WO2024083137A1 - 稠合杂芳烃类化合物、其组合物及用途 - Google Patents

稠合杂芳烃类化合物、其组合物及用途 Download PDF

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WO2024083137A1
WO2024083137A1 PCT/CN2023/125104 CN2023125104W WO2024083137A1 WO 2024083137 A1 WO2024083137 A1 WO 2024083137A1 CN 2023125104 W CN2023125104 W CN 2023125104W WO 2024083137 A1 WO2024083137 A1 WO 2024083137A1
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membered
alkyl
compound
cycloalkyl
optionally substituted
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PCT/CN2023/125104
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English (en)
French (fr)
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余健
杨阳
周牧星
孙天文
高冬林
戎嘉明
李正涛
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海南先声再明医药股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present disclosure relates to a novel fused heteroaromatic hydrocarbon compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and use thereof as a KIF18A inhibitor in preventing or treating related diseases.
  • Cancer is often characterized by unregulated cell proliferation. Damage to one or more genes in the cell proliferation pathway can cause the loss of normal regulation of cell proliferation. These dysregulated genes can encode various tumor suppressors or oncogene proteins, leading to unchecked cell cycle progression and cell proliferation. Various kinases and kinesins have been identified to play a key role in the cell cycle, mitosis regulation and progression of normal cells and cancer cells.
  • Kinesins are molecular motors that play an important role in cell division and intracellular vesicle and organelle transport. Mitotic kinesins play a role in spindle assembly, chromosome segregation, centrosome separation, and many other aspects. Based on sequence homology within the so-called “motor domain”, human kinesins are classified into 14 subfamilies, the activity of which drives unidirectional movement along microtubules. The non-motor domains of these proteins are responsible for attachment to "cargoes"; "cargoes” can be one of a variety of different membranous organelles, signal transduction scaffolding systems, and chromosomes.
  • Kinesins use the energy of ATP hydrolysis to move "cargoes" along polarized microtubules. Therefore, kinesins are often referred to as "plus-end” or "minus-end” directed motor proteins.
  • the KIF18A gene belongs to the kinesin-8 subfamily and is a plus-end directed motor protein. KIF18A is thought to affect the movement of the plus end of the centromere microtubule to control correct chromosome positioning and maintain spindle tension. Removal of human KIF18A leads to longer spindles in HeLa cervical cancer cells, increased chromosome oscillations in metaphase of mitosis, and activation of the hammer assembly checkpoint. Therefore, KIF18A may be a viable target for cancer therapy.
  • KIF18A is overexpressed in many types of cancer.
  • KIF18A gene deletion, knockout or inhibition affects the mitotic spindle.
  • inhibition of KIF18A induces mitotic arrest, ultimately leading to mitotic catastrophe in cancer cells or mitotic slippage in interphase, which leads to apoptosis of cancer cells.
  • inhibitors of KIF18A can be developed into a promising anticancer drug.
  • the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
  • X 1 is selected from N, O, S, NR 4 or CR 4 ;
  • X 2 is selected from N or CR 4 , or X 2 is absent;
  • X 3 and X 4 are each independently selected from N or C;
  • X 5 and X 6 are each independently selected from N or CR 4 ;
  • each R 4 is independently selected from H, halogen, C 1 -C 6 alkyl, OH, NH 2 , O(C 1 -C 4 alkyl), NH(C 1 -C 4 alkyl) or N(C 1 -C 4 alkyl) 2 , said C 1 -C 6 alkyl, O(C 1 -C 4 alkyl), NH(C 1 -C 4 alkyl) or N(C 1 -C 4 alkyl) 2 being optionally substituted with one or more R 4b ;
  • R 1 is selected from H or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted by one or more halogens;
  • Ring A is selected from C 6 -C 20 aryl, 5-20 membered heteroaryl or 4-20 membered heterocyclyl, wherein the C 6 -C 20 aryl, 5-20 membered heteroaryl or 4-20 membered heterocyclyl is optionally substituted with one or more R 1a ;
  • the R 5 is selected from H or C 1 -C 4 alkyl
  • the R 5a and R 5b are each independently selected from C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl, or the R 5a , R 5b and the atoms to which they are connected together form a 4-7 membered heterocyclyl
  • L 2 is selected from a chemical bond or C 1 -C 4 alkylene
  • R y is selected from
  • R 2 is selected from OH, NH 2 , C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkynyl, in,
  • the OH, NH 2 , C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl or C 2 -C 10 alkynyl is optionally substituted by one or more R 2b ;
  • n, m1, m2, p are each independently selected from 0, 1 or 2;
  • i, j, k are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • Ring Q is selected from C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl or 4-7 membered heterocyclyl, wherein the C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl or 4-7 membered heterocyclyl is optionally substituted by one or more R 2b ;
  • Y is selected from O, S or NH
  • each R x is independently selected from halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl, said OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted with one or more R xb , when When the same carbon atom on the cycloalkyl group is substituted by two R x at the same time, the two R x can also form a C 3 -C 10 cycloalkyl group, a C 3 -C 10 cycloalkenyl group or a 4-10 membered heterocyclic group together with the carbon atom, and the C 3 -C 10 cycloalkyl group, the C 3 -C 10 cycloalkenyl group or the 4-10 membered heterocycl
  • each R 1a is independently selected from halogen, CN, OH, NH 2 , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 5 -C 10 cycloalkenyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, said OH, NH 2 , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl, C 5 -C 10 cycloalkenyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl being optionally substituted with one or more R 1b ;
  • Each of R 1b , R 2b , R 3b , R 4b , R xb is independently selected from halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 Cycloalkyl, 4-7 membered heterocyclyl, O(C 1 -C 4 alkyl), NH(C 1 -C 4 alkyl) or N(C 1 -C 4 alkyl) 2 , wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, O(C 1 -C 4 alkyl), NH(C 1 -C 4 alkyl) or N(C 1 -C 4 alkyl) 2 is optionally substituted with one or more R c ;
  • Each R c is independently selected from halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, O(C 1 -C 4 alkyl), NH(C 1 -C 4 alkyl) or N(C 1 -C 4 alkyl) 2 ;
  • Ring A is selected from C 9 -C 10 aryl, 5-membered heteroaryl, pyridonyl, azapyridonyl, 8-14-membered bicyclic or tricyclic heterocyclyl, 12-20-membered tetracyclic heterocyclyl or 8-14-membered bicyclic or tricyclic heteroaryl, wherein the C 9 -C 10 aryl, 5-membered heteroaryl, pyridonyl, azapyridonyl, 8-14-membered bicyclic or tricyclic heterocyclyl, 12-20-membered tetracyclic heterocyclyl or 8-14-membered bicyclic or tricyclic heteroaryl is optionally substituted with one or more R 1a ; and/or,
  • R 2 is selected from OH, NH 2 , C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkynyl,
  • the OH, NH2 , C1 - C10 alkyl, C3 - C10 cycloalkyl or C2 - C10 alkynyl is optionally substituted by one or more R2b , n, m1, m2, p are each independently selected from 0, 1 or 2, i, j, k are each independently selected from 0, 1, 2, 3, 4, 5 or 6, Rx1 and Rx2 and the carbon atom to which they are attached together form a C3 - C6 cycloalkyl, C3 - C6 cycloalkenyl or 4-7 membered heterocyclyl, the C3 - C6 cycloalkyl, C3 - C6 cycloalkenyl or 4-7 membered heterocyclyl is optionally substituted by one or more R2
  • R 3 is selected from L 1 -L 2 -R y
  • R 5 is selected from H or C 1 -C 4 alkyl
  • L 2 is selected from C 1 -C 4 alkylene optionally substituted by one or more R 3b
  • R y is selected from C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by one or more R 3b .
  • X 2 is selected from N or CR 4 , wherein:
  • Ring A is selected from 5-membered heteroaryl, pyridonyl, azapyridonyl, 8-14-membered bicyclic or tricyclic heterocyclyl, 12-20-membered tetracyclic heterocyclyl or 8-14-membered bicyclic or tricyclic heteroaryl, wherein the 5-membered heteroaryl, pyridonyl, azapyridonyl, 8-14-membered bicyclic or tricyclic heterocyclyl, 12-20-membered tetracyclic heterocyclyl or 8-14-membered bicyclic or tricyclic heteroaryl is optionally substituted with one or more R 1a ; and/or,
  • R 2 is selected from OH, NH 2 , C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 2 -C 10 alkynyl,
  • the OH, NH2 , C1 - C10 alkyl, C3 - C10 cycloalkyl or C2 - C10 alkynyl is optionally substituted by one or more R2b , n, m1, m2, p are each independently selected from 0, 1 or 2, i, j, k are each independently selected from 0, 1, 2, 3, 4, 5 or 6, Rx1 and Rx2 and the carbon atom to which they are attached together form a C3 - C6 cycloalkyl, C3 - C6 cycloalkenyl or 4-7 membered heterocyclyl, the C3 - C6 cycloalkyl, C3 - C6 cycloalkenyl or 4-7 membered heterocyclyl is optionally substituted by one or more R2
  • R 3 is selected from L 1 -L 2 -R y
  • R 5 is selected from H or C 1 -C 4 alkyl
  • L 2 is selected from C 1 -C 4 alkylene optionally substituted by one or more R 3b
  • R y is selected from C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl optionally substituted by one or more R 3b .
  • X 2 is absent, X 1 is selected from N, O, S or NR 4 , and R 4 is selected from H or C 1 -C 6 alkyl.
  • X 2 is absent and X 1 is selected from N, O, S or NCH 3 .
  • X 1 and X 2 are each independently selected from N or CR 4 , and R 4 is selected from H or C 1 -C 6 alkyl.
  • X 1 and X 2 are each independently selected from N or CH.
  • X 5 and X 6 are each independently selected from CH.
  • R 1 is selected from H or C 1 -C 6 alkyl.
  • R 1 is selected from H.
  • R 3 is selected from L 1 -L 2 -R y
  • L 1 is selected from —NH—, —O—, —S—, —S( ⁇ O)—, —SO 2 —, —C( ⁇ O)—, —NHSO 2 —, —NH(C ⁇ O)—
  • the R 5a and R 5b are each independently selected from a C 1 -C 4 alkyl group, or the R 5a , R 5b and the atoms to which they are connected together form a 4-7 membered heterocyclic group
  • L 2 is selected from a chemical bond or a C 1 -C 4 alkylene group
  • R y is selected from H, a C 3 -C 6 cycloalkyl group or a 4-7 membered heterocyclic group, and each of the above C 1 -C 4 alkyl groups, C 1 -C 4 alkylene groups, C 3 -C 6 cycloalkyl groups or 4-7 membered heterocycl
  • each R 3b is independently selected from halogen, CN, OH, or NH 2 .
  • R 3 is selected from L 1 -L 2 -R y ,
  • L 2 is selected from C 1 -C 4 alkylene,
  • R y is selected from H, and the C 1 -C 4 alkylene is optionally substituted with one or more halogen, CN, OH, or NH 2 .
  • R 3 is selected from L 1 -L 2 -R y , L 1 is selected from -NHSO 2 -, L 2 is selected from C 1 -C 4 alkylene, and R y is selected from H, wherein the C 1 -C 4 alkylene is optionally substituted with one or more halogens or OH.
  • R3 is selected from
  • R3 is selected from
  • R3 is selected from
  • n, ml, m2, and p are each independently selected from 0, 1, or 2.
  • n, m1, and p are each independently selected from 1, and m2 is selected from 0.
  • i, j, k are each independently selected from 0, 1, 2 or 3.
  • R x1 and R x2 and the carbon atom to which they are attached together form a C 3 -C 6 cycloalkyl or a 4-7 membered heterocyclyl, which is optionally substituted with one or more R 2b .
  • Ring Q is selected from C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl, wherein the C 3 -C 6 cycloalkyl or 4-7 membered heterocyclyl is optionally substituted with one or more R 2b .
  • Y 1 is selected from O, S or NH.
  • Y 1 is selected from NH.
  • R 2b is selected from halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-7 membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-7 membered heterocyclyl is optionally substituted with one or more halogen or CN.
  • R 2b is selected from C 1 -C 4 alkyl, which is optionally substituted with one or more halogens (eg , F).
  • R x is selected from halogen, CN, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-7 membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-7 membered heterocyclyl is optionally substituted with one or more R xb .
  • R xb is selected from halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-7 membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-7 membered heterocyclyl is optionally substituted with one or more halogen or CN.
  • R 2 is selected from C 3 -C 6 cycloalkyl, C 2 -C 6 alkynyl, in:
  • the C 3 -C 6 cycloalkyl or C 2 -C 6 alkynyl is optionally substituted by one or more R 2b ;
  • the two R x can also form a C 3 -C 6 cycloalkyl group, a C 3 -C 6 cycloalkenyl group or a 4-7 membered heterocyclic group together with the carbon atom, and the C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkenyl group or the 4-7 membered heterocyclic group is optionally substituted by one or more R xb ;
  • n, m1, m2, p, i, j, k, R x1 , R x2 , Y 1 , R 2b , R x , R xb and ring Q are as defined above.
  • R2 is selected from in:
  • the two R x can also form a C 3 -C 6 cycloalkyl group, a C 3 -C 6 cycloalkenyl group or a 4-7 membered heterocyclic group together with the carbon atom, and the C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkenyl group or the 4-7 membered heterocyclic group is optionally substituted by one or more R xb ;
  • n, m1, m2, p, i, j, k, R x1 , R x2 , Y 1 , R 2b , R x , R xb and ring Q are as defined above.
  • R2 is selected from in:
  • the * carbon atom in is simultaneously substituted by two R x , and the two R x and the * carbon atom together form a C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl or 4-7 membered heterocyclyl, and the C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl or 4-7 membered heterocyclyl is optionally substituted by one or more R xb ;
  • n, k, Y 1 , R 2b , R x and R xb are as defined above.
  • R2 is selected from in:
  • the * carbon atom in is simultaneously substituted by two R x , and the two R x and the * carbon atom together form a C 3 -C 6 cycloalkyl group, and the C 3 -C 6 cycloalkyl group is optionally substituted by one or more R xb ;
  • R2 is selected from
  • R2 is selected from
  • Ring A is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, 11-14 membered tricyclic heteroaryl, 8-14 membered bicyclic heterocyclyl, 11-14 membered tricyclic heterocyclyl, or 12-20 membered tetracyclic heterocyclyl, wherein the C 6 -C 10 aryl, 5-10 membered heteroaryl, 11-14 membered tricyclic heteroaryl, 8-14 membered bicyclic heterocyclyl, 11-14 membered tricyclic heterocyclyl, or 12-20 membered tetracyclic heterocyclyl is optionally substituted with one or more R 1a .
  • Ring A is selected from phenyl, 5-10 membered heteroaryl, 11-14 membered tricyclic heterocyclyl, 11-14 membered tricyclic heteroaryl, or 12-20 membered tetracyclic heterocyclyl, wherein the phenyl, 5-10 membered heteroaryl, 11-14 membered tricyclic heterocyclyl, 11-14 membered tricyclic heteroaryl, or 12-20 membered tetracyclic heterocyclyl is optionally substituted with one or more R 1a .
  • Ring A is selected from phenyl, 5-10 membered heteroaryl, 11-14 membered tricyclic heterocyclyl, or 11-14 membered tricyclic heteroaryl, wherein the phenyl, 5-10 membered heteroaryl, 11-14 membered tricyclic heterocyclyl, or 11-14 membered tricyclic heteroaryl is optionally substituted with one or more R 1a .
  • Ring A is selected from the following groups optionally substituted with one or more R 1a : phenyl, pyrimidinyl,
  • Ring A is selected from phenyl, pyrimidinyl, The phenyl group, pyrimidinyl group, Optionally substituted with one or more R 1a .
  • Ring A is selected from phenyl, pyrimidinyl, The phenyl group, pyrimidinyl group, Optionally substituted with one or more R 1a .
  • Ring A is selected from Said Optionally substituted with one or more R 1a .
  • each R 1a is independently selected from halogen, CN, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-7 membered heterocyclyl, said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-7 membered heterocyclyl is optionally substituted with one or more R 1b , said R 1b is independently selected from halogen, CN, OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, O(C 1 -C 4 alkyl), NH(C 1 -C 4 alkyl), or N(C 1 -C 4 alkyl) 2 .
  • each R 1a is independently selected from halogen, C 1 -C 6 alkyl, or 4-7 membered heterocyclyl, wherein the C 1 -C 6 alkyl or 4-7 membered heterocyclyl is optionally substituted with one or more halogen (eg, F).
  • halogen eg, F
  • each R 1a is independently selected from C 1 -C 6 alkyl or 4-7 membered heterocyclyl, wherein the C 1 -C 6 alkyl or 4-7 membered heterocyclyl is optionally substituted with one or more halogens (eg, F).
  • halogens eg, F
  • each R 1a is independently selected from F, CF 3 CH 2 CH 2 or
  • each R 1a is independently selected from methyl, CF 3 CH 2 CH 2 or
  • Ring A is selected from
  • Ring A is selected from
  • Ring A is selected from
  • Ring A is selected from 5-membered heteroaryl, pyridonyl, azapyridonyl, 11-14-membered tricyclic heterocyclyl or 8-14-membered bicyclic or tricyclic heteroaryl, wherein the 5-membered heteroaryl, pyridonyl, azapyridonyl, 11-14-membered tricyclic heterocyclyl or 8-14-membered bicyclic or tricyclic heteroaryl is optionally substituted with one or more R 1a , wherein R 1a is as defined above; and/or,
  • R 2 is selected from The n, m1, m2, p, i, j, k, R x1 , R x2 , Y 1 , R 2b and ring Q are any of the above definitions; and/or,
  • Ring A is selected from Said Optionally substituted with one or more R 1a , each R 1a is independently selected from C 1 -C 6 alkyl or 4-7 membered heterocyclyl, wherein the C 1 -C 6 alkyl or 4-7 membered heterocyclyl is optionally substituted with one or more halogen (eg, F), for example, ring A is selected from and / or,
  • R 2 is selected from The Y 1 , n, k, and R 2b are as defined above, for example, R 2 is selected from
  • Ring A is selected from C 9 -C 10 aryl, 8-14 membered bicyclic or tricyclic heterocyclyl, 12-20 membered tetracyclic heterocyclyl, 8-14 membered bicyclic or tricyclic heteroaryl, wherein the C 9 -C 10 aryl, 8-14 membered bicyclic or tricyclic heterocyclyl, 12-20 membered tetracyclic heterocyclyl, 8-14 membered bicyclic or tricyclic heteroaryl is optionally substituted with one or more R 1a , wherein R 1a is as defined above.
  • Ring A is selected from
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable Acceptable auxiliary materials.
