WO2025201531A1 - Composé tricyclique et son utilisation - Google Patents

Composé tricyclique et son utilisation

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Publication number
WO2025201531A1
WO2025201531A1 PCT/CN2025/085858 CN2025085858W WO2025201531A1 WO 2025201531 A1 WO2025201531 A1 WO 2025201531A1 CN 2025085858 W CN2025085858 W CN 2025085858W WO 2025201531 A1 WO2025201531 A1 WO 2025201531A1
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Prior art keywords
alkyl
membered
ring
deuterium
alkoxy
Prior art date
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Pending
Application number
PCT/CN2025/085858
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English (en)
Chinese (zh)
Inventor
陈洁
刘志强
吴雨航
谢德伟
陈斌
王绍晖
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Zhongge Biological Technology Co Ltd
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Shenzhen Zhongge Biological Technology Co Ltd
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Publication of WO2025201531A1 publication Critical patent/WO2025201531A1/fr
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Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicinal chemistry, and specifically relates to a tricyclic compound and its use.
  • CIN Chromosomal instability
  • Kinesins are molecular motors that play important roles in cell division and the transport of intracellular vesicles and organelles. Mitotic kinesins play a role in multiple aspects of spindle assembly, chromosome segregation, centrosome separation, and dynamics. Human kinesins are classified into 14 subfamilies based on sequence homology within the motor domain. KIF18A, a member of the kinesin-8 family, is specifically expressed during the G2/M phase of mitosis and plays a key role in maintaining bipolar spindle integrity during cell division, thereby regulating chromosome positioning. KIF18A uses energy released by ATP hydrolysis to move along microtubules toward the positive pole within the cell.
  • microtubule dynamic instability Localized at the positive end of microtubules, it regulates microtubule dynamic instability, exerting an activity similar to that of a microtubule depolymerase.
  • KIF18A regulates spindle microtubule dynamics and chromosome amplitude, playing a crucial role in the timely alignment of chromosomes during mitosis, maintaining genomic stability, and successfully completing mitosis.
  • KIF18A is an important factor affecting the proliferation of CIN tumor cells.
  • tumor cells with CIN characteristics exhibit mitotic fragility associated with spindle assembly checkpoint (SAC) activation, multipolar spindle formation, and induction of apoptosis, leading to mitotic arrest, cell cycle arrest, and apoptosis.
  • SAC spindle assembly checkpoint
  • KIF18A is an essential gene for abnormal somatic cell division, but CIN tumor cells are highly sensitive to KIF18A knockout. Therefore, small molecule inhibitors of KIF18A can selectively target tumor cells with CIN characteristics. Compared with other drugs targeting mitotic mechanisms, KIF18A inhibition does not affect the proliferation of normal cells.
  • the present application provides a compound of formula (I) or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs,
  • L is selected from *-NR 2 -CO-, *-CO-NR 2 -, *-NR 2 CONR 2 - or a 5-6 membered heteroaryl group, where * represents connection with ring A;
  • R2 is selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl;
  • R x1e and R x1f are each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, and C1-C6 haloalkyl;
  • X 2 , X 3 , and X 4 are selected from N or CR 3 ;
  • R 3 is each independently selected from hydrogen, deuterium, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyC1-C6 alkyl, -OR 3a , -SR 3a , -NR 3b R 3c , -C(O)NR 3b R 3c , -NR 3e C(O)R 3e , -C(O)R 3e , -C(O)OR 3e , -OC(O)R 3e , -S(O)R 3e , -S(O) 2 R 3e , C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-9 membered heterocyclyl, or two R 3 and the atoms to which they are attached combine to form a 5-10 membered ring;
  • R 3b , R 3c are each independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyC1-C6 alkyl, or R 3b , R 3c and the nitrogen atom to which they are attached together form a 3-7 membered heterocyclic ring, wherein the 3-7 membered heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, thiol, oxo, thioxo, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) 2 ;
  • R 1a is each independently selected from hydrogen, deuterium, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, 4-9 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 aryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 4-9 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 aryl is optionally substituted with deuterium, halogen, cyano, amino, hydroxy, carboxyl, thiol, C1-C6 alkyl, C1-C6 alkoxy, hydroxyC1-C6 alkyl, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) 2 , C3-C8 cycloalkyl, 4-9 membered heterocyclyl, -S(O)(C1-C6 al
  • R 1b is each independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, C3-C8 cycloalkyl or 4-9 membered heterocyclyl;
  • n is selected from 0, 1, 2, or 3;
  • n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • R x is not
  • X 2 , X 3 , X 4 , R 1 , R x , L, Ra , R b , R c , m, and n are as defined above.
