6 fluoroalkyl
  • the C 1-6 alkyl is selected from F, Cl, Br, I, C 1 -C 3 alkoxy
  • R 16 and R 17 are each independently selected from H, C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O)C 1-6 alkyl, -C(O )C 1-6 fluoroalkyl, -C(O)C 6-10 aryl, -C(O)C 3-10
  • the attached nitrogen atoms or C atoms together form a 3-6 membered heterocycloalkyl or cycloalkyl group that is unsubstituted or is independently selected from one or more Halogen, -CN, -OH, -SH, -OC 1-3 alkyl, amino, C 1-3 alkyl, -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , NHC ( O)C 1-3 , C 1-3 haloalkyl, C 1-3 hydroxyalkyl, -C(O)H, -C(O)C 1-3 alkyl, -C(O)OH, -C (O)O C 1-3 alkyl, -C(O)NH 2 , -C(O)NHC 1-3 alkyl, -C(O)N(C 1-3 alkyl) 2 , C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, 3-6 membered heterocyclo
  • the aryl groups are each independently a monocyclic or condensed ring group, and the 4- to 15-membered heterocycloalkyl and 5-10-membered heteroaryl groups each independently contain 1, 2 or 3 independently selected from N, O, and heteroatoms of S; preferably, R 4A is selected from unsubstituted or by one or more independently selected from F, -CH 3 , -C 2 H 5 , -OH, -OCH 3 , -C(O) CH 3 , -NH 2 , -C(O)NHCH 3 , -COOH, -NH(CH 3 ) 2 , -C(O)N(CH 3 ) 2 , -CN and -CF 3 substituents substituted C 3-10 cycloalkyl, 4-15 membered heterocycloalkyl, 5-10 membered heteroaryl and C 6-10 aryl, the C 3-10 The cycloalkyl group and the 4- to 15-membered heterocycloalkyl
  • R 1A is selected from the following groups:
  • R 2A is selected from the following groups:
  • R 4A is selected from the following groups
  • the present invention also provides a compound having the structural formula shown in Formula I or a pharmaceutically acceptable salt thereof,
  • R 1 is a heterocycloalkyl group containing at least one nitrogen atom, and the heterocycloalkyl group is unsubstituted or substituted by one or more halogen, C 1-6 alkyl, C 1-6 fluoroalkyl , C 1-6 alkylene C 3-10 cycloalkyl and C 3-10 cycloalkyl substituents are substituted;
  • R 2 is a C 6-10 aryl group that is unsubstituted or substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 fluoroalkyl, hydroxyl, and alkoxy;
  • R 3 is an aryl group that is unsubstituted or optionally substituted with one, two or more substituents independently selected from halogen, carboxyl, amide, alkyl, alkylamino, haloalkyl and cyano, 4 to 15 One-membered cycloalkyl, or 4 to 15-membered heterocycloalkyl with 1-2 N, O or S heteroatoms;
  • R 4 is absent, or is unsubstituted or optionally substituted with one, two or more substituents independently selected from halogen, carboxyl, alkyl, alkylamino, haloalkyl and cyano having 1-2 Any of 4 to 15 membered heterocycloalkyl groups with N, O, or S heteroatoms; and
  • R 23 is selected from H and halogen. Preferably, R 23 is selected from H and F.
  • R 1 is selected from
  • R 2 is selected from
  • R 3 is unsubstituted or substituted by one or more A three-membered ternary substituted group selected from halogen, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene, C 3-10 cycloalkyl and C 3-10 cycloalkyl.
  • Monocyclic alkyl four-membered monocyclic alkyl, five-membered monocyclic alkyl, six-membered monocyclic alkyl, seven-membered spirocycloalkyl, eight-membered spirocycloalkyl, nine-membered spirocycloalkyl, ten-membered spiro Cycloalkyl, eleven-membered spirocycloalkane, nine-membered fused cycloalkyl or ten-membered fused cycloalkyl, seven-membered bridged cycloalkyl, eight-membered bridged cycloalkyl, nine-membered bridged cycloalkyl, ten-membered bridged ring Alkyl, and eleven-membered bridged cycloalkane; the bridged cycloalkyl is preferably
  • R 3 is selected from unsubstituted or optionally selected from halogen, carboxyl, amide, alkyl, alkylamino, haloalkyl or cyano by one, two or more The following groups are substituted by the substituents of the group:
  • R 3 is unsubstituted or heteroatom H is substituted by halogen, carboxyl, amide, alkyl, alkylamino, haloalkyl or cyano.
  • R 4 is unsubstituted or optionally substituted by one, two or more independently selected from halogen, carboxyl, alkyl, alkylamino, haloalkyl or cyano. replaced
  • R 4 is a substituted heterocycloalkyl group
  • the heterocycloalkyl group is selected from The substituent group is attached to the heteroatom; preferably, the substituent group is selected from -F, -CH 3 , -OCH 3 , -NH 2 , -COOH, Either -CN or -CF 3 .
  • R 4 is a cycloalkyl or heterocycloalkyl group
  • the R 3 is a C 6-10 aryl group, preferably a phenyl group
  • the R 4 is connected to the aryl group The para or meta position of the carbon atom connecting the alkynyl group.
  • the present invention also provides a compound having the structural formula shown in Formula II or a pharmaceutically acceptable salt thereof,
  • R 6 is an aryl group that is unsubstituted or optionally substituted with one, two or more substituents independently selected from halogen, carboxyl, alkyl, alkylamino, haloalkyl or cyano, 4 to 15 yuan. Cycloalkyl, or 4 to 15 membered heterocycloalkyl with 1-2 N, O or S heteroatoms;
  • R 7 is absent, alternatively, selected from H, amide, cyano, or unsubstituted or optionally modified by one, 4- to 15-membered heterocycloalkyl groups having 1-2 N, O or S heteroatoms substituted by two or more substituents independently selected from halogen, carboxyl, alkyl, alkylamino, haloalkyl and cyano any of;
  • R 7 is C 1-6 alkylene C 3-10 heterocycloalkyl, which is unsubstituted or optionally modified by one, two or more independently selected from halogen, carboxyl, alkyl , alkylamino, haloalkyl and cyano substituents; preferably, R 7 is C 1-3 alkylene C 5-8 heterocycloalkyl, and the heterocycloalkyl has 1 to 3 independent choices. Heteroatoms from N, O and S;
  • R 8 is a heterocycloalkyl group containing two nitrogen atoms, which is unsubstituted or substituted by one or more selected from halogen, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene C 3-10 cycloalkyl and C 3-10 cycloalkyl substituents are substituted;
  • R 8 is a 4 to 15 membered heterocycloalkyl group having 1 to 2 heteroatoms independently selected from N, O, and S, which heterocycloalkyl group is unsubstituted or substituted by one or more heteroatoms selected from halogen , C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene, C 3-10 cycloalkyl and C 3-10 cycloalkyl substituents, preferably, R 8 has 1-2 5 to 8-membered heterocycloalkyl groups of heteroatoms that are independently N or O, the heterocycloalkyl group is unsubstituted or substituted by one or more selected from halogen, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-3 alkylene, C 3-6 cycloalkyl and C 3-6 cycloalkyl substituents; and
  • R 22 is selected from H, halogen, amide, cyano or haloalkyl.
  • R 23 is selected from H, F, Cl, Br and I.
  • R 8 is selected from any of them.
  • R 6 is unsubstituted or optionally substituted by one, two or more independently selected from halogen, carboxyl, alkyl, alkylamino, haloalkyl or cyano. replaced
  • R 6 is unsubstituted or heteroatom H is substituted by halogen, carboxyl, alkyl, alkylamino, haloalkyl or cyano.
  • R 7 is selected from Any heterocycloalkyl group in .
  • R 7 is a heteroatom H substituted
  • the substituent group is selected from -F, -CH 3 , -OCH 3 , -NH 2 , -COOH, Either -CN or -CF 3 .
  • R 7 is a cycloalkyl or heterocycloalkyl group
  • the R 6 is a C 6-10 aryl group, preferably a phenyl group
  • the R 7 is connected to the aryl group The para or meta position of the carbon atom connecting the alkynyl group.
  • the present invention also provides a pharmaceutical composition, which is characterized by comprising a compound as described in any one of the above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or auxiliary material.
  • the present invention also provides the use of a compound as described above or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above in the preparation of a medicament for the treatment or prevention of diseases or conditions mediated by WDR5; preferably
  • the WDR5-mediated disease or condition is cancer; preferably, the cancer is selected from the group consisting of leukemia; preferably, the cancer is selected from the group consisting of acute promyelocytic leukemia, acute myeloid leukemia, acute myeloid leukemia (AML) and acute myelogenous leukemia. Nuclear cell leukemia.
  • the present invention also provides a compound as described above or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above, which is used to treat or prevent diseases or disorders mediated by WDR5; preferably, the disease or disorder is Cancer; preferably, the cancer is selected from the group consisting of leukemia; preferably, the cancer is selected from the group consisting of acute promyelocytic leukemia, acute myeloid leukemia, acute myeloid leukemia (AML), and acute monocytic leukemia.
  • the disease or disorder is Cancer
  • the cancer is selected from the group consisting of leukemia; preferably, the cancer is selected from the group consisting of acute promyelocytic leukemia, acute myeloid leukemia, acute myeloid leukemia (AML), and acute monocytic leukemia.
  • the present invention also provides a method for treating or preventing diseases or conditions mediated by WDR5, comprising administering to a subject in need a therapeutically effective amount of a compound as described above or a pharmaceutically acceptable salt thereof or as described above.
  • Pharmaceutical composition Preferably, the disease or condition is cancer; Preferably, the cancer is selected from leukemia; Preferably, the cancer is selected from acute promyelocytic leukemia, acute myelogenous leukemia, acute myeloid leukemia ( AML) and acute monocytic leukemia.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably from 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -two Methylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methyl Hexyl, 3-methylhexyl, 4-methylhexyl
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably independently selected from H atoms, D atoms, halogens, alkyl Substituted with one or more substituents of base, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
  • heteroalkyl refers to an alkyl group in which one or more -CH2 -s are substituted with heteroatoms selected from NH, O and S or one or more -CH-s are substituted with N atoms; wherein Alkyl is as defined above; heteroalkyl may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, said substituents being preferably independently optionally selected from H atoms , one or more of D atom, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl substituted by substituents.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl or cycloalkyl is as defined herein.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from H atoms, D atoms, halogens, alkyl groups, alkoxy groups , substituted by one or more substituents of haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
  • alkynyl refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, where alkyl is as defined above.
  • the alkynyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyl groups, hydroxyl groups, Substituted with one or more substituents of hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g. 3, 4, 5, 6, 7 and 8) carbon atoms, more preferably containing 4 to 7 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, Cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.
  • Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably independently selected from the group consisting of hydrogen atoms, halogens, alkyl groups, Substituted with one or more substituents from alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
  • heterocycloalkyl refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O)m( where m is an integer from 0 to 2) heteroatoms, but does not include the ring part of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon.
  • 1 to 4 eg 1, 2, 3 and 4
  • 1 to 4 eg 1, 2, 3 and 4
  • 3 to 8 ring atoms of which 1 to 3 are heteroatoms
  • Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl , homopiperazinyl, etc.
  • Heterocycloalkyl may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently selected from hydrogen atoms, halogens, alkyl groups , alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl substituted by one or more substituents.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group having a conjugated ⁇ electron system, preferably 6 to 10 members , such as phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably independently selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkyl groups, Substituted with one or more substituents of oxygen, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 (eg, 1, 2, 3, and 4) heteroatoms, and from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • the heteroaryl group is preferably 5 to 10 yuan (such as 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.
  • the heteroaryl ring includes a heteroaryl group as described above fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.
  • Heteroaryl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, which substituents are preferably independently selected from the group consisting of hydrogen atoms, halogens, alkyl groups, Substituted with one or more substituents from alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxyl groups, where alkyl is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance does or does not occur.
  • optionally substituted cyclopropyl means that the cyclopropyl group may but need not be substituted, and this description includes both the case where the cyclopropyl group is substituted and the case where the cyclopropyl group is unsubstituted.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art is able to determine possible or impossible substitutions without undue effort (either experimentally or theoretically).
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present disclosure, which are safe and effective when used in mammals, and have due biological activity.
  • Step 5 Synthesis of 5-((4-fluorophenyl)ethynyl)-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)aniline
  • Step 2 Synthesis of methyl 4-(difluoromethyl)-6-methoxynicotinate
  • the cell line MV4-11 used in the present invention was purchased from ATCC, product number CRL-9591; the cell line MOLM-13 was purchased from Kebai Biotech, product number CBP60678; the cell line HL60 was purchased from ATCC, product number CCL-240.
  • the 5-FAM label probe and WDR5 protein used in the FP test were synthesized by GenScript. Dilute the probe stock solution to 5nM with phosphate buffer and add 50 ⁇ l per well to a black 96-well plate; at the same time, dilute the WDR5 protein to 25nM with phosphate buffer and add 50 ⁇ l per well into a black 96-well plate. After diluting the test compound with DMSO to 100 ⁇ M, it was gradually diluted with phosphate buffer to prepare a 12 concentration gradient series with the highest concentration of 1 ⁇ M, and 25 ⁇ l per well was added to a black 96-well plate. After incubation on a room temperature shaker in the dark for 30 minutes, a multifunctional microplate reader was used for measurement, with an excitation wavelength of 485 nm and a detection wavelength of 535 nm.
  • Cells were seeded (MV4-11 cells or MOLM-13 cells at 7500 cells/well; HL60 cells at 12500 cells/well) into 96-well plates in 180 ⁇ l of culture medium (IMDM containing 10% FBS, Gibco), each After adding 20 ⁇ l of culture medium containing test compounds at different concentrations to the wells (ten concentration ranges with final concentrations ranging from 0 to 100 ⁇ M), the cells were cultured in a humidified incubator at 37°C and 5% CO for four days.
  • IMDM 10% FBS, Gibco
  • the compounds of Examples 1-115 provided by the present invention have higher or equivalent affinity to WDR5 than positive drugs, and the detection results in MV4-11, MOLM-13 and HL60 cell lines are also It shows that the compounds provided by the present invention have higher or equivalent inhibitory activity on WDR5 compared with positive drugs.

Abstract

Provided are a compound used as a WDR5 inhibitor or a pharmaceutically acceptable salt thereof, and a use of the compound in preparation of a drug. The compound has high affinity to WDR5, and compared with the prior art, has higher inhibitory activity.

Description

一种用作WDR5抑制剂的化合物或其可药用盐及其应用A compound used as a WDR5 inhibitor or a pharmaceutically acceptable salt thereof and applications thereof 技术领域Technical field
本发明属于化学药物技术领域，具体涉及一种具有抑制WDR5活性的化合物，及其组合物和应用。The invention belongs to the technical field of chemical drugs, and specifically relates to a compound with WDR5-inhibiting activity, its composition and application.
背景技术Background technique
WDR5是所有六种哺乳动物组蛋白H3K4甲基转移酶的共同亚基。WDR5具有334个氨基酸并含有7个典型的WD40重复结构域，每个结构域含有约40个氨基酸。结构研究表明WD40重复形成七叶片螺旋桨折叠，每个叶片由四股反平行片组成。这种结构特性表明WDR5具有许多暴露表面，使其能够成为与其它蛋白质相互作用的衔接子。此外，下拉实验(Pull-down assay)表明WDR5优选结合二甲基化组蛋白H3K4肽。WDR5 is a common subunit of all six mammalian histone H3K4 methyltransferases. WDR5 has 334 amino acids and contains 7 typical WD40 repeat domains, each domain containing approximately 40 amino acids. Structural studies show that WD40 repeats to form a seven-blade propeller fold, with each blade consisting of four anti-parallel strands. This structural feature suggests that WDR5 has many exposed surfaces, allowing it to serve as an adapter for interaction with other proteins. In addition, pull-down assays indicate that WDR5 preferentially binds dimethylated histone H3K4 peptides.
组蛋白甲基化在许多生物学过程中起关键作用，是表观遗传调控领域的主要研究内容。组蛋白H3K4的甲基转移酶MLL1基因易位重排会导致白血病。研究表明，超过70％的婴儿白血病患者携带涉及11号染色体的易位，导致MLL1基因与其它基因的融合。大约10％的成人急性髓性白血病(AML)患者中也发现了MLL1易位。MLL1基因重排后，与其他伴侣蛋白基因发生融合，形成融合基因，表达具有致癌作用的MLL融合蛋白。由MLL1异常引起的白血病的治疗常规化疗不理想，预后不良，目前也尚无靶向药物，所以迫切需要针对该疾病的生物学性质开发新的治疗药物。研究表明，MLL1的染色体易位只发生在单等位基因上，因而，同时还存在一个野生型的MLL1。研究发现，如果敲除野生型MLL1等位基因，单独的MLL融合蛋白是不能导致白血病的，说明野生型MLL1的酶催化活性对MLL1融合蛋白诱发白血病生成是必需的。因此，若能够特异性地抑制野生型MLL1的酶催化活性或能实现治疗白血病的目的。现有研究还发现，MLL1单独催化H3K4甲基化活性很差，并且仅能催化单甲基化；而当MLL1结合WDR5、RbBP5、Ash2L和DPY30形成复合物时，酶催化活性则大大提升，尤其是对H3K4me2的催化活性。MLL1通过其C-端WIN motif部分与WDR5直接相互作用，介导MLL1 SET催化域与其他蛋白复合物相互作用。有研究者在敲除WDR5后，发现H3K4me2/3水平下降，Hox基因的表达下调。因此，利用小分子抑制剂干扰MLL1-WDR5的蛋白-蛋白相互作用是抑制MLL1的酶催化活性、下调Hox和Meis-1基因表达、进而阻断白血病进展的一种有效手段。Histone methylation plays a key role in many biological processes and is a major research topic in the field of epigenetic regulation. Translocation and rearrangement of the histone H3K4 methyltransferase MLL1 gene can lead to leukemia. Research shows that more than 70% of infants with leukemia carry a translocation involving chromosome 11, resulting in the fusion of the MLL1 gene with other genes. MLL1 translocations are also found in approximately 10% of adult patients with acute myeloid leukemia (AML). After the MLL1 gene is rearranged, it fuses with other chaperone genes to form a fusion gene that expresses an oncogenic MLL fusion protein. Conventional chemotherapy for the treatment of leukemia caused by MLL1 abnormalities is not ideal and the prognosis is poor. There are currently no targeted drugs, so there is an urgent need to develop new therapeutic drugs based on the biological properties of the disease. Studies have shown that chromosomal translocation of MLL1 only occurs on a single allele, therefore, there is also a wild-type MLL1. The study found that if the wild-type MLL1 allele is knocked out, the MLL fusion protein alone cannot cause leukemia, indicating that the enzymatic activity of wild-type MLL1 is necessary for the MLL1 fusion protein to induce leukemia. Therefore, if the enzymatic activity of wild-type MLL1 can be specifically inhibited, the purpose of treating leukemia may be achieved. Existing studies have also found that MLL1 alone has poor catalytic activity in H3K4 methylation and can only catalyze monomethylation; when MLL1 combines with WDR5, RbBP5, Ash2L and DPY30 to form a complex, the enzyme catalytic activity is greatly improved, especially Is the catalytic activity for H3K4me2. MLL1 directly interacts with WDR5 through its C-terminal WIN motif portion, mediating the interaction of the MLL1 SET catalytic domain with other protein complexes. After knocking out WDR5, some researchers found that H3K4me2/3 levels decreased and the expression of Hox genes was downregulated. Therefore, using small molecule inhibitors to interfere with the protein-protein interaction of MLL1-WDR5 is an effective means to inhibit the enzymatic activity of MLL1, downregulate the expression of Hox and Meis-1 genes, and thereby block the progression of leukemia.
已报道特异性针对Win位点的抑制剂OICR-9429，属于破坏WDR5-MLL1相互作用的更加传统的小分子抑制剂的集合(Bolshan等人，2013；Chen等人，2018；Grebien等人，2015；Li等人，2016a；Li等人，2016b；Senisterra等人，2013)。OICR-9429是有效的(Kd＝30nM)且选择性的WDR5化学探针。最近的研究已表明OICR-9429或其类似物有效降低疾病相关细胞的数量的增长，所述细胞例如患者AML细胞、MLL易位细胞、李-法美尼综合征(LFS)成纤维细胞、胰腺导管腺癌(PDAC),神经母细胞瘤细胞、和肌纤维相关卫星细胞。在US20180086767A1中也公开了二氢-5H-吡咯并[1,2-c]咪唑已作为新型WDR5抑制剂。但当前针对WDR5开发的抑制剂，仍处于临床前 开发阶段，因而，当前仍有需要和必要进一步研究开发更多针对WDR5特定位点的抑制剂。The inhibitor OICR-9429, which specifically targets the Win site, has been reported and belongs to the collection of more traditional small molecule inhibitors that disrupt the WDR5-MLL1 interaction (Bolshan et al., 2013; Chen et al., 2018; Grebien et al., 2015 ; Li et al., 2016a; Li et al., 2016b; Senisterra et al., 2013). OICR-9429 is a potent (K d =30 nM) and selective WDR5 chemical probe. Recent studies have shown that OICR-9429 or its analogs effectively reduce the growth of the number of disease-associated cells, such as patient AML cells, MLL translocated cells, Li-Fraumeni syndrome (LFS) fibroblasts, pancreatic Ductal adenocarcinoma (PDAC), neuroblastoma cells, and myofiber-associated satellite cells. It is also disclosed in US20180086767A1 that dihydro-5H-pyrrolo[1,2-c]imidazole has been used as a new WDR5 inhibitor. However, the inhibitors currently developed for WDR5 are still in preclinical stage. In the development stage, therefore, there is still a need and necessity for further research and development of more inhibitors targeting specific sites of WDR5.
发明内容Contents of the invention
针对现有技术对抑制WDR5特定位点的需求，本发明设计并提供了对WDR5具有更显著的抑制活性、且具有相当成药性的新型化合物。In response to the existing technology's demand for inhibiting specific sites of WDR5, the present invention designs and provides new compounds with more significant inhibitory activity against WDR5 and considerable pharmaceutical properties.
本发明一方面提供了一种具有式Ⅰ0所示结构式的化合物或其可药用盐，
In one aspect, the present invention provides a compound having the structural formula shown in formula I0 or a pharmaceutically acceptable salt thereof,
其中，R1A是未取代的或取代的含有至少一个氮原子的3-15元杂环烷基，所述3-15元杂环烷基为单环杂环烷基、稠环杂环烷基、螺环杂环烷基或桥环杂环烷基，所述取代的含有至少一个氮原子的3-15元杂环烷基被选自下述的一个、两个、三个或更多个取代基取代：卤素、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、-OR9、-SR9、亚烷基-OR9、亚烷基-SR9、-NR10R11、亚烷基-CR9R10R11和亚烷基-NR10R11，其中任选地，所述烷基、杂烷基、烯基、炔基、环烷基、杂环烷基、亚烷基、芳基、和杂芳基各自独立地被选自卤素、烷基、杂烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、烯基、炔基、烷基氨基、烷基酰基、烷基氧基酰基、烷基氨基酰基、芳基和杂芳基中的一个或多个取代基所取代；Wherein, R 1A is an unsubstituted or substituted 3-15-membered heterocycloalkyl group containing at least one nitrogen atom, and the 3-15-membered heterocycloalkyl group is a monocyclic heterocycloalkyl group or a fused-ring heterocycloalkyl group. , spirocyclic heterocycloalkyl or bridged heterocycloalkyl, the substituted 3-15 membered heterocycloalkyl containing at least one nitrogen atom is selected from one, two, three or more of the following Substituent substitution: halogen, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR 9 , -SR 9 , alkylene- OR 9 , alkylene-SR 9 , -NR 10 R 11 , alkylene-CR 9 R 10 R 11 and alkylene-NR 10 R 11 , wherein optionally, the alkyl, heteroalkyl, Alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylene, aryl, and heteroaryl are each independently selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, Hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and hetero Substituted by one or more substituents in the aryl group;
R2A是未取代的或取代的芳基、杂芳基或杂环烷基，所述杂芳基或杂环烷基各自独立地含有1、2或3个各自独立选自N、O或S的杂原子，任选地，所述未取代的或取代的芳基和杂芳基各自独立地稠和于杂环烷基或环烷基，所述取代的芳基、杂芳基和杂环烷基各自独立地被选自下述的一个、两个、三个、四个或更多个取代基取代：卤素、＝O、＝S、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、-OR12、-SR12、亚烷基-OR12、亚烷基-SR12、-NR13R14、亚烷基-CR12R13R14和亚烷基-NR13R14，其中任选地，所述烷基、杂烷基、烯基、炔基、环烷基、杂环烷基、亚烷基、芳基、和杂芳基各自独立地被选自卤素、烷基、杂烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、烯基、炔基、烷基氨基、烷基酰基、烷基氧基酰基、烷基氨基酰基、芳基和杂芳基中的一个或多个取代基所取代；R 2A is an unsubstituted or substituted aryl, heteroaryl or heterocycloalkyl group, each of the heteroaryl or heterocycloalkyl groups independently contains 1, 2 or 3 atoms each independently selected from N, O or S optionally, the unsubstituted or substituted aryl and heteroaryl groups are each independently fused to the heterocycloalkyl or cycloalkyl group, and the substituted aryl, heteroaryl and heterocyclic Each alkyl group is independently substituted with one, two, three, four or more substituents selected from the following: halogen, =O, =S, alkyl, haloalkyl, heteroalkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR 12 , -SR 12 , alkylene -OR 12 , alkylene -SR 12 , -NR 13 R 14 , alkylene -CR 12 R 13 R 14 and alkylene -NR 13 R 14 , wherein optionally, the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylene, Aryl, and heteroaryl are each independently selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl Substituted with one or more substituents from alkyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl;
R3A是未取代的或取代的芳基、杂芳基、环烷基或杂环烷基，所述未取代的或取代的环烷基和杂环烷基各自独立地为单环、稠环、桥环、或螺环基 团，所述未取代的或取代的芳基和杂芳基各自独立地为单环或稠环基团，任选地，所述未取代的或取代的芳基和杂芳基各自独立地稠和于杂环烷基或环烷基，任选地，所述取代的芳基、杂芳基、环烷基和杂环烷基各自独立地被选自下述的一个或更多个取代基取代：卤素、-CN、烷基、杂烷基、烯基、炔基、卤代烷基、＝O、＝S、OR15、-SR15、-SO2R15、-NR16R17、亚烷基-CR15R16R17、R4A、亚烷基R4A、亚烯基R4A、亚炔基R4A、-O亚烷基R4A、-S亚烷基R4A、亚烷基NR16R17、亚烷基OR15、亚烷基SR15、-O亚烷基NR16R17、-S亚烷基NR16R17、-O亚烷基OR15、S亚烷基OR15、-O亚烷基SR15、SC1-6亚烷基SR15、-C(O)OR15、-C(O)R15、-C(S)OR15、-C(S)NR16R17和-C(O)NR16R17，其中任选地，所述烷基、杂烷基、烯基、炔基、和亚烷基各自独立地被选自卤素、烷基、杂烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、烯基、炔基、烷基氨基、烷基酰基、烷基氧基酰基、烷基氨基酰基、芳基和杂芳基中的一个或多个取代基所取代；R 3A is an unsubstituted or substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, and the unsubstituted or substituted cycloalkyl and heterocycloalkyl groups are each independently a monocyclic or condensed ring , bridged ring, or spirocyclic group group, the unsubstituted or substituted aryl group and heteroaryl group are each independently a monocyclic or condensed ring group, optionally, the unsubstituted or substituted aryl group and heteroaryl group are each independently condensed and for heterocycloalkyl or cycloalkyl, optionally, the substituted aryl, heteroaryl, cycloalkyl and heterocycloalkyl are each independently selected from one or more substituents below Substitution: halogen, -CN, alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, =O, =S, OR 15 , -SR 15 , -SO 2 R 15 , -NR 16 R 17 , alkylene Group -CR 15 R 16 R 17 , R 4A , alkylene R 4A , alkenylene R 4A , alkynylene R 4A , -O alkylene R 4A , -S alkylene R 4A , alkylene NR 16 R 17 , alkylene group OR 15 , alkylene group SR 15 , -O alkylene group NR 16 R 17 , -S alkylene group NR 16 R 17 , -O alkylene group OR 15 , S alkylene group OR 15 , -O alkylene SR 15 , SC 1-6 alkylene SR 15 , -C(O)OR 15 , -C(O)R 15 , -C(S)OR 15 , -C(S)NR 16 R 17 and -C(O)NR 16 R 17 , wherein optionally, the alkyl, heteroalkyl, alkenyl, alkynyl, and alkylene groups are each independently selected from halogen, alkyl, heteroalkyl Base, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxy Substituted with one or more substituents from acyl, alkylaminoacyl, aryl and heteroaryl;
R4A选自未取代的或被一个或多个独立地选自卤素、-CN、＝O、＝S、-OR18、-SR18、-NR19R20、C1-6卤代烷基、C1-6烷基、-C(O)R18、-C(O)OR18、-C(O)NR19R20、-S(O)C1-6烷基、-SO2R18、C6-10芳基、5-10元杂芳基、C3-15环烷基、3-15元杂环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-15环烷基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基、C1-6亚烷基R18、C1-6亚烷基OR18、C1-6亚烷基SR18、C1-6亚烷基-CR18R19R20、C1-6亚烷基NR19R20、-OC1-6亚烷基NR19R20、-SC1-6亚烷基NR19R20、-OC1-6亚烷基OR18、SC1-6亚烷基OR18、-OC1-6亚烷基SR18、OC1-6亚烷基SR18、-C(S)OR18、和-C(S)NR19R20中的取代基取代的C3-15环烷基、3-15元杂环烷基、5-15元杂芳基和C6-10芳基，所述C3-15环烷基和3至15元杂环烷基各自独立地为单环、稠环、桥环、或螺环基团，所述C6-10芳基和5至15元杂芳基各自独立地为单环或稠环基团；R 4A is selected from unsubstituted or one or more independently selected from halogen, -CN, =O, =S, -OR 18 , -SR 18 , -NR 19 R 20 , C 1-6 haloalkyl, C 1-6 alkyl, -C(O)R 18 , -C(O)OR 18 , -C(O)NR 19 R 20 , -S(O)C 1-6 alkyl, -SO 2 R 18 , C 6-10 aryl, 5-10 membered heteroaryl, C 3-15 cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 Alkylene C 3-15 cycloalkyl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl, C 1-6 alkylene R 18 , C 1-6 alkylene Group OR 18 , C 1-6 alkylene group SR 18 , C 1-6 alkylene group -CR 18 R 19 R 20 , C 1-6 alkylene group NR 19 R 20 , -OC 1-6 alkylene group NR 19 R 20 , -SC 1-6 alkylene NR 19 R 20 , -OC 1-6 alkylene OR 18 , SC 1-6 alkylene OR 18 , -OC 1-6 alkylene SR 18 , OC C 3-15 cycloalkyl, 3-15 membered heterocycloalkyl, substituted by substituents in 1-6 alkylene SR 18 , -C(S)OR 18 , and -C(S)NR 19 R 20 , 5-15-membered heteroaryl and C 6-10 aryl, the C 3-15 cycloalkyl and 3 to 15-membered heterocycloalkyl are each independently a single ring, condensed ring, bridged ring, or spirocyclic group group, the C 6-10 aryl group and the 5 to 15-membered heteroaryl group are each independently a monocyclic or condensed ring group;
R9和R12每次出现时各自独立地选自H、烷基、卤代烷基、环烷基、杂环烷基、-C(O)烷基、-C(O)卤代烷基、-C(O)O烷基、-C(O)NH烷基、-SO2烷基、-SO2HN烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基和C1-6亚烷基环烷基，任选地，所述烷基、环烷基、杂环烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基芳基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基和C1-6亚烷基环烷基各自独立地被选自卤素、烷基、杂烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、芳基和杂芳基中的一个或多个取代基所取代；Each occurrence of R 9 and R 12 is independently selected from H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, -C(O)alkyl, -C(O)haloalkyl, -C( O)O alkyl, -C(O)NH alkyl, -SO 2 alkyl, -SO 2 HN alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl and C 1-6 alkylene cycloalkyl, optionally, the alkyl, ring Alkyl, heterocycloalkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene aryl, C 1-6 alkylene heteroaryl, C 1-6 alkylene Heterocycloalkyl and C 1-6 alkylenecycloalkyl are each independently selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro , substituted by one or more substituents in cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
R10、R11、R13、和R14每次出现时各自独立地选自H、烷基、卤代烷基、环烷基、杂环烷基、-C(O)烷基、-C(O)卤代烷基、-C(O)O烷基、-C(O)NH烷基、-SO2烷基、-SO2HN烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基芳基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基和C1-6亚烷基环烷基，任选地，所述烷基、环烷基、杂环烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基芳基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基和C1-6亚烷基环烷基被被选自卤素、烷基、杂烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、芳基和杂芳基中的一个或多个取代基所取代；或者，R10和R11与其相连的C 或N原子一起形成未取代的或被一个或多个选自卤素、C1-6杂烷基、C1-6羟烷基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C6-10芳基、5-10元杂芳基、-CN、-OH、C1-6烷基、OC1-6烷基、C1-6卤代烷基、-OC1-6卤代烷基、-C(O)C1-6烷基、-C(O)C1-6卤代烷基、-C(O)C1-6烷基、-C(O)NHC1-6烷基、-SO2C1-6烷基、-SO2HNC1-6烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C5-10杂芳基、C1-6亚烷基C3-6杂环烷基和C1-6亚烷基C3-6环烷基中的取代基取代的3-10元环烷基或3-10元杂环烷基；或者，R13和R14与其相连的C或N原子一起形成未取代的或被一个或多个选自卤素、C1-6杂烷基、C1-6羟烷基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C6-10芳基、5-10元杂芳基、-CN、-OH、C1-6烷基、OC1-6烷基、C1-6卤代烷基、-OC1-6卤代烷基、-C(O)C1-6烷基、-C(O)C1-6卤代烷基、-C(O)C1-6烷基、-C(O)NHC1-6烷基、-SO2C1-6烷基、-SO2HNC1-6烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C5-10杂芳基、C1-6亚烷基C3-6杂环烷基和C1-6亚烷基C3-6环烷基中的取代基取代的3-10元环烷基或杂环烷基；Each occurrence of R 10 , R 11 , R 13 , and R 14 is independently selected from H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, -C(O)alkyl, -C(O )Haloalkyl, -C(O)O alkyl, -C(O)NH alkyl, -SO 2 alkyl, -SO 2 HN alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene aryl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl and C 1-6 alkylene cycloalkyl, optionally, the alkyl Base, cycloalkyl, heterocycloalkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene aryl, C 1-6 alkylene heteroaryl, C 1-6 Alkyleneheterocycloalkyl and C 1-6 alkylenecycloalkyl are selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro Substituted with one or more substituents of alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; alternatively, R 10 and R 11 are connected to the C Or N atoms together form unsubstituted or one or more selected from halogen, C 1-6 heteroalkyl, C 1-6 hydroxyalkyl, amino, nitro, C 3-6 cycloalkyl, 3-6 Membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OH, C 1-6 alkyl, OC 1-6 alkyl, C 1-6 haloalkyl, -OC 1-6 haloalkyl, -C(O)C 1-6 alkyl, -C(O)C 1-6 haloalkyl, -C(O)C 1-6 alkyl, -C(O)NHC 1- 6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 HNC 1-6 alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aromatic Substitution in base, C 1-6 alkylene C 5-10 heteroaryl, C 1-6 alkylene C 3-6 heterocycloalkyl and C 1-6 alkylene C 3-6 cycloalkyl 3-10-membered cycloalkyl or 3-10-membered heterocycloalkyl substituted; alternatively, R 13 and R 14 together with the C or N atom to which they are connected form an unsubstituted or one or more selected from halogen, C 1-6 heteroalkyl, C 1-6 hydroxyalkyl, amino, nitro, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl Base, -CN, -OH, C 1-6 alkyl, OC 1-6 alkyl, C 1-6 haloalkyl, -OC 1-6 haloalkyl, -C(O)C 1-6 alkyl, - C(O)C 1-6 haloalkyl, -C(O)C 1-6 alkyl, -C(O)NHC 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 HNC 1 -6 alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 5-10 heteroaryl, C 1 3-10 membered cycloalkyl or heterocycloalkyl substituted by substituents in -6 alkylene C 3-6 heterocycloalkyl and C 1-6 alkylene C 3-6 cycloalkyl;
R15每次出现时各自独立地选自H、烷基、卤代烷基、环烷基、杂环烷基、-C(O)烷基、-C(O)卤代烷基、-C(O)O烷基、-C(O)NH烷基、-SO2烷基、-SO2HN烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基芳基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基和C1-6亚烷基环烷基，任选地，所述烷基、环烷基、杂环烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基芳基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基和C1-6亚烷基环烷基各自独立地被选自卤素、烷基、杂烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、芳基和杂芳基中的一个或多个取代基所取代；Each occurrence of R 15 is independently selected from H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, -C(O)alkyl, -C(O)haloalkyl, -C(O)O Alkyl, -C(O)NH alkyl, -SO 2 alkyl, -SO 2 HN alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene aryl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl and C 1-6 alkylene cycloalkyl, optionally, the alkyl, cycloalkyl, heterocycloalkyl , C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene aryl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl and C 1 -6 alkylenecycloalkyl groups are each independently selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycle Substituted with one or more substituents in alkyl, aryl and heteroaryl;
R16和R17各自独立地选自H、烷基、卤代烷基、-C(O)烷基、-C(O)卤代烷基、-C(O)芳基、-C(O)环烷基、-C(O)杂芳基、-C(O)杂环烷基、-C(O)O烷基、-C(O)O卤代烷基、-C(O)O芳基、-C(O)O环烷基、-C(O)O杂芳基、-C(O)O杂环烷基、-C(O)NH烷基、-C(O)NHC1-6卤代烷基、-C(O)NH芳基、-C(O)NH环烷基、-C(O)NH杂芳基、-C(O)NH杂环烷基、-SO2烷基、-SO2C1-6卤代烷基、-SO2芳基、-SO2环烷基、-SO2杂芳基、-SO2杂环烷基、环烷基、杂环烷基、杂芳基、芳基、亚烷基环烷基、亚烷基芳基、亚烷基杂芳基、亚烷基杂环烷基和C1-6亚烷基OC1-6烷基，任选地，所述烷基、卤代烷基、-C(O)烷基、-C(O)卤代烷基、-C(O)芳基、-C(O)环烷基、-C(O)杂芳基、-C(O)杂环烷基、-C(O)O烷基、-C(O)O卤代烷基、-C(O)O芳基、-C(O)O环烷基、-C(O)O杂芳基、-C(O)O杂环烷基、-C(O)NH烷基、-C(O)NHC1-6卤代烷基、-C(O)NH芳基、-C(O)NH环烷基、-C(O)NH杂芳基、-C(O)NH杂环烷基、-SO2烷基、-SO2C1-6卤代烷基、-SO2芳基、-SO2环烷基、-SO2杂芳基、-SO2杂环烷基、环烷基、杂环烷基、杂芳基、芳基、亚烷基环烷基、亚烷基芳基、亚烷基杂芳基、亚烷基杂环烷基和C1-6亚烷基OC1-6烷基各自独立地被选自卤素、烷基、杂烷基、卤代烷基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、芳基、杂芳基、-OR18、-SR18、-NR19R20、-C(O)R18、-C(O)OR18、-C(O)NR19R20、-S(O)C1-6烷基、-SO2C1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基环烷基、C1-6亚烷基 杂芳基、C1-6亚烷基杂环烷基中的一个或多个取代基所取代；或者，R16和R17与它们所连接的氮原子或C原子一起形成3-10元杂环烷基或环烷基，所述3-10元杂环烷基和环烷基是未取代的或被一个或多个独立地选自卤素、-CN、硝基、-OR18、-SR18、-NR19R20、C1-6烷基、C1-6杂烷基、C1-6羟烷基、-C(O)R18、-C(O)OR18、-C(O)N R19R20、-S(O)C1-6烷基、-SO2C1-6烷基、C6-10芳基、5-10元杂芳基、C3-10环烷基、3-15元杂环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基杂芳基、C1-6亚烷基R18、C1-6亚烷基OR18、C1-6亚烷基SR18和C1-6亚烷基NR19R20中的取代基取代；R 16 and R 17 are each independently selected from H, alkyl, haloalkyl, -C(O)alkyl, -C(O)haloalkyl, -C(O)aryl, -C(O)cycloalkyl , -C(O)heteroaryl, -C(O)heterocycloalkyl, -C(O)Oalkyl, -C(O)Ohaloalkyl, -C(O)Oaryl, -C( O)O cycloalkyl, -C(O)O heteroaryl, -C(O)O heterocycloalkyl, -C(O)NH alkyl, -C(O)NHC 1-6 haloalkyl, - C(O)NH aryl, -C(O)NH cycloalkyl, -C(O)NH heteroaryl, -C(O)NH heterocycloalkyl, -SO 2 alkyl, -SO 2 C 1 -6 Haloalkyl, -SO 2 aryl, -SO 2 cycloalkyl, -SO 2 heteroaryl, -SO 2 heterocycloalkyl, cycloalkyl , heterocycloalkyl, heteroaryl, aryl, ylidene Alkylcycloalkyl, alkylenearyl, alkyleneheteroaryl, alkyleneheterocycloalkyl and C 1-6 alkyleneOC 1-6 alkyl, optionally, the alkyl, Haloalkyl, -C(O)alkyl, -C(O)haloalkyl, -C(O)aryl, -C(O)cycloalkyl, -C(O)heteroaryl, -C(O) Heterocycloalkyl, -C(O)O alkyl, -C(O)O haloalkyl, -C(O)O aryl, -C(O)O cycloalkyl, -C(O)O heteroaryl base, -C(O)O heterocycloalkyl, -C(O)NH alkyl, -C(O)NHC 1-6 haloalkyl, -C(O)NH aryl, -C(O)NH ring Alkyl, -C(O)NH heteroaryl, -C(O)NH heterocycloalkyl, -SO 2 alkyl, -SO 2 C 1-6 haloalkyl, -SO 2 aryl, -SO 2 ring Alkyl, -SO2heteroaryl , -SO2heterocycloalkyl , cycloalkyl, heterocycloalkyl, heteroaryl, aryl, alkylenecycloalkyl, alkylenearyl, alkylene Heteroaryl, alkyleneheterocycloalkyl, and C 1-6 alkylene OC 1-6 alkyl are each independently selected from the group consisting of halogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, cyano, Amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR 18 , -SR 18 , -NR 19 R 20 , -C(O)R 18 , -C(O)OR 18 , -C(O)NR 19 R 20 , -S(O)C 1-6 alkyl, -SO 2 C 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1- 6 alkylenecycloalkyl, C 1-6 alkylene Substituted with one or more substituents of heteroaryl, C 1-6 alkylene heterocycloalkyl; alternatively, R 16 and R 17 together with the nitrogen atom or C atom to which they are connected form a 3-10 membered heteroaryl group. Cycloalkyl or cycloalkyl, the 3-10 membered heterocycloalkyl and cycloalkyl are unsubstituted or independently selected from one or more halogen, -CN, nitro, -OR 18 , -SR 18 , -NR 19 R 20 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 hydroxyalkyl, -C(O)R 18 , -C(O)OR 18 , -C( O)N R 19 R 20 , -S(O)C 1-6 alkyl, -SO 2 C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl base, 3-15 membered heterocycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene heteroaryl , C 1-6 alkylene R 18 , C 1-6 alkylene OR 18 , C 1-6 alkylene SR 18 and C 1-6 alkylene NR 19 R 20 are substituted by substituents;
R18选自H、烷基、C1-6卤代烷基、-C(O)烷基、-C(O)卤代烷基、环烷基、3杂环烷基、芳基、杂芳基、亚烷基芳基、亚烷基杂芳基、亚烷基环烷基和亚烷基杂环烷基，任选地，所述烷基、C1-6卤代烷基、-C(O)烷基、-C(O)卤代烷基、环烷基、杂环烷基、芳基、杂芳基、亚烷基芳基、亚烷基杂芳基、亚烷基环烷基和亚烷基杂环烷基各自独立地被一个或多个选自卤素、-CN、烷基、卤代烷基、-OH、-SH、烷氧基、-O卤代烷基、-S烷基、-S卤代烷基、-NH2、-NH烷基、-N(C1-6烷基)(C1-6烷基)、-C(O)烷基、-C(O)卤代烷基、-C(O)OH、-C(O)O烷基、-C(O)NH2、-C(O)NHC1-6烷基、-C(O)N(C1-6烷基)(C1-6烷基)、-SO2C1-6烷基、-S(O)烷基、C6-10芳基、5-10元杂芳基、C3-10环烷基、3-10元杂环烷基、亚烷基芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基、C1-6羟基烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基SH、C1-6亚烷基SC1-6烷基、C1-6亚烷基NH2、C1-6亚烷基NHC1-6烷基和C1-6亚烷基N(C1-6烷基)(C1-6烷基)中的取代基取代；R 18 is selected from H, alkyl, C 1-6 haloalkyl, -C(O) alkyl, -C(O) haloalkyl, cycloalkyl, 3-heterocycloalkyl, aryl, heteroaryl, ylidene Alkylaryl, alkyleneheteroaryl, alkylenecycloalkyl and alkyleneheterocycloalkyl, optionally, the alkyl, C 1-6 haloalkyl, -C(O)alkyl , -C(O)haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylenearyl, alkyleneheteroaryl, alkylenecycloalkyl and alkyleneheterocycle Each alkyl group is independently selected from one or more halogen, -CN, alkyl, haloalkyl, -OH, -SH, alkoxy, -O haloalkyl, -S alkyl, -S haloalkyl, -NH 2. -NH alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -C(O) alkyl, -C(O) haloalkyl, -C(O)OH, - C(O)O alkyl, -C(O)NH 2 , -C(O)NHC 1-6 alkyl, -C(O)N(C 1-6 alkyl)(C 1-6 alkyl) , -SO 2 C 1-6 alkyl, -S(O) alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl , alkylene aryl, C 1-6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl, C 1-6 hydroxyl Alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene SH, C 1-6 alkylene SC 1-6 alkyl, C 1-6 alkylene NH 2 , Substituents in C 1-6 alkylene NHC 1-6 alkyl and C 1-6 alkylene N(C 1-6 alkyl) (C 1-6 alkyl);
R19和R20各自独立地选自H、烷基、卤代烷基、-C(O)烷基、-C(O)氟烷基、环烷基、杂环烷基、杂芳基、芳基、亚烷基芳基、亚烷基环烷基、亚烷基杂芳基、亚烷基杂环烷基、-C(O)芳基、-C(O)环烷基、-C(O)杂芳基、-C(O)杂环烷基、-C(O)OC1-6烷基、-C(O)OC1-6卤代烷基、-C(O)OC6-10芳基、-C(O)OC3-10环烷基、-C(O)OC4-10杂芳基、-C(O)OC3-15杂环烷基、-C(O)NH烷基、-C(O)NHC1-6卤代烷基、-C(O)NHC6-10芳基、-C(O)NHC3-10环烷基、-C(O)NHC4-10杂芳基、-C(O)NHC3-15杂环烷基、-SO2C1-6烷基、-SO2C1-6卤代烷基、-SO2C6-10芳基、-SO2C3-10环烷基、-SO2C4-10杂芳基、和-SO2C3-15杂环烷基，任选地，所述烷基、卤代烷基、-C(O)烷基、-C(O)氟烷基、环烷基、杂环烷基、杂芳基、芳基、亚烷基芳基、亚烷基环烷基、亚烷基杂芳基、亚烷基杂环烷基、-C(O)芳基、-C(O)环烷基、-C(O)杂芳基、-C(O)杂环烷基、-C(O)OC1-6烷基、-C(O)OC1-6卤代烷基、-C(O)OC6-10芳基、-C(O)OC3-10环烷基、-C(O)OC4-10杂芳基、-C(O)OC3-15杂环烷基、-C(O)NH烷基、-C(O)NHC1-6卤代烷基、-C(O)NHC6-10芳基、-C(O)NHC3-10环烷基、-C(O)NHC4-10杂芳基、-C(O)NHC3-15杂环烷基、-SO2C1-6烷基、-SO2C1-6卤代烷基、-SO2C6-10芳基、-SO2C3-10环烷基、-SO2C4-10杂芳基、和-SO2C3-15杂环烷基被一个或多个独立地选自卤素、-CN、烷基、卤代烷基、-OH、-SH、烷氧基、卤代烷氧基、-SC1-6烷基、-SC1-6卤代烷基、-NH2、烷基氨基、烷基酰基、卤代烷基酰基、-C(O)OH、烷氧基酰基、-C(O)NH2、烷基氨基酰基、-SO2C1-6烷基、-S(O)C1-6烷基、C6-10 芳基、杂芳基、环烷基、杂环烷基、-C1-6亚烷基芳基、C1-6亚烷基环烷基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基、羟基烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基SH、C1-6亚烷基SC1-6烷基、C1-6亚烷基NH2、C1-6亚烷基NHC1-6烷基和-C1-6亚烷基N(C1-6烷基)(C1-6烷基)中的一个或多取代基取代；或者，R19和R20与它们所连接的氮原子或C原子一起形成3-10元杂环烷基或环烷基，所述3-10元杂环烷基和环烷基是未取代的或被一个或多个选自卤素、-CN、硝基、C1-6烷基、C1-6卤代烷基、-OH、SH、-OC1-6烷基、-OC1-6卤代烷基、-SC1-6烷基、-SC1-6卤代烷基、-NH2、-NHC1-6烷基、-N(C1-6烷基)(C1-6烷基)、-C(O)C1-6烷基、-C(O)C1-6氟烷基、-C(O)OH、-C(O)OC1-6烷基、-C(O)NH2、-C(O)NHC1-6烷基、-C(O)N(C1-6烷基)(C1-6烷基)、-SO2C1-6烷基、-S(O)C1-6烷基、C6-10芳基、5-10元杂芳基、C3-10环烷基、3-15元杂环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基、C1-6亚烷基OH、C1-6亚烷基OC1-6烷基、C1-6亚烷基SH、C1-6亚烷基SC1-6烷基、C1-6亚烷基NH2、C1-6亚烷基NHC1-6烷基和C1-6亚烷基N(C1-6烷基)(C1-6烷基)中的取代基取代；和R 19 and R 20 are each independently selected from H, alkyl, haloalkyl, -C(O)alkyl, -C(O)fluoroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl , alkylene aryl, alkylenecycloalkyl, alkyleneheteroaryl, alkyleneheterocycloalkyl, -C(O)aryl, -C(O)cycloalkyl, -C(O )Heteroaryl, -C(O)heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)OC 1-6 haloalkyl, -C(O)OC 6-10 aryl , -C(O)OC 3-10 cycloalkyl, -C(O)OC 4-10 heteroaryl, -C(O)OC 3-15 heterocycloalkyl, -C(O)NH alkyl, -C(O)NHC 1-6 haloalkyl, -C(O)NHC 6-10 aryl, -C(O)NHC 3-10 cycloalkyl, -C(O)NHC 4-10 heteroaryl, -C(O)NHC 3-15 heterocycloalkyl, -SO 2 C 1-6 alkyl, -SO 2 C 1-6 haloalkyl, -SO 2 C 6-10 aryl, -SO 2 C 3- 10 cycloalkyl, -SO 2 C 4-10 heteroaryl, and -SO 2 C 3-15 heterocycloalkyl, optionally, the alkyl, haloalkyl, -C(O)alkyl, - C(O)fluoroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, alkylenearyl, alkylenecycloalkyl, alkyleneheteroaryl, alkyleneheterocycloalkyl base, -C(O)aryl, -C(O)cycloalkyl, -C(O)heteroaryl, -C(O)heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)OC 1-6 haloalkyl, -C(O)OC 6-10 aryl, -C(O)OC 3-10 cycloalkyl, -C(O)OC 4-10 heteroaryl, -C(O)OC 3-15 heterocycloalkyl, -C(O)NH alkyl, -C(O)NHC 1-6 haloalkyl, -C(O)NHC 6-10 aryl, -C( O)NHC 3-10 cycloalkyl, -C(O)NHC 4-10 heteroaryl, -C(O)NHC 3-15 heterocycloalkyl, -SO 2 C 1-6 alkyl, -SO 2 C 1-6 haloalkyl, -SO 2 C 6-10 aryl, -SO 2 C 3-10 cycloalkyl, -SO 2 C 4-10 heteroaryl, and -SO 2 C 3-15 heterocycloalkyl The group is one or more independently selected from halogen, -CN, alkyl, haloalkyl, -OH, -SH, alkoxy, haloalkoxy, -SC 1-6 alkyl, -SC 1-6 haloalkyl , -NH 2 , alkylamino, alkylaminoacyl, haloalkylacyl, -C(O)OH, alkoxyacyl, -C(O)NH 2 , alkylaminoacyl, -SO 2 C 1-6 alkyl Base, -S(O)C 1-6 alkyl, C 6-10 Aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -C 1-6 alkylene aryl, C 1-6 alkylene cycloalkyl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl, hydroxyalkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene SH, C 1-6 alkylene SC 1-6 alkyl base, C 1-6 alkylene NH 2 , C 1-6 alkylene NHC 1-6 alkyl and -C 1-6 alkylene N (C 1-6 alkyl) (C 1-6 alkyl ) is substituted with one or more substituents; alternatively, R 19 and R 20 together with the nitrogen atom or C atom to which they are connected form a 3-10 membered heterocycloalkyl or cycloalkyl group, and the 3-10 membered heterocycle Alkyl and cycloalkyl are unsubstituted or substituted by one or more selected from halogen, -CN, nitro, C 1-6 alkyl, C 1-6 haloalkyl, -OH, SH, -OC 1-6 Alkyl, -OC 1-6 haloalkyl, -SC 1-6 alkyl, -SC 1-6 haloalkyl , -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) ( C 1-6 alkyl), -C(O)C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl, -C(O)OH, -C(O)OC 1-6 alkyl base, -C(O)NH 2 , -C(O)NHC 1-6 alkyl, -C(O)N(C 1-6 alkyl)(C 1-6 alkyl), -SO 2 C 1 -6 alkyl, -S(O)C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl , C 1-6 alkylene OH, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene SH, C 1-6 alkylene SC 1-6 alkyl, C 1- Substituents in 6 alkylene NH 2 , C 1-6 alkylene NHC 1-6 alkyl and C 1-6 alkylene N (C 1-6 alkyl) (C 1-6 alkyl) ;and
R21选自H、羟基、氨基、烷基、烷氧基和卤素。R 21 is selected from H, hydroxyl, amino, alkyl, alkoxy and halogen.
