WO2024067465A1 - Kif18a抑制剂 - Google Patents

Kif18a抑制剂 Download PDF

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WO2024067465A1
WO2024067465A1 PCT/CN2023/121036 CN2023121036W WO2024067465A1 WO 2024067465 A1 WO2024067465 A1 WO 2024067465A1 CN 2023121036 W CN2023121036 W CN 2023121036W WO 2024067465 A1 WO2024067465 A1 WO 2024067465A1
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alkyl
membered
alkoxy
halogenated
independently selected
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PCT/CN2023/121036
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English (en)
French (fr)
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刘斌
郭东满
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山东轩竹医药科技有限公司
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medical technology, and specifically to a KIF18A inhibitor, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, a pharmaceutical composition and a preparation containing the compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, a method for preparing the compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof, and use of the compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof in preparing a drug for treating and/or preventing diseases mediated by KIF18A and related diseases.
  • Kinesin molecules are motor proteins that use microtubules as tracks and play an important role in organelle migration, tissue and organ development, signal transduction, mitosis, meiosis and other processes.
  • Various microtubule-associated proteins (MAPs) of the kinesin-8 family of kinesins regulate the dynamic instability of microtubules by affecting the polymerization and depolymerization of microtubules. It is reported that the kinesin family is closely related to the invasion, metastasis and poor prognosis of various cancers. An increasing number of kinesin family members are believed to be associated with the occurrence and progression of tumors.
  • KIF18A is a member of the kinesin-8 family and is a multifunctional protein that uses adenosine triphosphate (ATP) hydrolysis to generate force and move along microtubules. It is involved in a variety of cellular functions, including cell division, cell movement, microtubule dynamics and organelle transport. KIF18A affects cell differentiation and cancer development. Studies have shown that KIF18A is associated with tumor behavior and can be used as a potential biomarker for breast cancer, colorectal cancer and hepatocellular carcinoma.
  • ATP adenosine triphosphate
  • CIN chromosomal instability
  • KIF18A Altered microtubule dynamics in mitotic CIN cells render them particularly dependent on KIF18A to reduce kinetochore-microtubule turnover and restrict microtubule growth.
  • centrosome fragmentation occurs, and mitotic progression slows or stops.
  • KIF18A is largely dispensable for the proliferation of diploid somatic cells in vivo but is essential for the proliferation of CIN tumor cells.
  • CIN tumor cells Upon inhibition of KIF18A, CIN tumor cells exhibit mitotic delays, multipolar spindles, and increased cell death. Therefore, KIF18A may be an effective target for specific inhibition of CIN tumor cell growth while having relatively low toxicity in somatic, diploid cells.
  • inhibitors targeting KIF18A will provide new ideas and strategies for the treatment of different types of tumors.
  • the object of the present invention is to provide a KIF18A inhibitor and its application.
  • the specific technical scheme is as follows:
  • the present invention first provides a compound represented by general formula (I), a pharmaceutically acceptable salt, an ester or a stereoisomer thereof:
  • X 1 and X 4 are independently selected from N or CR a ;
  • X 2 and X 3 are independently selected from N or C;
  • Ring A is selected from 5-12 membered cycloalkyl, 5-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, 5-12 membered bridged cyclyl or 5-12 membered bridged heterocyclyl;
  • Each of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, -C(O)-NH 2 , -S(O) 2 -NH 2 or -(L) m -H, -(L) m -C 1-6 alkyl, -(L) m -C 2-6 alkenyl, -(L) m -C 2-6 alkynyl, -(L) m -C 2-6 styryl ...
  • Each Q 1 and each Q 2 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl, carboxyl C 1-6 alkyl, amino C 1-6 alkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, C 1-6 alkylamino, di(C 1-6 alkyl)amino, -C(O)-NH 2 , C 1-6 alkylcarbonyl, C 1-6 alkyloxycarbonyl, C 1-6 alkylsulfonyl, C 1-6 alkylaminosulfonyl, C 1-6 alkylsulfonylamino, C 1-6 alkyl-OC 1-4 alkylene, halo C 1-6 alkyl-OC 1-4 alkylene or 3-12 membered cycloalkyl, 3-12 membered
  • Each L is independently selected from -C(O)-, -O-, -S-, -S(O)-, -S(O) 2- , -NRc- , -S(O)( NRc )-, -CRa1Rb- ;
  • each Ra , each Ra1 , and each Rb are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di( C1-6 alkyl)amino, C1-6 alkylaminoacyl, C1-6 alkylamido, C1-6 alkylsulfonylamino , C1-6 alkylaminosulfonyl, haloC1-6 alkyl, haloC1-6 alkoxy, hydroxyC1-6 alkyl, aminoC1-6 alkyl, carboxylC1-6 alkyl, -(L) m -6-10 membered aryl, -(L) m - 5-12 membered heteroaryl, -(L) m -3-8 membered cycloalkyl, or -(L) m -3-8 membered heterocyclyl;
  • Each R c is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, carboxy C 1-6 alkyl;
  • Each m and n are independently an integer from 0 to 6;
  • p is selected from 0, 1, 2 or 3.
  • X 1 , X 2 , X 3 and X 4 is N.
  • X 1 , X 2 , X 3 and X 4 are N.
  • the compound shown in the above scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 1 is selected from CR a .
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X1 is N.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X2 is C.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X2 is N.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X3 is C.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X3 is N.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X 4 is selected from CR a .
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein X4 is selected from N.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from a 5-10 membered cycloalkyl, a 5-10 membered heterocyclyl, a 6-10 membered aryl or a 5-10 membered heteroaryl.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein Ring A is selected from a 5-6-membered monocycloalkyl, a 5-6-membered monoheterocyclic group, an 8-10-membered fused cyclic group, an 8-10-membered fused heterocyclic group, a phenyl group, a 5-6-membered monoheteroaryl, an 8-10-membered fused aryl or an 8-10-membered fused heteroaryl.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein Ring A is selected from a 5-6-membered single heteroaryl, an 8-10-membered fused heterocyclic group or an 8-10-membered fused heteroaryl group.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from a 5-6-membered nitrogen-containing monoheteroaryl, an 8-10-membered nitrogen-containing fused heterocyclic group or an 8-10-membered nitrogen-containing fused heteroaryl group.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from cyclopentanyl, cyclohexanyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl, 2-pyri
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein ring A is selected from phenyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or 8-10 membered nitrogen-containing fused heterocyclic group.
  • ring A is selected from phenyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl
  • the compound shown in the above scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein, Selected from the following structures,
  • each Ra , each R1 , each Q1 and n are as described in any of the above technical solutions.
  • the compound shown in the above scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein, Selected from the following structures,
  • each Ra , each R1 , each Q1 and n are as described in any of the above technical solutions.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, or -(L) m -C 1-6 alkyl, -(L) m -C 1-6 alkoxy, halo-substituted C 1-6 alkyl, halo-substituted C 1-6 alkoxy, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl which is optionally substituted with 1 to 4 substituents Q 2.
  • each R 1 , R 2 , R 3 , R 4 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo-substituted C 1-6 alkyl or halo-substituted C 1-6 alkoxy.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, fluorine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5 is selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro, or -(L) m -C 1-6 alkyl, -(L) m -C 1-6 alkoxy, -(L) m -3-10 membered cycloalkyl, -(L) m -3-10 membered heterocyclyl, -(L) m -6-10 membered aryl, -(L) m -5-10 membered heteroaryl, -(L) m -5-11 membered spirocyclyl, -(L) m -5-11 membered spiroheterocyclyl, which is optionally substituted with 1-4 substituents Q 2.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5 is selected from -(L) m -C 1-6 alkyl, -(L) m -C 1-6 alkoxy, -(L) m -5-10 membered cycloalkyl, -(L) m -5-10 membered heterocyclyl, -(L) m -7-11 membered spirocyclyl, -(L) m -7-11 membered spiroheterocyclyl, which is optionally substituted with 1-4 substituents Q 2.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5 is selected from a 5-6 membered heterocyclyl or a 7-10 membered spiroheterocyclyl optionally substituted with 1-3 substituents Q 2 .
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 5 is selected from a 5-6-membered nitrogen-containing heterocyclic group or a 7-9-membered nitrogen-containing spiroheterocyclic group optionally substituted with 1-3 substituents Q 2 .
  • the compound, pharmaceutically acceptable salt, ester or stereoisomer thereof shown in the aforementioned scheme wherein R 5 is selected from an 8-membered nitrogen-containing spiro heterocyclic group optionally substituted by 1-3 substituents Q 2 .
  • each L is independently selected from -C(O)-, -S(O)-, -S(O) 2 -, -NR c -, -S(O)(NR c )-, -CR a1 R b -.
  • each L is independently selected from -S(O) 2 -, -NR c -, -CR a1 R b -.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 6 is selected from -S(O) 2 H, -C(O)H, -C(O)N(R c ) 2 , -N(R c )S(O) 2 -C 1-6 alkyl, -N(R c )-C 1-6 alkyl, -N(R c )S(O) 2 -3-6 membered cycloalkyl, -N(R c )S(O) 2 -3-6 membered heterocyclyl, -S(O) 2 N(R c )-C 1-6 alkyl, -S(O) 2 N(R c )-3-6 membered cycloalkyl, -S(O) 2 N(R c )-3-6 membered heterocyclyl, -S(O) 2 N(R c )-3-6 membered heterocyclyl,
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 6 is selected from -S(O) 2 H, -C(O)H, -C(O)N(R c ) 2 , -N(R c )S(O) 2 -C 1-6 alkyl, -N(R c )-C 1-6 alkyl, -N(R c )S(O) 2 -3-6 membered cycloalkyl, -N(R c )S(O) 2 -3-6 membered heterocyclyl, -S(O) 2 N(R c )-C 1-6 alkyl, -S(O) 2 N(R c )-3-6 membered cycloalkyl, -S(O) 2 N(R c )-3-6 membered heterocyclyl, -S(O) 2 N(R c )-3-6 membered heterocyclyl,
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R6 is selected from -S(O) 2H , -N( Rc )S(O) 2 - C1-6alkyl , -N( Rc ) -C1-6alkyl , -S(O) 2N ( Rc ) -C1-6alkyl , -S(O) 2 - C1-6alkyl , optionally substituted with 1-3 substituents Q2.
  • the compound shown in the above scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein R 6 is selected from the following structures:
  • each -Q 1 and each Q 2 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, carboxyl C 1-6 alkyl , amino C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-4 alkyl-OC 1-3 alkylene, halo C 1-4 alkyl-OC 1-3 alkylene or 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl which is optionally substituted with 1 to 3 substituents q.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each Q 1 and each Q 2 are independently selected from halogen, carboxyl, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, hydroxy C 1-6 alkyl, carboxyl C 1-6 alkyl, C 1-3 alkyl-OC 1-2 alkylene , halo C 1-3 alkyl - OC 1-2 alkylene or 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with 1-3 substituents q.
  • each Q 1 , each Q 2 are independently selected from fluorine, chlorine, bromine, iodine, carboxyl, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, methylamino, ethylamino, dimethylamino, methyl-O-methylene, methyl-O-ethylene, monofluoromethyl-O-methylene,
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each q is independently selected from halogen, hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkyl, halo-substituted C 1-4 alkoxy.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each q is independently selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
  • each Ra , each Ra1 and each Rb are independently selected from hydrogen, halogen, amino, hydroxyl, carboxyl, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di( C1-6 alkyl)amino, halo-substituted C1-6 alkyl, halo-substituted C1-6 alkoxy, hydroxyl C1-6 alkyl, amino C1-6 alkyl or carboxyl C1-6 alkyl.
  • each Ra , each Ra1 , and each Rb are independently selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, halo-substituted C1-6 alkyl or halo-substituted C1-6 alkoxy.
  • each Ra , each Ra1 and each Rb are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, carboxyl, hydroxyl, cyano, amino, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, ethylamino, dimethylamino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
  • each Ra , each Ra1 and each Rb are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.
  • each Ra , each Ra1 and each Rb are independently selected from hydrogen or methyl.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R c is independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkyl, halo C 1-4 alkoxy, hydroxy C 1-4 alkyl, amino C 1-4 alkyl or carboxy C 1-4 alkyl.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each R c is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each m is independently an integer of 0-4.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each m is independently selected from 0, 1, 2 or 3.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each n is independently an integer of 0-4.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein each n is independently selected from 0, 1, 2, 3.
  • the compound shown in the aforementioned scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein p is selected from 0 or 1.
  • the compound shown in the above scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein,
  • Ring A is selected from a 5-6 membered monocycloalkyl group, a 5-6 membered monoheterocyclic group, an 8-10 membered fused cyclic group, an 8-10 membered fused heterocyclic group, a phenyl group, a 5-6 membered monoheteroaryl group, an 8-10 membered fused aryl group or an 8-10 membered fused heteroaryl group;
  • Each of R 1 , R 2 , R 3 and R 4 is independently selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro or -(L) m -C 1-6 alkyl, -(L) m -C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl which is optionally substituted with 1 to 4 substituents Q 2;
  • R 5 is selected from hydrogen, halogen, cyano, carboxyl, hydroxyl, amino, nitro or -(L) m -C 1-6 alkyl, -(L) m -C 1-6 alkoxy, -(L) m -3-10 membered cycloalkyl, -(L) m -3-10 membered heterocyclyl, -(L) m -6-10 membered aryl, -(L) m -5-10 membered heteroaryl, -(L) m -5-11 membered spirocyclyl, -(L) m -5-11 membered spiroheterocyclyl, which is optionally substituted with 1 to 4 substituents Q 2;
  • Each L is independently selected from -S(O) 2 -, -NR c -, and -CR a1 R b -;
  • R is selected from -S(O) 2H , -C(O)H, -C(O)N(Rc), -N( Rc )S(O) 2 - C1-6alkyl , -N( Rc ) -C1-6alkyl , -N( Rc )S(O) 2-3-6- memberedcycloalkyl, -N( Rc )S(O) 2-3-6 -memberedheterocyclyl, -S(O)2N( Rc ) -C1-6alkyl , -S(O) 2N ( Rc ) -3-6 -memberedcycloalkyl, -S(O) 2N ( Rc )-3-6-memberedheterocyclyl, -S(O) 2 -C1-6alkyl, -S( O ) 2-3-6 -memberedcycloalkyl, -S(O) 2-3-6 -memberedheterocyclyl, -
  • each Ra , each Ra1 , and each Rb are independently selected from hydrogen, halogen, amino, hydroxy, carboxyl, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, di( C1-6 alkyl)amino, haloC1-6 alkyl, haloC1-6 alkoxy, hydroxyC1-6 alkyl, aminoC1-6 alkyl, or carboxylC1-6 alkyl;
  • Each R c is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy;
  • each Q 1 and each Q 2 are independently selected from halogen, carboxyl, hydroxyl, cyano, nitro, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, carboxyl C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, C 1-4 alkyl-OC 1-3 alkylene, halogenated C 1-4 alkyl-OC 1-3 alkylene, or 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl or phenyl which is optionally substituted with 1-3 substituents q; each q is independently selected from halogen, hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy
  • Each m and n are independently an integer from 0 to 4.
  • p is selected from 0 or 1.
  • the compound shown in the above scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein,
  • Ring A is selected from a 5-6 membered monoheteroaryl, an 8-10 membered fused heterocyclic group or an 8-10 membered fused heteroaryl group;
  • R 1 , R 2 , R 3 and R 4 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy;
  • R 5 is selected from -(L) m -C 1-6 alkyl, -(L) m -C 1-6 alkoxy, -(L) m -5-10 membered cycloalkyl, -(L) m -5-10 membered heterocyclyl, -(L) m -7-11 membered spirocyclyl, -(L) m -7-11 membered spiroheterocyclyl, which are optionally substituted with 1 to 4 substituents Q 2;
  • Each L is independently selected from -S(O) 2 -, -NR c -, -CR a1 R b -;
  • R6 is selected from -S(O) 2H , -N( Rc )S(O) 2 - C1-6 alkyl, -N(Rc)S(O)2-3-6-membered cycloalkyl, -N( Rc )-C1-6 alkyl, -N( Rc )S(O) 2-3-6 -membered heterocyclyl, -S(O)2N( Rc ) -C1-6 alkyl, -S(O) 2N (Rc)-3-6-membered cycloalkyl, -S(O) 2N ( Rc ) -3-6-membered heterocyclyl, -S(O) 2 - C1-6 alkyl, -S( O )2-3-6-membered cycloalkyl, -S(O) 2-3-6-membered heterocyclyl, -S(O)2-C1-6 alkyl , -S(O) 2-3-6 -membered cycloalky
  • the compound shown in the above scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein,
  • Ring A is selected from cyclopentyl, cyclohexyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, dihydroimidazolyl, pyrazolidinyl, dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridinyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl
  • Each of R 1 , R 2 , R 3 and R 4 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy.
  • R 5 is selected from 5-6 membered heterocyclyl or 7-10 membered spiroheterocyclyl optionally substituted by 1-3 substituents Q 2 ;
  • R 6 is selected from -S(O) 2 H, -N(R c )S(O) 2 -C 1-6 alkyl, -N(R c )-C 1-6 alkyl, -S(O) 2 N(R c )-C 1-6 alkyl, -S(O) 2 -C 1-6 alkyl , optionally substituted with 1 to 3 substituents Q 2;
  • Each Ra and each Rb are independently selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl or halogenated C1-6 alkoxy;
  • Each R c is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy;
  • Each Q 1 and each Q 2 are independently selected from halogen, carboxyl, hydroxyl, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-3 alkyl-OC 1-2 alkylene, halogenated C 1-3 alkyl-OC 1-2 alkylene or 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with 1-3 substituents q; each q is independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy;
  • n is selected from 0, 1 or 2;
  • p is selected from 0 or 1.
  • the compound shown in the above scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein,
  • R 1 , R 2 , R 3 and R 4 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy;
  • Each Ra is independently selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl or halogenated C1-6 alkoxy;
  • R 5 is selected from the following structures optionally substituted by 1 to 3 substituents Q 2 :
  • R6 is selected from the following structures:
  • Each Q 1 is independently selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-3 alkyl-OC 1-2 alkylene, halogenated C 1-3 alkyl-OC 1-2 alkylene or 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl optionally substituted with 1-3 substituents q; each q is independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy;
  • Each Q 2 is independently selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy;
  • n is selected from 0, 1 or 2.
  • the compound shown in the above scheme has the structure shown in formula (II),
  • X 5 is selected from N or CH; t is selected from 0, 1 or 2;
  • Ring A, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 4 , R 6 , each Q 1 , each Q 2 , n and p are as defined in any of the preceding schemes.
  • the compound shown in the above scheme its pharmaceutically acceptable salt, its ester or its stereoisomer, wherein,
  • X 5 is N
  • Each R 1 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy;
  • R 2 , R 3 , and R 4 are each independently hydrogen
  • R6 is selected from the following structures:
  • R 6 is selected from the following structures:
  • Each Q 1 is independently selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-3 alkyl-OC 1-2 alkylene, halogenated C 1-3 alkyl-OC 1-2 alkylene or 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl optionally substituted with 1-3 substituents q; each q is independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy;
  • Each Q 2 is independently selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy;
  • Each Ra is independently selected from hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl or halogenated C1-6 alkoxy;
  • n is selected from 0, 1 or 2.
  • the compound shown in the above scheme has the structure shown in formula (III),
  • X 5 is selected from N or CH; t is selected from 0, 1 or 2;
  • Ring A, X 1 , X 2 , X 3 , X 4 , R 1 , R 6 , each Q 1 , each Q 2 , n, and p are as defined in any of the preceding schemes.
  • the compound shown in the above scheme has the structure shown in formula (III'),
  • t is selected from 0, 1 or 2;
  • Ring A, X 2 , X 3 , X 4 , R 1 , R 6 , each Q 1 , each Q 2 , n, and p are as defined in any of the preceding schemes.
  • the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has a structure shown in formula (III-1), formula (III-2), formula (III-3) or formula (III-4),
  • the compound shown in the above scheme has the structure shown in formula (IV),
  • t is selected from 0, 1 or 2;
  • Ring A, X 3 , R 1 , Ra , R 6 , each Q 1 , each Q 2 , and n are as defined in any of the preceding schemes.
  • the compound shown in the above scheme has the structure shown in formula (IV-1),
  • t is selected from 0, 1 or 2;
  • R 1 , Ra , R 6 , each Q 1 , each Q 2 , and n are as defined in any of the preceding schemes.
  • the compound shown in the above scheme has the structure shown in formula (IV-2),
  • t is selected from 0, 1 or 2;
  • R 1 , Ra , R 6 , each Q 1 , each Q 2 , and n are as defined in any of the preceding schemes.
  • the compound shown in the above scheme has the structure shown in formula (IV-3),
  • t is selected from 0, 1 or 2;
  • R 1 , Ra , R 6 , each Q 1 , each Q 2 , and n are as defined in any of the preceding schemes.
  • the compound shown in the above scheme has the structure shown in formula (IV-4),
  • t is selected from 0, 1 or 2;
  • R 1 , Ra , R 6 , Q 1 and each Q 2 are as defined in any of the above schemes.
  • the compound shown in the above scheme has the structure shown in formula (IV-5),
  • R 1 , Ra , R 6 , each Q 1 , and n are as defined in any of the above schemes.
  • the compound shown in the above scheme has the structure shown in formula (IV-5),
  • R 6 is selected from the following structures:
  • R 1 , Ra , each Q 1 , and n are as defined in any of the preceding schemes.
  • the compound shown in the above scheme has the structure shown in formula (IV-6),
  • R 1 , Ra , R 6 , each Q 1 , and n are as defined in any of the above schemes.
  • the compound shown in the above scheme has the structure shown in formula (IV-6),
  • R 6 is selected from the following structures:
  • R 1 , Ra , each Q 1 , and n are as defined in any of the preceding schemes.
  • the compound shown in the above scheme, its pharmaceutically acceptable salt, its ester or its stereoisomer has the structure shown in formula (IV-7),
  • R 1 , Ra , R 6 , each Q 1 , and n are as defined in any of the above schemes.
  • the compound shown in the above scheme has the structure shown in formula (IV-7),
  • R 6 is selected from the following structures:
  • R 1 , Ra , each Q 1 , and n are as defined in any of the preceding schemes.
  • the compound shown in the above scheme has the structure shown in formula (IV-8),
  • R 1 , Ra , R 6 , and Q 1 are as defined in any of the above schemes.
  • the compound shown in the above scheme has the structure shown in formula (IV-8),
  • R 6 is selected from the following structures:
  • R 1 , Ra and Q 1 are as defined in any of the above schemes.
  • the structure of the provided compound, its pharmaceutically acceptable salt or its stereoisomer is as follows:
  • the present invention also provides a pharmaceutical composition, which contains the aforementioned compound, its pharmaceutically acceptable salt, ester or stereoisomer thereof, and one or more second therapeutically active agents.
  • the pharmaceutical composition also contains one or more pharmaceutically acceptable carriers and/or diluents.
  • the second therapeutic agent described in the present invention includes but is not limited to growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, antimetabolites, antimitotic agents, angiogenesis inhibitors, biological response modifiers, antihormones, and anticancer drugs.
  • the present invention also provides a pharmaceutical preparation, which contains the aforementioned compound, its pharmaceutically acceptable salt, ester or stereoisomer, and one or more pharmaceutical carriers and/or diluents; the pharmaceutical preparation is any dosage form that is clinically or pharmaceutically acceptable.
  • the above-mentioned pharmaceutical preparations can be administered to patients or subjects who need such treatment by oral, parenteral, rectal or pulmonary administration.
  • the pharmaceutical composition can be made into oral preparations, for example, conventional oral solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc.
  • suitable fillers, binders, disintegrants, lubricants, etc. can be added.
  • parenteral administration the above-mentioned pharmaceutical preparations can also be made into injections, including injections, sterile powders for injection and concentrated solutions for injection.
  • additives can be omitted or appropriate additives can be added according to the properties of the drugs.
  • the pharmaceutical composition can be made into suppositories, etc.
  • the pharmaceutical composition can be made into inhalants or sprays, etc.
  • the pharmaceutical carrier and/or diluent available in the pharmaceutical composition of the present invention or the pharmaceutical preparation can be any conventional carrier and/or diluent in the pharmaceutical preparation field, and the selection of specific carrier and/or diluent will depend on the mode of administration or disease type and state for treating a specific patient.
  • the preparation method of the suitable pharmaceutical composition for a specific mode of administration is completely within the knowledge of the pharmaceutical field technician.