  • the present disclosure relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating a KIF18A-related disease.
  • the present disclosure relates to the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a drug for preventing or treating tumors.
  • the present disclosure relates to the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating a KIF18A-related disease.
  • the present disclosure relates to the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating tumors.
  • the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a KIF18A-related disease.
  • the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating tumors.
  • the present disclosure also relates to a method for treating a KIF18A-related disease, which comprises administering to a patient a therapeutically effective amount of a pharmaceutical preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in the present disclosure.
  • the present disclosure also relates to a method for treating tumors, which comprises administering to a patient a therapeutically effective amount of a pharmaceutical preparation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in the present disclosure.
  • the KIF18A-related disease is selected from a tumor.
  • tautomer refers to functional group isomers resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present disclosure may exhibit tautomerism.
  • Tautomeric compounds may exist in two or more interconvertible species.
  • Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates.
  • the present disclosure includes all tautomeric forms of the compounds.
  • stereoisomer refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.
  • the compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • Specific geometric or stereoisomeric forms may be cis and trans isomers, E-type and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention.
  • asymmetric carbon atoms such as alkyl groups
  • substituents such as alkyl groups
  • all of these isomers and their mixtures involved in the substituents are also included in the compounds of the present invention.
  • the compounds of the present disclosure containing asymmetric atoms can be isolated in optically pure forms or racemic forms, and optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • an ethyl group is "optionally" substituted with one or more halogens, which means that the ethyl group may be unsubstituted (CH 2 CH 3 ), monosubstituted (CH 2 CH 2 F, CH 2 CH 2 Cl, etc.), polysubstituted (CHFCH 2 F, CH 2 CHF 2 , CHFCH 2 Cl, CH 2 CHCl 2 , etc.) or fully substituted (CF 2 CF 3 , CF 2 CCl 3 , CCl 2 CCl 3 , etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or cannot be synthesized will be introduced.
  • any variable eg, Ra , Rb
  • its definition is independent at each occurrence. For example, if a group is substituted with 2 Rb , each Rb has an independent option.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
  • connection direction of the connecting group mentioned in this article is not specified, the connection direction is arbitrary.
  • L1 in the structural unit L1 - L2 - Ry is selected from “ -NR5SO2- ", L1 can be connected to L2 - Ry from left to right to form " -NR5SO2 - L2 - Ry ", or can be connected to L2 - Ry from right to left to form " -SO2NR5 - L2 - Ry ".
  • a substituent cross-links two atoms on a ring, it means that the substituent can be bonded to any atom on the ring. It means that the substituent R 2b can be bonded to any bondable ring atom of the lactam ring.
  • Cm - Cn refers to an integer number of carbon atoms in the range of mn.
  • C1 - C10 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n +1 , which may be linear or branched.
  • C1 - C10 alkyl is understood to mean a linear or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • alkyl group examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 -C 1 -C 1 -C 1 -C 1 -C 1
  • C 1 -C 4 alkyl may be understood to mean a straight-chain or branched saturated alkyl group having 1 to 4 carbon atoms.
  • the "C 1 -C 10 alkyl” may include a range such as “C 1 -C 6 alkyl” or “C 1 -C 4 alkyl”, and the “C 1 -C 6 alkyl” may further include “C 1 -C 4 alkyl”.
  • alkoxy refers to a group resulting from the loss of a hydrogen atom from a hydroxyl group of a straight or branched alcohol, and may be understood as an “alkyloxy” or “alkyl-O-".
  • C 1 -C 10 alkoxy may be understood as a “C 1 -C 10 alkyloxy” or “C 1 -C 10 alkyl-O-”;
  • C 1 -C 6 alkoxy may be understood as a "C 1 -C 6 alkyloxy” or "C 1 -C 6 alkyl-O-".
  • the "C 1 -C 10 alkoxy” may include a “C 1 -C 6 alkoxy” and a “C 1 -C 3 alkoxy", and the "C 1 -C 6 alkoxy” may further include a "C 1 -C 3 alkoxy”.
  • alkenyl refers to an unsaturated fatty acid group consisting of a straight or branched chain of carbon and hydrogen atoms and having at least one double bond. Aliphatic hydrocarbon group.
  • C 2 -C 10 alkenyl is understood to mean a straight or branched unsaturated hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and "C 2 -C 10 alkenyl” may include "C 2 -C 6 alkenyl", “C 2 -C 4 alkenyl", C 2 or C 3 alkenyl. It is understood that in the case where the alkenyl contains more than one double bond, the double bonds may be separated or conjugated with each other.
  • alkenyl group examples include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.
  • alkynyl refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond.
  • C 2 -C 10 alkynyl may be understood to mean a straight or branched unsaturated hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • Examples of “C 2 -C 10 alkynyl” include, but are not limited to, ethynyl (-C ⁇ CH), propynyl (-C ⁇ CCH 3, -CH 2 C ⁇ CH), but-1-ynyl, but-2-ynyl or but-3-ynyl.
  • C 2 -C 10 alkynyl may include “C 2 -C 3 alkynyl", examples of “C 2 -C 3 alkynyl” include ethynyl (-C ⁇ CH), prop-1-ynyl (-C ⁇ CCH 3 ), prop-2-ynyl (-CH 2 C ⁇ CH).
  • cycloalkyl refers to a fully saturated carbocyclic group that exists in the form of a monocyclic, condensed, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is generally a 3-20-membered ring.
  • C 3 -C 10 cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring carbon atoms, and specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo [2.2.1] heptyl), bicyclo [2.2.2] octyl, adamantyl, spiro [4.5] decyl, etc.
  • C 3 -C 10 cycloalkyl may include “C 5 -C 10 cycloalkyl” and “C 3 -C 6 cycloalkyl” and other ranges.
  • C 3 -C 6 cycloalkyl refers to a cycloalkyl group having 3, 4, 5 or 6 ring carbon atoms.
  • cycloalkyloxy may be understood as “cycloalkyl-O-”.
  • C 3 -C 10 cycloalkenyl refers to an incompletely saturated non-aromatic carbocyclic group having at least one carbon-carbon double bond and existing in the form of a monocyclic ring, a condensed ring, a bridged ring or a spirocyclic ring, and having 3 to 10 ring carbon atoms.
  • C 5 -C 10 cycloalkenyl refers to a cycloalkenyl group having 5, 6, 7, 8, 9 or 10 ring carbon atoms.
  • C 3 -C 6 cycloalkenyl refers to a cycloalkenyl group having 3, 4, 5 or 6 ring carbon atoms.
  • cycloalkenyl group examples include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cycloheptadienyl, etc.
  • N nitrogen atom
  • O oxygen atom
  • S sulfur atom
  • P phosphorus atom
  • the fused, spiro or bridged ring may be bicyclic, tricyclic, tetracyclic or pentacyclic.
  • the term "4-20 membered heterocyclyl” refers to a heterocyclyl having 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms, and the ring atoms thereof contain 1 to 8 heteroatoms or heteroatomic groups independently selected from the above.
  • the term "4-14 membered heterocyclyl” refers to a heterocyclyl having 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, and the ring atoms thereof contain 1 to 8 heteroatoms or heteroatomic groups independently selected from the above.
  • the term "4-10 membered heterocyclyl” refers to a heterocyclyl having 4, 5, 6, 7, 8, 9 or 10 ring atoms, and the ring atoms thereof contain 1 to 5 heteroatoms or heteroatomic groups independently selected from the above.
  • the "4-10 membered heterocyclyl” may include a "4-7 membered heterocyclyl".
  • the term “4-7 membered heterocyclyl” refers to a heterocyclyl having 4, 5, 6 or 7 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatoms groups independently selected from the above-mentioned heteroatoms in the ring atoms.
  • 8-14 membered bicyclic or tricyclic heterocyclyl refers to a bicyclic or tricyclic heterocyclyl having 8, 9, 10, 11, 12, 13 or 14 ring atoms, and containing 1-8 heteroatoms or heteroatoms groups independently selected from the above-mentioned heteroatoms in the ring atoms.
  • 11-14 membered tricyclic heterocyclyl refers to a tricyclic heterocyclyl having 11, 12, 13 or 14 ring atoms, and containing 1-8 heteroatoms or heteroatoms groups independently selected from the above-mentioned heteroatoms in the ring atoms.
  • 4-membered monoheterocyclyl refers to a 4-7 membered heterocyclyl in monocyclic form.
  • 4-membered heterocyclic groups include, but are not limited to, azetidinyl or oxetanyl;
  • 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl;
  • specific examples of 6-membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazin
  • the heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopentyl pyrrol-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl.
  • the heterocyclic group may be a benzo-fused ring group of the above 4-7-membered heterocyclic group, specific examples of which include, but are not limited to, dihydroisoquinolinyl and the like.
  • “4-10 membered heterocyclyl” may include “5-10 membered heterocyclyl", “4-7 membered heterocyclyl”, “5-6 membered heterocyclyl”, “6-8 membered heterocyclyl”, “4-10 membered heterocycloalkyl”, “5-10 membered heterocycloalkyl”, “4-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, “6-8 membered heterocycloalkyl”, etc., and “4-7 membered heterocyclyl” may further include "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", “4-7 membered heterocycloalkyl”, “4-6 membered heterocycloalkyl”, "5-6 membered heterocyclo
  • heterocyclyloxy may be understood as “heterocyclyl-O-”.
  • 4-10 membered heterocycloalkyl refers to a heterocycloalkyl group having 4, 5, 6, 7, 8, 9 or 10 ring atoms, wherein the ring atoms of the heterocycloalkyl group contain 1 to 5 heteroatoms or heteroatomic groups independently selected from the above.
  • “4-10 membered heterocycloalkyl” includes “4-7 membered heterocycloalkyl”, wherein specific examples of 4 membered heterocycloalkyl include but are not limited to azetidinyl, oxetanyl or thietanyl; specific examples of 5 membered heterocycloalkyl include but are not limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl or tetrahydropyrazolyl; specific examples of 6 membered heterocycloalkyl include but are not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxane, thi
  • heterocycloalkyloxy may be read as “heterocycloalkyl-O-”.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ electron system.
  • the aryl group may have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms.
  • C 6 -C 20 aryl is understood to mean an aryl group having 6 to 20 carbon atoms.
  • a ring having 6 carbon atoms such as phenyl; or a ring having 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl; or a ring having 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl; or a ring having 13 carbon atoms (“C 13 aryl”), such as fluorenyl; or a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • C 6 -C 10 aryl is understood to mean an aryl group having 6 to 10 carbon atoms, for example a ring having 6 carbon atoms (“C 6 aryl”), such as phenyl; or a ring having 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl; or a ring having 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
  • aryloxy may be understood as “aryl-O-”.
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C aromatic ring groups, which usually have 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms, and contain 1-8, preferably 1-5 heteroatoms independently selected from N, O and S.
  • the term “5-20 membered heteroaryl” is understood to include such monocyclic, bicyclic or tricyclic aromatic ring systems: which have 5-20 ring atoms, and contain 1-8, for example 1-5 heteroatoms independently selected from N, O and S.
  • 8-14 membered bicyclic or tricyclic heteroaryl refers to an aromatic fused bicyclic or tricyclic ring system with 8, 9, 10, 11, 12, 13 or 14 ring atoms, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C aromatic ring groups.
  • 11-14 membered tricyclic heteroaryl refers to an aromatic fused tricyclic ring system having 11, 12, 13 or 14 ring atoms, wherein at least one ring atom is selected from N, O, S, and the remaining ring atoms are C.
  • 5-10 membered heteroaryl is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, such as 5 or 6 or 9 or 10 ring atoms, and containing 1-5, such as 1-3 heteroatoms independently selected from N, O and S.
  • the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or azinyl, or
  • 5-6 membered heteroaryl or “5-6 membered monoheteroaryl” refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1-3, for example 1-2 heteroatoms independently selected from N, O and S.
  • heteroaryloxy may be read as “heteroaryl-O-”.
  • azapyridinone refers to a pyridinone group (such as ) is replaced by 1 or 2 N atoms (including but not limited to ).
  • halo or halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to an -OH group.
  • cyano refers to a -CN group.
  • mercapto refers to a -SH group.
  • amino refers to a -NH2 group.
  • nitro refers to the -NO2 group.
  • terapéuticaally effective amount means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein.
  • the amount of a compound of the present disclosure that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and the present disclosure.
  • prevention means administering the compounds or formulations described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in an individual (e.g., a mammal), particularly when such individual (e.g., a mammal) is susceptible to the disease state but has not yet been diagnosed as having the disease state.
  • subject includes mammals and non-mammals.
  • mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc.
  • non-human mammals include, but are not limited to, birds and fish, etc.
  • the mammal is a human.
  • patient and “subject” are used interchangeably.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or an organic acid, and a salt formed between a compound and an inorganic base or an organic base.
  • composition refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient.
  • the purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • the present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes of open compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, respectively.
  • Certain isotopically labeled compounds of the present disclosure can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability.
  • Positron emitting isotopes, such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present disclosure can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an unlabeled reagent.
  • compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of the disclosed compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or sugar-coated core.
  • suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.
  • the daily dosage is 0.01 mg/kg to 200 mg/kg body weight, preferably 0.05 mg/kg to 50 mg/kg body weight, more preferably 0.1 mg/kg to 30 mg/kg body weight, in the form of single or divided doses.
  • the compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining the embodiments with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.
  • the ratios expressed for mixed solvents are volume mixing ratios.
  • % refers to weight %.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the unit of NMR shift is 10 -6 (ppm).
  • the solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 " refers to the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
  • the eluent or mobile phase may be a mixed eluent or mobile phase consisting of two or more solvents, the ratio of which is
  • the volume ratio of methanol to dichloromethane such as "0-10% methanol/dichloromethane" means that the volume ratio of methanol to dichloromethane in the mixed eluent or mobile phase is 0:100-10:100.
  • step 5 of Example 1 By the same method as step 5 of Example 1, using compound 3g (20 mg, 0.1 mmol) and compound 1f (36 mg, 0.1 mmol) as raw materials, compound 3h (15 mg) was synthesized and purified.
  • step 5 of Example 1 By the same method as step 5 of Example 1, using compound 4e (75 mg, 0.3 mmol) and compound 1f (108 mg, 0.3 mmol) as raw materials, compound 4f (67 mg) was synthesized and purified.
  • step 6 compound 4f (17 mg, 0.03 mmol) and methanesulfonamide (9.5 mg, 0.1 mmol) was used as the raw material, and compound 5 (6 mg) was synthesized and purified.
  • step 3 of Example 4 compound 7c (80 mg, 0.28 mmol) was used as starting material to synthesize and purify compound 7d (40 mg).
  • step 5 of Example 1 By the same method as step 5 of Example 1, using compound 7d (25 mg, 0.1 mmol) and compound 1f (36 mg, 0.1 mmol) as raw materials, compound 7e (35 mg) was synthesized and purified.
  • step 6 of Example 1 By the same method as step 6 of Example 1, using compound 7e (30 mg, 0.053 mmol) and compound 1i (12 mg, 0.1 mmol) as raw materials, compound 7 (12 mg) was synthesized and purified.
  • step 5 of Example 1 By the same method as step 5 of Example 1, using compound 8g (50 mg, 0.2 mmol) and compound 1f (72 mg, 0.2 mmol) as raw materials, compound 8h (72 mg) was synthesized and purified.
  • step 6 of Example 1 By the same method as step 6 of Example 1, using compound 8h (40 mg, 0.07 mmol) and methanesulfonamide (19 mg, 0.2 mmol) as raw materials, compound 8 (27 mg) was synthesized and purified.
  • step 5 of Example 1 By the same method as step 5 of Example 1, using compound 9d (55 mg, 0.22 mmol) and compound 1f (94 mg, 0.26 mmol) as raw materials, compound 9e (70 mg) was synthesized and purified.
  • step 4 of Example 3 By the same method as step 4 of Example 3, using compound 10e (100 mg, 0.35 mmol) and tert-butyl carbamate 10f (164 mg, 1.4 mmol) as raw materials, compound 10g (95 mg) was synthesized and purified.
  • n-butyl lithium (1.6 M, 1.0 mL) was slowly added dropwise to a solution of compound 11c (231 mg, 1.64 mmol) in anhydrous tetrahydrofuran (20 mL), and the mixture was stirred at -78°C for 30 min.
  • a solution of compound 11b (270 mg, 655 ⁇ mol) in tetrahydrofuran (15 mL) was slowly added dropwise to the above reaction solution, and the mixture continued to react fully at -78°C.
  • DMF (239 mg, 3.27 mmol) was added dropwise to the reaction solution, and the mixture continued to react fully at -78°C.
  • step 5 of Example 1 By the same method as step 5 of Example 1, using compound 12f (20 mg, 0.1 mmol) and compound 1f (36 mg, 0.1 mmol) as raw materials, compound 12g (16 mg) was synthesized and purified.
  • Test Example 1 KIF18A enzyme activity assay
  • the amount of ADP generated in the reaction is detected to reflect the KIF18A enzyme activity.
  • the human KIF18A (1-376aa) protease used in the experiment was expressed by Panchao Biotechnology and stored at -80°C (freeze-thaw no more than 5 times).
  • the detection kit (ADP-Glo TM Kinase Assay) was purchased from Promega, with the catalog number V9101, and was stored at -30°C. The kit detects enzyme activity by measuring the ADP generated in the enzyme reaction. KIF18A enzyme generates ADP with ATP, and the remaining ATP in the reaction is consumed by the ADP-Glo reagent. The ADP generated in the KIF18A enzyme reaction is reduced to ATP by the detection reagent. Under the action of Ultra-Glo TM luciferase, ATP reacts with luciferin to emit light, and the luminescent signal is positively correlated with the KIF18A enzyme activity.
  • the compound was diluted 3 times with a starting concentration of 10 ⁇ M, and 10 concentration points were diluted.
  • the compound and pure DMSO (control) were added to each well of a 384-well plate using an Echo instrument.
  • the total volume of the compound and DMSO was 100 nL.
  • the instrument obtained the sample concentration of gradient dilution by different ratios.
  • KIF18A enzyme reaction buffer was prepared: 15 nM Tris, 10 mM MgCl 2 , 0.01% Pluronic F-68, 1 ⁇ Taxol, and 50 ⁇ g/mL microtubule.
  • KIF18A was mixed with the reaction buffer and added to a 384-well plate.
  • ATP Km 70 ⁇ M
  • 10 ⁇ L ADP-Glo TM reagent was mixed with 10 ⁇ L reaction mixture and incubated at room temperature for 40 minutes.
  • 20 ⁇ L ADP-Glo TM detection reagent was added and incubated at room temperature for 30 minutes.