在其中一个技术方案中，其中，In one of the technical solutions, where,
R1A是未取代的或取代的含有至少一个氮原子的3-15元杂环烷基，所述3-15元杂环烷基为单杂环烷基、稠环杂环烷基、螺环杂环烷基或桥环杂环烷基，所述取代的含有至少一个氮原子的3-15元杂环烷基被选自下述的一个、两个、三个或更多个取代基取代：卤素、C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C3-10杂环烷基、C6-10芳基、5-10元杂芳基、-OR9、-SR9、C1-6亚烷基-OR9、C1-6亚烷基-SR9、-NR10R11、C1-6亚烷基-CR9R10R11和C1-6亚烷基-NR10R11，其中任选地，所述C1-6烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、C1-6亚烷基、C3-10环烷基、C3-10杂环烷基、C6-10芳基、和5-10元杂芳基各自独立地被选自卤素、C1-6烷基、C1-6杂烷基、C1-6烷氧基、C1-6卤代烷基、羟基、C1-6羟烷基、氰基、氨基、硝基、C3-10环烷基、C3-10杂环烷基、C2-6烯基、C2-6炔基、C1-6烷基氨基、C1-6烷基酰基、C1-6烷基氧基酰基、C1-6烷基氨基酰基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；优选地，R1A是未取代的或或取代的含有至少一个氮原子的4-15元杂环烷基，所述4-15元杂环烷基为单杂环烷基、稠环杂环烷基、螺环杂环烷基或桥环杂环烷基，所述取代的含有至少一个氮原子的4-15元杂环烷基被选自下述的一个、两个、三个或更多个取代基取代：卤素、C1-6烷基、C1-6氟烷基、C3-6环烷基、C3-6杂环烷基、C6-10芳基、5-6元杂芳基、-OR9、-SR9、C1-6亚烷基OR9、C1-6亚烷基SR9、C1-6亚烷基-CR9R10R11、-NR10R11、和C1-6亚烷基NR10R11，其中，任选地，所述C1-6烷基、C1-6氟烷基、C3-6环烷基、C3-6杂环烷基、C6-10芳基、5-6元杂芳基和C1-6亚烷基，各自独立地被选自卤素、C1-3烷基、C1-3杂烷基、C1-3烷氧基、C1-3卤代烷基、羟基、C1-3羟烷基、氰基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C2-3烯基、C2-3炔基、C1-3烷基氨基、C1-3烷基酰基、C1-3烷基氧基酰基、C1-3烷基氨基酰基、C6-10芳基和5-6 元杂芳基中的一个或多个取代基所取代；在其中一个技术方案中，R 1A is an unsubstituted or substituted 3-15-membered heterocycloalkyl group containing at least one nitrogen atom, and the 3-15-membered heterocycloalkyl group is a monoheterocycloalkyl group, a fused ring heterocycloalkyl group, or a spiro ring Heterocycloalkyl or bridged heterocycloalkyl, the substituted 3-15 membered heterocycloalkyl containing at least one nitrogen atom is substituted with one, two, three or more substituents selected from the following : Halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, C 3- 10 heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OR 9 , -SR 9 , C 1-6 alkylene -OR 9 , C 1-6 alkylene -SR 9 , -NR 10 R 11 , C 1-6 alkylene -CR 9 R 10 R 11 and C 1-6 alkylene -NR 10 R 11 , wherein optionally, the C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylene, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently selected from halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxyl , C 1-6 hydroxyalkyl, cyano, amino, nitro, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 One of -6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkyloxyacyl, C 1-6 alkylaminoacyl, C 6-10 aryl and 5-10 membered heteroaryl or substituted by multiple substituents; preferably, R 1A is an unsubstituted or substituted 4-15-membered heterocycloalkyl group containing at least one nitrogen atom, and the 4-15-membered heterocycloalkyl group is a single heterocyclic ring Alkyl, fused ring heterocycloalkyl, spiro ring heterocycloalkyl or bridged ring heterocycloalkyl, the substituted 4-15 membered heterocycloalkyl containing at least one nitrogen atom is selected from the following one, Substitution of two, three or more substituents: halogen, C 1-6 alkyl, C 1-6 fluoroalkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 6- 10 aryl group, 5-6 membered heteroaryl group, -OR 9 , -SR 9 , C 1-6 alkylene group OR 9 , C 1-6 alkylene group SR 9 , C 1-6 alkylene group -CR 9 R 10 R 11 , -NR 10 R 11 , and C 1-6 alkylene NR 10 R 11 , wherein, optionally, the C 1-6 alkyl, C 1-6 fluoroalkyl, C 3- 6 cycloalkyl, C 3-6 heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl and C 1-6 alkylene, each independently selected from halogen, C 1-3 alkyl Base, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 haloalkyl , hydroxyl, C 1-3 hydroxyalkyl, cyano, amino, nitro, C 3-6 cycloalkyl , 3-6 membered heterocycloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkylamino, C 1-3 alkyl acyl, C 1-3 alkyloxyacyl, C 1-3 alkylaminoacyl, C 6-10 aryl and 5-6 Substituted with one or more substituents in the heteroaryl group; in one of the technical solutions,
R2A是未取代的或取代的C6-10芳基、5-10元杂芳基或3-10元杂环烷基，所述5-10元杂芳基和3-10元杂环烷各自独立地含有1、2或3个各自独立选自N、O或S的杂原子，任选地，所述未取代的或取代的C6-10芳基和5-10元杂芳基各自独立地稠和于3-15元的杂环烷基或环烷基，所述取代的C6-10芳基、5-10元杂芳基和3-10元杂环烷基各自独立地被选自下述的一个、两个、三个、四个或更多个取代基取代：卤素、＝O、＝S、C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基、5-10元杂芳基、-OR12、-SR12、C1-6亚烷基-OR12、C1-6亚烷基-SR12、-NR13R14、C1-6亚烷基-CR12R13R14和C1-6亚烷基-NR13R14，其中任选地，所述C1-6烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C3-10杂环基、C6-10芳基、C1-6亚烷基和5-10元杂芳基各自独立地被选自卤素、C1-6烷基、C1-6杂烷基、C1-6烷氧基、C1-6卤代烷基、羟基、C1-6羟烷基、氰基、氨基、硝基、C3-10环烷基、3-10元杂环基、C2-6烯基、C2-6炔基、C1-6烷基氨基、C1-6烷基酰基、C1-6烷基氧基酰基、C1-6烷基氨基酰基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；优选地R2A是未取代的或取代的C6-10芳基、5-6元杂芳基或3-6元杂环烷基，所述5-6元杂芳基和3-6元杂环烷基各自独立地含有1、2或3个各自独立选自N、O或S的杂原子，任选地，所述未取代的或取代的C6-10芳基和5-6元杂芳基各自独立地稠和于3、4、5、6、7、8或9元杂环烷基或环烷基，所述取代的C6-10芳基、5-6元杂芳基和3-6元杂环烷基各自独立地被选自下述的一个、两个、三个、四个或更多个取代基取代：F、Cl、Br、I、＝O、＝S、C1-6烷基、C1-6氟代烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-OR12、-SR12、C1-6亚烷基-OR12、C1-6亚烷基-SR12、-NR13R14、C1-6亚烷基-CR12R13R14和C1-6亚烷基-NR13R14，其中任选地，所述C1-6烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环基、C6-10芳基、和5-6元杂芳基各自独立地被选自F、Cl、Br、I、C1-6烷基、C1-6杂烷基、C1-6烷氧基、C1-6氟代烷基、羟基、C1-6羟烷基、氰基、氨基、硝基、C3-6环烷基、C3-6杂环基、C2-6烯基、C2-6炔基、C1-6烷基氨基、C1-6烷基酰基、C1-6烷基氧基酰基、C1-6烷基氨基酰基、C6-10芳基和5-6元杂芳基中的一个或多个取代基所取代，且当R2A是取代的C6-10芳基时，所述取代的C6-10杂芳基不被＝O或＝S取代；在其中一个技术方案中，R 2A is unsubstituted or substituted C 6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocycloalkyl, the 5-10 membered heteroaryl and 3-10 membered heterocycloalkyl Each independently contains 1, 2 or 3 heteroatoms each independently selected from N, O or S, optionally, each of the unsubstituted or substituted C 6-10 aryl and 5-10 membered heteroaryl Independently fused to a 3-15-membered heterocycloalkyl or cycloalkyl group, the substituted C 6-10 aryl, 5-10-membered heteroaryl and 3-10-membered heterocycloalkyl are each independently Substituted with one, two, three, four or more substituents selected from the following: halogen, =O, =S, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hetero Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -OR 12 , -SR 12 , C 1-6 alkylene -OR 12 , C 1-6 alkylene -SR 12 , -NR 13 R 14 , C 1-6 alkylene -CR 12 R 13 R 14 and C 1-6 alkylene-NR 13 R 14 , wherein optionally, the C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -10 cycloalkyl, C 3-10 heterocyclyl, C 6-10 aryl, C 1-6 alkylene and 5-10 membered heteroaryl are each independently selected from halogen, C 1-6 alkyl , C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 haloalkyl , hydroxyl, C 1-6 hydroxyalkyl, cyano, amino, nitro, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkyloxyacyl, C 1 -6 alkylaminoacyl, C 6-10 aryl and 5-10 membered heteroaryl are substituted with one or more substituents; preferably R 2A is unsubstituted or substituted C 6-10 aryl, 5-6 membered heteroaryl or 3-6 membered heterocycloalkyl, the 5-6 membered heteroaryl and 3-6 membered heterocycloalkyl each independently contain 1, 2 or 3 each independently selected from N , O or S heteroatoms, optionally, the unsubstituted or substituted C 6-10 aryl group and 5-6 membered heteroaryl group are each independently fused to 3, 4, 5, 6, 7, 8- or 9-membered heterocycloalkyl or cycloalkyl, the substituted C 6-10 aryl, 5-6-membered heteroaryl and 3-6-membered heterocycloalkyl are each independently selected from one of the following , two, three, four or more substituents substituted: F, Cl, Br, I, =O, =S, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1- 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -OR 12 , -SR 12 , C 1-6 alkylene -OR 12 , C 1-6 alkylene -SR 12 , -NR 13 R 14 , C 1-6 alkylene -CR 12 R 13 R 14 and C 1-6 alkylene-NR 13 R 14 , wherein optionally, the C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, and 5-6 membered heteroaryl are each independently selected from F, Cl, Br, I, C 1-6 alkyl Base, C 1-6 heteroalkyl group, C 1-6 alkoxy group, C 1-6 fluoroalkyl group, hydroxyl group, C 1-6 hydroxyalkyl group, cyano group, amino group, nitro group, C 3-6 ring Alkyl, C 3-6 heterocyclyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkyloxyacyl , C 1-6 alkylaminoacyl, C 6-10 aryl and 5-6 membered heteroaryl are substituted with one or more substituents, and when R 2A is a substituted C 6-10 aryl, The substituted C 6-10 heteroaryl group is not substituted by =O or =S; in one of the technical solutions,
R3A是未取代的或取代的6至14元芳基、5至14元杂芳基、3至15元环烷基或3至15元杂环烷基，所述未取代的或取代的3至15元环烷基和3至15元杂环烷基各自独立地为单环、稠环、桥环、或螺环基团，所述未取代的或取代的6至14元芳基和5至14元杂芳基各自独立地为单环或稠环基团，任选地，所述未取代的或取代的6至14元芳基和5至14元杂芳基各自独立地稠和于3-6元杂环烷基或3-6元环烷基，任选地，所述取代的6至14元芳基、5至14杂芳基、3至15元环烷基和3至15元杂环烷基各自独立地被选自下述的一个或更多个取代基取代：卤素、-CN、C1-6烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、＝O、＝S、OR15、-SR15、-SO2R15、-NR16R17、 C1-6亚烷基-CR15R16R17、R4A、C1-6亚烷基R4A、C2-6亚烯基R4A、C2-6亚炔基R4A、-OC1-6亚烷基R4A、-SC1-6亚烷基R4A、C1-6亚烷基NR16R17、C1-6亚烷基OR15、C1-6亚烷基SR15、-OC1-6亚烷基NR16R17、-SC1-6亚烷基NR16R17、-OC1-6亚烷基OR15、SC1-6亚烷基OR15、-OC1-6亚烷基SR15、SC1-6亚烷基SR15、-C(O)OR15、-C(O)R15、-C(S)OR15、-C(S)NR16R17和-C(O)NR16R17，其中任选地，所述C1-6烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、和C1-6亚烷基各自独立地被选自卤素、C1-6烷基、C1-6杂烷基、C1-6烷氧基、C1-6卤代烷基、羟基、C1-6羟烷基、氰基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C2-6烯基、C2-6炔基、C1-6烷基氨基、C1-6烷基酰基、C1-6烷基氧基酰基、C1-6烷基氨基酰基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；优选地，R3A选自未取代的或被一个或多个选自卤素、-CN、C1-6烷基、C1-6氟烷基、＝O、＝S、OR15、-SR15、-SO2R15、-NR16R17、C1-6亚烷基-CR15R16R17、R4A、C1-6亚烷基R4A、C2-6亚烯基R4A、-OC1-6亚烷基R4A、-SC1-6亚烷基R4A、C1-6亚烷基N R16R17、C1-6亚烷基OR15、C1-6亚烷基SR15、-OC1-6亚烷基NR16R17、-SC1-6亚烷基N R16R17、-OC1-6亚烷基OR15、SC1-6亚烷基OR15、-OC1-6亚烷基SR15、SC1-6亚烷基SR15、-C(O)OR15、-C(O)R15、-C(S)OR15、-C(S)N R16R17和-C(O)N R16R17中的取代基取代的C6-10芳基、5-10元杂芳基、C4-15环烷基和4-15元杂环烷基，所述C4-15环烷基和4至15元杂环烷基各自独立地为单环、稠环、桥环、或螺环基团，所述C6-10芳基和5至10元杂芳基各自独立地为单环或稠环基团，任选地，所述C6-10芳基和5至10元杂芳基各自独立地稠和于5-6元杂环烷基或5-6元环烷基；在其中一个技术方案中，R4A选自未取代的或被一个或多个独立地选自卤素、-CN、-OR18、-SR18、-NR19R20、C1-6氟烷基、C1-6烷基、-C(O)R18、-C(O)OR18、-C(O)NR19R20、-S(O)C1-6烷基、-SO2C1-6烷基、C6-10芳基、5-10元杂芳基、C3-10环烷基、3-15元杂环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C3-10杂芳基、C1-6亚烷基杂环烷基、C1-6亚烷基R18、C1-6亚烷基OR18、C1-6亚烷基SR18、C1-6亚烷基-CR18R19R20和C1-6亚烷基NR19R20中的取代基取代的C3-10环烷基、4-15元杂环烷基、5-10元杂芳基和C6-10芳基，所述C3-10环烷基和4至15元杂环烷基各自独立地为单环、稠环、桥环、或螺环基团，所述C6-10芳基和5至10元杂芳基各自独立地为单环或稠环基团；在其中一个技术方案中，R9和R12每次出现时，各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、-C(O)C1-6烷基、-C(O)C1-6卤代烷基、-C(O)OC1-6烷基、-C(O)NHC1-6烷基、-SO2C1-6烷基、-SO2HNC1-6烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基C3-10杂环烷基和C1-6亚烷基C3-10环烷基，任选地，所述C1-6烷基、C3-10环烷基、C3-10杂环烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基C3-6杂环烷基和C1-6亚烷基C3-6环烷基各自独立被选自卤素、C1-6烷基、C1-6杂烷基、C1-6烷氧基、C1-6卤代烷基、羟基、C1-6羟烷基、氰基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；优选地，R9和R12每次出现时各自独立选自H、C1-6烷基、C1-6氟烷基、-C(O)C1-6 烷基、C(O)C1-6氟烷基、C3-6环烷基、和3-6元杂环烷基，任选地，所述C1-6烷基、C3-6环烷基和3-6元杂环烷基各自独立地被选自F、Cl、Br、I、C1-C3烷基、C1-C3烷氧基、C1-C3卤代烷基、羟基、和C1-C3羟烷基中的一个或多个取代基所取代；在其中一个技术方案中，R 3A is an unsubstituted or substituted 6- to 14-membered aryl group, a 5- to 14-membered heteroaryl group, a 3- to 15-membered cycloalkyl group, or a 3 to 15-membered heterocycloalkyl group, and the unsubstituted or substituted 3A To 15-membered cycloalkyl and 3 to 15-membered heterocycloalkyl are each independently a monocyclic, fused ring, bridged ring, or spirocyclic group, and the unsubstituted or substituted 6 to 14-membered aryl and 5 to 14-membered heteroaryl groups are each independently a monocyclic or fused ring group, optionally, the unsubstituted or substituted 6- to 14-membered aryl groups and 5- to 14-membered heteroaryl groups are each independently fused to 3-6 membered heterocycloalkyl or 3-6 membered cycloalkyl, optionally, the substituted 6 to 14 membered aryl, 5 to 14 heteroaryl, 3 to 15 membered cycloalkyl and 3 to 15 Each membered heterocycloalkyl group is independently substituted with one or more substituents selected from the following: halogen, -CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, =O, =S, OR 15 , -SR 15 , -SO 2 R 15 , -NR 16 R 17 , C 1-6 alkylene -CR 15 R 16 R 17 , R 4A , C 1-6 alkylene R 4A , C 2-6 alkenylene R 4A , C 2-6 alkynylene R 4A , -OC 1-6 alkylene R 4A , -SC 1-6 alkylene R 4A , C 1-6 alkylene NR 16 R 17 , C 1-6 alkylene OR 15 , C 1-6 alkylene SR 15 , -OC 1-6 alkylene NR 16 R 17 , -SC 1-6 alkylene NR 16 R 17 , -OC 1-6 alkylene OR 15 , SC 1-6 alkylene OR 15 , - OC 1-6 alkylene SR 15 , SC 1-6 alkylene SR 15 , -C(O)OR 15 , -C(O)R 15 , -C(S)OR 15 , -C(S)NR 16 R 17 and -C(O)NR 16 R 17 , wherein optionally, the C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 alkylene are each independently selected from halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxyl, C 1 -6 hydroxyalkyl, cyano, amino, nitro, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl One or more of C 1-6 alkyl acyl, C 1-6 alkyloxyacyl, C 1-6 alkylaminoacyl, C 6-10 aryl and 5-10 membered heteroaryl Substituted by substituents; preferably, R 3A is selected from unsubstituted or by one or more selected from halogen, -CN, C 1-6 alkyl, C 1-6 fluoroalkyl, =O, =S, OR 15 , -SR 15 , -SO 2 R 15 , -NR 16 R 17 , C 1-6 alkylene group -CR 15 R 16 R 17 , R 4A , C 1-6 alkylene group R 4A , C 2-6 Alkenylene R 4A , -OC 1-6 alkylene R 4A , -SC 1-6 alkylene R 4A , C 1-6 alkylene N R 16 R 17 , C 1-6 alkylene OR 15 , C 1-6 alkylene SR 15 , -OC 1-6 alkylene NR 16 R 17 , -SC 1-6 alkylene NR 16 R 17 , -OC 1-6 alkylene OR 15 , SC 1- 6 alkylene OR 15 , -OC 1-6 alkylene SR 15 , SC 1-6 alkylene SR 15 , -C(O)OR 15 , -C(O)R 15 , -C(S)OR 15 , -C(S)N R 16 R 17 and -C(O)N R 16 R 17 substituted C 6-10 aryl, 5-10 membered heteroaryl, C 4-15 cycloalkyl and 4-15 membered heterocycloalkyl, the C 4-15 cycloalkyl and 4 to 15 membered heterocycloalkyl are each independently a monocyclic, fused ring, bridged ring, or spirocyclic group, and the C 6 -10 aryl and 5 to 10 membered heteroaryl are each independently a monocyclic or condensed ring group, optionally, the C 6-10 aryl and 5 to 10 membered heteroaryl are each independently fused with 5-6 membered heterocycloalkyl or 5-6 membered cycloalkyl; in one of the technical solutions, R 4A is selected from unsubstituted or one or more independently selected from halogen, -CN, -OR 18 , -SR 18 , -NR 19 R 20 , C 1-6 fluoroalkyl group, C 1-6 alkyl group, -C(O)R 18 , -C(O)OR 18 , -C(O)NR 19 R 20 , -S(O)C 1-6 alkyl, -SO 2 C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-15 membered Heterocycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene C 3-10 heteroaryl, C 1-6 alkylene heterocycloalkyl, C 1-6 alkylene R 18 , C 1-6 alkylene OR 18 , C 1-6 alkylene SR 18 , C 1-6 alkylene -CR Substituents in 18 R 19 R 20 and C 1-6 alkylene NR 19 R 20 substituted C 3-10 cycloalkyl, 4-15 membered heterocycloalkyl, 5-10 membered heteroaryl and C 6 -10 aryl group, the C 3-10 cycloalkyl group and the 4 to 15-membered heterocycloalkyl group are each independently a monocyclic, condensed ring, bridged ring, or spirocyclic group, the C 6-10 aryl group and 5 to 10-membered heteroaryl groups are each independently a monocyclic or condensed ring group; in one of the technical solutions, each time R 9 and R 12 appear, they are each independently selected from H, C 1-6 alkyl , C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, -C(O)C 1-6 alkyl, -C(O)C 1-6 haloalkyl, - C(O)OC 1-6 alkyl, -C(O)NHC 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 HNC 1-6 alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene C 3-10 heterocycloalkyl base and C 1-6 alkylene C 3-10 cycloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1- 6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene C 3- 6Heterocycloalkyl and C 1-6 alkylene C 3-6 cycloalkyl are each independently selected from halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxyl, C 1-6 hydroxyalkyl, cyano, amino, nitro, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5 -Substituted by one or more substituents in the 10-membered heteroaryl group; preferably, R 9 and R 12 are each independently selected from H, C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O)C 1-6 Alkyl, C(O)C 1-6 fluoroalkyl, C 3-6 cycloalkyl, and 3-6 membered heterocycloalkyl, optionally, the C 1-6 alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently selected from F, Cl, Br, I, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl , hydroxyl, and one or more substituents in C 1 -C 3 hydroxyalkyl; in one of the technical solutions,
R10、R11、R13、和R14每次出现时各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、-C(O)C1-6烷基、-C(O)C1-6卤代烷基、-C(O)OC1-6烷基、-C(O)NHC1-6烷基、-SO2C1-6烷基、-SO2HNC1-6烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基杂环烷基和C1-6亚烷基C3-环烷基，任选地，所述C1-6烷基、C3-10环烷基、3-6元杂环烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基杂环烷基和C1-6亚烷基C3-6环烷基各自独立地被选自卤素、C1-6烷基、C1-6杂烷基、C1-6烷氧基、C1-6卤代烷基、羟基、C1-6羟烷基、氰基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；或者，R10和R11与其相连的C或N原子一起各自独立地形成未取代的或被一个或多个选自卤素、C1-3杂烷基、C1-3烷氧基、C1-3羟烷基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C6-10芳基、5-10元杂芳基、-CN、-OH、C1-3烷基、OC1-3烷基、C1-3氟烷基、-OC1-3氟烷基、-C(O)C1-3烷基、-C(O)C1-3氟烷基、-C(O)C1-3烷基、-C(O)NHC1-3烷基、-SO2C1-3烷基、-SO2HNC1-3烷基、C1-3亚烷基OC1-3烷基、C1-3亚烷基C6-10芳基、C1-3亚烷基C4-10杂芳基、C1-3亚烷基C3-6杂环烷基和C1-3亚烷基C3-6环烷基中的取代基取代的3-6元环烷基或3-6元杂环烷基；或者，R13和R14与其相连的C或N原子一起各自独立地形成未取代的或被一个或多个选自卤素、C1-3杂烷基、C1-3烷氧基、C1-3羟烷基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C6-10芳基、5-10元杂芳基、-CN、-OH、C1-3烷基、OC1-3烷基、C1-3氟烷基、-OC1-3氟烷基、-C(O)C1-3烷基、-C(O)C1-3氟烷基、-C(O)C1-3烷基、-C(O)NHC1-3烷基、-SO2C1-3烷基、-SO2HNC1-3烷基、C1-3亚烷基OC1-3烷基、C1-3亚烷基C6-10芳基、C1-3亚烷基C4-10杂芳基、C1-3亚烷基C3-6杂环烷基和C1-3亚烷基C3-6环烷基中的取代基取代的3-6元环烷基或3-6元杂环烷基；在其中一个技术方案中，R15每次出现时，各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、-C(O)C1-6烷基、-C(O)C1-6卤代烷基、-C(O)OC1-6烷基、-C(O)NHC1-6烷基、-SO2C1-6烷基、-SO2HNC1-6烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基杂环烷基和C1-6亚烷基C3-10环烷基，任选地，所述C1-6烷基、C3-10环烷基、3-10元杂环烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基C3-10杂环烷基和C1-6亚烷基C3-10环烷基被选自卤素、C1-6烷基、C1-6杂烷基、C1-6烷氧基、C1-6卤代烷基、羟基、C1-6羟烷基、氰基、氨基、硝基、C3-6环烷基、C3-6杂环烷基、C6-10芳基和C5-10杂芳基中的一个或多个取代基所取代；优选地，R15选自H、C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、-C(O)C1-6氟烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基、5-10元杂芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基和C1-6亚烷 基C3-10杂环烷基，任选地，所述C1-6烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基、5-10元杂芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基和C1-6亚烷基C3-10杂环烷基各自被选自F、Cl、Br、I、C1-C3烷基、C1-C3烷氧基、C1-C3卤代烷基、羟基、C1-C3羟烷基、氰基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；在其中一个技术方案中，R16和R17各自独立地选自H、C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、-C(O)C1-6氟烷基、-C(O)C6-10芳基、-C(O)C3-10环烷基、-C(O)C4-10杂芳基、-C(O)C3-15杂环烷基、-C(O)OC1-6烷基、-C(O)OC1-6氟烷基、-C(O)OC6-10芳基、-C(O)OC3-10环烷基、-C(O)OC4-10杂芳基、-C(O)OC3-15杂环烷基、-C(O)NHC1-6烷基、-C(O)NHC1-6氟烷基、-C(O)NHC6-10芳基、-C(O)NHC3-10环烷基、-C(O)NHC4-10杂芳基、-C(O)NHC3-15杂环烷基、-SO2C1-6烷基、-SO2C1-6氟烷基、-SO2C6-10芳基、-SO2C3-10环烷基、-SO2C4-10杂芳基、-SO2C3-15杂环烷基、C3-10环烷基、3-15元杂环烷基、5-10元杂芳基、C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基和C1-6亚烷基C3-15杂环烷基，任选地，所述C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、-C(O)C1-6氟烷基、-C(O)C6-10芳基、-C(O)C3-10环烷基、-C(O)C4-10杂芳基、-C(O)C3-15杂环烷基、-C(O)OC1-6烷基、-C(O)OC1-6氟烷基、-C(O)OC6-10芳基、-C(O)OC3-10环烷基、-C(O)OC4-10杂芳基、-C(O)OC3-15杂环烷基、-C(O)NHC1-6烷基、-C(O)NHC1-6氟烷基、-C(O)NHC6-10芳基、-C(O)NHC3-10环烷基、-C(O)NHC4-10杂芳基、-C(O)NHC3-15杂环烷基、-SO2C1-6烷基、-SO2C1-6氟烷基、-SO2C6-10芳基、-SO2C3-10环烷基、-SO2C4-10杂芳基、-SO2C3-15杂环烷基、C3-10环烷基、3-15元杂环烷基、5-10元杂芳基、C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基和C1-6亚烷基C3-15杂环烷基各自独立被选自卤素、-CN、-OR18、-SR18、-NR19R20、C1-6烷基、C1-6卤代烷基、C1-6羟烷基、-C(O)R18、-C(O)OR18、-C(O)NR19R20、-S(O)C1-6烷基、-SO2C1-6烷基、C6-10芳基、5-10元杂芳基、C3-10环烷基、3-15元杂环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C4-10杂芳基、和C1-6亚烷基C3-15杂环烷基中的一个或多个取代基取代；或者，R16和R17与它们所连接的氮原子或C原子一起形成3-6元杂环烷基或环烷基，所述3-6元杂环烷基和环烷基是未取代的或被一个或多个独立地选自卤素、-CN、硝基、-OR18、-SR18、-NR19R20、C1-6烷基、C1-6杂烷基、C1-6羟烷基、-C(O)R18、-C(O)OR18、-C(O)N R19R20、-S(O)C1-6烷基、-SO2C1-6烷基、C6-10芳基、5-10元杂芳基、C3-10环烷基、3-10元杂环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基R18、C1-6亚烷基OR18、C1-6亚烷基SR18和C1-6亚烷基NR19R20中的取代基取代；在其中一个技术方案中，R18选自H、C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、-C(O)C1-6氟烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基、5-10元杂芳基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基C3-10环烷基和C1-6亚烷基C3-10杂环烷基，任选地，所述C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、-C(O)C1-6氟烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基、5-10元 杂芳基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基C3-10环烷基和C1-6亚烷基C3-10杂环烷基各自独立地各被一个或多个选自卤素、-CN、C1-6烷基、C1-6氟烷基、-OH、-SH、-OC1-6烷基、-OC1-6氟烷基、-SC1-6烷基、-SC1-6氟烷基、-NH2、-NHC1-6烷基、-N(C1-6烷基)(C1-6烷基)、-C(O)C1-6烷基、-C(O)C1-6氟烷基、-C(O)OH、-C(O)OC1-6烷基、-C(O)NH2、-C(O)NHC1-6烷基、-C(O)N(C1-6烷基)(C1-6烷基)、-SO2C1-6烷基、-S(O)C1-6烷基、C6-10芳基、5-10元杂芳基、C3-10环烷基、3-10元杂环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基、C1-6羟基烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基SH、C1-6亚烷基SC1-6烷基、C1-6亚烷基NH2、C1-6亚烷基NHC1-6烷基和C1-6亚烷基N(C1-6烷基)(C1-6烷基)中的取代基取代；在其中一个技术方案中，R 10 , R 11 , R 13 , and R 14 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered hetero Cycloalkyl, -C(O)C 1-6 alkyl, -C(O)C 1-6 haloalkyl, -C(O)OC 1-6 alkyl, -C(O)NHC 1-6 alkyl base, -SO 2 C 1-6 alkyl, -SO 2 HNC 1-6 alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene heterocycloalkyl and C 1-6 alkylene C 3- cycloalkyl, optionally, the C 1- 6 alkyl, C 3-10 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene heterocycloalkyl and C 1-6 alkylene C 3-6 cycloalkyl are each independently selected from halogen, C 1 -6 alkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxyl, C 1-6 hydroxyalkyl, cyano, amino, nitro, C 3-6 Substituted with one or more substituents in cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl; alternatively, R 10 and R 11 are connected to C or N atoms together independently form unsubstituted or substituted by one or more selected from halogen, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, amino, nitro, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OH, C 1-3 alkyl, OC 1-3 alkyl , C 1-3 fluoroalkyl, -OC 1-3 fluoroalkyl, -C(O)C 1-3 alkyl, -C(O)C 1-3 fluoroalkyl, -C(O)C 1 -3 alkyl, -C(O)NHC 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 HNC 1-3 alkyl, C 1-3 alkylene OC 1-3 alkyl , C 1-3 alkylene C 6-10 aryl, C 1-3 alkylene C 4-10 heteroaryl, C 1-3 alkylene C 3-6 heterocycloalkyl and C 1-3 3-6-membered cycloalkyl or 3-6-membered heterocycloalkyl substituted by substituents in alkylene C 3-6 cycloalkyl; alternatively, R 13 and R 14 are each independent together with the C or N atom to which they are connected. Form unsubstituted or by one or more selected from halogen, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, amino, nitro, C 3-6 cycloalkyl Base, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OH, C 1-3 alkyl, OC 1-3 alkyl, C 1-3 Fluoroalkyl, -OC 1-3 fluoroalkyl, -C(O)C 1-3 alkyl, -C(O)C 1-3 fluoroalkyl, -C(O)C 1-3 alkyl, -C(O)NHC 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 HNC 1-3 alkyl, C 1-3 alkyleneOC 1-3 alkyl, C 1-3 Alkylene C 6-10 aryl, C 1-3 alkylene C 4-10 heteroaryl, C 1-3 alkylene C 3-6 heterocycloalkyl and C 1-3 alkylene C 3 -3-6 -membered cycloalkyl or 3-6-membered heterocycloalkyl substituted by substituents in the 6-cycloalkyl group; in one of the technical solutions, each time R 15 appears, each is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, -C(O)C 1-6 alkyl, -C(O)C 1- 6 haloalkyl, -C(O)OC 1-6 alkyl, -C(O)NHC 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 HNC 1-6 alkyl, C 1 -6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene heterocycle Alkyl and C 1-6 alkylene C 3-10 cycloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 1 -6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene C 3 -10 heterocycloalkyl and C 1-6 alkylene C 3-10 cycloalkyl are selected from halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxyl, C 1-6 hydroxyalkyl, cyano, amino, nitro, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 6-10 aryl and C 5 -10 is substituted by one or more substituents in the heteroaryl group; preferably, R 15 is selected from H, C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O)C 1-6 alkyl base, -C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1- 6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl and C 1-6 alkylene base C 3-10 heterocycloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 Metaheteroaryl, C 1-6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl and C The 1-6 alkylene C 3-10 heterocycloalkyl groups are each selected from F, Cl, Br, I, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl , hydroxyl, C 1 -C 3 hydroxyalkyl, cyano, amino, nitro, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl substituted by one or more substituents in the base; in one of the technical solutions, R 16 and R 17 are each independently selected from H, C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O )C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl, -C(O)C 6-10 aryl, -C(O)C 3-10 cycloalkyl, -C(O )C 4-10 heteroaryl, -C(O)C 3-15 heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)OC 1-6 fluoroalkyl, -C (O)OC 6-10aryl , -C(O)OC 3-10cycloalkyl , -C(O)OC 4-10heteroaryl , -C(O)OC 3-15heterocycloalkyl , -C(O)NHC 1-6 alkyl, -C(O)NHC 1-6 fluoroalkyl, -C(O)NHC 6-10 aryl, -C(O)NHC 3-10 cycloalkyl, -C(O)NHC 4-10 heteroaryl, -C(O)NHC 3-15 heterocycloalkyl, -SO 2 C 1-6 alkyl, -SO 2 C 1-6 fluoroalkyl, -SO 2 C 6-10 aryl, -SO 2 C 3-10 cycloalkyl, -SO 2 C 4-10 heteroaryl, -SO 2 C 3-15 heterocycloalkyl, C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene C 6-10 Aryl, C 1-6 alkylene C 4-10 heteroaryl and C 1-6 alkylene C 3-15 heterocycloalkyl, optionally, the C 1-6 alkyl, C 1- 6- fluoroalkyl, -C(O)C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl, -C(O)C 6-10 aryl, -C(O)C 3- 10 cycloalkyl, -C(O)C 4-10 heteroaryl, -C(O)C 3-15 heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)OC 1-6 fluoroalkyl, -C(O)OC 6-10 aryl, -C(O)OC 3-10 cycloalkyl, -C(O)OC 4-10 heteroaryl, -C(O) OC 3-15 heterocycloalkyl, -C(O)NHC 1-6 alkyl, -C(O)NHC 1-6 fluoroalkyl, -C(O)NHC 6-10 aryl, -C(O )NHC 3-10 cycloalkyl, -C(O)NHC 4-10 heteroaryl, -C(O)NHC 3-15 heterocycloalkyl, -SO 2 C 1-6 alkyl, -SO 2 C 1-6 fluoroalkyl, -SO 2 C 6-10 aryl, -SO 2 C 3-10 cycloalkyl, -SO 2 C 4-10 heteroaryl, -SO 2 C 3-15 heterocycloalkyl , C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkylene, C 3-10 cycloalkyl, C 1 -6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl and C 1-6 alkylene C 3-15 heterocycloalkyl are each independently selected from halogen, - CN, -OR 18 , -SR 18 , -NR 19 R 20 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, -C(O)R 18 , -C(O )OR 18 , -C(O)NR 19 R 20 , -S(O)C 1-6 alkyl, -SO 2 C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl , C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 alkylene, C 6-10 aryl, C 1-6 alkylene, C 3-10 cycloalkyl, C 1- 6 alkylene C 4-10 heteroaryl, and C 1-6 alkylene C 3-15 heterocycloalkyl is substituted with one or more substituents; alternatively, R 16 and R 17 are with the ones to which they are connected. The nitrogen atoms or C atoms together form a 3-6 membered heterocycloalkyl or cycloalkyl group that is unsubstituted or is one or more independently selected from halogen, -CN, nitro, -OR 18 , -SR 18 , -NR 19 R 20 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 hydroxyalkyl, -C(O)R 18 , -C(O)OR 18 , -C(O)N R 19 R 20 , -S(O)C 1-6 alkyl, -SO 2 C 1-6 alkyl, C 6-10 aryl, 5- 10-membered heteroaryl, C 3-10 cycloalkyl, 3-10-membered heterocycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 3-10 cycloalkyl group, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene R 18 , C 1-6 alkylene OR 18 , C 1-6 alkylene SR 18 and C 1- The substituents in 6 alkylene NR 19 R 20 are substituted; in one of the technical solutions, R 18 is selected from H, C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O)C 1- 6 alkyl, -C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene C 3-10 cycloalkyl and C 1-6 alkylene C 3-10 heterocycloalkyl, optionally, the C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O)C 1-6 alkyl, -C(O)C 1- 6 fluoroalkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered Heteroaryl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene C 3-10 cycloalkyl and C 1 -6 alkylene C 3-10 heterocycloalkyl is each independently selected from one or more halogen, -CN, C 1-6 alkyl, C 1-6 fluoroalkyl, -OH, -SH, -OC 1-6 alkyl, -OC 1-6 fluoroalkyl, -SC 1-6 alkyl, -SC 1-6 fluoroalkyl, -NH 2 , -NHC 1-6 alkyl, -N( C 1-6 alkyl) (C 1-6 alkyl), -C(O)C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl, -C(O)OH, -C( O)OC 1-6 alkyl, -C(O)NH 2 , -C(O)NHC 1-6 alkyl, -C(O)N(C 1-6 alkyl)(C 1-6 alkyl ), -SO 2 C 1-6 alkyl, -S(O)C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-10 One-membered heterocycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene heteroaryl, C 1-6 Alkylene heterocycloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene SH, C 1-6 alkylene SC 1-6 Alkyl, C 1-6 alkylene NH 2 , C 1-6 alkylene NHC 1-6 alkyl and C 1-6 alkylene N (C 1-6 alkyl) (C 1-6 alkyl ) in the substituent substitution; in one of the technical solutions,
R19和R20各自独立地选自H、C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、-C(O)C1-6氟烷基、C3-10环烷基、3-15元杂环烷基、5-10元杂芳基、C6-10芳基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基C3-15杂环烷基、-C(O)C6-10芳基、-C(O)C3-10环烷基、-C(O)C4-10杂芳基、-C(O)C3-15杂环烷基、-C(O)OC1-6烷基、-C(O)OC1-6氟烷基、-C(O)OC6-10芳基、-C(O)OC3-10环烷基、-C(O)OC4-10杂芳基、-C(O)OC3-15杂环烷基、-C(O)NHC1-6烷基、-C(O)NHC1-6氟烷基、-C(O)NHC6-10芳基、-C(O)NHC3-10环烷基、-C(O)NHC4-10杂芳基、-C(O)NHC3-15杂环烷基、-SO2C1-6烷基、-SO2C1-6氟烷基、-SO2C6-10芳基、-SO2C3-10环烷基、-SO2C4-10杂芳基、和-SO2C3-15杂环烷基，任选地，所述C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、-C(O)C1-6氟烷基、C3-10环烷基、3-15元杂环烷基、5-10元杂芳基、C6-10芳基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基C3-15杂环烷基、-C(O)C6-10芳基、-C(O)C3-10环烷基、-C(O)C4-10杂芳基、-C(O)C3-15杂环烷基、-C(O)OC1-6烷基、-C(O)OC1-6氟烷基、-C(O)OC6-10芳基、-C(O)OC3-10环烷基、-C(O)OC4-10杂芳基、-C(O)OC3-15杂环烷基、-C(O)NHC1-6烷基、-C(O)NHC1-6氟烷基、-C(O)NHC6-10芳基、-C(O)NHC3-10环烷基、-C(O)NHC4-10杂芳基、-C(O)NHC3-15杂环烷基、-SO2C1-6烷基、-SO2C1-6氟烷基、-SO2C6-10芳基、-SO2C3-10环烷基、-SO2C4-10杂芳基、和-SO2C3-15杂环烷基被一个或多个独立地选自卤素、-CN、C1-6烷基、C1-6氟烷基、-OH、-SH、-OC1-6烷基、-OC1-6氟烷基、-SC1-6烷基、-SC1-6氟烷基、-NH2、-NHC1-6烷基、-N(C1-6烷基)(C1-6烷基)、-C(O)C1-6烷基、-C(O)C1-6氟烷基、-C(O)OH、-C(O)OC1-6烷基、-C(O)NH2、-C(O)NHC1-6烷基、-C(O)N(C1-6烷基)(C1-6烷基)、-SO2C1-6烷基、-S(O)C1-6烷基、C6-10芳基、5-10元杂芳基、C3-10环烷基、C3-15杂环烷基、-C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基C3-15杂环烷基、C1-6亚烷基OH、C1-6亚烷基OC1-6烷基、C1-6亚烷基SH、C1-6亚烷基SC1-6烷基、C1-6亚烷基NH2、C1-6亚烷基NHC1-6烷基和-C1-6亚烷基N(C1-6烷基)(C1-6烷基)中的一个或多取代基取代；或者，R19和R20与它们所连接的氮原子或C原子一起形成3-6元杂环烷基或环烷基，所述3-6元杂环烷基和环烷基是未取代的或被一个或多个选自卤素、-CN、硝基、C1-6烷基、C1-6氟烷 基、-OH、SH、-OC1-6烷基、-OC1-6氟烷基、-SC1-6烷基、-SC1-6氟烷基、-NH2、-NHC1-6烷基、-N(C1-6烷基)(C1-6烷基)、-C(O)C1-6烷基、-C(O)C1-6氟烷基、-C(O)OH、-C(O)OC1-6烷基、-C(O)NH2、-C(O)NHC1-6烷基、-C(O)N(C1-6烷基)(C1-6烷基)、-SO2C1-6烷基、-S(O)C1-6烷基、C6-10芳基、5-10元杂芳基、C3-10环烷基、3-15元杂环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基C3-10杂环烷基、C1-6亚烷基OH、C1-6亚烷基OC1-6烷基、C1-6亚烷基SH、C1-6亚烷基SC1-6烷基、C1-6亚烷基NH2、C1-6亚烷基NHC1-6烷基和C1-6亚烷基N(C1-6烷基)(C1-6烷基)中的取代基取代；在其中一个技术方案中，R21选自H、羟基、氨基、C1-6烷基、C1-6烷氧基、F、Cl、Br、和I。R 19 and R 20 are each independently selected from H, C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O)C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl Base, C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkylene, C 6-10 aryl, C 1 -6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene C 3-15 heterocycloalkyl, -C(O)C 6-10 aryl, -C(O)C 3-10 cycloalkyl, -C(O)C 4-10 heteroaryl, -C(O)C 3-15 heterocycloalkyl, -C(O )OC 1-6 alkyl, -C(O)OC 1-6 fluoroalkyl, -C(O)OC 6-10 aryl, -C(O)OC 3-10 cycloalkyl, -C(O )OC 4-10 heteroaryl, -C(O)OC 3-15 heterocycloalkyl, -C(O)NHC 1-6 alkyl, -C(O)NHC 1-6 fluoroalkyl, -C (O)NHC 6-10 aryl, -C(O)NHC 3-10 cycloalkyl, -C(O)NHC 4-10 heteroaryl, -C(O)NHC 3-15 heterocycloalkyl, -SO 2 C 1-6 alkyl, -SO 2 C 1-6 fluoroalkyl, -SO 2 C 6-10 aryl, -SO 2 C 3-10 cycloalkyl, -SO 2 C 4-10 hetero Aryl, and -SO 2 C 3-15 heterocycloalkyl, optionally, the C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O)C 1-6 alkyl, - C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene C 3-15 hetero Cycloalkyl, -C(O)C 6-10 aryl, -C(O)C 3-10 cycloalkyl, -C(O)C 4-10 heteroaryl, -C(O)C 3- 15 Heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)OC 1-6 fluoroalkyl, -C(O)OC 6-10 aryl, -C(O)OC 3 -10 cycloalkyl, -C(O)OC 4-10 heteroaryl, -C(O)OC 3-15 heterocycloalkyl, -C(O)NHC 1-6 alkyl, -C(O) NHC 1-6 fluoroalkyl, -C(O)NHC 6-10 aryl, -C(O)NHC 3-10 cycloalkyl, -C(O)NHC 4-10 heteroaryl, -C(O )NHC 3-15 heterocycloalkyl, -SO 2 C 1-6 alkyl, -SO 2 C 1-6 fluoroalkyl, -SO 2 C 6-10 aryl, -SO 2 C 3-10 cycloalkyl base, -SO 2 C 4-10 heteroaryl, and -SO 2 C 3-15 heterocycloalkyl are one or more independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 Fluoroalkyl, -OH, -SH, -OC 1-6 alkyl, -OC 1-6 fluoroalkyl, -SC 1-6 alkyl, -SC 1-6 fluoroalkyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -C(O)C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH 2 , -C(O)NHC 1-6 alkyl, -C(O)N(C 1-6 Alkyl) (C 1-6 alkyl), -SO 2 C 1-6 alkyl, -S(O)C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, C 3-15 heterocycloalkyl, -C 1-6 alkylene, C 6-10 aryl, C 1-6 alkylene, C 3-10 cycloalkyl, C 1-6 Alkylene C 4-10 heteroaryl, C 1-6 alkylene C 3-15 heterocycloalkyl, C 1-6 alkylene OH, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene SH, C 1-6 alkylene SC 1-6 alkyl, C 1-6 alkylene NH 2 , C 1-6 alkylene NHC 1-6 alkyl and -C 1 -6 Alkylene N (C 1-6 alkyl) (C 1-6 alkyl) is substituted with one or more substituents; alternatively, R 19 and R 20 form together with the nitrogen atom or C atom to which they are connected 3-6 membered heterocycloalkyl or cycloalkyl, the 3-6 membered heterocycloalkyl and cycloalkyl are unsubstituted or substituted by one or more selected from halogen, -CN, nitro, C 1- 6 alkyl, C 1-6 fluoroalkyl base, -OH, SH, -OC 1-6 alkyl, -OC 1-6 fluoroalkyl, -SC 1-6 alkyl, -SC 1-6 fluoroalkyl, -NH 2 , -NHC 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -C(O)C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl, -C( O)OH, -C(O)OC 1-6 alkyl, -C(O)NH 2 , -C(O)NHC 1-6 alkyl, -C(O)N(C 1-6 alkyl) (C 1-6 alkyl), -SO 2 C 1-6 alkyl, -S(O)C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene, C 3-10 heterocycloalkyl, C 1-6 alkylene OH, C 1-6 alkylene OC 1-6 alkyl, C 1-6 Alkylene SH, C 1-6 alkylene SC 1-6 alkyl, C 1-6 alkylene NH 2 , C 1-6 alkylene NHC 1-6 alkyl and C 1-6 alkylene The substituents in N(C 1-6 alkyl)(C 1-6 alkyl) are substituted; in one of the technical solutions, R 21 is selected from H, hydroxyl, amino, C 1-6 alkyl, C 1- 6Alkoxy , F, Cl, Br, and I.
在其中一个技术方案中，其特征在于，In one of the technical solutions, it is characterized by:
R1A是未取代的或取代的含有至少一个氮原子的4-10元杂环烷基，所述4-10元杂环烷基为单环杂环烷基、稠环杂环烷基、螺环杂环烷基或桥环杂环烷基，所述取代的含有至少一个氮原子的4-10元杂环烷基被选自下述的一个、两个、三个或更多个取代基取代：F、Cl、Br、I、、C1-3烷基、C1-3氟烷基、C3-6环烷基、3-6元杂环烷基、OR9、-SR9、C1-3亚烷基OH、C1-3亚烷基-CR9R10R11、、-NR10R11、和C1-3亚烷基NR10R11，其中，任选地，所述C1-3烷基、C1-3氟烷基、C3-6环烷基、3-6元杂环烷基、C1-3亚烷基OH、C1-3亚烷基-CR9R10R11和C1-3亚烷基NR10R11，各自独立地被选自F、Cl、Br、I、C1-3烷基、C1-3烷氧基、C1-3卤代烷基、羟基、C1-3羟烷基、氰基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C2-3烯基、C2-3炔基、C1-3烷基氨基、C1-3烷基酰基、C1-3烷基氧基酰基、C1-3烷基氨基酰基、C6-10芳基和5-6元杂芳基中的一个或多个取代基所取代，优选地，所述取代的含有至少一个氮原子的4-10元杂环烷基被选自下述的一个、两个、三个或更多个取代基取代：F、Cl、Br、I、甲基、乙基、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-CH2CH2F、环丙基、环丙基亚甲基、环丁基、环丁基亚甲基、环戊基、环戊基亚甲基、环己基、环己基亚甲基、甲氧基、氨基、和羟基；优选地，所述R1A选自未取代或被一个或多个取代基取代的以下基团：
R 1A is an unsubstituted or substituted 4-10-membered heterocycloalkyl group containing at least one nitrogen atom, and the 4-10-membered heterocycloalkyl group is a monocyclic heterocycloalkyl group, a condensed ring heterocycloalkyl group, or a spiro group. Cyclic heterocycloalkyl or bridged cyclic heterocycloalkyl, the substituted 4-10 membered heterocycloalkyl containing at least one nitrogen atom is selected from one, two, three or more substituents below Substitution: F, Cl, Br, I,, C 1-3 alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, OR 9 , -SR 9 , C 1-3 alkylene OH, C 1-3 alkylene -CR 9 R 10 R 11 , -NR 10 R 11 , and C 1-3 alkylene NR 10 R 11 , wherein, optionally, The C 1-3 alkyl group, C 1-3 fluoroalkyl group, C 3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C 1-3 alkylene OH, C 1-3 alkylene group -CR 9 R 10 R 11 and C 1-3 alkylene NR 10 R 11 , each independently selected from F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, hydroxyl, C 1-3 hydroxyalkyl, cyano, amino, nitro, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 2-3 alkenyl, C 2 -3 alkynyl, C 1-3 alkylamino, C 1-3 alkyl acyl, C 1-3 alkyloxyacyl, C 1-3 alkylaminoacyl, C 6-10 aryl and 5-6 The substituted heteroaryl group is substituted with one or more substituents. Preferably, the substituted 4-10-membered heterocycloalkyl group containing at least one nitrogen atom is selected from one, two, three or More substituents: F, Cl, Br, I, methyl, ethyl, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclobutylmethylene, cyclopentyl, cyclopentylmethylene, cyclohexyl, cyclohexylmethylene, methoxy, amino , and hydroxyl; preferably, the R 1A is selected from the following groups that are unsubstituted or substituted by one or more substituents:
所述取代基选自F、Cl、Br、I、C1-3烷基、C1-3氟烷基、C3-6环烷基、3-6元杂环烷基、OR9、-SR9、C1-3亚烷基OH、C1-3亚烷基-CR9R10R11、-NR10R11、和C1-3亚烷基NR10R11，其中，任选地，所述C1-3烷基、C1-3氟烷基、C3-6环烷基、3-6元杂环烷基、C1-3亚烷基OH、C1-3亚烷基-CR9R10R11和C1-3亚烷基NR10R11，各自独立地被选自F、Cl、Br、I、C1-3烷基、C1-3烷氧基、C1-3卤代 烷基、羟基、C1-3羟烷基、氰基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C2-3烯基、C2-3炔基、C1-3烷基氨基、C1-3烷基酰基、C1-3烷基氧基酰基、C1-3烷基氨基酰基、C6-10芳基和5-6元杂芳基中的一个或多个所取代；优选地，所述R1A选自未取代或被一个或多个取代基取代的以下基团：
The substituent is selected from F, Cl, Br, I, C 1-3 alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, OR 9 , - SR 9 , C 1-3 alkylene OH, C 1-3 alkylene -CR 9 R 10 R 11 , -NR 10 R 11 , and C 1-3 alkylene NR 10 R 11 , wherein optionally Ground, the C 1-3 alkyl group, C 1-3 fluoroalkyl group, C 3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C 1-3 alkylene OH, C 1-3 alkylene group Alkyl-CR 9 R 10 R 11 and C 1-3 alkylene NR 10 R 11 , each independently selected from F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy , C 1-3 halogenated Alkyl, hydroxyl, C 1-3 hydroxyalkyl, cyano, amino, nitro, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 2-3 alkenyl, C 2-3 alkyne group, C 1-3 alkylamino, C 1-3 alkyl acyl, C 1-3 alkyloxyacyl, C 1-3 alkylaminoacyl, C 6-10 aryl and 5-6 membered heteroaryl substituted by one or more of the groups; preferably, the R 1A is selected from the following groups that are unsubstituted or substituted by one or more substituents:
所述取代基选自：F、Cl、Br、I、甲基、乙基、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-CH2CH2F、环丙基、环丙基亚甲基、环丁基、环丁基亚甲基、环戊基、环戊基亚甲基、环己基、环己基亚甲基、甲氧基、氨基、和羟基；其中，R9、R10、和R11如权利要求1或2中所定义，优选地，R9每次出现时各自独立选自H、C1-3烷基、C1-3氟烷基、-C(O)C1-3烷基、C(O)C1-3氟烷基、C3-6环烷基、和3-6元杂环烷基；R10和R11每次出现时各自独立地选自H、C1-3烷基、C1-3卤代烷基、C3-6环烷基、3-6元杂环烷基、-C(O)C1-3烷基、-C(O)C1-3卤代烷基、-C(O)OC1-3烷基、-C(O)NHC1-3烷基、C1-6亚烷基C3-6杂环烷基和C1-6亚烷基C3-6环烷基，或者，R10和R11与其相连的C或N原子一起各自独立地形成未取代的或被一个或多个选自卤素、C1-3羟烷基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C6-10芳基、5-6元杂芳基、-CN、-OH、C1-3烷基、OC1-3烷基、C1-3氟烷基、-OC1-3氟烷基、-C(O)C1-3烷基、-C(O)C1-3氟烷基、-C(O)C1-3烷基、-C(O)NHC1-3烷基、C1-3亚烷基OC1-3烷基、C1-3亚烷基C3-6杂环烷基和C1-3亚烷基C3-6环烷基中的取代基取代的3-6元环烷基或3-6元杂环烷基；在其中一个技术方案中，R2A是未取代的或取代的C6-10芳基、5-6元杂芳基或5-6元杂环烷基，所述5-6元杂芳基和5-6元杂环烷基各自独立地含有1、2或3个各自独立选自N、O或S的杂原子，任选地，所述未取代的或取代的C6-10芳基和5-6元杂芳基各自独立地稠和于5、6、7、8、或9元杂环烷基或环烷基，所述取代的C6-10芳基、5-6元杂芳基和5-6元杂环烷基各自独立地被选自下述的一个、两个、三个、四个或更多个取代基取代：F、Cl、Br、I、＝O、＝S、C1-3烷基、C1-3氟代烷基、C1-3烷氧基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-OH、-SH、C1-3亚烷基-OH、C1-3亚烷基-SH、氨基、和C1-3亚烷基-N(C1-3烷基)2，且当R2A是取代的C6-10芳基时，所述取代的C6-10杂芳基不被＝O或＝S取代；优选地，R2A选自： The substituent is selected from: F, Cl, Br, I, methyl, ethyl, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclobutylmethylene, cyclopentyl, cyclopentylmethylene, cyclohexyl, cyclohexylmethylene, methoxy, amino , and hydroxyl; wherein, R 9 , R 10 , and R 11 are as defined in claim 1 or 2. Preferably, R 9 is independently selected from H, C 1-3 alkyl, C 1- 3- fluoroalkyl, -C(O)C 1-3 alkyl, C(O)C 1-3 fluoroalkyl, C 3-6 cycloalkyl, and 3-6 membered heterocycloalkyl; R 10 and Each occurrence of R 11 is independently selected from H, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C(O)C 1-3 alkyl, -C(O)C 1-3 haloalkyl, -C(O)OC 1-3 alkyl, -C(O)NHC 1-3 alkyl, C 1-6 alkylene C 3-6 heterocycloalkyl and C 1-6 alkylene C 3-6 cycloalkyl, or R 10 and R 11 together with the C or N atom to which they are attached independently form unsubstituted or substituted by one or more Each is selected from halogen, C 1-3 hydroxyalkyl, amino, nitro, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, -CN, -OH, C 1-3 alkyl, OC 1-3 alkyl, C 1-3 fluoroalkyl, -OC 1-3 fluoroalkyl, -C(O)C 1-3 alkyl, - C(O)C 1-3 fluoroalkyl, -C(O)C 1-3 alkyl, -C(O)NHC 1-3 alkyl, C 1-3 alkyleneOC 1-3 alkyl, 3-6 -membered cycloalkyl or 3-6-membered heterocycle substituted by substituents in C 1-3 alkylene C 3-6 heterocycloalkyl and C 1-3 alkylene C 3-6 cycloalkyl Alkyl; in one of the technical solutions, R 2A is an unsubstituted or substituted C 6-10 aryl group, a 5-6 membered heteroaryl group or a 5-6 membered heterocycloalkyl group, and the 5-6 membered heteroaryl group Aryl and 5-6 membered heterocycloalkyl each independently contain 1, 2 or 3 heteroatoms each independently selected from N, O or S, optionally, the unsubstituted or substituted C 6-10 Aryl and 5-6-membered heteroaryl are each independently condensed with 5, 6, 7, 8, or 9-membered heterocycloalkyl or cycloalkyl, and the substituted C 6-10 aryl, 5-6 Each of the 5-6-membered heteroaryl and 5-6-membered heterocycloalkyl is independently substituted with one, two, three, four or more substituents selected from the following: F, Cl, Br, I, =O , =S, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl , 5-6 membered heteroaryl, -OH, -SH, C 1-3 alkylene-OH, C 1-3 alkylene-SH, amino, and C 1-3 alkylene-N(C 1 -3 alkyl) 2 , and when R 2A is a substituted C 6-10 aryl group, the substituted C 6-10 heteroaryl group is not substituted by =O or =S; preferably, R 2A is selected from:
中的任一种，其中，R5A每次出现时各自独立地选自F、Cl、Br、I、C1-3烷基、C1-3氟烷基、C1-3烷氧基和氨基，优选地各自独立地选自F、Cl、Br、I、甲基、二氟甲基、三氟甲基、氟甲基、甲氧基和氨基；n每次出现时各自独立地为0、1、2或3；和/或 Any of, wherein each occurrence of R 5A is independently selected from F, Cl, Br, I, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-3 alkoxy and Amino groups are preferably each independently selected from F, Cl, Br, I, methyl, difluoromethyl, trifluoromethyl, fluoromethyl, methoxy and amino; each occurrence of n is independently 0 , 1, 2 or 3; and/or
R3A选自未取代的或被一个或多个选自卤素、-CN、C1-3烷基、C1-3氟烷基、＝O、＝S、OR15、-NR16R17、R4A、C1-3亚烷基R4A、C1-6亚烷基NR16R17、-C(O)OR15、-C(O)R15、和-C(O)NR16R17中的取代基取代的C6-10芳基、5-10元杂芳基、C4-11环烷基和4-11元杂环烷基，所述C4-11环烷基和4至11元杂环烷基各自独立地为单环、稠环、桥环、或螺环基团，所述4至11元杂环烷基和所述5至10元杂芳基各自独立地包含1、2或3个选自N、O和S的杂原子，所述C6-10芳基和5至10元杂芳基各自独立地为单环或稠环基团，任选地，所述C6-10芳基和5至10元杂芳基各自独立地稠和于5-6元杂环烷基或5-6元环烷基；优选地，R3A选自未取代的或被一个或多个选自卤素、-CN、C1-3烷基、C1-3氟烷基、＝O、＝S、OR15、-NR16R17、R4A、C1-3亚烷基R4A、C1-6亚烷基NR16R17、-C(O)OR15、-C(O)R15、和-C(O)NR16R17中的取代基取代的下述基团：R 3A is selected from unsubstituted or one or more selected from halogen, -CN, C 1-3 alkyl, C 1-3 fluoroalkyl, =O, =S, OR 15 , -NR 16 R 17 , R 4A , C 1-3 alkylene R 4A , C 1-6 alkylene NR 16 R 17 , -C(O)OR 15 , -C(O)R 15 , and -C(O)NR 16 R C 6-10 aryl, 5-10 membered heteroaryl, C 4-11 cycloalkyl and 4-11 membered heterocycloalkyl substituted by the substituents in 17 , the C 4-11 cycloalkyl and 4 to 11-membered heterocycloalkyl groups are each independently a monocyclic, fused ring, bridged ring, or spirocyclic group, and the 4- to 11-membered heterocycloalkyl groups and the 5- to 10-membered heteroaryl groups each independently include 1, 2 or 3 heteroatoms selected from N, O and S, the C 6-10 aryl group and the 5 to 10-membered heteroaryl group are each independently a monocyclic or condensed ring group, optionally, the The C 6-10 aryl group and the 5- to 10-membered heteroaryl group are each independently condensed with a 5-6-membered heterocycloalkyl group or a 5-6-membered cycloalkyl group; preferably, R 3A is selected from unsubstituted or substituted One or more selected from halogen, -CN, C 1-3 alkyl, C 1-3 fluoroalkyl, =O, =S, OR 15 , -NR 16 R 17 , R 4A , C 1-3 alkylene The following are substituted by the substituents in the group R 4A , C 1-6 alkylene NR 16 R 17 , -C(O)OR 15 , -C(O)R 15 , and -C(O)NR 16 R 17 Group:
R15、R16、R17、和R4A如权利要求1或2中所定义，优选地，R15选自H、C1-6烷基、C1-6氟烷基、C(O)C1-6烷基、和C(O)C1-6氟烷基，任选地，所述C1-6烷基被选自F、Cl、Br、I、C1-C3烷氧基、羟基、氰基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C6-10芳基和5-6元杂芳基中的一个或多个取代基所取代；优选地，R16和R17各自独立地选自H、C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、-C(O)C1-6氟烷基、-C(O)C6-10芳基、-C(O)C3-10环烷基、-C(O)C4-10杂芳基、-C(O)C3-15杂环烷基、-C(O)OC1-6烷基、-C(O)OC1-6氟烷基、-C(O)OC6-10芳基、-C(O)OC3-10环烷基、-C(O)OC3-15杂环烷基、-C(O)NHC1-6烷基、-C(O)NHC1-6氟烷基、-C(O)NHC6-10芳基、-C(O)NHC3-10环烷基、-C(O)NHC4-10杂芳基、-C(O)NHC3-15杂环烷基、C3-10环烷基、3-15元杂环烷基、5-10元杂芳基、C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基和C1-6亚烷基C3-15杂环烷基，任选地，所述C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、-C(O)C1-6氟烷基、-C(O)C6-10芳基、-C(O)C3-10环烷基、-C(O)C4-10杂芳基、-C(O)C3-15杂环烷基、-C(O)OC1-6烷基、-C(O)OC1-6氟烷基、-C(O)OC6-10芳基、-C(O)OC3-10环烷基、-C(O)OC4-10杂芳基、-C(O)OC3-15杂环烷基、-C(O)NHC1-6烷基、-C(O)NHC1-6氟烷基、-C(O)NHC6-10芳基、-C(O)NHC3-10环烷基、-C(O)NHC4-10杂芳基、-C(O)NHC3-15杂环烷基、C3-10环烷基、3-15元杂环烷基、5-10元杂芳基、C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基和C1-6亚烷基C3-15杂环烷基各自独立被选自卤素、-CN、-OH、-SH、C1-3烷基、-OC1-3烷基、氨基、-NHC1-3烷基、-N(C1-3烷基)2、NHC(O)C1-3、C1-3卤代烷基、C1-3羟烷基、-C(O)H、-C(O)C1-3烷基、-C(O)OH、-C(O)O C1-3烷基、-C(O)NH2、-C(O)NHC1-3烷基、-C(O)N(C1-3烷基)2、C6-10芳基、5-6元杂芳基、C3-6环烷基、3-6元杂环烷基、C1-3亚烷基C6-10芳基、C1-3亚烷基C3-6环烷基、C1-3亚烷基C4-10杂芳基、和C1-3亚烷基C3-6杂环烷基中的一个或多个取代基取代，或者，R16和R17与它们所连接的氮原子或C原子一起形成3-6元杂环烷基或环烷基，所述3-6元杂环烷基和环烷基是未取代的或被一个或多个独立地选自卤素、-CN、-OH、-SH、-OC1-3烷基、氨基、C1-3烷基、-NHC1-3烷基、-N(C1-3烷基)2、NHC(O)C1-3、C1-3卤代烷基、C1-3羟烷基、-C(O)H、-C(O)C1-3烷基、-C(O)OH、-C(O)O C1-3烷基、-C(O)NH2、-C(O)NHC1-3烷基、-C(O)N(C1-3烷基)2、C6-10芳基、5-6元杂芳基、C3-6环烷基、3-6元杂环烷基、C1-3亚烷基C6-10芳基、 C1-3亚烷基C3-6环烷基、C1-3亚烷基C4-10杂芳基、C1-3亚烷基NHC1-3烷基、C1-3亚烷基N(C1-3烷基)2、C1-3亚烷基NH2和C1-3亚烷基C3-6杂环烷基中的一个或多个取代基取代；优选地，R4A选自未取代的或被一个或多个独立地选自卤素、-CN、-OH、-SH、C1-3烷基、-OC1-3烷基、氨基、-NHC1-3烷基、-N(C1-3烷基)2、NHC(O)C1-3烷基、C1-3卤代烷基、C1-3羟烷基、-C(O)H、-C(O)C1-3烷基、-C(O)OH、-C(O)O C1-3烷基、-C(O)NH2、-C(O)NHC1-3烷基、-C(O)N(C1-3烷基)2、C6-10芳基、5-6元杂芳基、C3-6环烷基、3-6元杂环烷基、C1-3亚烷基C6-10芳基、C1-3亚烷基C3-6环烷基、C1-3亚烷基C4-10杂芳基、和C1-3亚烷基C3-6杂环烷基中的一个或多个取代基取代的C3-10环烷基、4-15元杂环烷基、5-10元杂芳基和C6-10芳基，所述C3-10环烷基和4至15元杂环烷基各自独立地为单环、稠环、桥环、或螺环基团，所述C6-10芳基和5至10元杂芳基各自独立地为单环或稠环基团，所述4至15元杂环烷基和5-10元杂芳基各自独立地包含有1、2或3个独立选自N、O、和S的杂原子；优选地，R4A选自未取代的或被一个或多个独立地选自F、-CH3、-C2H5、-OH、-OCH3、-C(O)CH3、-NH2、-C(O)NHCH3、-COOH、-NH(CH3)2、-C(O)N(CH3)2、 -CN和-CF3的取代基所取代的C3-10环烷基、4-15元杂环烷基、5-10元杂芳基和C6-10芳基，所述C3-10环烷基和4至15元杂环烷基各自独立地为单环、稠环、桥环、或螺环基团，所述C6-10芳基和5至10元杂芳基各自独立地为单环或稠环基团，所述4至15元杂环烷基和5-10元杂芳基各自独立地包含有1、2或3个独立选自N、O、和S的杂原子； R 15 , R 16 , R 17 , and R 4A are as defined in claim 1 or 2. Preferably, R 15 is selected from H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O) C 1-6 alkyl, and C(O)C 1-6 fluoroalkyl, optionally, the C 1-6 alkyl is selected from F, Cl, Br, I, C 1 -C 3 alkoxy One or more substitutions among hydroxyl, cyano, amino, nitro, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-6 membered heteroaryl substituted with a group; preferably, R 16 and R 17 are each independently selected from H, C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O)C 1-6 alkyl, -C(O )C 1-6 fluoroalkyl, -C(O)C 6-10 aryl, -C(O)C 3-10 cycloalkyl, -C(O)C 4-10 heteroaryl, -C( O)C 3-15 heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)OC 1-6 fluoroalkyl, -C(O)OC 6-10 aryl, -C (O)OC 3-10 cycloalkyl, -C(O)OC 3-15 heterocycloalkyl, -C(O)NHC 1-6 alkyl, -C(O)NHC 1-6 fluoroalkyl, -C(O)NHC 6-10aryl , -C(O)NHC 3-10cycloalkyl , -C(O)NHC 4-10heteroaryl , -C(O)NHC 3-15heterocycloalkyl Base, C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkylene, C 3-10 cycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl and C 1-6 alkylene C 3-15 heterocycloalkyl, optionally, the C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O)C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl, -C(O)C 6-10 aromatic base, -C(O)C 3-10 cycloalkyl, -C(O)C 4-10 heteroaryl, -C(O)C 3-15 heterocycloalkyl, -C(O)OC 1- 6 alkyl, -C(O)OC 1-6 fluoroalkyl, -C(O)OC 6-10 aryl, -C(O)OC 3-10 cycloalkyl, -C(O)OC 4- 10 heteroaryl, -C(O)OC 3-15 heterocycloalkyl, -C(O)NHC 1-6 alkyl, -C(O)NHC 1-6 fluoroalkyl, -C(O)NHC 6-10aryl , -C(O)NHC 3-10cycloalkyl , -C(O)NHC 4-10heteroaryl , -C(O)NHC 3-15heterocycloalkyl , C 3-10 Cycloalkyl, 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkylene, C 3-10 cycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl and C 1-6 alkylene C 3-15 heterocycloalkyl are each independently selected from halogen, -CN, -OH, -SH, C 1-3 alkyl, -OC 1-3 alkyl, amino, -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , NHC(O)C 1-3 , C 1-3 haloalkyl, C 1-3 hydroxyalkyl, -C(O)H, -C(O)C 1-3 alkyl, -C(O)OH, -C(O)O C 1-3 alkyl base, -C(O)NH 2 , -C(O)NHC 1-3 alkyl, -C(O)N(C 1-3 alkyl) 2 , C 6-10 aryl, 5-6 membered hetero Aryl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-3 alkylene C 6-10 aryl, C 1-3 alkylene C 3-6 cycloalkyl, C 1-3 alkylene C 4-10 heteroaryl, and C 1-3 alkylene C 3-6 heterocycloalkyl are substituted with one or more substituents, or R 16 and R 17 are substituted with one or more substituents of C 1-3 alkylene C 3-6 heterocycloalkyl. The attached nitrogen atoms or C atoms together form a 3-6 membered heterocycloalkyl or cycloalkyl group that is unsubstituted or is independently selected from one or more Halogen, -CN, -OH, -SH, -OC 1-3 alkyl, amino, C 1-3 alkyl, -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , NHC ( O)C 1-3 , C 1-3 haloalkyl, C 1-3 hydroxyalkyl, -C(O)H, -C(O)C 1-3 alkyl, -C(O)OH, -C (O)O C 1-3 alkyl, -C(O)NH 2 , -C(O)NHC 1-3 alkyl, -C(O)N(C 1-3 alkyl) 2 , C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-3 alkylene C 6-10 aryl, C 1-3 alkylene C 3-6 cycloalkyl, C 1-3 alkylene C 4-10 heteroaryl, C 1-3 alkylene NHC 1-3 alkyl, C 1-3 alkylene Substituted with one or more substituents of N(C 1-3 alkyl) 2 , C 1-3 alkylene NH 2 and C 1-3 alkylene C 3-6 heterocycloalkyl; preferably, R 4A is selected from unsubstituted or by one or more independently selected from halogen, -CN, -OH, -SH, C 1-3 alkyl, -OC 1-3 alkyl, amino, -NHC 1-3 Alkyl, -N(C 1-3 alkyl) 2 , NHC(O)C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl , -C(O)H, -C (O)C 1-3 alkyl, -C(O)OH, -C(O)O C 1-3 alkyl, -C(O)NH 2 , -C(O)NHC 1-3 alkyl, - C(O)N(C 1-3 alkyl) 2 , C 6-10 aryl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1- 3 alkylene C 6-10 aryl, C 1-3 alkylene C 3-6 cycloalkyl, C 1-3 alkylene C 4-10 heteroaryl, and C 1-3 alkylene C C 3-10 cycloalkyl, 4-15 membered heterocycloalkyl, 5-10 membered heteroaryl and C 6-10 aryl substituted by one or more substituents in 3-6 heterocycloalkyl, so The C 3-10 cycloalkyl and 4 to 15-membered heterocycloalkyl groups are each independently a monocyclic, fused ring, bridged ring, or spirocyclic group, and the C 6-10 aryl and 5 to 10-membered heterocyclic alkyl groups are each independently a monocyclic, condensed ring, bridged ring, or spirocyclic group. The aryl groups are each independently a monocyclic or condensed ring group, and the 4- to 15-membered heterocycloalkyl and 5-10-membered heteroaryl groups each independently contain 1, 2 or 3 independently selected from N, O, and heteroatoms of S; preferably, R 4A is selected from unsubstituted or by one or more independently selected from F, -CH 3 , -C 2 H 5 , -OH, -OCH 3 , -C(O) CH 3 , -NH 2 , -C(O)NHCH 3 , -COOH, -NH(CH 3 ) 2 , -C(O)N(CH 3 ) 2 , -CN and -CF 3 substituents substituted C 3-10 cycloalkyl, 4-15 membered heterocycloalkyl, 5-10 membered heteroaryl and C 6-10 aryl, the C 3-10 The cycloalkyl group and the 4- to 15-membered heterocycloalkyl group are each independently a monocyclic, condensed ring, bridged ring, or spirocyclic group, and the C 6-10 aryl group and the 5- to 10-membered heteroaryl group are each independently It is a monocyclic or condensed ring group, and the 4- to 15-membered heterocycloalkyl and 5-10-membered heteroaryl groups each independently contain 1, 2 or 3 heteroatoms independently selected from N, O, and S. ;
其中，波形线表示连接点。Among them, wavy lines represent connection points.
在其中一个技术方案中，其特征在于，In one of the technical solutions, it is characterized by:
R1A选自下述基团：R 1A is selected from the following groups:
在其中一个技术方案中， In one of the technical solutions,
R2A选自下述基团：R 2A is selected from the following groups:
在其中一个技术方案中， In one of the technical solutions,
R4A选自下述基团
R 4A is selected from the following groups
其中，波形线表示连接点。Among them, wavy lines represent connection points.
本发明还提供了一种具有式Ⅰ所示结构式的化合物或其可药用盐，
The present invention also provides a compound having the structural formula shown in Formula I or a pharmaceutically acceptable salt thereof,
其中，R1是至少含有一个氮原子的杂环烷基，所述杂环烷基是未取代的或被一个或多个选自卤素、C1-6烷基、C1-6氟烷基、C1-6亚烷基C3-10环烷基和C3-10环烷基的取代基取代；Wherein, R 1 is a heterocycloalkyl group containing at least one nitrogen atom, and the heterocycloalkyl group is unsubstituted or substituted by one or more halogen, C 1-6 alkyl, C 1-6 fluoroalkyl , C 1-6 alkylene C 3-10 cycloalkyl and C 3-10 cycloalkyl substituents are substituted;
R2为未取代或被选自卤素、C1-6烷基、C1-6氟烷基、羟基、和烷氧基中一个或多个的取代基取代的C6-10芳基；R 2 is a C 6-10 aryl group that is unsubstituted or substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 fluoroalkyl, hydroxyl, and alkoxy;
或被选自卤素、C1-6烷基、C1-6氟烷基、羟基、烷氧基、＝O和＝S中一个或多个的取代基取代的含有1、2或3个各自独立选自N、O或S的杂原子的杂芳基；Or substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 fluoroalkyl, hydroxyl, alkoxy, =O and =S containing 1, 2 or 3 each Heteroaryl groups with heteroatoms independently selected from N, O or S;
R3为未取代或任选地经一个、两个或多个独立选自卤素、羧基、酰胺基、烷基、烷胺基、卤代烷基和氰基的取代基取代的芳基、4至15元环烷基，或者，具有1-2个N、O或S杂原子的4至15元杂环烷基；R 3 is an aryl group that is unsubstituted or optionally substituted with one, two or more substituents independently selected from halogen, carboxyl, amide, alkyl, alkylamino, haloalkyl and cyano, 4 to 15 One-membered cycloalkyl, or 4 to 15-membered heterocycloalkyl with 1-2 N, O or S heteroatoms;
R4不存在，或者是未取代或任选地经一个、两个或多个独立选自卤素、羧基、烷基、烷胺基、卤代烷基和氰基的取代基取代的具有1-2个N、O或S杂原子的4至15元杂环烷基中的任一种；和R 4 is absent, or is unsubstituted or optionally substituted with one, two or more substituents independently selected from halogen, carboxyl, alkyl, alkylamino, haloalkyl and cyano having 1-2 Any of 4 to 15 membered heterocycloalkyl groups with N, O, or S heteroatoms; and
R23选自H和卤素，优选，R23选自H和F。R 23 is selected from H and halogen. Preferably, R 23 is selected from H and F.
在其中一个技术方案中，其特征在于，R1选自 In one of the technical solutions, it is characterized in that R 1 is selected from
中的任一个。 any of them.
在其中一个技术方案中，其特征在于，R2选自In one of the technical solutions, it is characterized in that R 2 is selected from
中的任一种； any of;
其中，R5每次出现各自独立地选自F、Cl、Br、I、C1-6烷基、C1-6氟烷基、C1-6烷氧基或氨基；n＝0，1，2或3。Wherein, each occurrence of R 5 is independently selected from F, Cl, Br, I, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkoxy or amino; n=0,1 , 2 or 3.
在其中一个技术方案中，其特征在于，所述R3为未取代的或被一个或多 个选自卤素、C1-6烷基、C1-6氟烷基亚、C1-6亚烷基C3-10环烷基和C3-10环烷基的取代基取代的三元单环烷基、四元单环烷基、五元单环烷基、六元单环烷基、七元螺环烷基、八元螺环烷基、九元螺环烷基、十元螺环烷基、十一元螺环烷烃、九元稠环烷基或十元稠环烷基、七元桥环烷基、八元桥环烷基、九元桥环烷基、十元桥环烷基、和十一元桥环烷烃；所述桥环环烷基优选为 In one of the technical solutions, it is characterized in that R 3 is unsubstituted or substituted by one or more A three-membered ternary substituted group selected from halogen, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene, C 3-10 cycloalkyl and C 3-10 cycloalkyl. Monocyclic alkyl, four-membered monocyclic alkyl, five-membered monocyclic alkyl, six-membered monocyclic alkyl, seven-membered spirocycloalkyl, eight-membered spirocycloalkyl, nine-membered spirocycloalkyl, ten-membered spiro Cycloalkyl, eleven-membered spirocycloalkane, nine-membered fused cycloalkyl or ten-membered fused cycloalkyl, seven-membered bridged cycloalkyl, eight-membered bridged cycloalkyl, nine-membered bridged cycloalkyl, ten-membered bridged ring Alkyl, and eleven-membered bridged cycloalkane; the bridged cycloalkyl is preferably
在其中一个技术方案中，其特征在于，R3选自未取代或任选地经一个、两个或多个独立选自卤素、羧基、酰胺基、烷基、烷胺基、卤代烷基或氰基的取代基取代的以下基团：
In one of the technical solutions, it is characterized in that R 3 is selected from unsubstituted or optionally selected from halogen, carboxyl, amide, alkyl, alkylamino, haloalkyl or cyano by one, two or more The following groups are substituted by the substituents of the group:
在其中一个技术方案中，其特征在于，R3为未取代或杂原子的H被卤素、羧基、酰胺基、烷基、烷胺基、卤代烷基或氰基取代的 In one of the technical solutions, it is characterized in that R 3 is unsubstituted or heteroatom H is substituted by halogen, carboxyl, amide, alkyl, alkylamino, haloalkyl or cyano.
在其中一个技术方案中，其特征在于，R4为未取代或任选地经一个、两个或多个独立选自卤素、羧基、烷基、烷胺基、卤代烷基或氰基的取代基取代的 In one of the technical solutions, it is characterized in that R 4 is unsubstituted or optionally substituted by one, two or more independently selected from halogen, carboxyl, alkyl, alkylamino, haloalkyl or cyano. replaced
在其中一个技术方案中，其特征在于，当R4为取代的杂环烷基时，所述杂环烷基选自取代基团连接到杂原子上；优选地，所述取代基团选自-F、-CH3、-OCH3、-NH2、-COOH、-CN和-CF3中的任一种。In one of the technical solutions, it is characterized in that when R 4 is a substituted heterocycloalkyl group, the heterocycloalkyl group is selected from The substituent group is attached to the heteroatom; preferably, the substituent group is selected from -F, -CH 3 , -OCH 3 , -NH 2 , -COOH, Either -CN or -CF 3 .
在其中一个技术方案中，其特征在于，当R4为环烷基或杂环烷基时，所述R3为C6-10芳基，优选为苯基，所述R4连接到芳基中连接炔基的碳原子的对位或间位。In one of the technical solutions, it is characterized in that when R 4 is a cycloalkyl or heterocycloalkyl group, the R 3 is a C 6-10 aryl group, preferably a phenyl group, and the R 4 is connected to the aryl group The para or meta position of the carbon atom connecting the alkynyl group.
本发明还提供一种具有式Ⅱ所示结构式的化合物或其可药用盐，
The present invention also provides a compound having the structural formula shown in Formula II or a pharmaceutically acceptable salt thereof,
其中，R6为未取代或任选地经一个、两个或多个独立选自卤素、羧基、烷基、烷胺基、卤代烷基或氰基的取代基取代的芳基、4至15元环烷基，或者，具有1-2个N、O或S杂原子的4至15元杂环烷基；Wherein, R 6 is an aryl group that is unsubstituted or optionally substituted with one, two or more substituents independently selected from halogen, carboxyl, alkyl, alkylamino, haloalkyl or cyano, 4 to 15 yuan. Cycloalkyl, or 4 to 15 membered heterocycloalkyl with 1-2 N, O or S heteroatoms;
R7不存在，或者，选自H、酰胺基、氰基、或者未取代或任选地经一个、 两个或多个独立选自卤素、羧基、烷基、烷胺基、卤代烷基和氰基的取代基取代的具有1-2个N、O或S杂原子的4至15元杂环烷基中的任一种；R 7 is absent, alternatively, selected from H, amide, cyano, or unsubstituted or optionally modified by one, 4- to 15-membered heterocycloalkyl groups having 1-2 N, O or S heteroatoms substituted by two or more substituents independently selected from halogen, carboxyl, alkyl, alkylamino, haloalkyl and cyano any of;
或者R7为C1-6亚烷基C3-10杂环烷基，所述杂环烷基是未取代或任选地经一个、两个或多个独立选自卤素、羧基、烷基、烷胺基、卤代烷基和氰基的取代基取代；优选地，R7为C1-3亚烷基C5-8杂环烷基，所述杂环烷基具有1-3个独立选自N、O和S的杂原子；Or R 7 is C 1-6 alkylene C 3-10 heterocycloalkyl, which is unsubstituted or optionally modified by one, two or more independently selected from halogen, carboxyl, alkyl , alkylamino, haloalkyl and cyano substituents; preferably, R 7 is C 1-3 alkylene C 5-8 heterocycloalkyl, and the heterocycloalkyl has 1 to 3 independent choices. Heteroatoms from N, O and S;
R8是含有两个氮原子的杂环烷基，所述杂环烷基是未取代的或被一个或多个选自卤素、C1-6烷基、C1-6氟烷基、C1-6亚烷基C3-10环烷基和C3-10环烷基的取代基取代；R 8 is a heterocycloalkyl group containing two nitrogen atoms, which is unsubstituted or substituted by one or more selected from halogen, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene C 3-10 cycloalkyl and C 3-10 cycloalkyl substituents are substituted;
或者，R8是具有1-2个独立选自N、O和S的杂原子的4至15元杂环烷基，所述杂环烷基是未取代的或被一个或多个选自卤素、C1-6烷基、C1-6氟烷基、C1-6亚烷基C3-10环烷基和C3-10环烷基的取代基取代，优选地，R8是具有1-2个独立为N或O的杂原子的5至8元杂环烷基，所述杂环烷基是未取代的或被一个或多个选自卤素、C1-3烷基、C1-3氟烷基、C1-3亚烷基C3-6环烷基和C3-6环烷基的取代基取代；和Alternatively, R 8 is a 4 to 15 membered heterocycloalkyl group having 1 to 2 heteroatoms independently selected from N, O, and S, which heterocycloalkyl group is unsubstituted or substituted by one or more heteroatoms selected from halogen , C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene, C 3-10 cycloalkyl and C 3-10 cycloalkyl substituents, preferably, R 8 has 1-2 5 to 8-membered heterocycloalkyl groups of heteroatoms that are independently N or O, the heterocycloalkyl group is unsubstituted or substituted by one or more selected from halogen, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-3 alkylene, C 3-6 cycloalkyl and C 3-6 cycloalkyl substituents; and
R22选自H、卤素、酰胺基、氰基或卤代烷基，优选，R23选自H、F、Cl、Br和I。R 22 is selected from H, halogen, amide, cyano or haloalkyl. Preferably, R 23 is selected from H, F, Cl, Br and I.
在其中一个技术方案中，其特征在于，R8选自 中的任一个。In one of the technical solutions, it is characterized in that R 8 is selected from any of them.
在其中一个技术方案中，其特征在于，R6为未取代或任选地经一个、两个或多个独立选自卤素、羧基、烷基、烷胺基、卤代烷基或氰基的取代基 取代的 In one of the technical solutions, it is characterized in that R 6 is unsubstituted or optionally substituted by one, two or more independently selected from halogen, carboxyl, alkyl, alkylamino, haloalkyl or cyano. replaced
在其中一个技术方案中，其特征在于，R6为未取代或杂原子的H被卤素、羧基、烷基、烷胺基、卤代烷基或氰基取代的 In one of the technical solutions, it is characterized in that R 6 is unsubstituted or heteroatom H is substituted by halogen, carboxyl, alkyl, alkylamino, haloalkyl or cyano.
在其中一个技术方案中，其特征在于，R7选自 中的任一杂环烷基。In one of the technical solutions, it is characterized in that R 7 is selected from Any heterocycloalkyl group in .
在其中一个技术方案中，其特征在于，当R7为杂原子的H被取代的时，所述取代基团选自-F、-CH3、-OCH3、-NH2、-COOH、-CN和-CF3中的任一种。In one of the technical solutions, it is characterized in that when R 7 is a heteroatom H substituted When , the substituent group is selected from -F, -CH 3 , -OCH 3 , -NH 2 , -COOH, Either -CN or -CF 3 .
在其中一个技术方案中，其特征在于，当R7为环烷基或杂环烷基时，所述R6为C6-10芳基，优选为苯基，所述R7连接到芳基中连接炔基的碳原子的对位或间位。In one of the technical solutions, it is characterized in that when R 7 is a cycloalkyl or heterocycloalkyl group, the R 6 is a C 6-10 aryl group, preferably a phenyl group, and the R 7 is connected to the aryl group The para or meta position of the carbon atom connecting the alkynyl group.
在其中一个技术方案中，其特征在于，所述化合物选自 中的任一个。In one of the technical solutions, it is characterized in that the compound is selected from any of them.
本发明还提供一种药物组合物，其特征在于，包含如上文所述任一项所述的化合物或其可药用盐，以及药学上可接受的载体和/辅料。The present invention also provides a pharmaceutical composition, which is characterized by comprising a compound as described in any one of the above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or auxiliary material.
本发明还提供如前文所述的化合物或其可药用盐或如前文所述的药物组合物在制备用于治疗或预防由WDR5介导的疾病或病症的的药物中的应用；优选所述WDR5介导的疾病或病症是癌症；优选地，所述癌症选自白血病；优选地，所述癌症选自急性早幼粒细胞白血病、急性粒细胞白血病、急性髓性白血病(AML)和急性单核细胞白血病。The present invention also provides the use of a compound as described above or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above in the preparation of a medicament for the treatment or prevention of diseases or conditions mediated by WDR5; preferably The WDR5-mediated disease or condition is cancer; preferably, the cancer is selected from the group consisting of leukemia; preferably, the cancer is selected from the group consisting of acute promyelocytic leukemia, acute myeloid leukemia, acute myeloid leukemia (AML) and acute myelogenous leukemia. Nuclear cell leukemia.
本发明还提供如前文所述的化合物或其可药用盐或如前文所述的药物组合物，其用于治疗或预防由WDR5介导的疾病或病症；优选地，所述疾病或病症为癌症；优选地，所述癌症选自白血病；优选地，所述癌症选自急性早幼粒细胞白血病、急性粒细胞白血病、急性髓性白血病(AML)、和急性单核细胞白血病。The present invention also provides a compound as described above or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above, which is used to treat or prevent diseases or disorders mediated by WDR5; preferably, the disease or disorder is Cancer; preferably, the cancer is selected from the group consisting of leukemia; preferably, the cancer is selected from the group consisting of acute promyelocytic leukemia, acute myeloid leukemia, acute myeloid leukemia (AML), and acute monocytic leukemia.
本发明还提供一种治疗或预防由WDR5介导的疾病或病症的方法，包括对有需要的受试者施用治疗有效量的前文所述的化合物或其可药用盐或如前文所述的药物组合物；优选地，所述疾病或病症为癌症；优选地，所述癌症选自白血病；优选地，所述癌症选自急性早幼粒细胞白血病、急性粒细胞白血病、急性髓性白血病(AML)和急性单核细胞白血病。The present invention also provides a method for treating or preventing diseases or conditions mediated by WDR5, comprising administering to a subject in need a therapeutically effective amount of a compound as described above or a pharmaceutically acceptable salt thereof or as described above. Pharmaceutical composition; Preferably, the disease or condition is cancer; Preferably, the cancer is selected from leukemia; Preferably, the cancer is selected from acute promyelocytic leukemia, acute myelogenous leukemia, acute myeloid leukemia ( AML) and acute monocytic leukemia.
定义以及详细说明Definition and detailed description
本文所考虑的术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子的烷基，更优选为含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二 甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自H原子、D原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、芳基、杂芳基中的一个或多个取代基所取代。The term "alkyl" as contemplated herein refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably from 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -two Methylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methyl Hexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl , 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5 -Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl , 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl , 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers, etc. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably independently selected from H atoms, D atoms, halogens, alkyl Substituted with one or more substituents of base, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
术语“杂烷基”指烷基中的一个或多个-CH2-被选自NH、O和S的杂原子所取代或者一个或多个-CH-被选N原子取代；其中所述的烷基如上所定义；杂烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自H原子、D原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、芳基、杂芳基中的一个或多个取代基所取代。The term "heteroalkyl" refers to an alkyl group in which one or more -CH2 -s are substituted with heteroatoms selected from NH, O and S or one or more -CH-s are substituted with N atoms; wherein Alkyl is as defined above; heteroalkyl may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, said substituents being preferably independently optionally selected from H atoms , one or more of D atom, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl substituted by substituents.
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基或环烷基的定义本文所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自H原子、D原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、芳基、杂芳基中的一个或多个取代基所取代。The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl or cycloalkyl is as defined herein. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from H atoms, D atoms, halogens, alkyl groups, alkoxy groups , substituted by one or more substituents of haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
术语“炔基”指分子中含有碳碳三键的烷基化合物，其中烷基的定义如上所述。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、芳基和杂芳基中的一个或多个取代基所取代。The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, where alkyl is as defined above. The alkynyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyl groups, hydroxyl groups, Substituted with one or more substituents of hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
术语“环烷基”指饱和或部分不饱和单环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至8个(例如3、4、5、6、7和8个)碳原子，更优选包含4至7个碳原子。单环环烷基的非限制性实例包括环丙基、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、环庚三烯基、环辛基等。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g. 3, 4, 5, 6, 7 and 8) carbon atoms, more preferably containing 4 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, Cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.
环烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、芳基、杂芳基中的一个或多个取代基所取代。Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably independently selected from the group consisting of hydrogen atoms, halogens, alkyl groups, Substituted with one or more substituents from alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
术语“杂环烷基”指饱和或部分不饱和单环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个(例如3、4、5、6、7、8、9、10、11和12个)环原子，其中1～4个(例如1、2、3和4个)是杂原子；更优选包含3至8个环原子，其中1-3是杂原子；更优选包含3至6个环原子，其中1-3个是杂原子；最优选包含5或6个环原子，其中1-3个是杂原子。单环杂环烷基的非限制性实例包括吡咯烷基、四氢吡喃基、1,2.3.6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O)m( where m is an integer from 0 to 2) heteroatoms, but does not include the ring part of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. Preferably it contains 3 to 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) are hetero atoms; more preferably 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl , homopiperazinyl, etc.
杂环烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、芳基、杂芳基中的一个或多个取代基所取代。Heterocycloalkyl may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently selected from hydrogen atoms, halogens, alkyl groups , alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl substituted by one or more substituents.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环包括如上所述的芳基环稠合于杂芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为芳基环。芳基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、芳基、杂芳基中的一个或多个取代基所取代The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6 to 10 members , such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. Aryl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and the substituents are preferably independently selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkyl groups, Substituted with one or more substituents of oxygen, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl
术语“杂芳基”指包含1至4个(例如1、2、3和4个)杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元(例如5、6、7、8、9或10元)，更优选为5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、三唑基、四唑基等。所述杂芳基环包括如上述的杂芳基稠合于芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、芳基、杂芳基中的一个或多个取代基所取代。术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 (eg, 1, 2, 3, and 4) heteroatoms, and from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10 yuan (such as 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl group as described above fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. Heteroaryl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, which substituents are preferably independently selected from the group consisting of hydrogen atoms, halogens, alkyl groups, Substituted with one or more substituents from alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl. The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
术语“羟烷基”指被一个或多个羟基取代的烷基，其中烷基如上所定义。The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, where alkyl is as defined above.