  • the pharmaceutical carrier and/or diluent can include conventional solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, adhesives, lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, and antioxidants, etc. in the pharmaceutical composition. If necessary, flavoring agents, preservatives, and sweeteners, etc. can also be added to the pharmaceutical composition.
  • the present invention also provides the use of the aforementioned compound, its pharmaceutically acceptable salt, ester or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition in the preparation of a drug for treating and/or preventing KIF18A-mediated diseases and related diseases; the KIF18A-mediated diseases and related diseases are selected from cancer or benign tumors.
  • the present invention also provides the use of the aforementioned compound, its pharmaceutically acceptable salt, ester or stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition in the treatment and/or prevention of KIF18A-mediated diseases and related diseases; the KIF18A-mediated diseases and related diseases are selected from cancer or benign tumors.
  • the present invention also provides a method for treating a disease, comprising administering a therapeutically effective amount of the aforementioned compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, the aforementioned pharmaceutical preparation or the aforementioned pharmaceutical composition to a patient in need thereof, wherein the disease is a KIF18A-mediated disease and related diseases; the KIF18A-mediated disease and related diseases are selected from cancer or benign tumors.
  • the cancer or benign tumor includes but is not limited to melanoma, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, brain cancer, head and neck cancer, thyroid cancer, lung cancer, bronchial cancer, esophageal cancer, gastric cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, colon cancer, bladder cancer, prostate cancer, testicular cancer, skin cancer, bone cancer and blood tumor;
  • the lung cancer includes but is not limited to small cell lung cancer and non-small cell lung cancer;
  • the blood tumor includes but is not limited to leukemia, lymphoma, myeloma;
  • the brain cancer includes but is not limited to glioma, neuroblastoma, astrocytoma, meningioma.
  • halogen refers to fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
  • halogenated means that any hydrogen in the substituent may be replaced by one or more halogens which are the same or different. "Halogen” is as defined above.
  • C 1-6 alkyl refers to a straight or branched alkyl group containing 1 to 6 carbon atoms, including, for example, “C 1-5 alkyl”, “C 1-4 alkyl”, “C 1-3 alkyl”, “C 1-2 alkyl”, “C 2-6 alkyl”, “C 2-5 alkyl”, “C 2-4 alkyl", “C 2-3 alkyl”, “C 3-6 alkyl”, “C 3- 5 alkyl”, “C 3-4 alkyl", “C 4-6 alkyl", “C 4-5 alkyl", "C Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1- ethylpropyl , n-hexyl, iso
  • C 1-6 alkylene refers to a group formed by removing a hydrogen atom from the above-mentioned C 1-6 alkyl, including, for example, “C 1-5 alkylene”, “C 1-4 alkylene”, “C 1-3 alkylene”, “C 1-2 alkylene”, “C 2-6 alkylene”, “C 2-5 alkylene”, “C 2-4 alkylene", “C 2-3 alkylene”, “C 3-6 alkylene", “C 3-5 alkylene", “C 3-4 alkylene”, “C 4-6 alkylene”, “C 4-5 alkylene", “C 5-6 alkylene”, etc.
  • C 1-4 alkylene refers to a specific example of C 1-6 alkylene containing 1 to 4 carbon atoms.
  • C 2-6 alkenyl refers to a linear or branched or cyclic alkenyl group with 2 to 6 carbon atoms containing at least one double bond, including, for example, “C 2-5 alkenyl”, “C 2-4 alkenyl”, “C 2-3 alkenyl”, etc.
  • Specific examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 2-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3- Methyl-1-pentenyl, 1-methyl-2-pentenyl, 3-methyl-2-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 2,2-dimethyl-3-
  • C 2-6 alkynyl refers to a straight or branched alkynyl group with 2 to 8 carbon atoms containing a triple bond, including, for example, “C 2-5 alkynyl”, “C 2-4 alkynyl”, “C 2-3 alkynyl”, etc.
  • Specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1,1-dimethyl-3-butynyl, 2-ethyl-3-butynyl, etc.
  • halogenated C 1-6 alkyl, hydroxyl C 1-6 alkyl, amino C 1-6 alkyl, carboxyl C 1-6 alkyl, halogenated C 1-6 alkoxy refers to a group formed by one to more (e.g., 1-4, 1-3, 1-2) halogen atoms, hydroxyl groups, amino groups, and carboxyl groups replacing the hydrogen atoms in the C 1-6 alkyl, C 1-6 alkylene, and C 1-6 alkoxy groups, respectively.
  • halogenated C 1-4 alkyl, hydroxyl C 1-4 alkyl, amino C 1-4 alkyl, carboxyl C 1-4 alkyl, halogenated C 1-4 alkoxy refers to a group formed by one to more (e.g., 1-4, 1-3, 1-2) halogen atoms, hydroxyl groups, and amino groups replacing the hydrogen atoms in the C 1-4 alkyl group and the C 1-4 alkoxy group, respectively.
  • the "3-12 membered cycloalkyl” mentioned in the present invention includes “3-8 membered cycloalkyl” and "7-12 membered condensed cycloalkyl”.
  • the "3-8 membered cycloalkyl” described in the present invention refers to a saturated or partially saturated monocyclic alkyl group containing 3-8 carbon atoms and not aromatic, including "3-8 membered saturated cycloalkyl” and “3-8 membered partially saturated cycloalkyl”; preferably “3-4 membered cycloalkyl", “3-5 membered cycloalkyl", “3-6 membered cycloalkyl”, “3-7 membered cycloalkyl”, “4-5 membered cycloalkyl”, “4-6 membered cycloalkyl”, “4-7 membered cycloalkyl”, “4-8 membered cycloalkyl”, “5-6 membered cycloalkyl”, “5-7 membered cycloalkyl”, “5-8 membered cycloalkyl”, “6-7 membered cycloalkyl”, “6-8 membered cycloalkyl”, “7-8 membered cycloalkyl
  • the "3-8 membered saturated cycloalkyl" described in the present invention refers to a saturated cycloalkyl group having 3-8 carbon atoms, including a saturated cycloalkyl group having 3-8 carbon atoms, including a saturated cycloalkyl group having 3-8 carbon atoms, including a saturated cycloalkyl group having 3-8 carbon atoms, including a saturated cycloalkyl group having 3-6 carbon atoms, including a saturated cycloalkyl group having 5-8 carbon atoms, including a saturated cycloalkyl group having 5-7 carbon atoms, including a saturated cycloalkyl group having 5-6 ...
  • cyclopropanyl (cyclopropyl), cyclobutanyl (cyclobutyl), cyclopentanyl (cyclopentyl), cyclohexanyl (cyclohexyl), cycloheptanyl (cycloheptyl), cyclooctyl (cyclooctyl), etc.
  • specific examples of the "3-8 membered partially saturated cycloalkyl” include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohex-1,3-diene, cyclohex-1,4-diene, cycloheptenyl, cyclohept-1,3-dienyl, cyclohept-1,4-dienyl, cyclohept-1,3,5-trienyl, cyclooctenyl, cyclopropenyl, cycl
  • the "7-12 membered fused heterocyclic group” described in the present invention refers to a saturated or partially saturated, non-aromatic cyclic group containing 7-12 ring atoms formed by two or more cyclic structures sharing two adjacent carbon atoms.
  • One ring in the fused ring can be an aromatic ring, but the fused ring as a whole does not have aromaticity; it includes "7-9 membered fused ring group", "9-10 membered fused ring group”, etc., and the fusion mode can be: 5-6 membered cycloalkyl and 5-6 membered cycloalkyl, benzo 5-6 membered cycloalkyl, benzo 5-6 membered saturated cycloalkyl, etc.
  • Examples include, but are not limited to, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.0]hexanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.2.0]octanyl, octahydropentalenyl, octahydro-1H-indenyl, decahydronaphthyl, tetradecahydrophenanthrenyl, bicyclo[3.1.0]hex-2-enyl, bicyclo[4.1.0]hept-3-enyl, bicyclo[3.2.0]hept-3-enyl, Bicyclo[4.2.0]oct-3-enyl, 1,2,3,3a-tetrahydropentalenyl, 2,3,3a,4,7,7a-hexahydro-1H-indenyl, 1,2,3,4,4a,5,6,8a-octahydronaphthyl, 1,2,4a,5,6,
  • the "3-12 membered heterocyclic group” described in the present invention includes “3-8 membered heterocyclic group” and "7-12 membered fused heterocyclic group”.
  • the "3-8 membered heterocyclic group” of the present invention refers to a saturated or partially saturated monocyclic group without aromaticity, which contains at least one heteroatom (e.g., 1, 2, 3, 4 or 5) and has 3-8 ring atoms, wherein the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom, and optionally, the ring atoms (e.g., carbon atoms, nitrogen atoms or sulfur atoms) in the ring structure can be oxidized.
  • the "3-8 membered heterocyclic group” of the present invention includes "3-8 membered saturated heterocyclic group” and "3-8 membered partially saturated heterocyclic group”.
  • the "3-8 membered heterocyclic group" of the present invention contains 1-3 heteroatoms; preferably, the "3-8 membered heterocyclic group” of the present invention contains 1-2 heteroatoms, and the heteroatoms are selected from nitrogen atoms and/or oxygen atoms; preferably, the "3-8 membered heterocyclic group” of the present invention contains 1 nitrogen atom.
  • the “3-8 membered heterocyclic group” is preferably a “3-7 membered heterocyclic group”, “3-6 membered heterocyclic group”, “4-7 membered heterocyclic group”, “4-6 membered heterocyclic group”, “6-8 membered heterocyclic group”, “5-7 membered heterocyclic group”, “5-6 membered heterocyclic group”, “3-6 membered saturated heterocyclic group”, “5-6 membered saturated heterocyclic group”, “3-6 membered nitrogen-containing heterocyclic group”, “3-6 membered saturated nitrogen-containing heterocyclic group”, “5-6 membered nitrogen-containing heterocyclic group”, “5-6 membered saturated nitrogen-containing heterocyclic group”, etc.
  • 3- to 8-membered heterocyclic group include, but are not limited to, aziridine, 2H-aziridine, diaziridine, 3H-diazirinyl, azetidinyl, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxadienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl
  • the "7-12 membered fused heterocyclic group” of the present invention refers to a saturated or partially saturated, non-aromatic cyclic group containing 7-12 ring atoms formed by two or more cyclic structures sharing two adjacent atoms, and at least one ring atom is a heteroatom, wherein one of the rings in the fused ring may be an aromatic ring, but the fused ring as a whole does not have aromaticity, and the heteroatom is a nitrogen atom, an oxygen atom and/or a sulfur atom, and optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure may be oxidized, including but not limited to "7-9 membered fused heterocyclic group", "8- The condensed form can be 5-6-membered heterocyclic group and 5-6-membered heterocyclic group, 5-6-membered heterocyclic group and 5-6-membered cycloalkyl, benzo 5-6-member
  • the "5-10 membered cycloalkyl group” described in the present invention is an example of a “3-12 membered cycloalkyl group” containing 5 to 10 ring atoms.
  • the "5-10 membered heterocycloalkyl” described in the present invention is an example of a “3-12 membered heterocycloalkyl" containing 5 to 10 ring atoms.
  • the "6-10 membered aryl group” described in the present invention refers to an aromatic cyclic group containing 6-10 ring carbon atoms, including "6-8 membered monocyclic aryl group” and "8-10 membered condensed ring aryl group”.
  • the "6-8 membered monocyclic aromatic group" described in the present invention refers to a monocyclic aromatic group containing 6-8 ring carbon atoms, examples of which include but are not limited to: phenyl, cyclooctatetraenyl, etc.; preferably phenyl.
  • the "8-10 membered fused ring aromatic group” described in the present invention refers to an unsaturated aromatic cyclic group containing 8-10 ring carbon atoms, which is formed by two or more cyclic structures sharing two adjacent atoms, preferably a "9-10 membered fused ring aromatic group", and specific examples include naphthyl and the like.
  • the "5-12 membered heteroaryl” of the present invention refers to an aromatic cyclic group containing 5-12 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom), for example, a 5-12 membered nitrogen-containing heteroaryl, a 5-12 membered oxygen-containing heteroaryl, a 5-12 membered sulfur-containing heteroaryl, etc. It includes "5-8 membered single heteroaryl" and "7-12 membered condensed heteroaryl".
  • the "5-8-membered single heteroaryl” of the present invention refers to a monocyclic cyclic group with aromaticity containing 5-8 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom).
  • a heteroatom such as a nitrogen atom, an oxygen atom or a sulfur atom.
  • the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the ring structure can be oxo-substituted.
  • "5-8-membered single heteroaryl” includes, for example, "5-7-membered single heteroaryl", "5-6-membered single heteroaryl", “5-6-membered nitrogen-containing single heteroaryl", "5-membered nitrogen-containing single heteroaryl” and the like.
  • 5-8 membered monocyclic heteroaryl include, but are not limited to, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azepine, 1,3-diazacycloheptatrienyl, azocyclo
  • the "7-12 membered fused heteroaryl" of the present invention refers to an unsaturated aromatic cyclic structure formed by two or more cyclic structures sharing two adjacent atoms, containing 7-10 ring atoms (at least one of which is a heteroatom, such as a nitrogen atom, an oxygen atom or a sulfur atom).
  • the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the cyclic structure may be oxo-substituted.
  • Including "8-10 membered fused heteroaryl", “7-9 membered fused heteroaryl”, etc., and the fusion mode can be benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, etc.; specific examples include but are not limited to: pyrrolopyrrole, pyrrolofuran, pyrazolopyrrole, pyrazolothiophene, furathiophene, pyrazolooxazole, benzofuranyl, benzisofuranyl, benzothiophenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl
  • the "5-12-membered bridged ring group” of the present invention refers to a structure containing 5-12 carbon atoms formed by two atoms that are not directly connected to each other shared by any two rings, and the "5-12-membered bridged ring” includes a 5-12-membered saturated bridged ring group and a 5-12-membered partially saturated bridged ring group.
  • a 5-10-membered bridged ring group a 5-8-membered bridged ring group, a 5-10-membered saturated bridged ring group, a 5-8-membered saturated bridged ring group, a 6-10-membered saturated bridged ring group, and a 7-12-membered partially saturated bridged ring group are used.
  • Specific examples include but are not limited to
  • the "5-12-membered bridged heterocyclic group" of the present invention refers to at least one ring carbon atom in the above 5-12-membered bridged heterocyclic group replaced by a heteroatom selected from O, S, and N, preferably 1-3 heteroatoms, and includes the case where the carbon atom, nitrogen atom, and sulfur atom can be oxidized, preferably a 5-10-membered bridged heterocyclic group, a 5-8-membered bridged heterocyclic group. Specific examples include but are not limited to:
  • the "5-12 membered spirocyclyl” of the present invention refers to a structure containing 5-12 carbon atoms formed by at least two rings sharing one atom. It includes 5-12 membered saturated spirocyclyl and 5-12 membered partially saturated spirocyclyl, including, for example, “5-10 membered saturated spirocyclyl”, “5-10 membered unsaturated spirocyclyl”, “5-8 membered spirocyclyl”, “5-8 membered saturated spirocyclyl”, “5-8 membered unsaturated spirocyclyl”, “7-11 membered spirocyclyl”, “7-10 membered spirocyclyl”, “7-9 membered spirocyclyl”, “8-10 membered spirocyclyl”, “8-11 membered spirocyclyl”, and specific examples of 5-12 membered saturated spirocyclyl include but are not limited to: A 5-12 membered
  • the "5-12 membered spiro heterocyclic group" of the present invention refers to a 5-12 membered spiro heterocyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N, preferably 1-3 heteroatoms, and includes the case where the carbon atom, nitrogen atom, and sulfur atom can be oxo-substituted.
  • spiro heterocyclic group Including, for example, 5-10 membered spiro heterocyclic group, 5-8 membered spiro heterocyclic group, 5-6 membered spiro heterocyclic group, 7-12 membered spiro heterocyclic group, 7-11 membered spiro heterocyclic group, 7-11 membered nitrogen-containing spiro heterocyclic group, 7-10 membered spiro heterocyclic group, 7-10 membered nitrogen-containing spiro heterocyclic group, 7-9 membered spiro heterocyclic group, 7-9 membered nitrogen-containing spiro heterocyclic group, 8 membered nitrogen-containing spiro heterocyclic group.
  • Specific examples include, but are not limited to:
  • the “pharmaceutically acceptable salt” described in the present invention refers to pharmaceutically acceptable acid and base addition salts, such as metal salts, ammonium salts, salts formed with organic acids, salts formed with organic bases, salts formed with inorganic acids, salts formed with acidic amino acids or basic amino acids, etc.
  • ester refers to a pharmaceutically acceptable ester, in particular to an ester that is hydrolyzed in vivo and includes an ester that is easily decomposed in the human body to leave the parent compound (the compound of general formula (I)) or its salt.
  • the "ester” of the present invention can be selected from the following groups: (1) carboxylic acid esters obtained by esterification with carboxylic acid compounds, wherein the non-carbonyl portion of the carboxylic acid compound is selected from, for example, C 1-20 straight or branched chain C1-6 straight chain or branched chain alkyl, C1-12 straight chain or branched chain alkyl, C1-8 straight chain or branched chain alkyl, C1-6 straight chain or branched chain alkyl (e.g. methyl, ethyl, n-propyl, tert-butyl or n-butyl), C1-6 alkoxy C1-6 alkyl (e.g.
  • C6-10 aryl C1-6 alkyl e.g. benzyl
  • C6-10 aryloxy C1-6 alkyl e.g. phenoxymethyl
  • C6-10 aryl e.g. phenyl, optionally substituted by, for example, halogen, C1-4 alkyl or C1-4 alkoxy or amino
  • sulfonate such as alkylsulfonyl or aralkylsulfonyl (e.g. methylsulfonyl)
  • amino acid ester e.g.
  • L-valyl or L-isoleucyl and (4) mono-, di- or triphosphate esters, etc.; (4) esters obtained by esterification with alcohol compounds, wherein the non-hydroxyl portion of the alcohol compound is selected from, for example, C C 1-20 straight chain or branched alkyl, C 1-12 straight chain or branched alkyl, C 1-8 straight chain or branched alkyl, C 1-6 straight chain or branched alkyl (e.g. methyl, ethyl, n-propyl, tert-butyl or n-butyl), C 1-6 alkoxy C 1-6 alkyl (e.g. methoxymethyl), C 6-10 aryl C 1-6 alkyl (e.g.
  • benzyl C 6-10 aryloxy C 1-6 alkyl (e.g. phenoxymethyl), C 6-10 aryl (e.g. phenyl, optionally substituted by, for example, halogen, C 1-4 alkyl or C 1-4 alkoxy or amino).
  • the "stereoisomer" of the present invention refers to when the compounds of the present invention contain one or more asymmetric centers, and thus can be used as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers.
  • the compounds of the present invention may have asymmetric centers, and such asymmetric centers each independently produce two optical isomers.
  • the scope of the present invention includes all possible optical isomers and their mixtures. If the compounds of the present invention contain olefin double bonds, unless otherwise specified, cis isomers and trans isomers are included.
  • the compounds of the present invention may exist in the form of tautomers (a kind of functional group isomers), which have different hydrogen attachment points through one or more double bond displacements, for example, a ketone and its enol form are keto-enol tautomers.
  • tautomers a kind of functional group isomers
  • a ketone and its enol form keto-enol tautomers.
  • Each tautomer and its mixture are included in the scope of the present invention.
  • Enantiomers, diastereomers, racemates, mesomorphs, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of all compounds are included in the scope of the present invention.
  • the “therapeutically effective amount” of the present invention refers to the amount of the aforementioned compound, pharmaceutical preparation, or pharmaceutical composition that can at least alleviate the symptoms of the patient's condition when administered to the patient.
  • the actual amount comprising the "therapeutically effective amount” will vary depending on a variety of circumstances, including but not limited to the specific condition being treated, the severity of the condition, the patient's physical and health condition, and the route of administration. A skilled medical practitioner can easily determine the appropriate amount using methods known in the medical field.
  • the compounds of the present invention have excellent KIF18A inhibitory activity and can treat and/or prevent KIF18A-mediated diseases and related diseases;
  • the compounds of the present invention have a good inhibitory effect on tumor cells
  • the compound of the present invention has a simple preparation process, high drug purity, stable quality, and is easy to carry out large-scale industrial production.
  • Test samples some compounds of the present invention, their chemical names and structures are shown in the preparation examples.
  • OVCAR3 TP53 mutant human ovarian cancer cells
  • MDA-MB-157 TP53 mutant human breast cancer cells
  • the culture medium for OVCAR3 cells was RPMI Medium 1640 + 20% FBS + 1% PS, and the culture medium for MDA-MB-157 cells was DMEM Medium + 10% FBS + 1% PS. The cells were tested in the logarithmic growth phase.
  • DMSO stock solution of the test compound The concentration of the stock solution of the test compound is 10 mM.
  • test compound stock solution was 10 mM, and was diluted 3 times in series, with a total of 9 concentrations. Then, 2 ⁇ L of the DMSO-diluted compound was added to 198 ⁇ L of culture medium to form the test compound working stock solution (the compound concentration was 10 times the final concentration, and the highest concentration was 100 ⁇ M).
  • the final concentrations of the tested compounds were: 10 ⁇ M, 3.33 ⁇ M, 1.11 ⁇ M, 370 nM, 123 nM, 41.1 nM, 13.7 nM, 4.57 nM, 1.52 nM.
  • Inhibition rate (%) 1-(test well reading + blank control well reading)/(DMSO solvent control well reading - blank control well reading) ⁇ 100%;
  • the compounds of the present invention can effectively inhibit the proliferation of OVCAR3 and MDA-MB-157 cells, indicating that the compounds of the present invention have clinical application potential in treating cancerous diseases with TP53 mutations.
  • Test sample the compound of the present invention, its structural formula and preparation method are shown in the preparation examples.
  • the compound of the present invention was prepared to 10 mM using DMSO as a test stock solution.
  • test stock solution was diluted 3-fold to 10 concentrations, with the highest concentration being 10 mM.
  • test compounds were 10000 nM, 3333.3 nM, 1111.1 nM, 370.4 nM, 123.5 nM, 41.2 nM, 13.7 nM, 4.57 nM, 1.52 nM, and 0.51 nM.
  • the inhibition rate (%inh) was calculated using the following formula:
  • Test compound inhibition rate (%inh) 100*(ave High control-cpd well)/(ave High control-ave Low control)
  • ave High control means the luminescent signal intensity of the positive control well without adding the compound
  • ave Low control means the luminescent signal intensity of the negative control well without enzyme
  • cpd well means: represents the luminescence signal intensity of the test compound
  • IC50 was calculated using XLfit.
  • Test sample Compound of the present invention, homemade, its chemical name and preparation method can be found in the preparation examples of each compound.
  • Test animals CD1 mice, female, 6 mice/administration route/compound.
  • Preparation method of blank solvent (1) Weigh 20g HPC (hydroxypropyl cellulose), slowly add to 500mL of stirring purified water, then add 1mL Tween 80, stir until clear and transparent, make up to 1000mL, stir evenly to obtain 2% HPC + 0.1% Tween 80.
  • IV (intravenous push) administration
  • the compound of the present invention e.g., 2.58 mg
  • DMA N,N-dimethylacetamide
  • Kolliphor HS15 polyethylene glycol-15-hydroxystearate
  • DPBS Dubren phosphate buffer
  • An appropriate amount of the example compound of the present invention (e.g., 10.16 mg) was weighed and placed in a tissue grinder.
  • a blank solvent (1) (e.g., 3.102 mL) was added and ground evenly at a speed of 1000 rpm to prepare a 3 mg/mL suspension solution as the PO administration solution of the test compound.
  • the IV dosage is 2.5 mg/kg, the dosage concentration is 0.5 mg/mL, and the dosage volume is 5 mL/kg.
  • the PO dose is 30 mg/kg, the dosing concentration is 3 mg/mL, and the dosing volume is 10 mL/kg.
  • Blood collection time points 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24h after administration, blood was collected according to the method shown in Table 4:
  • the protein precipitation method was used: 20 ⁇ L of plasma sample was taken, 200 ⁇ L of internal standard (acetonitrile solution containing 200 ng/mL of tolbutamide) was added, vortexed for 10 min, and then centrifuged at 4000 rpm for 20 min. 100 ⁇ L of supernatant was taken, 100 ⁇ L of water was added, and vortexed for 3 min. The drug concentration in plasma was analyzed by LC-MS/MS.
  • internal standard acetonitrile solution containing 200 ng/mL of tolbutamide
  • test results show that the compound of the present invention has good pharmacokinetic properties, a lower clearance rate, and a higher exposure and bioavailability.
  • DIPEA N,N-diisopropylethylamine
  • DMSO dimethyl sulfoxide
  • DEAD diethyl azodicarboxylate
  • RuPhos Pd G3 methanesulfonate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II)
  • Boc-NH 2 (1.1 g, 9.4 mmol), RuPhos Pd G3 (401 mg, 0.48 mmol) and cesium carbonate (4.7 g, 14.4 mmol) were added to a solution of Int-9 (1.0 g, 4.8 mmol) in 1,4-dioxane (40 mL), and the mixture was reacted at 100°C for 3 hours under nitrogen protection.
  • Example 3 6-Chloro-1H-pyrrolo[2,3-b]pyridine and iodopropane were used as raw materials, and the preparation method of Example 1 was referred to to prepare 4-((2-hydroxyethyl)sulfonamide)-N-(1-propyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide (Compound 3) 100 mg with a yield of 50.3%.
  • Tetrahydro-2H-pyran-4-ol (4.0 g, 39 mmol) was dissolved in DCM (40 mL), triethylamine (11.8 g, 117 mmol) was added, and methylsulfonyl chloride (4.9 g, 43 mmol) was added at 0°C. The mixture was reacted at 0°C for 1 hour, purified water was added to quench the mixture, the mixture was washed once, and the organic phase was concentrated to obtain 4.8 g of the target compound with a yield of 67.6%.
  • the target compound was prepared according to the preparation method of Example 1.
  • Example 1 6-Chloro-1H-pyrazolo[3,4-b]pyridine and 1-iodo-2-methoxyethane were used as raw materials, and the preparation method of Example 1 was referred to to prepare 4-((2-hydroxyethyl)sulfonamido)-N-(1-(2-methoxyethyl)-1H-pyrazolo[3,4-b]pyridine-6-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide.
  • Example 1 N-(1-(2-(difluoromethoxy)ethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide.