  • the chemiluminescent signal in each well was measured using an Envision plate reader (PerkinElmer, emission wavelength 400-700nm).
  • A, B, C and D are four parameters.
  • the IC50 value is further calculated by Xlfit as the compound concentration required for 50% enzyme activity inhibition in the best fitting curve.
  • the KIF18A inhibitory activity of the disclosed compounds is shown in Table 1.
  • Test Example 2 Proliferation inhibition test of the disclosed compounds on OVCAR-3 cells
  • Human ovarian cancer cell line OVCAR3 was purchased from ATCC (catalog number HTB-161 TM ), RPMI 1640 medium (Gibco#A1049101), penicillin-streptomycin (Gibco#15140122) and 0.25% Trypsin-EDTA (Gibco#25200056) were purchased from Gibco (USA), bovine insulin (Yisheng#40107ES60) was purchased from Yisheng, 384-well plates (Corning#CLS3765) were purchased from Corning (USA), and Cell-Titer Glo reagent (Promega#G7568) was purchased from Promega (USA).
  • OVCAR3 cells were cultured in RPMI 1640 complete medium (RPMI 1640 medium containing 20% fetal bovine serum, 10 ⁇ g/mL bovine insulin and 1% penicillin-streptomycin) at 37°C in a 5% CO2 incubator. Cells in the logarithmic growth phase were used for experiments.
  • RPMI 1640 complete medium RPMI 1640 medium containing 20% fetal bovine serum, 10 ⁇ g/mL bovine insulin and 1% penicillin-streptomycin
  • Cell proliferation activity detection Cell-Titer Glo reagent was used to detect the inhibition of compound proliferation on OVCAR3 cell line.
  • the compound prepared with DMSO and pure DMSO (control) were added to a 384-well plate using an Echo instrument.
  • the compound was diluted 3 times with a starting concentration of 30 ⁇ M for a total of 11 concentration points.
  • the volume of the added compound or DMSO was 100 nL.
  • OVCAR3 cells were digested and resuspended in RPMI 1640 complete medium, added to 384-well plates (1000 cells/50 ⁇ L/well), mixed with the compound, and cultured in a 37°C, 5% CO 2 incubator for 3 days. 25 ⁇ L Cell-Titer Glo reagent was added to each well, shaken and mixed, incubated for 10 minutes, and the Cell-Titer Glo reading was detected by Multimode Plate Reader.
  • a negative control group (Bottom) was set up, which consisted of the culture medium wells added with 0.2% DMSO, and was defined as 100% proliferation inhibition; a positive control group (Top) consisted of the OVCAR3 cell wells added with 0.2% DMSO.
  • Inhibition percentage (1-(Signal-Bottom)/(Top-Bottom)) ⁇ 100%.
  • the inhibitory activity of the disclosed compounds on OVCAR3 proliferation is shown in Table 2.
  • Test Example 3 CYP enzyme inhibition test of the disclosed compounds
  • Peak areas were calculated from the chromatograms.
  • the residual activity ratio (%) was calculated using the following formula:
  • Peak area ratio metabolite peak area / internal standard peak area
  • Residual activity ratio (%) peak area ratio of the test compound group / peak area ratio of the blank group
  • CYP half-maximal inhibition concentration (IC 50 ) was calculated using Excel XLfit 5.3.1.3.
  • the apparent permeability coefficient (P app ) of the drugs was determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) in a Caco-2 cell model.
  • Caco-2 cells were purchased from the American Type Culture Collection (ATCC), 4-hydroxyethylpiperazineethanesulfonic acid (HEPES) was purchased from Beijing Solebow Technology Co., Ltd., Hank's balanced salt solution (HBSS) and non-essential amino acids (NEAA) were purchased from Thermo Fisher Scientific, penicillin, streptomycin and trypsin/EDTA were purchased from Solebow, fetal bovine serum (FBS) and DMEM medium were purchased from Corning, HTS-96-well Transwell plates and other sterile consumables were purchased from Corning, and Millicell resistance measurement system was purchased from Millipore. purchased from Nexcelom Bioscience, Infinite 200 PRO microplate reader purchased from Tecan, and MTS2/4 orbital shaker purchased from IKA Labortechnik.
  • HPES 4-hydroxyethylpiperazineethanesulfonic acid
  • HBSS Hank's balanced salt solution
  • NEAA non-essential amino acids
  • FBS feta
  • Caco-2 cells were cultured in cell culture flasks.
  • the incubator was set at 37°C, 5% CO 2 , and relative humidity was maintained at 95%.
  • the cell confluence reached 70-90%, it could be used for inoculation of Transwell.
  • 50 ⁇ L of Cell culture medium add 25mL of cell culture medium to the lower culture plate. Place the culture plate in a 37°C, 5% CO 2 incubator for 1 hour before inoculating cells. After cell digestion, aspirate the cell suspension and transfer it to a round-bottom centrifuge tube and centrifuge at 120g for 5 minutes. Resuspend the cells in the culture medium to a final concentration of 6.86 ⁇ 10 5 cells/mL (cells/mL).
  • Caco-2 cells After about 14 days of culture, Caco-2 cells reach confluence and complete differentiation. At this point, they can be used for penetration tests.
  • Use a resistor meter (Millipore, USA) to measure the resistance of the monolayer membrane and record the resistance of each well. After the measurement, return the Transwell culture plate to the incubator. Calculation of resistance value: measured resistance value (ohms) ⁇ membrane area (cm 2 ) TEER value (ohm ⁇ cm 2 ). If the TEER value is ⁇ 230ohms ⁇ cm 2 , the well cannot be used for penetration tests.
  • a 1 mM DMSO stock solution of the test compound to be tested was diluted with transport buffer to obtain a 5 ⁇ M test solution.
  • the control compound digoxin or minoxidil was diluted with DMSO to 2 mM and diluted with the above transport buffer to 10 ⁇ M to obtain a control compound test solution.
  • DMSO was also diluted with the above transport buffer to a receiving end solution containing 0.5% DMSO.
  • the upper and lower transport devices were combined and incubated at 37°C for 2 hours.
  • the integrity of the cell monolayer membrane after 2 hours of incubation was evaluated by leakage of fluorescent yellow.
  • the fluorescent yellow stock solution was diluted to a final concentration of 100 ⁇ M using transport buffer (10 mM HEPES, pH 7.4). 100 ⁇ L of fluorescent yellow solution was added to each well of the upper Transwell insert, and 300 ⁇ L of transport buffer (10 mM HEPES, pH 7.4) was added to each well of the lower receiving plate. After incubation at 37°C for 30 minutes, 80 ⁇ L of solution was aspirated from the upper and lower layers of each well into a new 96-well plate. Fluorescence was measured using a microplate reader with an excitation wavelength of 485 nm and an emission wavelength of 530 nm.
  • the apparent permeability coefficient (P app , unit: cm/s ⁇ 10 -6 ) is calculated using the following formula:
  • VA is the volume of the receiving end solution (Ap ⁇ Bl is 0.3mL, Bl ⁇ Ap is 0.1mL), Area (membrane area) is the Transwell-96 well plate membrane area (0.143 cm 2 ); time is the incubation time (unit: s); [drug] receiver is the drug concentration at the receiving end; [drug] initial, donor is the initial drug concentration at the administration end.
  • the efflux ratio is calculated using the following formula:
  • P app(BA) is the apparent permeability from the base end to the top end
  • Papp(AB) is the apparent permeability from the apical end to the basal end.
  • the recovery rate (% recovery) was calculated using the following formula:
  • VA is the volume of the solution at the receiving end (unit: mL);
  • VD is the volume of the solution at the giving end (unit: mL).
  • the leakage rate (Percentage leakage (%) or LY (%) was calculated using the following formula:
  • I receiver (I receiving end ) refers to the fluorescence density of the receiving well (0.3mL)
  • I donor (I donor ) refers to the fluorescence density of the drug addition well (0.1mL), expressed as LY (%).
  • LY ⁇ 1.5% indicates that the monolayer cell membrane is intact. For individual LY> 1.5%
  • the final data can be adopted based on scientific judgment.
  • Test Example 5 In vitro metabolic stability test of rat hepatocytes
  • the concentration of the compounds in the reaction system was determined by LC/MS/MS to calculate the intrinsic clearance of the test compounds and to evaluate the in vitro metabolic stability in rat hepatocytes.
  • the samples were quantified by ion chromatograms.
  • the residual rate was calculated based on the peak area of the test compound or positive control.
  • the slope k was determined by linear regression of the natural logarithm of the residual rate against the incubation time using Microsoft Excel.
  • V incubation volume (0.25 mL);
  • N number of cells per well (0.125 ⁇ 10 6 cells)
  • Test Example 6 In vitro metabolic stability test of human hepatocytes
  • the concentration of the compounds in the reaction system was determined by LC/MS/MS to calculate the intrinsic clearance of the test compounds and to evaluate the in vitro metabolic stability in human hepatocytes.
  • the samples were quantified by ion chromatograms.
  • the residual rate was calculated based on the peak area of the test compound or positive control.
  • the slope k was determined by linear regression of the natural logarithm of the residual rate against the incubation time using Microsoft Excel.
  • V incubation volume (0.25 mL);
  • N number of cells per well (0.125 ⁇ 10 6 cells)
  • Test Example 7 Compound solid solubility (PBS pH 7.4) test
  • the solubility of the solid test compound in PBS pH 7.4 was determined by LC/MS/MS.
  • the obtained samples were tested by LC/MS/MS.
  • the sample solubility was calculated based on the peak area of the test compound solution and the standard concentration solution. The calculation formula is as follows:
  • sample is the solubility of the sample to be tested
  • Area ratio sample is the ratio of the sample peak area to the internal standard peak area in the sample to be tested
  • INJ VOL STD is the injection volume of the standard concentration solution
  • DF sample is the dilution factor of the sample solution to be tested
  • [STD] is the concentration of the standard concentration solution
  • INJ VOL sample is the injection volume of the sample solution to be tested
  • Area ratio STD is the ratio of the sample peak area to the internal standard peak area in the standard concentration solution.
  • the solubility of the test compounds in PBS pH 7.4 was determined by LC/MS/MS.
  • the obtained samples were tested by LC/MS/MS.
  • the sample solubility was calculated based on the peak area of the test compound solution and the standard concentration solution. The calculation formula is as follows:
  • sample is the solubility of the sample to be tested
  • Area ratio sample is the ratio of the sample peak area to the internal standard peak area in the sample to be tested
  • INJ VOL STD is the injection volume of the standard concentration solution
  • DF sample is the dilution factor of the sample solution to be tested
  • [STD] is the concentration of the standard concentration solution
  • INJ VOL sample is the injection volume of the sample solution to be tested
  • Area ratio STD is the ratio of the sample peak area to the internal standard peak area in the standard concentration solution.
  • Test Example 9 Pharmacokinetics of the compounds disclosed in this invention in rats
  • SD rats were used as test animals, and the drug concentration in the plasma at different times after intravenous injection and oral administration of the disclosed compound was determined by LC/MS/MS method to study the pharmacokinetic behavior of the disclosed compound in rats and evaluate its pharmacokinetic characteristics.
  • Each group included 3 healthy 6-8 week old male SD rats.
  • Intravenous administration Weigh a certain amount of drug, add 10% volume of N,N-dimethylacetamide, 33% volume of triethylene glycol and 57% volume of normal saline to prepare a 1 mg/mL colorless, clear and transparent liquid;
  • Intragastric administration Weigh a certain amount of drug, add 0.5% by mass of hydroxypropyl methylcellulose, 0.1% by volume of Tween 80 and 99.6% by volume of normal saline to prepare a 1 mg/mL white suspension.
  • the drugs were administered intravenously or orally after SD rats were fasted overnight.
  • Rats were intravenously administered with the disclosed compound, and 0.2 mL of blood was collected from the jugular vein at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration.
  • the blood was placed in a tube containing EDTA-K2, centrifuged at 4°C, 4000 rpm for 5 minutes to separate the plasma, and stored at -75°C.
  • rats were intragastrically administered with the disclosed compounds, and 0.2 mL of blood was collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, placed in a test tube containing EDTA-K2, and centrifuged at 4°C, 3500 rpm for 10 minutes to separate plasma, which was then stored at -75°C.
  • Test Example 10 In vitro evaluation of PXR activation potential in DPX2 cells
  • DMSO solutions of the test compound and control compound rifampicin solutions and dilute them to the respective test concentrations at 37°C with Puracyp dosing medium (Puracyp, Catalog No. D-500-100).
  • the final concentrations of the test compounds were 30 ⁇ M, 10 ⁇ M and 1 ⁇ M, respectively, and the final concentration of rifampicin was 20 ⁇ M.
  • the final concentration of DMSO in the test solution was 0.1%.
  • a 0.1% DMSO solution was prepared with Puracyp dosing medium as a control.
  • the medium in the 96-well culture plate was aspirated and washed twice with PBS. 50 ⁇ L of the diluted reagent in the CellTiter-Fluor TM Cell Viability Assay Kit (Promega, Cat. No. G6082) was added to each well and incubated at 37°C for 0.5 hours. The 96-well plate was cooled to room temperature and each well was measured with a microplate reader in fluorescence mode at an excitation wavelength of 400 nm. The fluorescence value at 505 nm was measured.
  • Normalized luciferase activity was determined by RLU/RFU, where RLU refers to the relative luminescence unit of each test compound at each dose, and RFU refers to the relative fluorescence unit of each test compound at each dose.
  • RLU refers to the relative luminescence unit of each test compound at each dose
  • RFU refers to the relative fluorescence unit of each test compound at each dose.
  • the RLU and RFU of the samples were the average of duplicate wells.
  • %Positive control (fold activation test compound -1)/(fold activation positive control compound -1)*100%
  • Fold of activation is the activation fold of PXR by the sample to be tested
  • RLU sample is the relative luminescence intensity of the sample to be tested
  • RFU sample is the relative fluorescence intensity of the sample to be tested
  • RLU vehicle is the relative luminescence intensity of the blank control
  • RFU vehicle is the relative fluorescence intensity of the blank control
  • Positive control is the activation rate of the test compound on PXR relative to the positive compound (rifampicin).