术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“氨基”指-NH2。 The term "amino" refers to -NH2 .
术语“氰基”指-CN。The term "cyano" refers to -CN.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选地取代的环丙基”意味着环丙基被取代可以但不必须存在，该说明包括环丙基被取代的情形和环丙基不被取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance does or does not occur. For example, "optionally substituted cyclopropyl" means that the cyclopropyl group may but need not be substituted, and this description includes both the case where the cyclopropyl group is substituted and the case where the cyclopropyl group is unsubstituted.
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art is able to determine possible or impossible substitutions without undue effort (either experimentally or theoretically).
“可药用盐”是指本公开化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性"Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which are safe and effective when used in mammals, and have due biological activity.
具体实施方式Detailed ways
主要中间体的合成Synthesis of major intermediates
一、N-(5-溴-2-(4-甲基哌嗪-1-基)苯基)-6-氧-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
1. N-(5-bromo-2-(4-methylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3- Synthesis of formamide
1.合成路线：
1.Synthetic route:
2.步骤1：4-(4-溴-2-硝基苯基)哌嗪-1-羧酸叔丁酯的合成
2. Step 1: Synthesis of tert-butyl 4-(4-bromo-2-nitrophenyl)piperazine-1-carboxylate
将4-溴-1-氟-2-硝基苯(6.6g,30mmol)，哌嗪-1-羧酸叔丁酯(5.59g,30mmol)溶于乙腈(60mL)，冰浴条件下滴加N,N-二异丙基乙胺(7.84mL,45mmol)。滴加完毕后，升温至80摄氏度搅拌过夜。反应结束后，真空除去溶剂，然后溶于二氯甲烷(35mL)，用盐水洗涤，合并有机相并用无水硫酸钠干燥。粗产品经硅胶柱层析纯化，洗脱剂MeOH:DCM＝2％～10％，得到目标化合物，黄色油状(11.34g,产率98％)。MS:[M+H]+＝332.16m/z.Dissolve 4-bromo-1-fluoro-2-nitrobenzene (6.6g, 30mmol) and piperazine-1-carboxylic acid tert-butyl ester (5.59g, 30mmol) in acetonitrile (60mL), and add dropwise under ice bath conditions N,N-diisopropylethylamine (7.84 mL, 45 mmol). After the dropwise addition is completed, the temperature is raised to 80 degrees Celsius and stirred overnight. After the reaction was completed, the solvent was removed in vacuo, then dissolved in dichloromethane (35 mL), washed with brine, the organic phases were combined and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography, eluent MeOH:DCM = 2% to 10%, to obtain the target compound as a yellow oil (11.34g, yield 98%). MS:[M+H] + =332.16m/z.
3.步骤2：1-(4-溴-2-硝基苯基)哌嗪的合成
3. Step 2: Synthesis of 1-(4-bromo-2-nitrophenyl)piperazine
将4-(4-溴-2-硝基苯基)哌嗪-1-羧酸叔丁酯(11.34g,29mmol)溶于二氯甲烷(30mL)，并滴加三氟乙酸(6.7mL,87mmol)，反应在室温下搅拌3小时。反应结束后，向反应液中加入水洗涤并分液，有机相用无水硫酸钠干燥。粗产品经硅胶柱层析纯化，洗脱剂MeOH:DCM＝2％～10％(1％三乙胺)，得到目标化合物，黄色油状(8.11g,产率97％)。MS:[M+H]+＝288.16m/z.Dissolve 4-(4-bromo-2-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester (11.34g, 29mmol) in dichloromethane (30mL), and add trifluoroacetic acid (6.7mL, 87 mmol) and the reaction was stirred at room temperature for 3 hours. After the reaction is completed, water is added to the reaction solution for washing and liquid separation, and the organic phase is dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography using eluent MeOH:DCM=2% to 10% (1% triethylamine) to obtain the target compound as a yellow oil (8.11g, yield 97%). MS:[M+H]+＝288.16m/z.
4.步骤3：1-(4-溴-2-硝基苯基)-4-甲基哌嗪的合成
4. Step 3: Synthesis of 1-(4-bromo-2-nitrophenyl)-4-methylpiperazine
冰浴下，向溶有1-(4-溴-2-硝基苯基)哌嗪(8.11g,28mmol)的二氯甲烷溶液(30mL)滴加N,N-二异丙基乙胺(7.4mL,42mmol)，搅拌1小时后，加入37％甲醛水溶液(4.6g,56mmol)和三乙酰氧基硼氢化钠(17.8g,84mmol)。反应回至室温并搅拌3小时。反应结束后，反应液加水洗涤，有机相干燥浓缩后经柱层析纯化,洗脱剂MeOH:DCM＝2％～10％，得到目标化合物，黄色油状(6.21g,产率73％)。MS:[M+H]+＝302.15m/z.Under ice bath, add N,N-diisopropylethylamine ( 7.4 mL, 42 mmol), after stirring for 1 hour, add 37% formaldehyde aqueous solution (4.6 g, 56 mmol) and sodium triacetoxyborohydride (17.8 g, 84 mmol). The reaction was allowed to return to room temperature and stirred for 3 hours. After the reaction, the reaction solution was washed with water, and the organic phase was dried and concentrated and then purified by column chromatography. The eluent was MeOH:DCM=2% to 10%, and the target compound was obtained as a yellow oil (6.21g, yield 73%). MS:[M+H] + =302.15m/z.
5.步骤4：5-溴-2-(4-甲基哌嗪-1-基)苯胺的合成
5. Step 4: Synthesis of 5-bromo-2-(4-methylpiperazin-1-yl)aniline
黄色油状，收率66.66％；将1-(4-溴-2-硝基苯基)-4-甲基哌嗪(1equiv.)溶于乙酸乙酯，加入二水合氯化亚锡(3equiv)。反应升温至70摄氏度搅拌过夜。反应结束后，用水洗涤，有机相干燥浓缩后，粗品经柱层析纯化。MS:[M+H]+＝272.19m/z.Yellow oil, yield 66.66%; Dissolve 1-(4-bromo-2-nitrophenyl)-4-methylpiperazine (1equiv.) in ethyl acetate, add stannous chloride dihydrate (3equiv.) . The reaction was warmed to 70°C and stirred overnight. After the reaction is completed, the mixture is washed with water, the organic phase is dried and concentrated, and the crude product is purified by column chromatography. MS:[M+H] + =272.19m/z.
6.步骤5：N-(5-溴-2-(4-甲基哌嗪-1-基)苯基)-6-氧-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
6. Step 5: N-(5-bromo-2-(4-methylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine -Synthesis of 3-carboxamide
黄色固体，收率24.58％；将5-溴-2-(4-甲基哌嗪-1-基)苯胺(1equiv.)，6-羟基-4-(三氟甲基)烟酸(1equiv.)和N,N,N’,N’-四甲基氯甲脒六氟盐酸盐(1.5equiv)溶于乙腈，搅拌15分钟后，加入N-甲基吡咯(2equiv.)。反应在室温下搅拌过夜。反应结束后，真空除去溶剂，加N,N-二甲基甲酰胺溶解过滤后，用制备级高效液相分析仪纯化产品。MS:[M+H]+＝461.23m/z.Yellow solid, yield 24.58%; 5-bromo-2-(4-methylpiperazin-1-yl)aniline (1equiv.), 6-hydroxy-4-(trifluoromethyl)nicotinic acid (1equiv.) ) and N,N,N',N'-tetramethylchloroformamidine hexafluorohydrochloride (1.5 equiv.) were dissolved in acetonitrile. After stirring for 15 minutes, N-methylpyrrole (2 equiv.) was added. The reaction was stirred at room temperature overnight. After the reaction is completed, the solvent is removed under vacuum, N,N-dimethylformamide is added to dissolve and filtered, and the product is purified with a preparative grade high performance liquid phase analyzer. MS:[M+H] + =461.23m/z.
二、(R)-N-(5-溴-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
2. (R)-N-(5-bromo-2-(3,4-dimethylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6 -Synthesis of dihydropyridine-3-carboxamide
1.合成路线：
1.Synthetic route:
2.步骤1：叔丁基(R)-4-(4-溴-2-硝基苯基)-2-甲基哌嗪-1-羧酸酯的合成
2. Step 1: Synthesis of tert-butyl (R)-4-(4-bromo-2-nitrophenyl)-2-methylpiperazine-1-carboxylate
黄色油状，收率78％；将4-溴-1-氟-2-硝基苯(1equiv.)，(R)-2-甲基哌嗪-1-羧酸叔丁酯(1equiv.)溶于乙腈，冰浴条件下滴加N,N-二异丙基乙胺(1.5equiv)，升温至80摄氏度度搅拌过夜。反应结束后，真空除去乙腈，然后溶于二氯甲烷，用盐水洗涤，合并有机相并用无水硫酸钠干燥。粗产品经硅胶柱层析纯化。MS:[M+H]+＝346.6m/z.Yellow oil, yield 78%; dissolve 4-bromo-1-fluoro-2-nitrobenzene (1equiv.), (R)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (1equiv.) Add N,N-diisopropylethylamine (1.5 equiv) dropwise to acetonitrile in an ice bath, raise the temperature to 80 degrees Celsius and stir overnight. After the reaction, the acetonitrile was removed in vacuo, then dissolved in dichloromethane, washed with brine, the organic phases were combined and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography. MS:[M+H] + =346.6m/z.
3.步骤2：(R)-1-(4-溴-2-硝基苯基)-3-甲基哌嗪的合成
3. Step 2: Synthesis of (R)-1-(4-bromo-2-nitrophenyl)-3-methylpiperazine
黄色油状，收率93.91％；将叔丁基(R)-4-(4-溴-2-硝基苯基)-2-甲基哌嗪-1-羧酸酯(1equiv.)溶于二氯甲烷，并滴加三氟乙酸(3equiv.)，反应在室温下搅拌3小时.反应结束后，向反应液加入水洗涤，有机相用无水硫酸钠干燥。粗产品经硅胶柱层析纯化。MS:[M+H]+＝302.21m/z.Yellow oil, yield 93.91%; dissolve tert-butyl (R)-4-(4-bromo-2-nitrophenyl)-2-methylpiperazine-1-carboxylate (1equiv.) in di Methyl chloride, and trifluoroacetic acid (3 equiv.) was added dropwise, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, water was added to the reaction solution for washing, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography. MS:[M+H] + =302.21m/z.
4.步骤3：(R)-4-(4-溴-2-硝基苯基)-1,2-二甲基哌嗪的合成
4. Step 3: Synthesis of (R)-4-(4-bromo-2-nitrophenyl)-1,2-dimethylpiperazine
黄色油状，收率82％；冰浴下，向溶有(R)-1-(4-溴-2-硝基苯基)-3-甲基哌嗪(1equiv.)的二氯甲烷溶液滴加N,N-二异丙基乙胺(1.5equiv)，搅拌1小时后，加入37％甲醛水溶液和三乙酰氧基硼氢化钠(3equiv)。反应回至室温并搅拌3小时。反应结束后，反应液加水洗涤，有机相干燥浓缩后经柱层析纯化。MS:[M+H]+＝316.22m/z.Yellow oil, yield 82%; under ice bath, drop into the dichloromethane solution dissolved (R)-1-(4-bromo-2-nitrophenyl)-3-methylpiperazine (1equiv.) Add N,N-diisopropylethylamine (1.5 equiv), stir for 1 hour, and then add 37% formaldehyde aqueous solution and sodium triacetoxyborohydride (3 equiv). The reaction was allowed to return to room temperature and stirred for 3 hours. After the reaction is completed, the reaction solution is washed with water, the organic phase is dried and concentrated and then purified by column chromatography. MS:[M+H] + =316.22m/z.
5.步骤4：(R)-5-溴-2-(3,4-二甲基哌嗪-1-基)苯胺的合成
5. Step 4: Synthesis of (R)-5-bromo-2-(3,4-dimethylpiperazin-1-yl)aniline
黄色油状，收率60％；将(R)-4-(4-溴-2-硝基苯基)-1,2-二甲基哌嗪(1equiv.)溶于乙酸乙酯，加入二水合氯化亚锡(3equiv)。反应升温至70摄氏度搅拌过夜。反应结束后，用水洗涤，有机相干燥浓缩后，粗品经柱层析纯化。MS:[M+H]+＝286.20m/z.Yellow oil, yield 60%; Dissolve (R)-4-(4-bromo-2-nitrophenyl)-1,2-dimethylpiperazine (1equiv.) in ethyl acetate, add dihydrate Stannous chloride (3equiv). The reaction was warmed to 70°C and stirred overnight. After the reaction is completed, the mixture is washed with water, the organic phase is dried and concentrated, and the crude product is purified by column chromatography. MS:[M+H] + =286.20m/z.
6.步骤5：(R)-N-(5-溴-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
6. Step 5: (R)-N-(5-bromo-2-(3,4-dimethylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)- Synthesis of 1,6-dihydropyridine-3-carboxamide
黄色固体，收率1.5％；将(R)-5-溴-2-(3,4-二甲基哌嗪-1-基)苯胺(1equiv.)，6-羟基-4-(三氟甲基)烟酸(1equiv.)和N,N,N’,N’-四甲基氯甲脒六氟盐酸盐(1.5equiv)溶于乙腈，搅拌15分钟后，加入N-甲基吡咯(2equiv.)。反应在室温下搅拌过夜。反应结束后，真空除去溶剂，加N,N-二甲基甲酰胺溶解过滤后，用制备级高效液相分析仪纯化产品。MS:[M+H]+＝475.24m/z.Yellow solid, yield 1.5%; (R)-5-bromo-2-(3,4-dimethylpiperazin-1-yl)aniline (1equiv.), 6-hydroxy-4-(trifluoromethyl (1 equiv.) and N,N,N',N'-tetramethylchloroformamidine hexafluorohydrochloride (1.5 equiv) were dissolved in acetonitrile. After stirring for 15 minutes, N-methylpyrrole ( 2equiv.). The reaction was stirred at room temperature overnight. After the reaction, the solvent was removed in vacuum, N,N-dimethylformamide was added to dissolve and filtered, and the product was purified with a preparative-grade high-performance liquid phase analyzer. MS:[M+H] + =475.24m/z.
三.(S)-N-(5-溴-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
3. (S)-N-(5-bromo-2-(3,4-dimethylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6 -Synthesis of dihydropyridine-3-carboxamide
1.合成路线：
1.Synthetic route:
2.步骤1：合成(S)-4-(4-溴-2-硝基苯基)-2-甲基哌嗪-1-羧酸叔丁酯
2. Step 1: Synthesis of (S)-4-(4-bromo-2-nitrophenyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester
黄色黏油，收率94.81％；将4-溴-1-氟-2-硝基苯(1equiv.)，(S)-2-甲基哌嗪-1-羧酸叔丁酯(1equiv.)溶于乙腈，冰浴条件下滴加N,N-二异丙基乙胺(1.5equiv)。滴加完毕后，升温至80摄氏度搅拌过夜。反应结束后，真空除去乙腈，然后溶于N,N-二甲基甲酰胺，用盐水洗涤，合并有机相并用无水硫酸钠干燥。粗产品经硅胶柱层析纯化。MS:[M+H]+＝344.15m/z.Yellow viscous oil, yield 94.81%; 4-bromo-1-fluoro-2-nitrobenzene (1equiv.), (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (1equiv.) Dissolve in acetonitrile, add N,N-diisopropylethylamine (1.5 equiv) dropwise under ice bath conditions. After the dropwise addition is completed, the temperature is raised to 80 degrees Celsius and stirred overnight. After the reaction, the acetonitrile was removed in vacuo, then dissolved in N,N-dimethylformamide, washed with brine, the organic phases were combined and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography. MS:[M+H] + =344.15m/z.
3.步骤2：(S)-1-(4-溴-2-硝基苯基)-3-甲基哌嗪的合成
3. Step 2: Synthesis of (S)-1-(4-bromo-2-nitrophenyl)-3-methylpiperazine
黄色油状，收率98.20％；将(S)-4-(4-溴-2-硝基苯基)-2-甲基哌嗪-1-羧酸 叔丁酯(1equiv.)溶于N,N-二甲基甲酰胺，并滴加三氟乙酸(3equiv.)，反应在室温下搅拌3小时.反应结束后，向反应液加入水洗涤，有机相用无水硫酸钠干燥。粗产品经硅胶柱层析纯化。MS:[M+H]+＝300.11m/z.Yellow oil, yield 98.20%; (S)-4-(4-bromo-2-nitrophenyl)-2-methylpiperazine-1-carboxylic acid Tert-butyl ester (1 equiv.) was dissolved in N,N-dimethylformamide, and trifluoroacetic acid (3 equiv.) was added dropwise. The reaction was stirred at room temperature for 3 hours. After the reaction was completed, water was added to the reaction solution for washing, and the organic The phase was dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography. MS:[M+H] + =300.11m/z.
4.步骤3：(S)-4-(4-溴-2-硝基苯基)-1,2-二甲基哌嗪的合成
4. Step 3: Synthesis of (S)-4-(4-bromo-2-nitrophenyl)-1,2-dimethylpiperazine
黄色油状，收率82.80％；冰浴下，向溶有(S)-1-(4-溴-2-硝基苯基)-3-甲基哌嗪(1equiv.)的二氯甲烷溶液滴加N,N-二异丙基乙胺(1.5equiv)，搅拌1小时后，加入37％甲醛水溶液和三乙酰氧基硼氢化钠(3equiv)。反应回至室温并搅拌3小时。反应结束后，反应液加水洗涤，有机相干燥浓缩后经柱层析纯化。MS:[M+H]+＝314.11m/z.Yellow oil, yield 82.80%; under ice bath, drop into the dichloromethane solution dissolved in (S)-1-(4-bromo-2-nitrophenyl)-3-methylpiperazine (1equiv.) Add N,N-diisopropylethylamine (1.5 equiv), stir for 1 hour, and then add 37% formaldehyde aqueous solution and sodium triacetoxyborohydride (3 equiv). The reaction was allowed to return to room temperature and stirred for 3 hours. After the reaction is completed, the reaction solution is washed with water, the organic phase is dried and concentrated and then purified by column chromatography. MS:[M+H] + =314.11m/z.
5.步骤4：(S)-5-溴-2-(3,4-二甲基哌嗪-1-基)苯胺的合成
5. Step 4: Synthesis of (S)-5-bromo-2-(3,4-dimethylpiperazin-1-yl)aniline
黄色油状，收率95.30％；将(S)-4-(4-溴-2-硝基苯基)-1,2-二甲基哌嗪(1equiv.)溶于乙酸乙酯，加入二水合氯化亚锡(3equiv)。反应升温至70摄氏度搅拌过夜。反应结束后，用水洗涤，有机相干燥浓缩后，粗品经柱层析纯化。MS:[M+H]+＝284.0m/z.Yellow oil, yield 95.30%; dissolve (S)-4-(4-bromo-2-nitrophenyl)-1,2-dimethylpiperazine (1equiv.) in ethyl acetate, add dihydrate Stannous chloride (3equiv). The reaction was warmed to 70°C and stirred overnight. After the reaction is completed, the mixture is washed with water, the organic phase is dried and concentrated, and the crude product is purified by column chromatography. MS:[M+H] + =284.0m/z.
6.步骤5：(S)-N-(5-溴-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
6. Step 5: (S)-N-(5-bromo-2-(3,4-dimethylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)- Synthesis of 1,6-dihydropyridine-3-carboxamide
黄色固体，收率8.41％；将(S)-5-溴-2-(3,4-二甲基哌嗪-1-基)苯胺(1equiv.)，6-羟基-4-(三氟甲基)烟酸(1equiv.)和N,N,N’,N’-四甲基氯甲脒六氟盐酸盐(1.5equiv)溶于乙腈，搅拌15分钟后，加入N-甲基吡咯(2equiv.)。反应在室温下搅拌过夜。反应结束后，真空除去溶剂，加N,N-二甲基甲酰胺溶解过滤后，用制备级高效液相分析仪纯化产品。MS:[M+H]+＝475.24m/z.Yellow solid, yield 8.41%; (S)-5-bromo-2-(3,4-dimethylpiperazin-1-yl)aniline (1equiv.), 6-hydroxy-4-(trifluoromethyl (1 equiv.) and N,N,N',N'-tetramethylchloroformamidine hexafluorohydrochloride (1.5 equiv.) were dissolved in acetonitrile. After stirring for 15 minutes, N-methylpyrrole ( 2equiv.). The reaction was stirred at room temperature overnight. After the reaction is completed, the solvent is removed under vacuum, N,N-dimethylformamide is added to dissolve and filtered, and the product is purified with a preparative grade high performance liquid phase analyzer. MS:[M+H] + =475.24m/z.
4.(S)-N-(5-溴-2-(3,4-二甲基哌嗪-1-基)苯基)-3-甲氧基苯甲酰胺的合成
4. Synthesis of (S)-N-(5-bromo-2-(3,4-dimethylpiperazin-1-yl)phenyl)-3-methoxybenzamide
黄色油状，收率92.85％；将(S)-5-溴-2-(3,4-二甲基哌嗪-1-基)苯胺(1equiv.)，间甲氧基苯甲酸(1equiv.)和N,N,N’,N’-四甲基氯甲脒六氟盐酸盐(1.5equiv)溶于乙腈，搅拌15分钟后，加入N-甲基吡咯(2equiv.)。反应在室温下搅拌过夜。反应结束后，真空除去溶剂，加N,N-二甲基甲酰胺溶解过滤后，用制备级高效液相分析仪纯化产品。MS:[M+H]+＝420.0m/z.Yellow oil, yield 92.85%; (S)-5-bromo-2-(3,4-dimethylpiperazin-1-yl)aniline (1equiv.), m-methoxybenzoic acid (1equiv.) Dissolve N,N,N',N'-tetramethylchloroformamidine hexafluorohydrochloride (1.5 equiv.) in acetonitrile. After stirring for 15 minutes, add N-methylpyrrole (2 equiv.). The reaction was stirred at room temperature overnight. After the reaction is completed, the solvent is removed under vacuum, N,N-dimethylformamide is added to dissolve and filtered, and the product is purified with a preparative grade high performance liquid phase analyzer. MS:[M+H] + =420.0m/z.
四、(S)-2-(3,4-二甲基哌嗪-1-基)-5-(4-氟苯基)乙炔基)苯胺
4. (S)-2-(3,4-dimethylpiperazin-1-yl)-5-(4-fluorophenyl)ethynyl)aniline
黄色油状，收率56％；将(S)-5-溴-2-(3,4-二甲基哌嗪-1-基)苯胺(1equiv)，对氟苯乙炔1.2equiv)，双三苯基膦二氯化钯(10％mol)，碘化亚铜(10％mol)和三乙胺(2equiv)溶于超干N,N-二甲基甲酰胺，用氮气置换5次，升温至100摄氏度反应3小时。反应结束后，抽滤，滤液用制备级高效液相色谱仪纯化。MS:[M+H]+＝324.35m/z.Yellow oil, yield 56%; combine (S)-5-bromo-2-(3,4-dimethylpiperazin-1-yl)aniline (1equiv), p-fluorophenyl acetylene 1.2equiv), bistriphenyl Phosphine palladium dichloride (10% mol), cuprous iodide (10% mol) and triethylamine (2 equiv) were dissolved in ultra-dry N,N-dimethylformamide, replaced with nitrogen 5 times, and heated to Reaction at 100 degrees Celsius for 3 hours. After the reaction, it was filtered by suction, and the filtrate was purified with a preparative-grade high-performance liquid chromatograph. MS:[M+H] + =324.35m/z.
五、5-((4-氟苯基)乙炔基)-2-((3R，5S)-3,4,5-三甲基哌嗪-1-基)苯胺的合成
5. Synthesis of 5-((4-fluorophenyl)ethynyl)-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)aniline
1.合成路线：
1.Synthetic route:
2.步骤1：叔丁基(3R,5S)-3,4,5-三甲基哌嗪-1-羧酸酯的合成
2. Step 1: Synthesis of tert-butyl (3R,5S)-3,4,5-trimethylpiperazine-1-carboxylate
冰浴下，向溶有叔丁基(3R，5S)-3,5-二甲基哌嗪-1-羧酸酯(4g,18.66mmol)的二氯甲烷溶液(40mL)滴加N,N-二异丙基乙胺(4.82g，37.33mmol)，搅拌1小时后，加入37％甲醛水溶液(2.24g,74.66mmol)和三乙酰氧基硼氢化钠(7.91g,37.33mmol)。反应回至室温并搅拌3小时。反应结束后，反应液加水洗涤，有机相干燥浓缩后经柱层析纯化,洗脱剂MeOH:DCM＝2％～10％，得到目标化合物，黄色油状(3.5g,产率82％)。MS:[M+H]+＝229.30m/z.Under ice bath, add N, N dropwise to the dichloromethane solution (40 mL) dissolved in tert-butyl (3R, 5S)-3,5-dimethylpiperazine-1-carboxylate (4g, 18.66mmol) -Diisopropylethylamine (4.82g, 37.33mmol), after stirring for 1 hour, add 37% formaldehyde aqueous solution (2.24g, 74.66mmol) and sodium triacetoxyborohydride (7.91g, 37.33mmol). The reaction was allowed to return to room temperature and stirred for 3 hours. After the reaction, the reaction solution was washed with water, and the organic phase was dried and concentrated and then purified by column chromatography. The eluent was MeOH:DCM = 2% to 10% to obtain the target compound as a yellow oil (3.5 g, yield 82%). MS:[M+H] + =229.30m/z.
步骤2：(2R，6S)-1,2,6-三甲基哌嗪的合成
Step 2 Synthesis of: (2R, 6S)-1,2,6-trimethylpiperazine
将叔丁基(3R,5S)-3,4,5-三甲基哌嗪-1-羧酸酯(3.4g,14.89mmol)溶于二氯甲烷(35mL)，并滴加三氟乙酸(2.92g,29.78mmol)，反应在室温下搅拌2小时。反应结束后，向反应液中加入水洗涤并分液，有机相用无水硫酸钠干燥。粗产品经硅胶柱层析纯化，洗脱剂MeOH:DCM＝2％～10％(1％三乙胺)，得到目标化合物，黄色油状(1.5g,产率78％)。MS:[M+H]+＝129.20m/z.Dissolve tert-butyl (3R,5S)-3,4,5-trimethylpiperazine-1-carboxylate (3.4g, 14.89mmol) in dichloromethane (35mL), and add trifluoroacetic acid ( 2.92g, 29.78mmol), the reaction was stirred at room temperature for 2 hours. After the reaction is completed, water is added to the reaction solution for washing and liquid separation, and the organic phase is dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography using eluent MeOH:DCM = 2% to 10% (1% triethylamine) to obtain the target compound as a yellow oil (1.5 g, yield 78%). MS:[M+H] + =129.20m/z.
步骤3：(2R,6S)-4-(4-溴-2-硝基苯基)-1,2,6-三甲基哌嗪的合成
Step 3 Synthesis of: (2R,6S)-4-(4-bromo-2-nitrophenyl)-1,2,6-trimethylpiperazine
将4-溴-1-氟-2-硝基苯(2.57g,11.70mmol)，(2R，6S)-1,2,6-三甲基哌嗪(1.5g,11.70mmol)溶于乙腈(30mL)，冰浴条件下滴加N,N-二异丙基乙胺(4.54g,35.1mmol)。滴加完毕后，升温至80℃搅拌过夜。反应结束后，真空除去溶剂，然后溶于二氯甲烷(10mL)，用盐水洗涤，合并有机相并用无水硫酸钠干燥。粗产品经硅胶柱层析纯化，洗脱剂MeOH:DCM＝2％～10％，得到目标化合物，黄色油状(2.30g,产率60％)。MS:[M+H]+＝328.23m/z. Dissolve 4-bromo-1-fluoro-2-nitrobenzene (2.57g, 11.70mmol), (2R, 6S)-1,2,6-trimethylpiperazine (1.5g, 11.70mmol) in acetonitrile ( 30mL), add N,N-diisopropylethylamine (4.54g, 35.1mmol) dropwise under ice bath conditions. After the dropwise addition is completed, the temperature is raised to 80°C and stirred overnight. After the reaction, the solvent was removed in vacuo, then dissolved in dichloromethane (10 mL), washed with brine, the organic phases were combined and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography, eluent MeOH:DCM = 2% to 10%, to obtain the target compound as a yellow oil (2.30g, yield 60%). MS:[M+H] + =328.23m/z.
步骤4：5-溴-2-((3R，5S)-3,4,5-三甲基哌嗪-1-基)苯胺的合成
Step 4: Synthesis of 5-bromo-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)aniline
黄色油状，收率66.66％；将(2R,6S)-4-(4-溴-2-硝基苯基)-1,2,6-三甲基哌嗪(1g,3.05mmol)溶于乙酸乙酯(20mL)，加入锌粉(1.99g,30.47mmol),冰浴下加入氯化铵固体(1.63g,30.47mmol),室温搅拌30min。反应结束后，将反应液抽滤，用乙酸乙酯洗涤滤饼，合并有机相，减压浓缩后，粗品经柱层析纯化。MS:[M+H]+＝298.22m/z.Yellow oil, yield 66.66%; dissolve (2R,6S)-4-(4-bromo-2-nitrophenyl)-1,2,6-trimethylpiperazine (1g, 3.05mmol) in acetic acid ethyl ester (20 mL), add zinc powder (1.99 g, 30.47 mmol), add ammonium chloride solid (1.63 g, 30.47 mmol) under ice bath, and stir at room temperature for 30 min. After the reaction, the reaction solution was filtered, the filter cake was washed with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the crude product was purified by column chromatography. MS:[M+H] + =298.22m/z.
步骤5：5-((4-氟苯基)乙炔基)-2-((3R，5S)-3,4,5-三甲基哌嗪-1-基)苯胺的合成
Step 5: Synthesis of 5-((4-fluorophenyl)ethynyl)-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)aniline
黄色油状，收率56％；将5-溴-2-((3R，5S)-3,4,5-三甲基哌嗪-1-基)苯胺(50mg,167μmol)，对氟苯乙炔(24mg,201μmol)，双三苯基膦二氯化钯(23.5mg,33.53μmol)，碘化亚铜(3.19mg,μmol)和碳酸铯(109mg,335.3μmol)溶于超干N,N-二甲基甲酰胺，用氮气置换5次，升温至100摄氏度反应3小时。反应结束后，抽滤，滤液用制备级高效液相色谱仪纯化。MS:[M+H]+＝338.40m/z.Yellow oil, yield 56%; 5-bromo-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)aniline (50mg, 167μmol), p-fluorophenylacetylene ( 24 mg, 201 μmol), bistriphenylphosphine palladium dichloride (23.5 mg, 33.53 μmol), copper iodide (3.19 mg, μmol) and cesium carbonate (109 mg, 335.3 μmol) were dissolved in ultradry N,N-bis Methylformamide was replaced with nitrogen 5 times, and the temperature was raised to 100 degrees Celsius and reacted for 3 hours. After the reaction, it was suction filtered, and the filtrate was purified with a preparative-grade high-performance liquid chromatograph. MS:[M+H] + =338.40m/z.
六.(S)-N-(5-溴-2-(3,4-二甲基哌嗪-1-基)-4-氟苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
6. (S)-N-(5-bromo-2-(3,4-dimethylpiperazin-1-yl)-4-fluorophenyl)-6-oxo-4-(trifluoromethyl Synthesis of )-1,6-dihydropyridine-3-carboxamide
1.合成路线：
1.Synthetic route:
2.步骤1：(S)-4-(4-溴-5-氟-2-硝基苯基)-2-甲基哌嗪-1-甲酸叔丁酯的合成
2. Step 1: Synthesis of (S)-4-(4-bromo-5-fluoro-2-nitrophenyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester
将2,4-二氟-5-溴硝基苯(5.0g,21.01mmol)溶于甲苯(25mL)，加入哌嗪-1-羧酸叔丁酯(4.21g,21.01mmol)和碳酸钾(8.71g,63.03mmol)。添加完毕后，升温至45摄氏度搅拌2小时。反应结束后，真空除去溶剂，然后溶于二氯甲烷(20mL)，合并有机相并用无水硫酸钠干燥。粗产品经硅胶柱层析纯化，洗脱剂MeOH:DCM＝2％～10％，得到目标化合物，黄色油状(7.26g,产率82.62％)。MS:[M+H]+＝362.09m/z.Dissolve 2,4-difluoro-5-bromonitrobenzene (5.0g, 21.01mmol) in toluene (25mL), add piperazine-1-carboxylic acid tert-butyl ester (4.21g, 21.01mmol) and potassium carbonate ( 8.71g, 63.03mmol). After the addition is completed, raise the temperature to 45 degrees Celsius and stir for 2 hours. After the reaction was completed, the solvent was removed in vacuo and then dissolved in dichloromethane (20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography, eluent MeOH:DCM = 2% to 10%, to obtain the target compound as a yellow oil (7.26g, yield 82.62%). MS:[M+H] + =362.09m/z.
步骤2：(S)-1-(4-溴-5-氟-2-硝基苯基)-3-甲基哌嗪的合成
Step 2: Synthesis of (S)-1-(4-bromo-5-fluoro-2-nitrophenyl)-3-methylpiperazine
将(S)-4-(4-溴-5-氟-2-硝基苯基)-2-甲基哌嗪-1-甲酸叔丁酯(7.26g,17.36mmol)溶于二氯甲烷(35mL)，并滴加三氟乙酸(15mL)，反应在室温下搅拌2小时。反应结束后，向反应液中加入水洗涤并分液，有机相用无水硫酸钠干燥。粗产品经硅胶柱层析纯化，洗脱剂MeOH:DCM＝2％～10％，得到目标化合物，黄色油状(5.5g,产率99.60％)。MS:[M+H]+＝318.08m/z.Dissolve (S)-4-(4-bromo-5-fluoro-2-nitrophenyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (7.26g, 17.36mmol) in dichloromethane ( 35 mL), and trifluoroacetic acid (15 mL) was added dropwise, and the reaction was stirred at room temperature for 2 hours. After the reaction is completed, water is added to the reaction solution for washing and liquid separation, and the organic phase is dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography, eluent MeOH:DCM = 2% to 10%, to obtain the target compound as a yellow oil (5.5g, yield 99.60%). MS:[M+H] + =318.08m/z.
步骤3：(S)-4-(4-溴-5-氟-2-硝基苯基)-1,2-二甲基哌嗪的合成
Step 3: Synthesis of (S)-4-(4-bromo-5-fluoro-2-nitrophenyl)-1,2-dimethylpiperazine
冰浴下，向溶有(S)-1-(4-溴-5-氟-2-硝基苯基)-3-甲基哌嗪(5.50g,17.29mmol)的二氯甲烷溶液(20mL)，滴加N,N-二异丙基乙胺(6.70g,51.86mmol)和37％甲醛水溶液(2.08g,69.15mmol)，搅拌30分钟后，缓慢加入三乙酰氧基硼氢化钠(10.99g,51.86mmol)。反应回至室温并搅拌3小时。反应结束后，反应液加水洗涤，有机相干燥浓缩后经柱层析纯化,洗脱剂MeOH:DCM＝2％～10％，得到目标化合物，黄色油状(5.72g,产率99.61％)。MS:[M+H]+＝332.09m/z.Under ice bath, add (S)-1-(4-bromo-5-fluoro-2-nitrophenyl)-3-methylpiperazine (5.50g, 17.29mmol) to a dichloromethane solution (20mL). ), add N,N-diisopropylethylamine (6.70g, 51.86mmol) and 37% formaldehyde aqueous solution (2.08g, 69.15mmol) dropwise. After stirring for 30 minutes, slowly add sodium triacetoxyborohydride (10.99 g, 51.86mmol). The reaction was allowed to return to room temperature and stirred for 3 hours. After the reaction, the reaction solution was washed with water, and the organic phase was dried and concentrated and then purified by column chromatography. The eluent was MeOH:DCM = 2% to 10% to obtain the target compound as a yellow oil (5.72g, yield 99.61%). MS:[M+H] + =332.09m/z.
步骤4：(S)-5-溴-2-(3,4-二甲基哌嗪-1-基)-4-氟苯胺的合成
Step 4: Synthesis of (S)-5-bromo-2-(3,4-dimethylpiperazin-1-yl)-4-fluoroaniline
棕色油状，收率79.17％；将(S)-4-(4-溴-5-氟-2-硝基苯基)-1,2-二甲基哌嗪(1equiv.)溶于醋酸和水(3：1)的混合溶液中，加入铁粉(5equiv)。反应在室温下搅拌2小时。反应结束后，用硅藻土过滤，待有机相干燥浓缩后，粗品经柱层析纯化。MS:[M+H]+＝302.17m/z. Brown oil, yield 79.17%; dissolve (S)-4-(4-bromo-5-fluoro-2-nitrophenyl)-1,2-dimethylpiperazine (1equiv.) in acetic acid and water To the mixed solution of (3:1), add iron powder (5equiv). The reaction was stirred at room temperature for 2 hours. After the reaction is completed, filter through diatomaceous earth. After the organic phase is dried and concentrated, the crude product is purified by column chromatography. MS:[M+H] + =302.17m/z.
步骤5(S)-N-(5-溴-2-(3,4-二甲基哌嗪-1-基)-4-氟苯基)-6-甲氧基-4-(三氟甲基)烟酰胺的合成
Step 5(S)-N-(5-bromo-2-(3,4-dimethylpiperazin-1-yl)-4-fluorophenyl)-6-methoxy-4-(trifluoromethyl Synthesis of nicotinamide
棕色油状，收率59.51％；将6-甲氧基-4-(三氟甲基)烟酸(1.2equiv.)，N,N,N’,N’-四甲基氯甲脒六氟盐酸盐(1.5equiv)和N-甲基吡咯(2equiv.)溶于乙腈，搅拌30分钟后，加入(S)-5-溴-2-(3,4-二甲基哌嗪-1-基)-4-氟苯胺(1equiv.)。反应在室温下搅拌过夜。反应结束后，真空除去溶剂，加N,N-二甲基甲酰胺溶解过滤后，用制备级高效液相分析仪纯化产品。MS:[M+H]+＝505.20m/z.Brown oil, yield 59.51%; 6-methoxy-4-(trifluoromethyl)nicotinic acid (1.2 equiv.), N,N,N',N'-tetramethylchloroformamidine hexafluoro salt Dissolve acid salt (1.5 equiv.) and N-methylpyrrole (2 equiv.) in acetonitrile. After stirring for 30 minutes, add (S)-5-bromo-2-(3,4-dimethylpiperazin-1-yl). )-4-fluoroaniline (1equiv.). The reaction was stirred at room temperature overnight. After the reaction, remove the solvent in vacuum, add N,N-dimethylformamide to dissolve and filter, and purify the product with a preparative-grade high-performance liquid phase analyzer. MS:[M+H] + =505.20m/z.
步骤6(S)-N-(5-溴-2-(3,4-二甲基哌嗪-1-基)-4-氟苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Step 6(S)-N-(5-bromo-2-(3,4-dimethylpiperazin-1-yl)-4-fluorophenyl)-6-oxo-4-(trifluoromethyl Synthesis of )-1,6-dihydropyridine-3-carboxamide
黄色固体，收率74.06％；将碘化钠(3equiv.)和三甲基氯硅烷(3equiv)溶于乙腈，置换氮气两至三次，搅拌30分钟后，加入(S)-N-(5-溴-2-(3,4-二甲基哌嗪-1-基)-4-氟苯基)-6-甲氧基-4-(三氟甲基)烟酰胺(1equiv.)。反应在80℃下搅拌4h。反应结束后，加水淬灭，真空除去溶剂，用乙酸乙酯萃取两至三次，取有机相得到产品。MS:[M+H]+＝491.09m/z. Yellow solid, yield 74.06%; dissolve sodium iodide (3equiv.) and trimethylsilyl chloride (3equiv.) in acetonitrile, replace nitrogen two to three times, stir for 30 minutes, add (S)-N-(5- Bromo-2-(3,4-dimethylpiperazin-1-yl)-4-fluorophenyl)-6-methoxy-4-(trifluoromethyl)nicotinamide (1equiv.). The reaction was stirred at 80 °C for 4 h. After the reaction is completed, add water to quench, remove the solvent in vacuo, extract with ethyl acetate two to three times, and take the organic phase to obtain the product. MS:[M+H] + =491.09m/z.
七.(S)-4-(二氟甲基)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(苯乙炔基)苯基)-6-氧代-1,6-二氢吡啶-3-甲酰胺
7. (S)-4-(Difluoromethyl)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(phenylacetynyl)phenyl)-6-oxo Generation-1,6-dihydropyridine-3-carboxamide
1.合成路线：
1.Synthetic route:
2.步骤1：4-甲酰基-6-甲氧基烟酸甲酯的合成
2. Step 1: Synthesis of methyl 4-formyl-6-methoxynicotinate
将5-溴-2-甲氧基异烟醛(3.0g,13.89mmol)溶于甲醇(18mL)，加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(1.02g,1.39mmol)和三乙胺(4.22g,41.66mmol)。添加完毕后，置换一氧化碳两至三次，升温至70摄氏度反应过夜。反应结束后，真空除去溶剂，然后溶于二氯甲烷(20mL)，合并有机相并用无水硫酸钠干燥。粗产品经硅胶柱层析纯化，洗脱剂PE:EA＝2％～20％，得到目标化合物，黄色油状(850mg,产率31.36％)。MS:[M+H]+＝196.15m/z.Dissolve 5-bromo-2-methoxyisonicotinal (3.0g, 13.89mmol) in methanol (18mL), and add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.02g, 1.39mmol) and triethylamine (4.22g, 41.66mmol). After the addition is completed, replace the carbon monoxide two to three times, raise the temperature to 70 degrees Celsius and react overnight. After the reaction was completed, the solvent was removed in vacuo and then dissolved in dichloromethane (20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography, eluent PE: EA = 2% to 20%, to obtain the target compound as a yellow oil (850 mg, yield 31.36%). MS:[M+H] + =196.15m/z.
步骤2：4-(二氟甲基)-6-甲氧基烟酸甲酯的合成
Step 2: Synthesis of methyl 4-(difluoromethyl)-6-methoxynicotinate
冰浴下，将4-甲酰基-6-甲氧基烟酸甲酯(850mg,4.36mmol)溶于二氯甲 烷(15mL)，并缓慢滴加二乙胺基三氟化硫(1.40g,8.71mmol)，反应回至室温并搅拌4小时。反应结束后，向反应液中加入水洗涤并分液，有机相用无水硫酸钠干燥。粗产品经硅胶柱层析纯化，洗脱剂PE:EA＝2％-50％，得到目标化合物，黄色油状(810mg,产率85.64％)。MS:[M+H]+＝218.16m/z.Dissolve 4-formyl-6-methoxynicotinic acid methyl ester (850 mg, 4.36 mmol) in dichloromethane under ice bath alkane (15 mL), and diethylamine sulfur trifluoride (1.40 g, 8.71 mmol) was slowly added dropwise, the reaction returned to room temperature and stirred for 4 hours. After the reaction is completed, water is added to the reaction solution for washing and liquid separation, and the organic phase is dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography, eluent PE:EA=2%-50%, to obtain the target compound as a yellow oil (810 mg, yield 85.64%). MS:[M+H] + =218.16m/z.
步骤3：4-(二氟甲基)-6-甲氧基烟酸的合成
Step 3: Synthesis of 4-(difluoromethyl)-6-methoxynicotinic acid
将4-(二氟甲基)-6-甲氧基烟酸甲酯(760mg,3.50mmol)溶于甲醇和水的混合溶液中(18mL)，加入氢氧化锂(419.02mg,17.50mmol)。反应在室温搅拌4小时。反应结束后，将反应液调至PH值至6-7之间，再浓缩后经柱层析纯化,洗脱剂H2O:ACN＝0～50％，得到目标化合物，黄色油状(550mg,产率77.37％)。MS:[M+H]+＝204.25m/z.Dissolve 4-(difluoromethyl)-6-methoxynicotinic acid methyl ester (760 mg, 3.50 mmol) in a mixed solution of methanol and water (18 mL), and add lithium hydroxide (419.02 mg, 17.50 mmol). The reaction was stirred at room temperature for 4 hours. After the reaction is completed, the reaction solution is adjusted to a pH value between 6 and 7, and then concentrated and purified by column chromatography. The eluent is H2O:ACN=0~50% to obtain the target compound as a yellow oil (550 mg, yield 77.37%). MS:[M+H] + =204.25m/z.
步骤4(S)-N-(5-溴-2-(3,4-二甲基哌嗪-1-基)苯基)-4-(二氟甲基)-6-甲氧基烟酰胺的合成
Step 4(S)-N-(5-bromo-2-(3,4-dimethylpiperazin-1-yl)phenyl)-4-(difluoromethyl)-6-methoxynicotinamide Synthesis
棕色油状，收率44.93％；将4-(二氟甲基)-6-甲氧基烟酸(1.2equiv.)，N,N,N’,N’-四甲基氯甲脒六氟盐酸盐(1.5equiv)和N-甲基吡咯(2equiv.)溶于乙腈，搅拌30分钟后，加入上步中间体化合物(1equiv.)。反应在室温下搅拌过夜。反应结束后，真空除去溶剂，加N,N-二甲基甲酰胺溶解过滤后，用制备级高效液相分析仪纯化产品。MS:[M+H]+＝469.30m/z.Brown oil, yield 44.93%; 4-(difluoromethyl)-6-methoxynicotinic acid (1.2 equiv.), N,N,N',N'-tetramethylchloroformamidine hexafluoro salt Dissolve acid salt (1.5 equiv.) and N-methylpyrrole (2 equiv.) in acetonitrile. After stirring for 30 minutes, add the intermediate compound (1 equiv.) from the previous step. The reaction was stirred at room temperature overnight. After the reaction is completed, the solvent is removed under vacuum, N,N-dimethylformamide is added to dissolve and filtered, and the product is purified with a preparative grade high performance liquid phase analyzer. MS:[M+H] + =469.30m/z.
步骤5(S)-N-(5-溴-2-(3,4-二甲基哌嗪-1-基)苯基)-4-(二氟甲基)-6-氧代-1,6-二氢吡啶-3-甲酰胺的合成
Step 5(S)-N-(5-bromo-2-(3,4-dimethylpiperazin-1-yl)phenyl)-4-(difluoromethyl)-6-oxo-1, Synthesis of 6-dihydropyridine-3-carboxamide
黄色固体，收率66.35％；将碘化钠(3equiv.)和三甲基氯硅烷(3equiv)溶于乙腈，置换氮气两至三次，搅拌30分钟后，加入(S)-N-(5-溴-2-(3,4-二甲基哌嗪-1-基)苯基)-4-(二氟甲基)-6-甲氧基烟酰胺(1equiv.)。反应 在80℃下搅拌4h。反应结束后，加水淬灭，真空除去溶剂，用乙酸乙酯萃取两至三次，取有机相得到产品。MS:[M+H]+＝455.25m/z.Yellow solid, yield 66.35%; dissolve sodium iodide (3equiv.) and trimethylsilyl chloride (3equiv.) in acetonitrile, replace nitrogen two to three times, stir for 30 minutes, add (S)-N-(5- Bromo-2-(3,4-dimethylpiperazin-1-yl)phenyl)-4-(difluoromethyl)-6-methoxynicotinamide (1equiv.). reaction Stir at 80°C for 4h. After the reaction is completed, add water to quench, remove the solvent in vacuo, extract with ethyl acetate two to three times, and take the organic phase to obtain the product. MS:[M+H] + =455.25m/z.
八、终产物合成路线8. Final product synthesis route
1、(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-((4-氟苯基)乙炔基)苯基)-芳基甲酰胺类化合物的合成
1. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-((4-fluorophenyl)ethynyl)phenyl)-arylcarboxamide compounds Synthesis
1)通用合成路线
1) General synthetic route
2)通用方法12) General method 1
将相应的胺(1eqv.)，相应的酸(1.2eqv)，N,N,N’,N’-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(1.5eqv.),N,N-二异丙基乙胺(2.0eqv.)溶于乙腈(1-3mL)，室温下搅拌过夜。反应结束后，抽滤，滤液经制备级高效液相色谱仪分离纯化。Combine the corresponding amine (1eqv.), the corresponding acid (1.2eqv.), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphoric acid Urea (1.5eqv.), N,N-diisopropylethylamine (2.0eqv.) were dissolved in acetonitrile (1-3mL), and stirred at room temperature overnight. After the reaction is completed, suction filtration is performed, and the filtrate is separated and purified by a preparative-grade high-performance liquid chromatograph.
2、((芳基乙炔基/环烷烃基乙炔基/杂环乙炔基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺类化合物的合成
2. ((arylethynyl/cycloalkylethynyl/heterocycloethynyl)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)-6-oxo -Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide compounds
1)合成路线：
1)Synthetic route:
2)通用方法2：2) General method 2:
将(S)-N-(5-溴-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺(1equiv)，相应的炔类化合物(1.2equiv)，双三苯基膦二氯化钯(10％mol)，碘化亚铜(10％mol)和三乙胺(2equiv)溶于超干N,N-二甲基甲酰胺，用氮气置换5次，升温至100摄氏度反应3小时。反应结束后，抽滤，滤液用制备级高效液相色谱仪纯化。(S)-N-(5-bromo-2-(3,4-dimethylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6- Dihydropyridine-3-carboxamide (1 equiv), the corresponding alkyne compound (1.2 equiv), bistriphenylphosphine palladium dichloride (10% mol), copper iodide (10% mol) and triethylamine (2equiv) was dissolved in ultra-dry N,N-dimethylformamide, replaced with nitrogen 5 times, heated to 100 degrees Celsius and reacted for 3 hours. After the reaction, it was suction filtered, and the filtrate was purified with a preparative-grade high-performance liquid chromatograph.
实施例1(S)-N-(5-(环己基炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
Example 1 (S)-N-(5-(cyclohexylynyl)-2-(3,4-dimethylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoro Methyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，收率33.41％；通过通用方法2得到目标产物。1H NMR(400MHz,Methanol-d4)δ:7.97(s,1H),7.91(s,1H),7.27-7.16(m,2H),6.92(s,1H),4.52(dt,J＝7.0,5.0Hz,1H),3.61(d,J＝11.9Hz,1H),3.50-3.34(m,2H),3.24(s,1H),3.16-3.01(m,1H),2.96(s,3H),2.92-2.77(m,1H),2.66-2.52(m,1H),1.93-1.84(m,2H),1.82-1.71(m,2H),1.61-1.45(m,3H),1.45-1.28(m,6H).MS:[M+H]+＝501.4m/z.Yellow solid, yield 33.41%; the target product was obtained by general method 2. 1 H NMR (400MHz, Methanol-d 4 ) δ: 7.97 (s, 1H), 7.91 (s, 1H), 7.27-7.16 (m, 2H), 6.92 (s, 1H), 4.52 (dt, J = 7.0 ,5.0Hz,1H),3.61(d,J＝11.9Hz,1H),3.50-3.34(m,2H),3.24(s,1H),3.16-3.01(m,1H),2.96(s,3H) ,2.92-2.77(m,1H),2.66-2.52(m,1H),1.93-1.84(m,2H),1.82-1.71(m,2H),1.61-1.45(m,3H),1.45-1.28( m,6H).MS:[M+H] + =501.4m/z.
实施例2.(S)-N-(5-(环戊炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
Example 2. (S)-N-(5-(cyclopentynyl)-2-(3,4-dimethylpiperazin-1-yl)phenyl)-6-oxo-4-(tris Fluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，收率36.32％；通过通用方法2得到目标产物。MS:[M+H]+＝487.2m/z.Yellow solid, yield 36.32%; the target product was obtained by general method 2. MS:[M+H] + =487.2m/z.
实施例3.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-氟苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
Example 3. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-fluorophenyl)ethynyl)phenyl)-6-oxo- 4-(Trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，收率33.66％；通过通用方法2得到目标产物。MS:[M+H]+＝513.2m/z.Yellow solid, yield 33.66%; the target product was obtained by general method 2. MS:[M+H] + =513.2m/z.
实施例4.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(4-氟苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 4. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(4-fluorophenyl)ethynyl)phenyl)-6-oxo- Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，收率79％；通过通用方法2得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.07(s,1H),8.00(s,1H),7.58-7.51(m,2H),7.40(dd,J＝8.3,1.9Hz,1H),7.28(d,J＝8.3Hz,1H),7.16-7.09(m,2H),6.94(s,1H),4.55-4.44(m,1H),3.63(d,J＝12.6Hz,1H),3.52-3.36(m,2H),3.20-3.05(m,2H),2.97(s,3H),2.93-2.80(m,1H),1.41(d,J＝6.5Hz,3H).MS:[M+H]+＝513.4m/z.White solid, yield 79%; the target product was obtained by general method 2. 1 H NMR (400MHz, Methanol-d 4 ) δ: 8.07 (s, 1H), 8.00 (s, 1H), 7.58-7.51 (m, 2H), 7.40 (dd, J = 8.3, 1.9Hz, 1H), 7.28(d,J＝8.3Hz,1H),7.16-7.09(m,2H),6.94(s,1H),4.55-4.44(m,1H),3.63(d,J＝12.6Hz,1H),3.52 -3.36(m,2H),3.20-3.05(m,2H),2.97(s,3H),2.93-2.80(m,1H),1.41(d,J＝6.5Hz,3H).MS:[M+ H] + =513.4m/z.
实施例5.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(吡啶-4-亚乙基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
Example 5. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(pyridin-4-ethylene)phenyl)-6-oxo-4 -(Trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，收率43％；通过通用方法2得到目标产物。1H NMR(400MHz,DMSO-d6)δ12.63(s,1H),9.62(s,1H),9.55(s,1H),8.65(d,J＝5.2Hz,2H),8.11(d,J＝1.8Hz,1H),7.57(d,J＝5.0Hz,2H),7.47–7.43(m,1H),7.27(d,J＝8.3Hz,1H),6.85(s,1H),3.33(dd,J＝29.9,15.9Hz,5H),3.07–3.00(m,1H),2.90–2.76(m,4H),1.28(d,J＝6.4Hz,3H).MS:[M+H]+＝496.3m/z.Yellow solid, yield 43%; the target product was obtained by general method 2. 1 H NMR (400MHz, DMSO-d 6 ) δ12.63 (s, 1H), 9.62 (s, 1H), 9.55 (s, 1H), 8.65 (d, J = 5.2Hz, 2H), 8.11 (d, J＝1.8Hz,1H),7.57(d,J＝5.0Hz,2H),7.47–7.43(m,1H),7.27(d,J＝8.3Hz,1H),6.85(s,1H),3.33( dd,J＝29.9,15.9Hz,5H),3.07–3.00(m,1H),2.90–2.76(m,4H),1.28(d,J＝6.4Hz,3H).MS:[M+H] + ＝496.3m/z.
实施例6.(S)-N-(5-((1-乙酰哌啶-4-基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 6. (S)-N-(5-((1-acetylpiperidin-4-yl)ethynyl)-2-(3,4-dimethylpiperazin-1-yl)phenyl)- Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，收率49.26％；通过通用方法1得到目标产物。1H NMR(600MHz,DMSO-d6)δ:12.60(brs,1H),9.56(brs,1H),9.51(s,1H),7.91(d,J＝1.4Hz,1H),7.22(dd,J＝8.4,2.0Hz,1H),7.16(d,J＝8.4Hz,1H),6.83(s,1H),3.88-3.86(m,1H),3.67-3.64(m,1H),3.54-3.52(m,1H),3.29-3.22(m,5H),3.14-3.10(m,1H),3.01-2.97(m,1H),3.00-2.85(m,4H),2.76-2.72(m,1H),2.00(s,3H),1.90-1.86(m,1H),1.83-1.78(m,1H),1.61-1.57(m,1H),1.49-1.44(m,1H),1.27(d,J＝6.4Hz,3H).；MS:[M+H]+＝543.59m/z.Yellow solid, yield 49.26%; the target product was obtained by general method 1. 1 H NMR (600MHz, DMSO-d 6 ) δ: 12.60 (brs, 1H), 9.56 (brs, 1H), 9.51 (s, 1H), 7.91 (d, J = 1.4Hz, 1H), 7.22 (dd, J＝8.4,2.0Hz,1H),7.16(d,J＝8.4Hz,1H),6.83(s,1H),3.88-3.86(m,1H),3.67-3.64(m,1H),3.54-3.52 (m,1H),3.29-3.22(m,5H),3.14-3.10(m,1H),3.01-2.97(m,1H),3.00-2.85(m,4H),2.76-2.72(m,1H) ,2.00(s,3H),1.90-1.86(m,1H),1.83-1.78(m,1H),1.61-1.57(m,1H),1.49-1.44(m,1H),1.27(d,J＝ 6.4Hz,3H).;MS:[M+H] + =543.59m/z.
实施例7.N-(5-((1-乙酰哌啶-3-基)乙炔基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 7. N-(5-((1-acetylpiperidin-3-yl)ethynyl)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)- Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
1.步骤1叔丁基3-((4-((S)-3,4-二甲基哌嗪-1-基)-3-(6-氧-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺基)苯基)乙炔基哌啶-1-羧酸酯的合成
1. Step 1 tert-butyl 3-((4-((S)-3,4-dimethylpiperazin-1-yl)-3-(6-oxo-4-(trifluoromethyl)-1) ,Synthesis of 6-dihydropyridine-3-carboxamido)phenyl)ethynylpiperidine-1-carboxylate
黄色油状，产率49.82％；通过通用方法2得到目标产物。Yellow oil, yield 49.82%; the target product was obtained by general method 2.
2.步骤2 N-(2-((S)-3,4-二甲基哌嗪-1-基)-5-(哌啶-3-亚乙基炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
2. Step 2 N-(2-((S)-3,4-dimethylpiperazin-1-yl)-5-(piperidin-3-ethylenyl)phenyl)-6-oxo Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色油状，收率100％；将叔丁基3-((4-((S)-3,4-二甲基哌嗪-1-基)-3-(6-氧-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺基)苯基)乙炔基哌啶-1-羧酸酯(1Yellow oil, yield 100%; tert-butyl 3-((4-((S)-3,4-dimethylpiperazin-1-yl)-3-(6-oxo-4-(trifluoro) Methyl)-1,6-dihydropyridine-3-carboxamido)phenyl)ethynylpiperidine-1-carboxylate (1
equiv.)溶于二氯甲烷，并滴加三氟乙酸(3equiv.)，反应在室温下搅拌3小时.反应结束后，减压除去多余溶剂，粗产品经高效液相色谱仪分离纯化。equiv.) was dissolved in dichloromethane, and trifluoroacetic acid (3 equiv.) was added dropwise, and the reaction was stirred at room temperature for 3 hours. After the reaction, excess solvent was removed under reduced pressure, and the crude product was separated and purified by high-performance liquid chromatography.
3.步骤3 N-(5-((1-乙酰哌啶-3-基)乙炔基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
3. Step 3 N-(5-((1-acetylpiperidin-3-yl)ethynyl)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)- Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，收率65.97％；通过通用方法1得到目标产物。1H NMR(400MHz,Methanol-d4)δ:7.98(brs,1H),7.95-7.93(m,1H),7.26-7.20(m,2H),6.93(s,1H),3.80-3.77(m,1H),3.70-3.59(m,2H),3.42-3.32(m,4H),3.27-3.23(m,1H),3.14-3.11(m,1H),3.01-2.83(m,5H),2.77-2.65(m,1H),2.17-2.12(m,3H),2.07-1.96(m,1H),1.92-1.80(m,2H),1.61-1.51(m,1H),1.40(d,J＝6.4Hz,3H).；MS:[M+H]+＝544.46m/z.Yellow solid, yield 65.97%; the target product was obtained by general method 1. 1 H NMR (400MHz, Methanol-d 4 ) δ: 7.98 (brs, 1H), 7.95-7.93 (m, 1H), 7.26-7.20 (m, 2H), 6.93 (s, 1H), 3.80-3.77 (m ,1H),3.70-3.59(m,2H),3.42-3.32(m,4H),3.27-3.23(m,1H),3.14-3.11(m,1H),3.01-2.83(m,5H),2.77 -2.65(m,1H),2.17-2.12(m,3H),2.07-1.96(m,1H),1.92-1.80(m,2H),1.61-1.51(m,1H),1.40(d,J＝ 6.4Hz,3H).;MS:[M+H] + =544.46m/z.
实施例8.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(苯乙炔基)苯基)-6-氧代 -4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
Example 8. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(phenylacetynyl)phenyl)-6-oxo -4-(Trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，收率28.7％；通过通用方法2得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.07-8.00(m,2H),7.52-7.50(m,2H),7.42-7.34(m,4H),7.30-7.28(m,1H),6.93(s,1H),4.49(dd,J＝13.9,6.9Hz,1H)，3.62(d,J＝9.9Hz,1H),3.46-3.37(m,2H),3.25-3.09(m,2H),3.05-2.85(m,4H),1.41(d,J＝6.4Hz,3H).；MS:[M+H]+＝496.2m/z.Yellow solid, yield 28.7%; the target product was obtained by general method 2. 1 H NMR (400MHz, Methanol-d 4 ) δ: 8.07-8.00 (m, 2H), 7.52-7.50 (m, 2H), 7.42-7.34 (m, 4H), 7.30-7.28 (m, 1H), 6.93 (s,1H),4.49(dd,J＝13.9,6.9Hz,1H),3.62(d,J＝9.9Hz,1H),3.46-3.37(m,2H),3.25-3.09(m,2H), 3.05-2.85(m,4H),1.41(d,J＝6.4Hz,3H).；MS:[M+H] + ＝496.2m/z.
实施例9.N-(5-((R)-1-乙酰哌啶-3-基)乙炔基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 9. N-(5-((R)-1-acetylpiperidin-3-yl)ethynyl)-2-((S)-3,4-dimethylpiperazin-1-yl)benzene Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
1.步骤1(S)-3-甲酰哌啶-1-羧酸叔丁酯的合成
1. Synthesis of step 1(S)-3-formylpiperidine-1-carboxylic acid tert-butyl ester
无色油状。在一个干燥支口瓶中加入DMSO(0.140mL,1.86mmol)和二氯甲烷(3mL)，用氮气置换空气后，降温至-78摄氏度。加入草酰氯(0.09mL,0.928mmol)的二氯甲烷(3mL)溶液。搅拌10分钟，加入(S)-3-(羟甲基)哌啶-1-羧酸叔丁酯(100mg,0.46mmol)的二氯甲烷(0.5mL)溶液。反应继续搅拌30分钟，之后缓慢加入三乙胺(0.32mL,2.32mmol)，继续搅拌30分钟后，缓慢回到室温，继续搅拌过夜。反应结束后，0-5摄氏度减压浓缩反应体系，粗品直接进行下一步反应。MS:[M+H]+＝158.08m/z.Colorless oil. Add DMSO (0.140 mL, 1.86 mmol) and dichloromethane (3 mL) to a dry branch-neck flask, replace the air with nitrogen, and then cool to -78 degrees Celsius. A solution of oxalyl chloride (0.09 mL, 0.928 mmol) in dichloromethane (3 mL) was added. After stirring for 10 minutes, a solution of (S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (100 mg, 0.46 mmol) in dichloromethane (0.5 mL) was added. The reaction was continued to stir for 30 minutes, and then triethylamine (0.32 mL, 2.32 mmol) was slowly added. After continuing to stir for 30 minutes, the reaction was slowly returned to room temperature, and stirring was continued overnight. After the reaction is completed, the reaction system is concentrated under reduced pressure at 0-5 degrees Celsius, and the crude product is directly used for the next reaction. MS:[M+H] + =158.08m/z.
2.步骤2(R)-3-乙炔基哌啶-1-羧酸叔丁酯的合成
2. Synthesis of step 2(R)-3-ethynylpiperidine-1-carboxylic acid tert-butyl ester
无色或黄色固体，两步收率50.1％；将(S)-3-甲酰哌啶-1-羧酸叔丁酯的粗品(0.46mmol)溶于甲醇，冰浴下加入(1-重氮-2-氧丙基)膦酸二甲酯(103微升,0.69mmol)，搅拌10分钟后，加入碳酸钾(127mg,0.92mmol)，30分钟后，室温搅拌过夜。反应结束后，减压除去多余溶剂，加水，用二氯甲烷萃取，有机相干燥后，0-5摄氏度下减压浓缩并与硅胶混合拌样，粗品经硅胶柱层析分离纯化。MS:[M+H]+＝154.09m/z.Colorless or yellow solid, two-step yield 50.1%; dissolve the crude product of (S)-3-formylpiperidine-1-carboxylic acid tert-butyl ester (0.46mmol) in methanol, add (1-heavy) in an ice bath Dimethyl nitrogen-2-oxypropyl)phosphonate (103 μl, 0.69 mmol) was stirred for 10 minutes, then potassium carbonate (127 mg, 0.92 mmol) was added, and after 30 minutes, the mixture was stirred at room temperature overnight. After the reaction is completed, remove excess solvent under reduced pressure, add water, and extract with dichloromethane. After drying the organic phase, concentrate under reduced pressure at 0-5 degrees Celsius and mix with silica gel to mix the sample. The crude product is separated and purified by silica gel column chromatography. MS:[M+H] + =154.09m/z.
3.步骤3叔丁基(R)-3-((4-((S)-3,4-二甲基哌嗪-1-基)-3-(6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺基)苯基)乙炔基)哌啶-1-羧酸酯的合成
3. Step 3 tert-butyl(R)-3-((4-((S)-3,4-dimethylpiperazin-1-yl)-3-(6-oxo-4-(trifluoro Synthesis of methyl)-1,6-dihydropyridine-3-carboxamido)phenyl)ethynyl)piperidine-1-carboxylate
黄色油状，产率35.2％；通过通用方法2得到目标产物。[M+H]+＝547.57m/z.Yellow oil, yield 35.2%; the target product was obtained by general method 2. [M+H] + =547.57m/z.
4.步骤4 N-(2-((S)-3,4-二甲基哌嗪-1-基)-5-((R)-哌啶-3-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
4. Step 4 N-(2-((S)-3,4-dimethylpiperazin-1-yl)-5-((R)-piperidin-3-yl)ethynyl)phenyl)- Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色油状，产率89.7％；将叔丁基(R)-4-(4-溴-2-硝基苯基)-2-甲基哌嗪-1-羧酸酯(1equiv.)溶于二氯甲烷，并滴加三氟乙酸(3equiv.)，反应在室温下搅拌3小时.反应结束后，减压除去多余溶剂，粗产品经高效液相色谱仪分离纯化。[M+H]+＝447.49m/z.Yellow oil, yield 89.7%; dissolve tert-butyl (R)-4-(4-bromo-2-nitrophenyl)-2-methylpiperazine-1-carboxylate (1equiv.) in di Methyl chloride, and trifluoroacetic acid (3 equiv.) was added dropwise, and the reaction was stirred at room temperature for 3 hours. After the reaction, excess solvent was removed under reduced pressure, and the crude product was separated and purified by high-performance liquid chromatography. [M+H] + =447.49m/z.
5.步骤5 N-(5-((R)-1-乙酰哌啶-3-基)乙炔基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
5. Step 5 N-(5-((R)-1-acetylpiperidin-3-yl)ethynyl)-2-((S)-3,4-dimethylpiperazin-1-yl)benzene Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，收率86％；将N-(2-((S)-3,4-二甲基哌嗪-1-基)-5-((R)-哌啶-3-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺(1equiv.)，乙酸(1.2equiv.)，N,N,N’,N’-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(1.5equiv.),N,N-二异丙基乙胺(2equiv.)溶于乙腈，室温下搅拌过夜。反应结束后，抽滤，滤液经制备级高效液相色谱仪分离纯化。1H NMR(400MHz,Methanol-d4)δ:7.99-7.91(m,2H),7.28-7.18(m,2H),6.92(s,1H),3.83-3.78(m,1H),3.70-3.59(m,2H),3.49-3.35(m,2H),3.28-3.23(m,1H),3.12-3.05(m,2H),2.96(s,3H),2.92-2.80(m,2H),2.72(ddd,J＝12.2,8.2,3.7Hz,1H),2.17-2.12(m,3H),2.05-1.95(m,1H),1.92-1.80(m,2H),1.64-1.48(m,2H),1.39(d,J＝6.4Hz,3H).；MS:[M+H]+＝544.45m/z.White solid, yield 86%; N-(2-((S)-3,4-dimethylpiperazin-1-yl)-5-((R)-piperidin-3-yl)ethynyl )Phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide (1equiv.), acetic acid (1.2equiv.), N,N,N', N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (1.5 equiv.), N, N-diisopropylethylamine (2 equiv.) were dissolved in acetonitrile , stir at room temperature overnight. After the reaction is completed, suction filtration is performed, and the filtrate is separated and purified by a preparative-grade high-performance liquid chromatograph. 1 H NMR (400MHz, Methanol-d 4 )δ:7.99-7.91(m,2H),7.28-7.18(m,2H),6.92(s,1H),3.83-3.78(m,1H),3.70-3.59 (m,2H),3.49-3.35(m,2H),3.28-3.23(m,1H),3.12-3.05(m,2H),2.96(s,3H),2.92-2.80(m,2H),2.72 (ddd,J＝12.2,8.2,3.7Hz,1H),2.17-2.12(m,3H),2.05-1.95(m,1H),1.92-1.80(m,2H),1.64-1.48(m,2H) ,1.39(d,J＝6.4Hz,3H).;MS:[M+H] + ＝544.45m/z.
实施例10.N-(2-((S)-3,4-二甲基哌嗪-1-基)-5-((S)-1-甲基哌啶-3-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 10. N-(2-((S)-3,4-dimethylpiperazin-1-yl)-5-((S)-1-methylpiperidin-3-yl)ethynyl) Synthesis of phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
1.步骤1(R)-3-甲酰哌啶-1-羧酸叔丁酯的合成
1. Synthesis of step 1(R)-3-formylpiperidine-1-carboxylic acid tert-butyl ester
无色油状。在一个干燥支口瓶中加入DMSO(0.140mL,1.86mmol)和二氯甲烷(3mL)，用氮气置换空气后，降温至-78摄氏度。加入草酰氯(0.09mL,0.928mmol)的二氯甲烷(3mL)溶液。搅拌10分钟，加入(R)-3-(羟甲基)哌啶-1-羧酸叔丁酯(100mg,0.46mmol)的二氯甲烷(0.5mL)溶液。反应继续搅拌30分钟，之后缓慢加入三乙胺(0.32mL,2.32mmol)，继续搅拌30分钟后，缓慢回 到室温，继续搅拌过夜。反应结束后，0-5摄氏度减压浓缩反应体系，粗品直接进行下一步反应。MS:[M+H]+＝158.10m/z.Colorless oil. Add DMSO (0.140 mL, 1.86 mmol) and dichloromethane (3 mL) to a dry branch-neck flask, replace the air with nitrogen, and then cool to -78 degrees Celsius. A solution of oxalyl chloride (0.09 mL, 0.928 mmol) in dichloromethane (3 mL) was added. After stirring for 10 minutes, a solution of (R)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (100 mg, 0.46 mmol) in dichloromethane (0.5 mL) was added. The reaction was continued to stir for 30 minutes, and then triethylamine (0.32 mL, 2.32 mmol) was slowly added. After continuing to stir for 30 minutes, the reaction was slowly returned to Bring to room temperature and continue stirring overnight. After the reaction is completed, the reaction system is concentrated under reduced pressure at 0-5 degrees Celsius, and the crude product is directly used for the next reaction. MS:[M+H] + =158.10m/z.
2.步骤2(S)-3-乙炔基哌啶-1-羧酸叔丁酯的合成
2. Synthesis of step 2(S)-3-ethynylpiperidine-1-carboxylic acid tert-butyl ester
无色或黄色固体，两步产率38.7％；将(R)-3-甲酰哌啶-1-羧酸叔丁酯的粗品(0.46mmol)溶于甲醇，冰浴下加入(1-重氮-2-氧丙基)膦酸二甲酯(103微升,0.69mmol)，搅拌10分钟后，加入碳酸钾(127mg,0.92mmol)，30分钟后，室温搅拌过夜。反应结束后，减压除去多余溶剂，加水，用二氯甲烷萃取，有机相干燥后，0-5摄氏度下减压浓缩并与硅胶混合拌样，粗品经硅胶柱层析分离纯化。MS:[M+H]+＝154.06m/z.Colorless or yellow solid, two-step yield 38.7%; Dissolve the crude product of (R)-3-formylpiperidine-1-carboxylic acid tert-butyl ester (0.46mmol) in methanol, add (1-heavy) in an ice bath Dimethyl nitrogen-2-oxypropyl)phosphonate (103 μl, 0.69 mmol) was stirred for 10 minutes, then potassium carbonate (127 mg, 0.92 mmol) was added, and after 30 minutes, the mixture was stirred at room temperature overnight. After the reaction is completed, remove excess solvent under reduced pressure, add water, and extract with dichloromethane. After drying the organic phase, concentrate under reduced pressure at 0-5 degrees Celsius and mix with silica gel to mix the sample. The crude product is separated and purified by silica gel column chromatography. MS:[M+H] + =154.06m/z.
3.步骤3叔丁基(S)-3-((4-((S)-3,4-二甲基哌嗪-1-基)-3-(6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺基)苯基)乙炔基)哌啶-1-羧酸酯的合成
3. Step 3 tert-butyl (S)-3-((4-((S)-3,4-dimethylpiperazin-1-yl)-3-(6-oxo-4-(trifluoro Synthesis of methyl)-1,6-dihydropyridine-3-carboxamido)phenyl)ethynyl)piperidine-1-carboxylate
黄色油状，产率27.6％；通过通用方法2得到目标产物。MS：Yellow oil, yield 27.6%; the target product was obtained by general method 2. MS:
[M+H]+＝602.54m/z.[M+H] + =602.54m/z.