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Abstract

提供了一类可用作KIF18A抑制剂的化合物、其药学上可接受的盐、其酯或其立体异构体，含有所述化合物、其药学上可接受的盐、其酯或其立体异构体的药物组合物及制剂，制备所述化合物、其药学上可接受的盐、其酯或其立体异构体的方法，以及所述化合物、其药学上可接受的盐、其酯或其立体异构体在制备治疗和/或预防由KIF18A介导的疾病及相关疾病的药物中的用途。

Description

KIF18A抑制剂 技术领域
本发明涉及医药技术领域，具体涉及KIF18A抑制剂、其药学上可接受的盐、其酯或其立体异构体，含有所述化合物、其药学上可接受的盐、其酯或其立体异构体的药物组合物及制剂，制备所述化合物、其药学上可接受的盐、其酯或其立体异构体的方法，以及所述化合物、其药学上可接受的盐、其酯或其立体异构体在制备治疗和/或预防由KIF18A介导的疾病及相关疾病的药物中的用途。
背景技术
驱动蛋白分子是以微管为轨道的马达蛋白，在细胞器迁移、组织器官发育、信号传导、有丝分裂、减数分裂等过程中发挥重要作用。驱动蛋白kinesin-8家族的多种微管结合蛋白(microtubule-associated protein，MAP)通过影响微管的聚合和解聚行使着调控微管动态不稳定性的功能。据报道，驱动蛋白家族与多种癌症的侵袭、转移和预后不良密切相关。越来越多的驱动蛋白家族成员被认为与肿瘤的发生和进展有关。KIF18A是kinesin-8家族的一员，是一种多功能蛋白，它利用三磷酸腺苷(ATP)水解产生力并沿着微管移动。它参与多种细胞功能，包括细胞分裂、细胞运动、微管动力学和细胞器运输。KIF18A会影响细胞分化以及癌症发展。已有研究表明，KIF18A与肿瘤行为有关，可用作乳腺癌、结直肠癌和肝细胞癌的潜在生物标志物。
遗传不稳定性是肿瘤细胞的共同特征，大量肿瘤细胞表现出染色体的频繁丢失或增加。这种染色体不稳定性(Chromosomal instability，CIN)主要是由于缺陷导致染色体和有丝分裂纺锤体微管之间的异常相互作用，进而增加染色体分离错误。与染色体稳定的细胞相比，CIN细胞显示纺锤体微管聚合增加，纺锤体微管和动粒之间的附着物周转减少，动粒是在有丝分裂染色体的着丝粒区域组装的特殊蛋白质结构。因此，CIN细胞可能特别容易受到针对微管细胞骨架的抗有丝分裂疗法的影响。
有丝分裂CIN细胞中改变的微管动力学使它们特别依赖KIF18A来减少动粒-微管周转并限制微管生长。在缺失KIF18A活性的情况下，会发生中心体断裂，并且有丝分裂进程会减慢或停止。KIF18A对于体内二倍体体细胞的增殖在很大程度上是可有可无的，但对于CIN肿瘤细胞的增殖是必需的。在抑制KIF18A后，CIN肿瘤细胞表现出有丝分裂延迟、多极纺锤体和细胞死亡增加。因此，KIF18A可能是特异性抑制CIN肿瘤细胞生长的有效靶点，同时在体细胞、二倍体细胞中具有相对较低的毒性。
综上所述，以KIF18A为靶点开发抑制剂将为不同类型肿瘤的治疗提供新的思路和策略。
发明内容
本发明的目的在于提供一种KIF18A抑制剂及其应用。具体技术方案如下：
在某些实施方案中，本发明首先提供了通式(I)所示的化合物、其药学上可接受的盐、其酯或其立体异构体：
其中，
X1、X4分别独立地选自N或CRa；
X2、X3分别独立地选自N或C；
环A选自5-12元环烷基、5-12元杂环基、6-10元芳基、5-12元杂芳基、5-12元螺环基、5-12元螺杂环基、5-12元桥环基或5-12元桥杂环基；
每一R1、R2、R3、R4、R5、R6分别独立地选自氢，卤素，氰基，羧基，羟基，氨基，硝基，-C(O)-NH2，-S(O)2-NH2或任选被1-4个取代基Q2取代的-(L)m-H、-(L)m-C1-6烷基、-(L)m-C2-6烯基、-(L)m-C2-6炔基、- (L)m-C1-6烷氧基、二(C1-6烷基)氨基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基、-(L)m-3-12元环烷基、-(L)m-3-12元杂环基、-(L)m-6-10元芳基、-(L)m-5-12元杂芳基、-(L)m-5-12元螺环基、-(L)m-5-12元螺杂环基、-(L)m-5-12元桥环基、-(L)m-5-12元桥杂环基；
每一Q1、每一Q2分别独立地选自卤素，羧基，羟基，氰基，硝基，氨基，C1-6烷基，C2-6烯基，C2-6炔基，C1-6烷氧基，羟基C1-6烷基，羧基C1-6烷基，氨基C1-6烷基，卤代C1-6烷基，卤代C1-6烷氧基，C1-6烷基氨基，二(C1-6烷基)氨基，-C(O)-NH2，C1-6烷基羰基，C1-6烷基氧基羰基，C1-6烷基磺酰基，C1-6烷基氨基磺酰基，C1-6烷基磺酰氨基，C1-6烷基-O-C1-4亚烷基，卤代C1-6烷基-O-C1-4亚烷基或任选被1-4个取代基q取代的3-12元环烷基、3-12元杂环基、6-10元芳基、5-12元杂芳基、5-12元螺环基、5-12元螺杂环基，所述取代基q分别独立地选自卤素、羟基、氨基、羧基、氰基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基；
每一L分别独立地选自-C(O)-、-O-、-S-、-S(O)-、-S(O)2-、-NRc-、-S(O)(NRc)-、-CRa1Rb-；
每一Ra、每一Ra1、每一Rb分别独立地选自氢、卤素、氨基、羟基、羧基、氰基、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、二(C1-6烷基)氨基、C1-6烷基氨酰基、C1-6烷基酰氨基、C1-6烷基磺酰氨基、C1-6烷基氨基磺酰基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基、-(L)m-6-10元芳基、-(L)m-5-12元杂芳基、-(L)m-3-8元环烷基或-(L)m-3-8元杂环基；
每一Rc分别独立地选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基；
每一m、n分别独立地为0-6的整数；
p选自0、1、2或3。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，X1、X2、X3、X4至少有一个为N。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，X1、X2、X3、X4至少有两个为N。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，X1选自CRa。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，X1为N。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，X2为C。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，X2为N。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，X3为C。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，X3为N。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，X4选自CRa。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，X4选自N。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，环A选自5-10元环烷基、5-10元杂环基、6-10元芳基或5-10元杂芳基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，环A选自5-6元单环烷基、5-6元单杂环基、8-10元稠环基、8-10元稠杂环基、苯基、5-6元单杂芳基、8-10元稠芳基或8-10元稠杂芳基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，环A选自5-6元单杂芳基、8-10元稠杂环基或8-10元稠杂芳基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，环A选自5-6元含氮单杂芳基、8-10元含氮稠杂环基或8-10元含氮稠杂芳基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中环A选自环戊烷基、环己烷基、二氢吡咯基、吡咯烷基、咪唑烷基、二氢咪唑基、吡唑烷基、二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、哌啶基、哌嗪基、吗啉基、苯基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、恶唑基、异恶唑基、恶二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基或8-10元含氮稠杂环基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，环A选自苯基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、恶唑基、异恶唑基、恶二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基或8-10元含氮稠杂环基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，选自以下结构，
每一Ra、每一R1、每一Q1、n的定义如前述技术方案任一项所述。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，选自以下结构，
每一Ra、每一R1、每一Q1、n的定义如前述技术方案任一项所述。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一R1、R2、R3、R4分别独立地选自氢，卤素，氰基，羧基，羟基，氨基，硝基，或任选被1-4个取代基Q2取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一R1、R2、R3、R4分别独立地选自氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一R1、R2、R3、R4分别独立地选自氢、氟、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基或三氟甲氧基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，R5选自氢，卤素，氰基，羧基，羟基，氨基，硝基，或任选被1-4个取代基Q2取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、-(L)m-3-10元环烷基、-(L)m-3-10元杂环基、-(L)m-6-10元芳基、-(L)m-5-10元杂芳基、-(L)m-5-11元螺环基、-(L)m-5-11元螺杂环基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，R5选自任选被1-4个取代基Q2取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、-(L)m-5-10元环烷基、-(L)m-5-10元杂环基、-(L)m-7-11元螺环基、-(L)m-7-11元螺杂环基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，R5选自任选被1-3个取代基Q2取代的5-6元杂环基或7-10元螺杂环基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，R5选自任选被1-3个取代基Q2取代的5-6元含氮杂环基或7-9元含氮螺杂环基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，R5选自任选被1-3个取代基Q2取代的8元含氮螺杂环基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，R5选自任选被1-3个取代基Q2取代的以下结构：
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，R5选自任选被1-3个取代基Q2取代的以下结构：
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一L分别独立地选自-C(O)-、-S(O)-、-S(O)2-、-NRc-、-S(O)(NRc)-、-CRa1Rb-。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一L分别独立地选自-S(O)2-、-NRc-、-CRa1Rb-。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，R6选自任选被1-4个取代基Q2取代的-S(O)2H、-C(O)H、-C(O)N(Rc)2、-N(Rc)S(O)2-C1-6烷基、-N(Rc)-C1-6烷基、-N(Rc)S(O)2-3-6元环烷基、-N(Rc)S(O)2-3-6元杂环基、-S(O)2N(Rc)-C1-6烷基、-S(O)2N(Rc)-3-6元环烷基、-S(O)2N(Rc)-3-6元杂环基、-S(O)2-C1-6烷基、-S(O)2-3-6元环烷基、-S(O)2-3-6元杂环基、-S(O)(NRc)-C1-6烷基、-S(O)(NRc)-3-6元环烷基、-S(O)(NRc)-3-6元杂环基、-N(Rc)C(O)-C1-6烷基、-N(Rc)C(O)-3-6元环烷基、-N(Rc)C(O)-3-6元杂环基、-C(O)N(Rc)-C1-6烷基、-C(O)N(Rc)-3-6元环烷基、-C(O)N(Rc)-3-6元杂环基、-C(O)-C1-6烷基、-C(O)-3-6元环烷基、-C(O)-3-6元杂环基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，R6选自任选被1-4个取代基Q2取代的-S(O)2H、-C(O)H、-C(O)N(Rc)2、-N(Rc)S(O)2-C1-6烷基、-N(Rc)-C1-6烷基、-N(Rc)S(O)2-3-6元环烷基、-N(Rc)S(O)2-3-6元杂环基、-S(O)2N(Rc)-C1-6烷基、-S(O)2N(Rc)-3-6元环烷基、-S(O)2N(Rc)-3-6元杂环基、-S(O)2-C1-6烷基、-S(O)2-3-6元环烷基、-S(O)2-3-6元杂环基、-S(O)(NRc)-C1-6烷基、-S(O)(NRc)-3-6元环烷基、-S(O)(NRc)-3-6元杂环基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，R6选自任选被1-3个取代基Q2取代的-S(O)2H、-N(Rc)S(O)2-C1-6烷基、-N(Rc)-C1-6烷基、-S(O)2N(Rc)-C1-6烷基、-S(O)2-C1-6烷基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，R6选自以下结构：
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每 一Q1、每一Q2分别独立地选自卤素，羧基，羟基，氰基，硝基，氨基，C1-6烷基，C1-6烷氧基，卤代C1-6烷基，卤代C1-6烷氧基，羟基C1-6烷基，羧基C1-6烷基，氨基C1-6烷基，C1-6烷基氨基，二(C1-6烷基)氨基，C1-4烷基-O-C1-3亚烷基，卤代C1-4烷基-O-C1-3亚烷基或任选被1-3个取代基q取代的3-6元环烷基、3-6元杂环烷基、5-6元杂芳基或苯基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一Q1、每一Q2分别独立地选自卤素，羧基，羟基，氨基，C1-6烷基，C1-6烷氧基，卤代C1-6烷基，卤代C1- 6烷氧基，羟基C1-6烷基，羧基C1-6烷基，C1-3烷基-O-C1-2亚烷基，卤代C1-3烷基-O-C1-2亚烷基或任选被1-3个取代基q取代的3-6元环烷基、3-6元杂环烷基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一Q1、每一Q2分别独立地选自氟，氯，溴，碘，羧基，羟基，氰基，氨基，甲基，乙基，丙基，异丙基，丁基，异丁基，仲丁基，叔丁基，甲氧基，乙氧基，丙氧基，异丙氧基，一氟甲基，二氟甲基，三氟甲基，一氟乙基，二氟乙基，三氟乙基，一氟甲氧基，二氟甲氧基，三氟甲氧基，羟基甲基，羟基乙基，甲基氨基，乙基氨基，二甲氨基，甲基-O-亚甲基，甲基-O-亚乙基，一氟甲基-O-亚甲基，一氟甲基-O-亚乙基，二氟甲基-O-亚甲基，二氟甲基-O-亚乙基，三氟甲基-O-亚甲基，三氟甲基-O-亚乙基，或任选被1-3个q取代的环丙基、环丁基、环戊基、环己基、氧杂环丙基、氧杂环丁基、四氢呋喃基、四氢吡喃基、氮杂环丁基、吡咯烷基、哌啶基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一q分别独立地选自卤素、羟基、氨基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一q分别独立地选自氟、氯、溴、碘、羟基、氨基、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基或三氟甲氧基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一Ra、每一Ra1、每一Rb分别独立地选自氢、卤素、氨基、羟基、羧基、氰基、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、二(C1-6烷基)氨基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基或羧基C1-6烷基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一Ra、每一Ra1、每一Rb分别独立地选自氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一Ra、每一Ra1、每一Rb分别独立地选自氢、氟、氯、溴、碘、羧基、羟基、氰基、氨基、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、甲氧基、乙氧基、丙氧基、异丙氧基、甲基氨基、乙基氨基、二甲氨基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基或三氟甲氧基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一Ra、每一Ra1、每一Rb分别独立地选自氢、氟、氯、溴、碘、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基或三氟甲氧基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一Ra、每一Ra1、每一Rb分别独立地选自氢或甲基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一Rc分别独立地选自氢、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基、羟基C1-4烷基、氨基C1-4烷基或羧基C1-4烷基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一Rc分别独立地选自氢、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、一氟甲基、二氟甲基、三氟甲基、一氟甲氧基、二氟甲氧基、三氟甲氧基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一m分别独立地为0-4的整数。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一m分别独立地选自0、1、2或3。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一n分别独立地为0-4的整数。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，每一n分别独立地选自0、1、2、3。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，p选自0或1。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
环A选自5-6元单环烷基、5-6元单杂环基、8-10元稠环基、8-10元稠杂环基、苯基、5-6元单杂芳基、8-10元稠芳基或8-10元稠杂芳基；
每一R1、R2、R3、R4分别独立地选自氢，卤素，氰基，羧基，羟基，氨基，硝基或任选被1-4个取代基Q2取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1- 6烷基；
R5选自氢，卤素，氰基，羧基，羟基，氨基，硝基或任选被1-4个取代基Q2取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、-(L)m-3-10元环烷基、-(L)m-3-10元杂环基、-(L)m-6-10元芳基、-(L)m-5-10元杂芳基、-(L)m-5-11元螺环基、-(L)m-5-11元螺杂环基；
每一L分别独立地选自-S(O)2-、-NRc-、-CRa1Rb-；
R6选自任选被1-4个取代基Q2取代的-S(O)2H、-C(O)H、-C(O)N(Rc)2、-N(Rc)S(O)2-C1-6烷基、-N(Rc)-C1-6烷基、-N(Rc)S(O)2-3-6元环烷基、-N(Rc)S(O)2-3-6元杂环基、-S(O)2N(Rc)-C1-6烷基、-S(O)2N(Rc)-3-6元环烷基、-S(O)2N(Rc)-3-6元杂环基、-S(O)2-C1-6烷基、-S(O)2-3-6元环烷基、-S(O)2-3-6元杂环基、-S(O)(NRc)-C1-6烷基、-S(O)(NRc)-3-6元环烷基、-S(O)(NRc)-3-6元杂环基、-N(Rc)C(O)-C1-6烷基、-N(Rc)C(O)-3-6元环烷基、-N(Rc)C(O)-3-6元杂环基、-C(O)N(Rc)-C1-6烷基、-C(O)N(Rc)-3-6元环烷基、-C(O)N(Rc)-3-6元杂环基、-C(O)-C1-6烷基、-C(O)-3-6元环烷基、-C(O)-3-6元杂环基；
每一Ra、每一Ra1、每一Rb分别独立地选自氢、卤素、氨基、羟基、羧基、氰基、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、二(C1-6烷基)氨基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基或羧基C1-6烷基；
每一Rc分别独立地选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基；
每一Q1、每一Q2分别独立地选自卤素，羧基，羟基，氰基，硝基，氨基，C1-6烷基，C1-6烷氧基，卤代C1-6烷基，卤代C1-6烷氧基，羟基C1-6烷基，羧基C1-6烷基，氨基C1-6烷基，C1-6烷基氨基，二(C1-6烷基)氨基，C1-4烷基-O-C1-3亚烷基，卤代C1-4烷基-O-C1-3亚烷基或任选被1-3个取代基q取代的3-6元环烷基、3-6元杂环烷基、5-6元杂芳基或苯基；每一q分别独立地选自卤素、羟基、氨基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基；
每一m、n分别独立地为0-4的整数；
p选自0或1。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
环A选自5-6元单杂芳基、8-10元稠杂环基或8-10元稠杂芳基；
每一R1、R2、R3、R4分别独立地选自氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基；
R5选自任选被1-4个取代基Q2取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、-(L)m-5-10元环烷基、-(L)m-5-10元杂环基、-(L)m-7-11元螺环基、-(L)m-7-11元螺杂环基；
每一L分别独立地选自-S(O)2-、-NRc-、-CRa1Rb-；
R6选自任选被1-3个取代基Q2取代的-S(O)2H、-N(Rc)S(O)2-C1-6烷基、-N(Rc)S(O)2-3-6元环烷基、-N(Rc)-C1-6烷基、-N(Rc)S(O)2-3-6元杂环基、-S(O)2N(Rc)-C1-6烷基、-S(O)2N(Rc)-3-6元环烷基、-S(O)2N(Rc)-3-6元杂环基、-S(O)2-C1-6烷基、-S(O)2-3-6元环烷基、-S(O)2-3-6元杂环基。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
环A选自环戊烷基、环己烷基、二氢吡咯基、吡咯烷基、咪唑烷基、二氢咪唑基、吡唑烷基、二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、哌啶基、哌嗪基、吗啉基、苯基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、恶唑基、异恶唑基、恶二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基或8-10元含氮稠杂环基；
每一R1、R2、R3、R4分别独立地选自氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷 氧基；
R5选自任选被1-3个取代基Q2取代的5-6元杂环基或7-10元螺杂环基；
R6选自任选被1-3个取代基Q2取代的-S(O)2H、-N(Rc)S(O)2-C1-6烷基、-N(Rc)-C1-6烷基、-S(O)2N(Rc)-C1-6烷基、-S(O)2-C1-6烷基；
每一Ra、每一Rb分别独立地选自氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基；
每一Rc分别独立地选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基；
每一Q1、每一Q2分别独立地选自卤素，羧基，羟基，氨基，C1-6烷基，C1-6烷氧基，卤代C1-6烷基，卤代C1-6烷氧基，C1-3烷基-O-C1-2亚烷基，卤代C1-3烷基-O-C1-2亚烷基或任选被1-3个取代基q取代的3-6元环烷基、3-6元杂环烷基；每一q分别独立地选自卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基；
n选自0、1或2；
p选自0或1。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
选自以下结构：
每一R1、R2、R3、R4分别独立地选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基；
每一Ra分别独立地选自氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基；
R5选自任选被1-3个取代基Q2取代的以下结构：
R6选自以下结构：
每一Q1分别独立地选自卤素，羟基，C1-6烷基，C1-6烷氧基，卤代C1-6烷基，卤代C1-6烷氧基，C1-3烷基-O-C1-2亚烷基，卤代C1-3烷基-O-C1-2亚烷基或任选被1-3个取代基q取代的3-6元环烷基、3-6元杂环烷基；每一q分别独立地选自卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基；
每一Q2分别独立地选自卤素、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基；
n选自0、1或2。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其具有式(II)所示的结构，
其中，X5选自N或CH；t选自0、1或2；
环A、X1、X2、X3、X4、R1、R2、R3、R4、R6、每一Q1、每一Q2、n、p的定义如前述方案任一项所述。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
X5为N；
每一R1选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基；
R2、R3、R4分别独立地为氢；
R6选自以下结构：