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Abstract

本发明提供一种新型的稠合杂芳烃类化合物或其药学可接受的盐，含有它们的药物组合物以及作为KIF18A抑制剂在预防或治疗相关疾病中的用途。

Description

稠合杂芳烃类化合物、其组合物及用途
本公开要求2022年10月19日向中国国家知识产权局提交的，专利申请号为202211281425.5，发明名称为“稠合杂芳烃类化合物、其组合物及用途”以及2023年7月28日向中国国家知识产权局提交的，专利申请号为202310947196.4，发明名称为“稠合杂芳烃类化合物、其组合物及用途”的中国专利申请的优先权和权益。上述在先申请的全文通过援引整体并入本文中。
技术领域
本公开涉及一种新型的稠合杂芳烃类化合物或其药学可接受的盐，含有它们的药物组合物以及作为KIF18A抑制剂在预防或治疗相关疾病中的用途。
背景技术
癌症的特征通常在于不受调节的细胞增殖。对细胞增殖通路的一个或更多基因的损伤可以引起细胞增殖的正常调节的丧失。这些失调的基因可以编码各种肿瘤抑制物或癌症基因蛋白，导致未经检查的细胞周期进展和细胞增殖。各种激酶和驱动蛋白已经被鉴定在正常细胞和癌细胞的细胞周期、有丝分裂调节和进展中起关键作用。
驱动蛋白是在细胞分裂和细胞内囊泡和细胞器运输中起重要作用的分子马达。有丝分裂驱动蛋白在纺锤体组件、染色体分离、中心体分离等多个方面起作用。基于所谓的“马达结构域”内的序列同源性，人驱动蛋白被分类为14个亚家族，该结构域ATP酶的活性驱动沿着微管单向运动。这些蛋白质的非马达结构域负责与“货物”附接；“货物”可以是各种不同的膜状细胞器、信号转导支架系统和染色体中的一种。驱动蛋白利用ATP水解的能量来沿着极化微管移动“货物”。因此，驱动蛋白通常被称为“正端”或“负端”定向马达蛋白。KIF18A基因属于驱动蛋白-8亚家族并且是一个正端定向马达蛋白。KIF18A被认为影响着丝粒微管的正端的移动以控制正确的染色体定位和保持纺锤体张力。人KIF18A的移除在HeLa宫颈癌细胞中导致更长的纺锤体，在有丝分裂中期增加染色体振荡并导致锤体组装检查点的激活。因此，KIF18A可能是癌症治疗的可行靶标。KIF18A在多种类型的癌症中过表达，此外，在癌细胞中，KIF18A基因缺失、敲除或抑制会影响有丝分裂纺锤体，特别是已发现抑制KIF18A来诱导有丝分裂的停滞，最终导癌症细胞有丝分裂灾变或分裂间期中有丝分裂滑脱后使得癌症细胞凋亡。
因此，KIF18A的抑制剂可以开发成一种有前途的抗癌药物。各研究机构对寻找KIF18A蛋白的抑制剂存在着强烈的兴趣。
发明内容
本公开提供一种式(I)所示化合物或其药学上可接受的盐：
其中，
X1选自N、O、S、NR4或CR4；
X2选自N或CR4，或者X2不存在；
X3、X4各自独立地选自N或C；
X5、X6各自独立地选自N或CR4；
每一个R4独立地选自H、卤素、C1-C6烷基、OH、NH2、O(C1-C4烷基)、NH(C1-C4烷基)或N(C1-C4烷基)2，所述C1-C6烷基、O(C1-C4烷基)、NH(C1-C4烷基)或N(C1-C4烷基)2任选被一个或多个R4b取代；
R1选自H或C1-C6烷基，所述C1-C6烷基任选被一个或多个卤素取代；
环A选自C6-C20芳基、5-20元杂芳基或4-20元杂环基，所述C6-C20芳基、5-20元杂芳基或4-20元杂环基任选被一个或多个R1a取代；
R3选自L1-L2-Ry，L1选自-NR5-、-O-、-S-、-S(＝O)-、-SO2-、-C(＝O)-、-NR5SO2-、-NR5(C＝O)-、-S＝N-、-NR5-S(＝O)(＝NR5)-、-S(＝O)(＝NR5)-、所述R5选自H或C1-C4烷基，所述R5a、R5b各自独立地选自C1-C4烷基、C3-C6环烷基或4-7元杂环基，或者所述R5a、R5b以及它们连接的原子共同形成4-7元杂环基，L2选自化学键或C1-C4亚烷基，Ry选自H、C3-C6环烷基或4-7元杂环基，上述每一个C1-C4烷基、C1-C4亚烷基、C3-C6环烷基或4-7元杂环基任选被一个或多个R3b取代；
R2选自OH、NH2、C1-C10烷基、C3-C10环烷基、C2-C10炔基、 其中，
所述OH、NH2、C1-C10烷基、C3-C10环烷基或C2-C10炔基任选被一个或多个R2b取代；
n、m1、m2、p各自独立地选自0、1或2；
i、j、k各自独立地选自0、1、2、3、4、5或6；
Rx1和Rx2以及它们连接的碳原子共同形成C3-C6环烷基、C3-C6环烯基或4-7元杂环基，所述C3-C6环烷基、C3-C6环烯基或4-7元杂环基任选被一个或多个R2b取代；
环Q选自C3-C6环烷基、C3-C6环烯基或4-7元杂环基，所述C3-C6环烷基、C3-C6环烯基或4-7元杂环基任选被一个或多个R2b取代；
Y1选自O、S或NH；
所述任选被一个或多个Rx取代，每一个Rx独立地选自卤素、CN、OH、NH2、C1-C6烷基、C3-C6环烷基或4-7元杂环基，所述OH、NH2、C1-C6烷基、C3-C6环烷基或4-7元杂环基任选被一个或多个Rxb取代，当上的同一个碳原子同时被两个Rx取代时，所述两个Rx还可以与该碳原子共同形成C3-C10环烷基、C3-C10环烯基或4-10元杂环基，所述C3-C10环烷基、C3-C10环烯基或4-10元杂环基任选被一个或多个Rxb取代；
每一个R1a独立地选自卤素、CN、OH、NH2、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、C5-C10环烯基、4-10元杂环基、C6-C10芳基或5-10元杂芳基，所述OH、NH2、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、C5-C10环烯基、4-10元杂环基、C6-C10芳基或5-10元杂芳基任选被一个或多个R1b取代；
每一个R1b、R2b、R3b、R4b、Rxb独立地选自卤素、CN、OH、NH2、C1-C6烷基、C3-C6 环烷基、4-7元杂环基、O(C1-C4烷基)、NH(C1-C4烷基)或N(C1-C4烷基)2，所述C1-C6烷基、C3-C6环烷基、4-7元杂环基、O(C1-C4烷基)、NH(C1-C4烷基)或N(C1-C4烷基)2任选被一个或多个Rc取代；
每一个Rc独立地选自卤素、CN、OH、NH2、C1-C6烷基、C3-C6环烷基、4-7元杂环基、O(C1-C4烷基)、NH(C1-C4烷基)或N(C1-C4烷基)2；
并且，当X2选自N或CR4时，其中：
环A选自C9-C10芳基、5元杂芳基、吡啶酮基、氮杂吡啶酮基、8-14元双环或三环杂环基、12-20元四环杂环基或8-14元双环或三环杂芳基，所述C9-C10芳基、5元杂芳基、吡啶酮基、氮杂吡啶酮基、8-14元双环或三环杂环基、12-20元四环杂环基或8-14元双环或三环杂芳基任选被一个或多个R1a取代；和/或，
R2选自OH、NH2、C1-C10烷基、C3-C10环烷基、C2-C10炔基、 所述OH、NH2、C1-C10烷基、C3-C10环烷基或C2-C10炔基任选被一个或多个R2b取代，n、m1、m2、p各自独立地选自0、1或2，i、j、k各自独立地选自0、1、2、3、4、5或6，Rx1和Rx2以及它们连接的碳原子共同形成C3-C6环烷基、C3-C6环烯基或4-7元杂环基，所述C3-C6环烷基、C3-C6环烯基或4-7元杂环基任选被一个或多个R2b取代，环Q选自C3-C6环烷基、C3-C6环烯基或4-7元杂环基，所述C3-C6环烷基、C3-C6环烯基或4-7元杂环基任选被一个或多个R2b取代，Y1选自O、S或NH；和/或，
R3选自L1-L2-Ry，L1选自-NR5-、-O-、-S-、-S(＝O)-、-SO2-、-C(＝O)-、-NR5SO2-、-NR5(C＝O)-、-S＝N-、-NR5-S(＝O)(＝NR5)-或-S(＝O)(＝NR5)-，R5选自H或C1-C4烷基，L2选自任选被一个或多个R3b取代的C1-C4亚烷基，Ry选自任选被一个或多个R3b取代的C3-C6环烷基或4-7元杂环基。
在一些实施方案中，当X2选自N或CR4时，其中：
环A选自5元杂芳基、吡啶酮基、氮杂吡啶酮基、8-14元双环或三环杂环基、12-20元四环杂环基或8-14元双环或三环杂芳基，所述5元杂芳基、吡啶酮基、氮杂吡啶酮基、8-14元双环或三环杂环基、12-20元四环杂环基或8-14元双环或三环杂芳基任选被一个或多个R1a取代；和/或，
R2选自OH、NH2、C1-C10烷基、C3-C10环烷基、C2-C10炔基、 所述OH、NH2、C1-C10烷基、C3-C10环烷基或C2-C10炔基任选被一个或多个R2b取代，n、m1、m2、p各自独立地选自0、1或2，i、j、k各自独立地选自0、1、2、3、4、5或6，Rx1和Rx2以及它们连接的碳原子共同形成C3-C6环烷基、C3-C6环烯基或4-7元杂环基，所述C3-C6环烷基、C3-C6环烯基或4-7元杂环基任选被一个或多个R2b取代，环Q选自C3-C6环烷基、C3-C6环烯基或4-7元杂环基，所述C3-C6环烷基、C3-C6环烯基或4-7元杂 环基任选被一个或多个R2b取代，Y1选自O、S或NH；和/或，
R3选自L1-L2-Ry，L1选自-NR5-、-O-、-S-、-S(＝O)-、-SO2-、-C(＝O)-、-NR5SO2-、-NR5(C＝O)-、-S＝N-、-NR5-S(＝O)(＝NR5)-或-S(＝O)(＝NR5)-，R5选自H或C1-C4烷基，L2选自任选被一个或多个R3b取代的C1-C4亚烷基，Ry选自任选被一个或多个R3b取代的C3-C6环烷基或4-7元杂环基。
在一些实施方案中，X2不存在，X1选自N、O、S或NR4，所述R4选自H或C1-C6烷基。
在一些实施方案中，X2不存在，X1选自N、O、S或NCH3。
在一些实施方案中，X1、X2各自独立地选自N或CR4，所述R4选自H或C1-C6烷基。
在一些实施方案中，X1、X2各自独立地选自N或CH。
在一些实施方案中，X5、X6各自独立地选自CH。
在一些实施方案中，结构单元选自
在一些实施方案中，结构单元选自
在一些实施方案中，R1选自H或C1-C6烷基。
在一些实施方案中，R1选自H。
在一些实施方案中，R3选自L1-L2-Ry，L1选自-NH-、-O-、-S-、-S(＝O)-、-SO2-、-C(＝O)-、-NHSO2-、-NH(C＝O)-或所述R5a、R5b各自独立地选自C1-C4烷基，或者所述R5a、R5b以及它们连接的原子共同形成4-7元杂环基，L2选自化学键或C1-C4亚烷基，Ry选自H、C3-C6环烷基或4-7元杂环基，上述每一个C1-C4烷基、C1-C4亚烷基、C3-C6环烷基或4-7元杂环基任选被一个或多个R3b取代。
在一些实施方案中，每一个R3b独立地选自卤素、CN、OH或NH2。
在一些实施方案中，R3选自L1-L2-Ry，L1选自-NH-、-O-、-S-、-S(＝O)-、-SO2-、-(C＝O)-、-NHSO2-或-NH(C＝O)-，L2选自C1-C4亚烷基，Ry选自H，所述C1-C4亚烷基任选被一个或多个卤素、CN、OH或NH2取代。
在一些实施方案中，R3选自L1-L2-Ry，L1选自-NHSO2-，L2选自C1-C4亚烷基，Ry选自H，所述C1-C4亚烷基任选被一个或多个卤素或OH取代。
在一些实施方案中，R3选自
在一些实施方案中，R3选自
在一些实施方案中，R3选自
在一些实施方案中，n、m1、m2、p各自独立地选自0、1或2。
在一些实施方案中，n、m1、p各自独立地选自1，m2选自0。
在一些实施方案中，i、j、k各自独立地选自0、1、2或3。
在一些实施方案中，Rx1和Rx2以及它们连接的碳原子共同形成C3-C6环烷基或4-7元杂环基，所述C3-C6环烷基或4-7元杂环基任选被一个或多个R2b取代。
在一些实施方案中，环Q选自C3-C6环烷基或4-7元杂环基，所述C3-C6环烷基或4-7元杂环基任选被一个或多个R2b取代。
在一些实施方案中，Y1选自O、S或NH。
在一些实施方案中，Y1选自NH。
在一些实施方案中，R2b选自卤素、CN、OH、NH2、C1-C6烷基、C3-C6环烷基或4-7元杂环基，所述C1-C6烷基、C3-C6环烷基或4-7元杂环基任选被一个或多个卤素或CN取代。
在一些实施方案中，R2b选自C1-C4烷基，所述C1-C4烷基任选被一个或多个卤素(例如F)取代。
在一些实施方案中，Rx选自卤素、CN、C1-C6烷基、C3-C6环烷基或4-7元杂环基，所述C1-C6烷基、C3-C6环烷基或4-7元杂环基任选被一个或多个Rxb取代。
在一些实施方案中，Rxb选自卤素、CN、OH、NH2、C1-C6烷基、C3-C6环烷基或4-7元杂环基，所述C1-C6烷基、C3-C6环烷基或4-7元杂环基任选被一个或多个卤素或CN取代。
在一些实施方案中，R2选自C3-C6环烷基、C2-C6炔基、 其中：
所述C3-C6环烷基或C2-C6炔基任选被一个或多个R2b取代；
所述任选被一个或多个Rx取代，当上的同一个碳原子同时被两个Rx取代时，所述两个Rx还可以与该碳原子共同形成C3-C6环烷基、C3-C6环烯基或4-7元杂环基，所述C3-C6环烷基、C3-C6环烯基或4-7元杂环基任选被一个或多个Rxb取代；
所述n、m1、m2、p、i、j、k、Rx1、Rx2、Y1、R2b、Rx、Rxb和环Q如上文任一定义。
在一些实施方案中，R2选自 其中：
所述任选被一个或多个Rx取代，当上的同一个碳原子同时被两个Rx取代时，所述两个Rx还可以与该碳原子共同形成C3-C6环烷基、C3-C6环烯基或4-7元杂环基，所述C3-C6环烷基、C3-C6环烯基或4-7元杂环基任选被一个或多个Rxb取代；
所述n、m1、m2、p、i、j、k、Rx1、Rx2、Y1、R2b、Rx、Rxb和环Q如上文任一定义。
在一些实施方案中，R2选自其中：
所述中的*碳原子同时被两个Rx取代，所述两个Rx与该*碳原子共同形成C3-C6环烷基、C3-C6环烯基或4-7元杂环基，所述C3-C6环烷基、C3-C6环烯基或4-7元杂环基任选被一个或多个Rxb取代；
所述n、k、Y1、R2b、Rx、Rxb如上文任一定义。
在一些实施方案中，R2选自其中：
所述中的*碳原子同时被两个Rx取代，所述两个Rx与该*碳原子共同形成C3-C6环烷基，所述C3-C6环烷基任选被一个或多个Rxb取代；
所述k、R2b、Rx、Rxb如上文任一定义。
在一些实施方案中，R2选自
在一些实施方案中，R2选自
在一些实施方案中，环A选自C6-C10芳基、5-10元杂芳基、11-14元三环杂芳基、8-14元双环杂环基、11-14元三环杂环基或12-20元四环杂环基，所述C6-C10芳基、5-10元杂芳基、11-14元三环杂芳基、8-14元双环杂环基、11-14元三环杂环基或12-20元四环杂环基任选被一个或多个R1a取代。
在一些实施方案中，环A选自苯基、5-10元杂芳基、11-14元三环杂环基、11-14元三环杂芳基或12-20元四环杂环基，所述苯基、5-10元杂芳基、11-14元三环杂环基、11-14元三环杂芳基或12-20元四环杂环基任选被一个或多个R1a取代。
在一些实施方案中，环A选自苯基、5-10元杂芳基、11-14元三环杂环基或11-14元三环杂芳基，所述苯基、5-10元杂芳基、11-14元三环杂环基或11-14元三环杂芳基任选被一个或多个R1a取代。
在一些实施方案中，环A选自任选被一个或多个R1a取代的以下基团：苯基、嘧啶基、
在一些实施方案中，环A选自苯基、嘧啶基、 所述苯基、嘧啶基、 任选被一个或多个R1a取代。
在一些实施方案中，环A选自苯基、嘧啶基、 所述苯基、嘧啶基、 任选被一个或多个R1a取代。
在一些实施方案中，环A选自 所述 任选被一个或多个R1a取代。
在一些实施方案中，每一个R1a独立地选自卤素、CN、C1-C6烷基、C3-C6环烷基或4-7元杂环基，所述C1-C6烷基、C3-C6环烷基或4-7元杂环基任选被一个或多个R1b取代，所述R1b独立地选自卤素、CN、OH、NH2、C1-C6烷基、C3-C6环烷基、4-7元杂环基、O(C1-C4烷基)、NH(C1-C4烷基)或N(C1-C4烷基)2。
在一些实施方案中，每一个R1a独立地选自卤素、C1-C6烷基或4-7元杂环基，所述C1-C6烷基或4-7元杂环基任选被一个或多个卤素(例如F)取代。
在一些实施方案中，每一个R1a独立地选自C1-C6烷基或4-7元杂环基，所述C1-C6烷基或4-7元杂环基任选被一个或多个卤素(例如F)取代。
在一些实施方案中，每一个R1a独立地选自F、CF3CH2CH2或
在一些实施方案中，每一个R1a独立地选自甲基、CF3CH2CH2或
在一些实施方案中，环A选自
在一些实施方案中，环A选自
在一些实施方案中，环A选自
在一些实施方案中，当X2选自N或CR4时，所述式(I)所示化合物，其中：
环A选自5元杂芳基、吡啶酮基、氮杂吡啶酮基、11-14元三环杂环基或8-14元双环或三环杂芳基，所述5元杂芳基、吡啶酮基、氮杂吡啶酮基、11-14元三环杂环基或8-14元双环或三环杂芳基任选被一个或多个R1a取代，所述R1a如上文任一定义；和/或，
R2选自所述n、m1、m2、p、i、j、k、Rx1、Rx2、Y1、R2b和环Q如上文任一定义；和/或，
R3选自L1-L2-Ry，其中，L1选自-NR5-、-O-、-S-、-S(＝O)-、-SO2-、-(C＝O)-、-NR5SO2-或-NR5(C＝O)-，R5选自H或C1-C4烷基，L2选自任选被一个或多个R3b取代的C1-C4亚烷基，Ry选自任选被一个或多个R3b取代的C3-C6环烷基或4-7元杂环基，所述R3b如上文任一定义。
在一些实施方案中，当X2选自N或CR4时，所述式(I)所示化合物，其中：
环A选自 所述 任选被一个或多个R1a取代，每一个R1a独立地选自C1-C6烷基或4-7元杂环基，所述C1-C6烷基或4-7元杂环基任选被一个或多个卤素(例如F)取代，例如，环A选自 和/或，
R2选自所述Y1、n、k、R2b如上文任一定义，例如，R2选自
在一些实施方案中，当X2选自N或CR4时，所述式(I)所示化合物，其中：
环A选自C9-C10芳基、8-14元双环或三环杂环基、12-20元四环杂环基、8-14元双环或三环杂芳基，所述C9-C10芳基、8-14元双环或三环杂环基、12-20元四环杂环基、8-14元双环或三环杂芳基任选被一个或多个R1a取代，所述R1a如上文任一定义。
在一些实施方案中，当X2选自N或CR4时，所述式(I)所示化合物，其中：
环A选自
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自以下化合物或其药学可接受的盐：



本公开还提供药物组合物，其包含式(I)所示化合物或其药学可接受的盐和药学上可接 受的辅料。
进一步地，本公开涉及式(I)所示的化合物或其药学上可接受的盐，或其药物组合物在制备用于预防或者治疗KIF18A相关疾病的药物中的用途。
进一步地，本公开涉及式(I)所示的化合物或其药学上可接受的盐，或其药物组合物在制备用于预防或者治疗肿瘤的药物中的用途。
进一步地，本公开涉及式(I)所示的化合物或其药学上可接受的盐，或其药物组合物在预防或者治疗KIF18A相关疾病中的用途。
进一步地，本公开涉及式(I)所示的化合物或其药学上可接受的盐，或其药物组合物在预防或者治疗肿瘤中的用途。
进一步地，本公开涉及用于预防或者治疗KIF18A相关疾病的式(I)化合物或其药学上可接受的盐，或其药物组合物。
进一步地，本公开涉及用于预防或者治疗肿瘤的式(I)化合物或其药学上可接受的盐，或其药物组合物。
本公开还涉及治疗KIF18A相关疾病的方法，该方法包括给以患者治疗有效量的包含本公开所述的式(I)化合物或其药学上可接受的盐的药物制剂。
本公开还涉及治疗肿瘤的方法，该方法包括给以患者治疗有效量的包含本公开所述的式(I)化合物或其药学上可接受的盐的药物制剂。
在一些实施方案中，KIF18A相关疾病选自肿瘤。
术语定义和说明
除非另有说明，本公开中所用的术语具有下列含义，本公开中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
本文中表示连接位点。
本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔实键和楔虚键表示一个立体中心的绝对构型，用直实键和直虚键表示一个立体中心的相对构型(如脂环化合物的顺反构型)。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本公开化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本公开包含化合物的所有互变异构形式。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和非对映异构体。
本公开的化合物可以具有不对称原子如碳原子、硫原子、氮原子、磷原子或不对称双键，因此本公开的化合物可以存在特定的几何或立体异构体形式。特定的几何或立体异构体形式可以是顺式和反式异构体、E型和Z型几何异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，以及其外消旋混合物或其它混合物，例如对映异构体或非对映体富集的混合物，以上所有这些异构体以及它们的混合物都属于本公开化合物的定义范围之内。烷基等取代基中可存在另外的不对称碳原子、不对称硫原子、不对称氮原子或不对称磷原子，所有取代基中涉及到的这些异构体以及它们的混合物，也均包括在本公开化 合物的定义范围之内。本公开的含有不对称原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来，光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被一个或多个卤素取代，是指乙基可以是未被取代的(CH2CH3)、单取代的(CH2CH2F、CH2CH2Cl等)、多取代的(CHFCH2F、CH2CHF2、CHFCH2Cl、CH2CHCl2等)或完全被取代的(CF2CF3、CF2CCl3、CCl2CCl3等)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
当任何变量(例如Ra、Rb)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。例如，如果一个基团被2个Rb所取代，则每个Rb都有独立的选项。
当一个连接基团的数量为0时，比如-(CH2)0-，表示该连接基团为键。