4.步骤4 N-(2-((S)-3,4-二甲基哌嗪-1-基)-5-((S)-哌啶-3-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
4. Step 4 N-(2-((S)-3,4-dimethylpiperazin-1-yl)-5-((S)-piperidin-3-yl)ethynyl)phenyl)- Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
无色油状，产率71.9％；将叔丁基(R)-4-(4-溴-2-硝基苯基)-2-甲基哌嗪-1-羧酸酯(1equiv.)溶于二氯甲烷，并滴加三氟乙酸(3equiv.)，反应在室温下搅拌3小时.反应结束后，减压除去多余溶剂，粗产品经制备级高效液相色谱分离纯化。[M+H]+＝502.48m/z.Colorless oil, yield 71.9%; dissolve tert-butyl (R)-4-(4-bromo-2-nitrophenyl)-2-methylpiperazine-1-carboxylate (1equiv.) in Dichloromethane, and trifluoroacetic acid (3 equiv.) was added dropwise, and the reaction was stirred at room temperature for 3 hours. After the reaction, excess solvent was removed under reduced pressure, and the crude product was separated and purified by preparative-grade high-performance liquid chromatography. [M+H] + =502.48m/z.
5.步骤5 N-(5-((S)-1-乙酰哌啶-3-基)乙炔基)-2-((S)-3,4-二甲基哌嗪-1-基) 苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
5. Step 5 N-(5-((S)-1-acetylpiperidin-3-yl)ethynyl)-2-((S)-3,4-dimethylpiperazin-1-yl) Synthesis of phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，收率50.75％；将N-(2-((S)-3,4-二甲基哌嗪-1-基)-5-((S)-哌啶-3-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺(1equiv.)，乙酸(1.2equiv.)，N,N,N’,N’-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(1.5equiv.),N,N-二异丙基乙胺(2equiv.)溶于乙腈，室温下搅拌过夜。反应结束后，抽滤，滤液经制备级高效液相色谱仪分离纯化。1H NMR(400MHz,Methanol-d4)δ:7.96–7.89(m,2H),7.24–7.16(m,2H),6.93(s,1H),3.68(d,J＝4.6Hz,1H),3.48(s,1H),3.16-2.04(m,4H),3.04-2.95(m,2H),2.94-2.88(m,1H),2.75-2.65(m,3H),2.63-2.56(m,2H),2.19-2.11(m,3H),2.06-1.98(m,2H),1.91-1.80(m,2H),1.63-1.56(m,1H),1.33(s,3H)；MS:[M+H]+＝544.44m/z.White solid, yield 50.75%; N-(2-((S)-3,4-dimethylpiperazin-1-yl)-5-((S)-piperidin-3-yl)ethynyl )Phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide (1equiv.), acetic acid (1.2equiv.), N,N,N', N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (1.5 equiv.), N, N-diisopropylethylamine (2 equiv.) were dissolved in acetonitrile , stir at room temperature overnight. After the reaction is completed, suction filtration is performed, and the filtrate is separated and purified by a preparative-grade high-performance liquid chromatograph. 1 H NMR (400MHz, Methanol-d 4 ) δ: 7.96–7.89 (m, 2H), 7.24–7.16 (m, 2H), 6.93 (s, 1H), 3.68 (d, J = 4.6Hz, 1H), 3.48(s,1H),3.16-2.04(m,4H),3.04-2.95(m,2H),2.94-2.88(m,1H),2.75-2.65(m,3H),2.63-2.56(m,2H ),2.19-2.11(m,3H),2.06-1.98(m,2H),1.91-1.80(m,2H),1.63-1.56(m,1H),1.33(s,3H); MS:[M+ H] + =544.44m/z.
实施例11.(S)-N-(5-((2,4-二氟苯基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
Example 11. (S)-N-(5-((2,4-difluorophenyl)ethynyl)-2-(3,4-dimethylpiperazin-1-yl)phenyl)-6 -Oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，收率71.4％；通过通用方法2得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.08-8.00(m,2H),7.62-7.26(m,1H),7.43-7.40(m,1H),7.31-7.28(m,1H),7.10-6.99(m,2H),6.93(s,1H),3.64-3.61(m,1H),3.49-3.31(m,4H),3.22-3.08(m,1H),3.01-2.84(m,4H),1.41(d,J＝6.4Hz,3H).MS:[M+H]+＝531.37m/z.Yellow solid, yield 71.4%; the target product was obtained by general method 2. 1 H NMR (400MHz, Methanol-d 4 ) δ: 8.08-8.00 (m, 2H), 7.62-7.26 (m, 1H), 7.43-7.40 (m, 1H), 7.31-7.28 (m, 1H), 7.10 -6.99(m,2H),6.93(s,1H),3.64-3.61(m,1H),3.49-3.31(m,4H),3.22-3.08(m,1H),3.01-2.84(m,4H) ,1.41(d,J＝6.4Hz,3H).MS:[M+H] + ＝531.37m/z.
实施例12.(S)-N-(5-((3,4-二氟苯基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
Example 12. (S)-N-(5-((3,4-difluorophenyl)ethynyl)-2-(3,4-dimethylpiperazin-1-yl)phenyl)-6 -Oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，收率21.4％；通过通用方法2得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.08(d,J＝1.8Hz,1H),7.99(s,1H),7.49-7.39(m,2H),7.37-7.27(m,3H),6.93(s,1H),3.64-3.61(m,1H),3.50-3.32(m,4H),3.15-3.09(m,1H),2.97(s,3H),2.92-2.86(m,1H),1.40(d,J＝6.4Hz,3H).MS:[M+H]+＝531.31m/z.Yellow solid, yield 21.4%; the target product was obtained by general method 2. 1 H NMR (400MHz, Methanol-d 4 ) δ: 8.08 (d, J = 1.8 Hz, 1H), 7.99 (s, 1H), 7.49-7.39 (m, 2H), 7.37-7.27 (m, 3H), 6.93(s,1H),3.64-3.61(m,1H),3.50-3.32(m,4H),3.15-3.09(m,1H),2.97(s,3H),2.92-2.86(m,1H), 1.40(d,J＝6.4Hz,3H).MS:[M+H] + ＝531.31m/z.
实施例13.(S)-4-((4-(3,4-二甲基哌嗪-1-基)-3-(6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺基)苯基)乙炔基)苯甲酸甲酯的合成
Example 13. (S)-4-((4-(3,4-dimethylpiperazin-1-yl)-3-(6-oxo-4-(trifluoromethyl)-1,6 -Synthesis of methyl dihydropyridine-3-carboxamido)phenyl)ethynyl)benzoate
1.步骤1 4-乙基苯甲酸甲酯的合成
1. Step 1 Synthesis of 4-ethylbenzoic acid methyl ester
黄色固体，收率93.98％；将对乙炔基苯甲酸(1eqv.)置于圆底烧瓶，加入N,N-二甲基甲酰胺溶解，加入碘甲烷(1.5eqv.)和碳酸钾(2eqv.)，室温搅拌2小时。反应结束后，反应体系加水，用乙酸乙酯萃取后，合并有机相并用大量水洗涤，有机相干燥浓缩后，经硅胶柱层析分离纯化。MS:[M+H]+＝161.08m/z.Yellow solid, yield 93.98%; place p-ethynylbenzoic acid (1eqv.) in a round-bottomed flask, add N,N-dimethylformamide to dissolve, add methyl iodide (1.5eqv.) and potassium carbonate (2eqv. ), stir at room temperature for 2 hours. After the reaction is completed, water is added to the reaction system, and after extraction with ethyl acetate, the organic phases are combined and washed with a large amount of water. After the organic phase is dried and concentrated, it is separated and purified by silica gel column chromatography. MS:[M+H] + =161.08m/z.
2.步骤2(S)-4-((4-(3,4-二甲基哌嗪-1-基)-3-(6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺基)苯基)乙炔基)苯甲酸甲酯的合成
2. Step 2(S)-4-((4-(3,4-dimethylpiperazin-1-yl)-3-(6-oxo-4-(trifluoromethyl)-1,6 -Synthesis of methyl dihydropyridine-3-carboxamido)phenyl)ethynyl)benzoate
黄色固体，收率25％；通过通用方法2得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.11(d,J＝1.7Hz,1H),8.04–7.99(m,3H),7.62(d,J＝8.3Hz,2H),7.44(dd,J＝8.3,1.8Hz,1H),7.30(d,J＝8.3Hz,1H),6.94(s,1H),3.92(s,3H),3.67-3.60(m,1H),3.51-3.32(m,4H),3.16-3.13(m,1H),2.97(s,3H),2.93-2.86(m,1H),1.41(d,J＝6.4Hz,3H).Yellow solid, yield 25%; the target product was obtained by general method 2. 1 H NMR (400MHz, Methanol-d 4 ) δ: 8.11 (d, J = 1.7Hz, 1H), 8.04–7.99 (m, 3H), 7.62 (d, J = 8.3Hz, 2H), 7.44 (dd, J＝8.3,1.8Hz,1H),7.30(d,J＝8.3Hz,1H),6.94(s,1H),3.92(s,3H),3.67-3.60(m,1H),3.51-3.32(m ,4H),3.16-3.13(m,1H),2.97(s,3H),2.93-2.86(m,1H),1.41(d,J=6.4Hz,3H).
MS:[M+H]+＝553.45m/z.MS:[M+H] + =553.45m/z.
实施例14.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(2-氟苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
Example 14. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(2-fluorophenyl)ethynyl)phenyl)-6-oxo- 4-(Trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，收率36.9％；通过通用方法2得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.05(d,J＝30.5Hz,2H),7.55(td,J＝7.9,1.8Hz,1H),7.47–7.36(m,2H),7.30(d,J＝8.3Hz,1H),7.24–7.15(m,2H),6.94(s,1H),3.63(d,J＝12.4Hz,1H),3.50–3.33(m,4H),3.20–3.09(m,1H),3.00–2.86(m,4H).1.41(d,J＝6.4Hz,3H).Yellow solid, yield 36.9%; the target product was obtained by general method 2. 1 H NMR (400MHz, Methanol-d 4 ) δ: 8.05 (d, J＝30.5Hz, 2H), 7.55 (td, J＝7.9, 1.8Hz, 1H), 7.47–7.36 (m, 2H), 7.30 ( d,J＝8.3Hz,1H),7.24–7.15(m,2H),6.94(s,1H),3.63(d,J＝12.4Hz,1H),3.50–3.33(m,4H),3.20–3.09 (m,1H),3.00–2.86(m,4H).1.41(d,J=6.4Hz,3H).
.MS:[M+H]+＝513.2m/z..MS:[M+H] + =513.2m/z.
实施例15.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(噻吩-3-亚甲炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
Example 15. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(thiophene-3-methylene)phenyl)-6-oxo- 4-(Trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，收率18.91％；通过通用方法2得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.05(d,J＝1.8Hz,1H),8.00(s,1H),7.46(dd,J＝5.2,1.1Hz,1H),7.38(dd,J＝8.3,1.9Hz,1H),7.31(dd,J＝3.6,1.1Hz,1H),7.28(d,J＝8.3Hz,1H),7.06(dd,J＝5.2,3.7Hz,1H),6.94(s,1H),3.63(d,J＝12.6Hz,1H),3.50–3.33(m,4H),3.17–3.08(m,1H),2.98(s,3H),2.88(dd,J＝13.5,10.9Hz,1H),1.41(d,J＝6.5Hz,3H).MS:[M+H]+＝501.2m/z.Yellow solid, yield 18.91%; the target product was obtained by general method 2. 1 H NMR (400MHz, Methanol-d 4 ) δ: 8.05 (d, J = 1.8 Hz, 1H), 8.00 (s, 1H), 7.46 (dd, J = 5.2, 1.1 Hz, 1H), 7.38 (dd, J＝8.3,1.9Hz,1H),7.31(dd,J＝3.6,1.1Hz,1H),7.28(d,J＝8.3Hz,1H),7.06(dd,J＝5.2,3.7Hz,1H), 6.94(s,1H),3.63(d,J＝12.6Hz,1H),3.50–3.33(m,4H),3.17–3.08(m,1H),2.98(s,3H),2.88(dd,J＝ 13.5,10.9Hz,1H),1.41(d,J＝6.5Hz,3H).MS:[M+H] + ＝501.2m/z.
实施例16.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(间甲苯基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
Example 16. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(m-tolyl)phenyl)-6-oxo-4-(trifluoro Methyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，收率24.82％；通过通用方法2得到目标产物。1H NMR(400MHz,Methanol-d4)δ8.08–8.05(m,1H),8.00(s,1H),7.40(dd,J＝8.3,1.8Hz,1H),7.34(s,1H),7.33-7.23(m,3H),7.19(d,J＝7.4Hz,1H),6.93(s,1H),3.64-3.61(m,1H),3.51-3.34(m,4H),3.18-3.09(m,1H),2.98(s,3H),2.94–2.85(m,1H),2.35(s,3H),1.41(d,J＝6.5Hz,3H).LC-MS(ESI):[M+H]+＝509.2m/z.Yellow solid, yield 24.82%; the target product was obtained by general method 2. 1 H NMR (400MHz, Methanol-d4) δ8.08–8.05 (m, 1H), 8.00 (s, 1H), 7.40 (dd, J = 8.3, 1.8Hz, 1H), 7.34 (s, 1H), 7.33 -7.23(m,3H),7.19(d,J＝7.4Hz,1H),6.93(s,1H),3.64-3.61(m,1H),3.51-3.34(m,4H),3.18-3.09(m ,1H),2.98(s,3H),2.94–2.85(m,1H),2.35(s,3H),1.41(d,J＝6.5Hz,3H).LC-MS(ESI):[M+H ] + =509.2m/z.
实施例17.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-((3-(乙基氨甲酰)苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 17. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-((3-(ethylcarbamoyl)phenyl)ethynyl)phenyl Synthesis of )-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
1.步骤1 N-乙基-3-乙炔基苯甲酰胺的合成
1. Step 1 Synthesis of N-ethyl-3-ethynylbenzamide
黄色或白色固体，收率81.8％；在圆底烧瓶中，将乙炔基苯甲酸(100mg,1equiv.)和N,N,N’,N’-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(390mg,1.5equiv.)溶解于二氯甲烷(5mL)，加入N,N-二异丙基乙胺(250微升,2equiv.)和 乙胺(75微升,2equiv.)常温下搅拌过夜。反应结束后，抽滤，用甲醇洗涤，将滤液减压浓缩后溶于N,N-二甲基甲酰胺，粗品经快速制备液相色谱仪分离纯化。LC-MS(ESI):[M+H]+＝174.19m/z.Yellow or white solid, yield 81.8%; in a round-bottom flask, combine ethynyl benzoic acid (100 mg, 1 equiv.) and N,N,N',N'-tetramethyl-O-(7-azepine Triazol-1-yl)urea hexafluorophosphate (390 mg, 1.5 equiv.) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (250 μL, 2 equiv.) and Ethylamine (75 μl, 2 equiv.) was stirred at room temperature overnight. After the reaction is completed, filter with suction and wash with methanol. The filtrate is concentrated under reduced pressure and dissolved in N,N-dimethylformamide. The crude product is separated and purified by rapid preparative liquid chromatography. LC-MS(ESI): [M+H] + =174.19m/z.
2.步骤2(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-((3-(乙基氨甲酰)苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
2. Step 2 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-((3-(ethylcarbamoyl)phenyl)ethynyl)phenyl Synthesis of )-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，29.8％；通过通用方法2得到目标产物。1H NMR(400MHz,DMSO-d6)δ12.63(s,1H),9.59(s,2H),8.60(t,J＝5.5Hz,1H),8.02(s,1H),7.98(d,J＝6.2Hz,1H),7.87(d,J＝7.8Hz,1H),7.70(d,J＝7.8Hz,1H),7.52(t,J＝7.8Hz,1H),7.41(dd,J＝8.2,1.9Hz,1H),7.26(d,J＝8.3Hz,1H),6.84(s,1H),3.55(d,J＝10.7Hz,1H),3.34-3.24(m,6H),3.07-3.00(m,1H),2.86(d,J＝4.2Hz,2H),2.83–2.73(m,2H),1.28(d,J＝6.4Hz,3H),1.13(t,J＝7.2Hz,3H)；LC-MS(ESI):[M+H]+＝566.67m/z.Yellow solid, 29.8%; the target product was obtained by general method 2. 1 H NMR (400MHz, DMSO-d 6 ) δ12.63 (s, 1H), 9.59 (s, 2H), 8.60 (t, J = 5.5Hz, 1H), 8.02 (s, 1H), 7.98 (d, J＝6.2Hz,1H),7.87(d,J＝7.8Hz,1H),7.70(d,J＝7.8Hz,1H),7.52(t,J＝7.8Hz,1H),7.41(dd,J＝ 8.2,1.9Hz,1H),7.26(d,J＝8.3Hz,1H),6.84(s,1H),3.55(d,J＝10.7Hz,1H),3.34-3.24(m,6H),3.07- 3.00(m,1H),2.86(d,J＝4.2Hz,2H),2.83–2.73(m,2H),1.28(d,J＝6.4Hz,3H),1.13(t,J＝7.2Hz,3H ); LC-MS(ESI): [M+H] + =566.67m/z.
实施例18.(S)-N-(5-((4-氰基苯基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
Example 18. (S)-N-(5-((4-cyanophenyl)ethynyl)-2-(3,4-dimethylpiperazin-1-yl)phenyl)-6-oxo Generation-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，收率7.56％；通过通用方法2得到目标产物。LC-MS(ESI):[M+H]+＝520.41m/z.Yellow solid, yield 7.56%; the target product was obtained by general method 2. LC-MS(ESI): [M+H] + =520.41m/z.
实施例19.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(4-(三氟甲基)苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
Example 19. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(4-(trifluoromethyl)phenyl)ethynyl)phenyl)- 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，收率4.33％；通过通用方法2得到目标产物。LC-MS(ESI):[M+H]+＝563.43m/z.Yellow solid, yield 4.33%; the target product was obtained by general method 2. LC-MS(ESI): [M+H] + =563.43m/z.
实施例20(S)-5-氨基-2-氯-N-(2-(3,4-二甲基哌嗪-1-基)-5-((4-氟苯基)乙炔基)苯基)-4-氟-3-甲基苯甲酰胺的合成
Example 20 (S)-5-amino-2-chloro-N-(2-(3,4-dimethylpiperazin-1-yl)-5-((4-fluorophenyl)ethynyl)benzene Synthesis of 4-fluoro-3-methylbenzamide
1)(S)-2-氯-N-(2-(3,4-二甲基哌嗪-1-基)-5-((4-氟苯基)乙炔基)苯基)-4-氟-3-甲基-5-硝基苯甲酰胺的合成
1)(S)-2-Chloro-N-(2-(3,4-dimethylpiperazin-1-yl)-5-((4-fluorophenyl)ethynyl)phenyl)-4- Synthesis of Fluoro-3-methyl-5-nitrobenzamide
黄色油状，产率55.25％；将5-氨基-2-氯-4-氟-3-甲基苯甲酸(1eqv.)置于干燥的单口瓶中，用氮气置换气体，将二氯亚砜(1.5eqv.)注射入瓶中，升温至90摄氏度，回流搅拌2小时。反应结束后，在氮气气氛减压除去多余的二氯亚砜，并重新密闭单口瓶，将新制的(S)-2-(3,4-二甲基哌嗪-1-基)-5-(4-氟苯基)乙炔基)苯胺的二氯甲烷溶液(1eqv.,1M)注射入单口瓶，室温下搅拌1小时。反应结束后，减压除去多余溶剂，粗品用制备级快速液相色谱仪分离纯化。LC-MS(ESI):[M+H]+＝539.36m/z. Yellow oil, yield 55.25%; place 5-amino-2-chloro-4-fluoro-3-methylbenzoic acid (1eqv.) in a dry one-mouth bottle, replace the gas with nitrogen, and add sulfoxide dichloride ( 1.5eqv.) was injected into the bottle, heated to 90 degrees Celsius, and stirred under reflux for 2 hours. After the reaction is completed, remove the excess thionyl chloride under reduced pressure in a nitrogen atmosphere, seal the single-neck bottle again, and add the newly prepared (S)-2-(3,4-dimethylpiperazin-1-yl)-5- A solution of (4-fluorophenyl)ethynyl)aniline in dichloromethane (1 eqv., 1 M) was injected into a single-mouth bottle and stirred at room temperature for 1 hour. After the reaction, excess solvent was removed under reduced pressure, and the crude product was separated and purified using a preparative-grade fast liquid chromatograph. LC-MS(ESI): [M+H] + =539.36m/z.
2)(S)-5-氨基-2-氯-N-(2-(3,4-二甲基哌嗪-1-基)-5-((4-氟苯基)乙炔基)苯基)-4-氟-3-甲基苯甲酰胺的合成
2)(S)-5-amino-2-chloro-N-(2-(3,4-dimethylpiperazin-1-yl)-5-((4-fluorophenyl)ethynyl)phenyl )-4-fluoro-3-methylbenzamide synthesis
将(S)-2-氯-N-(2-(3,4-二甲基哌嗪-1-基)-5-((4-氟苯基)乙炔基)苯基)-4-氟-3-甲基-5-硝基苯甲酰胺(S)-2-氯-N-(2-(3,4-二甲基哌嗪-1-基)-5-((4-氟苯基)乙炔基)苯基)-4-氟-3-甲基-5-硝基苯甲酰胺(1equiv.)溶于乙酸乙酯，加入二水合氯化亚锡(3equiv)。反应升温至70摄氏度搅拌过夜。反应结束后，用水洗涤，有机相干燥浓缩后，粗品经制备级高效液相色谱仪纯化。(S)-2-Chloro-N-(2-(3,4-dimethylpiperazin-1-yl)-5-((4-fluorophenyl)ethynyl)phenyl)-4-fluoro -3-Methyl-5-nitrobenzamide(S)-2-chloro-N-(2-(3,4-dimethylpiperazin-1-yl)-5-((4-fluorobenzene (ethynyl)phenyl)-4-fluoro-3-methyl-5-nitrobenzamide (1equiv.) was dissolved in ethyl acetate, and stannous chloride dihydrate (3equiv.) was added. The reaction was warmed to 70°C and stirred overnight. After the reaction is completed, the organic phase is washed with water, dried and concentrated, and the crude product is purified by preparative-grade high performance liquid chromatography.
黄色固体，收率19.8％；1H NMR(400MHz,Methanol-d4)δ8.21(d,J＝1.9Hz,1H),7.59–7.53(m,2H),7.39(dd,J＝8.3,1.9Hz,1H),7.28(d,J＝8.3Hz,1H),7.17–7.10(m,2H),6.92(d,J＝9.0Hz,1H),3.66-3.60(m,1H),3.46–3.41(m,1H),3.37(d,J＝12.1Hz,2H),3.34-3.32(m,1H),3.17–3.10(m,1H),2.98(s,3H),2.94-2.86(m,1H),2.33(d,J＝2.6Hz,3H),1.42(d,J＝6.4Hz,3H).；LC-MS(ESI):[M+H]+＝509.43m/z.Yellow solid, yield 19.8%; 1 H NMR (400MHz, Methanol-d 4 ) δ8.21 (d, J = 1.9 Hz, 1H), 7.59–7.53 (m, 2H), 7.39 (dd, J = 8.3, 1.9Hz,1H),7.28(d,J＝8.3Hz,1H),7.17–7.10(m,2H),6.92(d,J＝9.0Hz,1H),3.66-3.60(m,1H),3.46– 3.41(m,1H),3.37(d,J＝12.1Hz,2H),3.34-3.32(m,1H),3.17–3.10(m,1H),2.98(s,3H),2.94-2.86(m, 1H), 2.33 (d, J = 2.6 Hz, 3H), 1.42 (d, J = 6.4 Hz, 3H).; LC-MS (ESI): [M+H] + = 509.43m/z.
实施例21.S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-(9-甲基-3,9-二氮螺环[5.5]十一碳-3-基)苯基)乙炔基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 21.S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-(9-methyl-3,9-diazaspirocycle [5.5] Synthesis of undec-3-yl)phenyl)ethynyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
1.步骤1 9-(3-((三甲基硅基)乙炔基)苯基)-3,9-二氮螺环[5.5]十一烷-3-羧酸叔丁酯的合成
1. Step 1 Synthesis of 9-(3-((trimethylsilyl)ethynyl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester
粉色液体，产率44％；将((3-溴苯基)乙炔基)三甲基硅烷(200mg,789.85umol)，3,9-二氮螺环[5.5]十一碳-3-羧酸叔丁酯(200mg,786.24umol)，三(二亚苄基茚丙酮)二钯(70mg,76.50umol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(45mg,77.85umol)溶于10Ml四氢呋喃，用氮气置换三次，加入双三甲基硅基胺基锂(1.5mL,1M)，升温至80℃并搅拌一小时。反应结束后，将体系降至室温并抽滤，加水并用乙酸乙酯萃取，用无水硫酸钠干燥，合并有机相，粗品经制备液相色谱仪分离纯化得到目标化合物。LC-MS(ESI):[M+H]+＝427.49m/z.Pink liquid, yield 44%; ((3-bromophenyl)ethynyl)trimethylsilane (200mg, 789.85umol), 3,9-diazaspiro[5.5]undec-3-carboxylic acid Tert-butyl ester (200mg, 786.24umol), tris(dibenzylideneindylpropanone)dipalladium (70mg, 76.50umol) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (45mg , 77.85umol) was dissolved in 10Ml tetrahydrofuran, replaced with nitrogen three times, added lithium bistrimethylsilylamide (1.5mL, 1M), raised the temperature to 80°C and stirred for one hour. After the reaction, the system was lowered to room temperature and filtered, water was added and extracted with ethyl acetate, dried over anhydrous sodium sulfate, the organic phases were combined, and the crude product was separated and purified by preparative liquid chromatography to obtain the target compound. LC-MS(ESI): [M+H] + =427.49m/z.
2.步骤2 9-(3-乙炔基苯基)-3,9-二氮螺环[5.5]十一烷-3-羧酸叔丁酯的合成
2. Step 2 Synthesis of 9-(3-ethynylphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester
黄色固体，产率52％；将9-(3-((三甲基硅基)乙炔基)苯基)-3,9-二氮螺环[5.5]十一烷-3-羧酸叔丁酯(160mg,374.99umol)溶于10mL四氢呋喃,然后加入四丁基氟化铵(1.2mL,1.12mmol)，室温搅拌一小时。反应结束后，将体系抽滤，粗品经制备液相色谱仪分离纯化得到目标化合物。LC-MS(ESI):[M+H]+＝355.51m/z.Yellow solid, yield 52%; 9-(3-((trimethylsilyl)ethynyl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl Dissolve the ester (160mg, 374.99umol) in 10mL tetrahydrofuran, then add tetrabutylammonium fluoride (1.2mL, 1.12mmol) and stir at room temperature for one hour. After the reaction is completed, the system is suction-filtered, and the crude product is separated and purified by preparative liquid chromatography to obtain the target compound. LC-MS(ESI): [M+H] + =355.51m/z.
3.步骤3 3-(3-乙基苯基)-3,9-二氮螺环[5.5]十一烷的合成
3. Step 3 Synthesis of 3-(3-ethylphenyl)-3,9-diazaspiro[5.5]undecane
黄色液体；将9-(3-乙炔基苯基)-3,9-二氮螺环[5.5]十一烷-3-羧酸叔丁酯(30mg,84.63umol)和三氟乙酸(1.5mL)溶于8mL二氯甲烷，室温搅拌半小时。反应结束后，将体系减压浓缩得到粗品，粗品直接用于下一步反应。LC-MS(ESI):[M+H]+＝255.33m/z. Yellow liquid; combine 9-(3-ethynylphenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (30mg, 84.63umol) and trifluoroacetic acid (1.5mL ) was dissolved in 8 mL of methylene chloride and stirred at room temperature for half an hour. After the reaction, the system was concentrated under reduced pressure to obtain a crude product, which was directly used in the next reaction. LC-MS(ESI): [M+H] + =255.33m/z.
4.步骤4 3-(3-乙基苯基)-9-甲基-3,9-二氮螺环[5.5]十一烷的合成
4. Step 4 Synthesis of 3-(3-ethylphenyl)-9-methyl-3,9-diazaspiro[5.5]undecane
黄色液体，产率53％；将3-(3-乙基苯基)-3,9-二氮螺环[5.5]十一烷(80mg,314.49umol)和N,N-二异丙基乙胺(6滴)溶于30mL二氯甲烷,然后加入四丁基氟化铵(1.2mL,1.12mmol)和乙酸(4滴)，室温搅拌3小时后，加入醋酸硼氢化钠(60mg,954.78umol)，室温搅拌一小时。反应结束后，将体系抽滤，粗品经制备液相色谱仪分离纯化得到目标化合物。LC-MS(ESI):[M+H]+＝269.31m/z.Yellow liquid, yield 53%; combine 3-(3-ethylphenyl)-3,9-diazaspiro[5.5]undecane (80mg, 314.49umol) and N,N-diisopropylethyl Dissolve amine (6 drops) in 30 mL of methylene chloride, then add tetrabutylammonium fluoride (1.2 mL, 1.12 mmol) and acetic acid (4 drops). After stirring at room temperature for 3 hours, add sodium acetate borohydride (60 mg, 954.78 umol). ) and stir at room temperature for one hour. After the reaction is completed, the system is suction-filtered, and the crude product is separated and purified by preparative liquid chromatography to obtain the target compound. LC-MS(ESI): [M+H] + =269.31m/z.
5.步骤5((S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-(9-甲基-3,9-二氮螺环[5.5]十一碳-3-基)苯基)乙炔基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
5. Step 5((S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-(9-methyl-3,9-diazaspiro[ 5.5] Synthesis of undec-3-yl)phenyl)ethynyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率25％；通过通用方法2合成目标产物；1H NMR(600MHz,DMSO)δ12.65(s,1H),9.59(s,1H),8.07(d,J＝1.7Hz,1H),8.05-8.00(m,1H),7.37(dd,J＝8.3,1.9Hz,1H),7.26-7.23(m,2H),7.10(brs,1H),7.04-7.01(m,1H),6.94(d,J＝7.5Hz,1H),6.85(s,1H),3.78-3.75(m,2H),3.34-3.27(m,5H),3.22-3.19(m,4H),3.10-3.05(m,4H),2.87(d,J＝3.8Hz,2H),2.83-2.76(m,4H),1.87(d,J＝13.8Hz,2H),1.76-1.70(m,2H),1.53-1.45(m,4H),1.29(d,J＝6.4Hz,3H).；LC-MS(ESI):[M+H]+＝661.58m/z.White solid, yield 25%; the target product was synthesized by general method 2; 1 H NMR (600MHz, DMSO) δ12.65 (s, 1H), 9.59 (s, 1H), 8.07 (d, J = 1.7Hz, 1H ),8.05-8.00(m,1H),7.37(dd,J＝8.3,1.9Hz,1H),7.26-7.23(m,2H),7.10(brs,1H),7.04-7.01(m,1H), 6.94(d,J＝7.5Hz,1H),6.85(s,1H),3.78-3.75(m,2H),3.34-3.27(m,5H),3.22-3.19(m,4H),3.10-3.05( m,4H),2.87(d,J＝3.8Hz,2H),2.83-2.76(m,4H),1.87(d,J＝13.8Hz,2H),1.76-1.70(m,2H),1.53-1.45 (m, 4H), 1.29 (d, J = 6.4Hz, 3H).; LC-MS (ESI): [M+H] + = 661.58m/z.
实施例22.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-(9-甲基-3,9-二氮螺环[5.5]十一碳-3-基)苯基)乙炔基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 22. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-(9-methyl-3,9-diazaspiro[5.5 Synthesis of undec-3-yl)phenyl)ethynyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率18％；合成方法与(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-(9-甲基-3,9-二氮螺环[5.5]十一碳-3-基)苯基)乙炔基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成相同；1H NMR(600MHz,DMSO-d6)δ12.64(s,1H),9.72(s,1H),9.58(s,1H),9.35(s,1H),8.06(s,1H),8.03-7.95(m,1H),7.36(dd,J＝8.3,2.0Hz,1H),7.23(t,J＝7.9Hz,2H),6.87(d,J＝7.7Hz,1H),6.55(t,J＝2.0Hz,1H),6.46(dd,J＝8.3,2.4Hz,1H),3.66(d,J＝50.3Hz,3H),3.58-3.53(m,1H),3.45-3.38(m,3H),3.32-3.27(m,2H),3.01-2.93(m,2H),2.87(s,3H),2.78(d,J＝3.2Hz,3H),2.10(d,J＝13.8Hz,2H),1.90-1.82(m,2H),1.29(d,J＝6.4Hz,3H).；[M+H]+＝633.61m/z.White solid, yield 18%; the synthesis method is the same as (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-(9-methyl-3,9) -Diazaspiro[5.5]undec-3-yl)phenyl)ethynyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide The synthesis is the same; 1 H NMR (600MHz, DMSO-d 6 ) δ12.64(s,1H),9.72(s,1H),9.58(s,1H),9.35(s,1H),8.06(s,1H) ,8.03-7.95(m,1H),7.36(dd,J＝8.3,2.0Hz,1H),7.23(t,J＝7.9Hz,2H),6.87(d,J＝7.7Hz,1H),6.55( t,J＝2.0Hz,1H),6.46(dd,J＝8.3,2.4Hz,1H),3.66(d,J＝50.3Hz,3H),3.58-3.53(m,1H),3.45-3.38(m ,3H),3.32-3.27(m,2H),3.01-2.93(m,2H),2.87(s,3H),2.78(d,J＝3.2Hz,3H),2.10(d,J＝13.8Hz, 2H), 1.90-1.82 (m, 2H), 1.29 (d, J = 6.4Hz, 3H).; [M+H] + = 633.61m/z.
实施例23.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-吗啉苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 23. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-morpholinyl)ethynyl)phenyl)-6-oxo -Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
1.步骤1 4-(3-((三甲基硅基)乙炔基)苯基)吗啉的合成
1. Step 1 Synthesis of 4-(3-((trimethylsilyl)ethynyl)phenyl)morpholine
无色液体，产率41.9％；将((3-溴苯基)乙炔基)三甲基硅烷(200mg,789.85μmol)和吗啉(137.6mg,1.58mmol)溶于3mL四氢呋喃,然后加入三(二亚苄基茚丙酮)二钯(36mg)和2-二环己膦基-2'-(N,N-二甲胺)-联苯(31mg)。将体系密闭并氮气置换三次，然后加入双三甲基硅基胺基锂(1.5mL,4M inTHF),升温至80℃搅拌一小时。反应结束后，将体系降至室温并抽滤，加水并用乙酸 乙酯萃取，用无水硫酸钠干燥，合并有机相，粗品经制备液相色谱仪分离纯化得到目标化合物。[M+H]+＝260.27m/z.Colorless liquid, yield 41.9%; dissolve ((3-bromophenyl)ethynyl)trimethylsilane (200mg, 789.85μmol) and morpholine (137.6mg, 1.58mmol) in 3mL tetrahydrofuran, then add three ( Dibenzylidene indenacetone) dipalladium (36 mg) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (31 mg). The system was sealed and replaced with nitrogen three times, then lithium bistrimethylsilylamide (1.5 mL, 4 M inTHF) was added, and the temperature was raised to 80°C and stirred for one hour. After the reaction is completed, the system is lowered to room temperature and filtered, water is added and acetic acid is added. Extract with ethyl ester, dry with anhydrous sodium sulfate, combine the organic phases, and separate and purify the crude product with preparative liquid chromatography to obtain the target compound. [M+H] + =260.27m/z.
2.步骤2 4-(3-乙炔基苯基)吗啉的合成
2. Step 2 Synthesis of 4-(3-ethynylphenyl)morpholine
无色液体；将4-(3-((三甲基硅基)乙炔基)苯基)吗啉(86mg)溶于3mL四氢呋喃,然后加入四丁基氟化铵(994.5μL,1M inTHF)，室温搅拌一小时。反应结束后，将体系抽滤，粗品经制备液相色谱仪分离纯化得到目标化合物。[M+H]+＝255.33m/z.Colorless liquid; dissolve 4-(3-((trimethylsilyl)ethynyl)phenyl)morpholine (86mg) in 3mL tetrahydrofuran, then add tetrabutylammonium fluoride (994.5μL, 1M inTHF), Stir at room temperature for one hour. After the reaction is completed, the system is suction-filtered, and the crude product is separated and purified by preparative liquid chromatography to obtain the target compound. [M+H] + =255.33m/z.
3.步骤3(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-吗啉苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
3. Step 3(S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-morpholinophenyl)ethynyl)phenyl)-6-oxo -Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率32.9％；通过通用方法2合成目标产物；1H NMR(600MHz,DMSO-d6)δ12.62(s,1H),9.64(s,1H),9.57(s,1H),8.06(s,1H),8.01-7.98(m,1H),7.38-7.36(m,1H),7.28-7.23(m,2H),7.08(s,1H),7.02-6.97(m,2H),6.84(s,1H),3.74-3.72(m,4H),3.55-3.54(m,1H),3.32-3.25(m,4H),3.15–3.14(m,4H),3.06-3.01(m,1H),2.87(s,3H),2.81-2.76(m,1H),1.28(d,J＝6.4Hz,3H).；[M+H]+＝580.44m/z.White solid, yield 32.9%; the target product was synthesized by general method 2; 1 H NMR (600MHz, DMSO-d 6 ) δ12.62 (s, 1H), 9.64 (s, 1H), 9.57 (s, 1H), 8.06(s,1H),8.01-7.98(m,1H),7.38-7.36(m,1H),7.28-7.23(m,2H),7.08(s,1H),7.02-6.97(m,2H), 6.84(s,1H),3.74-3.72(m,4H),3.55-3.54(m,1H),3.32-3.25(m,4H),3.15–3.14(m,4H),3.06-3.01(m,1H ), 2.87 (s, 3H), 2.81-2.76 (m, 1H), 1.28 (d, J = 6.4Hz, 3H).; [M+H] + = 580.44m/z.
实施例24.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-(4-甲基哌嗪-1-基)苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 24. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-(4-methylpiperazin-1-yl)phenyl)acetylene Synthesis of (base)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
1.步骤1 1-甲基-4-(3-((三甲基硅基)乙炔基)苯基)哌嗪的合成
1. Step 1 Synthesis of 1-methyl-4-(3-((trimethylsilyl)ethynyl)phenyl)piperazine
棕色液体，产率69.7％；合成方法与步骤1 4-(3-((三甲基硅基)乙炔基)苯基)吗啉的合成相同。[M+H]+＝273.31m/z.Brown liquid, yield 69.7%; the synthesis method is the same as the synthesis of 4-(3-((trimethylsilyl)ethynyl)phenyl)morpholine in step 1. [M+H] + =273.31m/z.
2.步骤2 4-(3-乙炔基苯基)吗啉的合成
2. Step 2 Synthesis of 4-(3-ethynylphenyl)morpholine
棕色液体，产率45.3％；合成方法与步骤2 4-(3-乙炔基苯基)吗啉的合成相同。[M+H]+＝201.30m/z.Brown liquid, yield 45.3%; the synthesis method is the same as the synthesis of 4-(3-ethynylphenyl)morpholine in step 2. [M+H] + =201.30m/z.
3.步骤3(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-(4-甲基哌嗪-1-基)苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
3. Step 3(S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-(4-methylpiperazin-1-yl)phenyl)acetylene Synthesis of (base)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率13.5％；通过通用方法2合成目标产物；1H NMR(600MHz,DMSO-d6)δ12.64(s,1H),9.74(s,1H),9.59(s,1H),8.08(s,1H),7.98(s,1H),7.37-7.35(m,1H),7.32-7.29(m,1H),7.25-7.23(m,1H),7.19-7.18(m,1H),7.07-7.02(m,2H),6.84(s,1H),3.93-3.92(m,2H),3.55-3.50(m,4H),3.29-2.27(m,2H),3.16–3.14(m,2H),3.06-2.99(m,4H),2.86(brs,6H),2.80-2.76(m,1H),1.28(d,J＝6.4Hz,3H).；[M+H]+＝593.49m/z.Yellow solid, yield 13.5%; the target product was synthesized by general method 2; 1 H NMR (600MHz, DMSO-d 6 ) δ12.64 (s, 1H), 9.74 (s, 1H), 9.59 (s, 1H), 8.08(s,1H),7.98(s,1H),7.37-7.35(m,1H),7.32-7.29(m,1H),7.25-7.23(m,1H),7.19-7.18(m,1H), 7.07-7.02(m,2H),6.84(s,1H),3.93-3.92(m,2H),3.55-3.50(m,4H),3.29-2.27(m,2H),3.16–3.14(m,2H ),3.06-2.99(m,4H),2.86(brs,6H),2.80-2.76(m,1H),1.28(d,J＝6.4Hz,3H).；[M+H] + ＝593.49m/ z.
实施例25.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(4-(甲基氨甲酰)苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 25. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(4-(methylcarbamoyl)phenyl)ethynyl)phenyl) -Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率22.4％；通过通用方法2合成目标产物；1H NMR(600MHz,DMSO-d6)δ12.63(s,1H),9.60(s,2H),8.56-8.54(m,1H),8.11-8.07(m,1H),8.05-7.96(m,1H),7.88(d,J＝8.3Hz,2H),7.65(d,J＝8.3Hz,2H),7.42(dd,J＝8.3,1.8Hz,1H),7.26(d,J＝8.3Hz,1H),6.85(s,1H),3.58-3.53(m,1H),3.30-3.26(m,2H),3.08-3.01(m,1H),2.87(s,3H),2.83-2.76(m,4H),2.03-1.96(m,1H),1.28(d,J＝6.0Hz,3H).；[M+H]+＝552.41m/z.Yellow solid, yield 22.4%; the target product was synthesized by general method 2; 1 H NMR (600MHz, DMSO-d 6 ) δ12.63 (s, 1H), 9.60 (s, 2H), 8.56-8.54 (m, 1H) ),8.11-8.07(m,1H),8.05-7.96(m,1H),7.88(d,J＝8.3Hz,2H),7.65(d,J＝8.3Hz,2H),7.42(dd,J＝ 8.3,1.8Hz,1H),7.26(d,J＝8.3Hz,1H),6.85(s,1H),3.58-3.53(m,1H),3.30-3.26(m,2H),3.08-3.01(m ,1H),2.87(s,3H),2.83-2.76(m,4H),2.03-1.96(m,1H),1.28(d,J＝6.0Hz,3H).;[M+H] + =552.41 m/z.
实施例26.(S)-N-(5-((3-乙酰基-3-氮杂螺环[5.5]十一碳-9-基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 26. (S)-N-(5-((3-acetyl-3-azaspiro[5.5]undec-9-yl)ethynyl)-2-(3,4-dimethyl Synthesis of piperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率93％；合成方法与N-(5-((1-乙酰哌啶-2-基)乙炔基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成相同；1H NMR(600MHz,Methanol-d4)δ7.98(s,1H),7.95(d,J＝1.8Hz,1H),7.28-7.24(m,1H),7.23(d,J＝12.4Hz,1H),6.95(s,1H),3.63(d,J＝12.4Hz,1H),3.59-3.55(m,2H),3.53-3.49(m,2H),3.46-3.43(m,1H),3.38-3.34(m,1H),3.31-3.26(m,2H),3.14-3.07(m,1H),2.99(s,3H),2.89-2.85(m,1H),2.67-2.62(m,1H),2.10(s,3H),1.90-1.84(m,2H),1.80-1.76(m,2H),1.70-1.64(m,2H),1.62-1.59(m,1H),1.54-1.48(m,2H),1.44-1.34(m,6H).；[M+H]+＝612.54m/z.Yellow solid, yield 93%; the synthesis method is the same as N-(5-((1-acetylpiperidin-2-yl)ethynyl)-2-((S)-3,4-dimethylpiperazine-1) The synthesis of -yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide is the same; 1 H NMR (600MHz, Methanol-d 4 ) δ7. 98(s,1H),7.95(d,J＝1.8Hz,1H),7.28-7.24(m,1H),7.23(d,J＝12.4Hz,1H),6.95(s,1H),3.63(d ,J＝12.4Hz,1H),3.59-3.55(m,2H),3.53-3.49(m,2H),3.46-3.43(m,1H),3.38-3.34(m,1H),3.31-3.26(m ,2H),3.14-3.07(m,1H),2.99(s,3H),2.89-2.85(m,1H),2.67-2.62(m,1H),2.10(s,3H),1.90-1.84(m ,2H),1.80-1.76(m,2H),1.70-1.64(m,2H),1.62-1.59(m,1H),1.54-1.48(m,2H),1.44-1.34(m,6H).; [M+H] + =612.54m/z.
实施例27.N-(5-((4-氟苯基)乙炔基)-2-((3R，5S)-3,4,5-三甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 27. N-(5-((4-fluorophenyl)ethynyl)-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)phenyl)- Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率39.8％；通过通用方法2合成目标产物；1H NMR(400MHz,DMSO-d6)δ:12.62(brs,1H),9.59(s,1H),9.29(brs,1H),8.10(d,J＝1.6Hz,1H),7.96(s,1H),7.65-7.61(m,2H),7.38(dd,J＝8.3,1.8Hz,1H),7.28(t,J＝8.9Hz,2H),7.23(d,J＝8.3Hz,1H),6.84(s,1H),3.55-3.48(m,2H),3.35-3.32(m,2H),2.88-2.80(m,5H),1.31(d,J＝6.4Hz,6H).[M+H]+＝527.39m/z.Yellow solid, yield 39.8%; the target product was synthesized by general method 2; 1 H NMR (400MHz, DMSO-d 6 ) δ: 12.62 (brs, 1H), 9.59 (s, 1H), 9.29 (brs, 1H), 8.10(d,J＝1.6Hz,1H),7.96(s,1H),7.65-7.61(m,2H),7.38(dd,J＝8.3,1.8Hz,1H),7.28(t,J＝8.9Hz ,2H),7.23(d,J=8.3Hz,1H),6.84(s,1H),3.55-3.48(m,2H),3.35-3.32(m,2H),2.88-2.80(m,5H), 1.31(d,J＝6.4Hz,6H).[M+H] + ＝527.39m/z.
1.步骤1 6-氯-N-(5-((4-氟苯基)乙炔基)-2-((3R，5S)-3,4,5-三甲基哌嗪-1-基)苯基)-4-(三氟甲基)烟酰胺的合成
1. Step 1 6-chloro-N-(5-((4-fluorophenyl)ethynyl)-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl) Synthesis of phenyl)-4-(trifluoromethyl)nicotinamide
黄色油状，收率23.8％；在圆底烧瓶中，6-氯-4-(三氟甲基)烟酸(52Yellow oil, yield 23.8%; in a round-bottom flask, 6-chloro-4-(trifluoromethyl)nicotinic acid (52
mg,0.230mmol)和N,N,N’,N’-四甲基氯甲脒六氟磷酸盐(129.37mg,0.461mg, 0.230mmol) and N,N,N’,N’-tetramethylchloroformamidine hexafluorophosphate (129.37mg, 0.461
mmol)溶解于乙腈(1mL)，加入N-甲基吡咯(46.75mg,0.576mmol)，搅拌半小时后，加入5-((4-氟苯基)乙炔基)-2-((3R，5S)-3,4,5-三甲基哌嗪-1-基)苯胺(101.13mg,0.299mmol)，常温下搅拌过夜。反应结束后，抽滤，用甲醇洗涤，将滤液减压浓缩后溶于N,N-二甲基甲酰胺，粗品经快速制备液相色谱仪分离纯化MS:[M+H]+＝545.39m/z.mmol) was dissolved in acetonitrile (1 mL), N-methylpyrrole (46.75 mg, 0.576 mmol) was added, and after stirring for half an hour, 5-((4-fluorophenyl)ethynyl)-2-((3R, 5S) was added )-3,4,5-trimethylpiperazin-1-yl)aniline (101.13 mg, 0.299 mmol), stir at room temperature overnight. After the reaction, filter with suction and wash with methanol. The filtrate is concentrated under reduced pressure and dissolved in N,N-dimethylformamide. The crude product is separated and purified by rapid preparative liquid chromatography. MS: [M+H] + =545.39m /z.
2.步骤2 N-(5-((4-氟苯基)乙炔基)-2-((3R，5S)-3,4,5-三甲基哌嗪-1-基)苯基)-6-甲氧基-4-(三氟甲基)烟酰胺的合成
2. Step 2 N-(5-((4-fluorophenyl)ethynyl)-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)phenyl)- Synthesis of 6-methoxy-4-(trifluoromethyl)nicotinamide
黄色油状，收率83.7％；在圆底烧瓶中，加入6-氯-N-(5-((4-氟苯基)乙炔基)-2-((3R，5S)-3,4,5-三甲基哌嗪-1-基)苯基)-4-(三氟甲基)烟酰胺(30mg,0.055mmol),1mL甲醇和1mL纯化水，加入氢氧化钠(11mg,0.275mmol)，搅拌溶清后，升温至90摄氏度并搅拌过夜。反应结束后，抽滤，将滤液减压浓缩后溶于N,N-二甲基甲酰胺，粗品经快速制备液相色谱仪分离纯化。MS:Yellow oil, yield 83.7%; in a round-bottomed flask, add 6-chloro-N-(5-((4-fluorophenyl)ethynyl)-2-((3R,5S)-3,4,5 -Trimethylpiperazin-1-yl)phenyl)-4-(trifluoromethyl)nicotinamide (30mg, 0.055mmol), 1mL methanol and 1mL purified water, add sodium hydroxide (11mg, 0.275mmol), After stirring to dissolve, raise the temperature to 90 degrees Celsius and stir overnight. After the reaction is completed, suction filtration is performed, and the filtrate is concentrated under reduced pressure and dissolved in N,N-dimethylformamide. The crude product is separated and purified by rapid preparative liquid chromatography. MS:
[M+H]+＝542.42m/z.[M+H] + =542.42m/z.
3.步骤3 N-(5-((4-氟苯基)乙炔基)-2-((3R，5S)-3,4,5-三甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
3. Step 3 N-(5-((4-fluorophenyl)ethynyl)-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)phenyl)- Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，收率73.6％；在圆底烧瓶中，加入N-(5-((4-氟苯基)乙炔基)-2-((3R，5S)-3,4,5-三甲基哌嗪-1-基)苯基)-6-甲氧基-4-(三氟甲基)烟酰胺(7mg,0.013mmol)和1mL 1,4-二氧六环，加入1mL氯化氢溶液(4M in dioxane)，搅拌溶清后，升温至60摄氏度并搅拌3h。反应结束后，抽滤，将滤液减压浓缩后溶于N,N-二甲基甲酰胺，粗品经快速制备液相色谱仪分离纯化1H NMR(400MHz,DMSO-d6)δ:12.62(brs,1H),9.59(s,1H),9.29(brs,1H),8.10(d,J＝1.6Hz,1H),7.96(s,1H),7.65-7.61(m,2H),7.38(dd,J＝8.3,1.8Hz,1H),7.28(t,J＝8.9Hz,2H),7.23(d,J＝8.3Hz,1H),6.84(s,1H),3.55-3.48(m,2H),3.35-3.32(m,2H),2.88-2.80(m,5H),1.31(d,J＝6.4Hz,6H).[M+H]+＝527.39m/z.White solid, yield 73.6%; in a round-bottomed flask, add N-(5-((4-fluorophenyl)ethynyl)-2-((3R,5S)-3,4,5-trimethyl Piperazin-1-yl)phenyl)-6-methoxy-4-(trifluoromethyl)nicotinamide (7mg, 0.013mmol) and 1mL 1,4-dioxane, add 1mL hydrogen chloride solution (4M in dioxane), stir to dissolve, raise the temperature to 60 degrees Celsius and stir for 3 hours. After the reaction was completed, the filtrate was concentrated under reduced pressure and dissolved in N,N-dimethylformamide. The crude product was separated and purified by rapid preparative liquid chromatography. 1 H NMR (400MHz, DMSO-d 6 ) δ: 12.62 ( brs,1H),9.59(s,1H),9.29(brs,1H),8.10(d,J＝1.6Hz,1H),7.96(s,1H),7.65-7.61(m,2H),7.38(dd ,J＝8.3,1.8Hz,1H),7.28(t,J＝8.9Hz,2H),7.23(d,J＝8.3Hz,1H),6.84(s,1H),3.55-3.48(m,2H) ,3.35-3.32(m,2H),2.88-2.80(m,5H),1.31(d,J＝6.4Hz,6H).[M+H] + ＝527.39m/z.
实施例28.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(4-(4-甲基哌嗪-1-基)苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 28. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(4-(4-methylpiperazin-1-yl)phenyl)acetylene Synthesis of (base)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率22％；合成方法与(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-(9-甲基-3,9-二氮螺环[5.5]十一碳-3-基)苯基)乙炔基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成相同；1H NMR(600MHz,DMSO-d6)δ12.64(s,1H),9.80-9.60(m,2H),9.57(s,1H),8.03-7.98(m,2H),7.45(d,J＝8.8Hz,2H),7.34-7.32(m,1H),7.24-7.20(m,1H),7.04(d,J＝8.9Hz,2H),6.85(s,1H),3.96(brs,2H),3.56-3.48(m,2H),3.33-3.22(m,2H),3.19-3.09(m,2H),3.09-2.98(m,3H),2.90-2.74(m,6H),2.03-1.96(m,1H),1.29(d,J＝6.4Hz,3H).；[M+H]+＝593.55m/z.White solid, yield 22%; the synthesis method is the same as (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-(9-methyl-3,9) -Diazaspiro[5.5]undec-3-yl)phenyl)ethynyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide The synthesis is the same; 1 H NMR (600MHz, DMSO-d 6 ) δ12.64 (s, 1H), 9.80-9.60 (m, 2H), 9.57 (s, 1H), 8.03-7.98 (m, 2H), 7.45 ( d,J＝8.8Hz,2H),7.34-7.32(m,1H),7.24-7.20(m,1H),7.04(d,J＝8.9Hz,2H),6.85(s,1H),3.96(brs ,2H),3.56-3.48(m,2H),3.33-3.22(m,2H),3.19-3.09(m,2H),3.09-2.98(m,3H),2.90-2.74(m,6H),2.03 -1.96(m,1H),1.29(d,J＝6.4Hz,3H).; [M+H] + ＝593.55m/z.
实施例29.(S)-N-(5-((3-乙酰氨基苯基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 29. (S)-N-(5-((3-acetylaminophenyl)ethynyl)-2-(3,4-dimethylpiperazin-1-yl)phenyl)-6-oxo Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率32％；通过通用方法2合成目标产物；1H NMR(600MHz,DMSO-d6)δ:12.64(s,1H),10.07(s,1H),9.74(s,1H),9.60(s,1H),8.07-8.04(m,1H),8.02-7.96(m,1H),7.89(s,1H),7.50-7.48(m,1H),7.40-7.38(m,1H),7.36-7.32(m,1H),7.25-7.20(m,2H),6.84(s,1H),3.41-3.39(m,1H),3.34-3.26(m,4H),3.06-3.02(m,1H),2.86-2.86(m,3H),2.82-2.76(m,1H),2.06(s,3H),1.28(d,J＝6.4Hz,3H).；[M+H]+＝552.42m/z.White solid, yield 32%; the target product was synthesized by general method 2; 1 H NMR (600MHz, DMSO-d 6 ) δ: 12.64 (s, 1H), 10.07 (s, 1H), 9.74 (s, 1H), 9.60(s,1H),8.07-8.04(m,1H),8.02-7.96(m,1H),7.89(s,1H),7.50-7.48(m,1H),7.40-7.38(m,1H), 7.36-7.32(m,1H),7.25-7.20(m,2H),6.84(s,1H),3.41-3.39(m,1H),3.34-3.26(m,4H),3.06-3.02(m,1H ),2.86-2.86(m,3H),2.82-2.76(m,1H),2.06(s,3H),1.28(d,J＝6.4Hz,3H).；[M+H] + ＝552.42m/ z.
实施例30.N-(3'-(吗啉甲基)-4-((3R，5S)-3,4,5-三甲基哌嗪-1-基)-(1,1'-联苯基)-3-基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 30. N-(3'-(morpholinmethyl)-4-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)-(1,1'-linked Synthesis of phenyl)-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率63％；通过通用方法2合成目标产物；1H NMR(600MHz,DMSO-d6)δ9.84(s,1H),9.68(s,1H),8.20(d,J＝1.8Hz,1H),8.01(s,1H),7.76(s,1H),7.69(d,J＝7.9Hz,1H),7.57(t,J＝7.7Hz,1H),7.52-7.48(m,2H),7.29(d,J＝8.4Hz,1H),6.83(s,1H),4.43(s,2H),3.73-3.69(m,2H),3.67-3.65(m,2H),3.52-3.48(m,4H),3.31-3.23(m,4H),2.95-2.89(m,2H),2.87(s,3H),1.33(d,J＝6.4Hz,6H).；[M+H]+＝584.50m/z.Yellow solid, yield 63%; the target product was synthesized by general method 2; 1 H NMR (600MHz, DMSO-d 6 ) δ9.84 (s, 1H), 9.68 (s, 1H), 8.20 (d, J = 1.8 Hz,1H),8.01(s,1H),7.76(s,1H),7.69(d,J＝7.9Hz,1H),7.57(t,J＝7.7Hz,1H),7.52-7.48(m,2H ),7.29(d,J＝8.4Hz,1H),6.83(s,1H),4.43(s,2H),3.73-3.69(m,2H),3.67-3.65(m,2H),3.52-3.48( m,4H),3.31-3.23(m,4H),2.95-2.89(m,2H),2.87(s,3H),1.33(d,J＝6.4Hz,6H).; [M+H] + = 584.50m/z.
实施例31.(S)-N-(5-((3-(7-氧-2-氮杂螺环[3.5]壬-2-基)苯基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 31. (S)-N-(5-((3-(7-oxo-2-azaspiro[3.5]non-2-yl)phenyl)ethynyl)-2-(3,4 -Synthesis of dimethylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率23％；合成方法和(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-吗啉苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成相同；1H NMR(600MHz,DMSO-d6)δ12.63(s,1H),9.57-9.56(m,1H),8.05(d,J＝1.7Hz,1H),8.00(d,J＝5.3Hz,1H),7.37(dd,J＝8.3,1.9Hz,1H),7.25-7.18(m,2H),6.84-6.83(m,2H),6.56(s,1H),6.47(dd,J＝8.2,1.7Hz,1H),3.63(s,4H),3.56-3.55(m,4H),3.46-3.23(m,4H),3.12-2.99(m,1H),2.87(d,J＝4.1Hz,3H),2.82-2.77(m,2H),1.77-1.71(m,4H),1.29(d,J＝6.5Hz,3H).；[M+H]+＝620.53m/z.White solid, yield 23%; synthesis method and (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-morpholinophenyl)ethynyl)benzene base)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide is synthesized in the same way; 1 H NMR (600MHz, DMSO-d 6 ) δ12.63 (s, 1H),9.57-9.56(m,1H),8.05(d,J＝1.7Hz,1H),8.00(d,J＝5.3Hz,1H),7.37(dd,J＝8.3,1.9Hz,1H), 7.25-7.18(m,2H),6.84-6.83(m,2H),6.56(s,1H),6.47(dd,J＝8.2,1.7Hz,1H),3.63(s,4H),3.56-3.55( m,4H),3.46-3.23(m,4H),3.12-2.99(m,1H),2.87(d,J＝4.1Hz,3H),2.82-2.77(m,2H),1.77-1.71(m, 4H), 1.29 (d, J＝6.5Hz, 3H).; [M+H] + ＝620.53m/z.
实施例32.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-(吗啉甲基)苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 32. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-(morpholinylmethyl)phenyl)ethynyl)phenyl)- Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率13.2％；合成方法与(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-吗啉苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成相同；1H NMR(600MHz,DMSO-d6)δ:12.68(s,1H),10.13(s,1H),9.93(s,1H),9.63(s,1H),8.13(s,1H),7.99(s,1H),7.75-7.66(m,1H),7.53(s,1H),7.39-7.37(m,1H),7.27-7.26(m,1H),6.85(s,1H),4.38(s,2H),3.97(s,2H),3.64(s,2H),3.56-3.55(m,1H),3.39-3.29(m,6H),3.12-3.04(m,3H),2.87(s,3H),2.82-2.71(m,1H),1.29(d,J＝6.4Hz,3H).；[M+H]+＝594.47m/z.White solid, yield 13.2%; the synthesis method is the same as (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-morpholinophenyl)ethynyl)benzene base)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide is synthesized in the same way; 1 H NMR (600MHz, DMSO-d 6 ) δ: 12.68 (s, 1H),10.13(s,1H),9.93(s,1H),9.63(s,1H),8.13(s,1H),7.99(s,1H),7.75-7.66(m,1H),7.53(s ,1H),7.39-7.37(m,1H),7.27-7.26(m,1H),6.85(s,1H),4.38(s,2H),3.97(s,2H),3.64(s,2H), 3.56-3.55(m,1H),3.39-3.29(m,6H),3.12-3.04(m,3H),2.87(s,3H),2.82-2.71(m,1H),1.29(d,J＝6.4 Hz,3H).;[M+H] + =594.47m/z.
实施例33.(S)-N-(5-(3-(二甲氨基)甲基)苯基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 33. (S)-N-(5-(3-(dimethylamino)methyl)phenyl)ethynyl)-2-(3,4-dimethylpiperazin-1-yl)phenyl Synthesis of )-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率14.43％；通过通用方法2合成目标产物；1H NMR(600MHz,DMSO-d6)δ:12.67(s,1H),9.85-9.80(m,1H),8.13(s,1H),7.98(s,1H),7.75(s,1H),7.67-7.66(m,1H),7.55-7.54(m,2H),7.39-7.37(m,1H),7.27-7.25(m,1H),6.85(s,1H),4.31(s,2H),3.56-3.55(m,1H),3.37-3.29(m,4H),3.08-3.04(m,1H),2.87(s,3H),2.82-2.80(m,1H),2.78-2.76(m,6H),1.29(d,J＝6.4Hz,3H).；[M+H]+＝552.51m/z.White solid, yield 14.43%; the target product was synthesized by general method 2; 1 H NMR (600MHz, DMSO-d 6 ) δ: 12.67 (s, 1H), 9.85-9.80 (m, 1H), 8.13 (s, 1H) ),7.98(s,1H),7.75(s,1H),7.67-7.66(m,1H),7.55-7.54(m,2H),7.39-7.37(m,1H),7.27-7.25(m,1H ),6.85(s,1H),4.31(s,2H),3.56-3.55(m,1H),3.37-3.29(m,4H),3.08-3.04(m,1H),2.87(s,3H), 2.82-2.80(m,1H),2.78-2.76(m,6H),1.29(d,J＝6.4Hz,3H).; [M+H] + ＝552.51m/z.
实施例34.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(4-(吗啉甲基)苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 34. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(4-(morpholinylmethyl)phenyl)ethynyl)phenyl)- Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率14.2％；合成方法和(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-吗啉苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成相同；1H NMR(600MHz,DMSO-d6)δ12.65(s,1H),9.61-9.58(m,1H),8.11-7.94(m,2H),7.68-7.55(m,4H),7.43-7.37(m,1H),7.26(d,J＝8.3Hz,1H),6.85(s,1H),4.39(brs,2H),3.98(brs,2H),3.71-3.52(m,4H),3.32-3.24(m,4H),3.19-2.97(m,4H),2.91-2.75(m,4H),1.29(d,J＝6.4Hz,3H).；[M+H]+＝594.55m/z.White solid, yield 14.2%; synthesis method and (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-morpholinophenyl)ethynyl)benzene base)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide is synthesized in the same way; 1 H NMR (600MHz, DMSO-d 6 ) δ12.65 (s, 1H),9.61-9.58(m,1H),8.11-7.94(m,2H),7.68-7.55(m,4H),7.43-7.37(m,1H),7.26(d,J＝8.3Hz,1H) ,6.85(s,1H),4.39(brs,2H),3.98(brs,2H),3.71-3.52(m,4H),3.32-3.24(m,4H),3.19-2.97(m,4H),2.91 -2.75(m,4H),1.29(d,J＝6.4Hz,3H).; [M+H] + ＝594.55m/z.
实施例35.(S)-N-(5-((3-(3-氧-9-氮杂螺环[5.5]十一碳-9-基)苯基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 35. (S)-N-(5-((3-(3-oxo-9-azaspiro[5.5]undec-9-yl)phenyl)ethynyl)-2-(3 ,Synthesis of 4-dimethylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率13.4％；合成方法和(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-吗啉苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成相同；1H NMR(600MHz,DMSO-d6)δ12.64(s,1H),9.59(s,1H),8.08-7.94(m,2H),7.38-7.37(m,1H),7.25-7.20(m,2H),7.12-7.09(m,1H),7.04-7.00(m,1H),6.93(d,J＝7.3Hz,1H),6.85(s,1H),3.60-3.54(m,5H),3.35-3.24(m,4H),3.24-3.17(m,4H),3.06-3.02(m,1H),2.90-2.73(m,4H),1.68-1.55(m,4H),1.51-1.42(m,4H),1.29(d,J＝6.4Hz,3H).；[M+H]+＝648.54m/z.White solid, yield 13.4%; synthesis method and (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-morpholinophenyl)ethynyl)benzene base)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide is synthesized in the same way; 1 H NMR (600MHz, DMSO-d 6 ) δ 12.64 (s, 1H),9.59(s,1H),8.08-7.94(m,2H),7.38-7.37(m,1H),7.25-7.20(m,2H),7.12-7.09(m,1H),7.04-7.00( m,1H),6.93(d,J＝7.3Hz,1H),6.85(s,1H),3.60-3.54(m,5H),3.35-3.24(m,4H),3.24-3.17(m,4H) ,3.06-3.02(m,1H),2.90-2.73(m,4H),1.68-1.55(m,4H),1.51-1.42(m,4H),1.29(d,J＝6.4Hz,3H).; [M+H] + =648.54m/z.
实施例36.(S)-N-(5-(苯并[d]恶唑-2-亚甲炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 36. (S)-N-(5-(benzo[d]oxazole-2-methylinyl)-2-(3,4-dimethylpiperazin-1-yl)phenyl) -Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率60％；通过通用方法2合成目标产物；1H NMR(600MHz,DMSO-d6)δ12.66(s,1H),9.73(s,1H),8.19(s,1H),8.01(s,1H),7.83(d,J＝7.9Hz,1H),7.78(d,J＝8.2Hz,1H),7.60(d,J＝7.9Hz,1H),7.54(t,J＝7.7Hz,1H),7.48(t,J＝7.6Hz,1H),7.31(d,J＝8.2Hz,1H),6.85(s,1H),3.82-3.69(m,1H),3.55-3.51(m,2H),3.27-3.24(m,2H),3.09(s,1H),2.86-2.77(m,4H),1.26(d,J＝30.2Hz,3H).；[M+H]+＝536.36m/z.Yellow solid, yield 60%; the target product was synthesized by general method 2; 1 H NMR (600MHz, DMSO-d 6 ) δ12.66 (s, 1H), 9.73 (s, 1H), 8.19 (s, 1H), 8.01(s,1H),7.83(d,J＝7.9Hz,1H),7.78(d,J＝8.2Hz,1H),7.60(d,J＝7.9Hz,1H),7.54(t,J＝7.7 Hz,1H),7.48(t,J＝7.6Hz,1H),7.31(d,J＝8.2Hz,1H),6.85(s,1H),3.82-3.69(m,1H),3.55-3.51(m ,2H),3.27-3.24(m,2H),3.09(s,1H),2.86-2.77(m,4H),1.26(d,J＝30.2Hz,3H).;[M+H] + =536.36 m/z.
实施例37.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-(7-乙基-2,7-二氮螺环[3.5]壬-2-基)苯基)乙炔基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 37. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-(7-ethyl-2,7-diazaspirocycle [3.5 Synthesis of ]non-2-yl)phenyl)ethynyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率19.2％；合成方法与(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-(9-甲基-3,9-二氮螺环[5.5]十一碳-3-基)苯基)乙炔基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成相同；1H NMR(600MHz,DMSO-d6)δ12.65(s,1H),9.58(s,1H),8.05-7.98(m,1H),7.66-7.54(m,2H),7.36-7.35(m,1H),7.24-7.20(m,2H),6.89-6.83(m,1H),6.56(s,1H),6.47(d,J＝8.0Hz,1H),3.70-3.62(m,4H),3.53-3.41(m,4H),3.11(s,3H),2.91-2.81(m,4H),2.13-2.08(m,2H),2.02-1.94(m,1H),1.91-1.87(m,2H),1.30-1.21(m,10H).；[M+H]+＝:647.56m/z.aWhite solid, yield 19.2%; the synthesis method is the same as (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-(9-methyl-3,9) -Diazaspiro[5.5]undec-3-yl)phenyl)ethynyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide The synthesis is the same; 1 H NMR (600MHz, DMSO-d 6 ) δ12.65(s,1H),9.58(s,1H),8.05-7.98(m,1H),7.66-7.54(m,2H),7.36- 7.35(m,1H),7.24-7.20(m,2H),6.89-6.83(m,1H),6.56(s,1H),6.47(d,J＝8.0Hz,1H),3.70-3.62(m, 4H),3.53-3.41(m,4H),3.11(s,3H),2.91-2.81(m,4H),2.13-2.08(m,2H),2.02-1.94(m,1H),1.91-1.87( m,2H),1.30-1.21(m,10H).；[M+H] + ＝:647.56m/za
实施例38.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-(9-乙基-3,9-二氮螺环[5.5]十一碳-3-基)苯基)乙炔基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 38. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-(9-ethyl-3,9-diazaspirocycle [5.5 Synthesis of undec-3-yl)phenyl)ethynyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率16.3％；合成方法与(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-(9-甲基-3,9-二氮螺环[5.5]十一碳-3-基)苯基)乙炔基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成相同；1H NMR(600MHz,DMSO-d6)δ12.65(s,1H),9.75(s,1H),9.59-9.57(m,1H),8.07(d,J＝1.7Hz,1H),7.40-7.34(m,1H),7.26-7.20(m,2H),7.11(d,J＝9.5Hz,1H),7.04-7.01(m,1H),6.94(d,J＝7.5Hz,1H),6.85(s,1H),3.56-3.54(m,2H),3.36-3.30(m,4H),3.24-3.18(m,3H),3.16-3.11(m,3H),3.07-2.99(m,3H),2.87-2.87(m,2H),2.82-2.77(m,1H),2.02-1.97(m,1H),1.90-1.87(m,2H),1.76-1.69(m,2H),1.53-1.46(m,4H),1.29(d,J＝6.4Hz,3H),1.24(s,3H).；[M+H]+＝675.58m/z.White solid, yield 16.3%; the synthesis method is the same as (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-(9-methyl-3,9) -Diazaspiro[5.5]undec-3-yl)phenyl)ethynyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide The synthesis is the same; 1 H NMR (600MHz, DMSO-d 6 ) δ12.65 (s, 1H), 9.75 (s, 1H), 9.59-9.57 (m, 1H), 8.07 (d, J = 1.7Hz, 1H) ,7.40-7.34(m,1H),7.26-7.20(m,2H),7.11(d,J＝9.5Hz,1H),7.04-7.01(m,1H),6.94(d,J＝7.5Hz,1H ),6.85(s,1H),3.56-3.54(m,2H),3.36-3.30(m,4H),3.24-3.18(m,3H),3.16-3.11(m,3H),3.07-2.99(m ,3H),2.87-2.87(m,2H),2.82-2.77(m,1H),2.02-1.97(m,1H),1.90-1.87(m,2H),1.76-1.69(m,2H),1.53 -1.46 (m, 4H), 1.29 (d, J = 6.4Hz, 3H), 1.24 (s, 3H).; [M+H] + = 675.58m/z.
实施例39.(S)-N-(5-((7-乙酰基-7-氮杂螺环[3.5]壬-2-基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 39. (S)-N-(5-((7-acetyl-7-azaspiro[3.5]non-2-yl)ethynyl)-2-(3,4-dimethylpiperidine Synthesis of oxazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率46％；合成方法与N-(5-((1-乙酰哌啶-2-基)乙炔基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成相同；1H NMR(600MHz,Methanol-d4)δ7.97(s,1H),7.92(d,J＝2.4Hz,1H),7.22(dd,J＝17.9,8.4Hz,2H),6.93(s,1H),3.53-3.51(m,1H),3.49-3.45(m,2H),3.43-3.40(m,2H),3.33-3.32(m,2H),3.27-3.24(m,2H),3.19-3.18(m,1H),3.11-3.07(m,1H),2.96(s,3H),2.87-2.85(m,1H),2.33-2.29(m,2H),2.08-2.07(m,3H),2.02-1.98(m,2H),1.72-1.67(m,2H),1.64-1.60(m,2H),1.39(d,J＝6.5Hz,3H).；[M+H]+＝584.43m/z.Yellow solid, yield 46%; the synthesis method is the same as N-(5-((1-acetylpiperidin-2-yl)ethynyl)-2-((S)-3,4-dimethylpiperazine-1) The synthesis of -yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide is the same; 1 H NMR (600MHz, Methanol-d 4 ) δ7. 97(s,1H),7.92(d,J＝2.4Hz,1H),7.22(dd,J＝17.9,8.4Hz,2H),6.93(s,1H),3.53-3.51(m,1H),3.49 -3.45(m,2H),3.43-3.40(m,2H),3.33-3.32(m,2H),3.27-3.24(m,2H),3.19-3.18(m,1H),3.11-3.07(m, 1H),2.96(s,3H),2.87-2.85(m,1H),2.33-2.29(m,2H),2.08-2.07(m,3H),2.02-1.98(m,2H),1.72-1.67( m, 2H), 1.64-1.60 (m, 2H), 1.39 (d, J = 6.5Hz, 3H).; [M+H] + = 584.43m/z.