优选地，R6选自以下结构：
选自以下结构：
优选地，选自以下结构：
每一Q1分别独立地选自卤素，羟基，C1-6烷基，C1-6烷氧基，卤代C1-6烷基，卤代C1-6烷氧基，C1-3烷基-O-C1-2亚烷基，卤代C1-3烷基-O-C1-2亚烷基或任选被1-3个取代基q取代的3-6元环烷基、3-6元杂环烷基；每一q分别独立地选自卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基；
每一Q2分别独立地选自卤素、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基；
每一Ra分别独立地选自氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基；
n选自0、1或2。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其具有式(III)所示的结构，
其中，X5选自N或CH；t选自0、1或2；
环A、X1、X2、X3、X4、R1、R6、每一Q1、每一Q2、n、p的定义如前述方案任一项所述。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其具有式(III’)所示的结构，
其中，t选自0、1或2；
环A、X2、X3、X4、R1、R6、每一Q1、每一Q2、n、p的定义如前述方案任一项所述。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其具有式(III-1)、式(III-2)、式(III-3)或式(III-4)所示的结构，
其中，环A、X1、X2、X3、X4、R1、每一Q1、每一Q2、n、p、t的定义如前述方案任一项所述。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其具有式(IV)所示的结构，
其中，t选自0、1或2；
环A、X3、R1、Ra、R6、每一Q1、每一Q2、n的定义如前述方案任一项所述。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其具有式(IV-1)所示的结构，
其中，t选自0、1或2；
R1、Ra、R6、每一Q1、每一Q2、n的定义如前述方案任一项所述。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其具有式(IV-2)所示的结构，
其中，t选自0、1或2；
R1、Ra、R6、每一Q1、每一Q2、n的定义如前述方案任一项所述。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其具有式(IV-3)所示的结构，
其中，t选自0、1或2；
R1、Ra、R6、每一Q1、每一Q2、n的定义如前述方案任一项所述。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其具有式(IV-4)所示的结构，
其中，t选自0、1或2；
R1、Ra、R6、Q1、每一Q2的定义如前述方案任一项所述。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其具有式(IV-5)所示的结构，
其中，R1、Ra、R6、每一Q1、n的定义如前述方案任一项所述。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其具有式(IV-5)所示的结构，
其中，R6选自以下结构：
R1、Ra、每一Q1、n的定义如前述方案任一项所述。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其具有式(IV-6)所示的结构，
其中，R1、Ra、R6、每一Q1、n的定义如前述方案任一项所述。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其具有式(IV-6)所示的结构，
其中，R6选自以下结构：
R1、Ra、每一Q1、n的定义如前述方案任一项所述。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其具有式(IV-7)所示的结构，
其中，R1、Ra、R6、每一Q1、n的定义如前述方案任一项所述。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其具有式(IV-7)所示的结构，
其中，R6选自以下结构：
R1、Ra、每一Q1、n的定义如前述方案任一项所述。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其具有式(IV-8)所示的结构，
其中，R1、Ra、R6、Q1的定义如前述方案任一项所述。
在某些实施方案中，前述方案所示的化合物、其药学上可接受的盐、其酯或其立体异构体，其具有式(IV-8)所示的结构，
其中，R6选自以下结构：
R1、Ra、Q1的定义如前述方案任一项所述。
本发明的一些实施方式中，所提供的化合物、其药学上可接受的盐或其立体异构体的结构如下所示：