当其中一个变量选自化学键或不存在时，表示其连接的两个基团直接相连，比如A-L-Z中L代表键时表示该结构实际上是A-Z。
当本文中涉及到的连接基团若没有指明其连接方向，则其连接方向是任意的。例如当结构单元L1-L2-Ry中的L1选自“-NR5SO2-”时，此时L1既可以按照与从左到右的方向连接L2-Ry构成“-NR5SO2-L2-Ry”，也可以按照从右到左的方向连接L2-Ry构成“-SO2NR5-L2-Ry”。
当一个取代基交叉连接到一个环上的两个原子时，表示该取代基可以与这个环上的任意原子相键合。例如，结构单元表示取代基R2b可与内酰胺环的任意可键合的环原子键合。
本文中的Cm-Cn是指具有m-n范围中的整数个碳原子。例如“C1-C10”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子或10个碳原子。
术语“烷基”是指通式为CnH2n+1的烃基，该烷基可以是直链或支链的。术语“C1-C10烷基”可理解为表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链或支链饱和烃基。所述烷基的具体实例包括但不限于甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1，2-二甲基丙基、新戊基、1，1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、2，3-二甲基丁基、1，3-二甲基丁基或1，2-二甲基丁基等；术语“C1-C6烷基”可理解为表示具有1至6个碳原子的烷基，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、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等。术语“C1-C4烷基”可理解为表示具有1至4个碳原子的直链或支链饱和烷基。所述“C1-C10烷基”可以包含“C1-C6烷基”或“C1-C4烷基”等范围，所述“C1-C6烷基”可以进一步包含“C1-C4烷基”。
术语“烷氧基”是指直链或支链醇类失去羟基上的氢原子产生的基团，可理解为“烷基氧基”或“烷基-O-”。术语“C1-C10烷氧基”可理解为“C1-C10烷基氧基”或“C1-C10烷基-O-”；术语“C1-C6烷氧基”可理解为“C1-C6烷基氧基”或“C1-C6烷基-O-”。所述“C1-C10烷氧基”可以包含“C1-C6烷氧基”和“C1-C3烷氧基”等范围，所述“C1-C6烷氧基”可以进一步包含“C1-C3烷氧基”。
术语“烯基”是指由碳原子和氢原子组成的直链或支链的且具有至少一个双键的不饱和脂 肪族烃基。术语“C2-C10烯基”可理解为表示直链或支链的不饱和烃基，其包含一个或多个双键并且具有2、3、4、5、6、7、8、9或10个碳原子，“C2-C10烯基”可以包含“C2-C6烯基”、“C2-C4烯基”、C2或C3烯基。可理解，在所述烯基包含多于一个双键的情况下，所述双键可相互分离或共轭。所述烯基的具体实例包括但不限于乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基或(Z)-1-甲基丙-1-烯基等。
术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基。术语“C2-C10炔基”可理解为表示直链或支链的不饱和烃基，其包含一个或多个三键并且具有2、3、4、5、6、7、8、9或10个碳原子。“C2-C10炔基”的实例包括但不限于乙炔基(-C≡CH)、丙炔基(-C≡CCH3、-CH2C≡CH)、丁-1-炔基、丁-2-炔基或丁-3-炔基。“C2-C10炔基”可以包含“C2-C3炔基”，“C2-C3炔基”实例包括乙炔基(-C≡CH)、丙-1-炔基(-C≡CCH3)、丙-2-炔基(-CH2C≡CH)。
术语“环烷基”是指完全饱和的且以单环、稠环、桥环或螺环等形式存在的碳环基团。除非另有指示，该碳环通常为3至20元环。术语“C3-C10环烷基”是指具有3、4、5、6、7、8、9或10个环碳原子的环烷基，所述环烷基的具体实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基，降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基、螺[4.5]癸烷基等。术语“C3-C10环烷基”可以包含“C5-C10环烷基”和“C3-C6环烷基”等范围。术语“C3-C6环烷基”是指具有3、4、5或6个环碳原子的环烷基。
术语“环烷基氧基”可理解为“环烷基-O-”。
术语“C3-C10环烯基”是指不完全饱和的具有至少一个碳-碳双键且以单环、稠环、桥环或螺环等形式存在的非芳香族碳环基，其具有3～10个环碳原子。术语“C5-C10环烯基”是指环碳原子数为5、6、7、8、9、10的环烯基。术语“C3-C6环烯基”是指环碳原子数为3、4、5、6的环烯基。所述环烯基的具体实例包括但不限于环戊烯基、环戊二烯基、环己烯基、环己二烯基、环庚烯基或环庚二烯基等。
术语“杂环基”是指完全饱和的或部分饱和的(整体上不是具有芳香性的杂芳族)单环、稠环、螺环或桥环基团，其环原子中含有1-8个(例如1-5个、1-3个或1-2个)杂原子或杂原子团(即含有杂原子的原子团)，所述“杂原子或杂原子团”包括但不限于氮原子(N)、氧原子(O)、硫原子(S)、磷原子(P)、硼原子(B)、-S(＝O)2-、-S(＝O)-、-P(＝O)2-、-P(＝O)-、-NH-、-S(＝O)(＝NH)-、-C(＝O)NH-或-NHC(＝O)NH-等，所述稠环、螺环或桥环可以是双环、三环、四环或五环。术语“4-20元杂环基”是指环原子数目为4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20的杂环基，且其环原子中含有1-8个独立选自上文所述的杂原子或杂原子团。术语“4-14元杂环基”是指环原子数目为4、5、6、7、8、9、10、11、12、13或14的杂环基，且其环原子中含有1-8个独立选自上文所述的杂原子或杂原子团。术语“4-10元杂环基”是指环原子数目为4、5、6、7、8、9或10的杂环基，且其环原子中含有1-5个独立选自上文所述的杂原子或杂原子团。“4-10元杂环基”可以包含“4-7元杂环基”。术语“4-7元杂环基”是指环原子数目为4、5、6或7的杂环基，且其环原子中含有1、2、3、4或5个独立选自上文所述的杂原子或杂原子团。术语“8-14元双环或三环杂环基”是指环原子数目为8、9、10、11、12、13或14的双环或三环杂环基，且其环原子中含有1-8个独立选自上文所述的杂原子或杂原子团。术语“11-14元三环杂环基”是指环原子数目为11、12、13或14的三环杂环基，且其环原子中含有1-8个独立选自上文所述的杂原子或杂原子团。术语“4-7元单杂环基”是指单环形式的4-7元杂环基。4元杂环基的具体实例包括但不限于氮杂环丁烷基或氧杂环丁烷基；5元杂环基的具体实例包括但不限于四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基、4,5-二氢噁唑基或2,5-二氢-1H-吡咯基；6元杂环基的具体实例包括但不限于四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基、三噻烷基、四氢吡啶基或4H-[1,3,4]噻二嗪基；7元杂环基的具体实例包括但不限于二氮杂环庚烷基。所述杂环基还可以是双环基，其中，5,5元双环基的具体实例包括但不限于六氢环戊 并[c]吡咯-2(1H)-基；5,6元双环基的具体实例包括但不限于六氢吡咯并[1,2-a]吡嗪-2(1H)-基、5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪基或5,6,7,8-四氢咪唑并[1,5-a]吡嗪基。任选地，所述杂环基可以是上述4-7元杂环基的苯并稠合环基，具体实例包括但不限于二氢异喹啉基等。“4-10元杂环基”可以包含“5-10元杂环基”、“4-7元杂环基”、“5-6元杂环基”、“6-8元杂环基”、“4-10元杂环烷基”、“5-10元杂环烷基”、“4-7元杂环烷基”、“5-6元杂环烷基”、“6-8元杂环烷基”等范围，“4-7元杂环基”进一步可以包含“4-6元杂环基”、“5-6元杂环基”、“4-7元杂环烷基”、“4-6元杂环烷基”、“5-6元杂环烷基”等范围。本公开中尽管有些双环或三环类杂环基部分地含有一个苯环或一个杂芳环，但所述杂环基整体上仍是无芳香性的。
术语“杂环基氧基”可理解为“杂环基-O-”。
术语“杂环烷基”是指完全饱和的且以单环、稠合环、桥环或螺环等形式存在的环状基团，其环的环原子中含有1-5个杂原子或杂原子团(即含有杂原子的原子团)，所述“杂原子或杂原子团”包括但不限于氮原子(N)、氧原子(O)、硫原子(S)、磷原子(P)、硼原子(B)、-S(＝O)2-、-S(＝O)-、-NH-、-S(＝O)(＝NH)-、-C(＝O)NH-或-NHC(＝O)NH-等。术语“4-10元杂环烷基”是指环原子数目为4、5、6、7、8、9或10的杂环烷基，且其环原子中含有1-5个独立选自上文所述的杂原子或杂原子团。“4-10元杂环烷基”包括“4-7元杂环烷基”，其中，4元杂环烷基的具体实例包括但不限于吖丁啶基、噁丁环基或噻丁环基；5元杂环烷基的具体实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基或四氢吡唑基；6元杂环烷基的具体实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基或1,4-二噻烷基；7元杂环烷基的具体实例包括但不限于氮杂环庚烷基、氧杂环庚烷基或硫杂环庚烷基。
术语“杂环烷基氧基”可理解为“杂环烷基-O-”。
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。术语“C6-C20芳基”可理解为具有6～20个碳原子的芳基。例如具有6个碳原子的环(“C6芳基”)，例如苯基；或者具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基；或者具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基；或者具有13个碳原子的环(“C13芳基”)，例如芴基；或者是具有14个碳原子的环(“C14芳基”)，例如蒽基。术语“C6-C10芳基”可理解为具有6～10个碳原子的芳基。例如具有6个碳原子的环(“C6芳基”)，例如苯基；或者具有9个碳原子的环(“C9芳基”)，例如茚满基或茚基；或者具有10个碳原子的环(“C10芳基”)，例如四氢化萘基、二氢萘基或萘基。
术语“芳基氧基”可理解为“芳基-O-”。
术语“杂芳基”是指具有芳香性的单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C的芳香环基，其通常具有5、6、7、8、9、10、11、12、13、14个环原子，且其包含1-8个，优选1-5个独立选自N、O和S的杂原子。术语“5-20元杂芳基”可理解为包括这样的单环、双环或三环芳族环系：其具有5-20个环原子，且其包含1-8个，例如1-5个独立选自N、O和S的杂原子。术语“8-14元双环或三环杂芳基”是指具有8、9、10、11、12、13或14个环原子的芳香性稠合双环或三环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C的芳香环基。术语“11-14元三环杂芳基”是指具有11、12、13或14个环原子的芳香性稠合三环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C的芳香环基。术语“5-10元杂芳基”可理解为包括这样的单环或双环芳族环系：其具有5、6、7、8、9或10个环原子，例如5或6或9或10个环原子，且其包含1-5个，例如1-3个独立选自N、O和S的杂原子。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基或噻二唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基或异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基或三嗪基等以及它们的苯并衍生物，例如喹啉基、喹唑啉基或异喹啉基等；或吖辛因基、 吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基或吩噁嗪基等。术语“5-6元杂芳基”或“5-6元单杂芳基”指具有5或6个环原子的芳族环系，且其包含1-3个，例如1-2个独立选自N、O和S的杂原子。
术语“杂芳基氧基”可理解为“杂芳基-O-”。
术语“氮杂吡啶酮基”是指吡啶酮基(如)上的环C原子被1个或2个N原子替代后的基团(包括但不限于)。
术语“卤”或“卤素”是指氟、氯、溴或碘。
术语“羟基”是指-OH基团。
术语“氰基”是指-CN基团。
术语“巯基”是指-SH基团。
术语“氨基”是指-NH2基团。
术语“硝基”是指-NO2基团。
术语“治疗有效量”意指(i)治疗特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本公开化合物的用量。构成“治疗有效量”的本公开化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括预防疾病或疾病状态在个体(例如哺乳动物)中出现，特别是当这类个体(例如哺乳动物)易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
术语“个体”包括哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。非人哺乳动物的实例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方案中，所述哺乳动物为人。术语“患者”和“个体”可互换地使用。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指药学上可接受的酸或碱的盐，包括化合物与无机酸或有机酸形成的盐，以及化合物与无机碱或有机碱形成的盐。
术语“药物组合物”是指一种或多种本公开的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本公开的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising可理解为开放的、非排他性的意义，即“包括但不限于”。
本公开还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公 开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。
某些同位素标记的本公开化合物(例如用3H及14C标记)可用于化合物和/或底物组织分布分析中。氚化(即3H)和碳-14(即14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如15O、13N、11C和18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本公开化合物。
本公开的药物组合物可通过将本公开的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本公开化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本公开的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本公开的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂或矫味剂等。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
本文所述的通式(Ⅰ)化合物的所有施用方法中，每天给药的剂量为0.01mg/kg到200mg/kg体重，优选为0.05mg/kg到50mg/kg体重，更优选0.1mg/kg到30mg/kg体重，以单独或分开剂量的形式。
本公开的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其它化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本公开的实施例。
本公开具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本公开的化学变化及其所需的试剂和物料。为了获得本公开的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
具体实施方式
下面通过实施例对发明进行详细描述，但并不意味着对本公开任何不利限制。本文已经详细地描述了本公开，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本公开精神和范围的情况下针对本公开具体实施方式进行各种改变和改进将是显而易见的。本公开所使用的所有试剂是市售的，无需进一步纯化即可使用。
除非另作说明，混合溶剂表示的比例是体积混合比例。
除非另作说明，否则，％是指重量百分比wt％。
化合物经手工或软件命名，市售化合物采用供应商目录名称。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10-6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)；“IC50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。
洗脱剂或流动相可由两种或两种以上溶剂组成的混合洗脱剂或流动相，其比值为各溶剂 的体积比，如“0～10％甲醇/二氯甲烷”表示混合洗脱剂或流动相中的甲醇与二氯甲烷的体积用量比为0:100～10:100。
实施例1化合物1的合成
步骤一：化合物1c的合成
将化合物1a(2.18g,10mmol)，二异丙基乙胺(DIPEA，3.10g,24mmol)加入到DMSO(15mL)中，然后再加入化合物1b的盐酸盐(1.48g,10mmol)，反应液在室温下充分反应。向反应体系中加入水(60mL)，用乙酸乙酯(30mLx2)萃取，合并有机相用饱和食盐水洗涤，无水硫酸镁干燥，过滤后旋干，通过快速柱层析纯化(石油醚：乙酸乙酯＝7：1)得到化合物1c(2.85g)。
步骤二：化合物1d的合成
将化合物1c(1.55g,5mmol)，2,4-二甲氧基苄胺(0.69g,5mmol)和DIPEA(0.77g,6mmol)加入到N-甲基吡咯烷酮(10mL)中，反应液在120℃下充分反应。向反应体系中加入水(40mL)，用乙酸乙酯(20mLx2)萃取，合并有机相用饱和食盐水洗涤，无水硫酸镁干燥，过滤后旋干，通过快速柱层析纯化(石油醚：乙酸乙酯＝10：1)得到化合物1d(1.75g)。
步骤三：化合物1e的合成
将化合物1d(1.7g,4mmol)溶解于二氯甲烷(20mL)中，加入三氟乙酸(5mL)，反应液在室温下充分反应。直接在真空下除去挥发物，所得固体通过快速柱层析纯化(石油醚：乙酸乙酯＝4：1)得到化合物1e(0.92g)。
MS m/z(ESI):306.1[M+H]+.
步骤四：化合物1f的合成
将化合物1e(306mg,1mmol)加入到原甲酸三乙酯(4mL)中，加入醋酸酐(0.1mL)，反应液在140℃下充分反应。直接在真空下除去挥发物，得到化合物1f(0.35g)。
步骤五：化合物1h的合成
将化合物1f(72mg,0.2mmol)和化合物1g(37mg,0.2mmol)加入到醋酸(0.2mL)中，反应液在120℃下充分反应。向反应体系中加入水(4mL)，用二氯甲烷(2mLx2)萃取，合并有机相用饱和食盐水洗涤，无水硫酸镁干燥，过滤后旋干，通过快速柱层析纯化(石油醚：二氯甲烷＝1：1)得到化合物1h(45mg)。
MS m/z(ESI):499.2[M+H]+.
步骤六：化合物1的合成
将化合物1h(25mg,50μmol),化合物1i(7.5mg,60μmol)，磷酸钾(21mg,100μmol)和(1R,2R)-N,N'-二甲基-1,2-环己二胺(7mg,50μmol)加入到DMF(0.2mL)中，然后加入碘化亚铜(9.5mg,50μmol)，反应液在95℃氮气保护下充分反应。反应液冷却后直接通过快速反相柱层析纯化(乙腈：水，50-95％)得到化合物1(6mg)。
MS m/z(ESI):544.4[M+H]+.
1H NMR(400MHz,DMSO-d6)δ13.46(s,1H),10.79(s,1H),8.86(s,1H),8.75(d,J＝8.4Hz,1H),8.24(d,J＝7.7Hz,1H),8.03(d,J＝7.6Hz,1H),7.75(d,J＝8.3Hz,1H),7.63(t,J＝7.6Hz,1H),7.58–7.46(m,4H),3.82(t,J＝6.1Hz,2H),3.51(t,J＝6.2Hz,2H),2.93(t,J＝11.1Hz,2H),2.65–2.53(m,3H),1.24(d,J＝10.4Hz,2H),1.10(d,J＝13.0Hz,2H),0.44(br,4H).
实施例2化合物2的合成
步骤一：化合物2c的合成
将化合物2a(1.0g,5.66mmol)，化合物2b(1.22g,5.66mmol)和三乙胺(1.14g,11.3mmol)加入到DMF(10mL)中，反应液在室温下充分反应。向体系中加入水(20mL)，用乙酸乙酯(20mL*3)萃取，合并有机相并用饱和食盐水洗涤，无水硫酸镁干燥，过滤后旋干，通过快速柱层析纯化(石油醚：乙酸乙酯＝10：1)得到化合物2c(960mg)。
MS m/z(ESI):372.4[M+H]+.
步骤二：化合物2d的合成
将化合物2c(744mg,2mmol)和铁粉(559mg,10mmol)加入到醋酸(5mL)中，反应液在室温下充分反应。向体系中加入水(20mL)，用乙酸乙酯(10mL*3)萃取，合并有机相并用饱和食盐水洗涤，无水硫酸镁干燥，过滤后旋干，通过快速柱层析纯化(石油醚：乙酸乙酯＝5：1)得到化合物2d(560mg)。
MS m/z(ESI):342.3[M+H]+.