  • the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs,
  • Rx is selected from C3-C8 membered monocyclic cycloalkenyl, C6-C11 spirocyclic cycloalkenyl, C6-C11 fused ring cycloalkenyl, C6-C11 bridged ring cycloalkenyl, 4-7 membered monocyclic heterocyclyl, 6-11 membered spirocyclic heterocyclyl, 6-11 membered fused ring heterocyclyl, 6-11 membered bridged ring heterocyclyl; the C3-C8 membered monocyclic cycloalkenyl, C6-C11 spirocyclic cycloalkenyl, C6-C11 fused ring cycloalkenyl, C6-C11 bridged ring cycloalkenyl, 6-11 membered spirocyclic heterocyclyl, 6-11 membered fused ring heterocyclyl, 6-11 membered bridged ring heterocyclyl are each independently
  • R x1a are each independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl;
  • R x1b and R x1c are each independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyC1-C6 alkyl, or R x1b , R x1c and the nitrogen atom to which they are attached together form a 3-7 membered saturated or partially unsaturated heterocyclic ring, which is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, thiol, oxo, thioxo, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl);
  • RX is selected from 4-7 membered monocyclic heterocyclyl, 6-11 membered spirocyclic heterocyclyl;
  • R x1e and R x1f are each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, and C1-C6 haloalkyl;
  • R x1a are each independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, hydroxy C1-C6 alkyl;
  • RX is selected from 4-7 membered monocyclic heterocyclyl, 6-11 membered spirocyclic heterocyclyl;
  • R x1e and R x1f are each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, and C1-C6 haloalkyl.
  • R x is selected from C8-C11 spirocyclic cycloalkenyl, C8-C11 fused-ring cycloalkenyl, C7-C9 bridged-ring cycloalkenyl, 6-9-membered bridged-ring heterocyclyl, 6-9-membered spirocyclic heterocyclyl; the 6-9-membered bridged-ring heterocyclyl and 6-9-membered spirocyclic heterocyclyl contain at least one N atom; the C8-C11 spirocyclic cycloalkenyl, C8-C11 fused-ring cycloalkenyl, C7-C9 bridged-ring cycloalkenyl, 6-9-membered bridged-ring heterocyclyl and 6-9-membered spirocyclic heterocyclyl are each independently optionally substituted by one or more R x1 , each R x1 being independently selected from deuterium, halogen,
  • Rx is selected from C8-C11 spirocyclic cycloalkenyl, C8-C10 fused-ring cycloalkenyl, C7-C9 bridged-ring cycloalkenyl, 6-9-membered bridged-ring heterocyclyl, 6-9-membered spirocyclic heterocyclyl; the 6-9-membered bridged-ring heterocyclyl, 6-9-membered spirocyclic heterocyclyl contains at least one N atom; the cycloalkenyl is connected to ring D through an alkenyl group, and the 6-9-membered bridged-ring heterocyclyl and 6-9-membered spirocyclic heterocyclyl are connected to ring D through a N atom; the C8-C11 spirocyclic cycloalkenyl, C8-C10 fused-ring cycloalkenyl, C7-C9 bridged-ring cycloalkenyl;
  • R x1b and R x1c are each independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyC1-C4 alkyl, or R x1b and R x1c , together with the nitrogen atom to which they are attached, form a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered saturated or partially unsaturated heterocyclic ring, wherein the 3-membered, 4-membered, 5-membered, 6-membered or 7-membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, thiol, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl) or -N(C1-C4 alkyl);
  • Rx is selected from
  • the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs,
  • L is selected from *-NR 2 -CO-, *-CO-NR 2 -, *-NR 2 CONR 2 - or a 5-6 membered heteroaryl group, and * represents connection with ring A;
  • R2 is selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 deuterated alkyl, C1-C4 haloalkyl;
  • R2 is selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 deuterated alkyl, C1-C4 haloalkyl;
  • L is selected from *-NR 2 -CO-, * represents connection to ring A;
  • L is selected from a 5-membered heteroaryl group having 1, 2, or 3 nitrogen heteroatoms and 0 or 1 heteroatom selected from oxygen or sulfur;
  • L is selected from *-NR 2 -CO-, * indicates connection with ring A; represents a 5-membered heteroaryl group, Y 1 and Y 5 are each independently C or N , and Y 2 , Y 3 , and Y 4 are each independently N, NH, O , S , or CH ; Each independently represents a single bond or a double bond; two are not double bonds at the same time; when Y 2 , Y 3 , Y 4 are O, S or NH, the is a single bond;
  • L is selected from *-NR 2 -CO- or * indicates connection with ring A;
  • L is selected from *-NH-CO-, * indicates connection with ring A;
  • X 2 , X 3 , and X 4 are selected from N or CR 3 ;
  • R 3 is each independently selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl, -OR 3a , -SR 3a , -NR 3b R 3c , -C(O)NR 3b R 3c , -NR 3e C(O)R 3e , -C(O)R 3e , -C(O)OR 3e , -OC(O)R 3e , -S(O)R 3e , -S(O) 2 R 3e , C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclyl, or two R 3 and the atoms to which they are attached combine to form a 5-10 membered ring; and/or
  • R 3b , R 3c are each independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyC1-C4 alkyl, or R 3b , R 3c and the nitrogen atom to which they are attached together form a 3-7 membered saturated or partially unsaturated heterocyclic ring, wherein the 3-7 membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, thiol, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl) 2 ;