实施例40.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(2-甲基-2-氮杂螺[3.5]壬-7-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 40. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(2-methyl-2-azaspiro[3.5]nonan-7-yl) Synthesis of )ethynyl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率58％；合成方法与(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(1-甲基氮杂环丁烷-3-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成相同；1H NMR(600MHz,DMSO-d6)δ12.64(s,1H),9.53(s,1H),7.97(s,1H),7.91(s,1H),7.18(dd,J＝8.3,1.5Hz,1H),7.15(d,J＝8.3Hz,1H),6.84(s,1H),4.02-3.96(m,1H),3.92-3.87(m,1H),3.77-3.68(m,2H),3.54-3.52(m,1H),3.27-3.21(m,4H),3.03-2.99(m,1H),2.88-2.82(m,6H),2.80-2.74(m,1H),2.62-2.62(m,1H),1.97-1.94(m,2H),1.85-1.82(m,1H),1.76-1.74(m,1H),1.62-1.52(m,3H),1.43-1.42(m,1H),1.28(d,J＝6.4Hz,3H).；[M+H]+＝556.60m/z.Yellow solid, yield 58%; the synthesis method is the same as (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(1-methylazetidine-3) -The synthesis of -ethynyl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide is the same; 1 H NMR (600MHz, DMSO-d 6 )δ12.64(s,1H),9.53(s,1H),7.97(s,1H),7.91(s,1H),7.18(dd,J=8.3,1.5Hz,1H),7.15(d,J ＝8.3Hz,1H),6.84(s,1H),4.02-3.96(m,1H),3.92-3.87(m,1H),3.77-3.68(m,2H),3.54-3.52(m,1H), 3.27-3.21(m,4H),3.03-2.99(m,1H),2.88-2.82(m,6H),2.80-2.74(m,1H),2.62-2.62(m,1H),1.97-1.94(m ,2H),1.85-1.82(m,1H),1.76-1.74(m,1H),1.62-1.52(m,3H),1.43-1.42(m,1H),1.28(d,J＝6.4Hz,3H ).;[M+H] + =556.60m/z.
实施例41.(S)-N-(5-((3-(氮杂环丁烷-1-基甲基)苯基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧基-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 41. (S)-N-(5-((3-(azetidin-1-ylmethyl)phenyl)ethynyl)-2-(3,4-dimethylpiperazine- Synthesis of 1-yl)phenyl)-6-oxy-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
1.步骤1 3-乙炔基苯甲醛的合成
1. Step 1 Synthesis of 3-ethynylbenzaldehyde
黄色液体，产率45.7％；合成方法与(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-乙炔基苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成相同.Yellow liquid, yield 45.7%; the synthesis method is the same as (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-ethynylphenyl)-6-oxo-4 The synthesis of -(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide is the same.
2.步骤2(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-甲酰基苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
2. Step 2 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-formylphenyl)ethynyl)phenyl)-6-oxo -Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率36％；通过通用方法2合成目标产物；[M+H]+＝523.50m/z.Yellow solid, yield 36%; the target product was synthesized by general method 2; [M+H] + =523.50m/z.
3.步骤3 6-氯-N-(5-((4-氟苯基)乙炔基)-2-((3R，5S)-3,4,5-三甲基哌嗪-1-基)苯基)-4-(三氟甲基)烟酰胺的合成
3. Step 3 6-chloro-N-(5-((4-fluorophenyl)ethynyl)-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl) Synthesis of phenyl)-4-(trifluoromethyl)nicotinamide
白色固体，产率23.8％；将(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-甲酰基苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺(20mg,38.28μmol)和氮杂环丁烷(4.37mg,76.55μmol)溶于2mL DCM,加入氰基硼氢化钠(7.22mg,114.83μmol),氮气置换三次后室温搅拌2小时。反应结束后，反应液先后经制备薄层色谱板(DCM:MeOH＝10:1,1％TEA)和制备液相色谱仪(ACN:H2O＝5-50％)分离纯化得到目标化合物。；1H NMR(600MHz,Methanol-d4)δ8.15(s,1H),8.01(s,1H),7.70-7.62(m,2H),7.53(t,J＝7.7Hz,1H),7.48(d,J＝7.7Hz,1H),7.42(d,J＝8.2Hz,1H),7.33(d,J＝8.0Hz,1H),6.96(s,1H),4.40(s,2H),4.22-4.15(m,4H),3.66-3.64(m,1H),3.47-3.44(m,1H),3.40-3.38(m,1H),3.27-3.24(m,2H),3.21-3.18(m,1H),2.99-2.92(m,4H),1.72-1.60(m,2H),1.43(d,J＝6.3Hz,3H).；[M+H]+＝564.54m/z.White solid, yield 23.8%; (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-formylphenyl)ethynyl)phenyl) -6-Oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide (20 mg, 38.28 μmol) and azetidine (4.37 mg, 76.55 μmol) were dissolved in 2 mL DCM , add sodium cyanoborohydride (7.22 mg, 114.83 μmol), replace with nitrogen three times and stir at room temperature for 2 hours. After the reaction, the reaction solution was separated and purified by preparative thin layer chromatography (DCM:MeOH=10:1, 1% TEA) and preparative liquid chromatography (ACN:H 2 O=5-50%) to obtain the target compound. ; 1 H NMR (600MHz, Methanol-d 4 ) δ8.15 (s, 1H), 8.01 (s, 1H), 7.70-7.62 (m, 2H), 7.53 (t, J = 7.7Hz, 1H), 7.48 (d,J＝7.7Hz,1H),7.42(d,J＝8.2Hz,1H),7.33(d,J＝8.0Hz,1H),6.96(s,1H),4.40(s,2H),4.22 -4.15(m,4H),3.66-3.64(m,1H),3.47-3.44(m,1H),3.40-3.38(m,1H),3.27-3.24(m,2H),3.21-3.18(m, 1H), 2.99-2.92 (m, 4H), 1.72-1.60 (m, 2H), 1.43 (d, J = 6.3Hz, 3H).; [M+H] + = 564.54m/z.
实施例42.N-(5-((4-氟苯基)乙炔基)-2-(4-甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 42. N-(5-((4-fluorophenyl)ethynyl)-2-(4-methylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl Synthesis of 1,6-dihydropyridine-3-carboxamide
黄色固体，收率21.2％；通过通用方法2得到目标产物。1H NMR(400MHz,Methanol-d4)δ8.09(d,J＝1.9Hz,1H),8.02(s,1H),7.60-7.54(m,2H),7.44-7.40(m,1H),7.30(d,J＝8.3Hz,1H),7.19-7.10(m,2H),6.96(s,1H),3.62(d,J＝11.6Hz,2H),3.30-3.27(m,4H),3.11(d,J＝12.9Hz,2H),2.98(s,3H).MS:[M+H]+＝499.39m/z.Yellow solid, yield 21.2%; the target product was obtained by general method 2. 1 H NMR (400MHz, Methanol-d 4 ) δ8.09 (d, J = 1.9 Hz, 1H), 8.02 (s, 1H), 7.60-7.54 (m, 2H), 7.44-7.40 (m, 1H), 7.30(d,J＝8.3Hz,1H),7.19-7.10(m,2H),6.96(s,1H),3.62(d,J＝11.6Hz,2H),3.30-3.27(m,4H),3.11 (d, J＝12.9Hz, 2H), 2.98 (s, 3H).MS: [M+H] + ＝499.39m/z.
实施例43.N-(5-((1-乙酰哌啶-2-基)乙炔基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 43. N-(5-((1-acetylpiperidin-2-yl)ethynyl)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)- Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
1.步骤1 2-(4-((S)-3,4-二甲基哌嗪-1-基)-3-(6-氧-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺基)苯基)乙炔基哌啶-1-羧酸叔丁酯的合成
1. Step 1 2-(4-((S)-3,4-dimethylpiperazin-1-yl)-3-(6-oxo-4-(trifluoromethyl)-1,6-di Synthesis of Hydropyridine-3-carboxamido)phenyl)ethynylpiperidine-1-carboxylic acid tert-butyl ester
黄色油状，产率42.36％；通过通用方法2合成目标产物；[M+H]+＝602.52m/z.Yellow oil, yield 42.36%; the target product was synthesized by general method 2; [M+H] + =602.52m/z.
2.步骤2 N-(2-((S)-3,4-二甲基哌嗪-1-基)-5-(哌啶-2-亚乙基炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
2. Step 2 N-(2-((S)-3,4-dimethylpiperazin-1-yl)-5-(piperidin-2-ethylenyl)phenyl)-6-oxo Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色油状，产率100％；将2-(4-((S)-3,4-二甲基哌嗪-1-基)-3-(6-氧-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺基)苯基)乙炔基哌啶-1-羧酸叔丁酯(1equiv.)溶于二氯甲烷，并滴加三氟乙酸(3equiv.)，反应在室温下搅拌3小时.反应结束后，减压除去多余溶剂，粗产品经制备级高效液相色谱分离纯化；[M+H]+＝502.45m/z.Yellow oil, yield 100%; 2-(4-((S)-3,4-dimethylpiperazin-1-yl)-3-(6-oxo-4-(trifluoromethyl)- 1,6-Dihydropyridine-3-carboxamido)phenyl)ethynylpiperidine-1-carboxylic acid tert-butyl ester (1equiv.) was dissolved in dichloromethane, and trifluoroacetic acid (3equiv.) was added dropwise. The reaction was stirred at room temperature for 3 hours. After the reaction, excess solvent was removed under reduced pressure, and the crude product was separated and purified by preparative-grade high performance liquid chromatography; [M+H] + =502.45m/z.
3.步骤3 N-(5-((1-乙酰哌啶-2-基)乙炔基)-2-((S)-3,4-二甲基哌嗪-1-基)苯 基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
3. Step 3 N-(5-((1-acetylpiperidin-2-yl)ethynyl)-2-((S)-3,4-dimethylpiperazin-1-yl)benzene Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率79.54％；将N-(2-((S)-3,4-二甲基哌嗪-1-基)-5-(哌啶-2-亚乙基炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺(1equiv.)，乙酸(1.2equiv.)，N,N,N’,N’-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(1.5equiv.),N,N-二异丙基乙胺(2equiv.)溶于乙腈，室温下搅拌过夜。反应结束后，抽滤，滤液经制备级高效液相色谱仪分离纯化；1H NMR(600MHz,DMSO-d6)δ12.63(brs,1H),9.55(s,1H),7.99(s,1H),7.92(s,1H),7.28-7.27(m,1H),7.18-7.17(m,1H),6.83(s,1H),3.76-3.74(m,1H),3.29–3.22(m,5H),3.05-2.99(m,2H),2.85(d,J＝4.3Hz,3H),2.79-2.74(m,2H),2.09-2.03(m,3H),2.03-1.98(m,1H),1.81-1.79(m,1H),1.69-1.67(m,1H),1.59-1.57(m,1H),1.47-1.39(m,2H),1.27(d,J＝6.4Hz,3H).；[M+H]+＝544.47m/z.Yellow solid, yield 79.54%; N-(2-((S)-3,4-dimethylpiperazin-1-yl)-5-(piperidin-2-ethylenyl)phenyl )-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide (1equiv.), acetic acid (1.2equiv.), N,N,N',N'- Tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (1.5 equiv.), N, N-diisopropylethylamine (2 equiv.) were dissolved in acetonitrile at room temperature. Stir overnight. After the reaction, the filtrate was filtered and the filtrate was separated and purified by preparative high-performance liquid chromatography; 1 H NMR (600MHz, DMSO-d 6 ) δ12.63 (brs, 1H), 9.55 (s, 1H), 7.99 (s, 1H),7.92(s,1H),7.28-7.27(m,1H),7.18-7.17(m,1H),6.83(s,1H),3.76-3.74(m,1H),3.29–3.22(m, 5H),3.05-2.99(m,2H),2.85(d,J＝4.3Hz,3H),2.79-2.74(m,2H),2.09-2.03(m,3H),2.03-1.98(m,1H) ,1.81-1.79(m,1H),1.69-1.67(m,1H),1.59-1.57(m,1H),1.47-1.39(m,2H),1.27(d,J=6.4Hz,3H).; [M+H] + =544.47m/z.
实施例44.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(吡啶-2-亚乙基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 44. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(pyridin-2-ethylene)phenyl)-6-oxo-4 Synthesis of -(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率31.84％；通过通用方法2合成目标产物；1H NMR(600MHz,DMSO-d6)δ:11.18(s,1H),9.65(s,1H),8.61-8.60(m,1H),8.12(s,1H),7.98-7.96(m,1H),7.87-7.84(m,1H),7.67-7.65(m,1H),7.45-7.41(m,2H),7.27-7.24(m,1H),6.84(s,1H),3.37-3.31(m,5H),3.10-3.08(m,1H),2.88-2.78(m,4H),1.29(d,J＝6.4Hz,3H).；[M+H]+＝496.42m/z.Yellow solid, yield 31.84%; the target product was synthesized by general method 2; 1 H NMR (600MHz, DMSO-d 6 ) δ: 11.18 (s, 1H), 9.65 (s, 1H), 8.61-8.60 (m, 1H) ),8.12(s,1H),7.98-7.96(m,1H),7.87-7.84(m,1H),7.67-7.65(m,1H),7.45-7.41(m,2H),7.27-7.24(m ,1H),6.84(s,1H),3.37-3.31(m,5H),3.10-3.08(m,1H),2.88-2.78(m,4H),1.29(d,J＝6.4Hz,3H). ;[M+H] + =496.42m/z.
实施例45.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(吡啶-3-亚甲炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 45. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(pyridin-3-methylene)phenyl)-6-oxo- Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率39.8％；通过通用方法2合成目标产物；1H NMR(400MHz,DMSO-d6)δ:12.62(brs,1H),9.60(s,1H),9.53(brs,1H),8.77-8.76(m,1H),8.60-8.58(m,1H),8.10(d,J＝1.6Hz,1H),8.01-8.00(m,1H),7.49-7.46(m,1H),7.43(dd,J＝8.4,1.6Hz,1H),7.26(d,J＝8.4Hz,1H),6.85(s,1H),3.59-3.57(m,1H),3.34-3.25(m,4H),3.06-3.00(m,1H),2.89–2.77(m,4H),1.28(d,J＝6.4Hz,3H).；[M+H]+＝496.39m/z.Yellow solid, yield 39.8%; the target product was synthesized by general method 2; 1 H NMR (400MHz, DMSO-d 6 ) δ: 12.62 (brs, 1H), 9.60 (s, 1H), 9.53 (brs, 1H), 8.77-8.76(m,1H),8.60-8.58(m,1H),8.10(d,J＝1.6Hz,1H),8.01-8.00(m,1H),7.49-7.46(m,1H),7.43( dd,J＝8.4,1.6Hz,1H),7.26(d,J＝8.4Hz,1H),6.85(s,1H),3.59-3.57(m,1H),3.34-3.25(m,4H),3.06 -3.00(m,1H),2.89–2.77(m,4H),1.28(d,J＝6.4Hz,3H).; [M+H] + ＝496.39m/z.
实施例46.(S)-N-(5-(2-乙酰基-2-氮杂螺环[3.3]庚烷-6-基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 46. (S)-N-(5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)ethynyl)-2-(3,4-dimethylpiper Synthesis of oxazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
1.步骤1叔丁基(S)-6-(4-(3,4-二甲基哌嗪-1-基)-3-(6-氧基-4-(三氟甲基)-1,6-二氢吡啶-3-羧酰胺基)苯基)乙炔基)-2-氮杂螺环[3.3]庚烷-2-羧酸酯的合成
1. Step 1 tert-butyl (S)-6-(4-(3,4-dimethylpiperazin-1-yl)-3-(6-oxy-4-(trifluoromethyl)-1 ,Synthesis of 6-dihydropyridine-3-carboxamido)phenyl)ethynyl)-2-azaspiro[3.3]heptane-2-carboxylate
黄色油状，产率40％；通过通用方法2合成目标产物；[M+H]+＝614.61m/z.Yellow oil, yield 40%; the target product was synthesized by general method 2; [M+H] + =614.61m/z.
2.步骤2(S)-N-(5-(2-氮杂螺环[3.3]庚烷-6-基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
2. Step 2 (S)-N-(5-(2-azaspiro[3.3]heptan-6-yl)ethynyl)-2-(3,4-dimethylpiperazin-1-yl Synthesis of )phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色油状，产率100％；将叔丁基(S)-6-(4-(3,4-二甲基哌嗪-1-基)-3-(6-氧基-4-(三氟甲基)-1,6-二氢吡啶-3-羧酰胺基)苯基)乙炔基)-2-氮杂螺环[3.3]庚烷-2-羧酸酯(1equiv.)溶于二氯甲烷，并滴加三氟乙酸(3equiv.)，反应在室温下搅拌3小时.反应结束后，减压除去多余溶剂，粗产品经制备级高效液相色谱分离纯化；[M+H]+＝514.48m/z.Yellow oil, yield 100%; tert-butyl (S)-6-(4-(3,4-dimethylpiperazin-1-yl)-3-(6-oxy-4-(trifluoro Methyl)-1,6-dihydropyridine-3-carboxamido)phenyl)ethynyl)-2-azaspiro[3.3]heptane-2-carboxylate (1equiv.) dissolved in dichloro methane, and trifluoroacetic acid (3equiv.) was added dropwise, and the reaction was stirred at room temperature for 3 hours. After the reaction, excess solvent was removed under reduced pressure, and the crude product was separated and purified by preparative-grade high-performance liquid chromatography; [M+H] + = 514.48m/z.
3.步骤3(S)-N-(5-(2-乙酰基-2-氮杂螺环[3.3]庚烷-6-基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
3. Step 3 (S)-N-(5-(2-acetyl-2-azaspiro[3.3]heptan-6-yl)ethynyl)-2-(3,4-dimethylpiper Synthesis of oxazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率74％；将(S)-N-(5-(2-氮杂螺环[3.3]庚烷-6-基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺(1equiv.)，乙酸(1.2equiv.)，N,N,N’,N’-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(1.5equiv.),N,N-二异丙基乙胺(2equiv.)溶于乙腈，室温下搅拌过夜。反应结束后，抽滤，滤液经制备级高效液相色谱仪分离纯化；1H NMR(600MHz,Methanol-d4)δ7.98(d,J＝6.6Hz,2H),7.24(s,2H),6.95(s,1H),3.63-3.62(m,1H),3.44-3.38(m,3H),3.31-3.26(m,3H),2.98(s,3H),2.86(s,3H),2.48-2.45(m,1H),2.32-2.29(m,1H),2.12-2.07(m,4H),1.87-1.74(m,3H),1.42(d,J＝6.4Hz,3H).；[M+H]+＝556.44m/z.Yellow solid, yield 74%; (S)-N-(5-(2-azaspiro[3.3]heptan-6-yl)ethynyl)-2-(3,4-dimethylpiperidine Azin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide (1equiv.), acetic acid (1.2equiv.), N, N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (1.5equiv.), N,N-diisopropylethylamine (2equiv. .) Dissolve in acetonitrile and stir at room temperature overnight. After the reaction was completed, the filtrate was separated and purified by preparative high-performance liquid chromatography; 1 H NMR (600MHz, Methanol-d4) δ7.98 (d, J = 6.6 Hz, 2H), 7.24 (s, 2H), 6.95(s,1H),3.63-3.62(m,1H),3.44-3.38(m,3H),3.31-3.26(m,3H),2.98(s,3H),2.86(s,3H),2.48- 2.45(m,1H),2.32-2.29(m,1H),2.12-2.07(m,4H),1.87-1.74(m,3H),1.42(d,J＝6.4Hz,3H).;[M+ H] + =556.44m/z.
实施例47.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-((1-甲基-1H-苯并[d]咪唑-2-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 47. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-((1-methyl-1H-benzo[d]imidazol-2-yl) Synthesis of )ethynyl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
1.步骤1 1-甲基-2-((三甲基硅烷基)乙炔基)-1H-苯并[d]咪唑的合成
1. Step 1 Synthesis of 1-methyl-2-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazole
黄色固体，产率48％；将2-溴-1-甲基-1H-苯并[d]咪唑(1equiv)，双三苯基磷二氯化钯(0.1equiv)，碘化亚铜(0.1equiv)和三乙胺(3equiv)溶于DMF,氮气保护，然后将三甲基乙炔基硅(3equiv)注射入反应体系，80度油浴搅拌3小时，反应结束后用乙酸乙酯萃取，盐水洗涤，将有机相经硅胶板纯化(EA：PE＝1：5)，合成目标产物；[M+H]+＝229.26m/z.Yellow solid, yield 48%; 2-bromo-1-methyl-1H-benzo[d]imidazole (1equiv), bistriphenylphosphonium dichloride (0.1equiv), copper iodide (0.1equiv) equiv) and triethylamine (3equiv) were dissolved in DMF, protected by nitrogen, and then trimethylethynylsilane (3equiv) was injected into the reaction system, stirred in an 80-degree oil bath for 3 hours, and extracted with ethyl acetate after the reaction, and saline Wash, purify the organic phase through silica gel plate (EA: PE=1:5), and synthesize the target product; [M+H] + =229.26m/z.
2.步骤2(2-乙基-1-甲基-1H-苯并[d]咪唑的合成
2. Step 2 (Synthesis of 2-ethyl-1-methyl-1H-benzo[d]imidazole
黄色固状，产率81％；将1-甲基-2-((三甲基硅烷基)乙炔基)-1H-苯并[d]咪唑(1equiv.)溶于四氢呋喃，然后往里面加入1M的四丁基氟化铵(2equiv.)，反应在室温下搅拌1小时.反应结束后，减压除去多余溶剂，粗产品经硅胶板分离纯化(EA：PE＝1：3)；[M+H]+＝157.22m/z.Yellow solid, yield 81%; dissolve 1-methyl-2-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazole (1equiv.) in tetrahydrofuran, and then add 1M to it Tetrabutylammonium fluoride (2equiv.), the reaction was stirred at room temperature for 1 hour. After the reaction, the excess solvent was removed under reduced pressure, and the crude product was separated and purified on a silica gel plate (EA:PE=1:3); [M+ H] + =157.22m/z.
3.步骤3(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-((1-甲基-1H-苯并[d]咪唑-2-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
3. Step 3(S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-((1-methyl-1H-benzo[d]imidazol-2-yl) Synthesis of )ethynyl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率33％；将((S)-N-(5-溴-2-(3,4-二甲基哌嗪-1-基) 苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺(1equiv)，(2-乙基-1-甲基-1H-苯并[d]咪唑(2equiv)，双环己基磷二氯化钯(0.2equiv),碘化亚铜(0.2equiv)和碳酸铯(4equiv)溶于DMF，氮气保护，110度油浴搅拌三小时。反应结束后，抽滤，滤液经制备级高效液相色谱仪分离纯化；1H NMR(600MHz,DMSO-d6)δ12.63(s,1H),9.67(s,1H),8.16(d,J＝1.8Hz,1H),8.02(s,1H),7.67(d,J＝8.1Hz,1H),7.63(d,J＝8.1Hz,1H),7.58(dd,J＝8.3,2.0Hz,1H),7.39–7.36(m,1H),7.33–7.28(m,2H),6.85(s,1H),3.96(s,3H),3.38(dd,J＝20.0,12.8Hz,4H),3.13–3.04(m,2H),2.90–2.80(m,4H),1.30(d,J＝6.4Hz,3H).；[M+H]+＝549.2m/z.Yellow solid, yield 33%; ((S)-N-(5-bromo-2-(3,4-dimethylpiperazin-1-yl) Phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide (1equiv), (2-ethyl-1-methyl-1H-benzo[ d] Imidazole (2 equiv), dicyclohexylphosphorus palladium dichloride (0.2 equiv), cuprous iodide (0.2 equiv) and cesium carbonate (4 equiv) were dissolved in DMF, protected by nitrogen, and stirred in an oil bath at 110 degrees for three hours. The reaction was completed After that, it was suction filtered, and the filtrate was separated and purified by preparative-grade high-performance liquid chromatography; 1 H NMR (600MHz, DMSO-d6) δ12.63 (s, 1H), 9.67 (s, 1H), 8.16 (d, J = 1.8 Hz,1H),8.02(s,1H),7.67(d,J＝8.1Hz,1H),7.63(d,J＝8.1Hz,1H),7.58(dd,J＝8.3,2.0Hz,1H), 7.39–7.36(m,1H),7.33–7.28(m,2H),6.85(s,1H),3.96(s,3H),3.38(dd,J＝20.0,12.8Hz,4H),3.13–3.04( m, 2H), 2.90–2.80 (m, 4H), 1.30 (d, J = 6.4Hz, 3H).; [M+H] + = 549.2m/z.
实施例48.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-甲基-3-氮杂螺环[5.5]十一碳-9-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 48. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-methyl-3-azaspiro[5.5]undecane- Synthesis of 9-yl)ethynyl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
1.步骤1叔丁基(S)-9-(4-(3,4-二甲基哌嗪-1-基)-3-(6-氧基-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺)苯基)乙炔基)-3-氮杂螺环[5.5]十一烷-3-羧酸酯的合成
1. Step 1 tert-butyl (S)-9-(4-(3,4-dimethylpiperazin-1-yl)-3-(6-oxy-4-(trifluoromethyl)-1 ,Synthesis of 6-dihydropyridine-3-carboxamide)phenyl)ethynyl)-3-azaspiro[5.5]undecane-3-carboxylate
黄色油状，产率77％；通过通用方法2合成目标产物；[M+H]+＝670.71m/z.Yellow oil, yield 77%; the target product was synthesized by general method 2; [M+H] + =670.71m/z.
2.步骤2(S)-N-(5-(3-氮杂螺环[5.5]十一碳-9-基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
2. Step 2 (S)-N-(5-(3-azaspiro[5.5]undec-9-yl)ethynyl)-2-(3,4-dimethylpiperazine-1- Synthesis of (base)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色油状，产率100％；将叔丁基(S)-9-(4-(3,4-二甲基哌嗪-1-基)-3-(6-氧基-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺)苯基)乙炔基)-3-氮杂螺环[5.5]十一烷-3-羧酸酯(1equiv.)溶于二氯甲烷，并滴加三氟乙酸(3equiv.)，反应在室温下搅拌3小时.反应结束后，减压除去多余溶剂，粗产品经制备级高效液相色谱分离纯化；[M+H]+＝570.57m/z. Yellow oil, yield 100%; tert-butyl (S)-9-(4-(3,4-dimethylpiperazin-1-yl)-3-(6-oxy-4-(trifluoro Methyl)-1,6-dihydropyridine-3-carboxamide)phenyl)ethynyl)-3-azaspiro[5.5]undecane-3-carboxylate (1equiv.) dissolved in dichloro methane, and trifluoroacetic acid (3equiv.) was added dropwise, and the reaction was stirred at room temperature for 3 hours. After the reaction, excess solvent was removed under reduced pressure, and the crude product was separated and purified by preparative-grade high-performance liquid chromatography; [M+H] + = 570.57m/z.
3.步骤3(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-甲基-3-氮杂螺环[5.5]十一碳-9-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
3. Step 3(S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-methyl-3-azaspiro[5.5]undecane- Synthesis of 9-yl)ethynyl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率58％；将(S)-N-(5-(3-氮杂螺环[5.5]十一碳-9-基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺(1equiv.)，乙酸(1.2equiv.)，N,N,N’,N’-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(1.5equiv.),N,N-二异丙基乙胺(2equiv.)溶于乙腈，室温下搅拌过夜。反应结束后，抽滤，滤液经制备级高效液相色谱仪分离纯化；1H NMR(600MHz,Methanol-d4)δ7.97(s,2H),7.24(s,2H),6.95(s,1H),3.63(s,1H),3.44-3.42(m,1H),3.38-3.36(m,2H),3.29-3.25(m,1H),3.17-3.13(m,3H),2.99(s,3H),2.89(s,3H),2.69(s,2H),2.12-2.10(m,2H),2.02-1.99(m,2H),1.93-1.80(m,3H),1.70–1.58(m,5H),1.55-1.52(m,1H),1.42(d,J＝4.7Hz,4H).；[M+H]+＝584.61m/z.Yellow solid, yield 58%; (S)-N-(5-(3-azaspiro[5.5]undec-9-yl)ethynyl)-2-(3,4-dimethyl Piperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide (1 equiv.), acetic acid (1.2 equiv.), N ,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (1.5equiv.),N,N-diisopropylethylamine ( 2equiv.) was dissolved in acetonitrile and stirred at room temperature overnight. After the reaction was completed, the filtrate was separated and purified by preparative high-performance liquid chromatography; 1 H NMR (600MHz, Methanol-d4) δ7.97 (s, 2H), 7.24 (s, 2H), 6.95 (s, 1H) ),3.63(s,1H),3.44-3.42(m,1H),3.38-3.36(m,2H),3.29-3.25(m,1H),3.17-3.13(m,3H),2.99(s,3H ),2.89(s,3H),2.69(s,2H),2.12-2.10(m,2H),2.02-1.99(m,2H),1.93-1.80(m,3H),1.70–1.58(m,5H ), 1.55-1.52 (m, 1H), 1.42 (d, J = 4.7Hz, 4H).; [M+H] + = 584.61m/z.
实施例49.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(1-甲基-1H-吡唑-4-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 49. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(1-methyl-1H-pyrazol-4-yl)ethynyl)benzene Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率72％；通过通用方法2合成目标产物；1H NMR(400MHz, DMSO-d6)δ12.60(s,1H),9.53(s,1H),8.07(s,1H),8.02(d,J＝1.7Hz,1H),7.97(s,1H),7.69(s,1H),7.29(dd,J＝8.2,1.8Hz,1H),7.21(d,J＝8.3Hz,1H),6.84(s,1H),3.85(s,3H),3.56-3.63(m,1H),3.36-3.23(m,4H),3.05-2.99(m,1H),2.89-2.73(m,4H),1.28(d,J＝6.4Hz,3H).:[M+H]+＝499.45m/z.Yellow solid, yield 72%; the target product was synthesized by general method 2; 1 H NMR (400MHz, DMSO-d6)δ12.60(s,1H),9.53(s,1H),8.07(s,1H),8.02(d,J＝1.7Hz,1H),7.97(s,1H),7.69(s, 1H),7.29(dd,J＝8.2,1.8Hz,1H),7.21(d,J＝8.3Hz,1H),6.84(s,1H),3.85(s,3H),3.56-3.63(m,1H ),3.36-3.23(m,4H),3.05-2.99(m,1H),2.89-2.73(m,4H),1.28(d,J＝6.4Hz,3H).:[M+H] + ＝499.45 m/z.
实施例50.N-(5-((1R，3S，5S，7S)-金刚烷-2-基)乙炔基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 50. N-(5-((1R,3S,5S,7S)-adamant-2-yl)ethynyl)-2-((S)-3,4-dimethylpiperazine-1- Synthesis of (base)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率32％；通过通用方法2合成目标产物；1H NMR(400MHz,Methanol-d4)δ,7.92(s,1H),7.73(s,1H),7.12(dd,J＝8.3,1.8Hz,1H),7.07(d,J＝8.3Hz,1H),6.81(s,1H),2.97-2.92(m,2H),2.82-2.76(m,2H),2.42-2.22(m,6H),1.95(s,3H),1.90(m,6H),1.68(m,6H),0.99(s,3H).；[M+H]+＝553.54m/z.Yellow solid, yield 32%; the target product was synthesized by general method 2; 1 H NMR (400MHz, Methanol-d4) δ, 7.92 (s, 1H), 7.73 (s, 1H), 7.12 (dd, J = 8.3, 1.8Hz,1H),7.07(d,J＝8.3Hz,1H),6.81(s,1H),2.97-2.92(m,2H),2.82-2.76(m,2H),2.42-2.22(m,6H ),1.95(s,3H),1.90(m,6H),1.68(m,6H),0.99(s,3H).; [M+H] + =553.54m/z.
实施例51.N-(5-(环己炔基)-2-(3R，5S)-3,4,5-三甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 51. N-(5-(cyclohexynyl)-2-(3R,5S)-3,4,5-trimethylpiperazin-1-yl)phenyl)-6-oxo-4 Synthesis of -(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
1.步骤1 N-(5-溴-2-(3R，5S)-3,4,5-三甲基哌嗪-1-基)苯基)-6-氧-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
1. Step 1 N-(5-bromo-2-(3R,5S)-3,4,5-trimethylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl Synthesis of )-1,6-dihydropyridine-3-carboxamide
黄色固体，收率22％；将5-溴-2-((3R，5S)-3,4,5-三甲基哌嗪-1-基)苯胺(1equiv.)，6-羟基-4-(三氟甲基)烟酸(1equiv.)和N,N,N’,N’-四甲基氯甲脒六氟盐酸盐(1.5equiv)溶于乙腈，搅拌15分钟后，加入N-甲基吡咯(2equiv.)。反应在室温下搅拌过夜。反应结束后，真空除去溶剂，加N,N-二甲基甲酰胺溶解过滤后，用制备级高效液相分析仪纯化产品。MS:[M+H]+＝487.29m/z.Yellow solid, yield 22%; 5-bromo-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)aniline (1equiv.), 6-hydroxy-4- (Trifluoromethyl)nicotinic acid (1 equiv.) and N,N,N',N'-tetramethylchloroformamidine hexafluorohydrochloride (1.5 equiv.) were dissolved in acetonitrile. After stirring for 15 minutes, N- Methylpyrrole (2equiv.). The reaction was stirred at room temperature overnight. After the reaction is completed, the solvent is removed under vacuum, N,N-dimethylformamide is added to dissolve and filtered, and the product is purified with a preparative grade high performance liquid phase analyzer. MS:[M+H] + =487.29m/z.
2.步骤2 N-(5-(环己炔基)-2-(3R，5S)-3,4,5-三甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
2. Step 2 N-(5-(cyclohexynyl)-2-(3R,5S)-3,4,5-trimethylpiperazin-1-yl)phenyl)-6-oxo-4 Synthesis of -(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色油状，产率50％；通过通用方法2合成目标产物；1H NMR(400MHz,DMSO-d6)δ12.47(s,1H),9.40(s,1H),7.90(s,1H),7.75(d,J＝1.6Hz,1H),7.14(dd,J＝8.3,1.9Hz,1H),7.05(d,J＝8.3Hz,1H),6.81(s,1H),2.94(s,1H),2.92(s,1H),2.65-2.58(m,1H),2.46-2.29(m,4H),2.19(s,3H),1.88-1.77(m,2H),1.71-1.63(m,2H),1.53-1.31(m,6H),0.99(d,J＝5.9Hz,6H).；[M+H]+＝515.46m/z. Yellow oil, yield 50%; the target product was synthesized by general method 2; 1 H NMR (400MHz, DMSO-d6) δ12.47 (s, 1H), 9.40 (s, 1H), 7.90 (s, 1H), 7.75 (d,J＝1.6Hz,1H),7.14(dd,J＝8.3,1.9Hz,1H),7.05(d,J＝8.3Hz,1H),6.81(s,1H),2.94(s,1H) ,2.92(s,1H),2.65-2.58(m,1H),2.46-2.29(m,4H),2.19(s,3H),1.88-1.77(m,2H),1.71-1.63(m,2H) ,1.53-1.31(m,6H),0.99(d,J＝5.9Hz,6H).;[M+H] + ＝515.46m/z.
实施例52.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(四氢-2H-吡喃-4-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 52. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(tetrahydro-2H-pyran-4-yl)ethynyl)phenyl) -Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率70％；通过通用方法2合成目标产物；1H NMR(600MHz,DMSO-d6)δ12.61(s,1H),9.52(s,1H),7.97(s,1H),7.92(d,J＝1.4Hz,1H),7.22(dd,J＝8.3,1.9Hz,1H),7.17(d,J＝8.3Hz,1H),6.84(s,1H),3.82-3.78(m,2H),3.55-3.53(m,1H),3.46-3.46(m,1H),3.44-3.44(m,1H),3.29-3.24(m,4H),3.02-2.97(m,1H),2.91-2.88(m,1H),2.86-2.84(m,3H),2.76-2.72(m,1H),1.87-1.82(m,2H),1.63-1.57(m,2H),1.27(d,J＝6.5Hz,3H).；[M+H]+＝503.40m/z.White solid, yield 70%; the target product was synthesized by general method 2; 1 H NMR (600MHz, DMSO-d6) δ12.61 (s, 1H), 9.52 (s, 1H), 7.97 (s, 1H), 7.92 (d,J＝1.4Hz,1H),7.22(dd,J＝8.3,1.9Hz,1H),7.17(d,J＝8.3Hz,1H),6.84(s,1H),3.82-3.78(m, 2H),3.55-3.53(m,1H),3.46-3.46(m,1H),3.44-3.44(m,1H),3.29-3.24(m,4H),3.02-2.97(m,1H),2.91- 2.88(m,1H),2.86-2.84(m,3H),2.76-2.72(m,1H),1.87-1.82(m,2H),1.63-1.57(m,2H),1.27(d,J＝6.5 Hz,3H).;[M+H] + =503.40m/z.
实施例53.(S)-N-(5-(4-氯苯基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 53. (S)-N-(5-(4-chlorophenyl)ethynyl)-2-(3,4-dimethylpiperazin-1-yl)phenyl)-6-oxo- Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色油状，产率76％；通过通用方法2合成目标产物；1H NMR(400MHz,DMSO-d6)δ12.62(s,1H),9.58(s,1H),8.07(d,J＝1.7Hz,1H),7.99(s,1H),7.59(d,J＝8.5Hz,2H),7.49(d,J＝8.5Hz,2H),7.39(dd,J＝8.2,1.8Hz,1H),7.24(d,J＝8.2Hz,1H),6.84(s,1H),3.75(brs,1H),3.37-3.23(m,4H),3.07-3.02(m,1H),2.91-2.77(m,4H),1.28(d,J＝6.4Hz,3H).；[M+H]+＝529.34m/z. Yellow oil, yield 76%; the target product was synthesized by general method 2; 1 H NMR (400MHz, DMSO-d6) δ12.62 (s, 1H), 9.58 (s, 1H), 8.07 (d, J = 1.7Hz ,1H),7.99(s,1H),7.59(d,J＝8.5Hz,2H),7.49(d,J＝8.5Hz,2H),7.39(dd,J＝8.2,1.8Hz,1H),7.24 (d,J＝8.2Hz,1H),6.84(s,1H),3.75(brs,1H),3.37-3.23(m,4H),3.07-3.02(m,1H),2.91-2.77(m,4H ), 1.28 (d, J = 6.4Hz, 3H).; [M+H] + = 529.34m/z.
实施例54. 6-氧代-N-(5-(四氢-2H-吡喃-4-基)乙炔基)-2-(3R，5S)-3,4,5-三甲基哌嗪-1-基)苯基)-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 54. 6-Oxo-N-(5-(tetrahydro-2H-pyran-4-yl)ethynyl)-2-(3R,5S)-3,4,5-trimethylpiperazine Synthesis of -1-yl)phenyl)-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率32％；通过通用方法2合成目标产物；1H NMR(600MHz,Methanol-d4)δ7.99-7.97(m,2H),7.28(d,J＝8.3Hz,1H),7.23(d,J＝8.4Hz,1H),6.95(s,1H),3.96-3.91(m,2H),3.59-3.55(m,2H),3.52-3.48(m,2H),3.30(brs,2H),3.00(s,3H),2.94-2.88(m,3H),1.96-1.91(m,2H),1.76-1.70(m,2H),1.44(d,J＝6.5Hz,6H).；[M+H]+＝517.48m/z.White solid, yield 32%; the target product was synthesized by general method 2; 1 H NMR (600MHz, Methanol-d4) δ7.99-7.97 (m, 2H), 7.28 (d, J = 8.3Hz, 1H), 7.23 (d,J＝8.4Hz,1H),6.95(s,1H),3.96-3.91(m,2H),3.59-3.55(m,2H),3.52-3.48(m,2H),3.30(brs,2H ),3.00(s,3H),2.94-2.88(m,3H),1.96-1.91(m,2H),1.76-1.70(m,2H),1.44(d,J＝6.5Hz,6H).;[ M+H] + =517.48m/z.
实施例55.N-(2-(S)-3,4-二甲基哌嗪-1-基)-5-(1s，4R)-4-羟基-4-甲基环己基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 55. N-(2-(S)-3,4-dimethylpiperazin-1-yl)-5-(1s,4R)-4-hydroxy-4-methylcyclohexyl)ethynyl) Synthesis of phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率13％；通过通用方法2合成目标产物；1H NMR(400MHz,Methanol-d4)δ7.97(s,1H),7.92(s,1H),7.25-7.20(m,2H),6.93(s,1H),3.63-3.60(m,1H),3.42-3.37(m,2H),3.27-3.23(m,2H),3.14-3.08(m,1H),2.97(s,3H),2.89-2.82(m,1H),2.78-2.73(m,1H),2.02-1.95(m,2H),1.81-1.73(m,2H),1.65-1.57(m,2H),1.56-1.49(m,2H),1.40(d,J＝6.3Hz,3H),1.22(s,3H).；[M+H]+＝531.51m/z. White solid, yield 13%; the target product was synthesized by general method 2; 1 H NMR (400MHz, Methanol-d4) δ7.97 (s, 1H), 7.92 (s, 1H), 7.25-7.20 (m, 2H) ,6.93(s,1H),3.63-3.60(m,1H),3.42-3.37(m,2H),3.27-3.23(m,2H),3.14-3.08(m,1H),2.97(s,3H) ,2.89-2.82(m,1H),2.78-2.73(m,1H),2.02-1.95(m,2H),1.81-1.73(m,2H),1.65-1.57(m,2H),1.56-1.49( m, 2H), 1.40 (d, J = 6.3Hz, 3H), 1.22 (s, 3H).; [M+H] + = 531.51m/z.
实施例56.N-(2-(S)-3,4-二甲基哌嗪-1-基)-5-((1r，4S)-4-羟基-4-甲基环己基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 56. N-(2-(S)-3,4-dimethylpiperazin-1-yl)-5-((1r,4S)-4-hydroxy-4-methylcyclohexyl)ethynyl Synthesis of )phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率11％；通过通用方法2合成目标产物；1H NMR(400MHz,Methanol-d4)δ7.97(s,1H),7.91(s,1H),7.25-7.17(m,2H),6.92(s,1H),3.62-3.59(m,1H),3.43-3.35(m,2H),3.27-3.22(m,2H),3.14-3.07(m,1H),2.96(s,3H),2.89-2.79(m,1H),2.53-2.45(m,1H),1.87-1.76(m,4H),1.74-1.70(m,2H),1.48-1.42(m,2H),1.39(d,J＝6.4Hz,3H),1.19(s,3H).；[M+H]+＝531.50m/z.White solid, yield 11%; the target product was synthesized by general method 2; 1 H NMR (400MHz, Methanol-d4) δ7.97 (s, 1H), 7.91 (s, 1H), 7.25-7.17 (m, 2H) ,6.92(s,1H),3.62-3.59(m,1H),3.43-3.35(m,2H),3.27-3.22(m,2H),3.14-3.07(m,1H),2.96(s,3H) ,2.89-2.79(m,1H),2.53-2.45(m,1H),1.87-1.76(m,4H),1.74-1.70(m,2H),1.48-1.42(m,2H),1.39(d, J＝6.4Hz,3H),1.19(s,3H).; [M+H] + ＝531.50m/z.
实施例57.(S)-N-(5-(3-奥卡西罗[5.5]十一碳-9-基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成Example 57. (S)-N-(5-(3-Ocasiro[5.5]undec-9-yl)ethynyl)-2-(3,4-dimethylpiperazine-1- Synthesis of (base)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色油状，产率57％；通过通用方法2合成目标产物；1H NMR(400MHz,
Yellow oil, yield 57%; the target product was synthesized by general method 2; 1 H NMR (400MHz,
Methanol-d4)δ13.40(s,1H),10.30(s,1H),8.85-8.62(m,2H),8.03-7.94(m,2H),7.64(s,1H),4.39-4.27(m,4H),4.08-4.02(m,6H),3.91-3.74(m,2H),3.68-3.64(m,2H),3.63-3.36(m,3H),2.63-2.43(m,4H),2.42-2.30(m,2H),2.28-2.20(m,2H),2.19-2.11(m,2H),2.08(d,J＝6.4Hz,3H).；[M+H]+＝571.53m/z. Methanol-d4)δ13.40(s,1H),10.30(s,1H),8.85-8.62(m,2H),8.03-7.94(m,2H),7.64(s,1H),4.39-4.27(m ,4H),4.08-4.02(m,6H),3.91-3.74(m,2H),3.68-3.64(m,2H),3.63-3.36(m,3H),2.63-2.43(m,4H),2.42 -2.30(m,2H),2.28-2.20(m,2H),2.19-2.11(m,2H),2.08(d,J＝6.4Hz,3H).；[M+H] + ＝571.53m/z .
实施例58.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-(4-羟基-4-甲基哌啶-1-基)甲基)苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 58. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-(4-hydroxy-4-methylpiperidin-1-yl) Synthesis of methyl)phenyl)ethynyl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色油状，产率77％；通过通用方法2合成目标产物；1H NMR(600MHz,DMSO-d6)δ12.63(s,1H),10.30(s,1H),9.55(s,1H),8.85-8.62(m,2H),7.99(s,1H),7.92(s,1H),7.28-7.27(m,2H),7.18-7.18(m,1H),6.83(s,1H),4.41(dd,J＝17.3,5.7Hz,2H),3.76-3.74(m,1H),3.29–3.22(m,5H),3.05–2.99(m,2H),2.85–2.75(m,5H),2.09-2.03(m,3H),2.03-1.98(m,1H),1.81-1.79(m,1H),1.69-1.67(m,1H),1.59-1.57(m,1H),1.47–1.39(m,2H),1.27(d,J＝6.4Hz,3H).；[M+H]+＝622.58m/z.Yellow oil, yield 77%; the target product was synthesized by general method 2; 1 H NMR (600MHz, DMSO-d6) δ12.63 (s, 1H), 10.30 (s, 1H), 9.55 (s, 1H), 8.85 -8.62(m,2H),7.99(s,1H),7.92(s,1H),7.28-7.27(m,2H),7.18-7.18(m,1H),6.83(s,1H),4.41(dd ,J＝17.3,5.7Hz,2H),3.76-3.74(m,1H),3.29–3.22(m,5H),3.05–2.99(m,2H),2.85–2.75(m,5H),2.09-2.03 (m,3H),2.03-1.98(m,1H),1.81-1.79(m,1H),1.69-1.67(m,1H),1.59-1.57(m,1H),1.47–1.39(m,2H) ,1.27(d,J＝6.4Hz,3H).;[M+H] + ＝622.58m/z.
实施例59.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(7-甲基-7-氮杂螺[3.5]壬-2-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 59. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(7-methyl-7-azaspiro[3.5]nonan-2-yl Synthesis of )ethynyl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率57％；合成方法与(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(1-甲基氮杂环丁烷-3-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成相同；1H NMR(400MHz,DMSO-d6)δ12.62(s,1H),9.51(s,1H),8.03-7.84(m,2H),7.25-7.10(m,2H),6.83(s,1H),3.56-3.50(m,2H),3.32-3.18(m,7H),3.09-2.78(m,6H),2.75-2.73(m,3H),2.41-2.29(m,1H),2.23-2.13(m,1H),2.02-1.84(m,4H),1.75-1.56(m,2H),1.27(d,J＝6.4Hz,3H).；[M+H]+＝556.54m/z. White solid, yield 57%; the synthesis method is the same as (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(1-methylazetidine-3) The synthesis of -ethynyl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide is the same; 1 H NMR (400MHz, DMSO-d6) δ12.62(s,1H),9.51(s,1H),8.03-7.84(m,2H),7.25-7.10(m,2H),6.83(s,1H),3.56-3.50(m,2H), 3.32-3.18(m,7H),3.09-2.78(m,6H),2.75-2.73(m,3H),2.41-2.29(m,1H),2.23-2.13(m,1H),2.02-1.84(m ,4H),1.75-1.56(m,2H),1.27(d,J＝6.4Hz,3H).; [M+H] + ＝556.54m/z.
实施例60.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(2-甲基-2-氮杂螺[3.3]庚烷-6-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 60. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(2-methyl-2-azaspiro[3.3]heptane-6- Synthesis of ethynyl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率76％；合成方法与(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(1-甲基氮杂环丁烷-3-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成相同；1H NMR(400MHz,DMSO-d6)δ12.65(s,1H),9.54(s,1H),8.04-7.85(m,2H),7.24-7.12(m,2H),6.82(s,1H),4.31-4.13(m,2H),4.02-3.92(m,2H),3.54-3.51(m,2H),3.30-3.14(m,4H),3.05-3.03(m,1H),2.85(s,3H),2.79-2.75(m,4H),2.68-2.56(m,2H),2.43-2.30(m,2H),1.28(d,J＝6.4Hz,3H).；[M+H]+＝528.49m/z.White solid, yield 76%; the synthesis method is the same as (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(1-methylazetidine-3) The synthesis of -ethynyl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide is the same; 1 H NMR (400MHz, DMSO-d6) δ12.65(s,1H),9.54(s,1H),8.04-7.85(m,2H),7.24-7.12(m,2H),6.82(s,1H),4.31-4.13(m,2H), 4.02-3.92(m,2H),3.54-3.51(m,2H),3.30-3.14(m,4H),3.05-3.03(m,1H),2.85(s,3H),2.79-2.75(m,4H ), 2.68-2.56 (m, 2H), 2.43-2.30 (m, 2H), 1.28 (d, J = 6.4Hz, 3H).; [M+H] + = 528.49m/z.
实施例61.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(3-(3-羟基-3-甲基氮杂环丁烷-1-基)甲基)苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 61. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(3-(3-hydroxy-3-methylazetidine-1) Synthesis of -methyl)phenyl)ethynyl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色油状，产率77％；通过通用方法2合成目标产物；[M+H]+＝594.54m/z. Yellow oil, yield 77%; the target product was synthesized by general method 2; [M+H] + =594.54m/z.
实施例62.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(咪唑[1,2-a]吡啶-3-亚乙基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 62. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(imidazole[1,2-a]pyridin-3-ethylene)phenyl Synthesis of )-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色油状，产率17％；通过通用方法2合成目标产物；1H NMR(600MHz,DMSO-d6)δ12.64(s,1H),9.61(s,1H),8.68(d,J＝6.7Hz,1H),8.15(s,2H),8.01(s,1H),7.79(d,J＝9.0Hz,1H),7.54(dd,J＝14.1,5.8Hz,2H),7.30(d,J＝8.3Hz,1H),7.25-7.23(m,1H),6.86(s,1H),3.58-3.56(m,1H),3.36-3.30(m,4H),3.08-3.04(m,1H),2.89-2.81(m,4H),1.30(d,J＝6.4Hz,3H).；[M+H]+＝535.40m/z.Yellow oil, yield 17%; the target product was synthesized by general method 2; 1 H NMR (600MHz, DMSO-d6) δ12.64 (s, 1H), 9.61 (s, 1H), 8.68 (d, J = 6.7Hz ,1H),8.15(s,2H),8.01(s,1H),7.79(d,J＝9.0Hz,1H),7.54(dd,J＝14.1,5.8Hz,2H),7.30(d,J＝ 8.3Hz,1H),7.25-7.23(m,1H),6.86(s,1H),3.58-3.56(m,1H),3.36-3.30(m,4H),3.08-3.04(m,1H),2.89 -2.81(m,4H),1.30(d,J＝6.4Hz,3H).; [M+H] + ＝535.40m/z.
实施例63.(S)-N-(5-(4,4-二氟环己基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 63. (S)-N-(5-(4,4-difluorocyclohexyl)ethynyl)-2-(3,4-dimethylpiperazin-1-yl)phenyl)-6- Synthesis of oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率39％；通过通用方法2合成目标产物；1H NMR(600MHz,Methanol-d4)δ8.00(s,1H),7.96(s,1H),7.28(d,J＝8.0Hz,1H),7.24(d,J＝8.3Hz,1H),6.95(s,1H),3.63(d,J＝10.0Hz,1H),3.42(d,J＝16.2Hz,2H),3.29(d,J＝4.2Hz,2H),3.13(d,J＝10.9Hz,1H),2.98(s,3H),2.86(d,J＝14.1Hz,2H),2.15–2.10(m,2H),1.986-2.021(m,2H),1.93(d,J＝13.3Hz,2H),1.816-1.844(m,2H),1.42(d,J＝6.3Hz,3H).；[M+H]+＝537.78m/z. White solid, yield 39%; the target product was synthesized by general method 2; 1 H NMR (600MHz, Methanol-d 4 ) δ8.00 (s, 1H), 7.96 (s, 1H), 7.28 (d, J = 8.0 Hz,1H),7.24(d,J＝8.3Hz,1H),6.95(s,1H),3.63(d,J＝10.0Hz,1H),3.42(d,J＝16.2Hz,2H),3.29( d,J＝4.2Hz,2H),3.13(d,J＝10.9Hz,1H),2.98(s,3H),2.86(d,J＝14.1Hz,2H),2.15–2.10(m,2H), 1.986-2.021(m,2H),1.93(d,J＝13.3Hz,2H),1.816-1.844(m,2H),1.42(d,J＝6.3Hz,3H).; [M+H] + = 537.78m/z.
实施例64.(S)-N-(5-(环己基炔基)-2-(六氢吡咯[1,2-a]吡嗪-2(1H)-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 64. (S)-N-(5-(cyclohexylynyl)-2-(hexahydropyrrole[1,2-a]pyrazin-2(1H)-yl)phenyl)-6-oxo Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率24％；通过通用方法2合成目标产物；1H NMR(600MHz,DMSO-d6)δ12.61(s,1H),9.47(s,1H),8.04(s,1H),7.94(s,1H),7.17(d,J＝8.8Hz,2H),6.83(s,1H),3.70-3.55(m,1H),3.22-3.11(m,3H),3.05-2.99(m,1H),2.94-2.86(m,1H),3.22-3.13(m,2H),3.06-2.90(m,2H),2.84-2.75(m,1H),2.68-2.58(m,1H),2.11-1.95(m,2H),1.86-1.76(m,2H),1.73-1.60(m,2H),1.56-1.40(m,3H),1.39-1.22(m,3H).；[M+H]+＝513.45m/z.White solid, yield 24%; the target product was synthesized by general method 2; 1 H NMR (600MHz, DMSO-d6) δ12.61 (s, 1H), 9.47 (s, 1H), 8.04 (s, 1H), 7.94 (s,1H),7.17(d,J＝8.8Hz,2H),6.83(s,1H),3.70-3.55(m,1H),3.22-3.11(m,3H),3.05-2.99(m,1H ),2.94-2.86(m,1H),3.22-3.13(m,2H),3.06-2.90(m,2H),2.84-2.75(m,1H),2.68-2.58(m,1H),2.11-1.95 (m,2H),1.86-1.76(m,2H),1.73-1.60(m,2H),1.56-1.40(m,3H),1.39-1.22(m,3H).; [M+H] + = 513.45m/z.
实施例65.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(2-甲基-1-氧代-1,2,3,4-四氢异喹啉-6-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 65. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(2-methyl-1-oxo-1,2,3,4- Synthesis of tetrahydroisoquinolin-6-yl)ethynyl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率17％；通过通用方法2合成目标产物；1H NMR(600MHz,DMSO-d6)δ12.63(s,1H),9.55(s,1H),7.99(s,1H),7.95(d,J＝6.4Hz,1H),7.92(s,1H),7.85(s,1H),7.63(d,J＝6.6Hz,1H),7.28-7.27(m,1H),7.18-7.18(m,1H),6.83(s,1H),3.64–3.52(m,2H),3.10(s,3H),3.05–2.93(m,2H),2.25–2.15(m,2H),2.09-2.03(m,3H),1.93(s,3H),1.81-1.72(m,2H),1.27(d,J＝6.4Hz,3H).；[M+H]+＝578.23m/z. White solid, yield 17%; the target product was synthesized by general method 2; 1 H NMR (600MHz, DMSO-d6) δ12.63 (s, 1H), 9.55 (s, 1H), 7.99 (s, 1H), 7.95 (d,J＝6.4Hz,1H),7.92(s,1H),7.85(s,1H),7.63(d,J＝6.6Hz,1H),7.28-7.27(m,1H),7.18-7.18( m,1H),6.83(s,1H),3.64–3.52(m,2H),3.10(s,3H),3.05–2.93(m,2H),2.25–2.15(m,2H),2.09-2.03( m, 3H), 1.93 (s, 3H), 1.81-1.72 (m, 2H), 1.27 (d, J = 6.4Hz, 3H).; [M+H] + = 578.23m/z.
实施例66.-N-(5-(环己基乙炔基)-2-(3-乙基-4-甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 66. -N-(5-(cyclohexylethynyl)-2-(3-ethyl-4-methylpiperazin-1-yl)phenyl)-6-oxo-4-(trifluoro Synthesis of methyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率56％；通过通用方法2合成目标产物；1H NMR(600MHz,Methanol-d4)δ7.98(d,J＝25.1Hz,2H),7.25(s,2H),6.95(s,1H),3.62(d,J＝12.1Hz,1H),3.40–3.35(m,1H),3.31–3.20(m,2H),3.11(t,J＝13.3Hz,1H),2.96(d,J＝41.6Hz,4H),2.65–2.59(m,1H),2.09–2.01(m,1H),1.93–1.87(m,2H),1.77-1.81(m,2H),1.66-1.72(m,1H),1.61–1.51(m,3H),1.45–1.31(m,4H),1.03(t,J＝7.4Hz,3H).[M+H]+＝515.27m/z.White solid, yield 56%; the target product was synthesized by general method 2; 1 H NMR (600MHz, Methanol-d4) δ7.98 (d, J = 25.1Hz, 2H), 7.25 (s, 2H), 6.95 (s ,1H),3.62(d,J＝12.1Hz,1H),3.40–3.35(m,1H),3.31–3.20(m,2H),3.11(t,J＝13.3Hz,1H),2.96(d, J＝41.6Hz,4H),2.65–2.59(m,1H),2.09–2.01(m,1H),1.93–1.87(m,2H),1.77-1.81(m,2H),1.66-1.72(m, 1H),1.61–1.51(m,3H),1.45–1.31(m,4H),1.03(t,J＝7.4Hz,3H).[M+H] + ＝515.27m/z.
实施例67.N-(5-(环己基乙炔基)-2-(4-甲基哌啶-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 67. N-(5-(cyclohexylethynyl)-2-(4-methylpiperidin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1, Synthesis of 6-dihydropyridine-3-carboxamide
白色固体，产率12％；通过通用方法2合成目标产物；1H NMR(600MHz,Methanol-d4)δ8.11(s,1H),7.38–7.31(m,3H),6.96(s,1H),3.65(d,J＝12.2Hz,2H),3.09–3.03(m,3H),2.21(t,J＝7.6Hz,1H),2.13–2.09(m,4H),2.08–2.02(m,2H),1.96(d,J＝12.6Hz,2H),1.93–1.89(m,2H),1.79(dd,J＝8.2,5.2Hz,2H),1.64–1.52(m,5H),1.39–1.44(m,4H).[M+H]+＝486.29m/z.White solid, yield 12%; the target product was synthesized by general method 2; 1 H NMR (600MHz, Methanol-d4) δ8.11 (s, 1H), 7.38–7.31 (m, 3H), 6.96 (s, 1H) ,3.65(d,J＝12.2Hz,2H),3.09–3.03(m,3H),2.21(t,J＝7.6Hz,1H),2.13–2.09(m,4H),2.08–2.02(m,2H ),1.96(d,J＝12.6Hz,2H),1.93–1.89(m,2H),1.79(dd,J＝8.2,5.2Hz,2H),1.64–1.52(m,5H),1.39–1.44( m,4H).[M+H] + =486.29m/z.
实施例68.(R)-N-(5-(环己基乙炔基)-2-(3-(氟甲基)-4-甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
Example 68. (R)-N-(5-(cyclohexylethynyl)-2-(3-(fluoromethyl)-4-methylpiperazin-1-yl)phenyl)-6-oxo -4-(Trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，收率9.74％；通过通用方法2得到目标产物。1H NMR(600MHz,DMSO-d6)δ12.59(s,1H),9.49(s,1H),7.95(d,J＝47.2Hz,2H),7.18(s,1H),7.12(s,1H),6.83(s,1H),4.75(s,2H),2.87(d,J＝89.6Hz,4H),2.63(dd,J＝11.1,5.4Hz,2H),2.39(s,1H),2.08(s,2H),1.83(d,J＝10.9Hz,2H),1.74–1.60(m,2H),1.48(dq,J＝18.8,9.4,7.8Hz,3H),1.34(t,J＝9.7Hz,2H),1.24(s,3H).MS:[M+H]+＝519.42m/z.White solid, yield 9.74%; the target product was obtained by general method 2. 1 H NMR (600MHz, DMSO-d6) δ12.59 (s, 1H), 9.49 (s, 1H), 7.95 (d, J = 47.2Hz, 2H), 7.18 (s, 1H), 7.12 (s, 1H) ),6.83(s,1H),4.75(s,2H),2.87(d,J＝89.6Hz,4H),2.63(dd,J＝11.1,5.4Hz,2H),2.39(s,1H),2.08 (s,2H),1.83(d,J＝10.9Hz,2H),1.74–1.60(m,2H),1.48(dq,J＝18.8,9.4,7.8Hz,3H),1.34(t,J＝9.7 Hz,2H),1.24(s,3H).MS:[M+H] + =519.42m/z.
实施例69.(S)-N-(5-(双环[2.2.2]辛-1-基炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
Example 69. (S)-N-(5-(bicyclo[2.2.2]oct-1-ylynyl)-2-(3,4-dimethylpiperazin-1-yl)phenyl)- 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，收率22.47％；通过通用方法2得到目标产物。1H NMR(600MHz,DMSO-d6)δ12.60(s,1H),9.49(s,1H),7.96(s,1H),7.83(s,1H),7.13(t,J＝10.4Hz,1H),6.82(s,1H),6.54(s,1H),3.51(s,2H),3.22(s,3H),2.97(s,2H),2.78(d,J＝66.1Hz,3H),2.66–2.50(m,6H),1.74(dd,J＝9.4,6.1Hz,3H),1.60–1.49(m,4H),1.25(d,J＝12.7Hz,3H).MS:[M+H]+＝527.20m/z.White solid, yield 22.47%; the target product was obtained by general method 2. 1 H NMR (600MHz, DMSO-d 6 ) δ12.60 (s, 1H), 9.49 (s, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.13 (t, J = 10.4Hz, 1H),6.82(s,1H),6.54(s,1H),3.51(s,2H),3.22(s,3H),2.97(s,2H),2.78(d,J＝66.1Hz,3H), 2.66–2.50(m,6H),1.74(dd,J＝9.4,6.1Hz,3H),1.60–1.49(m,4H),1.25(d,J＝12.7Hz,3H).MS:[M+H ]+＝527.20m/z.
实施例70.N-(5-(环己基乙炔基)-2-((3R，5S)-3,4,5-三甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 70. N-(5-(cyclohexylethynyl)-2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)phenyl)-6-oxo- Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，收率23.68％；通过通用方法2得到目标产物。1H NMR(600MHz,DMSO-d6)δ12.63(s,1H),9.49(d,J＝19.4Hz,1H),9.32(s,1H),7.94(d,J＝2.0Hz,1H),7.19(dd,J＝8.3,2.0Hz,1H),7.14(d,J＝8.3Hz,1H),6.83(s,1H),3.47(t,J＝15.2Hz,2H),3.32–3.25(m,2H),2.88–2.79(m,4H),1.88–1.33(m,10H),1.31(d,J＝6.4Hz,6H),1.25(d,J＝12.7Hz,2H).MS:[M+H]+＝515.19m/z.White solid, yield 23.68%; the target product was obtained by general method 2. 1 H NMR (600MHz, DMSO-d 6 ) δ12.63 (s, 1H), 9.49 (d, J = 19.4Hz, 1H), 9.32 (s, 1H), 7.94 (d, J = 2.0Hz, 1H) ,7.19(dd,J＝8.3,2.0Hz,1H),7.14(d,J＝8.3Hz,1H),6.83(s,1H),3.47(t,J＝15.2Hz,2H),3.32–3.25( m,2H),2.88–2.79(m,4H),1.88–1.33(m,10H),1.31(d,J＝6.4Hz,6H),1.25(d,J＝12.7Hz,2H).MS:[ M+H] + =515.19m/z.
实施例71.(S)-N-(5-(环己基亚乙基)-2-(3,4-二甲基哌嗪-1-基)-4-氟苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 71. (S)-N-(5-(cyclohexylidene)-2-(3,4-dimethylpiperazin-1-yl)-4-fluorophenyl)-6-oxo -Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，收率7.90％；通过通用方法2得到目标产物。1H NMR(600MHz,DMSO-d6)δ12.62(s,1H),9.58(d,J＝9.8Hz,1H),8.00(d,J＝26.7Hz,1H),7.76(dd,J＝19.3,7.8Hz,1H),7.12(d,J＝11.0Hz,1H),6.83(s,1H),3.53(d,J＝12.2Hz,1H),3.45–3.36(m,2H),3.33–3.12(m,3H),3.02(t,J＝12.6Hz,1H),2.85(d,J＝4.2Hz,2H),2.78(dd,J＝13.4,8.4Hz,1H),2.69(dt,J＝10.4,5.5Hz,1H),1.87–1.76(m,2H),1.68(d,J＝11.9Hz,2H),1.54–1.43(m,3H),1.42–1.30(m,3H),1.27(d,J＝6.5Hz,3H).MS:[M+H]+＝519.29m/z.White solid, yield 7.90%; the target product was obtained by general method 2. 1 H NMR (600MHz, DMSO-d6) δ12.62 (s, 1H), 9.58 (d, J = 9.8Hz, 1H), 8.00 (d, J = 26.7Hz, 1H), 7.76 (dd, J = 19.3 ,7.8Hz,1H),7.12(d,J＝11.0Hz,1H),6.83(s,1H),3.53(d,J＝12.2Hz,1H),3.45–3.36(m,2H),3.33–3.12 (m,3H),3.02(t,J＝12.6Hz,1H),2.85(d,J＝4.2Hz,2H),2.78(dd,J＝13.4,8.4Hz,1H),2.69(dt,J＝ 10.4,5.5Hz,1H),1.87–1.76(m,2H),1.68(d,J＝11.9Hz,2H),1.54–1.43(m,3H),1.42–1.30(m,3H),1.27(d ,J＝6.5Hz,3H).MS:[M+H] + ＝519.29m/z.
实施例72.(S)-N-(5-((3-(7-氧杂-2-氮杂螺[3.5]壬-2-基)苯基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)-4-氟苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 72. (S)-N-(5-((3-(7-oxa-2-azaspiro[3.5]non-2-yl)phenyl)ethynyl)-2-(3,4 -Synthesis of -dimethylpiperazin-1-yl)-4-fluorophenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，收率11.01％；通过通用方法2得到目标产物。1H NMR(600MHz,DMSO-d6)δ12.63(s,1H),9.64(d,J＝12.8Hz,1H),7.91(dd,J＝21.4,7.7Hz,1H),7.23–7.20(m,1H),7.00–6.35(m,6H),3.73(s,12H),3.45–3.34(m,3H),2.90–2.78(m,4H),1.78–1.71(m,3H),1.27(dd,J＝17.6,9.8Hz,3H).White solid, yield 11.01%; the target product was obtained by general method 2. 1H NMR (600MHz, DMSO-d 6 ) δ12.63(s,1H),9.64(d,J＝12.8Hz,1H),7.91(dd,J＝21.4,7.7Hz,1H),7.23–7.20(m ,1H),7.00–6.35(m,6H),3.73(s,12H),3.45–3.34(m,3H),2.90–2.78(m,4H),1.78–1.71(m,3H),1.27(dd ,J=17.6,9.8Hz,3H).
MS:[M+H]+＝638.48m/z.MS:[M+H] + =638.48m/z.
实施例73.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-4-氟-5-((3-(7-甲基-2,7-二氮杂双环[3.5]壬-2-基)苯基)乙炔)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
Example 73. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-4-fluoro-5-((3-(7-methyl-2,7-di Azabicyclo[3.5]non-2-yl)phenyl)ethynyl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，收率21.71％；通过通用方法2得到目标产物。1H NMR(600MHz,DMSO-d6)δ12.66(s,1H),9.66(d,J＝16.0Hz,1H),8.01(d,J＝27.6Hz,1H),7.97–7.89(m,1H),7.30–7.14(m,2H),6.93–6.77(m,2H),6.63–6.40(m,2H),3.70(s,2H),3.62(s,3H),3.55(d,J＝11.8Hz,2H),3.40(d,J＝4.7Hz,4H),3.24(d,J＝11.1Hz,1H),3.07(t,J＝12.0Hz,1H),3.02–2.92(m,2H),2.87(d,J＝3.8Hz,2H),2.84–2.80(m,1H),2.78(d,J＝4.5Hz,3H),2.11(d,J＝13.8Hz,2H),1.87(td,J＝14.1,4.1Hz,2H),1.28(dd,J＝10.5,6.6Hz,3H).MS:[M+H]+＝651.37m/z.White solid, yield 21.71%; the target product was obtained by general method 2. 1 H NMR (600MHz, DMSO-d 6 ) δ12.66 (s, 1H), 9.66 (d, J = 16.0Hz, 1H), 8.01 (d, J = 27.6Hz, 1H), 7.97–7.89 (m, 1H),7.30–7.14(m,2H),6.93–6.77(m,2H),6.63–6.40(m,2H),3.70(s,2H),3.62(s,3H),3.55(d,J＝ 11.8Hz,2H),3.40(d,J＝4.7Hz,4H),3.24(d,J＝11.1Hz,1H),3.07(t,J＝12.0Hz,1H),3.02–2.92(m,2H) ,2.87(d,J＝3.8Hz,2H),2.84–2.80(m,1H),2.78(d,J＝4.5Hz,3H),2.11(d,J＝13.8Hz,2H),1.87(td, J＝14.1,4.1Hz,2H),1.28(dd,J＝10.5,6.6Hz,3H).MS:[M+H] + ＝651.37m/z.
实施例74.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-4-氟-5-((4-氟-3-(7-氧杂-2-氮杂螺[3.5]壬-2-基)苯基)乙炔基)苯)-6-氧代-4-(三氟甲基)-1,6- 二氢吡啶-3-甲酰胺
Example 74. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-4-fluoro-5-((4-fluoro-3-(7-oxa-2) -Azaspiro[3.5]non-2-yl)phenyl)ethynyl)benzene)-6-oxo-4-(trifluoromethyl)-1,6- Dihydropyridine-3-carboxamide
步骤1((3-溴-4-氟苯基)乙炔基)三甲基硅烷的合成
Step 1 Synthesis of ((3-bromo-4-fluorophenyl)ethynyl)trimethylsilane
黄色液体，产率82.52％；将2-溴-1-氟-4-碘苯(556mg,1.95mmol)溶于10mL乙腈,然后加入双三苯基膦二氯化钯(130mg)，碘化亚铜(35mg)和三乙胺(5.85mL)。将体系密闭并氮气置换三次，然后加入乙基三甲基硅烷(191.28mg,1.95mmol)，室温搅拌一小时。反应结束后，真空除去溶剂，合并有机相并用无水硫酸钠干燥。粗品经制备液相色谱仪分离纯化得到目标化合物。Yellow liquid, yield 82.52%; dissolve 2-bromo-1-fluoro-4-iodobenzene (556mg, 1.95mmol) in 10mL acetonitrile, then add bistriphenylphosphine palladium dichloride (130mg), iodide Copper (35 mg) and triethylamine (5.85 mL). The system was sealed and replaced with nitrogen three times, then ethyltrimethylsilane (191.28 mg, 1.95 mmol) was added, and the mixture was stirred at room temperature for one hour. After the reaction, the solvent was removed in vacuo, the organic phases were combined and dried over anhydrous sodium sulfate. The crude product was separated and purified by preparative liquid chromatography to obtain the target compound.
步骤2 2-(2-氟-5-((三甲基甲硅烷基)乙炔基)苯基)-7-氧杂-2-氮杂螺[3.5]壬烷的合成
Step 2 Synthesis of 2-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-7-oxa-2-azaspiro[3.5]nonane
黄色液体，产率82.52％；将((3-溴苯基)乙炔基)三甲基硅烷(250mg,987.31μmol)和7-氧杂-2-氮杂螺[3.5]壬烷(125.57mg,987.31μmol)溶于6mL 四氢呋喃,然后加入三(二亚苄基茚丙酮)二钯(90mg)和2-二环己膦基-2'-(N,N-二甲胺)-联苯(57mg)。将体系密闭并氮气置换三次，然后加入双三甲基硅基胺基锂(5mL,1M inTHF),升温至80℃搅拌一小时。反应结束后，将体系降至室温并抽滤，加水并用乙酸乙酯萃取，用无水硫酸钠干燥，合并有机相，粗品经制备液相色谱仪分离纯化得到目标化合物。[M+H]+＝300.68m/z.Yellow liquid, yield 82.52%; ((3-bromophenyl)ethynyl)trimethylsilane (250mg, 987.31μmol) and 7-oxa-2-azaspiro[3.5]nonane (125.57mg, 987.31μmol) dissolved in 6mL Tetrahydrofuran, then tris(dibenzylideneindenacetone)dipalladium (90 mg) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (57 mg) were added. The system was sealed and replaced with nitrogen three times, then lithium bistrimethylsilylamide (5 mL, 1 M inTHF) was added, and the temperature was raised to 80°C and stirred for one hour. After the reaction, the system was lowered to room temperature and suction filtered, water was added and extracted with ethyl acetate, dried with anhydrous sodium sulfate, the organic phases were combined, and the crude product was separated and purified by preparative liquid chromatography to obtain the target compound. [M+H]+＝300.68m/z.
步骤3 2-(5-乙炔基-2-氟苯基)-7-氧杂-2-氮杂螺[3.5]壬烷的合成
Step 3 Synthesis of 2-(5-ethynyl-2-fluorophenyl)-7-oxa-2-azaspiro[3.5]nonane
黄色固体；将2-(2-氟-5-((三甲基甲硅烷基)乙炔基)苯基)-7-氧杂-2-氮杂螺[3.5]壬烷(200mg,667.80μmol)溶于5mL四氢呋喃,然后加入四丁基氟化铵(4mL,1M inTHF)，室温搅拌一小时。反应结束后，将体系抽滤，粗品经制备液相色谱仪分离纯化得到目标化合物。[M+H]+＝228.26m/z.Yellow solid; 2-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-7-oxa-2-azaspiro[3.5]nonane (200 mg, 667.80 μmol) Dissolve in 5mL of tetrahydrofuran, then add tetrabutylammonium fluoride (4mL, 1M inTHF), and stir at room temperature for one hour. After the reaction is completed, the system is suction-filtered, and the crude product is separated and purified by preparative liquid chromatography to obtain the target compound. [M+H]+＝228.26m/z.