步骤三：化合物2e的合成
将化合物2d(342mg,1mmol)溶于二氯甲烷(4mL)中，加入三氟乙酸(1mL)，反应液在室温下充分反应。在真空下除去挥发物，将得到的固体、碳酸铯(1.34g,4mmol)和催化剂BrettPhos-Pd-G3(甲磺酸(2-二环己基膦基-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2-氨基-1,1'-联苯-2-基)钯(II))(50mg)加至二氧六环(4mL)中，反应液在95℃氮气保护下充分反应。向体系中加入水(12mL)，用乙酸乙酯(12mL*2)萃取，合并有机相用饱和食盐水洗涤，无水硫酸镁干燥，过滤后旋干，通过快速柱层析纯化(石油醚：乙酸乙酯＝4：1)得到化合物2e(162mg)。
MS m/z(ESI):206.2[M+H]+.
步骤四：化合物2的合成
通过与化合物1合成实施例步骤五和步骤六一致的方法，使用化合物2e(21mg,0.1mmol)替换1g，合成并纯化获得化合物2(15mg)。
MS m/z(ESI):566.4[M+H]+.
1H NMR(400MHz,DMSO-d6)δ13.10(s,1H),10.69(s,1H),8.88(s,1H),8.21(d,J＝8.1Hz,1H),6.99(d,J＝8.0Hz,1H),4.78(d,J＝11.1Hz,1H),4.25(d,J＝10.0Hz,1H),4.15(t,J＝5.2Hz,2H),4.12(t,J＝7.8Hz,1H),3.43–3.12(m,3H),3.08–2.91(m,4H),2.67(t,J＝12.0Hz,1H),2.05–1.15(m,11H),0.42(br,4H).
实施例3化合物3的合成
步骤一：化合物3c的合成
将化合物3a(220mg,1.0mmol)，化合物3b(盐酸盐，135mg,1.0mmol)和碳酸铯(800mg,2.4mmol)加入到乙腈(4mL)中，混合物在60℃搅拌充分反应。向体系中加入水(20mL)，用乙酸乙酯(10mL x 3)萃取，合并有机相用饱和食盐水洗涤，无水硫酸镁干燥，过滤后旋干，通过快速柱层析纯化(石油醚：乙酸乙酯＝5：1)得到化合物3c(225mg)。
步骤二：化合物3d的合成
通过与实施例4步骤3一致的方法，使用化合物3c(200mg,0.67mmol)为原料，合成并纯化获得化合物3d(134mg)。
步骤三：化合物3e的合成
将化合物3d(100mg,0.37mmol)加入到乙腈(1mL)和水(0.1mL)中，在80℃下加碘(470mg,1.85mmol)，继续在该温度下搅拌充分反应。冷却至室温后，向体系中加入乙酸乙酯(5mL)，用饱和碳酸钠水溶液(5mL)和硫代硫酸钠溶液(5mL)洗涤，收集有机相用饱和食盐水洗涤，无水硫酸镁干燥，过滤旋干，通过快速柱层析纯化(石油醚：乙酸乙酯＝3：1)得到化合物3e(81mg)。
步骤四：化合物3f的合成
将化合物3e(80mg,0.3mmol)，氨基甲酸叔丁酯(42mg,0.36mmol)和碳酸铯(200mg,0.6mmol)加入到1,4-二氧六环(2mL)中，然后加入XantPhos(35mg,60μmol)和Pd2(dba)3(27mg,30μmol)，混合物在100℃充分反应。反应液过滤后旋干，通过快速柱层析纯化(石油醚：乙酸乙酯＝1：1)得到化合物3f(68mg)。
步骤五：化合物3g的合成
将化合物3f(60mg,0.2mmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(0.5mL)，反应液在室温下充分反应。在真空下除去挥发物，将得到化合物3g(35mg)。
步骤六：化合物3h的合成
通过与实施例1步骤5一致的方法，使用化合物3g(20mg,0.1mmol)和化合物1f(36mg,0.1mmol)为原料，合成并纯化获得化合物3h(15mg)。
步骤七：化合物3的合成
通过与实施例1步骤6一致的方法，使用化合物3h(15mg,0.03mmol)和化合物1i(12mg,0.1mmol)为原料，合成并纯化获得化合物3(6mg)。
MS m/z(ESI):562.2[M+H]+.
实施例4化合物4的合成
步骤一：化合物4b的合成
将化合物4a(1.0g,6mmol)溶于1,4-二氧六环(10mL)中，加入液溴(3.2g,20mmol)，混合物在室温下充分反应。向体系中加入饱和碳酸氢钠溶液(10mL)和硫代硫酸钠溶液(10mL)，用二氯甲烷(10mL x 3)萃取，合并有机相用饱和食盐水洗涤，无水硫酸镁干燥，过滤后滤液旋干，通过快速柱层析纯化(石油醚：乙酸乙酯＝8：1)得到化合物4b(0.9g)。
步骤二：化合物4d的合成
氮气保护下，将化合物4b(300mg,1.23mmol)和化合物4c(盐酸盐，192mg,1.2mmol),Pd2dba3(55mg,60μmol),RuPhos(57mg,120μmol),碳酸铯(885mg,2.8mmol)加入到DMF(8mL)中，混合物在110℃充分反应。冷却后，加入水(30mL)，用乙酸乙酯(20mL x 3)萃取水相，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，过快速柱层析纯化(石油醚:乙酸乙酯＝100:0-75:25)得到化合物4d(192mg)。
步骤三：化合物4e的合成
将化合物4d(100mg,0.35mmol)、氯化铵(191mg,3.5mmol)加入到乙醇(2mL)和水(0.5mL)中，然后加铁粉(98mg,1.75mmol)，反应液在80℃下充分反应。向体系中加入氢氧化钠水溶液(1N，5mL)，用乙酸乙酯(5mL x 3)萃取，合并有机相用饱和食盐水洗涤，无水硫酸镁干燥，过滤，滤液旋干得到化合物4e(78mg)。
步骤四：化合物4f的合成
通过与实施例1步骤5一致的方法，使用化合物4e(75mg,0.3mmol)和化合物1f(108mg,0.3mmol)为原料，合成并纯化获得化合物4f(67mg)。
步骤五：化合物4的合成
通过与实施例1步骤6一致的方法，使用化合物4f(17mg,0.03mmol)和化合物1i(12mg,0.1mmol)为原料，合成并纯化获得化合物4(9mg)。
MS m/z(ESI):615.3[M+H]+.
实施例5化合物5的合成
通过与实施例1步骤6一致的方法，使用化合物4f(17mg,0.03mmol)和甲磺酰胺(9.5 mg,0.1mmol)为原料，合成并纯化获得化合物5(6mg)。
MS m/z(ESI):585.2[M+H]+.
实施例6化合物6的合成
通过与实施例1步骤6一致的方法，使用化合物4f(17mg,0.03mmol)和乙磺酰胺(11mg,0.1mmol)为原料，合成并纯化获得化合物6(6mg)。
MS m/z(ESI):599.2[M+H]+.
实施例7化合物7的合成
步骤一：化合物7b的合成
将化合物7a(0.5g,3.1mmol)和N-溴代丁二酰亚胺(NBS，573mg,3.2mmol)加入浓硫酸(2mL)，混合物在60℃下充分反应。冷却后，将反应液缓缓倒入冰水(40mL)，用乙酸乙酯(40mL x 3)萃取，分液，合并的有机相通过无水硫酸钠干燥，过滤，滤液旋干，通过快速柱层析纯化(石油醚：乙酸乙酯＝12：1)得到化合物7b(500mg)。
步骤二：化合物7c的合成
通过与实施例4步骤2一致的方法，使用化合物7b(150mg,0.62mmol)和4c(盐酸盐，146mg,0.93mmol)为原料，合成并纯化获得化合物7c(99mg)。
步骤三：化合物7d的合成
通过与实施例4步骤3一致的方法，使用化合物7c(80mg,0.28mmol)为原料，合成并纯化获得化合物7d(40mg)。
步骤四：化合物7e的合成
通过与实施例1步骤5一致的方法，使用化合物7d(25mg,0.1mmol)和化合物1f(36mg,0.1mmol)为原料，合成并纯化获得化合物7e(35mg)。
步骤五：化合物7的合成
通过与实施例1步骤6一致的方法，使用化合物7e(30mg,0.053mmol)和化合物1i(12mg,0.1mmol)为原料，合成并纯化获得化合物7(12mg)。
MS m/z(ESI):613.3[M+H]+.
实施例8化合物8的合成
步骤一：化合物8c的合成
将化合物8a(1.0g,4.06mmol)，化合物8b(1.17g,4.88mmol)和碳酸钾(1.69g,12.2mmol)加入到丙酮(20mL)中，混合物加热至80℃充分反应。冷却至室温后倾入水(100mL)中，用乙酸乙酯(50mL x 3)萃取，合并有机相，通过无水硫酸钠干燥，过滤后旋干，通过快速柱层析纯化(石油醚：乙酸乙酯＝4：1)得到化合物8c(520mg)。
步骤二：化合物8d的合成
将氢氧化钠(132mg,3.31mmol)加入到化合物8c(0.52g,1.66mmol)的甲醇(4mL)、四氢呋喃(8mL)和水(2mL)的混合溶液中，混合物室温充分反应。将反应液倒入水(50mL)中，用稀盐酸调节pH至3，乙酸乙酯(30mL x 3)萃取，合并的有机相通过无水硫酸钠干燥、过滤并旋干，通过快速柱层析纯化(乙酸乙酯)化合物8d(350mg)。
步骤三：化合物8e的合成
将铜粉(133mg,2.10mmol)加入到化合物8d(300mg,1.05mmol)的喹啉(3mL)溶液中，混合物加热至200℃充分反应。冷却后，倾入水(50mL)中，用稀盐酸调节pH至6-7，乙酸乙酯(20mL x 3)萃取，合并的有机相通过无水硫酸钠干燥，过滤并旋干，过快速柱层析纯化(石油醚：乙酸乙酯＝10：1)得到化合物8e(120mg)。
步骤四：化合物8f的合成
通过与实施例4步骤2一致的方法，使用化合物8e(120mg,0.5mmol)和4c(盐酸盐，121mg,0.8mmol)为原料，合成并纯化获得化合物8f(89mg)。
步骤五：化合物8g的合成
通过与实施例4步骤3一致的方法，使用化合物8f(80mg,0.28mmol)为原料，合成并纯化获得化合物8g(50mg)。
步骤六：化合物8h的合成
通过与实施例1步骤5一致的方法，使用化合物8g(50mg,0.2mmol)和化合物1f(72mg,0.2mmol)为原料，合成并纯化获得化合物8h(72mg)。
步骤七：化合物8的合成
通过与实施例1步骤6一致的方法，使用化合物8h(40mg,0.07mmol)和甲磺酰胺(19mg,0.2mmol)为原料，合成并纯化获得化合物8(27mg)。
MS m/z(ESI):583.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.91(s,1H),10.50(s,1H),8.58(s,1H),8.08(d,J＝1.9Hz,1H),8.00(d,J＝2.2Hz,1H),7.41–7.31(m,2H),7.02(d,J＝1.9Hz,1H),7.01(d,J＝2.2Hz,1H),3.50(t,J＝5.6Hz,4H),3.26–3.22(m,2H),3.19(s,3H),2.94–2.82(m,2H),2.36–2.11(m,6H),1.16–1.03(m,2H),0.42(s,4H).
实施例9化合物9的合成
步骤一：化合物9b的合成
通过与实施例7步骤1一致的方法，使用化合物9a(800mg,4.84mmol)为原料，合成并纯化获得化合物9b(550mg)。
步骤二：化合物9c的合成
通过与实施例4步骤2一致的方法，使用化合物9b(300mg,1.23mmol)和4c(盐酸盐，213mg,1.35mmol)为原料，合成并纯化获得化合物9c(250mg)。
步骤三：化合物9d的合成
通过与实施例4步骤3一致的方法，使用化合物9c(100mg,0.35mmol)为原料，合成并纯化获得化合物9d(70mg)。
步骤四：化合物9e的合成
通过与实施例1步骤5一致的方法，使用化合物9d(55mg,0.22mmol)和化合物1f(94mg,0.26mmol)为原料，合成并纯化获得化合物9e(70mg)。
步骤五：化合物9的合成
通过与实施例1步骤6一致的方法，使用化合物9e(20mg,0.035mmol)和化合物1i(8.8mg,0.07mmol)为原料，合成并纯化获得化合物9(8mg)。
MS m/z(ESI):615.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.79(s,1H),8.48(s,1H),7.87(d,J＝1.5Hz,1H),7.33(d,J＝2.2Hz,1H),7.31(d,J＝2.1Hz,1H),7.06(d,J＝1.7Hz,1H),5.01(s,4H),3.78(t,J＝6.4Hz,2H),3.39–3.38(m,2H),3.23–3.13(m,6H),2.89–2.80(m,2H),2.35–2.23(m,2H),2.18–2.08(m,4H),1.14–1.03(m,2H),0.42(s,4H).
实施例10化合物10的合成
步骤一：化合物10c的合成
通过与实施例3步骤1一致的方法，使用化合物10a(1.56g,7.07mmol)和10b(盐酸盐,1.0g,6.43mmol)为原料，合成并纯化获得化合物10c(0.76g)。
步骤二：化合物10d的合成
通过与实施例3步骤2一致的方法，使用化合物10c(710mg,2.22mmol)为原料，合成 并纯化获得化合物10d(430mg)。
步骤三：化合物10e的合成
通过与实施例3步骤3一致的方法，使用化合物10d(290mg,1.0mmol)为原料，合成并纯化获得化合物10e(140mg)。
步骤四：化合物10g的合成
通过与实施例3步骤4一致的方法，使用化合物10e(100mg,0.35mmol)和氨基甲酸叔丁酯10f(164mg,1.4mmol)为原料，合成并纯化获得化合物10g(95mg)。
步骤五：化合物10h的合成
通过与实施例3步骤5一致的方法，使用化合物10g(90mg,0.28mmol)为原料，合成并纯化获得化合物10h(55mg)。
步骤六：化合物10i的合成
通过与实施例1步骤5一致的方法，使用化合物10h(22mg,0.1mmol)和化合物1f(36mg,0.1mmol)为原料，合成并纯化获得化合物10i(17mg)。
步骤七：化合物10的合成
通过与实施例1步骤6一致的方法，使用化合物10i(17mg,0.03mmol)和化合物1i(12mg,0.1mmol)为原料，合成并纯化获得化合物10(3mg)。
MS m/z(ESI):582.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ12.74(s,1H),8.67(dd,J＝8.1,1.1Hz,1H),8.53(s,1H),7.33–7.22(m,3H),7.16(dd,J＝8.1,1.0Hz,1H),4.58(dd,J＝12.2,6.6Hz,1H),4.43(d,J＝12.0Hz,1H),3.81–3.71(m,3H),3.60–3.54(m,1H),3.24–3.19(m,2H),3.06–2.95(m,2H),2.89–2.72(m,4H),0.89–0.79(m,2H),0.38–0.27(m,4H).
实施例11化合物11的合成
步骤一：化合物11b的合成
将化合物11a(1.0g,2.8mmol)，二异丙基乙胺(1.0g,8.0mmol)和O-(7-氮杂苯并三唑-1-基)-N,N,N,N-四甲基脲六氟磷酸盐(HATU,1.28g,3.36mmol)加入到DMF(10mL)中，超声1分钟后加入化合物二乙基胺(245mg,3.36mmol)，反应混合物在室温下充分反应。向反应体系中加入水(20mL)，用乙酸乙酯(20mL x 3)萃取，合并有机相用饱和食盐水洗涤，无水硫酸镁干燥，过滤后滤液旋干，通过快速柱层析纯化(石油醚：乙酸乙酯＝7：1)得到化合物11b(352mg)。
步骤二：化合物11d的合成
-78℃下，氮气保护下将正丁基锂(1.6M,1.0mL)缓慢滴加入化合物11c(231mg,1.64mmol)的无水四氢呋喃(20mL)溶液中，混合物在-78℃下搅拌30min，将化合物11b(270mg,655μmol)的四氢呋喃(15mL)溶液缓慢滴加至上述反应液中，混合物在-78℃下继续充分反应，将DMF(239mg,3.27mmol)滴加到反应液中，混合物继续在-78℃下充分反应，加入饱和氯化铵溶液淬灭反应，并用乙酸乙酯(60mL x 3)萃取，合并有机相，无水硫酸钠干 燥，过滤并浓缩滤液得到化合物11d(330mg，粗品)。
第三步：化合物11e的合成
将水合肼(89mg,1.50mmol,85％)加入化合物11d(330mg，粗品)的乙酸(5mL)溶液中，混合物在100℃下充分反应。冷却至室温后，在真空下除去挥发物，残渣经过快速柱层析(石油醚:乙酸乙酯＝3：1)分离得到化合物11e(160mg)。
第四步：化合物11f的合成
将三氯氧磷(113mg,740μmol)加入化合物11e(70mg,184μmol)的甲苯(1mL)溶液中，混合物在120℃下充分反应。冷却至室温后，在真空下除去挥发物得到化合物11f(70mg,粗品)的粗品。
第五步：化合物11g的合成
将化合物11f(70mg,粗品)和化合物7d(44mg,175μmol)溶于叔丁醇(1mL)中，混合物在90℃下充分反应。冷却至室温后，在真空下除去挥发物，残渣经过快速柱层析(石油醚:乙酸乙酯＝7:3)分离得到化合物11g(11mg)。
步骤六：化合物11的合成
通过与实施例1步骤6一致的方法，使用化合物11g(10mg,0.016mmol)和化合物1i(12mg,0.1mmol)为原料，合成并纯化获得化合物11(2mg)。
MS m/z(ESI):613.3[M+H]+.