  • R 3 is each independently selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl, -OR 3a , -SR 3a , -NR 3b R 3c , C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclyl, or two R 3 and the atoms to which they are attached combine to form a 5-10 membered ring; and/or
  • R 3b , R 3c are each independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyC1-C4 alkyl, or the nitrogen atom to which R 3b , R 3c are attached together to form a 3-7 membered saturated or partially unsaturated heterocyclic ring, wherein the 3-7 membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, thiol, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl) 2 ;
  • X 2 , X 3 , and X 4 are selected from N or CR 3 ;
  • R 3 is each independently selected from hydrogen, deuterium, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy C1-C4 alkyl, -OR 3a , -SR 3a , -NR 3b R 3c , C3-C6 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl, 4-7 membered heterocyclyl, or two R 3 and the atoms to which they are attached combine to form a 5-6 membered ring; and/or
  • R 3a is independently selected from hydrogen, deuterium, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, hydroxyC1-C4 alkyl;
  • R 3b , R 3c are each independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyC1-C4 alkyl, or the nitrogen atom to which R 3b , R 3c are attached together to form a 4-7 membered saturated or partially unsaturated heterocyclic ring, wherein the 4-7 membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, thiol, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl) 2 ;
  • R 3 is independently selected from hydrogen, halogen or C1-C4 alkyl
  • X 2 , X 3 , and X 4 are selected from CR 3 ;
  • R3 is hydrogen
  • for # indicates connection with L
  • R 3 is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OR 3a , -NR 3b R 3c , or two R 3 and the atoms to which they are attached combine to form a saturated, partially saturated or unsaturated 5-membered or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, in which case Has the following structure: G 1 , G 2 , G 3 , and G 4 represent CH or N, G 5 , G 6 , G 7 , and G 8 represent NH, O, S, or CH 2 , and # represents connection with L;
  • R 3b , R 3c are each independently selected from hydrogen, deuterium, C1-C4 alkyl, C1-C4 haloalkyl, hydroxyC1-C4 alkyl, or the nitrogen atom to which R 3b , R 3c are attached together to form a 4-7 membered saturated or partially unsaturated heterocyclic ring, wherein the 4-7 membered saturated or partially unsaturated heterocyclic ring is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, thiol, oxo, thioxo, amino, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl) 2 ;
  • R 3 is selected from hydrogen, halogen or C1-C4 alkyl
  • R 1 is -ZR 1a , wherein Z is a direct bond, -C1-C6 alkylene-, -C2-C8 alkenylene-, -C2-C8 alkynylene-, -C1-C6 alkylene-O-, -O-, -S-, -S( ⁇ O)-, -SO 2 -, -S ⁇ N-, -NR 1b -, -NR 1b SO 2 -, -SO 2 NR 1b -, -NR 1b -S( ⁇ O ) ( ⁇ NR 1b )-, -S ( ⁇ O)( ⁇ NR 1b )-NR 1b -, -S( ⁇ O )( ⁇ NR 1b )-, -C1-C6 alkylene-SO 2 -, -(C ⁇ O)-, -(C ⁇ O)NR 1b -, -NR 1b (C ⁇ O)-, -C ⁇ O)-,
  • R 1a is each independently selected from hydrogen, deuterium, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, 4-9 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 aryl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, 4-9 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 aryl is optionally substituted with deuterium, halogen, cyano, amino, hydroxy, carboxyl, thiol, C1-C6 alkyl, C1-C6 alkoxy, hydroxyC1-C6 alkyl, C1-C6 alkylthio, -NH(C1-C6 alkyl), -N(C1-C6 alkyl) 2 , C3-C8 cycloalkyl, 4-9 membered heterocyclyl, -S(O)(C1-C6 al
  • R 1b are each independently selected from hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, C3-C8 cycloalkyl or 4-9 membered heterocyclyl.
  • R 1 is -ZR 1a , wherein Z is a direct bond, -C1-C4 alkylene-, -C2-C6 alkenylene-, -C2-C6 alkynylene-, -C1-C4 alkylene-O-, -O-, -S-, -S( ⁇ O)-, -SO 2 -, -S ⁇ N-, -NR 1b -, -NR 1b SO 2 -, -SO 2 NR 1b -, -NR 1b -S ( ⁇ O)( ⁇ NR 1b )-, -S( ⁇ O)( ⁇ NR 1b )-NR 1b -, -S( ⁇ O) ( ⁇ NR 1b ) -, -C1-C4 alkylene-SO 2 R 1b -, -(C ⁇ O)-, -(C ⁇ O)NR 1b -,
  • R 1a is each independently selected from hydrogen, deuterium, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 aryl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, 5-10 membered heteroaryl, C6-C10 aryl is optionally substituted with deuterium, halogen, cyano, amino, hydroxy, carboxyl, thiol, C1-C4 alkyl, C1-C4 alkoxy, hydroxyC1-C4 alkyl, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl) 2 , C3-C6 cycloalkyl, 4-7 membered heterocyclyl, -S(O)(C1-C4 al
  • R 1a is each independently selected from hydrogen, deuterium, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted with deuterium, halogen, cyano, amino, hydroxy, carboxyl, thiol, C1-C4 alkyl, C1-C4 alkoxy, hydroxyC1-C4 alkyl, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl) 2 , C3-C6 cycloalkyl, 4-7 membered heterocyclyl;
  • R 1a is each independently selected from hydrogen, deuterium, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted with deuterium, halogen, cyano, amino, hydroxy, carboxyl, thiol, C1-C4 alkyl, C1-C4 alkoxy, hydroxyC1-C4 alkyl, C1-C4 alkylthio, -NH(C1-C4 alkyl), -N(C1-C4 alkyl) 2 , C3-C6 cycloalkyl, 4-7 membered heterocyclyl;
  • R 1a is each independently selected from C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted with hydroxy.