本发明还提供了一种药物组合物，其含有前述的化合物、其药学上可接受的盐、酯或其立体异构体，及一种或多种第二治疗活性剂，任选地，所述药物组合物还包含一种或多种药用载体和/或稀释剂。
本发明所述的第二治疗剂包括但不限于生长因子抑制剂、细胞周期抑制剂、拓扑异构酶抑制剂、抗代谢药、抗有丝分裂剂、血管发生抑制剂、生物反应修饰剂、抗激素剂、抗癌药物。
本发明还提供了一种药物制剂，其含有前述的化合物、其药学上可接受的盐、酯或其立体异构体，及一种或多种药用载体和/或稀释剂；所述药物制剂为临床上或药学上可接受的任一剂型。
在本发明的一些实施方式中，上述药物制剂可以以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者或受试者。用于口服给药时，所述药物组合物可制成口服制剂，例如可以制成常规的口服固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，上述药物制剂也可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配置注射剂时，可以不加入附加剂，也可以根据药物的性质加入适宜的附加剂。用于直肠给药时，所述药物组合物可制成栓剂等。用于经肺给药时，所述药物组合物可制成吸入剂或喷雾剂等。
本发明的药物组合物或药物制剂中可用的药用载体和/或稀释剂可以是药物制剂领域中任何常规的载体和/或稀释剂，特定载体和/或稀释剂的选择将取决于用于治疗特定患者的给药方式或疾病类型和状态。用于特定给药模式的合适药物组合物的制备方法完全在药物领域技术人员的知识范围内。例如，药用载体和/或稀释剂可以包括药学领域常规的溶剂、稀释剂、分散剂、助悬剂、表面活性剂、等渗剂、增稠剂、乳化剂、粘合剂、润滑剂、稳定剂、水合剂、乳化加速剂、缓冲剂、吸收剂、着色剂、离子交换剂、脱模剂、涂布剂、矫味剂、和抗氧化剂等。必要时，还可以在药物组合物中加入香味剂、防腐剂和甜味剂等。
本发明还提供了前述化合物、其药学上可接受的盐、酯或其立体异构体、前述的药物制剂或前述的药物组合物在制备用于治疗和/或预防KIF18A介导的疾病及相关疾病的药物中的用途；所述KIF18A介导的疾病及相关疾病选自癌症或良性肿瘤。
本发明还提供了前述化合物、其药学上可接受的盐、酯或其立体异构体、前述的药物制剂或前述的药物组合物在治疗/或预防KIF18A介导的疾病及相关疾病中的应用；所述KIF18A介导的疾病及相关疾病选自癌症或良性肿瘤。
本发明还提供了一种治疗疾病的方法，该方法包括向有需要的患者给药治疗有效量的前述的化合物、其药学上可接受的盐或其立体异构体、前述的药物制剂或前述的药物组合物，其中，所述疾病为KIF18A介导的疾病及相关疾病；所述KIF18A介导的疾病及相关疾病选自癌症或良性肿瘤。
所述癌症或良性肿瘤包括但不限于黑色素瘤、乳腺癌、卵巢癌、子宫内膜癌、子宫颈癌、脑癌、头颈癌、甲状腺癌、肺癌、支气管癌、食管癌、胃癌、肝癌、肾癌、胰腺癌、胆囊癌、结肠癌、膀胱癌、前列腺癌、罩丸癌、皮肤癌、骨癌及血液瘤；所述肺癌包括但不限于小细胞肺癌及非小细胞肺癌；所述血液瘤包括但不限于白血病、淋巴瘤、骨髓瘤；所述脑癌包括但不限于神经胶质瘤、神经母细胞瘤、星形细胞瘤、脑膜瘤。
在本申请的说明书和权利要求书中，化合物都是依据化学结构式而命名，如果表示同一化合物时化合物的命名和化学结构式不符，以化学结构式为准。
在本申请中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员通常理解的含义，然而为了更好地理解本发明，下面提供了部分术语的定义。当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不符的时候，以本申请所提供的术语的定义和解释为准。
本发明所述的“卤素”是指氟、氯、溴和碘，优选氟和氯。
本发明所述的“卤代”是指取代基中的任一氢可被一个或多个相同或不同的卤素取代。“卤素”如前文所定义。
本发明所述的“C1-6烷基”表示直链或支链的含有1-6个碳原子的烷基，包括例如“C1-5烷基”、“C1-4烷基”、“C1-3烷基”、“C1-2烷基”、“C2-6烷基”、“C2-5烷基”、“C2-4烷基”、“C2-3烷基”、“C3-6烷基”、“C3- 5烷基”、“C3-4烷基”、“C4-6烷基”、“C4-5烷基”、“C5-6烷基”等，具体实例包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、1,2-二甲基丙基等。本发明所述的“C1- 4烷基”指C1-6烷基中的含有1-4个碳原子的具体实例。
本发明所述的“C1-6亚烷基”指上述所述C1-6烷基去除一个氢原子形成的基团，包括例如“C1-5亚烷基”、“C1-4亚烷基”、“C1-3亚烷基”、“C1-2亚烷基”、“C2-6亚烷基”、“C2-5亚烷基”、“C2-4亚烷基”、“C2-3亚烷基”、“C3-6亚烷基”、“C3-5亚烷基”、“C3-4亚烷基”、“C4-6亚烷基”、“C4-5亚烷基”、“C5-6亚烷基”等，具体实例包括但不限于：亚甲基、亚乙基、亚丙基、亚丁基、亚戊基、亚己基等。本发明所述的“C1-4亚烷基”指C1-6亚烷基中的含有1-4个碳原子的具体实例。
本发明所述的“C2-6烯基”是指含有至少一个双键的碳原子数为2-6的直链或支链或环状的烯基，包括例如“C2-5烯基”、“C2-4烯基”、“C2-3烯基”等，具体实例包括但不限于：乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、1-甲基-2-丙烯基、1-戊烯基、2-戊烯基、3-戊烯基、2-甲基-1-丁烯基、3-甲基-1-丁烯基、2-甲基-3-丁烯基、1,1-二甲基-2-丙烯基、1-乙基-2-丙烯基、2-己烯基、3-己烯基、2-甲基-1-戊烯基、3-甲基-1-戊烯基、1-甲基-2-戊烯基、3-甲基-2-戊烯基、2-甲基-3-戊烯基、1-甲基-4-戊烯基、3-甲基-4-戊烯基、1,1-二甲基-3-丁烯基、1,2-二甲基-3-丁烯基、1,3-二甲基-2-丁烯基、2,2-二甲基-3-丁烯基、2,3-二甲基-2-丁烯基、2,3-二甲基-1-丁烯基、2-乙基-1-丁烯基、2-乙基-3-丁烯基等。
本发明所述的“C2-6炔基”是指含有三键的碳原子数为2-8的直链或支链的炔基，其中包括例如“C2-5炔基”、“C2-4炔基”、“C2-3炔基”等，具体实例包括但不限于：乙炔基、1-丙炔基、2-丁炔基、1-甲基-2-丙炔基、2-戊炔基、3-戊炔基、1-甲基-2-丁炔基、2-甲基-3-丁炔基、1,1-二甲基-2-丙炔基、1-乙基-2-丙炔基、2-己炔基、3-己炔基、1-甲基-2-戊炔基、1-甲基-3-戊炔基、2-甲基-3-戊炔基、1,1-二甲基-3-丁炔基、2-乙基-3-丁炔基等。
本文所述的“C1-6烷氧基、C1-6烷基氨基、二(C1-6烷基)氨基、C1-6烷基氨酰基、C1-6烷基酰氨基、C1-6烷基磺酰基、C1-6烷基磺酰氨基、C1-6烷基氨基磺酰基、C1-6烷基羰基、C1-6烷氧基羰基”是指以C1-6烷基-O-、C1-6烷基-NH-、(C1-6烷基)2-N-、C1-6烷基-NH-C(O)-、C1-6烷基-C(O)-NH-、C1-6烷基-S(O)2-、C1-6烷基-S(O)2-NH-、C1-6烷基-NH-S(O)2-、C1-6烷基-C(O)-、C1-6烷基-O-C(O)-方式形成的基团，其中“C1-6烷基”的定义如前文所述。
本文所述的“C1-4烷氧基、C1-4烷基氨基、二(C1-4烷基)氨基、C1-4烷基氨酰基、C1-4烷基酰氨基、C1-4烷基磺酰基、C1-4烷基磺酰氨基、C1-4烷基氨基磺酰基、C1-4烷基羰基、C1-4烷氧基羰基”是指以C1-4烷基-O-、C1-4烷基-NH-、(C1-4烷基)2-N-、C1-4烷基-NH-C(O)-、C1-4烷基-C(O)-NH-、C1-4烷基-S(O)2-、C1-4烷基-S(O)2-NH-、C1-4烷基-NH-S(O)2-、C1-4烷基-C(O)-、C1-4烷基-O-C(O)-方式形成的基团，其中“C1-4烷基”的定义如前文所述。
本文所述的“卤代C1-6烷基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基、卤代C1-6烷氧基”是指一至多个(例如1-4个、1-3个、1-2个)卤素原子、羟基、氨基、羧基分别取代C1-6烷基、C1-6亚烷基、C1-6烷氧基中的氢原子所形成的基团。
本文所述的“卤代C1-4烷基、羟基C1-4烷基、氨基C1-4烷基、羧基C1-4烷基、卤代C1-4烷氧基”是指一至多个(例如1-4个、1-3个、1-2个)卤素原子、羟基、氨基分别取代C1-4烷基、C1-4烷氧基中的氢原子所形成的基团。
本发明所述的“3-12元环烷基”是指包括“3-8元环烷基”和“7-12元稠环烷基”。
本发明所述的“3-8元环烷基”是指含有3-8个碳原子的饱和或部分饱和的且不具有芳香性的单环环状烷基，包括“3-8元饱和环烷基”和“3-8元部分饱和环烷基”；优选“3-4元环烷基”、“3-5元环烷基”、“3-6元环烷基”、“3-7元环烷基”、“4-5元环烷基”、“4-6元环烷基”、“4-7元环烷基”、“4-8元环烷基”、“5-6元环烷基”、“5-7元环烷基”、“5-8元环烷基”、“6-7元环烷基”、“6-8元环烷基”、“7-8元环烷基”、“3-6元饱和环烷基”、“5-8元饱和环烷基”、“5-7元饱和环烷基”、“5-6元饱和环烷基”等。所述的“3-8元饱和环烷基”的 具体实例包括但不限于：环丙烷基(环丙基)、环丁烷基(环丁基)、环戊烷基(环戊基)、环己烷基(环己基)、环庚烷基(环庚基)、环辛烷基(环辛基)等；所述的“3-8元部分饱和环烷基”的具体实例包括但不限于环丙烯基、环丁烯基、环戊烯基、环戊二烯基、环己烯基、环己-1,3-二烯、环己-1,4-二烯、环庚烯基、环庚-1,3-二烯基、环庚-1,4-二烯基、环庚-1,3,5-三烯基，环辛烯基、环辛-1,3-二烯基、环辛-1,4-二烯基、环辛-1,5-二烯基、环辛-1,3,5-三烯基、环辛四烯基等。
本发明所述的“7-12元稠杂环基”是指由两个或两个以上环状结构彼此共用两个相邻的碳原子所形成的含有7-12个环原子的、饱和或部分饱和的、非芳香性环状基团，所述的稠环中的一个环可以为芳香性环，但稠环整体不具备芳香性；包括“7-9元稠环基”、“9-10元稠环基”等，其稠和方式可以为：5-6元环烷基并5-6元环烷基、苯并5-6元环烷基、苯并5-6元饱和环烷基等。其实例包括但不限于：二环[3.1.0]己烷基、二环[4.1.0]庚烷基、二环[2.2.0]己烷基、二环[3.2.0]庚烷基、二环[4.2.0]辛烷基、八氢并环戊二烯基、八氢-1H-茚基、十氢化萘基、十四氢菲基、双环[3.1.0]己-2-烯基、双环[4.1.0]庚-3-烯基、双环[3.2.0]庚-3-烯基、双环[4.2.0]辛-3-烯基、1,2,3,3a-四氢并环戊二烯基、2,3,3a,4,7,7a-六氢-1H-茚基、1,2,3,4,4a,5,6,8a-八氢化萘基、1,2,4a,5,6,8a-六氢化萘基、1,2,3,4,5,6,7,8,9,10-十氢菲基、苯并环戊基、苯并环己基、苯并环己烯基、苯并环戊烯基等。
本发明所述的“3-12元杂环基”包括“3-8元杂环基”和“7-12元稠杂环基”。
本发明所述的“3-8元杂环基”是指至少含有一个杂原子(例如，含有1个、2个、3个、4个或5个)的且环原子数为3-8个的饱和或部分饱和的且不具有芳香性的单环环状基团，所述杂原子为氮原子、氧原子和/或硫原子，任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。本发明所述的“3-8元杂环基”包括“3-8元饱和杂环基”和“3-8元部分饱和杂环基”。优选地，本发明所述的“3-8元杂环基”含有1-3个杂原子；优选地，本发明所述的“3-8元杂环基”含有1-2个杂原子，且所述的杂原子选自氮原子和/或氧原子；优选地，本发明所述的“3-8元杂环基”含有1个氮原子。所述“3-8元杂环基”优选“3-7元杂环基”、“3-6元杂环基”、“4-7元杂环基”、“4-6元杂环基”、“6-8元杂环基”、“5-7元杂环基”、“5-6元杂环基”、“3-6元饱和杂环基”、“5-6元饱和杂环基”、“3-6元含氮杂环基”、“3-6元饱和含氮杂环基”、“5-6元含氮杂环基”、“5-6元饱和含氮杂环基”等。例如，仅包含1个或2个氮原子，或者，包含一个氮原子和其他的1个或2个杂原子(例如氧原子和/或硫原子)。“3-8元杂环基”的具体实例包括但不仅限于：氮杂环丙烷基、2H-氮杂环丙烷基、二氮杂环丙烷基、3H-二氮杂环丙烯基、氮杂环丁烷基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、1,4-二氧杂环己二烯基、四氢呋喃基、二氢吡咯基、吡咯烷基、咪唑烷基、4,5-二氢咪唑基、吡唑烷基、4,5-二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、噻唑烷基、哌啶基、四氢吡啶基、哌啶酮基、四氢吡啶酮基、二氢哌啶酮基、哌嗪基、吗啉基、4,5-二氢噁唑基、4,5-二氢异噁唑基、2,3-二氢异噁唑基、噁唑烷基、2H-1,2-噁嗪基、4H-1,2-噁嗪基、6H-1,2-噁嗪基、4H-1,3-噁嗪基、6H-1,3-噁嗪基、4H-1,4-噁嗪基、4H-1,3-噻嗪基、6H-1,3-噻嗪基、2H-吡喃基、2H-吡喃-2-酮基、3,4-二氢-2H-吡喃基等。
本发明所述“7-12元稠杂环基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的含有7-12个环原子的、且至少一个环原子为杂原子的、饱和或部分饱和的、非芳香性环状基团，所述的稠环中其中一个环可以为芳香性环，但稠环整体不具备芳香性，所述杂原子为氮原子、氧原子和/或硫原子，任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代，包括但不限于“7-9元稠杂环基”、“8-10元稠杂环基”、“9-10元稠杂环基”等，其稠和方式可以为5-6元杂环基并5-6元杂环基、5-6元杂环基并5-6元环烷基、苯并5-6元杂环基、苯并5-6元饱和杂环基、5-6元杂芳基并5-6元杂环基、5-6元杂芳基并5-6元饱和杂环基；5-6元杂芳基如前文所定义；所述“7-12元稠杂环基”具体实例包括但不仅限于：吡唑基并环己基、吡咯烷基并环丙基、环戊基并氮杂环丙基、吡咯烷基并环丁基、吡咯烷基并吡咯烷基、吡咯基并哌啶基、吡咯烷基并哌啶基、吡咯烷基并哌嗪基、吡咯烷基并吗啉基、哌啶基并吗啉基、苯并吡咯烷基、苯并环戊基、苯并环己基、苯并四氢呋喃基、苯并吡咯烷基、苯并咪唑烷基、苯并噁唑烷基、苯并噻唑烷基、苯并异噁唑烷基、苯并异噻唑烷基、苯并哌啶基、苯并吗啉基、苯并哌嗪基、苯并四氢吡喃基、吡啶并环戊基、吡啶并环己基、吡啶并四氢呋喃基、吡啶并吡咯烷基、吡啶并咪唑烷基、吡啶并噁唑烷基、吡啶并噻唑烷基、吡啶并异噁唑烷基、吡啶并异噻唑烷基、吡啶并哌啶基、吡啶并吗啉基、吡啶并哌嗪基、吡啶并四氢吡喃基、嘧啶并环戊基、嘧啶并环己基、嘧啶并四氢呋喃基、嘧啶并吡咯烷基、嘧啶并咪唑烷基、嘧啶并噁唑烷基、嘧啶并噻唑烷基、嘧啶并异噁唑烷基、嘧啶并异噻唑烷基、嘧啶并哌啶基、嘧啶并吗啉基、嘧啶并哌嗪基、嘧啶并四氢吡喃基；四氢咪唑并[4,5-c]吡啶基、3,4-二氢喹唑啉基、1,2-二氢喹喔 啉基、苯并[d][1,3]二氧杂环戊烯基、2H-色原烯基、2H-色原烯-2-酮基、4H-色烯基、4H-色烯-4-酮基、4H-1,3-苯并噁嗪基、4,6-二氢-1H-呋喃并[3,4-d]咪唑基、3a,4,6,6a-四氢-1H-呋喃并[3,4-d]咪唑基、4,6-二氢-1H-噻吩并[3,4-d]咪唑基、4,6-二氢-1H-吡咯并[3,4-d]咪唑基、八氢-苯并[d]咪唑基、十氢喹啉基、六氢噻吩并咪唑基、六氢呋喃并咪唑基、4,5,6,7-四氢-1H-苯并[d]咪唑基、八氢环戊烯并[c]吡咯基、4H-1,3-苯并噁嗪基等。
本发明所述的“5-10元环烷基”是“3-12元环烷基”中含有5-10个环原子的实例。
本发明所述的“5-10元杂环烷基”是“3-12元杂环烷基”中含有5-10个环原子的实例。
本发明所述的“6-10元芳基”是指含有6-10个环碳原子的具有芳香性的环状基团，包括“6-8元单环芳基”和“8-10元稠环芳基”。
本发明所述的“6-8元单环芳基”是指含有6-8个环碳原子的单环芳基，其实例包括但不限于：苯基、环辛四烯基等；优选苯基。
本发明所述的“8-10元稠环芳基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的、含有8-10个环碳原子的、不饱和的、具有芳香性的环状基团，优选“9-10元稠环芳基”，具体实例如萘基等。
本发明所述的“5-12元杂芳基”是指含有5-12个环原子(其中至少一个环原子为杂原子，例如氮原子、氧原子或硫原子)的具有芳香性的环状基团，例如可以是5-12元含氮杂芳基、5-12元含氧杂芳基、5-12元含硫杂芳基等。包括“5-8元单杂芳基”和“7-12元稠杂芳基”。
本发明所述的“5-8元单杂芳基”是指含有5-8个环原子(其中至少一个环原子为杂原子，例如氮原子、氧原子或硫原子)的具有芳香性的单环环状基团。任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。“5-8元单杂芳基”包括例如“5-7元单杂芳基”、“5-6元单杂芳基”、“5-6元含氮单杂芳基”、“5元含氮单杂芳基”等。“5-8元单环杂芳基”的具体实例包括但不仅限于呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、氮杂环庚三烯基、1,3-二氮杂环庚三烯基、氮杂环辛四烯基等。所述“5-6元杂芳基”是指5-8元杂芳基中含有5-6个环原子的具体实例。
本发明所述的“7-12元稠杂芳基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的、含有7-10个环原子(其中至少一个环原子为杂原子，例如氮原子、氧原子或硫原子)的、不饱和的具有芳香性的环状结构。任选地，环状结构中的环原子(例如碳原子、氮原子或硫原子)可以被氧代。包括“8-10元稠杂芳基”，“7-9元稠杂芳基”等，其稠和方式可以为苯并5-6元杂芳基、5-6元杂芳基并5-6元杂芳基等；具体实例包括但不限于：吡咯并吡咯、吡咯并呋喃、吡唑并吡咯、吡唑并噻吩、呋喃并噻吩、吡唑并噁唑、苯并呋喃基、苯并异呋喃基、苯并噻吩基、吲哚基、异吲哚基、苯并噁唑基、苯并咪唑基、吲唑基、苯并三唑基、喹啉基、2-喹啉酮基、4-喹啉酮基、1-异喹啉酮基、异喹啉基、吖啶基、菲啶基、苯并哒嗪基、酞嗪基、喹唑啉基、喹喔啉基、嘌呤基、萘啶基等。
本发明所述的“5-12元桥环基”是指任意两个环共用两不直接相连的原子形成的含有5-12个碳原子的结构，“5-12元桥环”包括5-12元饱和桥环基、5-12元部分饱和桥环基。优选5-10元桥环基、5-8元桥环基、5-10元饱和桥环基、5-8元饱和桥环基、6-10元饱和桥环基、7-12元部分饱和桥环基，具体实例包括但不仅限于
本发明所述的“5-12元桥杂环基”是指上述5-12元桥环基中的至少一个环碳原子被选自O、S、N的杂原子替代，优选1-3个杂原子，同时包括碳原子、氮原子和硫原子可以被氧代的情况，优选5-10元桥杂环基，5-8元桥杂环基。具体实例包括但不仅限于：
本发明所述“5-12元螺环基”是指一类至少有两个环共享一个原子形成的含有5-12个碳原子的结构。包含5-12元饱和螺环基和5-12元部分饱和螺环基，包括例如“5-10元饱和螺环基”、“5-10元不饱和螺环基”、“5-8元螺环基”、“5-8元饱和螺环基”、“5-8元不饱和螺环基”、“7-11元螺环基”、“7-10元螺环基”、“7-9元螺环基”、“8-10元螺环基”、“8-11元螺环基”，5-12元饱和螺环基具体实例包括但不仅限于： 等环状结构取代任意可取代的氢原子所形成的基团。5-12元部分饱和螺环基，是指该螺环基中至少有一个环为不饱和的环状基团，具体实例包括但不仅限于： 等环状结构取代任意可取代的氢原子所形成的基团。
本发明所述的“5-12元螺杂环基”是指5-12元螺环基中至少一个环碳原子被选自O、S、N的杂原子替代，优选1-3个杂原子，同时包括碳原子、氮原子和硫原子可以被氧代的情况。包括例如5-10元螺杂环基、5-8元螺杂环基、5-6元螺杂环基、7-12元螺杂环基、7-11元螺杂环基、7-11元含氮螺杂环基、7-10元螺杂环基、7-10元含氮螺杂环基、7-9元螺杂环基、7-9元含氮螺杂环基、8元含氮螺杂环基。具体实例包括但不仅限于：
本发明所述的“任选被…取代”包括“被取代”和“未被取代”两种情形。
本发明所述的“药学上可接受的盐”是指可药用的酸和碱的加成盐，例如金属盐、铵盐、与有机酸形成的盐、与有机碱形成的盐、与无机酸形成的盐、与酸性氨基酸或碱性氨基酸形成的盐等。
本发明所述的“酯”是指药学上可接受的酯，尤其指如下酯，其在活体内水解且包括容易在人体内分解留下母体化合物(通式(I)所述的化合物)或其盐的酯。本发明所述的“酯”例如可以选自下列各组：(1)通过与羧酸类化合物的酯化作用所获得的羧酸酯，其中羧酸类化合物的非羰基部分选自例如C1-20直链或支 链烷基、C1-12直链或支链烷基、C1-8直链或支链烷基、C1-6直链或支链烷基(例如甲基、乙基、正丙基、叔丁基或正丁基)、C1-6烷氧基C1-6烷基(例如甲氧基甲基)、C6-10芳基C1-6烷基(例如苄基)、C6-10芳氧基C1-6烷基(例如苯氧基甲基)、C6-10芳基(例如苯基，任选被例如卤素、C1-4烷基或C1-4烷氧基或氨基取代)；(2)磺酸酯，例如烷基磺酰基或芳烷基磺酰基(例如甲基磺酰基)；(3)氨基酸酯(例如L-缬氨酰基或L-异亮氨酰基)；和(4)单-、二-或三磷酸酯等；(4)通过与醇类化合物的酯化作用所获得的酯，其中醇类化合物的非羟基部分选自例如C1-20直链或支链烷基、C1-12直链或支链烷基、C1-8直链或支链烷基、C1-6直链或支链烷基(例如甲基、乙基、正丙基、叔丁基或正丁基)、C1-6烷氧基C1-6烷基(例如甲氧基甲基)、C6-10芳基C1-6烷基(例如苄基)、C6-10芳氧基C1-6烷基(例如苯氧基甲基)、C6-10芳基(例如苯基，任选被例如卤素、C1-4烷基或C1-4烷氧基或氨基取代)。
本发明所述的“立体异构体”是指当本发明化合物含有一个或多个不对称中心，因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物可以有不对称中心，这类不对称中心各自独立地产生两个光学异构体。本发明的范围包括所有可能的光学异构体和它们的混合物。本发明所述的化合物若含有烯烃双键，除非特别说明，包括顺式异构体和反式异构体。本发明所述的化合物可以以互变异构体(官能团异构体的一种)形式存在，其通过一个或多个双键位移而具有不同的氢的连接点，例如，酮和它的烯醇形式是酮-烯醇互变异构体。各互变异构体及其混合物都包括在本发明的范围中。所有化合物的对映异构体、非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物等，均包括在本发明范围中。
本发明所述的“治疗有效量”是指当给药到患者时至少能够减轻患者病症的症状的前述化合物、药物制剂、药物组合物的量。包含“治疗有效量”的实际量会根据多种情况而变化，多种情况包括但不限于所治疗的特定病症、病症的严重程度、患者的体格和健康状况以及给药途径。熟练的医疗从业者可容易地使用医疗领域中已知的方法确定合适的量。
发明的有益效果
(1)本发明化合物、其药学上可接受的盐、酯或其立体异构体具有优异的KIF18A抑制活性，能够治疗和/或预防KIF18A介导的疾病及相关疾病；
(2)本发明化合物对肿瘤细胞具有良好的抑制作用；
(3)本发明化合物、其药学上可接受的盐、酯或其立体异构体具有良好的药代动力学性质，作用更持久，生物利用度高；
(4)本发明化合物、其药学上可接受的盐、酯或其立体异构体具有良好的安全性；
(5)本发明化合物制备工艺简单，药品纯度高，质量稳定，易于进行大规模工业生产。
以下通过实验进一步阐述本发明实施例提供的化合物的有益效果，但不应将此理解为本发明实施例提供的化合物仅具有下列有益效果。
实验例1本发明化合物的体外细胞学活性
供试品：本发明部分化合物，其化学名称和结构见制备实施例。
下述实验中所用细胞株如下：
OVCAR3：TP53突变人卵巢癌细胞
MDA-MB-157：TP53突变人乳腺癌细胞
实验方法(CelltiterGlo assay)
1.准备细胞
1.1细胞培养：
所有细胞均为贴壁细胞，OVCAR3细胞培养基为RPMI Medium 1640+20％FBS+1％PS，MDA-MB-157细胞培养基为DMEM Medium+10％FBS+1％PS，细胞在对数生长期进行试验。
1.2细胞悬液制备：
收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上。调整到合适浓度，分别添加90μL细胞悬液至96孔板中。
表1细胞接种数目

2.配制测试化合物
2.1配制测试化合物DMSO储备液，测试化合物的储备液浓度为10mM。
2.2配制测试化合物工作储备液
测试化合物储备液10mM，3倍连续梯度稀释，共9个浓度。然后分别取2μL的DMSO梯度稀释的化合物加到198μL的培养液中，为测试化合物工作储备液(化合物浓度为终浓度的10倍，最高浓度为100μM)。
2.3化合物处理
在接种有细胞的96孔板中每孔加入10μL化合物工作储备液(10倍稀释，DMSO终浓度为0.1％)。
测试化合物的终浓度为：10μM，3.33μM，1.11μM，370nM，123nM，41.1nM，13.7nM，4.57nM，1.52nM。
2.4对照孔设置
溶剂对照：0.1％DMSO。
空白对照：培养液
2.5将96孔板置于37℃、5％CO2细胞培养箱中培养4天。
3.检测
融化CTG试剂并平衡96孔板至室温30分钟，每孔加入60μL试剂(Celltiter Glo assay kit)，振荡器震摇2min混匀(避光)，室温孵育20分钟(避光)。多功能酶标仪读取光信号值。
4.数据处理
1)抑制率(％)＝1-(测试物孔读数空白对照孔读数)/(DMSO溶剂对照孔读数-空白对照孔读数)×100％；
2)输入GraphPad Prism作图，得到曲线及IC50。
实验结果及结论
表2本发明化合物的体外细胞学活性(IC50,nM)
A：IC50<100nM；B：100nM≤IC50<200nM；C：200nM≤IC50<1μM；
由以上可知，本发明化合物可以有效地抑制OVCAR3、MDA-MB-157细胞的增殖，表明本发明化合物具有治疗TP53突变的癌性疾病的临床应用潜力。
实验例2本发明化合物的体外酶学活性
供试品：本发明化合物，其结构式、制备方法见制备例。
实验试剂：
实验方法：
1、化合物稀释
(1)使用DMSO配制本发明化合物至10mM，作为试验储备液。
(2)将试验储备液3倍梯度稀释至10个浓度，最高浓度为10mM。
(3)测试化合物终浓度为10000nM、3333.3nM、1111.1nM、370.4nM、123.5nM、41.2nM、13.7nM、4.57nM、1.52nM、0.51nM。
2、酶反应实验
(1)使用Echo 650将0.025μL化合物稀释液转移到384孔测定板的每个孔中，每列包含2个重复。
(2)向384孔检测板中加入2.5μL酶工作液，1000rpm离心1分钟。25℃孵育10分钟。
(3)添加2.5μL ATP工作溶液。25℃孵育60分钟。
(4)添加4μL ADP-Glo工作溶液。25℃孵育40分钟。
(5)加入8μL检测工作溶液。25℃孵育40分钟。
3、结果检测
(1)在BMG HTS高通量药筛多功能酶标仪上读取化学发光信号。
(2)收集数据。
4、数据分析
使用如下公式计算抑制率inhibition(％inh)：
供试品化合物抑制率(％inh)＝100*(ave High control-cpd well)/(ave High control-ave Low control)
其中，ave High control表示：不加化合物的阳性对照孔的发光信号强度；
ave Low control表示：不加酶的阴性对照孔的发光信号强度；
cpd well表示：表示供试品化合物的发光信号强度；
采用XLfit计算IC50。
实验结果：
表3本发明化合物对KIF18A的抑制活性
从上述实验结果可以看出，本发明化合物能够有效抑制KIF18A的活性，是有效的KIF18A抑制剂。
实验例3本发明化合物的小鼠体内药代动力学实验
供试品：本发明化合物，自制，其化学名称和制备方法见各化合物的制备实施例。
受试动物：CD1小鼠，雌性，6只/给药途径/化合物。
供试品溶液制备：
空白溶媒(1)的配制方法：称取20g HPC(羟丙基纤维素)，缓慢加入500mL搅拌着的纯化水中，再加入1mL吐温80，搅拌至澄清透明，定容到1000mL，搅拌均匀即得2％HPC+0.1％吐温80。
IV(静脉推注)给药：
称取本发明化合物适量(例如2.58mg)，加入DMA(N,N-二甲基乙酰胺)(例如489μL)，超声涡旋溶解，然后加入Kolliphor HS15(聚乙二醇-15-羟基硬脂酸酯)(例如489μL)，涡旋混匀，最后加入DPBS(杜氏磷酸盐缓冲液)(例如3.914mL)，涡旋混匀，制备得0.5mg/mL的澄清溶液，作为测试化合物的IV给药溶液。
PO(灌胃)给药：
称取本发明实施例化合物适量(例如10.16mg)，置于组织研磨器中，加入空白溶媒(1)(例如3.102mL)，以1000转/分钟的转速研磨均匀，制备得3mg/mL的混悬药液，作为测试化合物的PO给药药液。
实验方法
IV给药剂量为2.5mg/kg，给药浓度为0.5mg/mL，给药体积为5mL/kg。
PO给药剂量为30mg/kg，给药浓度为3mg/mL，给药体积为10mL/kg。
采血时间点：给药后0.083、0.25、0.5、1、2、4、6、8、24h，具体按表4所示方式采血：
表4
每个时间点通过眼内眦采集全血约50μL，放置到含有EDTA-K2抗凝剂的抗凝管中，在4℃条件下8000转/分钟离心6min得到血浆样品，血浆于-80℃冰箱冻存，待分析。
血浆样品分析
采用蛋白沉淀法：取血浆样品20μL，加入内标(含甲苯磺丁脲200ng/mL的乙腈溶液)200μL，涡旋10min后，然后4000转/分钟离心20分钟，取上清液100μL，再加入100μL水，涡旋混匀3min后，LC-MS/MS分析血浆中的药物浓度。
实验结果及结论
通过测试结果可知，本发明化合物具有良好的药代动力学性质，且具有较低的清除率，以及较高的暴露量和生物利用度。
具体实施方式
下面将结合具体实施例对本发明的技术方案进行描述，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
DMF：N,N-二甲基甲酰胺        EA：乙酸乙酯                 PE：石油醚
DCM：二氯甲烷                THF：四氢呋喃                DMA：N,N-二甲基乙酰胺
DIPEA：N,N-二异丙基乙胺      DMSO：二甲基亚砜             DEAD：偶氮二甲酸二乙酯
NaH：氢化钠                  TFA：三氟乙酸                SOCl2：氯化亚砜
CuI：碘化亚酮                 Boc-NH2：氨基甲酸叔丁酯
RuPhos Pd G3：甲磺酸(2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)
PdCl2(dppf)：(1,1'-双(二苯基膦基)二茂铁)二氯化钯
实施例1：4-((2-羟乙基)磺胺基)-N-(1-丙基-1H-吡唑并[3,4-b]吡啶-6-基)-2-(6-氮杂螺并[2.5]辛烷-6-基]苯甲酰胺的制备(化合物1)