实施例12化合物12的合成
步骤一：化合物12c的合成
将化合物12a(0.32g,1.0mmol)，化合物12b(0.22g,2.0mmol)，醋酸钯(11mg,0.05mmol)和2-二环己基膦-2,4,6-三异丙基联苯(XPhos,48mg,0.1mmol)加入到四氢呋喃(5mL)中，在氮气氛围下加入叔丁醇钾(0.34g,3.0mmol)，反应混合物在室温下充分反应。在真空下除去挥发物，残渣经过快速柱层析(石油醚:乙酸乙酯＝4：1)得到化合物12c(230mg)。
步骤二：化合物12e的合成
将化合物12c(0.2g,0.6mmol)和化合物12d(215mg,1.0mmol)加入到DMF(1mL)中，然后加入三乙胺(0.1g,1.0mmol)，反应混合物在50℃下充分反应。在真空下除去挥发物，残渣经过快速柱层析(石油醚:乙酸乙酯＝4：1)得到化合物12e(63mg)。
步骤三：化合物12f的合成
通过与实施例3步骤5一致的方法，使用化合物12e(61mg,0.2mmol)为原料，合成并纯化获得化合物12f(25mg)。
步骤四：化合物12g的合成
通过与实施例1步骤5一致的方法，使用化合物12f(20mg,0.1mmol)和化合物1f(36mg,0.1mmol)为原料，合成并纯化获得化合物12g(16mg)。
步骤五：化合物12的合成
通过与实施例1步骤6一致的方法，使用化合物12g(16mg,0.03mmol)和化合物1i(12 mg,0.1mmol)为原料，合成并纯化获得化合物12(4mg)。
MS m/z(ESI):562.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ13.12(s,1H),10.14(br,1H),8.70(s,1H),8.25(dd,J＝7.2,1.5Hz,1H),7.46(d,J＝2.1Hz,1H),7.39(d,J＝2.1Hz,1H),7.29–7.22(m,32H),4.95(br,1H),3.79(t,J＝6.3Hz,2H),3.43(t,J＝6.4Hz,2H),3.10–3.01(m,2H),2.92–2.72(m,6H),1.01(br,2H),1.80–1.65(m,4H),0.89–0.79(m,4H),0.35(s,4H).
生物活性评价
测试例1、KIF18A酶活实验
基于ADP-GloTM Kinase Assay，检测反应中生成的ADP量来反应KIF18A酶活。
1、实验仪器及材料
实验所用人KIF18A(1-376aa)蛋白酶，由磐超生物公司表达，-80℃保存(冻融不超过5次)。
检测用试剂盒(ADP-GloTM Kinase Assay)购自Promega公司，货号为V9101，-30℃保存。试剂盒是通过测定酶反应中生成的ADP来检测酶活。KIF18A酶与ATP生成ADP，反应中剩余的ATP被ADP-Glo试剂消耗掉，KIF18A酶反应中生成的ADP则会被检测试剂还原成ATP，ATP在Ultra-GloTM荧光素酶的作用下，与荧光素反应发光，发光信号与KIF18A酶活性正相关。
实验所需其它试剂及耗材信息如下
2、实验步骤
化合物以10μM为起始浓度，连续3倍稀释，稀释10个浓度点，使用Echo仪器将化合物及纯DMSO(对照)打到384孔板的每个孔里，化合物和DMSO总体积为100nL，仪器通过不同的比例来获得梯度稀释的样品浓度。配置KIF18A酶反应缓冲液：15nM Tris，10mM MgCl2，0.01％Pluronic F-68，1μΜTaxol，和50μg/mL microtubule。KIF18A与反应缓冲液混合加入384孔板中，室温孵育15分钟后将ATP(Km 70μM))加入到混合液中，室温孵育15分钟。将10μL ADP-GloTM试剂与10μL反应混合液混匀，室温孵育40分钟。最后加入20μL ADP-GloTM检测试剂，室温孵育30分钟。使用Envision读板仪(PerkinElmer，发射波长400-700nm)测量每个孔中的化学发光信号。实验中设置1列不加化合物与酶的孔(化学发光值作为[RLU]background)，1列不加化合物的孔(化学发光值作为[RLU]enzyme)，加药组化学发光值[RLU]cpd，化合物对增殖的抑制率按以下公式计算：Inhibition rate(％)＝([RLU]enzyme-[RLU]cpd)/([RLU]enzyme–[RLU]background)×100％，化合物对酶活的抑制活性IC50值用四参数Logistic Model方法计算。下列公式中x代表化合物浓度的对数形 式；F(x)代表效应值(该浓度条件下对酶活的抑制率)：F(x)＝(A+((B-A)/(1+((C/x)^D))))。A，B，C和D为四个参数。用Xlfit将IC50值进一步计算为最佳拟合曲线中50％酶活抑制所需的化合物浓度，本公开化合物的KIF18A抑制活性见表1。
表1：本公开化合物的KIF18A抑制活性
在上表中，用于指示结合活性的符号所表示含义为：“++++”表示待测化合物对酶抑制活性IC50范围为<300nM。
测试例2:本公开化合物对OVCAR-3细胞的增殖抑制测试
细胞与材料：人卵巢癌细胞系OVCAR3购于ATCC(货号HTB-161TM)，RPMI 1640培养基(Gibco#A1049101)，青霉素-链霉素(Gibco#15140122)和0.25％Trypsin-EDTA(Gibco#25200056)购于Gibco公司(美国)，牛胰岛素(翊圣#40107ES60)购于翊圣公司，384孔板(Corning#CLS3765)购于康宁公司(美国)，Cell-Titer Glo试剂(Promega#G7568)购于普洛麦格公司(美国)。
细胞培养：OVCAR3细胞用RPMI 1640完全培养基(含20％胎牛血清，10μg/mL牛胰岛素和1％青霉素-链霉素的RPMI 1640培养基)，于37℃、5％CO2培养箱中培养，处于对数生长期细胞方可用于实验。
细胞增殖活性检测：利用Cell-Titer Glo试剂检测化合物对OVCAR3细胞株增殖的抑制。使用Echo仪器将DMSO配制的化合物及纯DMSO(对照)加入384孔板中，获得化合物以30μM为起始浓度，连续3倍稀释，共11个浓度点，加入的化合物或DMSO体积为100nL。
消化OVCAR3细胞，并用RPMI 1640完全培养基重悬，加入到384孔板中(1000个细胞/50μL/孔)，与化合物混匀，置于37℃，5％CO2培养箱中培养3天。每孔加入25μL Cell-Titer Glo试剂，震荡混匀，孵育10分钟，Multimode Plate Reader仪器检测Cell-Titer Glo读值。
设阴性对照组(Bottom)，阴性对照组为加入0.2％DMSO的培养基孔，定义为100％增殖抑制；阳性对照组(Top)为加入0.2％DMSO的OVCAR3细胞孔。
数据分析：
计算增殖抑制百分数(％Inhibition)并用四参数公式：Y＝Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope)拟合曲线，获得化合物增殖抑制IC50。
抑制百分数：％Inhibition＝(1-(Signal-Bottom)/(Top-Bottom))×100％。
Signal：加入化合物孔的Cell-Titer Glo读值；
Bottom：阴性对照孔的Cell-Titer Glo读值；
Top：阳性对照孔的Cell-Titer Glo读值。
实验结果：
本公开化合物对OVCAR3增殖抑制活性见表2。
表2：本公开化合物对OVCAR3增殖抑制活性
测试例3:本公开化合物的CYP酶抑制测试
使用150个供体混合人肝微粒体(购自Corning,货号452117)评估人主要5个CYP亚型(CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4/5)的代表性底物代谢反应。通过液相色谱串联质谱(LC/MS/MS)测定不同浓度待测化合物对非那西丁(CYP1A2)、双氯芬酸钠(CYP2C9)、S-美芬妥英(CYP2C19)、丁呋洛尔盐酸盐(CYP2D6)、咪达唑仑(CYP3A4/5)代谢反应的影响。
将30μM非那西丁、10μM双氯芬酸钠、35μM S-美芬妥英、5μM丁呋洛尔盐酸盐、3μM咪达唑仑、1mM还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)、待测化合物(浓度分别为0.1、0.3、1、3、10、30μmol/L)或阳性化合物或空白对照与混合人肝微粒体(0.2mg/mL)的反应体系200μL(100mmol/L磷酸盐缓冲液，pH 7.4，含体积比分别为0.3％的DMSO、0.6％的乙腈、0.1％的甲醇)在37℃孵育5分钟。然后加入200μL含3％甲酸及40nM内标维拉帕米的乙腈溶液，4000rpm离心50分钟。置于冰上冷却20分钟，再4000rpm离心20分钟析出蛋白。取200μL上清液进行LC-MS/MS分析。
峰面积根据色谱图计算。
残余活性比例(％)用如下公式进行计算：
峰面积比例＝代谢产物峰面积/内标峰面积
残余活性比例(％)＝待测化合物组的峰面积比例/空白组的峰面积比例
CYP半数抑制浓度(IC50)通过Excel XLfit 5.3.1.3计算得到。
测试例4:Caco-2渗透性实验
通过Caco-2细胞模型利用液相色谱串联质谱(LC-MS/MS)测定分析药物的表观渗透系数(Papp)。
该测试例中，Caco-2细胞购自美国典型菌种保藏中心(ATCC)，4-羟乙基哌嗪乙磺酸(HEPES)购自北京索莱宝科技有限公司，汉克平衡盐溶液(HBSS)和非必需氨基酸(NEAA)购自赛默飞世尔科技公司，青霉素、链霉素和胰蛋白酶/EDTA购自索莱宝公司，胎牛血清(FBS)和DMEM培养基购自Corning公司，HTS-96孔Transwell板和其他无菌耗材购自Corning公司，Millicell电阻测定系统购自Millipore，购自Nexcelom Bioscience，Infinite 200 PRO酶标仪购自Tecan，MTS2/4 orbital摇床购自IKA Labortechnik。
第一步细胞培养和种板
将Caco-2培养于细胞培养瓶。培养箱设置为37℃、5％CO2、保证相对湿度95％。细胞汇合度达到70-90％时可用于接种Transwell。细胞接种前，向Transwell上室每孔中加入50μL 细胞培养基，下层培养板内加入25mL细胞培养基。将培养板置于37℃,5％CO2培养箱内孵育1小时后可用于接种细胞。细胞消化后，吸取细胞混悬液转移至圆底离心管120g离心5分钟。使用培养基重悬细胞，终浓度为6.86×105cells/mL(个细胞/mL)。将细胞悬液以50μL每孔加入到96孔Transwell培养板上室中，最终接种密度为2.4×105cells/cm2。接种后24小时开始换液，培养14-18天，隔一天换一次培养基。更换培养基过程如下：将Transwell小室与接收板分开，先弃掉接收板中培养基然后再弃掉Transwell小室培养基，最后每个小室加入75μL新鲜培养基，接收板加入25mL新鲜培养基。
第二步细胞单层膜完整性的评价
Caco-2经过大约14天培养后，达到汇合并完成分化。此时，可应用于穿透试验。用电阻仪(Millipore，USA)测量单层膜电阻，记录每孔电阻。测定结束后，将Transwell培养板放回培养箱。电阻值的计算：测定电阻值(ohms)×膜面积(cm2)＝TEER值(ohm·cm2)，若TEER值<230ohms·cm2，则该孔不能用于穿透试验。
第三步溶液配制
分别称取2.38g HEPES，0.35g碳酸氢钠，加900mL纯水让其溶解，然后加100mL 10×HBSS搅拌均匀，调pH至7.4，最后过滤得1L转运缓冲液(HBSS，10mM HEPES，pH 7.4)。
将1mM的待测受试化合物的DMSO溶液物储备液用转运缓冲液稀释得到5μM测试溶液。对照化合物地高辛或者米诺地尔用DMSO稀释到2mM，并用上述转运缓冲液稀释至10μM，得对照化合物测试溶液。另外，DMSO也用上述转运缓冲液稀释至含0.5％DMSO的接收端溶液。
第四步药物穿透试验
从培养箱中取出Transwell培养板。使用转运缓冲溶液(10mM HEPES,pH 7.4)缓冲液润洗细胞单层膜两次，37℃条件下孵育30分钟。
测定化合物由顶端到基底端的转运速率。向上层小室(顶端)每孔加入125μL测试溶液，并立即从顶端转移50μL溶液至200μL含内标(0.1μM甲苯磺丁脲)的乙腈中作为顶端到基底的初始样本。下层小室(基底端)每孔加入235μL接收端溶液。
测定化合物由基底端到顶端的转运速率。向上层小室(顶端)每孔加入285μL接收端溶液，并立即从顶端转移50μL溶液至200μL含内标(0.1μM甲苯磺丁脲)的乙腈中作为基底到顶端的初始样本。下层小室(基底端)每孔加入75μL测试溶液。
将上下的转运装置合并后，37℃条件下孵育2小时。
孵育完成后，分别从Transwell培养板上室和下室每孔取样50μL加入到新的样品管中。向样品管内加入200μL含内标(0.1μM甲苯磺丁脲)的乙腈，涡旋10分钟后，于3220g离心40分钟。吸取上清液150μL，与150μL水稀释之后进行LC-MS/MS分析。所有样品进行三次平行制备。
用荧光黄的渗漏评价孵育2小时后细胞单层膜的完整性，使用转运缓冲溶液(10mM HEPES，pH 7.4)稀释荧光黄储备液至最终浓度100μM。在上侧的Transwell插板的每个孔中加入荧光黄溶液100μL，下侧接收板的每个孔中加300μL转运缓冲溶液(10mM HEPES,pH 7.4)。37℃下孵育30分钟后，分别从每孔上下层吸出80μL溶液至一个新的96孔板中。使用酶标仪，激发波长485nm和发射波长530nm条件下进行荧光测定。
第五步数据分析
所有的计算都是使用微软Excel进行。用提取的离子色谱图测定峰面积。
表观渗透系数(Papp，单位：cm/s×10-6)用以下公式计算得出：
公式中：VA为接收端溶液的体积(Ap→Bl是0.3mL，Bl→Ap是0.1mL)，Area(膜面积) 为Transwell-96孔板膜面积(0.143cm2)；time(时间)为孵育时间(单位：s)；[drug]receiver([药物]接收端)为接收端药物浓度；[drug]initial，donor([药物]初始，供体)为给药端初始药物浓度。
外排率(Efflux ratio)使用以下的公式计算得出：
公式中：Papp(B-A)为由基底端到顶端的表观渗透系数；
Papp(A-B)为由顶端到基底端的表观渗透系数。
回收率("Percentage recovery"(％))使用以下的公式计算得出：
公式中：VA为接收端的溶液体积(单位：mL)；VD为给予端的溶液体积(单位：mL)。
渗漏率(Percentage leakage(％)或LY(％))使用以下的公式计算得出：
公式中：Ireceiver(I接收端)是指接收孔(0.3mL)的荧光密度，Idonor(I供体)是指加药孔(0.1mL)的荧光密度，用LY(％)表示。LY<1.5％表示单层细胞膜完好。对于个别LY>1.5％
的情况，如果Papp值和其它平行接近，基于科学的判断，最终数据可以采纳。
测试例5:大鼠肝细胞体外代谢稳定性检测
利用LC/MS/MS测定反应体系中的化合物浓度，以此来计算待测化合物的固有清除率，并评估在大鼠肝细胞中的体外代谢稳定性。
将198μL 0.5×106细胞/mL的大鼠肝细胞混合液和2.0μL 100μM的待测化合物或阳性对照加入孵育板起始反应。以37℃和900rpm进行孵育。分别在0，15，30，60，90和120分钟转移25μL孵育体系到终止板(每孔有150μL含100nM阿普唑仑、200nM咖啡因和100nM甲苯磺丁酰胺的乙腈)上。之后用涡旋混匀5分钟。在3220g的条件下将终止板离心45分钟。转移每个化合物的上清液100μL至96孔进样板中，之后加入100μL纯水稀释样品。
所得样品由离子色谱图定量。根据待测化合物或阳性对照的峰面积来计算残余率。斜率k使用Microsoft Excel由剩余率的自然对数值对孵育时间的线性回归测定。
固有清除率(in vitro CLint，μL/min/106细胞)根据下列等式由斜率值k计算：
in vitro CLint＝-kV/N
V＝孵育体积(0.25mL)；
N＝每个孔的细胞数(0.125×106细胞)
测试例6:人肝细胞体外代谢稳定性检测
利用LC/MS/MS测定反应体系中的化合物浓度，以此来计算待测化合物的固有清除率，并评估在人肝细胞中的体外代谢稳定性。
将198μL 0.5×106细胞/mL的人肝细胞混合液和2.0μL 100μM的待测化合物或阳性对照加入孵育板起始反应。以37℃和900rpm进行孵育。分别在0，15，30，60，90和120分钟转移25μL孵育体系到终止板(每孔有150μL含100nM阿普唑仑、200nM咖啡因和100nM甲苯磺丁酰胺的乙腈)上。之后用涡旋混匀5分钟。在3220g的条件下将终止板离心45分钟。 转移每个化合物的上清液100μL至96孔进样板中，之后加入100μL纯水稀释样品。
所得样品由离子色谱图定量。根据待测化合物或阳性对照的峰面积来计算残余率。斜率k使用Microsoft Excel由剩余率的自然对数值对孵育时间的线性回归测定。
测试表明，本公开化合物具有较好的代谢稳定性。
固有清除率(in vitro CLint，μL/min/106细胞)根据下列等式由斜率值计算：
in vitro CLint＝-kV/N
V＝孵育体积(0.25mL)；
N＝每个孔的细胞数(0.125×106细胞)
测试例7:化合物固体溶解度(PBS pH 7.4)测试
利用LC/MS/MS测定待测化合物固体在PBS pH 7.4的溶解度。
准确称取约1毫克的每种化合物的粉末到玻璃小瓶中，加入DMSO，体积为1mL每毫克化合物。每瓶加入1个搅拌子，并将溶解度样品瓶在25℃、1100转/分钟条件下振荡2小时，使粉末完全溶解配置成1mg/mL待测样品溶液。取5μL 1mg/mL的溶液与5μL PBS pH 7.4溶液混合于490μL含有内标的水和乙腈(1:1)中，配置成10μg/mL的待测样品标准浓度溶液。再取10μL 10μg/mL的溶液稀释于90μL含有内标的水和乙腈(1:1)中，配置成1μg/mL的待测样品标准浓度溶液。标准溶液的稀释倍数可以LC/MS响应信号强弱调整。
准确称取约1毫克的每种化合物的粉末到玻璃小瓶中，加入PBS pH 7.4溶液，体积为1mL每毫克化合物。每瓶加入1个搅拌子，并将溶解度样品瓶在25℃、1100转/分钟条件下振荡24小时。振荡结束后，取出搅拌子，将样品转移到滤板上用真空歧管过滤。过滤后的滤液用含有内标的水和乙腈的混合物(1:1)稀释。稀释因子可根据溶解度值和LC/MS响应信号强弱调整。
所得样品经LC/MS/MS检测。根据待测化合物溶液和标准浓度溶液的峰面积来计算样品溶解度。计算公式如下：
[Sample]([样品])为待测样品的溶解度；
Area ratiosample(面积比样品)为待测样品中样品峰面积与内标峰面积的比值；
INJ VOL STD为标准浓度溶液进样体积；
DFsample(DF样品)为待测样品溶液稀释倍数；
[STD]为标准浓度溶液的浓度；
INJ VOLsample(INJ VOL样品)为待测样品溶液进样体积；
Area ratio STD(面积比STD)为标准浓度溶液中样品峰面积与内标峰面积的比值。
测试例8:化合物溶解度(PBS pH 7.4)测试
利用LC/MS/MS测定待测化合物在PBS pH 7.4的溶解度。
取6μL 10mM的待测化合物DMSO溶液与194μLDMSO混合，配置成300μM的化合物溶液。取5μL该溶液与5μL PBS pH 7.4溶液混合于490μL含有内标的水和乙腈(1:1)中，配置成3μM的待测样品标准浓度溶液。标准溶液的稀释倍数可以LC/MS响应信号强弱调整。