  • R 1 is selected from
  • R 1 is selected from
  • R 1a is selected from C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, and the C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl is optionally substituted with halogen, hydroxyl, C1-C4 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl.
  • R 1a is selected from C1-C6 alkyl, which is optionally substituted with hydroxy.
  • the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs,
  • n 0, 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • each Ra is independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 haloalkoxy; and/or
  • n is selected from 0, 1, 2, 3, 4, 5 or 6;
  • R c is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, oxo, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl) 2 , or two R c attached to the same carbon atom and the carbon atom to which they are attached together form a 3-6 membered saturated or partially unsaturated ring; the C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl) 2 , two R c attached to the same carbon atom and the carbon atom to which they are attached together form a 3-6 membered saturated or partially unsaturated ring optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C1-C4 alkyl;
  • each R c is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, oxo, C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl) 2 , or two R c attached to the same carbon atom and the carbon atom to which they are attached together form a 3-6 membered saturated or partially unsaturated ring; the C1-C4 alkyl, C1-C4 alkoxy, -NH(C1-C4 alkyl), -N(C1-C4 alkyl) 2 , two R c attached to the same carbon atom and the carbon atom to which they are attached together form a 3-6 membered saturated or partially unsaturated ring optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, C1-C4 alkyl;
  • each R c is independently selected from hydrogen, halogen (eg, F), C1-C6 alkyl, or C1-C6 haloalkyl;
  • n is selected from 0, 1 or 2;
  • R c is independently selected from hydrogen, deuterium, fluorine, hydroxyl, oxo, methyl, ethyl, methoxy, ethoxy, deuterated methyl, difluoromethyl, trifluoromethyl, deuterated methoxy, or two R c attached to the same carbon atom and the carbon atom to which they are attached together constitute cyclopropyl, cyclobutyl, oxetane, or azetidine;
  • the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in any one of the structures of formula (II-1-1), (II-1-2), (II-1-3), (II-2-1), (II-2-2), and (II-2-3):
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , X 2 , X 3 , X 4 , R 1 , Ra and R c are as defined above.
  • the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in any one of the structures of formula (II-1-1"), (II-1-2"), (II-1-3"), (II-2-1"), (II-2-2"), and (II-2-3"):
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , X 2 , X 3 , X 4 , R 1a , Ra and R c are as defined above.
  • the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in any one of the structures of Formula (IV-1), (IV-2), (V-1), (V-2), (VI-1) or (VI-2):
  • X1 , X2 , X3 , X4 , R1, R2 , Ra , Rb , Rc , m , and n are as defined above.
  • the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in any one of the structures of Formula (IV-1-1), (IV-1-2), (IV-2-1), (IV-2-2), (V-1-1), (V-1-2), (V-2-1), (V-2-2), (VI-1-1), (VI-1-2), (VI-2-1) or (VI-2-2):
  • the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, as shown in any one of the structures of Formula (IV-1-1'), (IV-1-2'), (IV-2-1'), (IV-2-2'), (V-1-1'), (V-1-2'), (V-2-1'), (V-2-2'), (VI-1-1'), (VI-1-2'), (VI-2-1') or (VI-2-2'):
  • X 2 , X 3 , X 4 , R 1a , R 2 , Ra , and R c are as defined above.
  • the present application provides the compound or its stereoisomers, tautomers, diastereomers, racemates, cis- and trans-isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts, or prodrugs, wherein the compound is selected from the group consisting of the following compounds:
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, and a pharmaceutically acceptable diluent or carrier.
  • the present application provides a method for treating a condition that can be treated with a KIF18A inhibitor, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition as described above.
  • the condition is a cancer selected from the group consisting of: (a) a solid tumor or a hematogenic tumor selected from the group consisting of bladder cancer, endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) a hematopoietic tumor of the lymphoid lineage selected from the group consisting of leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkett lymphoma; (c) a hematopoietic n
  • the present application provides a method for treating a cell proliferation disorder in a subject, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or a pharmaceutical composition as described above.
  • the present application provides a method for inhibiting KIF18A in cells, comprising contacting the cells with a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions as described above.
  • the present application provides a use of a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or said pharmaceutical composition in the preparation of a medicament for treating a disease that can be treated with a KIF18A inhibitor.