1. 6-氯-1-丙基-1H-吡唑并[3,4-b]吡啶的制备(Int-1)
0℃下，于6-氯-1H-吡唑[3,4-b]吡啶(4.0g,26.0mmol)的DMF(90mL)中，加入NaH(1.6g,40.0mmol)反应30分钟，后加入碘代丙烷(5.3g,31.1mmol)。继续反应30分钟。体系加水淬灭，EA萃取有机相，干燥，浓缩，残留物经硅胶柱纯化(EA:PE＝1:4)，得目标化合物3.8g，收率74.8％。
2.(1-丙基-1H-吡唑并[3,4-b]吡啶-6-基)氨基甲酸叔丁酯的制备(Int-2)
向化合物Int-1(800mg,4.1mmol)的1,4-二氧六环(100mL)中，加入Boc-NH2(961mg,8.2mmol)、RuPhos Pd G3(343mg,0.41mmol)和碳酸铯(4.0g,12.3mmol)，氮气保护下，100℃下反应16小时。体系加水淬灭，EA萃取有机相，干燥，浓缩，残留物经硅胶柱纯化(EA:PE＝1:9)，得目标化合物1.0g，收率88.5％。
3. 1-丙基-1H-吡唑并[3,4-b]吡啶-6-胺的制备(Int-3)
25℃下，向化合物Int-2(1.0g,3.6mmol)的DCM(15mL)中，加入TFA(5mL)，反应1小时。反应完毕，减压除去溶剂，残留物加入DCM稀释，饱和碳酸氢钠调节pH至碱性，DCM萃取有机相，干燥，浓缩，残留物经硅胶柱纯化(EA:PE＝1:1)，得目标化合物500mg,收率78.4％。
4. 4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰氯的制备(Int-4)
25℃下，向4-碘-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酸(500mg,1.4mmol)的DCM(8mL)中，加入DMF(0.2mL)，0℃下再加入SOCl2(508mg,4.2mmol)，继续反应30分钟。反应完毕，反应液浓缩旋干直接用于下一步。
5. 4-碘-N-(1-丙基-1H-吡唑并[3,4-b]吡啶-6-基)-2-(6-氮杂螺并[2.5]辛烷-6-基]苯甲酰胺的制备(Int-5)
0℃下，于化合物Int-4(上步反应粗品)的DCM(10mL)中，加入磷酸钾(297mg,1.4mmol)、DIPEA(1.1g,8.5mmol)和化合物Int-3(247mg,1.4mmol)，25℃下继续反应2小时。反应完毕，饱和碳酸氢钠调节pH至碱性，DCM萃取有机相，干燥，浓缩，残留物经硅胶柱纯化(EA:PE＝1:1)，得目标化合物360mg，两步收率49.9％。
6. 4-((2-羟乙基)磺胺基)-N-(1-丙基-1H-吡唑并[3,4-b]吡啶-6-基)-2-(6-氮杂螺并[2.5]辛烷-6-基]苯甲酰胺的制备(化合物1)
于化合物Int-5(202mg,0.39mmol)的DMF(15mL)中，加入CuI(74mg,0.39mmol)、N-甲基甘氨酸(69mg,0.78mmol)、磷酸钾(414mg,2.0mmol)和2-羟基乙烷-1-磺酰胺(146mg,1.2mmol)，后在氮气保护下置于100℃下反应16小时。反应完毕，加水淬灭，EA萃取，浓缩，经硅胶柱纯化(EA:PE＝2:1)，得目标化合物136mg，收率67.7％。
分子式:C25H32N6O4S 分子量:512.6 LC-MS(M/e):513.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.68(s,1H),10.2(s,1H),8.27-8.22(m,2H),8.13-8.07(m,2H),7.32(d,J＝2.0Hz,1H),7.18-7.15(m,1H),4.95(s,1H),4.38-4.35(m,2H),3.77-3.76(m,2H),3.39-3.36(m,2H),3.04-3.03(m,4H),1.99-1.82(m,6H),0.89-0.88(m,3H),0.43-0.0.41(m,4H).
实施例2：4-((2-羟乙基)磺胺基)-N-(4-甲基-1-丙基-1H-吡唑并[3,4-b]吡啶-6-基)-2-(6-氮杂螺并[2.5]辛烷-6-基]苯甲酰胺的制备(化合物2)

1.(2,6-二氯-4-甲基吡啶-3-基)甲醇的制备(Int-6)
0℃下，于2,6-二氯-4-甲基烟酸(5.0g,24.3mmol)的THF(10mL)中，加入硼烷四氢呋喃溶液(97.2mL,97.2mmol)，50℃下反应16小时。体系加水淬灭，EA萃取有机相，干燥，浓缩，残留物经硅胶柱纯化(EA:PE＝1:2)，得目标化合物4.4g，收率94.4％。
2. 2,6-二氯-4-甲基烟醛的制备(Int-7)
于化合物Int-6(4.2g,21.9mmol)的DCM(100mL)中，加入氯铬酸吡啶(14.2g,65.9mmol)，25℃下反应2小时。反应液浓缩，残留物经硅胶柱纯化(EA:PE＝1:3)，得目标化合物3.9g，收率93.8％。
3. 6-氯-4-甲基-1H-吡唑并[3,4-b]吡啶的制备(Int-8)
于化合物Int-7(2.2g,11.6mmol)的正丁醇(33mL)中，加入水合肼(1.7g,33.4mmol)，125℃下反应16小时。反应液浓缩，残留物经硅胶柱纯化(DCM:甲醇＝20:1)，得目标化合物1.1g，收率56.7％。
4. 6-氯-4-甲基-1-丙基-1H-吡唑并[3,4-b]吡啶的制备(Int-9)
0℃下，于化合物Int-8(1.1g,6.6mmol)的DMF(25mL)中，加入NaH(396mg,9.9mmol)，反应30分钟，后加入碘代丙烷(1.3g,7.6mmol)，体系加水淬灭，EA萃取有机相，浓缩，残留物经硅胶柱纯化(EA:PE＝1:5)，得目标化合物1.0g，收率72.7％。
5.(4-甲基-1-丙基-1H-吡唑并[3,4-b]吡啶-6-基)氨基甲酸叔丁酯的制备(Int-10)
于化合物Int-9(1.0g,4.8mmol)的1,4-二氧六环(40mL)中，加入Boc-NH2(1.1g,9.4mmol)、RuPhos Pd G3(401mg,0.48mmol)和碳酸铯(4.7g,14.4mmol)，氮气保护下，100℃下反应3小时。体系加水淬灭，EA萃取有机相，干燥，浓缩，残留物经硅胶柱纯化(EA:PE＝1:9)，得目标化合物1.2g，收率86.6％。
6. 1-丙基-1H-吡唑并[3,4-b]吡啶-6-胺的制备(Int-11)
25℃下，于化合物Int-10(1.2g,3.6mmol)的DCM(24mL)中，加入TFA(8mL)，反应1小时。反应完毕，减压除去溶剂，残留物加入DCM稀释，饱和碳酸氢钠调节pH至碱性，DCM萃取有机相，干燥，浓缩，残留物经硅胶柱纯化(EA:PE＝1:1)，得目标化合物600mg，收率76.3％。
7. 4-碘-N-(4-甲基-1-丙基-1H-吡唑并[3,4-b]吡啶-6-基)-2-(6-氮杂螺并[2.5]辛烷-6-基]苯甲酰胺的制备(Int-12)
0℃下，于化合物Int-4(2.2mmol)的DCM(30mL)中，加入磷酸钾(467mg,2.2mmol)、DIPEA(1.7g,13.2mmol)和化合物Int-11(418mg,2.2mmol)，25℃下继续反应1小时。反应完毕，体系加水，DCM萃取有机相，干燥，浓缩，残留物经硅胶柱纯化(EA：PE＝1:9)，得目标化合物660mg，收率55.7％。
8. 4-((2-羟乙基)磺胺基)-N-(4-甲基-1-丙基-1H-吡唑并[3,4-b]吡啶-6-基)-2-(6-氮杂螺并[2.5]辛烷-6-基]苯甲酰胺的制备(化合物2)
于化合物Int-12(300mg,0.57mmol)的DMF(10mL)中，加入CuI(108mg,0.57mmol)、N-甲基甘氨酸(101mg,1.1mmol)和磷酸钾(605mg,2.8mmol)和2-羟基乙烷-1-磺酰胺(214mg,1.7mmol)，后在氮气保护下置于100℃下反应6小时。反应完毕，加水淬灭，EA萃取，浓缩，经硅胶柱纯化(EA:PE＝2:1)，得目标化合物100mg，收率33.5％。
分子式:C26H34N6O4S 分子量:526.7 LC-MS(M/e):527.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.53(s,1H),10.24(s,1H),8.14-8.07(m,3H),7.31(s,1H),7.178-7.15(m,1H),4.95(s,1H),4.38-4.32(m,2H),3.79-3.76(m,2H),3.39-3.33(m,2H),3.02-3.00(m,4H),2.61(s,3H),1.99-1.81(m,6H),0.85-0.70(m,3H),0.50-0.41(m,4H).
实施例3：4-((2-羟乙基)磺酰胺)-N-(1-丙基-1H-吡咯[2,3-b]吡啶-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备(化合物3)
选用6-氯-1H-吡咯[2,3-b]吡啶和碘代丙烷做原料，参照实施例1的制备方法，制备得到4-((2-羟乙基)磺酰胺)-N-(1-丙基-1H-吡咯[2,3-b]吡啶-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺(化合物3)100mg，收率50.3％。
分子式:C26H33N5O4S 分子量:511.64 LC-MS(M/e):512.31(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.24(s,1H),10.19(brs,1H),8.10～8.13(m,2H),7.95～7.99(m,1H),7.44(d,1H),7.30(s,1H),7.14～7.16(dd,1H),6.42(d,1H),4.98(brs,1H),4.18(t,2H),3.78(t,2H),3.37(t,2H),3.03(m,4H),1.81～1.99(m,4H),0.87(t,3H),0.42(m,4H).
实施例4：4-((2-羟乙基)磺胺基)-N-(4-甲基-1-丙基-1H-吡咯并[2,3-b]吡啶-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺的制备(化合物4)
1. 4-溴-1H-吡咯[2,3-b]吡啶氧化物的制备(Int-17)
1L反应瓶中依次加入400mL DCM和4-溴-1H-吡咯[2,3-b]吡啶(20.0g,111.7mmol)，20℃下分批加入间氯过氧苯甲酸(34.6g,167.6mmol)，20℃保温16小时。反应完毕，反应体系减压浓缩至剩余50mL，过滤，滤饼晾干得目标化合物20.0g，收率91.7％。
2. 4-溴-6-氯-1H-吡咯[2,3-b]吡啶的制备(Int-18)
1L反应瓶中依次加入400mL DMF和化合物Int-17(20.0g,93.0mmol)，50℃下滴加甲磺酰氯(26.6g,232.5mmol)，70℃反应2小时。反应完毕，降温至0℃，加入200mL水淬灭，加入50％氢氧化钠水溶液调pH＝7，过滤，滤饼经硅胶柱纯化(EA:PE＝1:10)，得目标化合物6.0g，收率27.9％。
3. 4-溴-6-氯-1-丙基-1H-吡咯[2,3-b]吡啶的制备(Int-19)
1L反应瓶中依次加入50mL DMA和化合物Int-18(5.0g,21.6mmol)，0℃下分批加入NaH(952mg,23.8mmol)，0℃保温0.5小时，滴加碘代丙烷(4.0g,23.8mmol)，20℃反应16小时。反应完毕，将反应液倒入冰水中淬灭，EA萃取，有机相减压浓缩干，粗品经硅胶柱纯化(EA:PE＝1:10)，得目标化合物3.0g，收率50.8％。
4. 6-氯-4-甲基-1-丙基-1H-吡咯[2,3-b]吡啶的制备(Int-20)
100mL反应瓶中依次加入30mL二氧六环，化合物Int-19(3.0g,11.0mmol)、甲基硼酸(1.0g,16.5mmol)、PdCl2(dppf)(400mg,0.55mmol)和磷酸钾(7.0g,33.0mmol)，氮气保护，100℃反应2小时。反应完毕，过滤，滤液减压浓缩干，粗品经硅胶柱纯化(EA:PE＝1:10)，得目标化合物500mg，收率21.7％。
5.(4-甲基-1-丙基-1H-吡咯并[2,3-b]吡啶-6-基)氨基甲酸叔丁酯的制备(Int-21)
100mL反应瓶中依次加入5mL二氧六环、化合物Int-20(500mg,2.4mmol)、Boc-NH2(562mg,4.8 mmol)、RuPhos Pd G3(100mg,0.16mmol)和碳酸铯(1.6g,4.8mmol)，氮气保护，100℃反应1小时。反应完毕，过滤，滤液减压浓缩干，粗品经硅胶柱纯化(EA:PE＝1:20)，得目标化合物200mg，收率28.9％。
6. 4-甲基-1-丙基-1H-吡咯并[2,3-b]吡啶-6-胺的制备(Int-22)
50mL反应瓶中依次加入5mLDCM和化合物Int-21(250mg,0.86mmol)，滴加TFA(5mL)，20℃反应2小时。反应完毕，减压浓缩干，粗品用50mLDCM溶解，加入碳酸氢钠水溶液调pH＝8，有机相干燥，过滤，减压浓缩干得目标化合物100mg，收率61.3％。
7. 4-碘-N-(4-甲基-1-丙基-1H-吡咯并[2,3-b]吡啶-6-基)-2-(6-氮杂螺环[2.5]辛烷-6-基]苯甲酰胺的制备(Int-23)
50mL反应瓶中依次加入5mL DCM，化合物Int-22(100mg,0.53mmol)、化合物Int-4(500mg,1.33mmol)和DIPEA(342mg,26.5mmol)，20℃反应1小时。反应完毕，反应体系经硅胶柱纯化(EA:PE＝1:10)，得目标化合物60mg，收率21.5％。
8. 4-((2-羟乙基)磺胺基)-N-(4-甲基-1-丙基-1H-吡咯并[2,3-b]吡啶-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺的制备(化合物4)
50mL反应瓶中依次加入2mL DMF、化合物Int-23(60mg,0.11mmol)、CuI(21mg,0.11mmol)、N-甲基甘氨酸(10mg,0.11mmol)和磷酸钾(70mg,0.33mmol)，50℃下反应5分钟，加入2-羟基乙烷-1-磺酰胺(21mg,0.11mmol)，100℃下反应1小时。反应完毕，加水淬灭，EA萃取，有机相减压浓缩干，粗品经高压制备液相纯化，得目标化合物6mg，收率10.1％。
分子式:C27H35N5O4S 分子量:525.67 LC-MS(M/e):526.32(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:11.54(s,1H),8.10～8.13(d,J＝8.4Hz,1H),8.03(s,1H),7.28～7.32(m,1H),7.14(m,1H),7.0(m,1H),6.52(m,1H),4.24～4.28(t,2H),4.10～4.16(t,2H),3.34～3.36(t,2H),3.11～3.13(m,4H),2.67(s,3H),1.89～1.98(m,2H),1.46～1.58(m,4H),0.98(t,3H),0.42(m,4H).
实施例5：4-((2-羟乙基)磺胺基)-N-(1-甲基-1H-吡唑并[3,4-b]吡啶-6-基)-2-(6-氮杂螺并[2.5]辛烷-6-基]苯甲酰胺的制备(化合物9)
选用6-氯-1H-吡唑[3,4-b]吡啶和碘代甲烷做原料，参照实施例1的制备方法，制备得到4-((2-羟乙基)磺酰胺)-N-(1-甲基-1H-吡唑[3,4-b]吡啶-6-基)-2-(6-氮杂螺并[2.5]辛烷-6-基]苯甲酰胺(化合物9)18mg，收率12.4％。
分子式:C23H28N6O4S 分子量:484.6 LC-MS(M/e):485.0(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.77(s,1H),10.26(s,1H),8.28-8.20(m,2H),8.13-8.08(m,2H),7.32(d,J＝2.0Hz,1H),7.18-7.15(m,1H),4.97(s,1H),4.01(s,3H),3.76-3.78(m,2H),3.40-3.37(m,2H),3.05-3.02(m,4H),1.99-1.84(m,4H),0.43(m,4H).
实施例6：4-((2-羟乙基)磺胺基)-N-(1-异丙基-1H-吡唑并[3,4-b]吡啶-6-基)-2-(6-氮杂螺并[2.5]辛烷-6-基]苯甲酰胺的制备(化合物10)