取15μL 10mM的待测化合物DMSO溶液，加入到485μL PBS pH 7.4溶液中。加入搅拌子，并将溶解度样品瓶在25℃、1100转/分钟条件下振荡2小时。振荡结束后，取出搅拌子，将样品转移到滤板上用真空歧管过滤。取5μL滤液与5μL PBS pH 7.4溶液混合于490μL 含有内标的水和乙腈(1:1)中，配置成待测溶液。稀释因子可根据溶解度值和LC/MS响应信号强弱调整。
所得样品经LC/MS/MS检测。根据待测化合物溶液和标准浓度溶液的峰面积来计算样品溶解度。计算公式如下：
[Sample]为待测样品溶解度；
Area ratiosample为待测样品中样品峰面积与内标峰面积的比值；
INJ VOL STD为标准浓度溶液进样体积；
DFsample为待测样品溶液稀释倍数；
[STD]为标准浓度溶液的浓度；
INJ VOLsample为待测样品溶液进样体积；
Area ratio STD为标准浓度溶液中样品峰面积与内标峰面积的比值。
测试例9:本公开化合物的大鼠体内药代动力学测试
以SD大鼠为受试动物，应用LC/MS/MS法测定了大鼠静脉注射以及灌胃给予本公开化合物后不同时刻血浆中的药物浓度。研究本公开化合物在大鼠体内的药代动力学行为，评价其药动学特征。
每组健康6-8周雄性SD大鼠3只。
静脉注射给药：称取一定量药物，加10％体积的N,N-二甲基乙酰胺、33％体积的三甘醇和57％体积的生理盐水配制成1mg/mL的无色澄清透明液体；
灌胃给药：称取一定量药物，加0.5％质量的羟丙甲纤维素、0.1％体积的吐温80和99.6％体积的生理盐水配制成1mg/mL的白色悬浊液。
SD大鼠禁食过夜后，静脉注射给药或者灌胃给药。
大鼠静脉注射给药本公开化合物，给药后0.083、0.25、0.5、1、2、4、8、24小时由颈静脉采血0.2mL，置于含EDTA-K2的试管中，4℃，4000转/分钟离心5分钟分离血浆，于-75℃保存。
或者大鼠灌胃给药本公开化合物，给药后0.25、0.5、1、2、4、8、24小时由颈静脉采血0.2mL，置于含EDTA-K2的试管中，4℃，3500转/分钟离心10分钟分离血浆，于-75℃保存。
测定不同浓度的药物灌胃给药后大鼠血浆中的待测化合物含量：取给药后各时刻的大鼠血浆30μL，加入内标地塞米松的乙腈溶液200μL(50ng/mL)，涡旋混合30秒，4℃，4700转/分钟离心15分钟，血浆样品取上清液加水稀释三倍，取2.0μL进行LC-MS/MS分析。
测试例10:在DPX2细胞中PXR激活潜在可能性的体外评估
配制待测化合物和对照化合物利福平溶液的DMSO溶液，并用Puracyp dosing medium(Puracyp，货号D-500-100)在37℃下稀释至各自的测试浓度。最终待测化合物浓度分别为30μM，10μM和1μM，利福平的最终浓度为20μM。测试液中DMSO的最终浓度为0.1％。另外用Puracyp dosing medium配置0.1％的DMSO溶液作为对照品。
将DPX2细胞悬浮在Puracyp Culture medium(Puracyp，货号C-500-100)中，细胞密度在4.5*105cell/mL。每孔取100μL置于96孔培养板上，37℃孵育24小时。用100μL的待测化合物溶液和对照化合物溶液替换96孔培养板适当孔中的培养基，每孔重复3次。置换完成后，37℃孵育24小时。再次用新配置的待测化合物测试液和利福平测试液置换培养基，每孔3次，并继续37℃孵育24小时。
将96孔培养板中的培养基吸出，并用PBS清洗两次。每孔加入50μL CellTiter-FluorTM细胞活力测定试剂盒(Promega，货号G6082)中按要求稀释后的试剂，并在37℃孵育0.5小时。将96孔板冷却至室温，在400nm激发波长下下，用酶标仪在荧光模式下测量每个孔 的在505nm的荧光值。再于每孔中加入50μL One-Glo荧光素酶测定系统(Promega，货号E6120)中按要求配置好的试剂，室温孵育5分钟。用流明计读出每孔的发光值。
归一化荧光素酶活性由RLU/RFU决定，其中RLU是指在每个剂量下，每个测试化合物的相对发光单位，RFU是指每个剂量下，每个测试化合物的相对荧光单位。样品的RLU和RFU分别为双复孔的平均值。
阳性对照百分比计算如下:
％Positive control＝(fold activationtest compound-1)/(fold activationpositive control compound-1)*100％
Fold of activation为待测样品对PXR激活倍数；
RLUsample为待测样品的相对发光强度；
RFUsample为待测样品的相对荧光强度；
RLUvehicle为空白对照的相对发光强度；
RFUvehicle为空白对照的相对荧光强度；
Positive control为待测化合物相对阳性化合物(利福平)对PXR的激活率。

Claims (18)

  1. 式(I)所示化合物或其药学上可接受的盐：
    其中，
    X1选自N、O、S、NR4或CR4；
    X2选自N或CR4，或者X2不存在；
    X3、X4各自独立地选自N或C；
    X5、X6各自独立地选自N或CR4；
    每一个R4独立地选自H、卤素、C1-C6烷基、OH、NH2、O(C1-C4烷基)、NH(C1-C4烷基)或N(C1-C4烷基)2，所述C1-C6烷基、O(C1-C4烷基)、NH(C1-C4烷基)或N(C1-C4烷基)2任选被一个或多个R4b取代；
    R1选自H或C1-C6烷基，所述C1-C6烷基任选被一个或多个卤素取代；
    环A选自C6-C20芳基、5-20元杂芳基或4-20元杂环基，所述C6-C20芳基、5-20元杂芳基或4-20元杂环基任选被一个或多个R1a取代；
    R3选自L1-L2-Ry，L1选自-NR5-、-O-、-S-、-S(＝O)-、-SO2-、-C(＝O)-、-NR5SO2-、-NR5(C＝O)-、-S＝N-、-NR5-S(＝O)(＝NR5)-、-S(＝O)(＝NR5)-、所述R5选自H或C1-C4烷基，所述R5a、R5b各自独立地选自C1-C4烷基、C3-C6环烷基或4-7元杂环基，或者所述R5a、R5b以及它们连接的原子共同形成4-7元杂环基，L2选自化学键或C1-C4亚烷基，Ry选自H、C3-C6环烷基或4-7元杂环基，上述每一个C1-C4烷基、C1-C4亚烷基、C3-C6环烷基或4-7元杂环基任选被一个或多个R3b取代；
    R2选自OH、NH2、C1-C10烷基、C3-C10环烷基、C2-C10炔基、 其中，
    所述OH、NH2、C1-C10烷基、C3-C10环烷基或C2-C10炔基任选被一个或多个R2b取代；
    n、m1、m2、p各自独立地选自0、1或2；
    i、j、k各自独立地选自0、1、2、3、4、5或6；
    Rx1和Rx2以及它们连接的碳原子共同形成C3-C6环烷基、C3-C6环烯基或4-7元杂环基，所述C3-C6环烷基、C3-C6环烯基或4-7元杂环基任选被一个或多个R2b取代；
    环Q选自C3-C6环烷基、C3-C6环烯基或4-7元杂环基，所述C3-C6环烷基、C3-C6环烯基或4-7元杂环基任选被一个或多个R2b取代；
    Y1选自O、S或NH；
    所述任选被一个或多个Rx取代，每一个Rx独立地选自卤素、CN、OH、NH2、C1-C6烷基、C3-C6环烷基或4-7元杂环基，所述OH、NH2、C1-C6烷基、C3-C6环烷基或4-7元杂环基任选被一个或多个Rxb取代，当上的同一个碳原子同时被两个Rx取代时，所述两个Rx还可以与该碳原子共同形成C3-C10环烷基、C3-C10环烯基或4-10元杂环基，所述C3-C10环烷基、C3-C10环烯基或4-10元杂环基任选被一个或多个Rxb取代；
    每一个R1a独立地选自卤素、CN、OH、NH2、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、C5-C10环烯基、4-10元杂环基、C6-C10芳基或5-10元杂芳基，所述OH、NH2、C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C10环烷基、C5-C10环烯基、4-10元杂环基、C6-C10芳基或5-10元杂芳基任选被一个或多个R1b取代；
    每一个R1b、R2b、R3b、R4b、Rxb独立地选自卤素、CN、OH、NH2、C1-C6烷基、C3-C6环烷基、4-7元杂环基、O(C1-C4烷基)、NH(C1-C4烷基)或N(C1-C4烷基)2，所述C1-C6烷基、C3-C6环烷基、4-7元杂环基、O(C1-C4烷基)、NH(C1-C4烷基)或N(C1-C4烷基)2任选被一个或多个Rc取代；
    每一个Rc独立地选自卤素、CN、OH、NH2、C1-C6烷基、C3-C6环烷基、4-7元杂环基、O(C1-C4烷基)、NH(C1-C4烷基)或N(C1-C4烷基)2；
    并且，当X2选自N或CR4时，其中：
    环A选自C9-C10芳基、5元杂芳基、吡啶酮基、氮杂吡啶酮基、8-14元双环或三环杂环基、12-20元四环杂环基或8-14元双环或三环杂芳基，所述C9-C10芳基、5元杂芳基、吡啶酮基、氮杂吡啶酮基、8-14元双环或三环杂环基、12-20元四环杂环基或8-14元双环或三环杂芳基任选被一个或多个R1a取代；和/或，
    R2选自OH、NH2、C1-C10烷基、C3-C10环烷基、C2-C10炔基、 所述OH、NH2、C1-C10烷基、C3-C10环烷基或C2-C10炔基任选被一个或多个R2b取代，n、m1、m2、p各自独立地选自0、1或2，i、j、k各自独立地选自0、1、2、3、4、5或6，Rx1和Rx2以及它们连接的碳原子共同形成C3-C6环烷基、C3-C6环烯基或4-7元杂环基，所述C3-C6环烷基、C3-C6环烯基或4-7元杂环基任选被一个或多个R2b取代，环Q选自C3-C6环烷基、C3-C6环烯基或4-7元杂环基，所述C3-C6环烷基、C3-C6环烯基或4-7元杂环基任选被一个或多个R2b取代，Y1选自O、S或NH；和/或，
    R3选自L1-L2-Ry，L1选自-NR5-、-O-、-S-、-S(＝O)-、-SO2-、-C(＝O)-、-NR5SO2-、-NR5(C＝O)-、-S＝N-、-NR5-S(＝O)(＝NR5)-或-S(＝O)(＝NR5)-，R5选自H或C1-C4烷基，L2选自任选被一个或多个R3b取代的C1-C4亚烷基，Ry选自任选被一个或多个R3b取代的C3-C6环烷基或4-7元杂环基。
  2. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，X2 不存在，X1选自N、O、S或NR4，所述R4选自H或C1-C6烷基；或者，
    X1、X2各自独立地选自N或CR4，所述R4选自H或C1-C6烷基；或者，
    X1、X2各自独立地选自N或CH。
  3. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，结构单元选自 或者，
    结构单元选自
  4. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，R1选自H或C1-C6烷基。
  5. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，R3选自L1-L2-Ry，L1选自-NH-、-O-、-S-、-S(＝O)-、-SO2-、-C(＝O)-、-NHSO2-、-NH(C＝O)-或所述R5a、R5b各自独立地选自C1-C4烷基，或者所述R5a、R5b以及它们连接的原子共同形成4-7元杂环基，L2选自化学键或C1-C4亚烷基，Ry选自H、C3-C6环烷基或4-7元杂环基，上述每一个C1-C4烷基、C1-C4亚烷基、C3-C6环烷基或4-7元杂环基任选被一个或多个R3b取代，每一个R3b独立地选自卤素、CN、OH或NH2；或者，
    R3选自L1-L2-Ry，L1选自-NH-、-O-、-S-、-S(＝O)-、-SO2-、-(C＝O)-、-NHSO2-或-NH(C＝O)-，L2选自C1-C4亚烷基，Ry选自H，所述C1-C4亚烷基任选被一个或多个卤素、CN、OH或NH2取代；或者，
    R3选自L1-L2-Ry，L1选自-NHSO2-，L2选自C1-C4亚烷基，Ry选自H，所述C1-C4亚烷基任选被一个或多个卤素或OH取代；或者，
    R3选自 或者，
    R3选自
  6. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，R2选自其中：
    所述任选被一个或多个Rx取代，当上的同一个碳原子同时被两个Rx取代时，所述两个Rx还可以与该碳原子共同形成C3-C6环烷基、C3-C6环烯基或4-7元杂环基，所述C3-C6环烷基、C3-C6环烯基或4-7元杂环基任选被一个或多个Rxb取代；或者，
    R2选自其中：
    所述中的*碳原子同时被两个Rx取代，所述两个Rx与该*碳原子共同形成C3-C6环烷基、C3-C6环烯基或4-7元杂环基，所述C3-C6环烷基、C3-C6环烯基或4-7元杂环基任选被一个或多个Rxb取代；或者，
    R2选自其中：
    所述中的*碳原子同时被两个Rx取代，所述两个Rx与该*碳原子共同形成C3-C6环烷基，所述C3-C6环烷基任选被一个或多个Rxb取代；或者，
    R2选自或者，
    R2选自
  7. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，环A选自C6-C10芳基、5-10元杂芳基、11-14元三环杂芳基、8-14元双环杂环基、11-14元三环杂环基或12-20元四环杂环基，所述C6-C10芳基、5-10元杂芳基、11-14元三环杂芳基、8-14元双环杂环基、11-14元三环杂环基或12-20元四环杂环基任选被一个或多个R1a取代；或者，
    环A选自苯基、5-10元杂芳基、11-14元三环杂环基、11-14元三环杂芳基或12-20元四环杂环基，所述苯基、5-10元杂芳基、11-14元三环杂环基、11-14元三环杂芳基或12-20元四环杂环基任选被一个或多个R1a取代；或者，
    环A选自苯基、5-10元杂芳基、11-14元三环杂环基或11-14元三环杂芳基，所述苯基、5-10元杂芳基、11-14元三环杂环基或11-14元三环杂芳基任选被一个或多个R1a取代；或者，
    环A选自任选被一个或多个R1a取代的以下基团：苯基、嘧啶基、 或者，
    环A选自 或者，
    环A选自
  8. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，当X2选自N或CR4时，所述环A选自C9-C10芳基、8-14元双环或三环杂环基、12-20元四环杂环基、8-14元双环或三环杂芳基，所述C9-C10芳基、8-14元双环或三环杂环基、12-20元四环杂环基、8-14元双环或三环杂芳基任选被一个或多个R1a取代；和/或，
    R2选自和/或，
    R3选自L1-L2-Ry，其中，L1选自-NR5-、-O-、-S-、-S(＝O)-、-SO2-、-(C＝O)-、-NR5SO2-或-NR5(C＝O)-，R5选自H或C1-C4烷基，L2选自任选被一个或多个R3b取代的C1-C4亚烷基，Ry选自任选被一个或多个R3b取代的C3-C6环烷基或4-7元杂环基。
  9. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，当X2选自N或CR4时，环A选自 所述 任选被一个或多个R1a取代，每一个R1a独立地选自C1-C6烷基或4-7元杂环基，所述C1-C6烷基或4-7元杂环基任选被一个或多个卤素(例如F)取代，优选地，环A选自 和/或，
    R2选自优选地，R2选自
  10. 根据权利要求1-9任一项所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，n、m1、m2、p各自独立地选自0、1或2；或者
    n、m1、p各自独立地选自1，m2选自0。
  11. 根据权利要求1-10任一项所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，i、j、k各自独立地选自0、1、2或3。
  12. 根据权利要求1-11任一项所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，Rx1和Rx2以及它们连接的碳原子共同形成C3-C6环烷基或4-7元杂环基，所述C3-C6环烷基或4-7元杂环基任选被一个或多个R2b取代。
  13. 根据权利要求1-12任一项所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，环Q选自C3-C6环烷基或4-7元杂环基，所述C3-C6环烷基或4-7元杂环基任选被一个或多个R2b取代。
  14. 根据权利要求1-13任一项所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，R2b选自卤素、CN、OH、NH2、C1-C6烷基、C3-C6环烷基或4-7元杂环基，所述C1-C6烷基、C3-C6环烷基或4-7元杂环基任选被一个或多个卤素或CN取代；或者
    R2b选自C1-C4烷基，所述C1-C4烷基任选被一个或多个卤素(例如F)取代。
  15. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其特征在于，所述化合物选自以下结构之一：



  16. 一种药物组合物，所述组合物包含权利要求1至15任一项的化合物或其药学上可接受的盐和药学上可接受的辅料。
  17. 权利要求1至15任一项的化合物或其药学上可接受的盐、或权利要求16所述的药物组合物在制备用于预防或者治疗KIF18A相关疾病的药物中的用途；优选地，所述KIF18A相关疾病为肿瘤。
  18. 一种治疗KIF18A相关疾病的方法，该方法包括给以患者治疗有效量的如权利要求1至15任一项所述的化合物或其药学上可接受的盐、或权利要求16所述的药物组合物。
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WO2020132649A1 (en) * 2018-12-20 2020-06-25 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
WO2021026100A1 (en) * 2019-08-02 2021-02-11 Amgen Inc. Pyridine derivatives as kif18a inhibitors
CN114269731A (zh) * 2019-08-02 2022-04-01 美国安进公司 Kif18a抑制剂
WO2022268230A1 (zh) * 2021-06-25 2022-12-29 杭州英创医药科技有限公司 作为kif18a抑制剂的化合物
CN116514777A (zh) * 2022-05-13 2023-08-01 上海湃隆生物科技有限公司 驱动蛋白kif18a抑制剂及其应用

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WO2020132649A1 (en) * 2018-12-20 2020-06-25 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
WO2021026100A1 (en) * 2019-08-02 2021-02-11 Amgen Inc. Pyridine derivatives as kif18a inhibitors
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