  • the condition is a cancer selected from the group consisting of: (a) a solid tumor or a hematogenic tumor selected from the group consisting of bladder cancer, endometrial cancer, squamous cell lung cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, esophageal cancer, gallbladder cancer, brain cancer, head and neck cancer, ovarian cancer, pancreatic cancer, gastric cancer, cervical cancer, thyroid cancer, prostate cancer, and skin cancer; (b) a hematopoietic tumor of the lymphoid lineage selected from the group consisting of leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma, and Burkett lymphoma; (c) a hematopoietic n
  • the present application provides a use of a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition thereof in the preparation of a drug for treating a cell proliferation disorder in a subject.
  • the present application provides a use of a compound represented by formula (I) or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition thereof in the preparation of a drug for inhibiting KIF18A in cells.
  • the compound represented by formula (I) provided by the present invention has a novel structure and good KIF18A inhibitory activity, and can be used for therapeutic, preventive, acute or chronic treatment of KIF18A-mediated diseases and disorders (including but not limited to cancer).
  • substituted refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • a 3-7 membered heterocyclic ring is optionally substituted with one or more deuterium groups, which means that the 3-7 membered heterocyclic ring may be unsubstituted, monosubstituted, polysubstituted, or fully substituted. 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 and/or cannot be synthesized will be introduced.
  • one or more means one or more than one, such as two, three, four, five, or ten, as appropriate.
  • substituents When a group is substituted with "one or more" substituents, it means that one or more hydrogen atoms on the group are replaced with one or more substituents from the specified group, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., substituents, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form stable compounds.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • alkyl is defined as a straight or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6 carbon atoms.
  • C1-6 alkyl refers to a linear or branched group (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl) of 1 to 6 carbon atoms.
  • C1-4 alkyl refers to a straight or branched aliphatic hydrocarbon chain (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) of 1 to 4 carbon atoms.
  • alkylene means a divalent straight or branched saturated aliphatic hydrocarbon group obtained by losing 1 H from an alkyl group as defined above.
  • the alkylene group has 1 to 12, for example 1 to 6 carbon atoms.
  • C1-6 alkylene refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene or n-hexylene).
  • C1-4 alkylene refers to a divalent straight or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene).
  • alkyl in the case where an alkyl group is part of a substituent and is connected to another group on both sides thereof, if the term “alkyl” is still used, the term “alkyl” is actually the corresponding alkylene group.
  • alkyl in “hydroxy C1-C6 alkyl-” is actually "C1-C6 alkylene".
  • alkoxy refers to -O-alkyl, wherein the alkyl group is as defined above.
  • C1-6 alkoxy refers to a linear or branched alkoxy group having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy, or n-hexyloxy).
  • C1-4 alkoxy refers to a linear or branched alkoxy group having 1 to 4 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy).
  • alkylthio refers to -S-alkyl, wherein the alkyl group is as defined above.
  • C1-6alkylthio refers to a linear or branched alkylthio group having 1 to 6 carbon atoms (e.g., methylthio, ethylthio, n-propylthio, isopropylthio, tert-butylthio, n-pentylthio, or n-hexylthio).
  • alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond.
  • C2-C10 alkenyl is understood to mean a linear 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.
  • C2-C10 alkenyl may include "C2-C8 alkenyl,” “C2-C6 alkenyl,” and "C2-C4 alkenyl.” It is understood that when the alkenyl group contains more than one double bond, the double bonds may be separated or conjugated.
  • 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.
  • C2-C10 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.
  • C2-C10 alkynyl may include "C2-C8 alkynyl", “C2-C6 alkynyl", “C2-C4 alkynyl”. Examples of “C2-C10 alkynyl” include, but are not limited to, ethynyl, propynyl, but-1-ynyl, but-2-ynyl or but-3-ynyl, etc.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.).
  • 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, fused, bridged, or spirocyclic ring, and having 3, 4, 5, 6, 7, 8, 9, 10, or 11 ring carbon atoms.
  • Specific examples of the cycloalkenyl group include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, wait.
  • the heterocyclyl group may be attached to the rest of the molecule via any one of the carbon atoms or the nitrogen atom (if present).
  • heterocyclyl may be a monocyclic or polycyclic ring system (polycyclic ring systems include, but are not limited to, bicyclic, tricyclic, tetracyclic or pentacyclic ring system groups).
  • a 3-11 membered heterocyclyl is a group having 3-11 (e.g., 3-7, 4-6, or 5-6) carbon atoms and heteroatoms in the ring, such as, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.
  • the heteroatoms of the heterocyclyl are selected from nitrogen, oxygen, or sulfur. In some embodiments, the heteroatoms of the heterocyclyl are selected from nitrogen or oxygen. In some embodiments, the heteroatoms of the heterocyclyl are selected from nitrogen. In some embodiments, the number of heteroatoms in the heterocyclyl is 1 or 2.
  • the heteroatom of the heterocyclic group is selected from nitrogen, and the number of heteroatoms is selected from 1; in some embodiments, the heterocyclic group is selected from 6-11 membered (e.g., 6, 7, 8, 9, 10 or 11 membered) saturated bridged or spiro heterocyclic groups, including 7-8 membered saturated bridged heterocyclic groups and 7-9 membered saturated spiro heterocyclic groups.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ electron system.