选用6-氯-1H-吡唑[3,4-b]吡啶和2-碘丙烷做原料，参照实施例1的制备方法，制备得到4-((2-羟乙基)磺胺基)-N-(1-异丙基-1H-吡唑并[3,4-b]吡啶-6-基)-2-(6-氮杂螺并[2.5]辛烷-6-基]苯甲酰胺(化合物10)44mg，收率29.6％。
分子式:C25H32N6O4S 分子量:512.6 LC-MS(M/e):513.0(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.73(s,1H),10.3(s,1H),8.23-8.27(m,2H),8.02-8.20(m,2H),7.31(s,1H),7.12-7.19(m,1H),5.05-5.15(m,1H),4.96(s,1H),3.77(s,2H),3.39-3.36(m,2H),3.04(s,4H),1.75-1.90(m,4H),1.55(d,J＝6.7Hz,6H),0.43-0.0.41(m,4H).
实施例7：4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛烷-6-基)-N-(1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-6-基]苯甲酰胺的制备(化合物11)
1.四氢-2H-吡喃-4-基甲磺酸酯的制备(Int-32)
将四氢-2H-吡喃-4-醇(4.0g,39mmol)溶于DCM(40mL)中，加入三乙胺(11.8g,117mmol)，0℃下加入甲基磺酰氯(4.9g,43mmol)，0℃反应1小时，加入纯化水淬灭，水洗一次，有机相经浓缩得目标化合物4.8g，收率67.6％。
2. 4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛烷-6-基)-N-(1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-6-基]苯甲酰胺的制备(化合物11)
选用6-氯-1H-吡唑[3,4-b]吡啶和化合物Int-32做原料，参照实施例1的制备方法，制备得到4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛烷-6-基)-N-(1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-6-基]苯甲酰胺(化合物11)40mg，收率26.8％。
分子式:C27H34N6O5S 分子量:554.7 LC-MS(M/e):555.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.52(s,1H),10.26(s,1H),8.27(m,2H),8.12-8.10(m,2H),7.32(m,1H),7.17-7.14(m,1H),4.95-4.92(m,2H),4.08-4.06(m,2H),3.78-3.75(m,2H),3.57-3.54(m,2H),3.51(m,2H),3.03(m,4H),2.33(m,2H),2.01-1.96(m,2H),1.80-1.45(m,4H),0.43-0.45(m,4H).
实施例8：4-(环丙基磺酰基)-N-(1-丙基-1H-吡唑并[3,4-b]吡啶-6-基)-2-(6-氮杂螺并[2.5]辛烷-6-基]苯甲酰胺的制备(化合物12)
于化合物Int-5(100mg,0.19mmol)的DMSO(2mL)中，加入CuI(4mg,0.021mmol)、L-脯氨酸(4mg,0.035mmol)、碳酸钾(5mg,0.036mmol)和环丙基亚磺酸钠(49mg,0.38mmol)，后在氮气保护下，置于微波140℃下反应1小时。反应完毕，加水淬灭，EA萃取，浓缩，经硅胶柱纯化(EA:PE＝1:2)，得目标化合物45mg，收率47.0％。
分子式:C26H31N5O3S 分子量:493.6 LC-MS(M/e):494.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.43(s,1H),8.40-8.30(m,2H),8.29-8.20(m,1H),8.15(s,1H),7.92(s,1H),7.89-7.80(m,1H),4.45-4.35(m,2H),3.20-3.3.12(m,4H),3.10-3.00(m,1H),2.05-1.85(m,2H),1.84-1.74(m,3H),1.35-1.10(m,4H),0.95-0.80(m,4H),0.50-0.35(m,4H).
实施例9：N-(3-氟-1-丙基-1H-吡唑并[3,4-b]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺的制备(化合物13)
1. 6-氯-3-氟-1-丙基-1H-吡唑并[3,4-b]吡啶的制备(Int-37)
于6-氯-1H-吡唑[3,4-b]吡啶(1.8g,9.2mmol)的乙腈(100mL)中，加入Selectfluor氟试剂(9.8g,27.7mmol)，80℃下，反应16小时。体系加水淬灭，EA萃取有机相，干燥，浓缩，残留物经硅胶柱纯化(DCM:PE＝3:1)，得目标化合物800mg，收率40.7％。
2.(3-氟-1-丙基-1H-吡唑并[3,4-b]吡啶-6-基)氨基甲酸叔丁酯的制备(Int-38)
于化合物Int-37(800mg,3.7mmol)的1,4-二氧六环(30mL)，Boc-NH2(867mg,7.4mmol)，RuPhos Pd G3(310mg,0.37mmol)和碳酸铯(3.6g,11.0mmol)，氮气保护下100℃下反应3小时。体系加水淬灭，EA萃取有机相，干燥，浓缩，残留物经硅胶柱纯化(DCM:PE＝2:3)，得目标化合物600mg，收率54.4％。
3. 3-氟-1-丙基-1H-吡唑并[3,4-b]吡啶-6-胺的制备(Int-39)
25℃下，于化合物Int-38(600mg,2.0mmol)的DCM(12mL)中，加入TFA(4mL)反应1小时。反应完毕，减压除去溶剂，残留物加入DCM稀释，饱和碳酸氢钠调节pH至碱性，DCM萃取有机相，干燥，浓缩，残留物经硅胶柱纯化(EA:PE＝1:3)，得目标化合物390mg，收率98.5％。
4.N-(3-氟-1-丙基-1H-吡唑并[3,4-b]吡啶-6-基)-4-碘-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺的制备(Int-40)
0℃下，于化合物Int-4(1.2mmol粗品)的DCM(10mL)中，加入磷酸钾(255mg,1.2mmol)、DIPEA(930mg,7.2mmol)和化合物Int-39(233mg,1.2mmol)，60℃下继续反应3小时。反应完毕，饱和碳酸氢钠调节pH至碱性，DCM萃取有机相，干燥，浓缩，残留物经硅胶柱纯化(EA:PE＝1:9)，得目标化合物250mg，收率39.8％。
5.N-(3-氟-1-丙基-1H-吡唑并[3,4-b]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺的制备(化合物13)
于化合物Int-40(110mg,0.219mmol)的DMF(10mL)中，加入CuI(40mg,0.21mmol)、N-甲基甘氨酸(37mg,0.42mmol)、磷酸钾(223mg,1.1mmol)和2-羟基乙烷-1-磺酰胺(79mg,0.63mmol)，后在氮气保护下置于100℃下反应1小时。反应完毕，加水淬灭，EA萃取，浓缩，经硅胶柱纯化(EA:PE＝2:1)，得目标化合物30mg，收率27.4％。
分子式:C25H31FN6O4S 分子量:530.6 LC-MS(M/e):531.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.89(s,1H),10.2(s,1H),8.30-8.29(m,2H),8.13-8.11(m,1H),7.32(s,1H),7.18-7.15(m,1H),4.97(s,1H),4.33-4.27(m,2H),3.79-3.77(m,2H),3.39-3.35(m,2H),3.04-3.00(m,4H),1.95-1.65(m,6H),0.95-0.88(m,3H),0.50-0.41(m,4H).
实施例10：N-(3-氟-1-异丙基-1H-吡唑并[3,4-b]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺的制备(化合物18)
选用6-氯-1H-吡唑[3,4-b]吡啶和碘代异丙烷作为起始原料，参照实施例9的制备方法，制备得到N-(3-氟-1-异丙基-1H-吡唑并[3,4-b]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺。
分子式:C25H31FN6O4S 分子量:530.21 LC-MS(M/e):531.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.94(s,1H),10.3(m,1H),8.26(m,2H),8.12-8.10(m,1H),7.32(m,1H),7.18(m,1H),5.03(m,1H),3.79-3.77(m,2H),3.55-3.53(m,2H),3.18-3.13(m,4H),2.03(m,1H),1.99-1.97(m,4H),1.55(m,6H),0.43-0.41(m,4H).
实施例11：N-(3-氟-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺(化合物20)
选用6-氯-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶作为起始原料，参照实施例9的制备方法，制备得到N-(3-氟-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-b]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺。
分子式:C27H33FN6O5S 分子量:572.7 LC-MS(M/e):573.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.72(s,1H),10.28(s,1H),8.33(m,2H),8.12-8.10(m,1H),7.33-7.32(m,1H),7.17-7.15(m,1H),4.98-4.96(m,1H),4.86-4.85(m,1H),4.07-4.04(m,2H),3.79-3.75(m,2H),3.53-3.51(m,2H),3.48(m,2H),3.03(m,4H),2.19-2.17(m,2H),2.11-2.08(m,2H),1.78-1.45(m,4H),0.43-0.0.45(m,4H).
实施例12：4-(环丙基磺酰基)-N-(1-丙基-1H-吡唑并[3,4-b]吡啶-6-基)-2-(6-氮杂螺并[2.5]辛烷-6-基]苯甲酰胺的制备(化合物22)
1. 2-((4-((1-丙基-1H-吡唑并[3,4-b]吡啶-6-基)氨基甲酰基)-3-(6-氮杂螺[2.5]辛烷-6-基]苯基)磺酰基)乙酸乙酯的制备(Int-50)
将化合物Int-5(200mg,0.39mmol)溶于DMSO(5mL)中，加入焦亚硫酸钾(129mg,0.58mmol)、甲酸钠(58mg,0.86mmol)、三苯基磷(16mg,0.06mmol)、1,10-二氮杂菲(11mg，0.06mmol)、四丁基溴化铵(187mg,0.58mmol)和醋酸钯(4mg,0.03mmol)，氮气保护下，在70℃反应45分钟，降温，加入溴乙酸乙酯(97mg,0.58mmol)，反应10min，反应完毕，加水淬灭，EA萃取，浓缩硅胶柱纯化(EA:PE＝55％)得到目标化合物150mg,收率71.8％。
2. 4-((2-羟乙基)磺酰基)-N-(1-丙基-1H-吡唑并[3,4-b]吡啶-6-基)-2-(6-氮杂螺并[2.5]辛烷-6-基]苯甲酰胺的制备(化合物22)
25℃下，将硼氢化锂(19mg，0.83mmol)加入含有化合物Int-50(150mg,0.28mmol)的THF(5mL)溶液，反应1小时。反应完毕，加水淬灭，EA萃取，浓缩硅胶柱纯化(EA:PE＝60％)，及EA打浆得目标化合物30mg,收率：20.8％。
分子式:C25H31N5O4S 分子量:497.6 LC-MS(M/e):498.0(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.47(s,1H),8.43-8.30(m,2H),8.24-8.21(m,1H),8.11(m,1H),7.96(m,1H),7.85-7.83(m,1H),4.95-4.93(m,1H),4.39-4.36(m,2H),3.76-3.71(m,2H)，3.59-3.56(m,2H),3.37-3.14(m,4H),2.03-1.90(m,2H),1.78(m,4H),0.92(m,3H),0.456(m,4H).
实施例13：N-(1-(3,3-二氟环丁基)-1H-吡唑并[3,4-b]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺的制备(化合物24)
1. 6-氯-1-(3,3-二氟环丁基)-1H-吡唑并[3,4-b]吡啶的制备(Int-51)
将6-氯-1H-吡唑[3,4-b]吡啶(1.4g,9.3mmol)、3,3-二氟环丁醇(1g,9.3mmol)和三苯基膦(3.2g,12mmol)溶于THF中，加入DEAD(2.4g,14mmol)，25℃反应4h。体系加水淬灭，EA萃取有机相，干燥，浓缩，残留物经硅胶柱纯化(EA:PE＝1:3)，得目标化合物750mg，收率33.4％。
2.N-(1-(3,3-二氟环丁基)-1H-吡唑并[3,4-b]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺的制备(化合物24)
使用化合物Int-51作为起始原料，参照实施例1的制备方法，制备得到目标化合物。
分子式:C26H30F2N6O4S 分子量:560.6 LC-MS(M/e):561.0(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.85(s,1H),10.3(s,1H),8.05-8.35(m,4H),7.25-7.35(m,1H),7.10-7.20(m,1H),5.22-5.32(m,1H),4.85-5.00(m,1H),3.77(s,4H),3.25(s,4H),3.04(s,4H),1.75-2.00(m,4H),0.40-0.50(m,4H).
实施例14：4-(环丙基磺酰基)-N-(1-(2,2-二氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺的制备(化合物25)
选用6-氯-1H-吡唑[3,4-b]吡啶和1,1-二氟-2-碘乙烷做原料，参照实施例1的制备方法，制备得到4-(环丙基磺酰基)-N-(1-(2,2-二氟乙基)-1H-吡唑并[3,4-b]吡啶-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺。
分子式:C25H27F2N5O3S 分子量:515.6 LC-MS(M/e):516.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.66(s,1H),8.37-8.25(m,4H),7.94(s,1H),7.85-7.83(m,1H),6.70-6.30(m,1H),4.95-4.75(m,2H),3.30-3.20(m,4H),3.10-3.05(m,1H),1.95-1.75(m,4H),1.30-1.10(m,4H),0.42-0.41(m,4H).
实施例15：4-(环丙基磺酰基)-N-(3-氟-1-丙基-1H-吡唑并[3,4-b]吡啶-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺的制备(化合物26)
将化合物Int-40(60mg,0.11mmol)、环丙烷亚磺酸钠(28mg,0.22mmol)、碳酸钾(3mg,0.02mmol)、CuI(2mg,0.01mmol)和L-脯氨酸(3mg,0.02mmol)加入到DMSO(2ml)溶液中，置换氮气后，微波140℃，反应1小时。反应完毕，加水淬灭，EA萃取，浓缩，粗品经(EA:PE＝1:1)打浆，得目标化合物16.6mg,收率29.5％。
分子式:C26H30FN5O3S 分子量:511.6 LC-MS(M/e):512.1(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.60(s,1H),8.20-8.40(m,3H),7.94(s,1H),7.85-7.95(m,1H),4.27(s,2H),3.16(s,4H),3.02-3.08(m,1H),1.60-1.80(m,6H),1.05-1.35(m,4H),0.88(t,3H),0.35-0.45(m,4H).
实施例16：4-(环丙基磺酰基)-N-(3-丙基-3H-[1,2,3]三唑并[4,5-b]吡啶-5-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备(化合物27)
1. 6-氯-3-硝基-N-丙基吡啶-2-胺的制备(Int-59)
将2,6-二氯-3-硝基吡啶(5.0g,25.9mmol)溶于THF(50mL)中，加入丙-1-胺盐酸盐(4.95g,51.8mmol)，加入DIPEA(13.4g,103.6mmol)，25℃反应16小时，浓缩剩余物柱层析(EA/正庚烷＝10％)得目标化合物5.0g，收率74.6％。
2. 6-氯-N2-丙基吡啶-2,3-二胺的制备(Int-60)
将化合物Int-59(4.5g,20.8mmol)溶于冰乙酸(45mL)中，加入铁粉(4.7g,83.2mmol)，25℃反应18小时，反应完毕。浓缩干，加入饱和碳酸氢钠溶液调节pH＝8，加入EA萃取，浓缩得目标化合物粗品4.5g。
3. 5-氯-3-丙基-3H-[1,2,3]三唑并[4,5-b]吡啶的制备(Int-61)
将化合物Int-60(1.7g,9.1mmol)溶于乙酸(15mL)中，加入亚硝酸钠(1.3g,18.2mmol)，25℃下反应1小时，加入水，25℃下反应0.5小时，反应完毕。加入饱和碳酸氢钠溶液淬灭，EA萃取两次，浓缩得目标化合物1.6g，收率90.2％。
4.(3-丙基-3H-[1,2,3]三唑并[4,5-b]吡啶-5-基)氨基甲酸叔丁酯的制备(Int-62)
将化合物Int-61(2.2g,11.2mmol)溶于1,4-二氧六环(20mL)，加入Boc-NH2(2.6g,22.4mmol)，加入RuPhos Pd G3(920mg,1.1mmol)和碳酸铯(11.0g,33.6mmol)，氮气保护下100℃下反应3小时，反应完毕。浓缩干，体系加饱和碳酸氢钠溶液淬灭，EA萃取两次，浓缩残留物经硅胶柱纯化(EA:PE＝40％)，得目标化合物1.8g，收率58.1％。
5. 3-丙基-3H-[1,2,3]三唑并[4,5-b]吡啶-5-胺的制备(Int-63)
将化合物Int-62(1.8g,6.5mmol)溶于DCM(20mL)，加入TFA(6mL)，25℃反应3小时。反应完毕，减压除去溶剂，饱和碳酸氢钠调节pH至8，EA萃取，干燥，浓缩得目标化合物(1.2g粗品)。
6. 4-碘-N-(3-丙基-3H-[1,2,3]三唑并[4,5-b]吡啶-5-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备(Int-64)
将化合物Int-4(1.2g)溶于DCM(8mL)中，加入磷酸钾(466mg,2.2mmol)、DIPEA(1.7g,13.2mmol)和化合物Int-63(400mg,2.2mmol)，25℃下继续反应4小时，反应完毕。浓缩残留物经硅胶柱纯化(EA:PE＝25％)，得目标化合物190mg，两步收率17.3％。
7. 4-(环丙基磺酰基)-N-(3-丙基-3H-[1,2,3]三唑并[4,5-b]吡啶-5-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备
将化合物Int-64(190mg,0.32mmol)溶于DMSO(5mL)，加入环丙烷磺酸钠(94mg,0.74mmol)、碳酸钾(10mg,0.074mmol)、CuI(7mg,0.037mmol)和L-脯氨酸(9mg,0.074mmol)，氮气保护下，微波140℃下反应1小时，反应完毕。加饱和碳酸氢钠水溶液淬灭，EA萃取，浓缩剩余物经硅胶柱纯化(EA:PE＝47％)，EA打浆，过滤，旋干得目标化合物60mg，收率33.0％。
分子式:C25H30N6O3S 分子量:494.6 LC-MS(M/e):495.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.62(s,1H),8.63-8.61(m,1H),8.46(m,1H),8.37(m,1H),7.94(m,1H),7.84-7.82(m,1H),4.61(m,2H),3.15(m,4H),3.04(m,1H),2.04-1.98(m,2H),1.74(m,4H),1.27(m,2H),1.20-1.11(m,2H),0.92-0.89(m,3H),0.41(m,4H).
实施例17：N-(1-环丙基-3-氟-1H-吡唑并[3,4-b]吡啶-6-基)-4-((2-羟乙基)磺酰基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺的制备(化合物28)
选用6-氯-1H-吡唑[3,4-b]吡啶和环丙基硼酸做原料，参照实施例9的制备方法，制备得到N-(1-环丙基-3-氟-1H-吡唑并[3,4-b]吡啶-6-基)-4-((2-羟乙基)磺酰基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺。分子式:C25H28FN5O4S 分子量:513.6 LC-MS(M/e):514.0(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.55(s,1H),8.30(s,3H),7.97(s,3H),7.80-7.85(m,1H),4.95(t,1H,J＝5.4Hz),3.70-3.75(m,2H),3.60-3.70(m,3H),3.15(s,4H),1.79(s,4H),1.10-1.40(m,4H),0.42(s,4H).
实施例18：4-((2-羟乙基)磺酰胺基)-N-(3-丙基-3H-[1,2,3]三唑并[4,5-b]吡啶-5-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备(化合物31)
将化合物Int-64(160mg,0.31mmol)溶于DMF(10mL)，加入CuI(59mg,0.31mmol)、N-甲基甘氨酸(55mg,0.62mmol)和磷酸钾(329mg,1.55mmol)和2-羟基乙烷-1-磺酰胺(116mg,0.93mmol)，氮气保护下，100℃下反应3小时，反应完毕。加饱和碳酸氢钠水溶液淬灭，EA萃取，浓缩，经硅胶柱纯化(EA:PE＝70％)，EA打浆，过滤，旋干得目标化合物15mg，收率9.4％。
分子式:C24H31N7O4S 分子量:513.6 LC-MS(M/e):514.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.98(s,1H),10.30(s,1H),8.59-8.57(m,1H),8.50(m,1H),8.14-8.12(m,1H),7.32(m,1H),7.17-7.15(m,1H),5.03(m,1H),4.63-4.59(m,2H),3.77-3.76(m,2H),3.03(m,4H),2.04-2.00(m,4H),1.91-1.67(m,4H),0.93-0.89(m,3H),0.43(m,4H).
实施例19：4-((2-羟乙基)磺酰基)-N-(3-丙基-3H-[1,2,3]三唑并[4,5-b]吡啶-5-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备(化合物32)
1. 2-((4-((3-丙基-3H-[1,2,3]三唑并[4,5-b]吡啶-5-基)氨基甲酰基)-3-(6-氮杂螺[2.5]辛烷-6-基)苯基)磺酰基)乙酸乙酯的制备(Int-71)
依次将化合物Int-64(180mg,0.35mmol)溶于DMSO(10mL)，加入焦亚硫酸钾(118mg,0.53mmol)、甲酸钠(52mg,0.77mmol)、三苯基磷(13mg,0.05mmol)、1,10-二氮杂菲(9mg,0.05mmol)、四丁基溴化铵(171mg,0.53mmol)和醋酸钯(7mg,0.03mmol)，氮气保护下，在70℃反应45分钟，降温，加入溴乙酸乙酯(89mg,0.53mmol)反应10min，反应完毕，加水淬灭，EA萃取，浓缩硅胶柱纯化(EA:PE＝1:1)得到目标化合物80mg,收率：42.9％。
2. 4-((2-羟乙基)磺酰基)-N-(3-丙基-3H-[1,2,3]三唑并[4,5-b]吡啶-5-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备
25℃下，将硼氢化锂(10mg,0.45mmol)加入含有化合物Int-71(80mg,0.15mmol)的THF(5mL)溶液，反应1小时。反应完毕，加水淬灭，EA萃取，浓缩硅胶柱纯化(EA:PE＝3:1)得粗品，经甲醇打浆目标化合物27mg,收率：36.1％。
分子式:C24H30N6O4S 分子量:498.6 LC-MS(M/e):499.0(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.70(s,1H),8.62-8.68(m,1H),8.42-8.50(m,1H),8.20-8.30(m,1H),7.96(s,1H),7.82-7.90(m,1H),4.96(t,1H,J＝5.4Hz),4.62(s,2H),3.70-3.80(m,2H),3.54-3.62(m,2H),3.15(s,4H),1.90-2.10(m,2H),1.74(s,4H),0.91(t,3H,J＝7.2Hz),0.41(s,4H).
实施例20：N-(1-(3,3-二氟环丁基)-1H-吡唑并[3,4-b]吡啶-6-基)-4-((2-羟乙基)磺酰基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺的制备(化合物33)
1. 2-((4-((1-(3,3-二氟环丁基)-1H-吡唑并[3,4-b]吡啶-6-基)氨基甲酰基)-3-(6-氮杂螺[2.5]辛烷-6-基苯基)磺酰基)乙酸乙酯的制备(Int-72)
依次将化合物Int-54(127mg,0.23mmol)溶于DMSO(5mL)，加入焦亚硫酸钾(77mg,0.35mmol)，甲酸钠(34mg,0.50mmol)，三苯基磷(9mg,0.034mmol)，1,10-二氮杂菲(6mg,0.033mmol)，四丁基溴化铵(111 mg,0.34mmol)和醋酸钯(4mg,0.018mmol)，氮气保护下，在70℃反应45分钟，降温至25℃，加入溴乙酸乙酯(58mg,0.35mmol)反应15分钟，反应完毕，加水淬灭，EA萃取，浓缩硅胶柱纯化(EA:PE＝1:2)得到目标化合物60mg,收率：45.3％。
2.N-(1-(3,3-二氟环丁基)-1H-吡唑并[3,4-b]吡啶-6-基)-4-((2-羟乙基)磺酰基)-2-(6-氮杂螺[2.5]辛烷-6-基]苯甲酰胺的制备
25℃下，于化合物Int-72(60mg,0.10mmol)的THF(4mL)溶液中，加入硼氢化锂(14mg,0.60mmol)反应1小时。反应完毕，加水淬灭，EA萃取，浓缩硅胶柱纯化(EA:PE＝1:1)得目标化合物25mg,收率：44.9％。
分子式:C26H29F2N5O4S 分子量:545.6 LC-MS(M/e):546.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.66(s,1H),8.40-8.20(m,4H),7.97(s,1H),7.84(d,J＝8.4Hz,1H),5.40-5.20(m,1H),4.96-4.94(m,1H),3.82-3.70(m,2H),3.68-3.55(m,2H),3.30-3.10(m,4H),1.90-1.75(m,4H),1.40-1.20(m,4H),0.50-0.40(m,4H).
实施例21：4-(环丙基磺酰基)-N-(1-(3,3-二氟环丁基)-1H-吡唑并[3,4-b]吡啶-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备
将化合物Int-54(100mg,0.18mmol)溶于DMSO(3mL)，加入环丙烷磺酸钠(46mg,0.36mmol)，碳酸钾(6mg,0.04mmol)和CuI(4mg,0.02mmol)和L-脯氨酸(5mg,0.04mmol)，氮气保护下，微波140℃下反应1小时，反应完毕。加饱和氯化铵水溶液淬灭，EA萃取，浓缩剩余物经硅胶柱纯化(EA:PE＝1:1)，得目标化合物20mg，收率：20.6％。
分子式:C27H29F2N5O3S 分子量:541.6 LC-MS(M/e):542.1(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.62(s,1H),8.50-8.40(m,1H),8.30-8.40(m,2H),8.25-8.29(m,2H),7.95(s,1H),7.80-7.90(m,1H),5.25-5.35(m,1H),3.45-3.50(m,2H),3.30-3.40(m,2H),3.16(s,4H),3.00-3.10(m,1H),1.99(s,4H),1.08-1.22(m,4H),0.45(s,4H).
实施例22：4-((2-羟乙基)磺酰胺基)-N-(1-(氧杂环丁烷-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备(化合物35)
选择6-氯-1H-吡唑[3,4-b]吡啶和氧杂环丁烷-3-基-4-甲基苯磺酸盐做原料，参照实施例7的制备方法，制备得到4-((2-羟乙基)磺酰胺基)-N-(1-(氧杂环丁烷-3-基)-1H-吡唑并[3,4-b]吡啶-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺。
分子式:C25H30N6O5S 分子量:526.6 LC-MS(M/e):527.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.25(s,1H),8.31-8.25(m,2H),8.21(m,1H),8.10-8.08(m,1H),7.30(m,1H),7.16-7.14(m,1H),5.98-5.95(m,1H),5.20-5.16(m,2H),5.03-5.01(m,2H),3.76(m,2H),3.46-3.45(m,2H),3.10-3.08(m,4H),1.90-1.62(m,4H),1.26(m,1H),0.43-0.46(m,4H).
实施例23：4-(环丙基磺酰基)-N-(3-丙基-3H-咪唑并[4,5-b]吡啶-5-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备(化合物38)
参照实施例16的制备方法，制备得到4-(环丙基磺酰基)-N-(3-丙基-3H-咪唑并[4,5-b]吡啶-5-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺(化合物38)8mg，收率4.2％。
分子式:C26H31N5O3S 分子量:493.6 LC-MS(M/e):494.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.24(s,1H),8.50-8.40(m,1H),8.37-8.27(m,2H),8.17(m,1H),7.91-7.84(m,1H),7.82(m,1H),4.23-4.20(m,2H),3.14(m,4H),3.04-3.00(m,1H),1.99-1.96(m,2H),1.90-1.77(m,4H),1.23(m,2H),1.19-1.18(m,2H),0.94(m,3H),0.40(m,4H).
实施例24：4-((2-羟乙基)磺酰胺基)-N-(1-(2-甲氧基乙基)-1H-吡唑[3,4-b]吡啶-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备(化合物55)
选用6-氯-1H-吡唑[3,4-b]吡啶和1-碘-2-甲氧基乙烷做原料，参照实施例1的制备方法，制备得到4-((2-羟乙基)磺酰胺基)-N-(1-(2-甲氧基乙基)-1H-吡唑[3,4-b]吡啶-6-基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺。
分子式:C25H32N6O5S 分子量:528.6 LC-MS(M/e):529.0(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.69(s,1H),10.3(s,1H),8.15-8.20(m,2H),8.00-8.10(m,2H),7.30(s,1H),7.06-7.10(m,1H),4.99-5.00(s,1H),4.50-4.60(m,2H),3.70-3.85(m,4H),3.30-3.40(m,2H),3.21(s,3H),3.02(s,4H),1.70-1.90(m,4H),0.35(s,4H).
实施例25：N-(1-(2-(二氟甲氧基)乙基)-1H-吡唑并[3,4-b]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备(化合物56)
1. 1-(2-((叔丁基二苯基硅烷基)氧基)乙基)-6-氯-1H-吡唑并[3,4-b]吡啶的制备(Int-85)
0℃下，于6-氯-1H-吡唑[3,4-b]吡啶(1.3g,8.5mmol)的DMF(50mL)中，加入NaH(60％)(680mg,17.0mmol)反应30分钟，后加入(2-溴乙氧基)(叔丁基)二苯基硅烷(3.7g,10.2mmol)。后置于25℃下继续反应5小时。体系加水淬灭，EA萃取有机相，干燥，浓缩，残留物经硅胶柱纯化(EA:PE＝1:10)，得目标化合物2.3g，收率：62.4％。
2. 2-(6-氯-1H-吡唑并[3,4-b]吡啶-1-基)乙烷-1-醇的制备(Int-86)
于化合物Int-85(2.3g,5.3mmol)的THF(20mL)中，加入四丁基氟化胺的THF溶液(1M,15.9mL,15.9mmol)，25℃下反应2小时。体系加水淬灭，EA萃取有机相，干燥，浓缩，残留物经硅胶柱纯化(EA:PE＝1:1)，得目标化合物800mg，收率：76.7％。
3. 6-氯-1-(2-(二氟甲氧基)乙基)-1H-吡唑[3,4-b]吡啶的制备(Int-87)
于化合物Int-86(1.0g,5.1mmol)的乙腈(30mL)中，加入CuI(486mg,2.6mmol)和2,2-二氟-2-(氟磺酰基)乙酸(1.8g,10.1mmol)。置于50℃下反应2小时。体系加饱和碳酸氢钠溶液淬灭，EA萃取有机相，干燥，浓缩，残留物经硅胶柱纯化(EA:PE＝1:5)，得目标化合物660mg，收率：52.7％。
4.N-(1-(2-(二氟甲氧基)乙基)-1H-吡唑并[3,4-b]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺的制备
选用Int-87做原料，参照实施例1的制备方法，制备得到N-(1-(2-(二氟甲氧基)乙基)-1H-吡唑并[3,4-b]吡啶-6-基)-4-((2-羟乙基)磺酰胺基)-2-(6-氮杂螺[2.5]辛烷-6-基)苯甲酰胺。
分子式:C25H30F2N6O5S 分子量:564.6 LC-MS(M/e):565.2(M+H+)
1H-NMR(400MHz,DMSO-d6)δ:13.79(s,1H),10.29(s,1H),8.28-8.22(m,2H),8.12-8.10(m,2H),7.33(s,1H),7.17(d,J＝8.8Hz,1H),6.59(t,J＝75.2Hz,1H),5.01-4.90(m,1H),4.65-4.63(m,2H),4.35-4.32(m,2H),3.78-3.74(m,2H),3.38-3.35(m,2H),3.15-3.00(m,4H),1.95-1.70(m,4H),0.42-0.41(m,4H).
此外，还使用与上述实施例相同或相似的方法制备得到了以下化合物：
以上对本发明所提供的KIF18A抑制剂及其应用进行了详细介绍。本文中应用了具体实施例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其中心思想。应当指出，对于本领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护。