步骤4(S)-N-(2-(3,4-二甲基哌嗪-1-基)-4-氟-5-((4-氟-3-(7-氧杂-2-氮杂螺[3.5]壬-2-基)苯基)乙炔基)苯)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Step 4(S)-N-(2-(3,4-dimethylpiperazin-1-yl)-4-fluoro-5-((4-fluoro-3-(7-oxa-2-nitrogen) Synthesis of heterospiro[3.5]non-2-yl)phenyl)ethynyl)benzene)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，收率12.47％；通过通用方法2得到目标产物。1H NMR(600MHz,DMSO-d6)δ12.64(s,1H),9.64(d,J＝13.6Hz,1H),8.01(d,J＝29.8Hz,1H),7.96–7.84(m,1H),7.25–7.17(m,1H),7.11(dd,J＝12.6,8.3Hz,1H),6.91–6.86(m,1H),6.84(s,1H),6.67(dd,J＝8.8,2.1Hz,1H),3.75(d,J＝2.1Hz,2H),3.59–3.52(m,4H),3.05(t,J＝12.3Hz,5H),2.94–2.67(m,4H),2.05–1.95(m,1H),1.75(p,J＝8.2,7.6Hz,5H),1.66–1.45(m,2H),1.28(d,J＝6.5Hz,2H).MS:[M+H]+＝656.37m/z. Yellow solid, yield 12.47%; the target product was obtained by general method 2. 1 H NMR (600MHz, DMSO-d 6 ) δ12.64 (s, 1H), 9.64 (d, J = 13.6Hz, 1H), 8.01 (d, J = 29.8Hz, 1H), 7.96–7.84 (m, 1H),7.25–7.17(m,1H),7.11(dd,J＝12.6,8.3Hz,1H),6.91–6.86(m,1H),6.84(s,1H),6.67(dd,J＝8.8, 2.1Hz,1H),3.75(d,J＝2.1Hz,2H),3.59–3.52(m,4H),3.05(t,J＝12.3Hz,5H),2.94–2.67(m,4H),2.05– 1.95(m,1H),1.75(p,J＝8.2,7.6Hz,5H),1.66–1.45(m,2H),1.28(d,J＝6.5Hz,2H).MS:[M+H] + ＝656.37m/z.
实施例75.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-((4-氟-3-(7-氧杂-2-氮杂螺[3.5]壬-2-基)苯基)乙炔基)苯)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
Example 75. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-((4-fluoro-3-(7-oxa-2-azaspiro) [3.5]Non-2-yl)phenyl)ethynyl)benzene)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，收率8.79％；通过通用方法2得到目标产物。1H NMR(400MHz,DMSO-d6)δ12.63(s,1H),9.57(s,1H),8.05(d,J＝1.8Hz,1H),8.00(d,J＝3.8Hz,1H),7.36(dd,J＝8.3,1.9Hz,1H),7.26–7.21(m,1H),7.13–7.05(m,1H),6.91–6.82(m,2H),6.68(dd,J＝8.8,1.8Hz,1H),3.70(t,J＝28.5Hz,10H),3.41–3.19(m,5H),2.84(dd,J＝22.8,4.4Hz,3H),1.81–1.69(m,4H),1.33–1.25(m,3H).MS:[M+H]+＝638.38m/z.White solid, yield 8.79%; the target product was obtained by general method 2. 1 H NMR (400MHz, DMSO-d 6 ) δ12.63 (s, 1H), 9.57 (s, 1H), 8.05 (d, J = 1.8Hz, 1H), 8.00 (d, J = 3.8Hz, 1H) ,7.36(dd,J＝8.3,1.9Hz,1H),7.26–7.21(m,1H),7.13–7.05(m,1H),6.91–6.82(m,2H),6.68(dd,J＝8.8, 1.8Hz,1H),3.70(t,J＝28.5Hz,10H),3.41–3.19(m,5H),2.84(dd,J＝22.8,4.4Hz,3H),1.81–1.69(m,4H), 1.33–1.25(m,3H).MS:[M+H] + =638.38m/z.
实施例76.(S)-N-(5-(环己基亚乙基)-2-(3,4-二甲基哌嗪-1-基)-3-氟苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 76. (S)-N-(5-(cyclohexylidene)-2-(3,4-dimethylpiperazin-1-yl)-3-fluorophenyl)-6-oxo -Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，收率71.06％。通过通用方法2合成目标产物。1H NMR(600MHz,DMSO-d6)δ12.64(s,1H),9.62(s,1H),8.04(s,1H),7.94(s,1H),7.07(dd,J＝12.5,1.5Hz,1H),6.85(s,1H),3.52-3.50(m,2H),3.29-3.26(m,2H),3.20-3.16(m,2H),3.12-3.07(m,1H),2.84(s,3H),2.66-2.63(m,1H),1.84-1.82(m,2H),1.70-1.64(m,2H),1.52-1.44(m,3H),1.37-1.31(m,3H),1.24(d,J＝6.4Hz,3H).；[M+H]+＝519.49m/z。White solid, yield 71.06%. The target product was synthesized by general method 2. 1 H NMR (600MHz, DMSO-d 6 ) δ12.64(s,1H),9.62(s,1H),8.04(s,1H),7.94(s,1H),7.07(dd,J＝12.5,1.5 Hz,1H),6.85(s,1H),3.52-3.50(m,2H),3.29-3.26(m,2H),3.20-3.16(m,2H),3.12-3.07(m,1H),2.84( s,3H),2.66-2.63(m,1H),1.84-1.82(m,2H),1.70-1.64(m,2H),1.52-1.44(m,3H),1.37-1.31(m,3H), 1.24 (d, J=6.4Hz, 3H).; [M+H] + =519.49m/z.
实施例77.(S)-4-(二氟甲基)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(苯乙炔基)苯基)-6-氧代-1,6-二氢吡啶-3-甲酰胺
Example 77. (S)-4-(difluoromethyl)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(phenylacetynyl)phenyl)-6 -Oxo-1,6-dihydropyridine-3-carboxamide
白色固体，收率11.45％；通过通用方法2得到目标产物。MS:[M+H]+＝477.40m/z.1H NMR(600MHz,DMSO-d6)δ12.44(s,1H),9.60(s,1H),8.02–7.97(m,2H),7.56(dd,J＝6.6,2.9Hz,2H),7.44(dd,J＝5.0,2.0Hz,3H),7.40(dd,J＝8.3,2.1Hz,1H),7.25(d,J＝8.3Hz,1H),7.09(t,J＝51.0Hz,1H),6.61(s,1H),3.56(d,J＝12.0Hz,1H),3.34–3.21(m,5H),3.04(t,J＝12.5Hz,1H),2.87(d,J＝4.7Hz,2H),2.84–2.77(m,1H),1.29(d,J＝6.4Hz,3H).White solid, yield 11.45%; the target product was obtained by general method 2. MS: [M+H] + ＝477.40m/z. 1 H NMR (600MHz, DMSO-d 6 ) δ12.44(s,1H),9.60(s,1H),8.02–7.97(m,2H), 7.56(dd,J＝6.6,2.9Hz,2H),7.44(dd,J＝5.0,2.0Hz,3H),7.40(dd,J＝8.3,2.1Hz,1H),7.25(d,J＝8.3Hz ,1H),7.09(t,J＝51.0Hz,1H),6.61(s,1H),3.56(d,J＝12.0Hz,1H),3.34–3.21(m,5H),3.04(t,J＝ 12.5Hz,1H),2.87(d,J＝4.7Hz,2H),2.84–2.77(m,1H),1.29(d,J＝6.4Hz,3H).
实施例78(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-乙炔基苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 78 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-ethynylphenyl)-6-oxo-4-(trifluoromethyl)- Synthesis of 1,6-dihydropyridine-3-carboxamide
1.步骤1(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(三甲基硅基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
1. Step 1 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(trimethylsilyl)ethynyl)phenyl)-6-oxo- Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色油状，收率10.52％；通过通用方法2得到目标产物。Yellow oil, yield 10.52%; the target product was obtained by general method 2.
MS:[M+H]+＝491.41m/z.MS:[M+H] + =491.41m/z.
2.步骤2(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-乙炔基苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
2. Step 2 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-ethynylphenyl)-6-oxo-4-(trifluoromethyl) -Synthesis of 1,6-dihydropyridine-3-carboxamide
黄色固体，收率84.42％；将(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(三甲基硅基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺溶于甲醇，加入2N碳酸钾水溶液，反应在常温下搅拌1小时。反应结束后，除去溶剂，粗品用制备级高效液相色谱仪分离纯化。1H NMR(400MHz,Methanol-d4)δ:8.02(dd,J＝16.5,10.6Hz,2H),7.34(dd,J＝8.3,1.9Hz,1H),7.24(d,J＝8.3Hz,1H),6.93(s,1H),4.51(q,J＝7.0Hz,1H),3.61(d,J＝12.2Hz,1H),3.17-3.05(m,3H),2.96(s,2H),2.88(d,J＝12.6Hz,2H),1.65(d,J＝7.0Hz,2H),1.39(d,J＝6.5Hz,3H).MS:[M+H]+＝419.2m/z.Yellow solid, yield 84.42%; (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(trimethylsilyl)ethynyl)phenyl)- 6-Oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide was dissolved in methanol, 2N aqueous potassium carbonate solution was added, and the reaction was stirred at room temperature for 1 hour. After the reaction, the solvent was removed, and the crude product was separated and purified using a preparative-grade high-performance liquid chromatograph. 1 H NMR (400MHz, Methanol-d4) δ: 8.02 (dd, J＝16.5, 10.6Hz, 2H), 7.34 (dd, J＝8.3, 1.9Hz, 1H), 7.24 (d, J＝8.3Hz, 1H ),6.93(s,1H),4.51(q,J＝7.0Hz,1H),3.61(d,J＝12.2Hz,1H),3.17-3.05(m,3H),2.96(s,2H),2.88 (d,J＝12.6Hz,2H),1.65(d,J＝7.0Hz,2H),1.39(d,J＝6.5Hz,3H).MS:[M+H] + ＝419.2m/z.
实施例79.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(1-甲基哌啶-4-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 79. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(1-methylpiperidin-4-yl)ethynyl)phenyl)- Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
1.步骤1叔丁基(S)-4-((4-(3,4-二甲基哌嗪-1-基)-3-(6-氧基-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺基)苯基)乙炔基)哌啶-1-羧酸酯的合成
1. Step 1 tert-butyl (S)-4-((4-(3,4-dimethylpiperazin-1-yl)-3-(6-oxy-4-(trifluoromethyl)- Synthesis of 1,6-dihydropyridine-3-carboxamido)phenyl)ethynyl)piperidine-1-carboxylate
黄色油状，产率5.2％；通过通用方法2得到目标产物。[M+H]+＝602.56m/z.Yellow oil, yield 5.2%; the target product was obtained by general method 2. [M+H] + =602.56m/z.
2.步骤2(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(哌啶-4-亚乙基炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
2. Step 2 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(piperidin-4-ethylenyl)phenyl)-6-oxo Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色油状，收率100％；将叔丁基(S)-4-((4-(3,4-二甲基哌嗪-1-基)-3-(6-氧基-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺基)苯基)乙炔基)哌啶-1-羧酸酯(1equiv.)溶于二氯甲烷，并滴加三氟乙酸(3equiv.)，反应在室温下搅拌3小时.反应结束后，减压除去多余溶剂，粗产品经高效液相色谱仪分离纯化。Yellow oil, yield 100%; tert-butyl (S)-4-((4-(3,4-dimethylpiperazin-1-yl)-3-(6-oxy-4-(tris) Fluoromethyl)-1,6-dihydropyridine-3-carboxamido)phenyl)ethynyl)piperidine-1-carboxylate (1equiv.) was dissolved in dichloromethane, and trifluoroacetic acid (1equiv.) was added dropwise 3equiv.), the reaction was stirred at room temperature for 3 hours. After the reaction, excess solvent was removed under reduced pressure, and the crude product was separated and purified by high-performance liquid chromatography.
3.步骤3(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(1-甲基哌啶-4-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
3. Step 3(S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(1-methylpiperidin-4-yl)ethynyl)phenyl)- Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，收率57.2％；将(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(哌啶-4-亚乙基炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺(1equiv.)溶解在二氯甲烷/甲醇体系中，加入乙酸(2equiv.)，然后加入37％甲醛水溶液(4equiv.)，搅拌1小时后，加入三乙酰氧基硼氢化钠(3equiv.)，反应在室温下搅拌过夜。反应结束后，减压除去多余溶剂，粗品经制备级高效液相色谱仪分离纯化。1H NMR(400MHz,Methanol-d4)δ:8.04-7.96(m,2H),7.35-7.21(m,2H),6.93(s,1H),3.63-3.60(m,1H),3.56-3.53(m,1H),3.51-3.45(m,1H),3.37-3.31(m,4H),3.26-3.25(m,1H),3.17-3.01(m,3H),2.98-2.84(m,7H),2.31-2.27(m,1H),2.10-2.04(m,2H),1.90-1.83(m,1H),1.39(d,J＝6.4Hz,3H).；MS:[M+H]+＝516.2m/z.Yellow solid, yield 57.2%; (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(piperidin-4-ethylenyl)phenyl )-6-Oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide (1equiv.) is dissolved in dichloromethane/methanol system, add acetic acid (2equiv.), and then 37% formaldehyde aqueous solution (4 equiv.) was added, and after stirring for 1 hour, sodium triacetoxyborohydride (3 equiv.) was added, and the reaction was stirred at room temperature overnight. After the reaction, excess solvent was removed under reduced pressure, and the crude product was separated and purified by preparative-grade high-performance liquid chromatography. 1 H NMR(400MHz, Methanol-d4)δ:8.04-7.96(m,2H),7.35-7.21(m,2H),6.93(s,1H),3.63-3.60(m,1H),3.56-3.53( m,1H),3.51-3.45(m,1H),3.37-3.31(m,4H),3.26-3.25(m,1H),3.17-3.01(m,3H),2.98-2.84(m,7H), 2.31-2.27(m,1H),2.10-2.04(m,2H),1.90-1.83(m,1H),1.39(d,J＝6.4Hz,3H).；MS:[M+H] + ＝516.2 m/z.
实施例80.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(1-甲基氮杂环丁烷-3-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 80. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(1-methylazetidin-3-yl)ethynyl)benzene Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
1.步骤1叔丁基(S)-3-((4-(3,4-二甲基哌嗪-1-基)-3-(6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺基)苯基)乙炔基)氮杂环丁-1-羧酸酯的合成
1. Step 1 tert-butyl (S)-3-((4-(3,4-dimethylpiperazin-1-yl)-3-(6-oxo-4-(trifluoromethyl)- Synthesis of 1,6-dihydropyridine-3-carboxamido)phenyl)ethynyl)azetidine-1-carboxylate
黄色油状，产率42.91％。通过通用方法2得到目标产物。[M+H]+＝574.2m/z.Yellow oil, yield 42.91%. The target product was obtained by general method 2. [M+H] + =574.2m/z.
2.步骤2(S)-N-(5-(氮杂环丁烷-3-亚乙基炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
2. Step 2 (S)-N-(5-(azetidine-3-ethylenyl)-2-(3,4-dimethylpiperazin-1-yl)phenyl)- Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色油状，产率100％；将叔丁基(S)-3-((4-(3,4-二甲基哌嗪-1-基)-3-(6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺基)苯基)乙炔基)氮杂环丁-1-羧酸酯(1equiv.)溶于二氯甲烷，并滴加三氟乙酸(3equiv.)，反应在室温下搅拌3小时.反应结束后，减压除去多余溶剂，粗产品经制备级高效液相色谱分离纯化。[M+H]+＝474.2m/z.Yellow oil, yield 100%; tert-butyl (S)-3-((4-(3,4-dimethylpiperazin-1-yl)-3-(6-oxo-4-(tri Fluoromethyl)-1,6-dihydropyridine-3-carboxamido)phenyl)ethynyl)azetidin-1-carboxylate (1equiv.) was dissolved in dichloromethane, and trifluoride was added dropwise Acetic acid (3 equiv.), the reaction was stirred at room temperature for 3 hours. After the reaction, excess solvent was removed under reduced pressure, and the crude product was separated and purified by preparative-grade high-performance liquid chromatography. [M+H] + =474.2m/z.
3.步骤3(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(1-甲基氮杂环丁烷-3-基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
3. Step 3(S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(1-methylazetidin-3-yl)ethynyl)benzene Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，收率47.25％；将(S)-N-(5-(氮杂环丁烷-3-亚乙基炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺(1equiv.)溶解在二氯甲烷/甲醇体系中，加入乙酸(2equiv.)，然后加入37％甲醛水溶液(4equiv.)，搅拌1小时后，加入三乙酰氧基硼氢化钠(3equiv.)，反应在室温下搅拌过夜。反应结束后，减压除去多余溶剂，粗品经制备级高效液相色谱仪分离纯化。White solid, yield 47.25%; (S)-N-(5-(azetidine-3-ethylenyl)-2-(3,4-dimethylpiperazin-1-yl) )Phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide (1equiv.) was dissolved in the dichloromethane/methanol system, and acetic acid (2equiv.) was added. ), then add 37% formaldehyde aqueous solution (4 equiv.), stir for 1 hour, add sodium triacetoxyborohydride (3 equiv.), and stir the reaction at room temperature overnight. After the reaction, excess solvent was removed under reduced pressure, and the crude product was separated and purified by preparative-grade high-performance liquid chromatography.
1H NMR(400MHz,Methanol-d4)δ:8.07(s,1H),7.97(s,1H),7.34-7.31(m,1H),7.27-7.25(m,1H),6.93(s,1H),4.00-3.94(m,2H),3.63-3.59(m,2H),3.50-3.38(m,2H),3.29-3.21(m,3H),3.17-3.06(m,2H),2.98-2.95(m,6H),2.91-2.85(m,1H),1.40(d,J＝6.4Hz,3H).；MS:[M+H]+＝488.2m/z. 1 H NMR(400MHz, Methanol-d4)δ:8.07(s,1H),7.97(s,1H),7.34-7.31(m,1H),7.27-7.25(m,1H),6.93(s,1H) ,4.00-3.94(m,2H),3.63-3.59(m,2H),3.50-3.38(m,2H),3.29-3.21(m,3H),3.17-3.06(m,2H),2.98-2.95( m, 6H), 2.91-2.85 (m, 1H), 1.40 (d, J = 6.4Hz, 3H).; MS: [M+H] + = 488.2m/z.
实施例81.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(呋喃-3-亚乙基炔基)苯基)-3-甲氧基苯甲酰胺
Example 81. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(furan-3-ethylideneynyl)phenyl)-3-methoxy benzamide
白色固体，收率36.2％；通过通用方法3得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.21(s,1H),8.12-8.10(m,1H),7.96-7.89(m,1H),7.80-7.70(m,2H),7.52-7.45(m,2H),7.39-7.36(m,1H),7.26(d,J＝8.4Hz,1H),7.20-7.18(m,1H),4.61(s,3H),3.47-3.46(m,1H),3.42-3.36(m,4H),3.18-3.00(m,5H),1.27(s,3H).MS:[M+H]+＝430.3m/z.White solid, yield 36.2%; the target product was obtained by general method 3. 1 H NMR (400MHz, Methanol-d4) δ: 8.21 (s, 1H), 8.12-8.10 (m, 1H), 7.96-7.89 (m, 1H), 7.80-7.70 (m, 2H), 7.52-7.45 ( m,2H),7.39-7.36(m,1H),7.26(d,J＝8.4Hz,1H),7.20-7.18(m,1H),4.61(s,3H),3.47-3.46(m,1H) ,3.42-3.36(m,4H),3.18-3.00(m,5H),1.27(s,3H).MS:[M+H] + =430.3m/z.
实施例82.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(吡啶-3-亚乙基炔基)苯基)-3-甲氧基苯甲酰胺的合成
Example 82. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(pyridine-3-ethylenyl)phenyl)-3-methoxy Synthesis of benzamide
黄色固体，收率28.49％；通过通用方法3得到目标产物。1H NMR(400MHz,CDCl3)δ:8.94(s,1H),8.74(s,1H),8.66(d,J＝4.5Hz,1H),7.80-7.76(m,1H),7.60-7.58(m,1H),7.47-7.39(m,3H),7.37-7.27(m,3H),7.14-7.12(m,1H),3.90(s,3H),3.82-3.79(m,1H),3.58-3.47(m,1H),3.43-3.31(m,1H),3.20-2.97(m,4H),2.91(s,3H),1.49(d,J＝6.4Hz,3H).MS:[M+H]+＝441.43m/z.Yellow solid, yield 28.49%; the target product was obtained by general method 3. 1 H NMR (400MHz, CDCl 3 ) δ: 8.94 (s, 1H), 8.74 (s, 1H), 8.66 (d, J = 4.5Hz, 1H), 7.80-7.76 (m, 1H), 7.60-7.58 ( m,1H),7.47-7.39(m,3H),7.37-7.27(m,3H),7.14-7.12(m,1H),3.90(s,3H),3.82-3.79(m,1H),3.58- 3.47(m,1H),3.43-3.31(m,1H),3.20-2.97(m,4H),2.91(s,3H),1.49(d,J＝6.4Hz,3H).MS:[M+H ] + =441.43m/z.
实施例83.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(吡啶-2-亚乙基炔基)苯基)-3-甲氧基苯甲酰胺的合成
Example 83. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(pyridine-2-ethylenyl)phenyl)-3-methoxy Synthesis of benzamide
黄色固体，收率33.24％；通过通用方法3得到目标产物。1H NMR(400MHz,Chloroform-d)δ8.92(s,1H),8.75(s,1H),8.70(d,J＝4.7Hz,1H),7.84(d,J＝7.7Hz,1H),7.63(d,J＝8.0Hz,1H),7.44(d,J＝8.2Hz,2H),7.38(dd,J＝11.8,4.7Hz,2H),7.13(d,J＝7.6Hz,1H),4.12(q,J＝7.2Hz,1H),3.90(s,2H),3.58–3.49(m,2H),3.44–3.34(m,2H),3.13(d,J＝10.4Hz,2H),2.92(s,3H),2.05(s,1H),1.29–1.23(m,3H).Yellow solid, yield 33.24%; the target product was obtained by general method 3. 1 H NMR (400MHz, Chloroform-d) δ8.92 (s, 1H), 8.75 (s, 1H), 8.70 (d, J = 4.7Hz, 1H), 7.84 (d, J = 7.7Hz, 1H), 7.63(d,J＝8.0Hz,1H),7.44(d,J＝8.2Hz,2H),7.38(dd,J＝11.8,4.7Hz,2H),7.13(d,J＝7.6Hz,1H), 4.12(q,J＝7.2Hz,1H),3.90(s,2H),3.58–3.49(m,2H),3.44–3.34(m,2H),3.13(d,J＝10.4Hz,2H),2.92 (s,3H),2.05(s,1H),1.29–1.23(m,3H).
MS:[M+H]+＝441.45m/z.MS:[M+H] + =441.45m/z.
实施例84.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(吡啶-4-亚乙基炔基)苯基)-3-甲氧基苯甲酰胺的合成
Example 84. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(pyridine-4-ethylenyl)phenyl)-3-methoxy Synthesis of benzamide
黄色固体，收率23.74％；通过通用方法3得到目标产物。1H NMR(400 MHz,Methanol-d4)δ:9.16(s,1H),8.60(d,J＝5.9Hz,1H),8.21(s,1H),7.62–7.44(m,6H),7.36(d,J＝8.3Hz,1H),7.26–7.21(m,1H),3.91(s,1H),3.85(d,J＝14.0Hz,2H),3.67(d,J＝11.6Hz,2H),3.45(d,J＝17.8Hz,2H),3.15(d,J＝1.7Hz,2H),2.98(d,J＝12.4Hz,3H),2.05(d,J＝4.9Hz,1H),1.31(s,3H).MS:[M+H]+＝441.45m/z.Yellow solid, yield 23.74%; the target product was obtained by general method 3. 1 H NMR(400 MHz, Methanol-d 4 )δ:9.16(s,1H),8.60(d,J＝5.9Hz,1H),8.21(s,1H),7.62–7.44(m,6H),7.36(d,J＝ 8.3Hz,1H),7.26–7.21(m,1H),3.91(s,1H),3.85(d,J＝14.0Hz,2H),3.67(d,J＝11.6Hz,2H),3.45(d, J＝17.8Hz,2H),3.15(d,J＝1.7Hz,2H),2.98(d,J＝12.4Hz,3H),2.05(d,J＝4.9Hz,1H),1.31(s,3H) .MS:[M+H] + =441.45m/z.
实施例85.(S)-4-((4-(3,4-二甲基哌嗪-1-基)-3-(3-甲氧基苯甲酰胺基)苯基)乙炔基)苯甲酸的合成
Example 85. (S)-4-((4-(3,4-dimethylpiperazin-1-yl)-3-(3-methoxybenzamido)phenyl)ethynyl)benzene Synthesis of formic acid
1.步骤1(S)-4-((4-(3,4-二甲基哌嗪-1-基)-3-(3-甲氧基苯甲酰胺基)苯基)乙炔基)苯甲酸甲酯的合成
1. Step 1 (S)-4-((4-(3,4-dimethylpiperazin-1-yl)-3-(3-methoxybenzamido)phenyl)ethynyl)benzene Synthesis of methyl formate
黄色油状，收率12.06％；通过通用方法3得到目标产物。Yellow oil, yield 12.06%; the target product was obtained by general method 3.
MS:[M+H]+＝498.4m/z.MS:[M+H] + =498.4m/z.
2.步骤2(S)-4-((4-(3,4-二甲基哌嗪-1-基)-3-(3-甲氧基苯甲酰胺基)苯基)乙炔基)苯甲酸的合成
2. Step 2 (S)-4-((4-(3,4-dimethylpiperazin-1-yl)-3-(3-methoxybenzamido)phenyl)ethynyl)benzene Synthesis of formic acid
黄色固体，收率70.74％；将(S)-4-((4-(3,4-二甲基哌嗪-1-基)-3-(3-甲氧基 苯甲酰胺基)苯基)乙炔基)苯甲酸甲酯(1eqv.)溶于甲醇/水体系，加入氢氧化钠固体(2equiv.),常温下搅拌过夜。反应结束后，经制备级高效液相色谱仪分离纯化。1H NMR(400MHz,CDCl3)δ:9.02(s,1H),8.76(s,1H),8.09(d,J＝8.4Hz,1H),7.64(d,J＝8.4Hz,1H),7.57–7.45(m,2H),7.44–7.31(m,4H),7.16(dd,J＝7.9,2.2Hz,1H),3.93(s,1H),3.56(d,J＝12.7Hz,2H),3.13(d,J＝10.5Hz,2H),2.90(d,J＝39.2Hz,4H),2.34–2.20(m,3H),1.53(d,J＝5.9Hz,1H),1.28(s,3H).MS:[M+H]+＝484.39m/z.Yellow solid, yield 70.74%; (S)-4-((4-(3,4-dimethylpiperazin-1-yl)-3-(3-methoxy) Benzamido)phenyl)ethynyl)methyl benzoate (1eqv.) was dissolved in the methanol/water system, added solid sodium hydroxide (2equiv.), and stirred at room temperature overnight. After the reaction is completed, it is separated and purified by preparative-grade high-performance liquid chromatography. 1 H NMR (400MHz, CDCl 3 ) δ: 9.02 (s, 1H), 8.76 (s, 1H), 8.09 (d, J = 8.4Hz, 1H), 7.64 (d, J = 8.4Hz, 1H), 7.57 –7.45(m,2H),7.44–7.31(m,4H),7.16(dd,J＝7.9,2.2Hz,1H),3.93(s,1H),3.56(d,J＝12.7Hz,2H), 3.13(d,J＝10.5Hz,2H),2.90(d,J＝39.2Hz,4H),2.34–2.20(m,3H),1.53(d,J＝5.9Hz,1H),1.28(s,3H ).MS:[M+H] + =484.39m/z.
实施例86.N-(5-((R)-1-乙酰哌啶-3-基)乙炔基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)-3-甲氧基苯甲酰胺的合成
Example 86. N-(5-((R)-1-acetylpiperidin-3-yl)ethynyl)-2-((S)-3,4-dimethylpiperazin-1-yl)benzene Synthesis of -3-methoxybenzamide
1.步骤1叔丁基(R)-3-((4-((S)-3,4-二甲基哌嗪-1-基)-3-(3-甲氧基苯甲酰胺基)苯基)乙炔基)哌啶-1-羧酸酯的合成
1. Step 1 tert-butyl(R)-3-((4-((S)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxybenzamide) Synthesis of phenyl)ethynyl)piperidine-1-carboxylate
黄色油状，收率9.76％；通过通用方法3得到目标产物。MS:Yellow oil, yield 9.76%; the target product was obtained by general method 3. MS:
[M+H]+＝547.57m/z.[M+H] + =547.57m/z.
2.步骤2 N-(2-((S)-3,4-二甲基哌嗪-1-基)-5-((R)-哌啶-3-基)乙炔基)苯基)-3-甲氧基苯甲酰胺的合成
2. Step 2 N-(2-((S)-3,4-dimethylpiperazin-1-yl)-5-((R)-piperidin-3-yl)ethynyl)phenyl)- Synthesis of 3-methoxybenzamide
黄色油状，收率89.7％；将叔丁基(R)-3-((4-((S)-3,4-二甲基哌嗪-1-基)-3-(3-甲氧基苯甲酰胺基)苯基)乙炔基)哌啶-1-羧酸酯(1equiv.)溶于二氯甲烷，并滴 加三氟乙酸(3equiv.)，反应在室温下搅拌3小时.反应结束后，减压除去多余溶剂，粗产品经制备级高效液相色谱分离纯化。MS:[M+H]+＝447.49m/z.Yellow oil, yield 89.7%; tert-butyl (R)-3-((4-((S)-3,4-dimethylpiperazin-1-yl))-3-(3-methoxy Benzamido)phenyl)ethynyl)piperidine-1-carboxylate (1equiv.) was dissolved in dichloromethane and added dropwise Trifluoroacetic acid (3 equiv.) was added, and the reaction was stirred at room temperature for 3 hours. After the reaction, excess solvent was removed under reduced pressure, and the crude product was separated and purified by preparative-grade high-performance liquid chromatography. MS:[M+H] + =447.49m/z.
3.步骤3 N-(5-((R)-1-乙酰哌啶-3-基)乙炔基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)-3-甲氧基苯甲酰胺的合成
3. Step 3 N-(5-((R)-1-acetylpiperidin-3-yl)ethynyl)-2-((S)-3,4-dimethylpiperazin-1-yl)benzene Synthesis of -3-methoxybenzamide
黄色固体，收率83％；通过通用方法1得到目标产物；1H NMR(400MHz,Methanol-d4)δ:8.05–8.00(m,1H),7.58–7.47(m,3H),7.31–7.19(m,3H),4.10(dd,J＝12.6,3.4Hz,1H),3.91(s,3H),3.85(dd,J＝14.3,5.3Hz,1H),3.78–3.61(m,3H),3.46–3.40(m,2H),3.18–3.08(m,2H),3.00(s,3H),2.93(dd,J＝18.3,4.8Hz,2H),2.75(dt,J＝8.5,4.4Hz,1H),2.17(d,J＝22.1Hz,3H),1.89(dq,J＝9.8,3.6Hz,2H),1.58(ddt,J＝13.5,6.9,3.9Hz,2H),1.41(d,J＝6.4Hz,3H).MS:[M+H]+＝489.48m/z.Yellow solid, yield 83%; the target product was obtained by general method 1; 1 H NMR (400MHz, Methanol-d 4 ) δ: 8.05–8.00 (m, 1H), 7.58–7.47 (m, 3H), 7.31–7.19 (m,3H),4.10(dd,J＝12.6,3.4Hz,1H),3.91(s,3H),3.85(dd,J＝14.3,5.3Hz,1H),3.78–3.61(m,3H), 3.46–3.40(m,2H),3.18–3.08(m,2H),3.00(s,3H),2.93(dd,J＝18.3,4.8Hz,2H),2.75(dt,J＝8.5,4.4Hz, 1H),2.17(d,J＝22.1Hz,3H),1.89(dq,J＝9.8,3.6Hz,2H),1.58(ddt,J＝13.5,6.9,3.9Hz,2H),1.41(d,J ＝6.4Hz,3H).MS:[M+H] + ＝489.48m/z.
实施例87(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(4-氟苯基)乙炔基)苯基)苯甲酰胺
Example 87 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(4-fluorophenyl)ethynyl)phenyl)benzamide
黄色固体，收率25％；通过通用方法1得到目标产物。1H NMR(400MHz,CDCl3)δ:8.93(s,1H),8.69(d,J＝1.5Hz,1H),7.91-7.89(m,2H),7.62-7.58(m,2H),7.55-7.51(m,2H),7.42-7.42(m,1H),7.37-7.35(m,1H),7.24-7.22(m,1H),7.10-7.05(m,2H),3.77-3.65(m,1H),3.49-3.37(m,2H),3.28-3.13(m,4H),2.96(s,3H),1.48(d,J＝5.7Hz,3H).；MS:[M+H]+＝428.44m/z.Yellow solid, yield 25%; the target product was obtained by general method 1. 1 H NMR (400MHz, CDCl 3 ) δ: 8.93 (s, 1H), 8.69 (d, J = 1.5Hz, 1H), 7.91-7.89 (m, 2H), 7.62-7.58 (m, 2H), 7.55- 7.51(m,2H),7.42-7.42(m,1H),7.37-7.35(m,1H),7.24-7.22(m,1H),7.10-7.05(m,2H),3.77-3.65(m,1H ),3.49-3.37(m,2H),3.28-3.13(m,4H),2.96(s,3H),1.48(d,J＝5.7Hz,3H).；MS:[M+H] + ＝428.44 m/z.
实施例88(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-((4-氟苯基)乙炔基)苯基)-2,3-二氢苯并[b][1,4]二恶英-5-甲酰胺
Example 88 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-((4-fluorophenyl)ethynyl)phenyl)-2,3-di Hydrobenzo[b][1,4]dioxin-5-carboxamide
黄色固体，收率43.25％；通过通用方法1得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.42(s,1H),7.64(dd,J＝7.8,1.5Hz,1H),7.61–7.53(m,2H),7.41–7.29(m,2H),7.22–7.10(m,3H),7.03(t,J＝7.9Hz,1H),4.60(s,2H),4.48–4.39(m,2H),3.71(d,J＝12.1Hz,1H),3.40(d,J＝12.5Hz,2H),3.19–3.10(m,1H),3.02(d,J＝21.9Hz,4H),1.46(d,J＝6.4Hz,3H),1.38–1.28(m,2H).MS:[M+H]+＝486.46m/z.Yellow solid, yield 43.25%; the target product was obtained by general method 1. 1 H NMR (400MHz, Methanol-d 4 ) δ: 8.42 (s, 1H), 7.64 (dd, J = 7.8, 1.5Hz, 1H), 7.61–7.53 (m, 2H), 7.41–7.29 (m, 2H) ),7.22–7.10(m,3H),7.03(t,J＝7.9Hz,1H),4.60(s,2H),4.48–4.39(m,2H),3.71(d,J＝12.1Hz,1H) ,3.40(d,J＝12.5Hz,2H),3.19–3.10(m,1H),3.02(d,J＝21.9Hz,4H),1.46(d,J＝6.4Hz,3H),1.38–1.28( m,2H).MS:[M+H] + =486.46m/z.
实施例89(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-((4-氟苯基)乙炔基)苯基)-2-氟苯甲酰胺
Example 89 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-((4-fluorophenyl)ethynyl)phenyl)-2-fluorobenzyl Amide
黄色固体，收率23.6％；通过通用方法1得到目标产物。1H NMR(400MHz,Chloroform-d)δ9.83(d,J＝15.3Hz,1H),8.86(s,1H),8.36–8.26(m,1H),7.64–7.58(m,1H),7.57–7.52(m,1H),7.45–7.39(m,1H),7.33(s,2H),7.24(dd,J＝13.1,8.4Hz,1H),7.08(t,J＝8.7Hz,1H),5.42–5.31(m,1H),3.81(d,J＝8.5Hz,2H),3.63–3.50(m,1H),3.44–3.35(m,1H),3.30–3.06(m,3H),2.98(s,1H),2.29–2.21(m,1H),2.09–2.00(m,3H).MS:[M+H]+＝446.39m/z.Yellow solid, yield 23.6%; the target product was obtained by general method 1. 1 H NMR (400MHz, Chloroform-d) δ9.83 (d, J＝15.3Hz, 1H), 8.86 (s, 1H), 8.36–8.26 (m, 1H), 7.64–7.58 (m, 1H), 7.57 –7.52(m,1H),7.45–7.39(m,1H),7.33(s,2H),7.24(dd,J＝13.1,8.4Hz,1H),7.08(t,J＝8.7Hz,1H), 5.42–5.31(m,1H),3.81(d,J＝8.5Hz,2H),3.63–3.50(m,1H),3.44–3.35(m,1H),3.30–3.06(m,3H),2.98( s,1H),2.29–2.21(m,1H),2.09–2.00(m,3H).MS:[M+H]+=446.39m/z.
实施例90.(R)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(4-氟苯基)乙炔基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 90. (R)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(4-fluorophenyl)ethynyl)phenyl)-6-oxo- Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，收率32.2％；通过通用方法2得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.35(s,1H),7.97(s,1H),7.55(dd,J＝8.8,5.4Hz,2H),7.38(d,J＝1.5Hz,2H),7.13(t,J＝8.8Hz,2H),6.92(s,1H),3.57(d,J＝12.1Hz,2H),3.14-2.98(m,3H),2.94(s,3H),2.01(d,J＝5.5Hz,1H),1.59(s,1H),1.38-1.25(m,3H).MS:[M+H]+＝513.37m/z.Yellow solid, yield 32.2%; the target product was obtained by general method 2. 1 H NMR (400MHz, Methanol-d 4 ) δ: 8.35 (s, 1H), 7.97 (s, 1H), 7.55 (dd, J = 8.8, 5.4Hz, 2H), 7.38 (d, J = 1.5Hz, 2H),7.13(t,J＝8.8Hz,2H),6.92(s,1H),3.57(d,J＝12.1Hz,2H),3.14-2.98(m,3H),2.94(s,3H), 2.01(d,J＝5.5Hz,1H),1.59(s,1H),1.38-1.25(m,3H).MS:[M+H] + ＝513.37m/z.
实施例91.N-(5-((1-乙酰哌啶-3-基)乙炔基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)-3-甲氧基苯甲酰胺的合成
Example 91. N-(5-((1-acetylpiperidin-3-yl)ethynyl)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)- Synthesis of 3-methoxybenzamide
1.步骤1叔丁基3-((4-((S)-3,4-二甲基哌嗪-1-基)-3-(3-甲氧基苯甲酰胺)苯基)乙炔基)哌啶-1-羧酸酯的合成
1. Step 1 tert-butyl 3-((4-((S)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxybenzamide)phenyl)ethynyl )Synthesis of piperidine-1-carboxylate
黄色油状，收率30.61％；通过通用方法3得到目标产物。MS:Yellow oil, yield 30.61%; the target product was obtained by general method 3. MS:
[M+H]+＝547.0m/z.[M+H] + =547.0m/z.
2.步骤2 N-(2-((S)-3,4-二甲基哌嗪-1-基)-5-(哌啶-3-亚乙基炔基)苯基)-3-甲氧基苯甲酰胺的合成
2. Step 2 N-(2-((S)-3,4-dimethylpiperazin-1-yl)-5-(piperidin-3-ethylenyl)phenyl)-3-methyl Synthesis of oxybenzamide
黄色油状，收率50.26％；将叔丁基3-((4-((S)-3,4-二甲基哌嗪-1-基)-3-(3-甲氧基苯甲酰胺)苯基)乙炔基)哌啶-1-羧酸酯置于圆底烧瓶，加入二氯甲烷溶解，加入三氟乙酸(3equiv.)，常温搅拌1小时，反应结束后，减压除去溶剂，粗品用快速制备液相色谱仪分离纯化。MS:[M+H]+＝224.3m/z.Yellow oil, yield 50.26%; tert-butyl 3-((4-((S)-3,4-dimethylpiperazin-1-yl)-3-(3-methoxybenzamide) Place phenyl)ethynyl)piperidine-1-carboxylate in a round-bottomed flask, add methylene chloride to dissolve, add trifluoroacetic acid (3equiv.), stir at room temperature for 1 hour, after the reaction is completed, remove the solvent under reduced pressure, and the crude product Separate and purify using rapid preparative liquid chromatography. MS:[M+H] + =224.3m/z.
3.步骤3 N-(5-((1-乙酰哌啶-3-基)乙炔基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)-3-甲氧基苯甲酰胺的合成
3. Step 3 N-(5-((1-acetylpiperidin-3-yl)ethynyl)-2-((S)-3,4-dimethylpiperazin-1-yl)phenyl)- Synthesis of 3-methoxybenzamide
黄色固体，收率46.87％；通过通用方法1得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.03(d,J＝7.4Hz,1H),7.59-7.47(m,3H),7.31-7.19(m,3H),3.91(s,3H),3.78-3.61(m,3H),3.46-3.37(m,5H),3.16-3.13(m,1H),3.00(s,3H),2.97-2.86(m,2H),2.75(td,J＝8.4,4.0Hz,1H),2.20(s,2H),2.15(s,1H),2.09-1.95(m,1H),1.94-1.75(m,2H),1.65-1.53(m,1H),1.41(d,J＝6.4Hz,3H).MS:[M+H]+＝489.46m/z.Yellow solid, yield 46.87%; the target product was obtained by general method 1. 1 H NMR (400MHz, Methanol-d 4 ) δ: 8.03 (d, J = 7.4Hz, 1H), 7.59-7.47 (m, 3H), 7.31-7.19 (m, 3H), 3.91 (s, 3H), 3.78-3.61(m,3H),3.46-3.37(m,5H),3.16-3.13(m,1H),3.00(s,3H),2.97-2.86(m,2H),2.75(td,J＝8.4 ,4.0Hz,1H),2.20(s,2H),2.15(s,1H),2.09-1.95(m,1H),1.94-1.75(m,2H),1.65-1.53(m,1H),1.41( d,J＝6.4Hz,3H).MS:[M+H] + ＝489.46m/z.
实施例92.N-(2-((S)-3,4-二甲基哌嗪-1-基)-5-((1-甲基哌啶-3-基)乙炔基)苯基)-3-甲氧基苯甲酰胺的合成
Example 92. N-(2-((S)-3,4-dimethylpiperazin-1-yl)-5-((1-methylpiperidin-3-yl)ethynyl)phenyl) -Synthesis of 3-methoxybenzamide
黄色固体，收率44.07％；将N-(2-((S)-3,4-二甲基哌嗪-1-基)-5-(哌啶-3-亚乙基炔基)苯基)-3-甲氧基苯甲酰胺(1equiv.)溶解在二氯甲烷/甲醇体系中，加入乙酸(2equiv.)，然后加入37％甲醛水溶液(4equiv.)，搅拌1小时后，加入三乙 酰氧基硼氢化钠(3equiv.)，反应在室温下搅拌过夜。反应结束后，减压除去多余溶剂，粗品经制备级高效液相色谱仪分离纯化。Yellow solid, yield 44.07%; N-(2-((S)-3,4-dimethylpiperazin-1-yl)-5-(piperidin-3-ethylenyl)phenyl )-3-Methoxybenzamide (1 equiv.) was dissolved in the dichloromethane/methanol system, added acetic acid (2 equiv.), then added 37% formaldehyde aqueous solution (4 equiv.), stirred for 1 hour, then added triethyl Sodium acyloxyborohydride (3 equiv.), the reaction was stirred at room temperature overnight. After the reaction, excess solvent was removed under reduced pressure, and the crude product was separated and purified by preparative-grade high-performance liquid chromatography.
1H NMR(400MHz,Methanol-d4)δ:8.12(d,J＝23.6Hz,1H),7.58–7.46(m,3H),7.33–7.18(m,3H),3.91(s,3H),3.79–3.70(m,1H),3.71–3.58(m,2H),3.50(d,J＝30.8Hz,3H),3.19(s,1H),3.00(s,3H),2.93(s,3H),2.31–2.13(m,2H),2.12–1.97(m,2H),1.84(q,J＝14.2,13.5Hz,1H),1.77–1.53(m,2H),1.41(d,J＝6.5Hz,3H),1.37–1.26(m,2H).MS:[M+H]+＝461.46m/z. 1 H NMR (400MHz, Methanol-d 4 ) δ: 8.12 (d, J = 23.6Hz, 1H), 7.58–7.46 (m, 3H), 7.33–7.18 (m, 3H), 3.91 (s, 3H), 3.79–3.70(m,1H),3.71–3.58(m,2H),3.50(d,J＝30.8Hz,3H),3.19(s,1H),3.00(s,3H),2.93(s,3H) ,2.31–2.13(m,2H),2.12–1.97(m,2H),1.84(q,J＝14.2,13.5Hz,1H),1.77–1.53(m,2H),1.41(d,J＝6.5Hz ,3H),1.37–1.26(m,2H).MS:[M+H]+＝461.46m/z.
实施例93.(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(1-甲基哌啶-4-基)乙炔基)苯基)-3-甲氧基苯甲酰胺的合成
Example 93. (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(1-methylpiperidin-4-yl)ethynyl)phenyl)- Synthesis of 3-methoxybenzamide
1.步骤2(S)-4-((4-(3,4-二甲基哌嗪-1-基)-3-(3-甲氧基苯甲酰胺基)苯基)乙炔基)哌啶-1-羧酸叔丁酯的合成
1. Step 2 (S)-4-((4-(3,4-dimethylpiperazin-1-yl)-3-(3-methoxybenzamido)phenyl)ethynyl)piper Synthesis of tert-butylpyridine-1-carboxylate
黄色油状，收率19.1％；通过通用方法3得到目标产物。MS:Yellow oil, yield 19.1%; the target product was obtained by general method 3. MS:
[M+H]+＝491.13m/z.[M+H] + =491.13m/z.
2.步骤2(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(哌啶-4-亚乙基炔基)苯基)-3-甲氧基苯甲酰胺的合成
2. Step 2 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(piperidin-4-ethylenyl)phenyl)-3-methyl Synthesis of oxybenzamide
黄色油状，收率19.1％；将(S)-4-((4-(3,4-二甲基哌嗪-1-基)-3-(3-甲氧基苯甲酰胺基)苯基)乙炔基)哌啶-1-羧酸叔丁酯(1equiv.)溶于二氯甲烷，并滴加三氟乙酸(3equiv.)，反应在室温下搅拌3小时.反应结束后，减压除去多余溶剂，粗产品经制备级高效液相色谱分离纯化。MS:[M+H]+＝491.13m/z.Yellow oil, yield 19.1%; (S)-4-((4-(3,4-dimethylpiperazin-1-yl)-3-(3-methoxybenzamido)phenyl ) Ethynyl) piperidine-1-carboxylic acid tert-butyl ester (1 equiv.) was dissolved in dichloromethane, and trifluoroacetic acid (3 equiv.) was added dropwise. The reaction was stirred at room temperature for 3 hours. After the reaction was completed, remove under reduced pressure. The excess solvent was separated and purified by preparative high-performance liquid chromatography. MS:[M+H] + =491.13m/z.
3.步骤3(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(1-甲基哌啶-4-基)乙炔基)苯基)-3-甲氧基苯甲酰胺的合成
3. Step 3(S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(1-methylpiperidin-4-yl)ethynyl)phenyl)- Synthesis of 3-methoxybenzamide
黄色油状，收率52.05％；将N-(2-((S)-3,4-二甲基哌嗪-1-基)-5-(哌啶-3-亚乙基炔基)苯基)-3-甲氧基苯甲酰胺(1equiv.)溶解在二氯甲烷/甲醇体系中，加入乙酸(2equiv.)，然后加入37％甲醛水溶液(4equiv.)，搅拌1小时后，加入三乙酰氧基硼氢化钠(3equiv.)，反应在室温下搅拌过夜。反应结束后，减压除去多余溶剂，粗品经制备级高效液相色谱仪分离纯化。Yellow oil, yield 52.05%; N-(2-((S)-3,4-dimethylpiperazin-1-yl)-5-(piperidin-3-ethylenyl)phenyl )-3-Methoxybenzamide (1 equiv.) was dissolved in the dichloromethane/methanol system, added acetic acid (2 equiv.), then added 37% formaldehyde aqueous solution (4 equiv.), stirred for 1 hour, then added triacetyl Sodium oxyborohydride (3 equiv.) and the reaction was stirred at room temperature overnight. After the reaction, excess solvent was removed under reduced pressure, and the crude product was separated and purified by preparative-grade high-performance liquid chromatography.
1H NMR(400MHz,Methanol-d4)δ:8.21(s,1H),7.60–7.45(m,3H),7.32–7.16(m,3H),3.91(s,3H),3.18(s,1H),3.13–3.00(m,3H),2.87(s,3H),2.73(d,J＝9.1Hz,2H),2.56(s,3H),2.21(dd,J＝11.2,4.0Hz,2H),2.08–1.93(m,2H),1.63(d,J＝7.9Hz,1H),1.39–1.28(m,5H),1.21(d,J＝5.5Hz,3H).MS:[M+H]+＝461.47m/z. 1 H NMR (400MHz, Methanol-d 4 ) δ: 8.21 (s, 1H), 7.60–7.45 (m, 3H), 7.32–7.16 (m, 3H), 3.91 (s, 3H), 3.18 (s, 1H) ),3.13–3.00(m,3H),2.87(s,3H),2.73(d,J＝9.1Hz,2H),2.56(s,3H),2.21(dd,J＝11.2,4.0Hz,2H) ,2.08–1.93(m,2H),1.63(d,J＝7.9Hz,1H),1.39–1.28(m,5H),1.21(d,J＝5.5Hz,3H).MS:[M+H] + =461.47m/z.
实施例94.((芳基乙炔基/环烷烃基乙炔基/杂环乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-3-甲氧基苯甲酰胺类化合物的合成
Example 94. ((arylethynyl/cycloalkylethynyl/heterocycloethynyl)-2-(3,4-dimethylpiperazin-1-yl)phenyl)-3-methoxybenzene Synthesis of formamide compounds
1.合成路线：
1.Synthetic route:
2.通用方法3：2. General method 3:
将(S)-N-(5-溴-2-(3,4-二甲基哌嗪-1-基)苯基)-3-甲氧基苯甲酰胺(1equiv)，相应的炔类化合物(1.2equiv)，双三苯基膦二氯化钯(10％mol)，碘化亚铜(10％mol)和三乙胺(2equiv)溶于超干N,N-二甲基甲酰胺，用氮气置换5次，升温至100摄氏度反应三小时。反应结束后，抽滤，滤液用制备级高效液相色谱仪纯化。(S)-N-(5-bromo-2-(3,4-dimethylpiperazin-1-yl)phenyl)-3-methoxybenzamide (1equiv), the corresponding acetylenic compound (1.2 equiv), bistriphenylphosphine palladium dichloride (10% mol), copper iodide (10% mol) and triethylamine (2 equiv) were dissolved in ultra-dry N,N-dimethylformamide, Replace with nitrogen 5 times, raise the temperature to 100 degrees Celsius and react for three hours. After the reaction, it was filtered by suction, and the filtrate was purified with a preparative-grade high-performance liquid chromatograph.
3.(S)-N-(5-((1-乙酰哌啶-4-基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-3-甲氧基苯甲酰胺的合成
3.(S)-N-(5-((1-acetylpiperidin-4-yl)ethynyl)-2-(3,4-dimethylpiperazin-1-yl)phenyl)-3- Synthesis of methoxybenzamide
1).步骤1(S)-4-((4-(3,4-二甲基哌嗪-1-基)-3-(3-甲氧基苯甲酰胺基)苯基)乙炔基)哌啶-1-羧酸叔丁酯的合成
1). Step 1 (S)-4-((4-(3,4-dimethylpiperazin-1-yl)-3-(3-methoxybenzamido)phenyl)ethynyl) Synthesis of piperidine-1-carboxylic acid tert-butyl ester
黄色油状，收率14.31％；通过通用方法3得到目标产物。MS:[M+H]+＝547m/z.Yellow oil, yield 14.31%; the target product was obtained by general method 3. MS:[M+H] + =547m/z.
2).步骤2(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(哌啶-4-亚乙基炔基)苯基)-3-甲氧基苯甲酰胺的合成
2). Step 2(S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(piperidine-4-ethylenyl)phenyl)-3- Synthesis of methoxybenzamide
黄色油状，收率62.19％；将(S)-4-((4-(3,4-二甲基哌嗪-1-基)-3-(3-甲氧基苯甲酰胺基)苯基)乙炔基)哌啶-1-羧酸叔丁酯(1equiv.)溶于二氯甲烷，并滴加三氟乙酸(3equiv.)，反应在室温下搅拌3小时.反应结束后，减压除去多余溶剂，粗产品经高效液相色谱仪分离纯化。MS:[M+H]+＝224.36m/z.Yellow oil, yield 62.19%; (S)-4-((4-(3,4-dimethylpiperazin-1-yl)-3-(3-methoxybenzamido)phenyl ) Ethynyl) piperidine-1-carboxylic acid tert-butyl ester (1 equiv.) was dissolved in dichloromethane, and trifluoroacetic acid (3 equiv.) was added dropwise. The reaction was stirred at room temperature for 3 hours. After the reaction was completed, remove under reduced pressure. The excess solvent and crude product were separated and purified by high performance liquid chromatography. MS:[M+H] + =224.36m/z.
3).步骤3(S)-N-(5-((1-乙酰哌啶-4-基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-3-甲氧基苯甲酰胺的合成
3). Step 3 (S)-N-(5-((1-acetylpiperidin-4-yl)ethynyl)-2-(3,4-dimethylpiperazin-1-yl)phenyl) -Synthesis of 3-methoxybenzamide
黄色固体，收率53.08％；通过通用方法1得到目标产物。Yellow solid, yield 53.08%; the target product was obtained by general method 1.
1H NMR(400MHz,Methanol-d4)δ8.05(d,J＝1.8Hz,1H),7.55–7.49(m,3H),7.28(dd,J＝5.3,3.5Hz,2H),7.24–7.19(m,1H),3.90(s,4H),3.81(ddd,J＝13.7,6.7,3.7Hz,1H),3.65(dt,J＝12.2,2.3Hz,1H),3.45(ddd,J＝8.1,5.5,3.3Hz,3H),3.41–3.35(m,3H),3.21–3.09(m,2H),3.00(s,3H),2.98–2.92(m,2H),2.90(d,J＝4.8Hz,1H),1.96(m,3H),1.75(m,1H),1.65(m,2H),1.37–1.28(m,2H).MS:[M+H]+＝489.47m/z. 1 H NMR (400MHz, Methanol-d 4 ) δ8.05 (d, J＝1.8Hz, 1H), 7.55–7.49 (m, 3H), 7.28 (dd, J＝5.3, 3.5Hz, 2H), 7.24– 7.19(m,1H),3.90(s,4H),3.81(ddd,J＝13.7,6.7,3.7Hz,1H),3.65(dt,J＝12.2,2.3Hz,1H),3.45(ddd,J＝ 8.1,5.5,3.3Hz,3H),3.41–3.35(m,3H),3.21–3.09(m,2H),3.00(s,3H),2.98–2.92(m,2H),2.90(d,J＝ 4.8Hz,1H),1.96(m,3H),1.75(m,1H),1.65(m,2H),1.37–1.28(m,2H).MS:[M+H] + =489.47m/z.
实施例95(S)-2-氯-N-(2-(3,4-二甲基哌嗪-1-基)-5-((4-氟苯基)乙炔基)苯基)苯甲酰胺
Example 95 (S)-2-chloro-N-(2-(3,4-dimethylpiperazin-1-yl)-5-((4-fluorophenyl)ethynyl)phenyl)benzyl Amide
黄色固体，收率75.57％；通过通用方法1得到目标产物。Yellow solid, yield 75.57%; the target product was obtained by general method 1.
1H NMR(400MHz,Methanol-d4)δ8.36–8.20(m,1H),7.69(dd,J＝7.3,1.9Hz,1H),7.63–7.48(m,5H),7.42(dd,J＝8.3,2.0Hz,1H),7.31(d,J＝8.3Hz,1H),7.22–7.11(m,2H),3.75–3.57(m,1H),3.22–3.07(m,2H),3.06–2.79(m,5H),1.43(d,J＝6.4Hz,3H),1.33(d,J＝17.0Hz,2H).MS:[M+H]+＝324.34m/z. 1 H NMR (400MHz, Methanol-d 4 ) δ8.36–8.20 (m, 1H), 7.69 (dd, J = 7.3, 1.9 Hz, 1H), 7.63–7.48 (m, 5H), 7.42 (dd, J ＝8.3,2.0Hz,1H),7.31(d,J＝8.3Hz,1H),7.22–7.11(m,2H),3.75–3.57(m,1H),3.22–3.07(m,2H),3.06– 2.79(m,5H),1.43(d,J＝6.4Hz,3H),1.33(d,J＝17.0Hz,2H).MS:[M+H] + ＝324.34m/z.
实施例96(S)-3-氯-N-(2-(3,4-二甲基哌嗪-1-基)-5-((4-氟苯基)乙炔基)苯基)苯甲酰胺
Example 96 (S)-3-chloro-N-(2-(3,4-dimethylpiperazin-1-yl)-5-((4-fluorophenyl)ethynyl)phenyl)benzyl Amide
黄色固体，收率39.44％；通过通用方法1得到目标产物。Yellow solid, yield 39.44%; the target product was obtained by general method 1.
1H NMR(400MHz,Methanol-d4)δ8.12(s,1H),8.02(t,J＝1.9Hz,1H),7.92(d,J＝7.7Hz,1H),7.68(ddd,J＝8.0,2.2,1.1Hz,1H),7.64–7.53(m,3H),7.44(dd,J＝8.3,2.0Hz,1H),7.33(d,J＝8.3Hz,1H),7.22–7.09(m,2H),3.64(s,1H),3.18(s,3H),3.07–2.84(m,4H),1.42(d,J＝6.5Hz,3H),1.33(d,J＝17.1Hz,2H).MS:[M+H]+＝462.32m/z. 1 H NMR (400MHz, Methanol-d 4 ) δ8.12 (s, 1H), 8.02 (t, J = 1.9Hz, 1H), 7.92 (d, J = 7.7Hz, 1H), 7.68 (ddd, J = 8.0,2.2,1.1Hz,1H),7.64–7.53(m,3H),7.44(dd,J＝8.3,2.0Hz,1H),7.33(d,J＝8.3Hz,1H),7.22–7.09(m ,2H),3.64(s,1H),3.18(s,3H),3.07–2.84(m,4H),1.42(d,J＝6.5Hz,3H),1.33(d,J＝17.1Hz,2H) .MS:[M+H] + =462.32m/z.
实施例97(S)-4-氯-N-(2-(3,4-二甲基哌嗪-1-基)-5-((4-氟苯基)乙炔基)苯基)苯甲酰胺
Example 97 (S)-4-chloro-N-(2-(3,4-dimethylpiperazin-1-yl)-5-((4-fluorophenyl)ethynyl)phenyl)benzyl Amide
黄色固体，收率51.57％；通过通用方法1得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.18(brs,1H),8.01-7.99(m,2H),7.62-7.55(m,4H),7.42(dd,J＝8.4,1.6Hz,1H),7.33(d,J＝8.4Hz,1H),7.20-7.10(m,2H),3.67-3.64(m,1H),3.50-3.37(m,4H),3.19-3.12(m,1H),3.06-2.89(m,4H),1.42(d,J＝6.4Hz,3H).；MS:[M+H]+＝462.35m/z.Yellow solid, yield 51.57%; the target product was obtained by general method 1. 1 H NMR (400MHz, Methanol-d4) δ: 8.18 (brs, 1H), 8.01-7.99 (m, 2H), 7.62-7.55 (m, 4H), 7.42 (dd, J＝8.4, 1.6Hz, 1H) ,7.33(d,J＝8.4Hz,1H),7.20-7.10(m,2H),3.67-3.64(m,1H),3.50-3.37(m,4H),3.19-3.12(m,1H),3.06 -2.89(m,4H),1.42(d,J＝6.4Hz,3H).；MS:[M+H] + ＝462.35m/z.
实施例98(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(4-氟苯基)乙炔基)苯基)-2-(三氟甲基)苯甲酰胺
Example 98 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(4-fluorophenyl)ethynyl)phenyl)-2-(trifluoromethyl benzamide
黄色固体，收率33.94％；通过通用方法1得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.16(d,J＝1.6Hz,1H),7.86-7.85(m,1H),7.81-7.78(m,1H),7.74-7.70(m,2H),7.60-7.51(m,2H),7.40(dd,J＝8.4,2.0Hz,1H),7.28(d,J＝8.4Hz,1H),7.15-7.10(m,2H),3.60-3.57(m,1H),3.43-3.31(brs,4H),3.18-3.04(m,1H),2.93(brs,4H),1.39(d,J＝6.4Hz,3H).；MS:[M+H]+＝496.36m/z.Yellow solid, yield 33.94%; the target product was obtained by general method 1. 1 H NMR (400MHz, Methanol-d4) δ: 8.16 (d, J = 1.6 Hz, 1H), 7.86-7.85 (m, 1H), 7.81-7.78 (m, 1H), 7.74-7.70 (m, 2H) ,7.60-7.51(m,2H),7.40(dd,J＝8.4,2.0Hz,1H),7.28(d,J＝8.4Hz,1H),7.15-7.10(m,2H),3.60-3.57(m ,1H),3.43-3.31(brs,4H),3.18-3.04(m,1H),2.93(brs,4H),1.39(d,J＝6.4Hz,3H).；MS:[M+H] + ＝496.36m/z.
实施例99(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(4-氟苯基)乙炔基)苯基)-3-(三氟甲基)苯甲酰胺
Example 99 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(4-fluorophenyl)ethynyl)phenyl)-3-(trifluoromethyl benzamide
黄色固体，收率36.33％；通过通用方法1得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.32-8.19(m,2H),8.13(brs,1H),7.96-7.94(m,1H),7.81-7.77(m,1H),7.59-7.50(m,2H),7.42(dd,J＝8.4,2.0Hz,1H),7.31(d,J＝8.4Hz,1H),7.16-7.11(m,2H),3.72-3.55(m,1H),3.50-3.30(m,4H),3.21-3.08(m,1H),2.95(brs,4H),1.39(d,J＝6.4Hz,3H).；MS:[M+H]+＝496.38m/z.Yellow solid, yield 36.33%; the target product was obtained by general method 1. 1 H NMR(400MHz, Methanol-d4)δ:8.32-8.19(m,2H),8.13(brs,1H),7.96-7.94(m,1H),7.81-7.77(m,1H),7.59-7.50( m,2H),7.42(dd,J＝8.4,2.0Hz,1H),7.31(d,J＝8.4Hz,1H),7.16-7.11(m,2H),3.72-3.55(m,1H),3.50 -3.30(m,4H),3.21-3.08(m,1H),2.95(brs,4H),1.39(d,J＝6.4Hz,3H).；MS:[M+H] + ＝496.38m/z .
实施例100(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(4-氟苯基)乙炔基)苯基)-4-(三氟甲基)苯甲酰胺
Example 100 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(4-fluorophenyl)ethynyl)phenyl)-4-(trifluoromethyl benzamide
黄色固体，收率51.13％；通过通用方法1得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.19-8.14(m,3H),7.91-7.89(m,2H),7.57-7.54(m,2H),7.42(dd,J＝8.4,2.0Hz,1H),7.32(d,J＝8.4Hz,1H),7.17-7.07(m,2H),3.65-3.62(m,1H),3.54-3.32(m,4H),3.20-3.10(m,1H),3.06-2.85(m,4H),1.40(d,J＝6.4Hz,3H).；MS:[M+H]+＝496.36m/z.Yellow solid, yield 51.13%; the target product was obtained by general method 1. 1 H NMR (400MHz, Methanol-d4) δ: 8.19-8.14 (m, 3H), 7.91-7.89 (m, 2H), 7.57-7.54 (m, 2H), 7.42 (dd, J＝8.4, 2.0Hz, 1H),7.32(d,J＝8.4Hz,1H),7.17-7.07(m,2H),3.65-3.62(m,1H),3.54-3.32(m,4H),3.20-3.10(m,1H) ,3.06-2.85(m,4H),1.40(d,J＝6.4Hz,3H).；MS:[M+H] + ＝496.36m/z.
实施例101(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(4-氟苯基)乙炔基)苯基)-3-氟苯甲酰胺的合成
Example 101 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(4-fluorophenyl)ethynyl)phenyl)-3-fluorobenzamide Synthesis
黄色固体，收率37.26％；通过通用方法1得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.11(brs,1H),7.81-7.72(m,2H),7.61-7.53(m,3H),7.42-7.37(m,2H),7.32-7.30(m,1H),7.15-7.11(m,2H),3.68-3.53(m,1H),3.48-3.43(m,4H),3.17-3.13(m,1H),3.05-2.80(m,4H),1.39(d,J＝6.4Hz,3H).；MS:[M+H]+＝446.37m/z.Yellow solid, yield 37.26%; the target product was obtained by general method 1. 1 H NMR (400MHz, Methanol-d4) δ: 8.11 (brs, 1H), 7.81-7.72 (m, 2H), 7.61-7.53 (m, 3H), 7.42-7.37 (m, 2H), 7.32-7.30 ( m,1H),7.15-7.11(m,2H),3.68-3.53(m,1H),3.48-3.43(m,4H),3.17-3.13(m,1H),3.05-2.80(m,4H), 1.39 (d, J = 6.4Hz, 3H).; MS: [M+H] + = 446.37m/z.
实施例102(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-((4-氟苯基)乙炔基)苯基)-4-氟苯甲酰胺
Example 102 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-((4-fluorophenyl)ethynyl)phenyl)-4-fluorobenzyl Amide
黄色固体，收率27.59％；通过通用方法1得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.12(brs,1H),8.06-8.00(m,2H),7.58-7.50(m,2H),7.38(dd,J＝8.4,2.0Hz,1H),7.33-7.26(m,3H),7.16-7.08(m,2H),3.52-3.44(m,1H),3.34-3.30(m,4H),3.12-3.11(m,1H),2.88(brs,4H),1.34(d,J＝6.4Hz,3H).；MS:[M+H]+＝446.38m/z.Yellow solid, yield 27.59%; the target product was obtained by general method 1. 1 H NMR (400MHz, Methanol-d4) δ: 8.12 (brs, 1H), 8.06-8.00 (m, 2H), 7.58-7.50 (m, 2H), 7.38 (dd, J＝8.4, 2.0Hz, 1H) ,7.33-7.26(m,3H),7.16-7.08(m,2H),3.52-3.44(m,1H),3.34-3.30(m,4H),3.12-3.11(m,1H),2.88(brs, 4H), 1.34 (d, J = 6.4Hz, 3H).; MS: [M+H] + = 446.38m/z.
实施例103(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(4-氟苯基)乙炔基)苯基)-2-甲氧基苯甲酰胺
Example 103 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(4-fluorophenyl)ethynyl)phenyl)-2-methoxybenzene Formamide
黄色固体，收率55.60％；通过通用方法1得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.43(brs,1H),8.11-8.09(m,1H),7.64-7.50(m,3H),7.39-7.24(m,3H),7.20-7.07(m,3H),4.14(s,3H),3.70-3.67(m,1H),3.53-3.32(m,4H),3.14-3.11(m,1H),3.05-2.87(m,4H),1.43(d,J＝6.4Hz,3H).；MS:[M+H]+＝458.36m/z.Yellow solid, yield 55.60%; the target product was obtained by general method 1. 1 H NMR (400MHz, Methanol-d4) δ: 8.43 (brs, 1H), 8.11-8.09 (m, 1H), 7.64-7.50 (m, 3H), 7.39-7.24 (m, 3H), 7.20-7.07 ( m,3H),4.14(s,3H),3.70-3.67(m,1H),3.53-3.32(m,4H),3.14-3.11(m,1H),3.05-2.87(m,4H),1.43( d, J＝6.4Hz, 3H).; MS: [M+H] + ＝458.36m/z.
实施例104(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(4-氟苯基)乙炔基)苯基)-3-甲氧基苯甲酰胺
Example 104 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(4-fluorophenyl)ethynyl)phenyl)-3-methoxybenzene Formamide
黄色固体，收率36.05％；通过通用方法1得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.13(brs,1H),7.61-7.45(m,5H),7.40(dd,J＝8.4,2.0Hz,1H),7.31-7.28(m,1H),7.23-7.17(m,1H),7.15-7.11(m,2H),3.88(s,3H),3.59-3.55(m,1H),3.28-3.07(m,5H),2.93(brs,4H),1.37(d,J＝6.4Hz,3H).；MS:[M+H]+＝458.39m/z.Yellow solid, yield 36.05%; the target product was obtained by general method 1. 1 H NMR (400MHz, Methanol-d4) δ: 8.13 (brs, 1H), 7.61-7.45 (m, 5H), 7.40 (dd, J = 8.4, 2.0Hz, 1H), 7.31-7.28 (m, 1H) ,7.23-7.17(m,1H),7.15-7.11(m,2H),3.88(s,3H),3.59-3.55(m,1H),3.28-3.07(m,5H),2.93(brs,4H) ,1.37(d,J＝6.4Hz,3H).;MS:[M+H] + ＝458.39m/z.
实施例105(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(4-氟苯基)乙炔基)苯基)-4-甲氧基苯甲酰胺
Example 105 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(4-fluorophenyl)ethynyl)phenyl)-4-methoxybenzene Formamide
黄色固体，收率39.35％；通过通用方法1得到目标产物。1H NMR(400 MHz,Methanol-d4)δ:8.14(brs,1H),7.97-7.95(m,2H),7.59-7.48(m,2H),7.38(dd,J＝8.4,2.0Hz,1H),7.29(d,J＝8.4Hz,1H),7.15-7.08(m,4H),3.89(s,3H),3.59-3.57(m,1H),3.42-3.32(m,4H),3.13-3.12(m,1H),3.00-2.85(m,4H),1.37(d,J＝6.4Hz,3H).；MS:[M+H]+＝458.39m/z.Yellow solid, yield 39.35%; the target product was obtained by general method 1. 1 H NMR(400 MHz, Methanol-d4)δ:8.14(brs,1H),7.97-7.95(m,2H),7.59-7.48(m,2H),7.38(dd,J＝8.4,2.0Hz,1H),7.29(d ,J＝8.4Hz,1H),7.15-7.08(m,4H),3.89(s,3H),3.59-3.57(m,1H),3.42-3.32(m,4H),3.13-3.12(m,1H ), 3.00-2.85 (m, 4H), 1.37 (d, J = 6.4Hz, 3H).; MS: [M+H] + = 458.39m/z.
实施例106(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(4-氟苯基)乙炔基)苯基)-3-甲基苯甲酰胺
Example 106 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(4-fluorophenyl)ethynyl)phenyl)-3-methylbenzyl Amide
黄色固体，收率52.74％；通过通用方法1得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.12(brs,1H),7.84-7.74(m,2H),7.55-7.51(m,2H),7.50-7.42(m,2H),7.40-7.38(m,1H),7.29(d,J＝8.3Hz,1H),7.15-7.10(m,2H),3.58(s,1H),3.48-3.31(m,4H),3.20-3.08(m,1H),3.00-2.86(m,4H),2.46(s,3H),1.38(d,J＝6.4Hz,3H).；MS:[M+H]+＝442.39m/z.Yellow solid, yield 52.74%; the target product was obtained by general method 1. 1 H NMR(400MHz, Methanol-d4)δ:8.12(brs,1H),7.84-7.74(m,2H),7.55-7.51(m,2H),7.50-7.42(m,2H),7.40-7.38( m,1H),7.29(d,J＝8.3Hz,1H),7.15-7.10(m,2H),3.58(s,1H),3.48-3.31(m,4H),3.20-3.08(m,1H) ,3.00-2.86(m,4H),2.46(s,3H),1.38(d,J＝6.4Hz,3H).;MS:[M+H] + ＝442.39m/z.
实施例107(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(4-氟苯基)乙炔基)苯基)-2,3-二氢苯并呋喃-4-甲酰胺
Example 107 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(4-fluorophenyl)ethynyl)phenyl)-2,3-dihydro Benzofuran-4-carboxamide
黄色固体，收率28.70％；通过通用方法1得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.21(brs,1H),7.57-7.50(m,2H),7.39-7.36(m,1H),7.31-7.29(m,3H),7.15-7.10(m,2H),6.98-6.93(m,1H),4.61(t,J＝8.8Hz,2H),3.61-3.46(m,3H),3.38-3.31(m,4H),3.23-3.19(m,1H),3.13-3.11(m,1H),2.92(s,3H),1.37(d,J＝6.4Hz,3H).；MS:[M+H]+＝470.40m/z.Yellow solid, yield 28.70%; the target product was obtained by general method 1. 1 H NMR (400MHz, Methanol-d4) δ: 8.21 (brs, 1H), 7.57-7.50 (m, 2H), 7.39-7.36 (m, 1H), 7.31-7.29 (m, 3H), 7.15-7.10 ( m,2H),6.98-6.93(m,1H),4.61(t,J＝8.8Hz,2H),3.61-3.46(m,3H),3.38-3.31(m,4H),3.23-3.19(m, 1H), 3.13-3.11 (m, 1H), 2.92 (s, 3H), 1.37 (d, J = 6.4Hz, 3H).; MS: [M+H] + = 470.40m/z.
实施例108(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(4-氟苯基)乙炔基)苯基)-4-甲基苯甲酰胺
Example 108 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(4-fluorophenyl)ethynyl)phenyl)-4-methylbenzyl Amide
黄色固体，收率32.23％；通过通用方法1得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.18(brs,1H),7.90(d,J＝8.2Hz,2H),7.62-7.53(m,2H),7.47-7.38(m,3H),7.32(d,J＝8.3Hz,1H),7.18-7.13(m,2H),3.60-3.52(m,1H),3.40-3.35(m,4H),3.20-3.12(m,1H),3.00-2.85(m,4H),2.47(s,3H),1.38(d,J＝6.4Hz,3H).；MS:[M+H]+＝442.43m/z.Yellow solid, yield 32.23%; the target product was obtained by general method 1. 1 H NMR (400MHz, Methanol-d4) δ: 8.18 (brs, 1H), 7.90 (d, J = 8.2Hz, 2H), 7.62-7.53 (m, 2H), 7.47-7.38 (m, 3H), 7.32 (d,J＝8.3Hz,1H),7.18-7.13(m,2H),3.60-3.52(m,1H),3.40-3.35(m,4H),3.20-3.12(m,1H),3.00-2.85 (m, 4H), 2.47 (s, 3H), 1.38 (d, J = 6.4Hz, 3H).; MS: [M+H] + = 442.43m/z.