  • C6-10 aryl means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl.
  • heteroaryl refers to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being, for example, oxygen, nitrogen or sulfur) and, in each case, may be benzo-fused.
  • heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl), thiadiazolyl and the like, and benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and benzo derivatives thereof.
  • ring includes any of the cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl groups described above, for example, “3-7 membered ring”, “5-7 membered ring”, “3-8 membered ring”, “5-10 membered ring” refers to cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl groups having 3-7 (3, 4, 5, 6, or 7), 5-7 (5, 6, or 7), 3-8 (3, 4, 5, 6, 7, or 8), or 5-10 (5, 6, 7, 8, 9, or 10) ring atoms.
  • halo or halogen group is defined to include F, Cl, Br, or I.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature.
  • stereoisomer refers to an isomer formed due to at least one asymmetric center.
  • asymmetric centers racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced.
  • Specific individual molecules can also exist as geometric isomers (cis/trans).
  • the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers).
  • Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc.
  • solid lines can be used Solid wedge or virtual wedge
  • the chemical bonds of the compounds of the present invention are depicted.
  • the use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.).
  • the use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist.
  • solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry.
  • the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof.
  • the compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
  • compositions of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention,” such various derivative forms of the compound are also intended to be encompassed.
  • a substituent crosses the bond connecting two ring atoms in a ring, it means that the substituent can be bonded to any atom in the ring (e.g.
  • the substituent F is cross-linked to the bond connecting the 2-carbon atom and the 3-carbon atom on the piperidine ring, indicating that F can be bonded to the 1-nitrogen, 2-carbon, 3-carbon, 4-carbon, 5-carbon, or 6-carbon.
  • any bondable position of the ring to which the cross-link extends can be bonded to the substituent indicated by the cross-link, for example
  • the cross bond extends from the furan ring to the benzene ring, indicating that the substituent cyano group indicated by the cross bond can be bonded to any bondable position on the furan ring and the benzene ring.
  • the cross bond only extends to the furan ring, not to the benzene ring, indicating that the substituent cyano group indicated by the cross bond can only be bonded to any bondable position on the furan ring. It means that the substituent R c can be bonded to any bondable ring atom of the ring C, and the substituent R a can be bonded to any bondable ring atom of the ring A.
  • Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate/carbonate, bisulfate/sulfate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrobromide/bromide, hydroiodide/iodide, maleate, malonate, methylsulfate, naphthoate (naphthylate), nicotinate, nitrate, orotate, oxalate, palmitate and other similar salts.
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, diethylamine, lysine, magnesium, meglumine, potassium and other similar salts.
  • esters refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acid or alcohol).
  • physiologically hydrolyzable esters which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acid or alcohol.
  • the compounds of the present invention themselves may also be esters.
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.
  • the compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol.
  • the amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.
  • metabolites of the compounds of the present invention i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, and the like of the administered compound.
  • the present invention includes metabolites of the compounds of the present invention, including compounds produced by contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity but are converted, for example, by hydrolytic cleavage, into compounds of the invention having the desired activity when administered to or onto the body.
  • prodrugs will be functional group derivatives of the compounds that are readily converted in vivo into the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association).
  • Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties” (e.g. as described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).
  • the present invention also encompasses compounds of the invention containing protecting groups.
  • protecting groups During any process for the preparation of the compounds of the invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the invention. This may be achieved by conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference.
  • the protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
  • the term "about” means within ⁇ 10%, preferably within ⁇ 5%, and more preferably within ⁇ 2% of the stated numerical value.
  • Some representative compounds of the present invention can be prepared by the following synthetic methods.
  • the reagents and conditions of each step can be selected from conventional reagents or conditions for such preparation methods in the art. After the structure of the compound of the present invention is disclosed, the above selection can be made by those skilled in the art based on the knowledge in the art. Unless otherwise specified, the raw materials in the preparation examples of this application were purchased from Bid Pharmaceuticals.
  • Step 2 Dissolve compound M1-2 (400 mg, 1.32 mmol) in toluene (8 mL), add p-toluenesulfonylhydrazide (295 mg, 1.58 mmol), and react at room temperature for 10 minutes. The reaction solution is quenched with ice water, extracted with EA, and the organic phase is washed with saturated NaCl solution, dried over anhydrous Na2SO4 , and concentrated under reduced pressure to obtain compound M1-3.
  • Step 6 Compound M1-6 (164 mg, 0.51 mmol) was dissolved in DCM (2 mL), and HCl/EA (3 mL) was added. The mixture was reacted at 25°C for 1 hour. The reaction solution was filtered, and the solid was neutralized with sodium bicarbonate solution, extracted, and dried to obtain compound M1.
  • Step 3 Dissolve compound M2-3 (954 mg, 2.58 mmol) in toluene (8 mL), add p-toluenesulfonyl hydrazide (528 mg, 2.84 mmol), and react at room temperature for 20 minutes. The reaction solution is quenched with ice water, extracted with EA, and the organic phase is washed with saturated NaCl solution, dried over anhydrous Na2SO4 , and concentrated under reduced pressure to obtain compound M2-4.