Claims (10)

  1. 式(I)所示的化合物、其药学上可接受的盐、其酯或其立体异构体，
    其中，
    X1、X4分别独立地选自N或CRa；
    X2、X3分别独立地选自N或C；
    环A选自5-12元环烷基、5-12元杂环基、6-10元芳基、5-12元杂芳基、5-12元螺环基、5-12元螺杂环基、5-12元桥环基或5-12元桥杂环基；
    每一R1、R2、R3、R4、R5、R6分别独立地选自氢，卤素，氰基，羧基，羟基，氨基，硝基，-C(O)-NH2，-S(O)2-NH2或任选被1-4个取代基Q2取代的-(L)m-H、-(L)m-C1-6烷基、-(L)m-C2-6烯基、-(L)m-C2-6炔基、-(L)m-C1-6烷氧基、二(C1-6烷基)氨基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基、-(L)m-3-12元环烷基、-(L)m-3-12元杂环基、-(L)m-6-10元芳基、-(L)m-5-12元杂芳基、-(L)m-5-12元螺环基、-(L)m-5-12元螺杂环基、-(L)m-5-12元桥环基、-(L)m-5-12元桥杂环基；
    每一Q1、每一Q2分别独立地选自卤素，羧基，羟基，氰基，硝基，氨基，C1-6烷基，C2- 6烯基，C2-6炔基，C1-6烷氧基，羟基C1-6烷基，羧基C1-6烷基，氨基C1-6烷基，卤代C1-6烷基，卤代C1-6烷氧基，C1-6烷基氨基，二(C1-6烷基)氨基，-C(O)-NH2，C1-6烷基羰基，C1-6烷基氧基羰基，C1-6烷基磺酰基，C1-6烷基氨基磺酰基，C1-6烷基磺酰氨基，C1-6烷基-O-C1-4亚烷基，卤代C1-6烷基-O-C1-4亚烷基或任选被1-4个取代基q取代的3-12元环烷基、3-12元杂环基、6-10元芳基、5-12元杂芳基、5-12元螺环基、5-12元螺杂环基，所述取代基q分别独立地选自卤素、羟基、氨基、羧基、氰基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基；
    每一L分别独立地选自-C(O)-、-O-、-S-、-S(O)-、-S(O)2-、-NRc-、-S(O)(NRc)-、-CRa1Rb-；
    每一Ra、每一Ra1、每一Rb分别独立地选自氢、卤素、氨基、羟基、羧基、氰基、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、二(C1-6烷基)氨基、C1-6烷基氨酰基、C1-6烷基酰氨基、C1-6烷基磺酰氨基、C1-6烷基氨基磺酰基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基、-(L)m-6-10元芳基、-(L)m-5-12元杂芳基、-(L)m-3-8元环烷基或-(L)m-3-8元杂环基；
    每一Rc分别独立地选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基、羧基C1-6烷基；
    每一m、n分别独立地为0-6的整数；
    p选自0、1、2或3。
  2. 如权利要求1所述的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
    环A选自5-6元单环烷基、5-6元单杂环基、8-10元稠环基、8-10元稠杂环基、苯基、5-6元单杂芳基、8-10元稠芳基或8-10元稠杂芳基；优选地，环A选自5-6元单杂芳基、8-10元稠杂环基或8-10元稠杂芳基；
    每一R1、R2、R3、R4分别独立地选自氢，卤素，氰基，羧基，羟基，氨基，硝基或任选被1-4个取代基Q2取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基；
    R5选自氢，卤素，氰基，羧基，羟基，氨基，硝基或任选被1-4个取代基Q2取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、-(L)m-3-10元环烷基、-(L)m-3-10元杂环基、-(L)m-6-10元芳基、-(L)m-5-10元杂芳基、-(L)m-5-11元螺环基、-(L)m-5-11元螺杂环基；优选地，R5选自任选被1-4个取代基Q2取代的-(L)m-C1-6烷基、-(L)m-C1-6烷氧基、-(L)m-5-10元环烷基、-(L)m-5-10元杂环基、-(L)m-7-11元螺环基、-(L)m-7-11元螺杂环基；
    每一L分别独立地选自-S(O)2-、-NRc-、-CRa1Rb-；
    R6选自任选被1-4个取代基Q2取代的-S(O)2H、-C(O)H、-C(O)N(Rc)2、-N(Rc)S(O)2-C1-6烷基、-N(Rc)-C1-6烷基、-N(Rc)S(O)2-3-6元环烷基、-N(Rc)S(O)2-3-6元杂环基、-S(O)2N(Rc)-C1- 6烷基、-S(O)2N(Rc)-3-6元环烷基、-S(O)2N(Rc)-3-6元杂环基、-S(O)2-C1-6烷基、-S(O)2-3-6元环烷基、-S(O)2-3-6元杂环基、-S(O)(NRc)-C1-6烷基、-S(O)(NRc)-3-6元环烷基、-S(O)(NRc)-3-6元杂环基、-N(Rc)C(O)-C1-6烷基、-N(Rc)C(O)-3-6元环烷基、-N(Rc)C(O)-3-6元杂环基、-C(O)N(Rc)-C1-6烷基、-C(O)N(Rc)-3-6元环烷基、-C(O)N(Rc)-3-6元杂环基、-C(O)-C1-6烷基、-C(O)-3-6元环烷基、-C(O)-3-6元杂环基；优选地，R6选自任选被1-3个取代基Q2取代的-S(O)2H、-N(Rc)S(O)2-C1-6烷基、-N(Rc)S(O)2-3-6元环烷基、-N(Rc)-C1-6烷基、-N(Rc)S(O)2-3-6元杂环基、-S(O)2N(Rc)-C1-6烷基、-S(O)2N(Rc)-3-6元环烷基、-S(O)2N(Rc)-3-6元杂环基、-S(O)2-C1-6烷基、-S(O)2-3-6元环烷基、-S(O)2-3-6元杂环基；
    每一Ra、每一Ra1、每一Rb分别独立地选自氢、卤素、氨基、羟基、羧基、氰基、C1-6烷基、C1-6烷氧基、C1-6烷基氨基、二(C1-6烷基)氨基、卤代C1-6烷基、卤代C1-6烷氧基、羟基C1-6烷基、氨基C1-6烷基或羧基C1-6烷基；
    每一Rc分别独立地选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基；
    每一Q1、每一Q2分别独立地选自卤素，羧基，羟基，氰基，硝基，氨基，C1-6烷基，C1- 6烷氧基，卤代C1-6烷基，卤代C1-6烷氧基，羟基C1-6烷基，羧基C1-6烷基，氨基C1-6烷基，C1-6烷基氨基，二(C1-6烷基)氨基，C1-4烷基-O-C1-3亚烷基，卤代C1-4烷基-O-C1-3亚烷基或任选被1-3个取代基q取代的3-6元环烷基、3-6元杂环烷基、5-6元杂芳基或苯基；每一q分别独立地选自卤素、羟基、氨基、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基；
    每一m、n分别独立地为0-4的整数；
    p选自0或1。
  3. 如权利要求1或2所述的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，环A选自环戊烷基、环己烷基、二氢吡咯基、吡咯烷基、咪唑烷基、二氢咪唑基、吡唑烷基、二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、4,5-二氢噻唑基、哌啶基、哌嗪基、吗啉基、苯基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、恶唑基、异恶唑基、恶二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、吡啶基、2-吡啶酮基、4-吡啶酮基、嘧啶基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基或8-10元含氮稠杂环基；
    每一R1、R2、R3、R4分别独立地选自氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基；
    R5选自任选被1-3个取代基Q2取代的5-6元杂环基或7-10元螺杂环基；
    R6选自任选被1-3个取代基Q2取代的-S(O)2H、-N(Rc)S(O)2-C1-6烷基、-N(Rc)-C1-6烷基、-S(O)2N(Rc)-C1-6烷基、-S(O)2-C1-6烷基；
    每一Ra、每一Ra1、每一Rb分别独立地选自氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1- 6烷基或卤代C1-6烷氧基；
    每一Rc分别独立地选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基；
    每一Q1、每一Q2分别独立地选自卤素，羧基，羟基，氨基，C1-6烷基，C1-6烷氧基，卤代C1-6烷基，卤代C1-6烷氧基，C1-3烷基-O-C1-2亚烷基，卤代C1-3烷基-O-C1-2亚烷基或任选被1-3个取代基q取代的3-6元环烷基、3-6元杂环烷基；每一q分别独立地选自卤素、C1-4烷基、C1-4烷氧基、卤代C1-4烷基、卤代C1-4烷氧基；
    n选自0、1或2；
    p选自0或1。
  4. 如权利要求1-3任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
    选自以下结构：
    每一R1、R2、R3、R4分别独立地选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基；
    每一Ra分别独立地选自氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基；
    R5选自任选被1-3个取代基Q2取代的以下结构：

    R6选自以下结构：
    每一Q1分别独立地选自卤素，羟基，C1-6烷基，C1-6烷氧基，卤代C1-6烷基，卤代C1-6烷氧基，C1-3烷基-O-C1-2亚烷基，卤代C1-3烷基-O-C1-2亚烷基或任选被1-3个取代基q取代的3-6元环烷基、3-6元杂环烷基；每一q分别独立地选自卤素、C1-4烷基、C1-4烷氧基、卤代C1- 4烷基、卤代C1-4烷氧基；
    每一Q2分别独立地选自卤素、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基、卤代C1-6烷氧基；
    n选自0、1或2。
  5. 如权利要求1-4任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体，其具有通式(II)所示的结构，
    其中，X5选自N或CH；t选自0、1或2；
    环A、X1、X2、X3、X4、R1、R2、R3、R4、R6、每一Q1、每一Q2、n、p的定义如权利要求1-4任一项所述。
  6. 如权利要求1-5任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体，其中，
    X5为N；
    每一R1选自氢、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基；
    R2、R3、R4分别独立地为氢；
    R6选自以下结构：
    选自以下结构：
    优选地，选自以下结构：
    每一Q1分别独立地选自卤素，羟基，C1-6烷基，C1-6烷氧基，卤代C1-6烷基，卤代C1-6烷氧基，C1-3烷基-O-C1-2亚烷基，卤代C1-3烷基-O-C1-2亚烷基或任选被1-3个取代基q取代的3-6元环烷基、3-6元杂环烷基；每一q分别独立地选自卤素、C1-4烷基、C1-4烷氧基、卤代C1- 4烷基、卤代C1-4烷氧基；
    每一Q2分别独立地选自卤素、羟基、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基；
    每一Ra分别独立地选自氢、卤素、C1-6烷基、C1-6烷氧基、卤代C1-6烷基或卤代C1-6烷氧基；
    n选自0、1或2。
  7. 如权利要求1所述的化合物、其药学上可接受的盐、其酯或其立体异构体，选自如下化合物：



  8. 一种药物制剂，其含有权利要求1-7中任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体，及一种或多种药用载体和/或稀释剂；所述药物制剂为临床上或药学上可接受的任一剂型。
  9. 一种药物组合物，其含有权利要求1-7中任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体，及一种或多种第二治疗活性剂；任选地，所述药物组合物还包含一种或多种药用载体和/或稀释剂。
  10. 权利要求1-7任一项所述的化合物、其药学上可接受的盐、其酯或其立体异构体、或权利要求8所述的药物制剂、或权利要求9所述的药物组合物在制备用于治疗和/或预防与KIF18A介导的疾病或相关疾病的药物中的用途；其中，所述与KIF18A介导的疾病或相关疾病选自癌症或良性肿瘤；所述癌症或良性肿瘤包括但不限于黑色素瘤、乳腺癌、卵巢癌、子宫内膜癌、子宫颈癌、脑癌、头颈癌、甲状腺癌、肺癌、支气管癌、食管癌、胃癌、肝癌、肾癌、胰腺癌、胆囊癌、结肠癌、膀胱癌、前列腺癌、罩丸癌、皮肤癌、骨癌及血液瘤；所述肺癌包括但不限于小细胞肺癌及非小细胞肺癌；所述血液瘤包括但不限于白血病、淋巴瘤、骨髓瘤；所述脑癌包括但不限于神经胶质瘤、神经母细胞瘤、星形细胞瘤、脑膜瘤。
PCT/CN2023/121036 2022-09-30 2023-09-25 Kif18a抑制剂 WO2024067465A1 (zh)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113226473A (zh) * 2018-12-20 2021-08-06 美国安进公司 Kif18a抑制剂
CN114302880A (zh) * 2019-08-02 2022-04-08 美国安进公司 Kif18a抑制剂
CN114391012A (zh) * 2019-08-02 2022-04-22 美国安进公司 作为kif18a抑制剂的吡啶衍生物
WO2023174175A1 (zh) * 2022-03-17 2023-09-21 微境生物医药科技(上海)有限公司 Kif18a抑制剂

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113226473A (zh) * 2018-12-20 2021-08-06 美国安进公司 Kif18a抑制剂
CN114302880A (zh) * 2019-08-02 2022-04-08 美国安进公司 Kif18a抑制剂
CN114391012A (zh) * 2019-08-02 2022-04-22 美国安进公司 作为kif18a抑制剂的吡啶衍生物
WO2023174175A1 (zh) * 2022-03-17 2023-09-21 微境生物医药科技(上海)有限公司 Kif18a抑制剂

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