实施例109(S)-N-(2-(3,4-二甲基哌嗪-1-基)-5-(4-氟苯基)乙炔基)苯基)-2-甲基苯甲酰胺
Example 109 (S)-N-(2-(3,4-dimethylpiperazin-1-yl)-5-(4-fluorophenyl)ethynyl)phenyl)-2-methylbenzyl Amide
黄色固体，收率42.48％；通过通用方法1得到目标产物。1H NMR(400MHz,Methanol-d4)δ:8.22(s,1H),7.57-7.52(m,3H),7.45-7.27(m,5H),7.18-7.08(m,2H),3.69-3.56(m,1H),3.45-3.31(m,7H),3.20-3.08(m,1H),3.00-2.86(m,4H),2.51(s,3H),1.40(d,J＝6.0Hz,3H).；MS:[M+H]+＝442.42m/z.Yellow solid, yield 42.48%; the target product was obtained by general method 1. 1 H NMR (400MHz, Methanol-d4) δ: 8.22 (s, 1H), 7.57-7.52 (m, 3H), 7.45-7.27 (m, 5H), 7.18-7.08 (m, 2H), 3.69-3.56 ( m,1H),3.45-3.31(m,7H),3.20-3.08(m,1H),3.00-2.86(m,4H),2.51(s,3H),1.40(d,J＝6.0Hz,3H) .；MS:[M+H] + =442.42m/z.
实施例110.(S)-N-(5-((3,5-双(三氟甲基)苯基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 110. (S)-N-(5-((3,5-bis(trifluoromethyl)phenyl)ethynyl)-2-(3,4-dimethylpiperazin-1-yl) Synthesis of phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率35％；通过通用方法2合成目标产物；1H NMR(600MHz,DMSO-d6)δ12.63(s,1H),9.61(s,1H),8.32(s,1H),8.16(s,1H),7.99(s,1H),7.63-7.61(m,1H),7.57-7.55(m,1H),7.48(d,J＝8.1Hz,1H),7.29(d,J＝8.2Hz,1H),6.85(s,1H),3.56-3.54(m,1H),3.32-3.25(m,4H),3.08-3.02(m,1H),2.86(s,3H),2.82-2.76(m,1H),1.29(d,J＝6.4Hz,3H).；[M+H]+＝631.37m/z.Yellow solid, yield 35%; the target product was synthesized by general method 2; 1 H NMR (600MHz, DMSO-d6) δ12.63 (s, 1H), 9.61 (s, 1H), 8.32 (s, 1H), 8.16 (s,1H),7.99(s,1H),7.63-7.61(m,1H),7.57-7.55(m,1H),7.48(d,J＝8.1Hz,1H),7.29(d,J＝8.2 Hz,1H),6.85(s,1H),3.56-3.54(m,1H),3.32-3.25(m,4H),3.08-3.02(m,1H),2.86(s,3H),2.82-2.76( m, 1H), 1.29 (d, J = 6.4Hz, 3H).; [M+H] + = 631.37m/z.
实施例111.N-(5-((4-氟苯基)乙炔基)-2-((3S，5S)-3,4,5-三甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 111. N-(5-((4-fluorophenyl)ethynyl)-2-((3S,5S)-3,4,5-trimethylpiperazin-1-yl)phenyl)- Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率47％；合成方法与N-(5-((4-氟苯基)乙炔基)-2-((3R，5S)-3,4,5-三甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成相同；1H NMR(600MHz,DMSO-d6)δ12.68(s,1H),9.91(s,1H),8.07(s,1H),7.94(d,J＝1.6Hz,1H),7.65-7.61(m,2H),7.41(dd,J＝8.3,2.0Hz,1H),7.31-7.25(m,3H),6.85(s,1H),3.76(s,2H),3.60(s,2H),3.12(s,2H),2.80(s,3H),1.34-1.29(m,6H).；[M+H]+＝527.35m/z.Yellow solid, yield 47%; the synthesis method is the same as N-(5-((4-fluorophenyl)ethynyl)-2-((3R,5S)-3,4,5-trimethylpiperazine-1) The synthesis of -yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide is the same; 1 H NMR (600MHz, DMSO-d6) δ12.68 (s,1H),9.91(s,1H),8.07(s,1H),7.94(d,J＝1.6Hz,1H),7.65-7.61(m,2H),7.41(dd,J＝8.3,2.0 Hz,1H),7.31-7.25(m,3H),6.85(s,1H),3.76(s,2H),3.60(s,2H),3.12(s,2H),2.80(s,3H),1.34 -1.29(m,6H).;[M+H] + =527.35m/z.
实施例112.(S)-N-(5-((2-乙酰基-2-氮杂螺环[3.5]壬-7-基)乙炔基)-2-(3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 112. (S)-N-(5-((2-acetyl-2-azaspiro[3.5]non-7-yl)ethynyl)-2-(3,4-dimethylpiper Synthesis of oxazin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率64％；合成方法与N-(5-((1-乙酰哌啶-2-基)乙炔基)-2-((S)-3,4-二甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成相同；1H NMR(600MHz,DMSO-d6)δ12.63(s,1H),9.52(s,1H),7.98(s,1H),7.91(s,1H),7.21-7.18(m,1H),7.15(d,J＝8.3Hz,1H),6.83(s,1H),3.79(s,1H),3.74(s,1H),3.51(s,1H),3.47(s,1H),3.40(s,1H),3.28-3.22(m,4H),3.03-2.98(m,1H),2.86-2,86(m,3H),2.81-2.72(m,2H),1.75-1.74(m,3H),1.61-1.46(m,8H),1.28(d,J＝6.4Hz,3H).；[M+H]+＝584.57m/z.Yellow solid, yield 64%; the synthesis method is the same as N-(5-((1-acetylpiperidin-2-yl)ethynyl)-2-((S)-3,4-dimethylpiperazine-1) The synthesis of -yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide is the same; 1 H NMR (600MHz, DMSO-d6) δ12.63 (s,1H),9.52(s,1H),7.98(s,1H),7.91(s,1H),7.21-7.18(m,1H),7.15(d,J＝8.3Hz,1H),6.83( s,1H),3.79(s,1H),3.74(s,1H),3.51(s,1H),3.47(s,1H),3.40(s,1H),3.28-3.22(m,4H),3.03 -2.98(m,1H),2.86-2,86(m,3H),2.81-2.72(m,2H),1.75-1.74(m,3H),1.61-1.46(m,8H),1.28(d, J＝6.4Hz,3H).; [M+H] + ＝584.57m/z.
实施例113.(S)-N-(5-(环己基炔基)-2-(八氢-2H-吡啶[1,2-a]吡嗪-2-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 113. (S)-N-(5-(cyclohexylynyl)-2-(octahydro-2H-pyridin[1,2-a]pyrazin-2-yl)phenyl)-6-oxo Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率17％；通过通用方法2合成目标产物1H NMR(400MHz,DMSO-d6)δ12.61(s,1H),9.47(s,1H),8.04(s,1H),7.94(s,1H),7.17(d,J＝8.8Hz,2H),6.83(s,1H),3.49-3.35(m,4H),3.27-3.17(m,4H),3.02-2.87(m,2H),2.84-2.75(m,1H),2.68-2.58(m,1H),1.88-1.76(m,4H),1.73-1.62(m,3H),1.56-1.42(m,4H),1.39-1.26(m,3H).；[M+H]+＝527.51m/z. White solid, yield 17%; the target product 1 H NMR (400MHz, DMSO-d6) was synthesized by general method 2 δ12.61(s,1H),9.47(s,1H),8.04(s,1H),7.94( s,1H),7.17(d,J＝8.8Hz,2H),6.83(s,1H),3.49-3.35(m,4H),3.27-3.17(m,4H),3.02-2.87(m,2H) ,2.84-2.75(m,1H),2.68-2.58(m,1H),1.88-1.76(m,4H),1.73-1.62(m,3H),1.56-1.42(m,4H),1.39-1.26( m,3H).;[M+H] + =527.51m/z.
实施例114.(S)-N-(5-(环己基乙炔基)-2-(4-(2-氟乙基)-3-甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 114. (S)-N-(5-(cyclohexylethynyl)-2-(4-(2-fluoroethyl)-3-methylpiperazin-1-yl)phenyl)-6- Synthesis of oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率9％；通过通用方法2合成目标产物；1H NMR(600MHz,Methanol-d4)δ8.23(s,1H),8.03(s,1H),7.26-7.22(m,2H),7.01(s,1H),4.78–4.76(m,1H),4.42(dt,J＝27.2,4.5Hz,2H),3.53(dd,J＝9.9,6.6Hz,1H),3.46(d,J＝12.6Hz,1H),3.26–3.21(m,2H),3.07–3.02(m,1H),2.83(dd,J＝12.7,10.8Hz,1H),2.65–2.59(m,1H),1.93–1.88(m,2H),1.79(d,J＝9.6Hz,2H),1.57(dq,J＝31.2,12.0,9.6Hz,3H),1.45–1.30(m,8H).[M+H]+＝533.48m/z.White solid, yield 9%; the target product was synthesized by general method 2; 1 H NMR (600MHz, Methanol-d4) δ8.23 (s, 1H), 8.03 (s, 1H), 7.26-7.22 (m, 2H) ,7.01(s,1H),4.78–4.76(m,1H),4.42(dt,J＝27.2,4.5Hz,2H),3.53(dd,J＝9.9,6.6Hz,1H),3.46(d,J ＝12.6Hz,1H),3.26–3.21(m,2H),3.07–3.02(m,1H),2.83(dd,J＝12.7,10.8Hz,1H),2.65–2.59(m,1H),1.93– 1.88(m,2H),1.79(d,J＝9.6Hz,2H),1.57(dq,J＝31.2,12.0,9.6Hz,3H),1.45–1.30(m,8H).[M+H] + =533.48m/z.
实施例115.(S)-N-(5-(环己基乙炔基)-2-(4-(2,2-二氟乙基)-3-甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 115. (S)-N-(5-(cyclohexylethynyl)-2-(4-(2,2-difluoroethyl)-3-methylpiperazin-1-yl)phenyl) -Synthesis of 6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，产率20％；通过通用方法2合成目标产物；1H NMR(600MHz,Methanol-d4)δ8.24(s,1H),8.02(s,1H),7.26–7.22(m,2H),7.03(s,1H),6.30(tt,J＝55.5,3.6Hz,1H),4.51(t,J＝14.1Hz,2H),3.55–3.45(m,2H),3.24(d,J＝12.9Hz,2H),3.04(t,J＝11.8Hz,1H),2.86–2.81(m,1H),2.65–2.59(m,1H),1.93–1.87(m,2H),1.79(d,J＝9.6Hz,2H),1.61–1.51(m,3H),1.41(t,J＝8.1Hz,3H),1.36(d,J＝6.4Hz,3H),1.31(s,1H).；[M+H]+＝551.46m/z. White solid, yield 20%; the target product was synthesized by general method 2; 1 H NMR (600MHz, Methanol-d4) δ8.24 (s, 1H), 8.02 (s, 1H), 7.26–7.22 (m, 2H) ,7.03(s,1H),6.30(tt,J＝55.5,3.6Hz,1H),4.51(t,J＝14.1Hz,2H),3.55–3.45(m,2H),3.24(d,J＝12.9 Hz,2H),3.04(t,J＝11.8Hz,1H),2.86–2.81(m,1H),2.65–2.59(m,1H),1.93–1.87(m,2H),1.79(d,J＝ 9.6Hz,2H),1.61–1.51(m,3H),1.41(t,J＝8.1Hz,3H),1.36(d,J＝6.4Hz,3H),1.31(s,1H).;[M+ H] + =551.46m/z.
实施例116.(S)-N-(5-(环己基乙炔基)-2-(4-环丙基-3-甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 116. (S)-N-(5-(cyclohexylethynyl)-2-(4-cyclopropyl-3-methylpiperazin-1-yl)phenyl)-6-oxo-4 Synthesis of -(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
黄色固体，产率15％；通过通用方法2合成目标产物；1H NMR(600MHz,Methanol-d4)δ8.01(s,1H),7.94(s,1H),7.26–7.20(m,2H),6.95(s,1H),3.75–3.66(m,2H),3.49–3.44(m,1H),3.27(s,2H),3.09(s,1H),2.89(d,J＝6.8Hz,1H),2.84–2.76(m,1H),2.64–2.59(m,1H),1.93–1.87(m,2H),1.79(d,J＝9.8Hz,2H),1.62–1.51(m,6H),1.40(q,J＝8.9Hz,3H),1.18(s,2H),1.01(s,1H),0.93(d,J＝6.9Hz,1H).[M+H]+＝527.50m/z.Yellow solid, yield 15%; the target product was synthesized by general method 2; 1 H NMR (600MHz, Methanol-d4) δ8.01 (s, 1H), 7.94 (s, 1H), 7.26–7.20 (m, 2H) ,6.95(s,1H),3.75–3.66(m,2H),3.49–3.44(m,1H),3.27(s,2H),3.09(s,1H),2.89(d,J＝6.8Hz,1H ),2.84–2.76(m,1H),2.64–2.59(m,1H),1.93–1.87(m,2H),1.79(d,J＝9.8Hz,2H),1.62–1.51(m,6H), 1.40(q,J＝8.9Hz,3H),1.18(s,2H),1.01(s,1H),0.93(d,J＝6.9Hz,1H).[M+H] + =527.50m/z.
实施例117.N-(5-(环己基乙炔基)-2-(1-甲基哌啶-4-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 117. N-(5-(cyclohexylethynyl)-2-(1-methylpiperidin-4-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1, Synthesis of 6-dihydropyridine-3-carboxamide
白色固体，产率19％；通过通用方法2合成目标产物；1H NMR(600MHz,MeOD)δ8.11(s,1H),7.54(s,1H),7.40–7.33(m,2H),6.95(s,1H),5.13–5.04(m,1H),3.19–3.13(m,3H),2.21(t,J＝7.6Hz,1H),2.15–2.10(m,5H),2.09–2.03(m,2H),1.99(d,J＝12.6Hz,2H),1.95–1.90(m,2H),1.81(dd,J＝8.2,5.2 Hz,2H),1.69–1.55(m,5H).[M+H]+＝485.95m/z.White solid, yield 19%; the target product was synthesized by general method 2; 1 H NMR (600MHz, MeOD) δ8.11 (s, 1H), 7.54 (s, 1H), 7.40–7.33 (m, 2H), 6.95 (s,1H),5.13–5.04(m,1H),3.19–3.13(m,3H),2.21(t,J＝7.6Hz,1H),2.15–2.10(m,5H),2.09–2.03(m ,2H),1.99(d,J＝12.6Hz,2H),1.95–1.90(m,2H),1.81(dd,J＝8.2,5.2 Hz,2H),1.69–1.55(m,5H).[M+H] + =485.95m/z.
实施例118.N-(5-(环己基乙炔基)-2-(哌啶-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
Example 118. N-(5-(cyclohexylethynyl)-2-(piperidin-1-yl)phenyl)-6-oxo-4-(trifluoromethyl)-1,6-dihydro Pyridine-3-carboxamide
黄色固体，收率7.07％；通过通用方法2得到目标产物。1H NMR(600MHz,DMSO-d6)δ12.53(s,1H),9.35(s,1H),7.90(s,1H),7.81(s,1H),7.14(dd,J＝8.2,1.8Hz,1H),7.07(d,J＝8.3Hz,1H),6.81(s,1H),2.85–2.71(m,4H),2.61(s,2H),1.81(s,2H),1.65(dd,J＝27.3,5.0Hz,5H),1.46(dd,J＝31.6,22.1Hz,5H),1.33(t,J＝9.4Hz,2H),1.24(s,1H).MS:[M+H]+＝472.20m/z.Yellow solid, yield 7.07%; the target product was obtained by general method 2. 1 H NMR (600MHz, DMSO-d 6 ) δ12.53(s,1H),9.35(s,1H),7.90(s,1H),7.81(s,1H),7.14(dd,J＝8.2,1.8 Hz,1H),7.07(d,J＝8.3Hz,1H),6.81(s,1H),2.85–2.71(m,4H),2.61(s,2H),1.81(s,2H),1.65(dd ,J＝27.3,5.0Hz,5H),1.46(dd,J＝31.6,22.1Hz,5H),1.33(t,J＝9.4Hz,2H),1.24(s,1H).MS:[M+H ] + =472.20m/z.
实施例119.(S)-N-(5-(环己基亚乙基)-2-(3-环丙基-4-甲基哌嗪-1-基)苯基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺的合成
Example 119. (S)-N-(5-(cyclohexylidene)-2-(3-cyclopropyl-4-methylpiperazin-1-yl)phenyl)-6-oxo- Synthesis of 4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
白色固体，收率20.69％；通过通用方法2得到目标产物。1H NMR(600MHz,DMSO-d6)δ12.64(s,1H),9.44(d,J＝8.4Hz,1H),7.99(s,1H),7.85(d,J＝28.8Hz,1H),7.21–7.19(m,2H),6.83(s,1H),3.56(d,J＝11.9Hz,2H),3.31–3.15(m,4H),3.03–2.99(m,1H),2.97(d,J＝4.2Hz,3H),2.93(d,J＝5.0Hz,1H),2.63–2.58(m,2H),1.86–1.80(m,2H),1.68(m,2H),1.54–1.42(m,4H),1.37–1.30(m,1H),0.58–0.42(m,2H),0.23–0.15(m,2H).MS:[M+H]+＝527.39m/z. White solid, yield 20.69%; the target product was obtained by general method 2. 1 H NMR (600MHz, DMSO-d 6 ) δ12.64 (s, 1H), 9.44 (d, J = 8.4Hz, 1H), 7.99 (s, 1H), 7.85 (d, J = 28.8Hz, 1H) ,7.21–7.19(m,2H),6.83(s,1H),3.56(d,J＝11.9Hz,2H),3.31–3.15(m,4H),3.03–2.99(m,1H),2.97(d ,J＝4.2Hz,3H),2.93(d,J＝5.0Hz,1H),2.63–2.58(m,2H),1.86–1.80(m,2H),1.68(m,2H),1.54–1.42( m,4H),1.37–1.30(m,1H),0.58–0.42(m,2H),0.23–0.15(m,2H).MS:[M+H] + =527.39m/z.
实验例 本发明化合物的部分药效学试验及结果Experimental Examples: Some pharmacodynamic tests and results of the compounds of the present invention
如无特殊说明，本发明使用的细胞系MV4-11均购自ATCC，货号CRL-9591；细胞系MOLM-13购自科佰生物，货号CBP60678；细胞系HL60购自ATCC货号CCL-240。Unless otherwise specified, the cell line MV4-11 used in the present invention was purchased from ATCC, product number CRL-9591; the cell line MOLM-13 was purchased from Kebai Biotech, product number CBP60678; the cell line HL60 was purchased from ATCC, product number CCL-240.
一、WDR5 FP试验测定：1. WDR5 FP test measurement:
用于FP试验的5-FAM标签探针和WDR5蛋白均由金斯瑞公司合成。将探针储备液用磷酸缓冲液稀释至5nM，每孔50μl加入黑色96孔板中；同时将WDR5蛋白用磷酸盐缓冲液稀释至25nM，每孔50μl加入黑色96孔板中。将测试化合物用DMSO稀释至100μM后，用磷酸盐缓冲液逐步稀释配制成最高浓度为1μM的12个浓度梯度系列，每孔25μl加入黑色96孔板中。室温摇床避光孵育30min后，使用多功能酶标仪进行测定，激发波长485nm，检测波长535nm。The 5-FAM label probe and WDR5 protein used in the FP test were synthesized by GenScript. Dilute the probe stock solution to 5nM with phosphate buffer and add 50μl per well to a black 96-well plate; at the same time, dilute the WDR5 protein to 25nM with phosphate buffer and add 50μl per well into a black 96-well plate. After diluting the test compound with DMSO to 100 μM, it was gradually diluted with phosphate buffer to prepare a 12 concentration gradient series with the highest concentration of 1 μM, and 25 μl per well was added to a black 96-well plate. After incubation on a room temperature shaker in the dark for 30 minutes, a multifunctional microplate reader was used for measurement, with an excitation wavelength of 485 nm and a detection wavelength of 535 nm.
二、细胞增殖测定：2. Cell proliferation measurement:
将细胞接种(MV4-11细胞或MOLM-13细胞以7500个细胞/孔；HL60细胞以12500个细胞/孔)到96孔板的180μl培养基(含有10％FBS的IMDM，Gibco)中，每孔加入20μl含不同浓度测试化合物的培养基(最终浓度为0～100μM的十个浓度范围)后，细胞在37℃，5％CO2潮湿的培养箱中培养四天。四天后，从培养箱中取出平板，每孔加入20μl的CCK8检测试剂，37℃孵育后(孵育时间：MV4-11细胞，4h；MOLM-13细胞，2.5h；HL60细胞，4h)，使用多功能酶标仪在450nm处进行测定。Cells were seeded (MV4-11 cells or MOLM-13 cells at 7500 cells/well; HL60 cells at 12500 cells/well) into 96-well plates in 180 μl of culture medium (IMDM containing 10% FBS, Gibco), each After adding 20 μl of culture medium containing test compounds at different concentrations to the wells (ten concentration ranges with final concentrations ranging from 0 to 100 μM), the cells were cultured in a humidified incubator at 37°C and 5% CO for four days. Four days later, take out the plate from the incubator, add 20 μl of CCK8 detection reagent to each well, and incubate at 37°C (incubation time: MV4-11 cells, 4h; MOLM-13 cells, 2.5h; HL60 cells, 4h). Use multiple Functional microplate reader performs measurement at 450nm.
表1.本发明化合物相关生物学活性




























Table 1. Related biological activities of the compounds of the present invention




























结论：in conclusion:
如表1所示的，本发明提供的实施例1-115化合物相比阳性药物与WDR5具有更高或相当的亲和度，在MV4-11、MOLM-13以及HL60细胞株中的检测结果也显示，本发明提供的化合物相比阳性药物对WDR5具有更高或相当的抑制活性。As shown in Table 1, the compounds of Examples 1-115 provided by the present invention have higher or equivalent affinity to WDR5 than positive drugs, and the detection results in MV4-11, MOLM-13 and HL60 cell lines are also It shows that the compounds provided by the present invention have higher or equivalent inhibitory activity on WDR5 compared with positive drugs.
本发明已经通过上述实施例进行了说明，但应当理解的是，上述实施例只是用于举例和说明的目的，而非意在将本发明限制于所描述的实施例范围内。此外本领域技术人员可以理解的是，本发明并不局限于上述实施例，根据本发明的教导还可以做出更多种的变型和修改，这些变型和修改均落在本发明所要求保护的范围以内。本发明的保护范围由附属的权利要求书及其等效范围所界定。 The present invention has been described through the above-mentioned embodiments, but it should be understood that the above-mentioned embodiments are only for the purpose of illustration and illustration, and are not intended to limit the present invention to the scope of the described embodiments. In addition, those skilled in the art can understand that the present invention is not limited to the above embodiments, and more variations and modifications can be made according to the teachings of the present invention. These variations and modifications all fall within the scope of the protection claimed by the present invention. within range. The protection scope of the present invention is defined by the appended claims and their equivalent scope.

Claims (25)

  1. 一种具有式Ⅰ0所示结构式的化合物或其可药用盐， A compound having the structural formula shown in formula I0 or a pharmaceutically acceptable salt thereof,
    其中，R1A是未取代的或取代的含有至少一个氮原子的3-15元杂环烷基，所述3-15元杂环烷基为单环杂环烷基、稠环杂环烷基、螺环杂环烷基或桥环杂环烷基，所述取代的含有至少一个氮原子的3-15元杂环烷基被选自下述的一个、两个、三个或更多个取代基取代：卤素、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、-OR9、-SR9、亚烷基-OR9、亚烷基-SR9、-NR10R11、亚烷基-CR9R10R11和亚烷基-NR10R11，其中任选地，所述烷基、杂烷基、烯基、炔基、环烷基、杂环烷基、亚烷基、芳基、和杂芳基各自独立地被选自卤素、烷基、杂烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、烯基、炔基、烷基氨基、烷基酰基、烷基氧基酰基、烷基氨基酰基、芳基和杂芳基中的一个或多个取代基所取代；Wherein, R 1A is an unsubstituted or substituted 3-15-membered heterocycloalkyl group containing at least one nitrogen atom, and the 3-15-membered heterocycloalkyl group is a monocyclic heterocycloalkyl group or a fused-ring heterocycloalkyl group. , spirocyclic heterocycloalkyl or bridged heterocycloalkyl, the substituted 3-15 membered heterocycloalkyl containing at least one nitrogen atom is selected from one, two, three or more of the following Substituent substitution: halogen, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR 9 , -SR 9 , alkylene- OR 9 , alkylene-SR 9 , -NR 10 R 11 , alkylene-CR 9 R 10 R 11 and alkylene-NR 10 R 11 , wherein optionally, the alkyl, heteroalkyl, Alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylene, aryl, and heteroaryl are each independently selected from the group consisting of halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, Hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and hetero Substituted by one or more substituents in the aryl group;
    R2A是未取代的或取代的芳基、杂芳基或杂环烷基，所述杂芳基或杂环烷基各自独立地含有1、2或3个各自独立选自N、O或S的杂原子，任选地，所述未取代的或取代的芳基和杂芳基各自独立地稠和于杂环烷基或环烷基，所述取代的芳基、杂芳基和杂环烷基各自独立地被选自下述的一个、两个、三个、四个或更多个取代基取代：卤素、＝O、＝S、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基、-OR12、-SR12、亚烷基-OR12、亚烷基-SR12、-NR13R14、亚烷基-CR12R13R14和亚烷基-NR13R14，其中任选地，所述烷基、杂烷基、烯基、炔基、环烷基、杂环烷基、亚烷基、芳基、和杂芳基各自独立地被选自卤素、烷基、杂烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、烯基、炔基、烷基氨基、烷基酰基、烷基氧基酰基、烷基氨基酰基、芳基和杂芳基中的一个或多个取代基所取代；R 2A is an unsubstituted or substituted aryl, heteroaryl or heterocycloalkyl group, each of the heteroaryl or heterocycloalkyl groups independently contains 1, 2 or 3 each independently selected from N, O or S heteroatoms, optionally, the unsubstituted or substituted aryl and heteroaryl are each independently fused to the heterocycloalkyl or cycloalkyl, the substituted aryl, heteroaryl and heterocyclic Each alkyl group is independently substituted with one, two, three, four or more substituents selected from the following: halogen, =O, =S, alkyl, haloalkyl, heteroalkyl, alkenyl, Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR 12 , -SR 12 , alkylene -OR 12 , alkylene -SR 12 , -NR 13 R 14 , alkylene -CR 12 R 13 R 14 and alkylene -NR 13 R 14 , wherein optionally, the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkylene, Aryl, and heteroaryl are each independently selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl Substituted with one or more substituents of base, alkenyl, alkynyl, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl;
    R3A是未取代的或取代的芳基、杂芳基、环烷基或杂环烷基，所述未取代的或取代的环烷基和杂环烷基各自独立地为单环、稠环、桥环、或螺环基团，所述未取代的或取代的芳基和杂芳基各自独立地为单环或稠环基团，任选地，所述未取代的或取代的芳基和杂芳基各自独立地稠和于杂环烷基或环烷基，任选地，所述取代的芳基、杂芳基、环烷基和杂环烷基各自独立地被选自下述的一个或更多个取代基取代：卤素、-CN、烷基、杂烷基、烯基、炔基、卤代烷基、＝O、＝S、OR15、-SR15、-SO2R15、-NR16R17、亚烷基-CR15R16R17、R4A、亚烷基R4A、亚烯基R4A、亚炔基R4A、-O亚烷基R4A、-S亚烷基R4A、亚烷基NR16R17、亚烷基OR15、亚烷基SR15、-O亚烷基NR16R17、-S亚烷基NR16R17、-O亚烷基OR15、S亚烷基OR15、-O亚烷基SR15、SC1-6亚烷基SR15、-C(O)OR15、-C(O)R15、-C(S)OR15、-C(S)NR16R17和-C(O)NR16R17，其中任选地，所述烷基、杂烷基、烯基、炔基、和亚烷基各自独立地被选自卤素、烷基、杂烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、烯基、炔基、烷基氨基、烷基酰基、烷基氧基酰基、烷基氨基酰基、芳基和杂芳基中的一个或多个取代基所取代；R 3A is an unsubstituted or substituted aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, and the unsubstituted or substituted cycloalkyl and heterocycloalkyl groups are each independently a monocyclic or condensed ring , bridged ring, or spirocyclic group, the unsubstituted or substituted aryl group and heteroaryl group are each independently a monocyclic or condensed ring group, optionally, the unsubstituted or substituted aryl group and heteroaryl are each independently fused to heterocycloalkyl or cycloalkyl, optionally, the substituted aryl, heteroaryl, cycloalkyl and heterocycloalkyl are each independently selected from the following Substituted with one or more substituents: halogen, -CN, alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, =O, =S, OR 15 , -SR 15 , -SO 2 R 15 , -NR 16 R 17 , alkylene group -CR 15 R 16 R 17 , R 4A , alkylene group R 4A , alkenylene group R 4A , alkynylene group R 4A , -O alkylene group R 4A , -S alkylene group Group R 4A , alkylene group NR 16 R 17 , alkylene group OR 15 , alkylene group SR 15 , -O alkylene group NR 16 R 17 , -S alkylene group NR 16 R 17 , -O alkylene group OR 15 , S alkylene OR 15 , -O alkylene SR 15 , SC 1-6 alkylene SR 15 , -C(O)OR 15 , -C(O)R 15 , -C(S)OR 15 , -C(S)NR 16 R 17 and -C(O)NR 16 R 17 , wherein optionally, the alkyl, heteroalkyl, alkenyl, alkynyl, and alkylene groups are each independently selected From halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkylamino, Substituted with one or more substituents from alkyl acyl, alkyloxyacyl, alkylaminoacyl, aryl and heteroaryl;
    R4A选自未取代的或被一个或多个独立地选自卤素、-CN、＝O、＝S、-OR18、-SR18、-NR19R20、C1-6卤代烷基、C1-6烷基、-C(O)R18、-C(O)OR18、-C(O)NR19R20、-S(O)C1-6烷基、-SO2R18、C6-10芳基、5-10元杂芳基、C3-15环烷基、3-15元杂环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-15环烷基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基、C1-6亚烷基R18、C1-6亚烷基OR18、C1-6亚烷基SR18、C1-6亚烷基-CR18R19R20、C1-6亚烷基NR19R20、-OC1-6亚烷基NR19R20、-SC1-6亚烷基NR19R20、-OC1-6亚烷基OR18、SC1-6亚烷基OR18、-OC1-6亚烷基SR18、OC1-6亚烷基SR18、-C(S)OR18、和-C(S)NR19R20中的取代基取代的C3-15环烷基、3-15元杂环烷基、5-15元杂芳基和C6-10芳基，所述C3-15环烷基和3至15元杂环烷基各自独立地为单环、稠环、桥环、或螺环基团，所述C6-10芳基和5至15元杂芳基各自独立地为单环或稠环基团；R 4A is selected from unsubstituted or one or more independently selected from halogen, -CN, =O, =S, -OR 18 , -SR 18 , -NR 19 R 20 , C 1-6 haloalkyl, C 1-6 alkyl, -C(O)R 18 , -C(O)OR 18 , -C(O)NR 19 R 20 , -S(O)C 1-6 alkyl, -SO 2 R 18 , C 6-10 aryl, 5-10 membered heteroaryl, C 3-15 cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 Alkylene C 3-15 cycloalkyl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl, C 1-6 alkylene R 18 , C 1-6 alkylene Group OR 18 , C 1-6 alkylene group SR 18 , C 1-6 alkylene group -CR 18 R 19 R 20 , C 1-6 alkylene group NR 19 R 20 , -OC 1-6 alkylene group NR 19 R 20 , -SC 1-6 alkylene NR 19 R 20 , -OC 1-6 alkylene OR 18 , SC 1-6 alkylene OR 18 , -OC 1-6 alkylene SR 18 , OC C 3-15 cycloalkyl, 3-15 membered heterocycloalkyl, substituted by substituents in 1-6 alkylene SR 18 , -C(S)OR 18 , and -C(S)NR 19 R 20 , 5-15-membered heteroaryl and C 6-10 aryl, the C 3-15 cycloalkyl and 3 to 15-membered heterocycloalkyl are each independently a single ring, condensed ring, bridged ring, or spirocyclic group group, the C 6-10 aryl group and the 5 to 15-membered heteroaryl group are each independently a monocyclic or condensed ring group;
    R9和R12每次出现时各自独立地选自H、烷基、卤代烷基、环烷基、杂环烷基、-C(O)烷基、-C(O)卤代烷基、-C(O)O烷基、-C(O)NH烷基、-SO2烷基、-SO2HN烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基和C1-6亚烷基环烷基，任选地，所述烷基、环烷基、杂环烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基芳基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基和C1-6亚烷基环烷基各自独立地被选自卤素、烷基、杂烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、芳基和杂芳基中的一个或多个取代基所取代；Each occurrence of R 9 and R 12 is independently selected from H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, -C(O)alkyl, -C(O)haloalkyl, -C( O)O alkyl, -C(O)NH alkyl, -SO 2 alkyl, -SO 2 HN alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl and C 1-6 alkylene cycloalkyl, optionally, the alkyl, ring Alkyl, heterocycloalkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene aryl, C 1-6 alkylene heteroaryl, C 1-6 alkylene Heterocycloalkyl and C 1-6 alkylenecycloalkyl are each independently selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro , substituted by one or more substituents in cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
    R10、R11、R13、和R14每次出现时各自独立地选自H、烷基、卤代烷基、环烷基、杂环烷基、-C(O)烷基、-C(O)卤代烷基、-C(O)O烷基、-C(O)NH烷基、-SO2烷基、-SO2HN烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基芳基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基和C1-6亚烷基环烷基，任选地，所述烷基、环烷基、杂环烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基芳基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基和C1-6亚烷基环烷基被被选自卤素、烷基、杂烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、芳基和杂芳基中的一个或多个取代基所取代；或者，R10和R11与其相连的C或N原子一起形成未取代的或被一个或多个选自卤素、C1-6杂烷基、C1-6羟烷基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C6-10芳基、5-10元杂芳基、-CN、-OH、C1-6烷基、OC1-6烷基、C1-6卤代烷基、-OC1-6卤代烷基、-C(O)C1-6烷基、-C(O)C1-6卤代烷基、-C(O)C1-6烷基、-C(O)NHC1-6烷基、-SO2C1-6烷基、-SO2HNC1-6烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C5-10杂芳基、C1-6亚烷基C3-6杂环烷基和C1-6亚烷基C3-6环烷基中的取代基取代的3-10元环烷基或3-10元杂环烷基；或者，R13和R14与其相连的C或N原子一起形成未取代的或被一个或多个选自卤素、C1-6杂烷基、C1-6羟烷基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C6-10芳基、5-10元杂芳基、-CN、-OH、C1-6烷基、OC1-6烷基、C1-6卤代烷基、-OC1-6卤代烷基、-C(O)C1-6烷基、-C(O)C1-6卤代烷基、-C(O)C1-6烷基、-C(O)NHC1-6烷基、-SO2C1-6烷基、-SO2HNC1-6烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C5-10杂芳基、C1-6亚烷基C3-6杂环烷基和C1-6亚烷基C3-6环烷基中的取代基取代的3-10元环烷基或杂环烷基；Each occurrence of R 10 , R 11 , R 13 , and R 14 is independently selected from H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, -C(O)alkyl, -C(O )Haloalkyl, -C(O)O alkyl, -C(O)NH alkyl, -SO 2 alkyl, -SO 2 HN alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene aryl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl and C 1-6 alkylene cycloalkyl, optionally, the alkyl Base, cycloalkyl, heterocycloalkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene aryl, C 1-6 alkylene heteroaryl, C 1-6 Alkyleneheterocycloalkyl and C 1-6 alkylenecycloalkyl are selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro Substituted with one or more substituents of base, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; alternatively, R 10 and R 11 together with the C or N atom to which they are attached form unsubstituted or are or more selected from halogen, C 1-6 heteroalkyl, C 1-6 hydroxyalkyl, amino, nitro, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aromatic Base, 5-10 membered heteroaryl, -CN, -OH, C 1-6 alkyl, OC 1-6 alkyl, C 1-6 haloalkyl, -OC 1-6 haloalkyl, -C(O) C 1-6 alkyl, -C(O)C 1-6 haloalkyl, -C(O)C 1-6 alkyl, -C(O)NHC 1-6 alkyl, -SO 2 C 1-6 Alkyl, -SO 2 HNC 1-6 alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 5 3-10 membered cycloalkyl substituted by substituents in -10 heteroaryl, C 1-6 alkylene C 3-6 heterocycloalkyl and C 1-6 alkylene C 3-6 cycloalkyl, or 3-10 membered heterocycloalkyl; alternatively, R 13 and R 14 together with the C or N atom to which they are connected form unsubstituted or one or more selected from halogen, C 1-6 heteroalkyl, C 1-6 Hydroxyalkyl, amino, nitro, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OH, C 1- 6 alkyl, OC 1-6 alkyl, C 1-6 haloalkyl, -OC 1-6 haloalkyl, -C(O)C 1-6 alkyl, -C(O)C 1-6 haloalkyl, -C(O)C 1-6 alkyl, -C(O)NHC 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 HNC 1-6 alkyl, C 1-6 alkylene Base OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 5-10 heteroaryl, C 1-6 alkylene C 3-6 heterocycle 3-10 membered cycloalkyl or heterocycloalkyl substituted by substituents in alkyl and C 1-6 alkylene C 3-6 cycloalkyl;
    R15每次出现时各自独立地选自H、烷基、卤代烷基、环烷基、杂环烷基、-C(O)烷基、-C(O)卤代烷基、-C(O)O烷基、-C(O)NH烷基、-SO2烷基、-SO2HN烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基芳基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基和C1-6亚烷基环烷基，任选地，所述烷基、环烷基、杂环烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基芳基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基和C1-6亚烷基环烷基各自独立地被选自卤素、烷基、杂烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、芳基和杂芳基中的一个或多个取代基所取代；Each occurrence of R 15 is independently selected from H, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, -C(O)alkyl, -C(O)haloalkyl, -C(O)O Alkyl, -C(O)NH alkyl, -SO 2 alkyl, -SO 2 HN alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene aryl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl and C 1-6 alkylene cycloalkyl, optionally, the alkyl, cycloalkyl, heterocycloalkyl , C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene aryl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl and C 1 -6 Alkylene cycloalkyl groups are each independently selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycle Substituted with one or more substituents in alkyl, aryl and heteroaryl;
    R16和R17各自独立地选自H、烷基、卤代烷基、-C(O)烷基、-C(O)卤代烷基、-C(O)芳基、-C(O)环烷基、-C(O)杂芳基、-C(O)杂环烷基、-C(O)O烷基、-C(O)O卤代烷基、-C(O)O芳基、-C(O)O环烷基、-C(O)O杂芳基、-C(O)O杂环烷基、-C(O)NH烷基、-C(O)NHC1-6卤代烷基、-C(O)NH芳基、-C(O)NH环烷基、-C(O)NH杂芳基、-C(O)NH杂环烷基、-SO2烷基、-SO2C1-6卤代烷基、-SO2芳基、-SO2环烷基、-SO2杂芳基、-SO2杂环烷基、环烷基、杂环烷基、杂芳基、芳基、亚烷基环烷基、亚烷基芳基、亚烷基杂芳基、亚烷基杂环烷基和C1-6亚烷基OC1-6烷基，任选地，所述烷基、卤代烷基、-C(O)烷基、-C(O)卤代烷基、-C(O)芳基、-C(O)环烷基、-C(O)杂芳基、-C(O)杂环烷基、-C(O)O烷基、-C(O)O卤代烷基、-C(O)O芳基、-C(O)O环烷基、-C(O)O杂芳基、-C(O)O杂环烷基、-C(O)NH烷基、-C(O)NHC1-6卤代烷基、-C(O)NH芳基、-C(O)NH环烷基、-C(O)NH杂芳基、-C(O)NH杂环烷基、-SO2烷基、-SO2C1-6卤代烷基、-SO2芳基、-SO2环烷基、-SO2杂芳基、-SO2杂环烷基、环烷基、杂环烷基、杂芳基、芳基、亚烷基环烷基、亚烷基芳基、亚烷基杂芳基、亚烷基杂环烷基和C1-6亚烷基OC1-6烷基各自独立地被选自卤素、烷基、杂烷基、卤代烷基、羟烷基、氰基、氨基、硝基、环烷基、杂环烷基、芳基、杂芳基、-OR18、-SR18、-NR19R20、-C(O)R18、-C(O)OR18、-C(O)NR19R20、-S(O)C1-6烷基、-SO2C1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基环烷基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基中的一个或多个取代基所取代；或者，R16和R17与它们所连接的氮原子或C原子一起形成3-10元杂环烷基或环烷基，所述3-10元杂环烷基和环烷基是未取代的或被一个或多个独立地选自卤素、-CN、硝基、-OR18、-SR18、-NR19R20、C1-6烷基、C1-6杂烷基、C1-6羟烷基、-C(O)R18、-C(O)OR18、-C(O)N R19R20、-S(O)C1-6烷基、-SO2C1-6烷基、C6-10芳基、5-10元杂芳基、C3-10环烷基、3-15元杂环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基杂芳基、C1-6亚烷基R18、C1-6亚烷基OR18、C1-6亚烷基SR18和C1-6亚烷基NR19R20中的取代基取代；R 16 and R 17 are each independently selected from H, alkyl, haloalkyl, -C(O)alkyl, -C(O)haloalkyl, -C(O)aryl, -C(O)cycloalkyl , -C(O)heteroaryl, -C(O)heterocycloalkyl, -C(O)Oalkyl, -C(O)Ohaloalkyl, -C(O)Oaryl, -C( O)O cycloalkyl, -C(O)O heteroaryl, -C(O)O heterocycloalkyl, -C(O)NH alkyl, -C(O)NHC 1-6 haloalkyl, - C(O)NH aryl, -C(O)NH cycloalkyl, -C(O)NH heteroaryl, -C(O)NH heterocycloalkyl, -SO 2 alkyl, -SO 2 C 1 -6 Haloalkyl, -SO 2 aryl, -SO 2 cycloalkyl, -SO 2 heteroaryl, -SO 2 heterocycloalkyl, cycloalkyl , heterocycloalkyl, heteroaryl, aryl, ylidene Alkylcycloalkyl, alkylenearyl, alkyleneheteroaryl, alkyleneheterocycloalkyl and C 1-6 alkyleneOC 1-6 alkyl, optionally, the alkyl, Haloalkyl, -C(O)alkyl, -C(O)haloalkyl, -C(O)aryl, -C(O)cycloalkyl, -C(O)heteroaryl, -C(O) Heterocycloalkyl, -C(O)O alkyl, -C(O)O haloalkyl, -C(O)O aryl, -C(O)O cycloalkyl, -C(O)O heteroaryl base, -C(O)O heterocycloalkyl, -C(O)NH alkyl, -C(O)NHC 1-6 haloalkyl, -C(O)NH aryl, -C(O)NH ring Alkyl, -C(O)NH heteroaryl, -C(O)NH heterocycloalkyl, -SO 2 alkyl, -SO 2 C 1-6 haloalkyl, -SO 2 aryl, -SO 2 ring Alkyl, -SO2heteroaryl , -SO2heterocycloalkyl , cycloalkyl, heterocycloalkyl, heteroaryl, aryl, alkylenecycloalkyl, alkylenearyl, alkylene Heteroaryl, alkyleneheterocycloalkyl, and C 1-6 alkylene OC 1-6 alkyl are each independently selected from the group consisting of halogen, alkyl, heteroalkyl, haloalkyl, hydroxyalkyl, cyano, Amino, nitro, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OR 18 , -SR 18 , -NR 19 R 20 , -C(O)R 18 , -C(O)OR 18 , -C(O)NR 19 R 20 , -S(O)C 1-6 alkyl, -SO 2 C 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1- Substituted with one or more substituents of 6 alkylenecycloalkyl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl; or, R 16 and R 17 are combined with them The attached nitrogen atoms or C atoms together form a 3-10 membered heterocycloalkyl or cycloalkyl group that is unsubstituted or independently selected from one or more From halogen, -CN, nitro, -OR 18 , -SR 18 , -NR 19 R 20 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 hydroxyalkyl, -C(O )R 18 , -C(O)OR 18 , -C(O)N R 19 R 20 , -S(O)C 1-6 alkyl, -SO 2 C 1-6 alkyl, C 6-10 aryl , 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 3- 10 cycloalkyl, C 1-6 alkylene heteroaryl, C 1-6 alkylene R 18 , C 1-6 alkylene OR 18 , C 1-6 alkylene SR 18 and C 1-6 Substituent substitution in alkylene NR 19 R 20 ;
    R18选自H、烷基、C1-6卤代烷基、-C(O)烷基、-C(O)卤代烷基、环烷基、3杂环烷基、芳基、杂芳基、亚烷基芳基、亚烷基杂芳基、亚烷基环烷基和亚烷基杂环烷基，任选地，所述烷基、C1-6卤代烷基、-C(O)烷基、-C(O)卤代烷基、环烷基、杂环烷基、芳基、杂芳基、亚烷基芳基、亚烷基杂芳基、亚烷基环烷基和亚烷基杂环烷基各自独立地被一个或多个选自卤素、-CN、烷基、卤代烷基、-OH、-SH、烷氧基、-O卤代烷基、-S烷基、-S卤代烷基、-NH2、-NH烷基、-N(C1-6烷基)(C1-6烷基)、-C(O)烷基、-C(O)卤代烷基、-C(O)OH、-C(O)O烷基、-C(O)NH2、-C(O)NHC1-6烷基、-C(O)N(C1-6烷基)(C1-6烷基)、-SO2C1-6烷基、-S(O)烷基、C6-10芳基、5-10元杂芳基、C3-10环烷基、3-10元杂环烷基、亚烷基芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基、C1-6羟基烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基SH、C1-6亚烷基SC1-6烷基、C1-6亚烷基NH2、C1-6亚烷基NHC1-6烷基和C1-6亚烷基N(C1-6烷基)(C1-6烷基)中的取代基取代；R 18 is selected from H, alkyl, C 1-6 haloalkyl, -C(O) alkyl, -C(O) haloalkyl, cycloalkyl, 3-heterocycloalkyl, aryl, heteroaryl, ylidene Alkylaryl, alkyleneheteroaryl, alkylenecycloalkyl and alkyleneheterocycloalkyl, optionally, the alkyl, C 1-6 haloalkyl, -C(O)alkyl , -C(O)haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylenearyl, alkyleneheteroaryl, alkylenecycloalkyl and alkyleneheterocycle Each alkyl group is independently selected from one or more halogen, -CN, alkyl, haloalkyl, -OH, -SH, alkoxy, -O haloalkyl, -S alkyl, -S haloalkyl, -NH 2. -NH alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -C(O) alkyl, -C(O) haloalkyl, -C(O)OH, - C(O)O alkyl, -C(O)NH 2 , -C(O)NHC 1-6 alkyl, -C(O)N(C 1-6 alkyl)(C 1-6 alkyl) , -SO 2 C 1-6 alkyl, -S(O) alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl , alkylene aryl, C 1-6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl, C 1-6 hydroxyl Alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene SH, C 1-6 alkylene SC 1-6 alkyl, C 1-6 alkylene NH 2 , Substituents in C 1-6 alkylene NHC 1-6 alkyl and C 1-6 alkylene N(C 1-6 alkyl) (C 1-6 alkyl);
    R19和R20各自独立地选自H、烷基、卤代烷基、-C(O)烷基、-C(O)氟烷基、环烷基、杂环烷基、杂芳基、芳基、亚烷基芳基、亚烷基环烷基、亚烷基杂芳基、亚烷基杂环烷基、-C(O)芳基、-C(O)环烷基、-C(O)杂芳基、-C(O)杂环烷基、-C(O)OC1-6烷基、-C(O)OC1-6卤代烷基、-C(O)OC6-10芳基、-C(O)OC3-10环烷基、-C(O)OC4-10杂芳基、-C(O)OC3-15杂环烷基、-C(O)NH烷基、-C(O)NHC1-6卤代烷基、-C(O)NHC6-10芳基、-C(O)NHC3-10环烷基、-C(O)NHC4-10杂芳基、-C(O)NHC3-15杂环烷基、-SO2C1-6烷基、-SO2C1-6卤代烷基、-SO2C6-10芳基、-SO2C3-10环烷基、-SO2C4-10杂芳基、和-SO2C3-15杂环烷基，任选地，所述烷基、卤代烷基、-C(O)烷基、-C(O)氟烷基、环烷基、杂环烷基、杂芳基、芳基、亚烷基芳基、亚烷基环烷基、亚烷基杂芳基、亚烷基杂环烷基、-C(O)芳基、-C(O)环烷基、-C(O)杂芳基、-C(O)杂环烷基、-C(O)OC1-6烷基、-C(O)OC1-6卤代烷基、-C(O)OC6-10芳基、-C(O)OC3-10环烷基、-C(O)OC4-10杂芳基、-C(O)OC3-15杂环烷基、-C(O)NH烷基、-C(O)NHC1-6卤代烷基、-C(O)NHC6-10芳基、-C(O)NHC3-10环烷基、-C(O)NHC4-10杂芳基、-C(O)NHC3-15杂环烷基、-SO2C1-6烷基、-SO2C1-6卤代烷基、-SO2C6-10芳基、-SO2C3-10环烷基、-SO2C4-10杂芳基、和-SO2C3-15杂环烷基被一个或多个独立地选自卤素、-CN、烷基、卤代烷基、-OH、-SH、烷氧基、卤代烷氧基、-SC1-6烷基、-SC1-6卤代烷基、-NH2、烷基氨基、烷基酰基、卤代烷基酰基、-C(O)OH、烷氧基酰基、-C(O)NH2、烷基氨基酰基、-SO2C1-6烷基、-S(O)C1-6烷基、C6-10芳基、杂芳基、环烷基、杂环烷基、-C1-6亚烷基芳基、C1-6亚烷基环烷基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基、羟基烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基SH、C1-6亚烷基SC1-6烷基、C1-6亚烷基NH2、C1-6亚烷基NHC1-6烷基和-C1-6亚烷基N(C1-6烷基)(C1-6烷基)中的一个或多取代基取代；或者，R19和R20与它们所连接的氮原子或C原子一起形成3-10元杂环烷基或环烷基，所述3-10元杂环烷基和环烷基是未取代的或被一个或多个选自卤素、-CN、硝基、C1-6烷基、C1-6卤代烷基、-OH、SH、-OC1-6烷基、-OC1-6卤代烷基、-SC1-6烷基、-SC1-6卤代烷基、-NH2、-NHC1-6烷基、-N(C1-6烷基)(C1-6烷基)、-C(O)C1-6烷基、-C(O)C1-6氟烷基、-C(O)OH、-C(O)OC1-6烷基、-C(O)NH2、-C(O)NHC1-6烷基、-C(O)N(C1-6烷基)(C1-6烷基)、-SO2C1-6烷基、-S(O)C1-6烷基、C6-10芳基、5-10元杂芳基、C3-10环烷基、3-15元杂环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基、C1-6亚烷基OH、C1-6亚烷基OC1-6烷基、C1-6亚烷基SH、C1-6亚烷基SC1-6烷基、C1-6亚烷基NH2、C1-6亚烷基NHC1-6烷基和C1-6亚烷基N(C1-6烷基)(C1-6烷基)中的取代基取代；和R 19 and R 20 are each independently selected from H, alkyl, haloalkyl, -C(O)alkyl, -C(O)fluoroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl , alkylene aryl, alkylenecycloalkyl, alkyleneheteroaryl, alkyleneheterocycloalkyl, -C(O)aryl, -C(O)cycloalkyl, -C(O )Heteroaryl, -C(O)heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)OC 1-6 haloalkyl, -C(O)OC 6-10 aryl , -C(O)OC 3-10 cycloalkyl, -C(O)OC 4-10 heteroaryl, -C(O)OC 3-15 heterocycloalkyl, -C(O)NH alkyl, -C(O)NHC 1-6 haloalkyl, -C(O)NHC 6-10 aryl, -C(O)NHC 3-10 cycloalkyl, -C(O)NHC 4-10 heteroaryl, -C(O)NHC 3-15 heterocycloalkyl, -SO 2 C 1-6 alkyl, -SO 2 C 1-6 haloalkyl, -SO 2 C 6-10 aryl, -SO 2 C 3- 10 cycloalkyl, -SO 2 C 4-10 heteroaryl, and -SO 2 C 3-15 heterocycloalkyl, optionally, the alkyl, haloalkyl, -C(O)alkyl, - C(O)fluoroalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, alkylenearyl, alkylenecycloalkyl, alkyleneheteroaryl, alkyleneheterocycloalkyl base, -C(O)aryl, -C(O)cycloalkyl, -C(O)heteroaryl, -C(O)heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)OC 1-6 haloalkyl, -C(O)OC 6-10 aryl, -C(O)OC 3-10 cycloalkyl, -C(O)OC 4-10 heteroaryl, -C(O)OC 3-15 heterocycloalkyl, -C(O)NH alkyl, -C(O)NHC 1-6 haloalkyl, -C(O)NHC 6-10 aryl, -C( O)NHC 3-10 cycloalkyl, -C(O)NHC 4-10 heteroaryl, -C(O)NHC 3-15 heterocycloalkyl, -SO 2 C 1-6 alkyl, -SO 2 C 1-6 haloalkyl, -SO 2 C 6-10 aryl, -SO 2 C 3-10 cycloalkyl, -SO 2 C 4-10 heteroaryl, and -SO 2 C 3-15 heterocycloalkyl The group is one or more independently selected from halogen, -CN, alkyl, haloalkyl, -OH, -SH, alkoxy, haloalkoxy, -SC 1-6 alkyl, -SC 1-6 haloalkyl , -NH 2 , alkylamino, alkylaminoacyl, haloalkylacyl, -C(O)OH, alkoxyacyl, -C(O)NH 2 , alkylaminoacyl, -SO 2 C 1-6 alkyl base, -S(O)C 1-6 alkyl, C 6-10 aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -C 1-6 alkylene aryl, C 1-6 ylene Alkylcycloalkyl, C 1-6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl, hydroxyalkyl, C 1-6 alkylene OC 1-6 alkyl, C 1- 6 alkylene SH, C 1-6 alkylene SC 1-6 alkyl, C 1-6 alkylene NH 2 , C 1-6 alkylene NHC 1-6 alkyl and -C 1-6 alkylene Alkyl N (C 1-6 alkyl) (C 1-6 alkyl) is substituted with one or more substituents; alternatively, R 19 and R 20 together with the nitrogen atom or C atom to which they are attached form 3-10 One-membered heterocycloalkyl or cycloalkyl, the 3-10-membered heterocycloalkyl and cycloalkyl are unsubstituted or substituted by one or more members selected from halogen, -CN, nitro, C 1-6 alkyl , C 1-6 haloalkyl, -OH, SH, -OC 1-6 alkyl, -OC 1-6 haloalkyl, -SC 1-6 alkyl, -SC 1-6 haloalkyl, -NH 2 , - NHC 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -C(O)C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl , -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH 2 , -C(O)NHC 1-6 alkyl, -C(O)N(C 1- 6 alkyl) (C 1-6 alkyl), -SO 2 C 1-6 alkyl, -S(O)C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 alkylene, C 6-10 aryl, C 1-6 alkylene, C 3-10 cycloalkyl, C 1-6 Alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl, C 1-6 alkylene OH, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene SH , C 1-6 alkylene SC 1-6 alkyl, C 1-6 alkylene NH 2 , C 1-6 alkylene NHC 1-6 alkyl and C 1-6 alkylene N (C 1 -6 alkyl) (C 1-6 alkyl) substituent substitution; and
    R21选自H、羟基、氨基、烷基、烷氧基和卤素。R 21 is selected from H, hydroxyl, amino, alkyl, alkoxy and halogen.