  • Step 1 Dissolve compound M3-1 (2000 mg, 8.5 mmol), 4,4-difluoropiperidine (1.25 g, 10.3 mmol), and N,N-diisopropylethylamine (2.21 g, 17.16 mmol) in NMP (10 mL) and react at 100°C under nitrogen for 12 hours.
  • the reaction mixture was quenched with water (20 mL) and separated with EA (40 mL).
  • the organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4 , and concentrated under reduced pressure.
  • Step 2 Dissolve compound M3-2 (1100 mg, 3.29 mmol) and N-amino-4-toluenesulfonamide (613 mg, 3.29 mmol) in toluene (10 mL) and react at room temperature for 0.5 h. The reaction mixture was quenched with water (10 mL) and separated with EA (40 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2SO4 , and concentrated under reduced pressure to obtain the crude product of compound M3-3, which was used directly in the next step without purification.
  • Step 5 Dissolve compound M3-5 (330 mg, 1.04 mmol), tert-butyl carbamate (244 mg, 2.08 mmol), cesium carbonate (1000 mg, 3.13 mmol), and palladium catalyst (CAS: 1599466-85-9; 88 mg, 0.1 mmol) in 1,4-dioxane (8 mL) and react at 90°C under nitrogen for 12 hours.
  • the reaction mixture was quenched with water (10 mL) and separated with EA (40 mL).
  • the organic phase was washed with saturated brine (10 mL ), dried over anhydrous Na2SO4 , and concentrated under reduced pressure.
  • Step 6 Compound M3-6 (160 mg, 0.32 mmol) was dissolved in hydrochloric acid-dioxane (2 mL) and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, neutralized with saturated sodium bicarbonate solution, extracted, dried, and concentrated to yield compound M3.
  • Step 2 Dissolve compound M9-2 (950 mg, 2.89 mmol) in toluene (10 mL), add p-toluenesulfonylhydrazide (647 mg, 3.47 mmol), and react at room temperature for 20 minutes. The reaction solution is quenched with ice water, extracted with EA, and the organic phase is washed with saturated NaCl solution, dried over anhydrous Na2SO4 , and concentrated under reduced pressure to obtain compound M9-3.
  • Step 6 Compound M9-6 (146 mg, 0.42 mmol) was dissolved in DCM (2 mL), and hydrochloric acid-dioxane (2 mL) was added. The mixture was reacted at 25°C for 1 hour. The reaction mixture was filtered, neutralized, extracted to dryness, and concentrated to yield compound M9. MS (ESI, pos. ion) m/z: 247.0 [M+1] + .
  • Step 2 Dissolve compound M10-2 (4.10 g, 13.75 mmol) in ultra-dry toluene (24 mL), add N-amino-4-methylbenzenesulfonamide (3.07 g, 16.50 mmol), and react at room temperature for 1 h. The reaction mixture is used directly in the next reaction.
  • Step 3 Add ultra-dry toluene (24 mL) to the reaction solution of the previous step (M10-3 reaction solution), add sodium hydride (0.71 g, 25.59 mmol) in an ice bath and N2 protection conditions, stir at 25°C for 0.5h, then react at 135°C for 10 minutes, dilute the reaction solution with ice water, extract with EA, wash the organic phase with saturated NaCl solution, dry over anhydrous Na2SO4 , and concentrate under reduced pressure. The crude product is prepared and purified to obtain compound M10-4.
  • Step 6 Compound M10-6 (450 mg, 1.42 mmol) was dissolved in 6 mL of ethyl acetate (2 M) hydrochloric acid and allowed to react at room temperature for 1 h. The reaction mixture was quenched with icy sodium bicarbonate solution and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4 , and concentrated under reduced pressure to yield compound M10. MS m/z (ESI): 217.0 [M+1] + .
  • Step 3 Dissolve compound 26-0-3 (600 mg, 2.13 mmol) in acetonitrile (18 mL). Add trimethylsilyl azide (491.65 mg, 4.27 mmol) in an ice-water bath and allow to react for 30 minutes. Then, slowly add tert-butyl nitrite (440.06 mg, 4.27 mmol) to the mixture. Warm the reaction mixture to room temperature and allow to react overnight. The reaction mixture is quenched with aqueous sodium hypochlorite and diluted with water. Extract with EA. The organic phase is washed with saturated NaCl solution, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure until a small amount of solvent remains. This affords the crude product of compound 26-0, which is used directly in the next step.
  • Step 2 Compound 1-2 (90 mg, 0.17 mmol), 2-hydroxyethanesulfonamide (41.37 mg, 0.33 mmol), potassium carbonate (45.69 mg, 0.33 mmol), and palladium catalyst (CAS: 1599466-89-3, 13.37 mg, 0.02 mmol) were added to 1,4-dioxane (4 mL) and reacted at 90°C under nitrogen for 1 hour.