  2. 如权利要求1所述的化合物或其可药用盐，其中，The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein,
    R1A是未取代的或取代的含有至少一个氮原子的3-15元杂环烷基，所述3-15元杂环烷基为单杂环烷基、稠环杂环烷基、螺环杂环烷基或桥环杂环烷基，所述取代的含有至少一个氮原子的3-15元杂环烷基被选自下述的一个、两个、三个或更多个取代基取代：卤素、C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C3-10杂环烷基、C6-10芳基、5-10元杂芳基、-OR9、-SR9、C1-6亚烷基-OR9、C1-6亚烷基-SR9、-NR10R11、C1-6亚烷基-CR9R10R11和C1-6亚烷基-NR10R11，其中任选地，所述C1-6烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、C1-6亚烷基、C3-10环烷基、C3-10杂环烷基、C6-10芳基、和5-10元杂芳基各自独立地被选自卤素、C1-6烷基、C1-6杂烷基、C1-6烷氧基、C1-6卤代烷基、羟基、C1-6羟烷基、氰基、氨基、硝基、C3-10环烷基、C3-10杂环烷基、C2-6烯基、C2-6炔基、C1-6烷基氨基、C1-6烷基酰基、C1-6烷基氧基酰基、C1-6烷基氨基酰基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；优选地，R1A是未取代的或或取代的含有至少一个氮原子的4-15元杂环烷基，所述4-15元杂环烷基为单杂环烷基、稠环杂环烷基、螺环杂环烷基或桥环杂环烷基，所述取代的含有至少一个氮原子的4-15元杂环烷基被选自下述的一个、两个、三个或更多个取代基取代：卤素、C1-6烷基、C1-6氟烷基、C3-6环烷基、C3-6杂环烷基、C6-10芳基、5-6元杂芳基、-OR9、-SR9、C1-6亚烷基OR9、C1-6亚烷基SR9、C1-6亚烷基-CR9R10R11、-NR10R11、和C1-6亚烷基NR10R11，其中，任选地，所述C1-6烷基、C1-6氟烷基、C3-6环烷基、C3-6杂环烷基、C6-10芳基、5-6元杂芳基和C1-6亚烷基，各自独立地被选自卤素、C1-3烷基、C1-3杂烷基、C1-3烷氧基、C1-3卤代烷基、羟基、C1-3羟烷基、氰基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C2-3烯基、C2-3炔基、C1-3烷基氨基、C1-3烷基酰基、C1-3烷基氧基酰基、C1-3烷基氨基酰基、C6-10芳基和5-6元杂芳基中的一个或多个取代基所取代；和/或R 1A is an unsubstituted or substituted 3-15-membered heterocycloalkyl group containing at least one nitrogen atom, and the 3-15-membered heterocycloalkyl group is a monoheterocycloalkyl group, a fused ring heterocycloalkyl group, or a spiro ring Heterocycloalkyl or bridged heterocycloalkyl, the substituted 3-15 membered heterocycloalkyl containing at least one nitrogen atom is substituted with one, two, three or more substituents selected from the following : Halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-10 cycloalkyl, C 3- 10 heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OR 9 , -SR 9 , C 1-6 alkylene -OR 9 , C 1-6 alkylene -SR 9 , -NR 10 R 11 , C 1-6 alkylene -CR 9 R 10 R 11 and C 1-6 alkylene -NR 10 R 11 , wherein optionally, the C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylene, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are each independently selected from halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxyl , C 1-6 hydroxyalkyl, cyano, amino, nitro, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1 One of -6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkyloxyacyl, C 1-6 alkylaminoacyl, C 6-10 aryl and 5-10 membered heteroaryl or substituted by multiple substituents; preferably, R 1A is an unsubstituted or substituted 4-15-membered heterocycloalkyl group containing at least one nitrogen atom, and the 4-15-membered heterocycloalkyl group is a single heterocyclic ring Alkyl, fused ring heterocycloalkyl, spiro ring heterocycloalkyl or bridged ring heterocycloalkyl, the substituted 4-15 membered heterocycloalkyl containing at least one nitrogen atom is selected from the following one, Substitution of two, three or more substituents: halogen, C 1-6 alkyl, C 1-6 fluoroalkyl, C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 6- 10 aryl group, 5-6 membered heteroaryl group, -OR 9 , -SR 9 , C 1-6 alkylene group OR 9 , C 1-6 alkylene group SR 9 , C 1-6 alkylene group -CR 9 R 10 R 11 , -NR 10 R 11 , and C 1-6 alkylene NR 10 R 11 , wherein, optionally, the C 1-6 alkyl, C 1-6 fluoroalkyl, C 3- 6 cycloalkyl, C 3-6 heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl and C 1-6 alkylene, each independently selected from halogen, C 1-3 alkyl Base, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 haloalkyl , hydroxyl, C 1-3 hydroxyalkyl, cyano, amino, nitro, C 3-6 cycloalkyl , 3-6 membered heterocycloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkylamino, C 1-3 alkyl acyl, C 1-3 alkyloxyacyl, Substituted with one or more substituents of C 1-3 alkylaminoacyl, C 6-10 aryl and 5-6 membered heteroaryl; and/or
    R2A是未取代的或取代的C6-10芳基、5-10元杂芳基或3-10元杂环烷基，所述5-10元杂芳基和3-10元杂环烷各自独立地含有1、2或3个各自独立选自N、O或S的杂原子，任选地，所述未取代的或取代的C6-10芳基和5-10元杂芳基各自独立地稠和于3-15元的杂环烷基或环烷基，所述取代的C6-10芳基、5-10元杂芳基和3-10元杂环烷基各自独立地被选自下述的一个、两个、三个、四个或更多个取代基取代：卤素、＝O、＝S、C1-6烷基、C1-6卤代烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、C3-10环烷基、3-10元杂环基、C6-10芳基、5-10元杂芳基、-OR12、-SR12、C1-6亚烷基-OR12、C1-6亚烷基-SR12、-NR13R14、C1-6亚烷基-CR12R13R14和C1-6亚烷基-NR13R14，其中任选地，所述C1-6烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、C3-10环烷基、C3-10杂环基、C6-10芳基、C1-6亚烷基和5-10元杂芳基各自独立地被选自卤素、C1-6烷基、C1-6杂烷基、C1-6烷氧基、C1-6卤代烷基、羟基、C1-6羟烷基、氰基、氨基、硝基、C3-10环烷基、3-10元杂环基、C2-6烯基、C2-6炔基、C1-6烷基氨基、C1-6烷基酰基、C1-6烷基氧基酰基、C1-6烷基氨基酰基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；优选地R2A是未取代的或取代的C6-10芳基、5-6元杂芳基或3-6元杂环烷基，所述5-6元杂芳基和3-6元杂环烷基各自独立地含有1、2或3个各自独立选自N、O或S的杂原子，任选地，所述未取代的或取代的C6-10芳基和5-6元杂芳基各自独立地稠和于3、4、5、6、7、8或9元杂环烷基或环烷基，所述取代的C6-10芳基、5-6元杂芳基和3-6元杂环烷基各自独立地被选自下述的一个、两个、三个、四个或更多个取代基取代：F、Cl、Br、I、＝O、＝S、C1-6烷基、C1-6氟代烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-OR12、-SR12、C1-6亚烷基-OR12、C1-6亚烷基-SR12、-NR13R14、C1-6亚烷基-CR12R13R14和C1-6亚烷基-NR13R14，其中任选地，所述C1-6烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6元杂环基、C6-10芳基、和5-6元杂芳基各自独立地被选自F、Cl、Br、I、C1-6烷基、C1-6杂烷基、C1-6烷氧基、C1-6氟代烷基、羟基、C1-6羟烷基、氰基、氨基、硝基、C3-6环烷基、C3-6杂环基、C2-6烯基、C2-6炔基、C1-6烷基氨基、C1-6烷基酰基、C1-6烷基氧基酰基、C1-6烷基氨基酰基、C6-10芳基和5-6元杂芳基中的一个或多个取代基所取代，且当R2A是取代的C6-10芳基时，所述取代的C6-10杂芳基不被＝O或＝S取代；和/或R 2A is unsubstituted or substituted C 6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocycloalkyl, the 5-10 membered heteroaryl and 3-10 membered heterocycloalkyl Each independently contains 1, 2 or 3 heteroatoms each independently selected from N, O or S, optionally, each of the unsubstituted or substituted C 6-10 aryl and 5-10 membered heteroaryl Independently fused to a 3-15-membered heterocycloalkyl or cycloalkyl group, the substituted C 6-10 aryl, 5-10-membered heteroaryl and 3-10-membered heterocycloalkyl are each independently Substituted with one, two, three, four or more substituents selected from the following: halogen, =O, =S, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hetero Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -OR 12 , -SR 12 , C 1-6 alkylene -OR 12 , C 1-6 alkylene -SR 12 , -NR 13 R 14 , C 1-6 alkylene -CR 12 R 13 R 14 and C 1-6 alkylene-NR 13 R 14 , wherein optionally, the C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -10 cycloalkyl, C 3-10 heterocyclyl, C 6-10 aryl, C 1-6 alkylene and 5-10 membered heteroaryl are each independently selected from halogen, C 1-6 alkyl , C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 haloalkyl , hydroxyl, C 1-6 hydroxyalkyl, cyano, amino, nitro, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkyloxyacyl, C 1 -6 alkylaminoacyl, C 6-10 aryl and 5-10 membered heteroaryl are substituted with one or more substituents; preferably R 2A is unsubstituted or substituted C 6-10 aryl, 5-6 membered heteroaryl or 3-6 membered heterocycloalkyl, the 5-6 membered heteroaryl and 3-6 membered heterocycloalkyl each independently contain 1, 2 or 3 each independently selected from N , O or S heteroatoms, optionally, the unsubstituted or substituted C 6-10 aryl group and 5-6 membered heteroaryl group are each independently fused to 3, 4, 5, 6, 7, 8- or 9-membered heterocycloalkyl or cycloalkyl, the substituted C 6-10 aryl, 5-6-membered heteroaryl and 3-6-membered heterocycloalkyl are each independently selected from one of the following , two, three, four or more substituents substituted: F, Cl, Br, I, =O, =S, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1- 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -OR 12 , -SR 12 , C 1-6 alkylene -OR 12 , C 1-6 alkylene -SR 12 , -NR 13 R 14 , C 1-6 alkylene -CR 12 R 13 R 14 and C 1-6 alkylene-NR 13 R 14 , wherein optionally, the C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, and 5-6 membered heteroaryl are each independently selected from F, Cl, Br, I, C 1-6 alkyl Base, C 1-6 heteroalkyl group, C 1-6 alkoxy group, C 1-6 fluoroalkyl group, hydroxyl group, C 1-6 hydroxyalkyl group, cyano group, amino group, nitro group, C 3-6 ring Alkyl, C 3-6 heterocyclyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylamino, C 1-6 alkyl acyl, C 1-6 alkyloxyacyl , C 1-6 alkylaminoacyl, C 6-10 aryl and 5-6 membered heteroaryl are substituted with one or more substituents, and when R 2A is a substituted C 6-10 aryl, The substituted C 6-10 heteroaryl group is not substituted by =O or =S; and/or
    R3A是未取代的或取代的6至14元芳基、5至14元杂芳基、3至15元环烷基或3至15元杂环烷基，所述未取代的或取代的3至15元环烷基和3至15元杂环烷基各自独立地为单环、稠环、桥环、或螺环基团，所述未取代的或取代的6至14元芳基和5至14元杂芳基各自独立地为单环或稠环基团，任选地，所述未取代的或取代的6至14元芳基和5至14元杂芳基各自独立地稠和于3-6元杂环烷基或3-6元环烷基，任选地，所述取代的6至14元芳基、5至14杂芳基、3至15元环烷基和3至15元杂环烷基各自独立地被选自下述的一个或更多个取代基取代：卤素、-CN、C1-6烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、＝O、＝S、OR15、-SR15、-SO2R15、-NR16R17、C1-6亚烷基-CR15R16R17、R4A、C1-6亚烷基R4A、C2-6亚烯基R4A、C2-6亚炔基R4A、-OC1-6亚烷基R4A、-SC1-6亚烷基R4A、C1-6亚烷基NR16R17、C1-6亚烷基OR15、C1-6亚烷基SR15、-OC1-6亚烷基NR16R17、-SC1-6亚烷基NR16R17、-OC1-6亚烷基OR15、SC1-6亚烷基OR15、-OC1-6亚烷基SR15、SC1-6亚烷基SR15、-C(O)OR15、-C(O)R15、-C(S)OR15、-C(S)NR16R17和-C(O)NR16R17，其中任选地，所述C1-6烷基、C1-6杂烷基、C2-6烯基、C2-6炔基、和C1-6亚烷基各自独立地被选自卤素、C1-6烷基、C1-6杂烷基、C1-6烷氧基、C1-6卤代烷基、羟基、C1-6羟烷基、氰基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C2-6烯基、C2-6炔基、C1-6烷基氨基、C1-6烷基酰基、C1-6烷基氧基酰基、C1-6烷基氨基酰基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；优选地，R3A选自未取代的或被一个或多个选自卤素、-CN、C1-6烷基、C1-6氟烷基、＝O、＝S、OR15、-SR15、-SO2R15、-NR16R17、C1-6亚烷基-CR15R16R17、R4A、C1-6亚烷基R4A、C2-6亚烯基R4A、-OC1-6亚烷基R4A、-SC1-6亚烷基R4A、C1-6亚烷基N R16R17、C1-6亚烷基OR15、C1-6亚烷基SR15、-OC1-6亚烷基NR16R17、-SC1-6亚烷基N R16R17、-OC1-6亚烷基OR15、SC1-6亚烷基OR15、-OC1-6亚烷基SR15、SC1-6亚烷基SR15、-C(O)OR15、-C(O)R15、-C(S)OR15、-C(S)N R16R17和-C(O)N R16R17中的取代基取代的C6-10芳基、5-10元杂芳基、C4-15环烷基和4-15元杂环烷基，所述C4-15环烷基和4至15元杂环烷基各自独立地为单环、稠环、桥环、或螺环基团，所述C6-10芳基和5至10元杂芳基各自独立地为单环或稠环基团，任选地，所述C6-10芳基和5至10元杂芳基各自独立地稠和于5-6元杂环烷基或5-6元环烷基；和/或R 3A is an unsubstituted or substituted 6- to 14-membered aryl group, a 5- to 14-membered heteroaryl group, a 3- to 15-membered cycloalkyl group, or a 3 to 15-membered heterocycloalkyl group, and the unsubstituted or substituted 3A to 15-membered cycloalkyl and 3 to 15-membered heterocycloalkyl are each independently a monocyclic, fused ring, bridged ring, or spirocyclic group, and the unsubstituted or substituted 6 to 14-membered aryl and 5 to 14-membered heteroaryl groups are each independently a monocyclic or fused ring group, optionally, the unsubstituted or substituted 6- to 14-membered aryl groups and 5- to 14-membered heteroaryl groups are each independently fused with 3-6 membered heterocycloalkyl or 3-6 membered cycloalkyl, optionally, the substituted 6 to 14 membered aryl, 5 to 14 heteroaryl, 3 to 15 membered cycloalkyl and 3 to 15 Each membered heterocycloalkyl group is independently substituted with one or more substituents selected from the following: halogen, -CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, =O, =S, OR 15 , -SR 15 , -SO 2 R 15 , -NR 16 R 17 , C 1-6 alkylene -CR 15 R 16 R 17 , R 4A , C 1-6 alkylene R 4A , C 2-6 alkenylene R 4A , C 2-6 alkynylene R 4A , -OC 1-6 alkylene R 4A , -SC 1-6 alkylene R 4A , C 1-6 alkylene NR 16 R 17 , C 1-6 alkylene OR 15 , C 1-6 alkylene SR 15 , -OC 1-6 alkylene NR 16 R 17 , -SC 1-6 alkylene NR 16 R 17 , -OC 1-6 alkylene OR 15 , SC 1-6 alkylene OR 15 , -OC 1-6 alkylene SR 15 , SC 1-6 Alkylene SR 15 , -C(O)OR 15 , -C(O)R 15 , -C(S)OR 15 , -C(S)NR 16 R 17 and -C(O)NR 16 R 17 , wherein optionally, the C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 alkylene groups are each independently Selected from halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxyl, C 1-6 hydroxyalkyl, cyano, amino, Nitro, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylamino, C 1-6 alkyl acyl, Substituted with one or more substituents among C 1-6 alkyloxyacyl, C 1-6 alkylaminoacyl, C 6-10 aryl and 5-10 membered heteroaryl; preferably, R 3A is selected Unsubstituted or selected from one or more halogen, -CN, C 1-6 alkyl, C 1-6 fluoroalkyl, =O, =S, OR 15 , -SR 15 , -SO 2 R 15 , -NR 16 R 17 , C 1-6 alkylene -CR 15 R 16 R 17 , R 4A , C 1-6 alkylene R 4A , C 2-6 alkenylene R 4A , -OC 1-6 Alkylene R 4A , -SC 1-6 alkylene R 4A , C 1-6 alkylene NR 16 R 17 , C 1-6 alkylene OR 15 , C 1-6 alkylene SR 15 , - OC 1-6 alkylene NR 16 R 17 , -SC 1-6 alkylene NR 16 R 17 , -OC 1-6 alkylene OR 15 , SC 1-6 alkylene OR 15 , -OC 1- 6 alkylene SR 15 , SC 1-6 alkylene SR 15 , -C(O)OR 15 , -C(O)R 15 , -C(S)OR 15 , -C(S)N R 16 R 17 and C 6-10 aryl, 5-10 membered heteroaryl, C 4-15 cycloalkyl and 4-15 membered heterocycloalkyl substituted by the substituents in -C(O)N R 16 R 17 , the C 4-15 cycloalkyl and 4 to 15 membered heterocycloalkyl are each independently a monocyclic, condensed ring, bridged ring, or spirocyclic group, and the C 6-10 aryl and 5 to 10 membered heteroaromatic Each group is independently a monocyclic or condensed ring group. Optionally, the C 6-10 aryl group and the 5- to 10-membered heteroaryl group are each independently fused to a 5-6-membered heterocycloalkyl group or a 5- 6-membered cycloalkyl; and/or
    R4A选自未取代的或被一个或多个独立地选自卤素、-CN、-OR18、-SR18、-NR19R20、C1-6氟烷基、C1-6烷基、-C(O)R18、-C(O)OR18、-C(O)NR19R20、-S(O)C1-6烷基、-SO2C1-6烷基、C6-10芳基、5-10元杂芳基、C3-10环烷基、3-15元杂环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C3-10杂芳基、C1-6亚烷基杂环烷基、C1-6亚烷基R18、C1-6亚烷基OR18、C1-6亚烷基SR18、C1-6亚烷基-CR18R19R20和C1-6亚烷基NR19R20中的取代基取代的C3-10环烷基、4-15元杂环烷基、5-10元杂芳基和C6-10芳基，所述C3-10环烷基和4至15元杂环烷基各自独立地为单环、稠环、桥环、或螺环基团，所述C6-10芳基和5至10元杂芳基各自独立地为单环或稠环基团；和/或R 4A is selected from unsubstituted or one or more independently selected from halogen, -CN, -OR 18 , -SR 18 , -NR 19 R 20 , C 1-6 fluoroalkyl, C 1-6 alkyl , -C(O)R 18 , -C(O)OR 18 , -C(O)NR 19 R 20 , -S(O)C 1-6 alkyl, -SO 2 C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 alkylene, C 6-10 aryl, C 1-6 alkylene Alkyl C 3-10 cycloalkyl, C 1-6 alkylene C 3-10 heteroaryl, C 1-6 alkylene heterocycloalkyl, C 1-6 alkylene R 18 , C 1- C substituted by substituents in 6 alkylene OR 18 , C 1-6 alkylene SR 18 , C 1-6 alkylene -CR 18 R 19 R 20 and C 1-6 alkylene NR 19 R 20 3-10 cycloalkyl, 4-15 membered heterocycloalkyl, 5-10 membered heteroaryl and C 6-10 aryl, each of the C 3-10 cycloalkyl and 4 to 15 membered heterocycloalkyl is independently a monocyclic, fused ring, bridged ring, or spirocyclic group, and the C 6-10 aryl group and the 5 to 10-membered heteroaryl group are each independently a monocyclic or fused ring group; and/or
    R9和R12每次出现时，各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、-C(O)C1-6烷基、-C(O)C1-6卤代烷基、-C(O)OC1-6烷基、-C(O)NHC1-6烷基、-SO2C1-6烷基、-SO2HNC1-6烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基C3-10杂环烷基和C1-6亚烷基C3-10环烷基，任选地，所述C1-6烷基、C3-10环烷基、C3-10杂环烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基C3-6杂环烷基和C1-6亚烷基C3-6环烷基各自独立被选自卤素、C1-6烷基、C1-6杂烷基、C1-6烷氧基、C1-6卤代烷基、羟基、C1-6羟烷基、氰基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；优选地，R9和R12每次出现时各自独立选自H、C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、C(O)C1-6氟烷基、C3-6环烷基、和3-6元杂环烷基，任选地，所述C1-6烷基、C3-6环烷基和3-6元杂环烷基各自独立地被选自F、Cl、Br、I、C1-C3烷基、C1-C3烷氧基、C1-C3卤代烷基、羟基、和C1-C3羟烷基中的一个或多个取代基所取代；和/或Each time R 9 and R 12 appear, they are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, -C (O)C 1-6 alkyl, -C(O)C 1-6 haloalkyl, -C(O)OC 1-6 alkyl, -C(O)NHC 1-6 alkyl, -SO 2 C 1-6 alkyl, -SO 2 HNC 1-6 alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene C 3-10 heterocycloalkyl and C 1-6 alkylene C 3-10 cycloalkyl, optionally, the C 1-6 Alkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1 -6 alkylene C 4-10 heteroaryl, C 1-6 alkylene C 3-6 heterocycloalkyl and C 1-6 alkylene C 3-6 cycloalkyl are each independently selected from halogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxyl, C 1-6 hydroxyalkyl, cyano, amino, nitro, C 3 -Substituted with one or more substituents of 6- cycloalkyl, 3-6-membered heterocycloalkyl, C 6-10 aryl and 5-10-membered heteroaryl; preferably, R 9 and R 12 each When present, each is independently selected from H, C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O)C 1-6 alkyl, C(O)C 1-6 fluoroalkyl, C 3- 6 cycloalkyl, and 3-6 membered heterocycloalkyl, optionally, the C 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are each independently selected from One or more of F, Cl, Br, I, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, hydroxyl, and C 1 -C 3 hydroxyalkyl Substituted by substituents; and/or
    R10、R11、R13、和R14每次出现时各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、-C(O)C1-6烷基、-C(O)C1-6卤代烷基、-C(O)OC1-6烷基、-C(O)NHC1-6烷基、-SO2C1-6烷基、-SO2HNC1-6烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基杂环烷基和C1-6亚烷基C3-环烷基，任选地，所述C1-6烷基、C3-10环烷基、3-6元杂环烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基杂环烷基和C1-6亚烷基C3-6环烷基各自独立地被选自卤素、C1-6烷基、C1-6杂烷基、C1-6烷氧基、C1-6卤代烷基、羟基、C1-6羟烷基、氰基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；或者，R10和R11与其相连的C或N原子一起各自独立地形成未取代的或被一个或多个选自卤素、C1-3杂烷基、C1-3烷氧基、C1-3羟烷基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C6-10芳基、5-10元杂芳基、-CN、-OH、C1-3烷基、OC1-3烷基、C1-3氟烷基、-OC1-3氟烷基、-C(O)C1-3烷基、-C(O)C1-3氟烷基、-C(O)C1-3烷基、-C(O)NHC1-3烷基、-SO2C1-3烷基、-SO2HNC1-3烷基、C1-3亚烷基OC1-3烷基、C1-3亚烷基C6-10芳基、C1-3亚烷基C4-10杂芳基、C1-3亚烷基C3-6杂环烷基和C1-3亚烷基C3-6环烷基中的取代基取代的3-6元环烷基或3-6元杂环烷基；或者，R13和R14与其相连的C或N原子一起各自独立地形成未取代的或被一个或多个选自卤素、C1-3杂烷基、C1-3烷氧基、C1-3羟烷基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C6-10芳基、5-10元杂芳基、-CN、-OH、C1-3烷基、OC1-3烷基、C1-3氟烷基、-OC1-3氟烷基、-C(O)C1-3烷基、-C(O)C1-3氟烷基、-C(O)C1-3烷基、-C(O)NHC1-3烷基、-SO2C1-3烷基、-SO2HNC1-3烷基、C1-3亚烷基OC1-3烷基、C1-3亚烷基C6-10芳基、C1-3亚烷基C4-10杂芳基、C1-3亚烷基C3-6杂环烷基和C1-3亚烷基C3-6环烷基中的取代基取代的3-6元环烷基或3-6元杂环烷基；和/或R 10 , R 11 , R 13 , and R 14 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered hetero Cycloalkyl, -C(O)C 1-6 alkyl, -C(O)C 1-6 haloalkyl, -C(O)OC 1-6 alkyl, -C(O)NHC 1-6 alkyl base, -SO 2 C 1-6 alkyl, -SO 2 HNC 1-6 alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene heterocycloalkyl and C 1-6 alkylene C 3- cycloalkyl, optionally, the C 1- 6 alkyl, C 3-10 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene heterocycloalkyl and C 1-6 alkylene C 3-6 cycloalkyl are each independently selected from halogen, C 1 -6 alkyl, C 1-6 heteroalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxyl, C 1-6 hydroxyalkyl, cyano, amino, nitro, C 3-6 Substituted with one or more substituents in cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl; alternatively, R 10 and R 11 are connected to C or N atoms together independently form unsubstituted or substituted by one or more selected from halogen, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, amino, nitro, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OH, C 1-3 alkyl, OC 1-3 alkyl , C 1-3 fluoroalkyl, -OC 1-3 fluoroalkyl, -C(O)C 1-3 alkyl, -C(O)C 1-3 fluoroalkyl, -C(O)C 1 -3 alkyl, -C(O)NHC 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 HNC 1-3 alkyl, C 1-3 alkylene OC 1-3 alkyl , C 1-3 alkylene C 6-10 aryl, C 1-3 alkylene C 4-10 heteroaryl, C 1-3 alkylene C 3-6 heterocycloalkyl and C 1-3 3-6-membered cycloalkyl or 3-6-membered heterocycloalkyl substituted by substituents in alkylene C 3-6 cycloalkyl; alternatively, R 13 and R 14 are each independent together with the C or N atom to which they are connected. Form unsubstituted or by one or more selected from halogen, C 1-3 heteroalkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, amino, nitro, C 3-6 cycloalkyl Base, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -CN, -OH, C 1-3 alkyl, OC 1-3 alkyl, C 1-3 Fluoroalkyl, -OC 1-3 fluoroalkyl, -C(O)C 1-3 alkyl, -C(O)C 1-3 fluoroalkyl, -C(O)C 1-3 alkyl, -C(O)NHC 1-3 alkyl, -SO 2 C 1-3 alkyl, -SO 2 HNC 1-3 alkyl, C 1-3 alkyleneOC 1-3 alkyl, C 1-3 Alkylene C 6-10 aryl, C 1-3 alkylene C 4-10 heteroaryl, C 1-3 alkylene C 3-6 heterocycloalkyl and C 1-3 alkylene C 3 -3-6 -membered cycloalkyl or 3-6-membered heterocycloalkyl substituted by substituents in the 6-cycloalkyl group; and/or
    R15每次出现时，各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、-C(O)C1-6烷基、-C(O)C1-6卤代烷基、-C(O)OC1-6烷基、-C(O)NHC1-6烷基、-SO2C1-6烷基、-SO2HNC1-6烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基杂环烷基和C1-6亚烷基C3-10环烷基，任选地，所述C1-6烷基、C3-10环烷基、3-10元杂环烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基C3-10杂环烷基和C1-6亚烷基C3-10环烷基被选自卤素、C1-6烷基、C1-6杂烷基、C1-6烷氧基、C1-6卤代烷基、羟基、C1-6羟烷基、氰基、氨基、硝基、C3-6环烷基、C3-6杂环烷基、C6-10芳基和C5-10杂芳基中的一个或多个取代基所取代；优选地，R15选自H、C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、-C(O)C1-6氟烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基、5-10元杂芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基和C1-6亚烷基C3-10杂环烷基，任选地，所述C1-6烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基、5-10元杂芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基和C1-6亚烷基C3-10杂环烷基各自被选自F、Cl、Br、I、C1-C3烷基、C1-C3烷氧基、C1-C3卤代烷基、羟基、C1-C3羟烷基、氰基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；和/或Each time R 15 appears, it is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, -C(O) C 1-6 alkyl, -C(O)C 1-6 haloalkyl, -C(O)OC 1-6 alkyl, -C(O)NHC 1-6 alkyl, -SO 2 C 1-6 Alkyl, -SO 2 HNC 1-6 alkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4 -10 heteroaryl, C 1-6 alkylene heterocycloalkyl and C 1-6 alkylene C 3-10 cycloalkyl, optionally, the C 1-6 alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4 -10 heteroaryl, C 1-6 alkylene C 3-10 heterocycloalkyl and C 1-6 alkylene C 3-10 cycloalkyl are selected from halogen, C 1-6 alkyl, C 1 -6 heteroalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, hydroxyl, C 1-6 hydroxyalkyl, cyano, amino, nitro, C 3-6 cycloalkyl, C 3- 6 heterocycloalkyl, C 6-10 aryl and C 5-10 heteroaryl are substituted with one or more substituents; preferably, R 15 is selected from H, C 1-6 alkyl, C 1- 6- fluoroalkyl, -C(O)C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6- 10 aryl, 5-10 membered heteroaryl, C 1-6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4 -10 heteroaryl and C 1-6 alkylene C 3-10 heterocycloalkyl, optionally, the C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl Base, C 6-10 aryl group, 5-10 membered heteroaryl group, C 1-6 alkylene group, C 3-10 cycloalkyl group, C 1-6 alkylene group, C 6-10 aryl group, C 1-6 Alkylene C 4-10 heteroaryl and C 1-6 alkylene C 3-10 heterocycloalkyl are each selected from F, Cl, Br, I, C 1 -C 3 alkyl, C 1 -C 3 alkoxy group, C 1 -C 3 haloalkyl group, hydroxyl group, C 1 -C 3 hydroxyalkyl group, cyano group, amino group, nitro group, C 3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C Substituted with one or more substituents in 6-10 aryl and 5-10 membered heteroaryl; and/or
    R16和R17各自独立地选自H、C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、-C(O)C1-6氟烷基、-C(O)C6-10芳基、-C(O)C3-10环烷基、-C(O)C4-10杂芳基、-C(O)C3-15杂环烷基、-C(O)OC1-6烷基、-C(O)OC1-6氟烷基、-C(O)OC6-10芳基、-C(O)OC3-10环烷基、-C(O)OC4-10杂芳基、-C(O)OC3-15杂环烷基、-C(O)NHC1-6烷基、-C(O)NHC1-6氟烷基、-C(O)NHC6-10芳基、-C(O)NHC3-10环烷基、-C(O)NHC4-10杂芳基、-C(O)NHC3-15杂环烷基、-SO2C1-6烷基、-SO2C1-6氟烷基、-SO2C6-10芳基、-SO2C3-10环烷基、-SO2C4-10杂芳基、-SO2C3-15杂环烷基、C3-10环烷基、3-15元杂环烷基、5-10元杂芳基、C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基和C1-6亚烷基C3-15杂环烷基，任选地，所述C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、-C(O)C1-6氟烷基、-C(O)C6-10芳基、-C(O)C3-10环烷基、-C(O)C4-10杂芳基、-C(O)C3-15杂环烷基、-C(O)OC1-6烷基、-C(O)OC1-6氟烷基、-C(O)OC6-10芳基、-C(O)OC3-10环烷基、-C(O)OC4-10杂芳基、-C(O)OC3-15杂环烷基、-C(O)NHC1-6烷基、-C(O)NHC1-6氟烷基、-C(O)NHC6-10芳基、-C(O)NHC3-10环烷基、-C(O)NHC4-10杂芳基、-C(O)NHC3-15杂环烷基、-SO2C1-6烷基、-SO2C1-6氟烷基、-SO2C6-10芳基、-SO2C3-10环烷基、-SO2C4-10杂芳基、-SO2C3-15杂环烷基、C3-10环烷基、3-15元杂环烷基、5-10元杂芳基、C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基和C1-6亚烷基C3-15杂环烷基各自独立被选自卤素、-CN、-OR18、-SR18、-NR19R20、C1-6烷基、C1-6卤代烷基、C1-6羟烷基、-C(O)R18、-C(O)OR18、-C(O)NR19R20、-S(O)C1-6烷基、-SO2C1-6烷基、C6-10芳基、5-10元杂芳基、C3-10环烷基、3-15元杂环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C4-10杂芳基、和C1-6亚烷基C3-15杂环烷基中的一个或多个取代基取代；或者，R16和R17与它们所连接的氮原子或C原子一起形成3-6元杂环烷基或环烷基，所述3-6元杂环烷基和环烷基是未取代的或被一个或多个独立地选自卤素、-CN、硝基、-OR18、-SR18、-NR19R20、C1-6烷基、C1-6杂烷基、C1-6羟烷基、-C(O)R18、-C(O)OR18、-C(O)NR19R20、-S(O)C1-6烷基、-SO2C1-6烷基、C6-10芳基、5-10元杂芳基、C3-10环烷基、3-10元杂环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基R18、C1-6亚烷基OR18、C1-6亚烷基SR18和C1-6亚烷基NR19R20中的取代基取代；和/或R 16 and R 17 are each independently selected from H, C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O)C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl base, -C(O)C 6-10 aryl, -C(O)C 3-10 cycloalkyl, -C(O)C 4-10 heteroaryl, -C(O)C 3-15 hetero Cycloalkyl, -C(O)OC 1-6 alkyl, -C(O)OC 1-6 fluoroalkyl, -C(O)OC 6-10 aryl, -C(O)OC 3-10 Cycloalkyl, -C(O)OC 4-10 heteroaryl, -C(O)OC 3-15 heterocycloalkyl, -C(O)NHC 1-6 alkyl, -C(O)NHC 1 -6 fluoroalkyl, -C(O)NHC 6-10 aryl, -C(O)NHC 3-10 cycloalkyl, -C(O)NHC 4-10 heteroaryl, -C(O)NHC 3-15 heterocycloalkyl, -SO 2 C 1-6 alkyl, -SO 2 C 1-6 fluoroalkyl, -SO 2 C 6-10 aryl, -SO 2 C 3-10 cycloalkyl, -SO 2 C 4-10 heteroaryl, -SO 2 C 3-15 heterocycloalkyl, C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6 -10 aryl, C 1-6 alkylene, C 3-10 cycloalkyl, C 1-6 alkylene, C 6-10 aryl, C 1-6 alkylene, C 4-10 heteroaryl and C 1-6 alkylene C 3-15 heterocycloalkyl, optionally, the C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O)C 1-6 alkyl, -C (O)C 1-6 fluoroalkyl, -C(O)C 6-10 aryl, -C(O)C 3-10 cycloalkyl, -C(O)C 4-10 heteroaryl, - C(O)C 3-15 heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)OC 1-6 fluoroalkyl, -C(O)OC 6-10 aryl, -C(O)OC 3-10 cycloalkyl, -C(O)OC 4-10 heteroaryl, -C(O)OC 3-15 heterocycloalkyl, -C(O)NHC 1-6 alkyl Base, -C(O)NHC 1-6 fluoroalkyl, -C(O)NHC 6-10 aryl, -C(O)NHC 3-10 cycloalkyl, -C(O)NHC 4-10 hetero Aryl, -C(O)NHC 3-15 heterocycloalkyl, -SO 2 C 1-6 alkyl, -SO 2 C 1-6 fluoroalkyl, -SO 2 C 6-10 aryl, -SO 2 C 3-10 cycloalkyl, -SO 2 C 4-10 heteroaryl, -SO 2 C 3-15 heterocycloalkyl, C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, 5 -10-membered heteroaryl, C 6-10 aryl, C 1-6 alkylene, C 3-10 cycloalkyl , C 1-6 alkylene, C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl and C 1-6 alkylene C 3-15 heterocycloalkyl are each independently selected from halogen, -CN, -OR 18 , -SR 18 , -NR 19 R 20 , C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, -C(O)R 18 , -C(O)OR 18 , -C(O)NR 19 R 20 , -S(O) C 1-6 alkyl, -SO 2 C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene C 4-10 heteroaryl, and C 1-6 alkylene Substituted with one or more substituents in the C 3-15 heterocycloalkyl group; alternatively, R 16 and R 17 together with the nitrogen atom or C atom to which they are attached form a 3-6 membered heterocycloalkyl or cycloalkyl group , the 3-6 membered heterocycloalkyl and cycloalkyl groups are unsubstituted or one or more independently selected from halogen, -CN, nitro, -OR 18 , -SR 18 , -NR 19 R 20 , C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 hydroxyalkyl, -C(O)R 18 , -C(O)OR 18 , -C(O)NR 19 R 20 , -S(O)C 1-6 alkyl, -SO 2 C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 3-10 membered hetero Cycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene C 4-10 heteroaryl, C 1 Substituent substitution in -6 alkylene R 18 , C 1-6 alkylene OR 18 , C 1-6 alkylene SR 18 and C 1-6 alkylene NR 19 R 20 ; and/or
    R18选自H、C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、-C(O)C1-6氟烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基、5-10元杂芳基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基C3-10环烷基和C1-6亚烷基C3-10杂环烷基，任选地，所述C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、-C(O)C1-6氟烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基、5-10元杂芳基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基C3-10环烷基和C1-6亚烷基C3-10杂环烷基各自独立地各被一个或多个选自卤素、-CN、C1-6烷基、C1-6氟烷基、-OH、-SH、-OC1-6烷基、-OC1-6氟烷基、-SC1-6烷基、-SC1-6氟烷基、-NH2、-NHC1-6烷基、-N(C1-6烷基)(C1-6烷基)、-C(O)C1-6烷基、-C(O)C1-6氟烷基、-C(O)OH、-C(O)OC1-6烷基、-C(O)NH2、-C(O)NHC1-6烷基、-C(O)N(C1-6烷基)(C1-6烷基)、-SO2C1-6烷基、-S(O)C1-6烷基、C6-10芳基、5-10元杂芳基、C3-10环烷基、3-10元杂环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基杂芳基、C1-6亚烷基杂环烷基、C1-6羟基烷基、C1-6亚烷基OC1-6烷基、C1-6亚烷基SH、C1-6亚烷基SC1-6烷基、C1-6亚烷基NH2、C1-6亚烷基NHC1-6烷基和C1-6亚烷基N(C1-6烷基)(C1-6烷基)中的取代基取代；和/或R 18 is selected from H, C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O)C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene C 3-10 cycloalkyl and C 1-6 alkylene C 3-10 heterocycloalkyl, optionally, the C 1-6 alkyl , C 1-6 fluoroalkyl, -C(O)C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl , C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene Alkyl C 3-10 cycloalkyl and C 1-6 alkylene C 3-10 heterocycloalkyl are each independently selected from one or more halogen, -CN, C 1-6 alkyl, C 1 -6 fluoroalkyl, -OH, -SH, -OC 1-6 alkyl, -OC 1-6 fluoroalkyl, -SC 1-6 alkyl, -SC 1-6 fluoroalkyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -C(O)C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl base, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH 2 , -C(O)NHC 1-6 alkyl, -C(O)N(C 1 -6 alkyl) (C 1-6 alkyl), -SO 2 C 1-6 alkyl, -S(O)C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl , C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C 1-6 alkylene, C 6-10 aryl, C 1-6 alkylene, C 3-10 cycloalkyl, C 1- 6 alkylene heteroaryl, C 1-6 alkylene heterocycloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene SH , C 1-6 alkylene SC 1-6 alkyl, C 1-6 alkylene NH 2 , C 1-6 alkylene NHC 1-6 alkyl and C 1-6 alkylene N (C 1 -6 alkyl) (C 1-6 alkyl) substituent substitution; and/or
    R19和R20各自独立地选自H、C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、-C(O)C1-6氟烷基、C3-10环烷基、3-15元杂环烷基、5-10元杂芳基、C6-10芳基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基C3-15杂环烷基、-C(O)C6-10芳基、-C(O)C3-10环烷基、-C(O)C4-10杂芳基、-C(O)C3-15杂环烷基、-C(O)OC1-6烷基、-C(O)OC1-6氟烷基、-C(O)OC6-10芳基、-C(O)OC3-10环烷基、-C(O)OC4-10杂芳基、-C(O)OC3-15杂环烷基、-C(O)NHC1-6烷基、-C(O)NHC1-6氟烷基、-C(O)NHC6-10芳基、-C(O)NHC3-10环烷基、-C(O)NHC4-10杂芳基、-C(O)NHC3-15杂环烷基、-SO2C1-6烷基、-SO2C1-6氟烷基、-SO2C6-10芳基、-SO2C3-10环烷基、-SO2C4-10杂芳基、和-SO2C3-15杂环烷基，任选地，所述C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、-C(O)C1-6氟烷基、C3-10环烷基、3-15元杂环烷基、5-10元杂芳基、C6-10芳基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基C3-15杂环烷基、-C(O)C6-10芳基、-C(O)C3-10环烷基、-C(O)C4-10杂芳基、-C(O)C3-15杂环烷基、-C(O)OC1-6烷基、-C(O)OC1-6氟烷基、-C(O)OC6-10芳基、-C(O)OC3-10环烷基、-C(O)OC4-10杂芳基、-C(O)OC3-15杂环烷基、-C(O)NHC1-6烷基、-C(O)NHC1-6氟烷基、-C(O)NHC6-10芳基、-C(O)NHC3-10环烷基、-C(O)NHC4-10杂芳基、-C(O)NHC3-15杂环烷基、-SO2C1-6烷基、-SO2C1-6氟烷基、-SO2C6-10芳基、-SO2C3-10环烷基、-SO2C4-10杂芳基、和-SO2C3-15杂环烷基被一个或多个独立地选自卤素、-CN、C1-6烷基、C1-6氟烷基、-OH、-SH、-OC1-6烷基、-OC1-6氟烷基、-SC1-6烷基、-SC1-6氟烷基、-NH2、-NHC1-6烷基、-N(C1-6烷基)(C1-6烷基)、-C(O)C1-6烷基、-C(O)C1-6氟烷基、-C(O)OH、-C(O)OC1-6烷基、-C(O)NH2、-C(O)NHC1-6烷基、-C(O)N(C1-6烷基)(C1-6烷基)、-SO2C1-6烷基、-S(O)C1-6烷基、C6-10芳基、5-10元杂芳基、C3-10环烷基、C3-15杂环烷基、-C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基C3-15杂环烷基、C1-6亚烷基OH、C1-6亚烷基OC1-6烷基、C1-6亚烷基SH、C1-6亚烷基SC1-6烷基、C1-6亚烷基NH2、C1-6亚烷基NHC1-6烷基和-C1-6亚烷基N(C1-6烷基)(C1-6烷基)中的一个或多取代基取代；或者，R19和R20与它们所连接的氮原子或C原子一起形成3-6元杂环烷基或环烷基，所述3-6元杂环烷基和环烷基是未取代的或被一个或多个选自卤素、-CN、硝基、C1-6烷基、C1-6氟烷基、-OH、SH、-OC1-6烷基、-OC1-6氟烷基、-SC1-6烷基、-SC1-6氟烷基、-NH2、-NHC1-6烷基、-N(C1-6烷基)(C1-6烷基)、-C(O)C1-6烷基、-C(O)C1-6氟烷基、-C(O)OH、-C(O)OC1-6烷基、-C(O)NH2、-C(O)NHC1-6烷基、-C(O)N(C1-6烷基)(C1-6烷基)、-SO2C1-6烷基、-S(O)C1-6烷基、C6-10芳基、5-10元杂芳基、C3-10环烷基、3-15元杂环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C4-10杂芳基、C1-6亚烷基C3-10杂环烷基、C1-6亚烷基OH、C1-6亚烷基OC1-6烷基、C1-6亚烷基SH、C1-6亚烷基SC1-6烷基、C1-6亚烷基NH2、C1-6亚烷基NHC1-6烷基和C1-6亚烷基N(C1-6烷基)(C1-6烷基)中的取代基取代；和/或R 19 and R 20 are each independently selected from H, C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O)C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl Base, C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkylene, C 6-10 aryl, C 1 -6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene C 3-15 heterocycloalkyl, -C(O)C 6-10 aryl, -C(O)C 3-10 cycloalkyl, -C(O)C 4-10 heteroaryl, -C(O)C 3-15 heterocycloalkyl, -C(O )OC 1-6 alkyl, -C(O)OC 1-6 fluoroalkyl, -C(O)OC 6-10 aryl, -C(O)OC 3-10 cycloalkyl, -C(O )OC 4-10 heteroaryl, -C(O)OC 3-15 heterocycloalkyl, -C(O)NHC 1-6 alkyl, -C(O)NHC 1-6 fluoroalkyl, -C (O)NHC 6-10 aryl, -C(O)NHC 3-10 cycloalkyl, -C(O)NHC 4-10 heteroaryl, -C(O)NHC 3-15 heterocycloalkyl, -SO 2 C 1-6 alkyl, -SO 2 C 1-6 fluoroalkyl, -SO 2 C 6-10 aryl, -SO 2 C 3-10 cycloalkyl, -SO 2 C 4-10 hetero Aryl, and -SO 2 C 3-15 heterocycloalkyl, optionally, the C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O)C 1-6 alkyl, - C(O)C 1-6 fluoroalkyl, C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 3-10 cycloalkyl, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene C 3-15 hetero Cycloalkyl, -C(O)C 6-10 aryl, -C(O)C 3-10 cycloalkyl, -C(O)C 4-10 heteroaryl, -C(O)C 3- 15 Heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)OC 1-6 fluoroalkyl, -C(O)OC 6-10 aryl, -C(O)OC 3 -10 cycloalkyl, -C(O)OC 4-10 heteroaryl, -C(O)OC 3-15 heterocycloalkyl, -C(O)NHC 1-6 alkyl, -C(O) NHC 1-6 fluoroalkyl, -C(O)NHC 6-10 aryl, -C(O)NHC 3-10 cycloalkyl, -C(O)NHC 4-10 heteroaryl, -C(O )NHC 3-15 heterocycloalkyl, -SO 2 C 1-6 alkyl, -SO 2 C 1-6 fluoroalkyl, -SO 2 C 6-10 aryl, -SO 2 C 3-10 cycloalkyl base, -SO 2 C 4-10 heteroaryl, and -SO 2 C 3-15 heterocycloalkyl are one or more independently selected from halogen, -CN, C 1-6 alkyl, C 1-6 Fluoroalkyl, -OH, -SH, -OC 1-6 alkyl, -OC 1-6 fluoroalkyl, -SC 1-6 alkyl, -SC 1-6 fluoroalkyl, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -C(O)C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH 2 , -C(O)NHC 1-6 alkyl, -C(O)N(C 1-6 Alkyl) (C 1-6 alkyl), -SO 2 C 1-6 alkyl, -S(O)C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, C 3-15 heterocycloalkyl, -C 1-6 alkylene, C 6-10 aryl, C 1-6 alkylene, C 3-10 cycloalkyl, C 1-6 Alkylene C 4-10 heteroaryl, C 1-6 alkylene C 3-15 heterocycloalkyl, C 1-6 alkylene OH, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene SH, C 1-6 alkylene SC 1-6 alkyl, C 1-6 alkylene NH 2 , C 1-6 alkylene NHC 1-6 alkyl and -C 1 -6 Alkylene N (C 1-6 alkyl) (C 1-6 alkyl) is substituted with one or more substituents; alternatively, R 19 and R 20 form together with the nitrogen atom or C atom to which they are connected 3-6 membered heterocycloalkyl or cycloalkyl, the 3-6 membered heterocycloalkyl and cycloalkyl are unsubstituted or substituted by one or more selected from halogen, -CN, nitro, C 1- 6 alkyl, C 1-6 fluoroalkyl, -OH, SH, -OC 1-6 alkyl, -OC 1-6 fluoroalkyl, -SC 1-6 alkyl, -SC 1-6 fluoroalkyl , -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -C(O)C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl, -C(O)OH, -C(O)OC 1-6 alkyl, -C(O)NH 2 , -C(O)NHC 1-6 alkyl, -C(O )N(C 1-6 alkyl)(C 1-6 alkyl), -SO 2 C 1-6 alkyl, -S(O)C 1-6 alkyl, C 6-10 aryl, 5- 10-membered heteroaryl, C 3-10 cycloalkyl, 3-15-membered heterocycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 3-10 cycloalkyl Base, C 1-6 alkylene C 4-10 heteroaryl, C 1-6 alkylene C 3-10 heterocycloalkyl, C 1-6 alkylene OH, C 1-6 alkylene OC 1-6 alkyl, C 1-6 alkylene SH, C 1-6 alkylene SC 1-6 alkyl, C 1-6 alkylene NH 2 , C 1-6 alkylene NHC 1-6 Substituent substitution in alkyl and C 1-6 alkylene N (C 1-6 alkyl) (C 1-6 alkyl); and/or
    R21选自H、羟基、氨基、C1-6烷基、C1-6烷氧基、F、Cl、Br、和I。R 21 is selected from H, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, F, Cl, Br, and I.
  3. [根据细则26改正 01.08.2023]
    如权利要求1或2所述的化合物或其可药用盐，其特征在于，    [Amended in accordance with Rule 26 01.08.2023]
    The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that,
    R1A是未取代的或取代的含有至少一个氮原子的4-10元杂环烷基，所述4-10元杂环烷基为单环杂环烷基、稠环杂环烷基、螺环杂环烷基或桥环杂环烷基，所述取代的含有至少一个氮原子的4-10元杂环烷基被选自下述的一个、两个、三个或更多个取代基取代：F、Cl、Br、I、、C1-3烷基、C1-3氟烷基、C3-6环烷基、3-6元杂环烷基、OR9、-SR9、C1-3亚烷基OH、C1-3亚烷基-CR9R10R11、、-NR10R11、和C1-3亚烷基NR10R11，其中，任选地，所述C1-3烷基、C1-3氟烷基、C3-6环烷基、3-6元杂环烷基、C1-3亚烷基OH、C1-3亚烷基-CR9R10R11和C1-3亚烷基NR10R11，各自独立地被选自F、Cl、Br、I、C1-3烷基、C1-3烷氧基、C1-3卤代烷基、羟基、C1-3羟烷基、氰基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C2-3烯基、C2-3炔基、C1-3烷基氨基、C1-3烷基酰基、C1-3烷基氧基酰基、C1-3烷基氨基酰基、C6-10芳基和5-6元杂芳基中的一个或多个取代基所取代，优选地，所述取代的含有至少一个氮原子的4-10元杂环烷基被选自下述的一个、两个、三个或更多个取代基取代：F、Cl、Br、I、甲基、乙基、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-CH2CH2F、环丙基、环丙基亚甲基、环丁基、环丁基亚甲基、环戊基、环戊基亚甲基、环己基、环己基亚甲基、甲氧基、氨基、和羟基；优选地，所述R1A选自未取代或被一个或多个取代基取代的以下基团： R 1A is an unsubstituted or substituted 4-10-membered heterocycloalkyl group containing at least one nitrogen atom, and the 4-10-membered heterocycloalkyl group is a monocyclic heterocycloalkyl group, a condensed ring heterocycloalkyl group, or a spiro group. Cyclic heterocycloalkyl or bridged cyclic heterocycloalkyl, the substituted 4-10 membered heterocycloalkyl containing at least one nitrogen atom is selected from one, two, three or more substituents below Substitution: F, Cl, Br, I,, C 1-3 alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, OR 9 , -SR 9 , C 1-3 alkylene OH, C 1-3 alkylene -CR 9 R 10 R 11 , -NR 10 R 11 , and C 1-3 alkylene NR 10 R 11 , wherein, optionally, The C 1-3 alkyl group, C 1-3 fluoroalkyl group, C 3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C 1-3 alkylene OH, C 1-3 alkylene group -CR 9 R 10 R 11 and C 1-3 alkylene NR 10 R 11 , each independently selected from F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, hydroxyl, C 1-3 hydroxyalkyl, cyano, amino, nitro, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 2-3 alkenyl, C 2 -3 alkynyl, C 1-3 alkylamino, C 1-3 alkyl acyl, C 1-3 alkyloxyacyl, C 1-3 alkylaminoacyl, C 6-10 aryl and 5-6 The substituted heteroaryl group is substituted with one or more substituents. Preferably, the substituted 4-10-membered heterocycloalkyl group containing at least one nitrogen atom is selected from one, two, three or More substituents: F, Cl, Br, I, methyl, ethyl, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclobutylmethylene, cyclopentyl, cyclopentylmethylene, cyclohexyl, cyclohexylmethylene, methoxy, amino , and hydroxyl; preferably, the R 1A is selected from the following groups that are unsubstituted or substituted by one or more substituents:
    所述取代基选自F、Cl、Br、I、C1-3烷基、C1-3氟烷基、C3-6环烷基、3-6元杂环烷基、OR9、-SR9、C1-3亚烷基OH、C1-3亚烷基-CR9R10R11、-NR10R11、和C1-3亚烷基NR10R11，其中，任选地，所述C1-3烷基、C1-3氟烷基、C3-6环烷基、3-6元杂环烷基、C1-3亚烷基OH、C1-3亚烷基-CR9R10R11和C1-3亚烷基NR10R11，各自独立地被选自F、Cl、Br、I、C1-3烷基、C1-3烷氧基、C1-3卤代烷基、羟基、C1-3羟烷基、氰基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C2-3烯基、C2-3炔基、C1-3烷基氨基、C1-3烷基酰基、C1-3烷基氧基酰基、C1-3烷基氨基酰基、C6-10芳基和5-6元杂芳基中的一个或多个所取代；优选地，所述R1A选自未取代或被一个或多个取代基取代的以下基团： The substituent is selected from F, Cl, Br, I, C 1-3 alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, OR 9 , - SR 9 , C 1-3 alkylene OH, C 1-3 alkylene -CR 9 R 10 R 11 , -NR 10 R 11 , and C 1-3 alkylene NR 10 R 11 , wherein optionally Ground, the C 1-3 alkyl group, C 1-3 fluoroalkyl group, C 3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, C 1-3 alkylene OH, C 1-3 alkylene group Alkyl-CR 9 R 10 R 11 and C 1-3 alkylene NR 10 R 11 , each independently selected from F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy , C 1-3 haloalkyl, hydroxyl, C 1-3 hydroxyalkyl, cyano, amino, nitro, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkylamino, C 1-3 alkyl acyl, C 1-3 alkyloxyacyl, C 1-3 alkylaminoacyl, C 6-10 aryl and 5 -Substituted with one or more of the 6-membered heteroaryl groups; preferably, the R 1A is selected from the following groups that are unsubstituted or substituted with one or more substituents:
    所述取代基选自：F、Cl、Br、I、甲基、乙基、-CF3、-CHF2、-CH2F、-CH2CF3、-CH2CHF2、-CH2CH2F、环丙基、环丙基亚甲基、环丁基、环丁基亚甲基、环戊基、环戊基亚甲基、环己基、环己基亚甲基、甲氧基、氨基、和羟基；其中，R9、R10、和R11如权利要求1或2中所定义，优选地，R9每次出现时各自独立选自H、C1-3烷基、C1-3氟烷基、-C(O)C1-3烷基、C(O)C1-3氟烷基、C3-6环烷基、和3-6元杂环烷基；R10和R11每次出现时各自独立地选自H、C1-3烷基、C1-3卤代烷基、C3-6环烷基、3-6元杂环烷基、-C(O)C1-3烷基、-C(O)C1-3卤代烷基、-C(O)OC1-3烷基、-C(O)NHC1-3烷基、C1-6亚烷基C3-6杂环烷基和C1-6亚烷基C3-6环烷基，或者，R10和R11与其相连的C或N原子一起各自独立地形成未取代的或被一个或多个选自卤素、C1-3羟烷基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C6-10芳基、5-6元杂芳基、-CN、-OH、C1-3烷基、OC1-3烷基、C1-3氟烷基、-OC1-3氟烷基、-C(O)C1-3烷基、-C(O)C1-3氟烷基、-C(O)C1-3烷基、-C(O)NHC1-3烷基、C1-3亚烷基OC1-3烷基、C1-3亚烷基C3-6杂环烷基和C1-3亚烷基C3-6环烷基中的取代基取代的3-6元环烷基或3-6元杂环烷基；和/或The substituent is selected from: F, Cl, Br, I, methyl, ethyl, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclobutylmethylene, cyclopentyl, cyclopentylmethylene, cyclohexyl, cyclohexylmethylene, methoxy, amino , and hydroxyl; wherein, R 9 , R 10 , and R 11 are as defined in claim 1 or 2. Preferably, R 9 is independently selected from H, C 1-3 alkyl, C 1- 3- fluoroalkyl, -C(O)C 1-3 alkyl, C(O)C 1-3 fluoroalkyl, C 3-6 cycloalkyl, and 3-6 membered heterocycloalkyl; R 10 and Each occurrence of R 11 is independently selected from H, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C(O)C 1-3 alkyl, -C(O)C 1-3 haloalkyl, -C(O)OC 1-3 alkyl, -C(O)NHC 1-3 alkyl, C 1-6 alkylene C 3-6 heterocycloalkyl and C 1-6 alkylene C 3-6 cycloalkyl, or R 10 and R 11 together with the C or N atom to which they are attached independently form unsubstituted or substituted by one or more Each is selected from halogen, C 1-3 hydroxyalkyl, amino, nitro, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, -CN, -OH, C 1-3 alkyl, OC 1-3 alkyl, C 1-3 fluoroalkyl, -OC 1-3 fluoroalkyl, -C(O)C 1-3 alkyl, - C(O)C 1-3 fluoroalkyl, -C(O)C 1-3 alkyl, -C(O)NHC 1-3 alkyl, C 1-3 alkyleneOC 1-3 alkyl, 3-6 -membered cycloalkyl or 3-6-membered heterocycle substituted by substituents in C 1-3 alkylene C 3-6 heterocycloalkyl and C 1-3 alkylene C 3-6 cycloalkyl alkyl; and/or
    R2A是未取代的或取代的C6-10芳基、5-6元杂芳基或5-6元杂环烷基，所述5-6元杂芳基和5-6元杂环烷基各自独立地含有1、2或3个各自独立选自N、O或S的杂原子，任选地，所述未取代的或取代的C6-10芳基和5-6元杂芳基各自独立地稠和于5、6、7、8、或9元杂环烷基或环烷基，所述取代的C6-10芳基、5-6元杂芳基和5-6元杂环烷基各自独立地被选自下述的一个、两个、三个、四个或更多个取代基取代：F、Cl、Br、I、＝O、＝S、C1-3烷基、C1-3氟代烷基、C1-3烷氧基、C3-6环烷基、3-6元杂环基、C6-10芳基、5-6元杂芳基、-OH、-SH、C1-3亚烷基-OH、C1-3亚烷基-SH、氨基、和C1-3亚烷基-N(C1-3烷基)2，且当R2A是取代的C6-10芳基时，所述取代的C6-10杂芳基不被＝O或＝S取代；优选地，R2A选自： 中的任一种，其中，R5A每次出现时各自独立地选自F、Cl、Br、I、C1-3烷基、C1-3氟烷基、C1-3烷氧基和氨基，优选地各自独立地选自F、Cl、Br、I、甲基、二氟甲基、三氟甲基、氟甲基、甲氧基和氨基；n每次出现时各自独立地为0、1、2或3；和/或R 2A is unsubstituted or substituted C 6-10 aryl, 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl, the 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl Each group independently contains 1, 2 or 3 heteroatoms each independently selected from N, O or S, optionally, the unsubstituted or substituted C 6-10 aryl group and 5-6 membered heteroaryl group Each is independently fused to a 5, 6, 7, 8, or 9-membered heterocycloalkyl or cycloalkyl group, and the substituted C 6-10 aryl, 5-6-membered heteroaryl and 5-6-membered heteroaryl Each cycloalkyl group is independently substituted with one, two, three, four or more substituents selected from the following: F, Cl, Br, I, =O, =S, C 1-3 alkyl , C 1-3 fluoroalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, - OH, -SH, C 1-3 alkylene-OH, C 1-3 alkylene-SH, amino, and C 1-3 alkylene-N(C 1-3 alkyl) 2 , and when R When 2A is a substituted C 6-10 aryl group, the substituted C 6-10 heteroaryl group is not substituted by =O or =S; preferably, R 2A is selected from: Any of, wherein each occurrence of R 5A is independently selected from F, Cl, Br, I, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-3 alkoxy and Amino groups are preferably each independently selected from F, Cl, Br, I, methyl, difluoromethyl, trifluoromethyl, fluoromethyl, methoxy and amino; each occurrence of n is independently 0 , 1, 2 or 3; and/or
    R3A选自未取代的或被一个或多个选自卤素、-CN、C1-3烷基、C1-3氟烷基、＝O、＝S、OR15、-NR16R17、R4A、C1-3亚烷基R4A、C1-6亚烷基NR16R17、-C(O)OR15、-C(O)R15、和-C(O)NR16R17中的取代基取代的C6-10芳基、5-10元杂芳基、C4-11环烷基和4-11元杂环烷基，所述C4-11环烷基和4至11元杂环烷基各自独立地为单环、稠环、桥环、或螺环基团，所述4至11元杂环烷基和所述5至10元杂芳基各自独立地包含1、2或3个选自N、O和S的杂原子，所述C6-10芳基和5至10元杂芳基各自独立地为单环或稠环基团，任选地，所述C6-10芳基和5至10元杂芳基各自独立地稠和于5-6元杂环烷基或5-6元环烷基；优选地，R3A选自未取代的或被一个或多个选自卤素、-CN、C1-3烷基、C1-3氟烷基、＝O、＝S、OR15、-NR16R17、R4A、C1-3亚烷基R4A、C1-6亚烷基NR16R17、-C(O)OR15、-C(O)R15、和-C(O)NR16R17中的取代基取代的下述基团： R15、R16、R17、和R4A如权利要求1或2中所定义，优选地，R15选自H、C1-6烷基、C1-6氟烷基、C(O)C1-6烷基、和C(O)C1-6氟烷基，任选地，所述C1-6烷基被选自F、Cl、Br、I、C1-C3烷氧基、羟基、氰基、氨基、硝基、C3-6环烷基、3-6元杂环烷基、C6-10芳基和5-6元杂芳基中的一个或多个取代基所取代；优选地，R16和R17各自独立地选自H、C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、-C(O)C1-6氟烷基、-C(O)C6-10芳基、-C(O)C3-10环烷基、-C(O)C4-10杂芳基、-C(O)C3-15杂环烷基、-C(O)OC1-6烷基、-C(O)OC1-6氟烷基、-C(O)OC6-10芳基、-C(O)OC3-10环烷基、-C(O)OC3-15杂环烷基、-C(O)NHC1-6烷基、-C(O)NHC1-6氟烷基、-C(O)NHC6-10芳基、-C(O)NHC3-10环烷基、-C(O)NHC4-10杂芳基、-C(O)NHC3-15杂环烷基、C3-10环烷基、3-15元杂环烷基、5-10元杂芳基、C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基和C1-6亚烷基C3-15杂环烷基，任选地，所述C1-6烷基、C1-6氟烷基、-C(O)C1-6烷基、-C(O)C1-6氟烷基、-C(O)C6-10芳基、-C(O)C3-10环烷基、-C(O)C4-10杂芳基、-C(O)C3-15杂环烷基、-C(O)OC1-6烷基、-C(O)OC1-6氟烷基、-C(O)OC6-10芳基、-C(O)OC3-10环烷基、-C(O)OC4-10杂芳基、-C(O)OC3-15杂环烷基、-C(O)NHC1-6烷基、-C(O)NHC1-6氟烷基、-C(O)NHC6-10芳基、-C(O)NHC3-10环烷基、-C(O)NHC4-10杂芳基、-C(O)NHC3-15杂环烷基、C3-10环烷基、3-15元杂环烷基、5-10元杂芳基、C6-10芳基、C1-6亚烷基C3-10环烷基、C1-6亚烷基C6-10芳基、C1-6亚烷基C4-10杂芳基和C1-6亚烷基C3-15杂环烷基各自独立被选自卤素、-CN、-OH、-SH、C1-3烷基、-OC1-3烷基、氨基、-NHC1-3烷基、-N(C1-3烷基)2、NHC(O)C1-3、C1-3卤代烷基、C1-3羟烷基、-C(O)H、-C(O)C1-3烷基、-C(O)OH、-C(O)O C1-3烷基、-C(O)NH2、-C(O)NHC1-3烷基、-C(O)N(C1-3烷基)2、C6-10芳基、5-6元杂芳基、C3-6环烷基、3-6元杂环烷基、C1-3亚烷基C6-10芳基、C1-3亚烷基C3-6环烷基、C1-3亚烷基C4-10杂芳基、和C1-3亚烷基C3-6杂环烷基中的一个或多个取代基取代，或者，R16和R17与它们所连接的氮原子或C原子一起形成3-6元杂环烷基或环烷基，所述3-6元杂环烷基和环烷基是未取代的或被一个或多个独立地选自卤素、-CN、-OH、-SH、-OC1-3烷基、氨基、C1-3烷基、-NHC1-3烷基、-N(C1-3烷基)2、NHC(O)C1-3、C1-3卤代烷基、C1-3羟烷基、-C(O)H、-C(O)C1-3烷基、-C(O)OH、-C(O)O C1-3烷基、-C(O)NH2、-C(O)NHC1-3烷基、-C(O)N(C1-3烷基)2、C6-10芳基、5-6元杂芳基、C3-6环烷基、3-6元杂环烷基、C1-3亚烷基C6-10芳基、C1-3亚烷基C3-6环烷基、C1-3亚烷基C4-10杂芳基、C1-3亚烷基NHC1-3烷基、C1-3亚烷基N(C1-3烷基)2、C1-3亚烷基NH2和C1-3亚烷基C3-6杂环烷基中的一个或多个取代基取代；优选地，R4A选自未取代的或被一个或多个独立地选自卤素、-CN、-OH、-SH、C1-3烷基、-OC1-3烷基、氨基、-NHC1-3烷基、-N(C1-3烷基)2、NHC(O)C1-3烷基、C1-3卤代烷基、C1-3羟烷基、-C(O)H、-C(O)C1-3烷基、-C(O)OH、-C(O)O C1-3烷基、-C(O)NH2、-C(O)NHC1-3烷基、-C(O)N(C1-3烷基)2、C6-10芳基、5-6元杂芳基、C3-6环烷基、3-6元杂环烷基、C1-3亚烷基C6-10芳基、C1-3亚烷基C3-6环烷基、C1-3亚烷基C4-10杂芳基、和C1-3亚烷基C3-6杂环烷基中的一个或多个取代基取代的C3-10环烷基、4-15元杂环烷基、5-10元杂芳基和C6-10芳基，所述C3-10环烷基和4至15元杂环烷基各自独立地为单环、稠环、桥环、或螺环基团，所述C6-10芳基和5至10元杂芳基各自独立地为单环或稠环基团，所述4至15元杂环烷基和5-10元杂芳基各自独立地包含有1、2或3个独立选自N、O、和S的杂原子；优选地，R4A选自未取代的或被一个或多个独立地选自F、-CH3、-C2H5、-OH、-OCH3、-C(O)CH3、-NH2、-C(O)NHCH3、-COOH、-NH(CH3)2、-C(O)N(CH3)2、-CN和-CF3的取代基所取代的C3-10环烷基、4-15元杂环烷基、5-10元杂芳基和C6-10芳基，所述C3-10环烷基和4至15元杂环烷基各自独立地为单环、稠环、桥环、或螺环基团，所述C6-10芳基和5至10元杂芳基各自独立地为单环或稠环基团，所述4至15元杂环烷基和5-10元杂芳基各自独立地包含有1、2或3个独立选自N、O、和S的杂原子；R 3A is selected from unsubstituted or one or more selected from halogen, -CN, C 1-3 alkyl, C 1-3 fluoroalkyl, =O, =S, OR 15 , -NR 16 R 17 , R 4A , C 1-3 alkylene R 4A , C 1-6 alkylene NR 16 R 17 , -C(O)OR 15 , -C(O)R 15 , and -C(O)NR 16 R C 6-10 aryl, 5-10 membered heteroaryl, C 4-11 cycloalkyl and 4-11 membered heterocycloalkyl substituted by the substituents in 17 , the C 4-11 cycloalkyl and 4 to 11-membered heterocycloalkyl groups are each independently a monocyclic, fused ring, bridged ring, or spirocyclic group, and the 4- to 11-membered heterocycloalkyl groups and the 5- to 10-membered heteroaryl groups each independently include 1, 2 or 3 heteroatoms selected from N, O and S, the C 6-10 aryl group and the 5 to 10-membered heteroaryl group are each independently a monocyclic or condensed ring group, optionally, the The C 6-10 aryl group and the 5- to 10-membered heteroaryl group are each independently condensed with a 5-6-membered heterocycloalkyl group or a 5-6-membered cycloalkyl group; preferably, R 3A is selected from unsubstituted or substituted One or more selected from halogen, -CN, C 1-3 alkyl, C 1-3 fluoroalkyl, =O, =S, OR 15 , -NR 16 R 17 , R 4A , C 1-3 alkylene The following are substituted by the substituents in the group R 4A , C 1-6 alkylene NR 16 R 17 , -C(O)OR 15 , -C(O)R 15 , and -C(O)NR 16 R 17 Group: R 15 , R 16 , R 17 , and R 4A are as defined in claim 1 or 2. Preferably, R 15 is selected from H, C 1-6 alkyl, C 1-6 fluoroalkyl, C(O) C 1-6 alkyl, and C(O)C 1-6 fluoroalkyl, optionally, the C 1-6 alkyl is selected from F, Cl, Br, I, C 1 -C 3 alkoxy One or more substitutions among hydroxyl, cyano, amino, nitro, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5-6 membered heteroaryl substituted with a group; preferably, R 16 and R 17 are each independently selected from H, C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O)C 1-6 alkyl, -C(O )C 1-6 fluoroalkyl, -C(O)C 6-10 aryl, -C(O)C 3-10 cycloalkyl, -C(O)C 4-10 heteroaryl, -C( O)C 3-15 heterocycloalkyl, -C(O)OC 1-6 alkyl, -C(O)OC 1-6 fluoroalkyl, -C(O)OC 6-10 aryl, -C (O)OC 3-10 cycloalkyl, -C(O)OC 3-15 heterocycloalkyl, -C(O)NHC 1-6 alkyl, -C(O)NHC 1-6 fluoroalkyl, -C(O)NHC 6-10aryl , -C(O)NHC 3-10cycloalkyl , -C(O)NHC 4-10heteroaryl , -C(O)NHC 3-15heterocycloalkyl Base, C 3-10 cycloalkyl, 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkylene, C 3-10 cycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl and C 1-6 alkylene C 3-15 heterocycloalkyl, optionally, the C 1-6 alkyl, C 1-6 fluoroalkyl, -C(O)C 1-6 alkyl, -C(O)C 1-6 fluoroalkyl, -C(O)C 6-10 aromatic base, -C(O)C 3-10 cycloalkyl, -C(O)C 4-10 heteroaryl, -C(O)C 3-15 heterocycloalkyl, -C(O)OC 1- 6 alkyl, -C(O)OC 1-6 fluoroalkyl, -C(O)OC 6-10 aryl, -C(O)OC 3-10 cycloalkyl, -C(O)OC 4- 10 heteroaryl, -C(O)OC 3-15 heterocycloalkyl, -C(O)NHC 1-6 alkyl, -C(O)NHC 1-6 fluoroalkyl, -C(O)NHC 6-10aryl , -C(O)NHC 3-10cycloalkyl , -C(O)NHC 4-10heteroaryl , -C(O)NHC 3-15heterocycloalkyl , C 3-10 Cycloalkyl, 3-15 membered heterocycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl, C 1-6 alkylene, C 3-10 cycloalkyl, C 1-6 alkylene C 6-10 aryl, C 1-6 alkylene C 4-10 heteroaryl and C 1-6 alkylene C 3-15 heterocycloalkyl are each independently selected from halogen, -CN, -OH, -SH, C 1-3 alkyl, -OC 1-3 alkyl, amino, -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , NHC(O)C 1-3 , C 1-3 haloalkyl, C 1-3 hydroxyalkyl, -C(O)H, -C(O)C 1-3 alkyl, -C(O)OH, -C(O)O C 1-3 alkyl base, -C(O)NH 2 , -C(O)NHC 1-3 alkyl, -C(O)N(C 1-3 alkyl) 2 , C 6-10 aryl, 5-6 membered hetero Aryl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-3 alkylene C 6-10 aryl, C 1-3 alkylene C 3-6 cycloalkyl, C 1-3 alkylene C 4-10 heteroaryl, and C 1-3 alkylene C 3-6 heterocycloalkyl are substituted with one or more substituents, or R 16 and R 17 are substituted with one or more substituents of C 1-3 alkylene C 3-6 heterocycloalkyl. The attached nitrogen atoms or C atoms together form a 3-6 membered heterocycloalkyl or cycloalkyl group that is unsubstituted or is independently selected from one or more Halogen, -CN, -OH, -SH, -OC 1-3 alkyl, amino, C 1-3 alkyl, -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 , NHC ( O)C 1-3 , C 1-3 haloalkyl, C 1-3 hydroxyalkyl, -C(O)H, -C(O)C 1-3 alkyl, -C(O)OH, -C (O)O C 1-3 alkyl, -C(O)NH 2 , -C(O)NHC 1-3 alkyl, -C(O)N(C 1-3 alkyl) 2 , C 6-10 Aryl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-3 alkylene C 6-10 aryl, C 1-3 alkylene C 3-6 cycloalkyl, C 1-3 alkylene C 4-10 heteroaryl, C 1-3 alkylene NHC 1-3 alkyl, C 1-3 alkylene N(C 1-3 alkyl (base) 2 , C 1-3 alkylene NH 2 and C 1-3 alkylene C 3-6 heterocycloalkyl are substituted with one or more substituents; preferably, R 4A is selected from unsubstituted or One or more independently selected from halogen, -CN, -OH, -SH, C 1-3 alkyl, -OC 1-3 alkyl, amino, -NHC 1-3 alkyl, -N(C 1 -3 alkyl) 2 , NHC(O)C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, -C(O)H, -C(O)C 1-3 alkyl base, -C(O)OH, -C(O)O C 1-3 alkyl, -C(O)NH 2 , -C(O)NHC 1-3 alkyl, -C(O)N(C 1 -3 alkyl) 2 , C 6-10 aryl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1-3 alkylene C 6-10 Aryl, C 1-3 alkylene C 3-6 cycloalkyl, C 1-3 alkylene C 4-10 heteroaryl, and C 1-3 alkylene C 3-6 heterocycloalkyl C 3-10 cycloalkyl, 4-15 membered heterocycloalkyl, 5-10 membered heteroaryl and C 6-10 aryl substituted by one or more substituents, the C 3-10 cycloalkyl and 4 to 15-membered heterocycloalkyl groups are each independently a monocyclic, fused ring, bridged ring, or spirocyclic group, and the C 6-10 aryl group and 5 to 10-membered heteroaryl group are each independently a monocyclic group. Or a fused ring group, the 4- to 15-membered heterocycloalkyl and 5-10-membered heteroaryl groups each independently contain 1, 2 or 3 heteroatoms independently selected from N, O, and S; preferably , R 4A is selected from unsubstituted or one or more independently selected from F, -CH 3 , -C 2 H 5 , -OH, -OCH 3 , -C(O)CH 3 , -NH 2 , - C(O)NHCH 3 , -COOH, -NH(CH 3 ) 2 , -C(O)N(CH 3 ) 2 , -CN and -CF 3 substituents substituted C 3-10 cycloalkyl, 4-15 membered heterocycloalkyl, 5-10 membered heteroaryl and C 6-10 aryl, the C 3-10 The cycloalkyl group and the 4- to 15-membered heterocycloalkyl group are each independently a monocyclic, condensed ring, bridged ring, or spirocyclic group, and the C 6-10 aryl group and the 5- to 10-membered heteroaryl group are each independently It is a monocyclic or condensed ring group, and the 4- to 15-membered heterocycloalkyl and 5-10-membered heteroaryl groups each independently contain 1, 2 or 3 heteroatoms independently selected from N, O, and S. ;
    其中，波形线表示连接点。Among them, wavy lines represent connection points.
  4. 如权利要求1-3任一项所述的化合物或其可药用盐，其特征在于，The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that,
    R1A选自下述基团： 和/或R 1A is selected from the following groups: and / or
    R2A选自下述基团： 和/或R 2A is selected from the following groups: and / or
    R4A选自下述基团 R 4A is selected from the following groups
    其中，波形线表示连接点。Among them, wavy lines represent connection points.
  5. 一种具有式Ⅰ所示结构式的化合物或其可药用盐， A compound having the structural formula shown in formula I or a pharmaceutically acceptable salt thereof,
    其中，R1是至少含有一个氮原子的杂环烷基，所述杂环烷基是未取代的或被一个或多个选自卤素、C1-6烷基、C1-6氟烷基、C1-6亚烷基C3-10环烷基和C3-10环烷基的取代基取代；Wherein, R 1 is a heterocycloalkyl group containing at least one nitrogen atom, and the heterocycloalkyl group is unsubstituted or substituted by one or more halogen, C 1-6 alkyl, C 1-6 fluoroalkyl , C 1-6 alkylene C 3-10 cycloalkyl and C 3-10 cycloalkyl substituents are substituted;
    R2为未取代或被选自卤素、C1-6烷基、C1-6氟烷基、羟基、和烷氧基中一个或多个的取代基取代的C6-10芳基；R 2 is a C 6-10 aryl group that is unsubstituted or substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 fluoroalkyl, hydroxyl, and alkoxy;
    或被选自卤素、C1-6烷基、C1-6氟烷基、羟基、烷氧基、＝O和＝S中一个或多个的取代基取代的含有1、2或3个各自独立选自N、O或S的杂原子的杂芳基；Or substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 fluoroalkyl, hydroxyl, alkoxy, =O and =S containing 1, 2 or 3 each Heteroaryl groups with heteroatoms independently selected from N, O or S;
    R3为未取代或任选地经一个、两个或多个独立选自卤素、羧基、酰胺基、烷基、烷胺基、卤代烷基和氰基的取代基取代的芳基、4至15元环烷基，或者，具有1-2个N、O或S杂原子的4至15元杂环烷基；R 3 is an aryl group that is unsubstituted or optionally substituted with one, two or more substituents independently selected from halogen, carboxyl, amide, alkyl, alkylamino, haloalkyl and cyano, 4 to 15 One-membered cycloalkyl, or 4 to 15-membered heterocycloalkyl with 1-2 N, O or S heteroatoms;
    R4不存在，或者是未取代或任选地经一个、两个或多个独立选自卤素、羧基、烷基、烷胺基、卤代烷基和氰基的取代基取代的具有1-2个N、O或S杂原子的4至15元杂环烷基中的任一种；和R 4 is absent, or is unsubstituted or optionally substituted with one, two or more substituents independently selected from halogen, carboxyl, alkyl, alkylamino, haloalkyl and cyano having 1-2 Any of 4 to 15 membered heterocycloalkyl groups with N, O, or S heteroatoms; and
    R23选自H和卤素，优选，R23选自H和F。R 23 is selected from H and halogen. Preferably, R 23 is selected from H and F.
  6. 如权利要求5所述的化合物，其特征在于，R1选自 中的任一个。The compound of claim 5, wherein R1 is selected from any of them.
  7. 如权利要求5所述的化合物，其特征在于，R2选自 中的任一种；The compound of claim 5, wherein R 2 is selected from any of;
    其中，R5每次出现各自独立地选自F、Cl、Br、I、C1-6烷基、C1-6氟烷基、C1-6烷氧基或氨基；n＝0，1，2或3。Wherein, each occurrence of R 5 is independently selected from F, Cl, Br, I, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkoxy or amino; n=0,1 , 2 or 3.
  8. 如权利要求5所述的化合物或其可药用盐，其特征在于，所述R3为未取代的或被一个或多个选自卤素、C1-6烷基、C1-6氟烷基亚、C1-6亚烷基C3-10环烷基和C3-10环烷基的取代基取代的三元单环烷基、四元单环烷基、五元单环烷基、六元单环烷基、七元螺环烷基、八元螺环烷基、九元螺环烷基、十元螺环烷基、十一元螺环烷烃、九元稠环烷基或十元稠环烷基、七元桥环烷基、八元桥环烷基、九元桥环烷基、十元桥环烷基、和十一元桥环烷烃；所述桥环环烷基优选为 The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 3 is unsubstituted or one or more selected from halogen, C 1-6 alkyl, C 1-6 fluoroalkyl Three-membered monocyclic alkyl group, four-membered monocyclic alkyl group, and five-membered monocyclic alkyl group substituted by substituents of base , C 1-6 alkylene group, C 3-10 cycloalkyl group and C 3-10 cycloalkyl group or Ten-membered fused cycloalkyl, seven-membered bridged cycloalkyl, eight-membered bridged cycloalkyl, nine-membered bridged cycloalkyl, ten-membered bridged cycloalkyl, and eleven-membered bridged cycloalkane; the bridged cycloalkyl Preferably
  9. 如权利要求5所述的化合物或其可药用盐，其特征在于，R3选自未取代或任选地经一个、两个或多个独立选自卤素、羧基、酰胺基、烷基、烷胺基、卤代烷基或氰基的取代基取代的以下基团： The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from unsubstituted or optionally one, two or more independently selected from halogen, carboxyl, amido, alkyl, The following groups substituted by alkylamino, haloalkyl or cyano substituents:
  10. 如权利要求5所述的化合物或其可药用盐，其特征在于，R3为未取代或杂原子的H被卤素、羧基、酰胺基、烷基、烷胺基、卤代烷基或氰基取代的 The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 3 is unsubstituted or heteroatom H is substituted by halogen, carboxyl, amido, alkyl, alkylamino, haloalkyl or cyano. of
  11. 如权利要求5所述的化合物或其可药用盐，其特征在于，R4为未取代或任选地经一个、两个或多个独立选自卤素、羧基、烷基、烷胺基、卤代烷基或氰基的取代基取代的 The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 4 is unsubstituted or optionally selected from halogen, carboxyl, alkyl, alkylamino, Substituted by haloalkyl or cyano substituents
  12. 如权利要求5所述的化合物或其可药用盐，其特征在于，当R4为取代的杂环烷基时，所述杂环烷基选自 取代基团连接到杂原子上；优选地，所述取代基团选自-F、-CH3、-OCH3、-NH2、-COOH、-CN和-CF3中的任一种。The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein when R 4 is a substituted heterocycloalkyl group, the heterocycloalkyl group is selected from The substituent group is attached to the heteroatom; preferably, the substituent group is selected from -F, -CH 3 , -OCH 3 , -NH 2 , -COOH, Either -CN or -CF 3 .
  13. 如权利要求5所述的化合物或其可药用盐，其特征在于，当R4为环烷基或杂环烷基时，所述R3为C6-10芳基，优选为苯基，所述R4连接到芳基中连接炔基的碳原子的对位或间位。The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein when R 4 is a cycloalkyl or heterocycloalkyl group, the R 3 is a C 6-10 aryl group, preferably phenyl, The R 4 is connected to the para or meta position of the carbon atom in the aryl group that is connected to the alkynyl group.
  14. 一种具有式Ⅱ所示结构式的化合物或其可药用盐， A compound having the structural formula shown in Formula II or a pharmaceutically acceptable salt thereof,
    其中，R6为未取代或任选地经一个、两个或多个独立选自卤素、羧基、烷基、烷胺基、卤代烷基或氰基的取代基取代的芳基、4至15元环烷基，或者，具有1-2个N、O或S杂原子的4至15元杂环烷基；Wherein, R 6 is an aryl group that is unsubstituted or optionally substituted with one, two or more substituents independently selected from halogen, carboxyl, alkyl, alkylamino, haloalkyl or cyano, 4 to 15 yuan. Cycloalkyl, or 4 to 15 membered heterocycloalkyl with 1-2 N, O or S heteroatoms;
    R7不存在，或者，选自H、酰胺基、氰基、或者未取代或任选地经一个、两个或多个独立选自卤素、羧基、烷基、烷胺基、卤代烷基和氰基的取代基取代的具有1-2个N、O或S杂原子的4至15元杂环烷基中的任一种；R 7 is absent, alternatively, selected from H, amide, cyano, or unsubstituted or optionally substituted by one, two or more independently selected from halogen, carboxyl, alkyl, alkylamino, haloalkyl and cyano Any of the 4 to 15-membered heterocycloalkyl groups having 1-2 N, O or S heteroatoms substituted by the substituent of the base;
    或者R7为C1-6亚烷基C3-10杂环烷基，所述杂环烷基是未取代或任选地经一个、两个或多个独立选自卤素、羧基、烷基、烷胺基、卤代烷基和氰基的取代基取代；优选地，R7为C1-3亚烷基C5-8杂环烷基，所述杂环烷基具有1-3个独立选自N、O和S的杂原子；Or R 7 is C 1-6 alkylene C 3-10 heterocycloalkyl, which is unsubstituted or optionally modified by one, two or more independently selected from halogen, carboxyl, alkyl , alkylamino, haloalkyl and cyano substituents; preferably, R 7 is C 1-3 alkylene C 5-8 heterocycloalkyl, and the heterocycloalkyl has 1 to 3 independent choices. Heteroatoms from N, O and S;
    R8是含有两个氮原子的杂环烷基，所述杂环烷基是未取代的或被一个或多个选自卤素、C1-6烷基、C1-6氟烷基、C1-6亚烷基C3-10环烷基和C3-10环烷基的取代基取代；R 8 is a heterocycloalkyl group containing two nitrogen atoms, which is unsubstituted or substituted by one or more selected from halogen, C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene C 3-10 cycloalkyl and C 3-10 cycloalkyl substituents are substituted;
    或者，R8是具有1-2个独立选自N、O和S的杂原子的4至15元杂环烷基，所述杂环烷基是未取代的或被一个或多个选自卤素、C1-6烷基、C1-6氟烷基、C1-6亚烷基C3-10环烷基和C3-10环烷基的取代基取代，优选地，R8是具有1-2个独立为N或O的杂原子的5至8元杂环烷基，所述杂环烷基是未取代的或被一个或多个选自卤素、C1-3烷基、C1-3氟烷基、C1-3亚烷基C3-6环烷基和C3-6环烷基的取代基取代；和Alternatively, R 8 is a 4 to 15 membered heterocycloalkyl group having 1 to 2 heteroatoms independently selected from N, O, and S, which heterocycloalkyl group is unsubstituted or substituted by one or more heteroatoms selected from halogen , C 1-6 alkyl, C 1-6 fluoroalkyl, C 1-6 alkylene, C 3-10 cycloalkyl and C 3-10 cycloalkyl substituents, preferably, R 8 has 1-2 5 to 8-membered heterocycloalkyl groups of heteroatoms that are independently N or O, the heterocycloalkyl group is unsubstituted or substituted by one or more selected from halogen, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-3 alkylene, C 3-6 cycloalkyl and C 3-6 cycloalkyl substituents; and
    R22选自H、卤素、酰胺基、氰基或卤代烷基，优选，R23选自H、F、Cl、Br和I。R 22 is selected from H, halogen, amide, cyano or haloalkyl. Preferably, R 23 is selected from H, F, Cl, Br and I.
  15. 如权利要求14所述的化合物，其特征在于，R8选自 中的任一个。The compound of claim 14, wherein R 8 is selected from any of them.
  16. 如权利要求14所述的化合物或其可药用盐，其特征在于，R6为未取代或任选地经一个、两个或多个独立选自卤素、羧基、烷基、烷胺基、卤代烷基或氰基的取代基取代的 The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein R 6 is unsubstituted or optionally selected from halogen, carboxyl, alkyl, alkylamino, Substituted by haloalkyl or cyano substituents
  17. 如权利要求14所述的化合物或其可药用盐，其特征在于，R6为未取代或杂原子的H被卤素、羧基、烷基、烷胺基、卤代烷基或氰基取代的 The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein R 6 is unsubstituted or heteroatom H is substituted by halogen, carboxyl, alkyl, alkylamino, haloalkyl or cyano.
  18. 如权利要求14所述的化合物或其可药用盐，其特征在于，R7选自 中的任一杂环烷基。The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from Any heterocycloalkyl group in .
  19. 如权利要求14所述的化合物或其可药用盐，其特征在于，当R7为杂原子的H被取代的时，所述取代基团选自-F、-CH3、-OCH3、-NH2、-COOH、-CN和-CF3中的任一种。The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein when R 7 is a heteroatom H substituted When , the substituent group is selected from -F, -CH 3 , -OCH 3 , -NH 2 , -COOH, Either -CN or -CF 3 .
  20. 如权利要求14所述的化合物或其可药用盐，其特征在于，当R7为环烷基或杂环烷基时，所述R6为C6-10芳基，优选为苯基，所述R7连接到芳基中连接炔基的碳原子的对位或间位。The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein when R 7 is a cycloalkyl or heterocycloalkyl group, the R 6 is a C 6-10 aryl group, preferably phenyl, The R 7 is connected to the para or meta position of the carbon atom in the aryl group that is connected to the alkynyl group.
  21. 如权利要求1所述的化合物或其可药用盐，其特征在于，所述化合物选自 中的任一个。The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of any of them.
  22. 一种药物组合物，其特征在于，包含如权利要求1-21中任一项所述的化合物或其可药用盐，以及药学上可接受的载体和/辅料。A pharmaceutical composition, characterized by comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or auxiliary material.
  23. 如权利要求1-21中任一项所述的化合物或其可药用盐或如权利要求22所述的药物组合物在制备用于治疗或预防由WDR5介导的疾病或病症的的药物中的应用；优选所述WDR5介导的疾病或病症是癌症；优选地，所述癌症选自白血病；优选地，所述癌症选自急性早幼粒细胞白血病、急性粒细胞白血病、急性髓性白血病(AML)和急性单核细胞白血病。The compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 22 in the preparation of a medicament for the treatment or prevention of diseases or conditions mediated by WDR5 Application; Preferably, the WDR5-mediated disease or disorder is cancer; Preferably, the cancer is selected from the group consisting of leukemia; Preferably, the cancer is selected from the group consisting of acute promyelocytic leukemia, acute myeloid leukemia, and acute myeloid leukemia. (AML) and acute monocytic leukemia.
  24. 权利要求1-21中任一项所述的化合物或其可药用盐或如权利要求22所述的药物组合物，其用于治疗或预防由WDR5介导的疾病或病症；优选地，所述疾病或病症为癌症；优选地，所述癌症选自白血病；优选地，所述癌症选自急性早幼粒细胞白血病、急性粒细胞白血病、急性髓性白血病(AML)、和急性单核细胞白血病。The compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 22, which is used to treat or prevent diseases or conditions mediated by WDR5; Preferably, the The disease or condition is cancer; preferably, the cancer is selected from leukemia; preferably, the cancer is selected from acute promyelocytic leukemia, acute myeloid leukemia, acute myeloid leukemia (AML), and acute monocytic leukemia leukemia.
  25. 一种治疗或预防由WDR5介导的疾病或病症的方法，包括对有需要的受试者施用治疗有效量的权利要求1-21中任一项所述的化合物或其可药用盐或如权利要求22所述的药物组合物；优选地，所述疾病或病症为癌症；优选地，所述癌症选自白血病；优选地，所述癌症选自急性早幼粒细胞白血病、急性粒细胞白血病、急性髓性白血病(AML)和急性单核细胞白血病。A method of treating or preventing a disease or condition mediated by WDR5, comprising administering to a subject in need a therapeutically effective amount of a compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof or as The pharmaceutical composition of claim 22; preferably, the disease or disorder is cancer; preferably, the cancer is selected from leukemia; preferably, the cancer is selected from acute promyelocytic leukemia, acute myelogenous leukemia , acute myeloid leukemia (AML) and acute monocytic leukemia.
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