  • the reaction solution was quenched with water and extracted with EA (20 mL). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4 , and concentrated under reduced pressure.
  • Step 2 Compound 2-1 (70 mg, 0.14 mmol), 2-hydroxyethanesulfonamide (25.84 mg, 0.21 mmol), cesium carbonate (89.71 mg, 0.28 mmol), and palladium catalyst (CAS: 1599466-89-3, 11.13 mg, 0.01 mmol) were added to 1,4-dioxane (4 mL) and reacted at 90°C under nitrogen for 1 hour.
  • the reaction solution was quenched with water and extracted with EA (20 mL). The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4 , and concentrated under reduced pressure.
  • Step 4 Compound 26-4 (175 mg, 0.33 mmol), 2-hydroxyethanesulfonamide (164.51 mg, 1.31 mmol), cesium carbonate (214.16 mg, 0.66 mmol), and palladium catalyst (CAS: 1599466-83-7, 30.24 mg, 0.03 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 95°C under nitrogen for 1 h. The reaction solution was quenched with water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4 , and concentrated under reduced pressure. The crude product was purified to afford compound 26. MS m/z (ESI): 577.3 [M+1] + .
  • Step 4 Dissolve compound 29-4 (98 mg, 0.17 mmol), 2-hydroxyethanesulfonamide (86 mg, 0.69 mmol), potassium carbonate (72 mg, 0.52 mmol), and a fourth-generation palladium catalyst (CAS: 1599466-89-3, 14 mg, 0.02 mmol) in 1,4-dioxane (3 mL) and react at 90°C under nitrogen for 1 h.
  • the reaction mixture was quenched with ice-cold water and extracted with EA. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4 , and concentrated under reduced pressure.
  • the crude product was purified to afford compound 29.
  • MS ESI, pos.
  • Test Example 1 In vitro inhibition of KIF18A activity by the compounds of the present invention (ADP-Glo assay)
  • IC50 values of the inhibitory activity of the compounds were calculated using Graphpad Prism software. The test results of some compounds are shown in Table 1 below.
  • A represents IC50 ⁇ 100 nM
  • B represents 100 nM ⁇ IC50 ⁇ 500 nM
  • C represents 500 nM ⁇ IC50 ⁇ 5000 nM
  • D represents IC50 > 5000 nM.
  • the following method was used to determine the effects of compounds of the present invention on the proliferation of human ovarian cancer cells, Ovcar-3 (HTB-161, ATCC).
  • Cells were cultured in RPMI-1640 complete medium supplemented with 20% fetal bovine serum, 0.01 mg/mL bovine insulin, 100 U penicillin, and 100 ⁇ g/mL streptomycin. This method was performed using the Promega Cell Titer-Glo kit (Cat. No. G7572).
  • test compound is dissolved in DMSO to prepare a 10mM stock solution, the stock solution is diluted according to the set test concentration, and the test compound at different concentrations is added to the cell test 384-well plate using ECHO. 400 Ovcar-3 cells in the logarithmic growth phase are inoculated into each well of the well plate to which the test compound has been added, so that the final concentration of the test compound in the reaction system is between 0.12nM-10 ⁇ M, and the cells are co-cultured in a cell culture incubator for 10 days.
  • the percentage inhibition of cell proliferation at each concentration of the test compound was calculated by comparing the values with those of the control group (0.1% DMSO). The data were analyzed by concentration-inhibition rate nonlinear regression analysis in GraphPad Prism 9 to obtain the IC50 value of the compound.
  • A indicates IC50 ⁇ 100 nM
  • B indicates 100 nM ⁇ IC50 ⁇ 500 nM
  • C indicates 500 nM ⁇ IC50 ⁇ 5000 nM
  • D indicates IC50 > 5000 nM.
  • the inhibitory effect of the compounds of the present invention on the KIF18A target was evaluated by testing the proliferation inhibitory effect of the compounds of the present invention on HCC1954 and HCC1395 cells.
  • HCC1954 (ATCC, CRL-2388) and HCC1395 (ATCC, CRL-2324) cells were cultured in RPMI-1640 complete medium (Gibco, A1049101) supplemented with 20% fetal bovine serum (Gibco, 10099141C), 100 U penicillin, and 100 ⁇ g/mL streptomycin (Gibco, 15140-122). This method was tested using the Promega Cell Titer-Glo kit (Promega: G7572).
  • HCC1954 cells tumor cells sensitive to KIF18A
  • HCC1395 cells tumor cells insensitive to KIF18A
  • the percentage inhibition of cell proliferation at each concentration of the test compound was calculated by comparing the values with those of the control group (0.1% DMSO). The data were analyzed by concentration-inhibition rate nonlinear regression analysis in GraphPad Prism 9 to obtain the IC50 value of the compound.
  • mice Male/female were divided into two groups: oral administration and intravenous administration, with three mice in each group. The mice were fasted for 10-14 hours before administration and had free access to water.
  • test compound was weighed according to the dosage and prepared into a dosage formulation of appropriate concentration (5 mL/kg and 10 mL/kg for intravenous and oral administration in mice and rats, respectively).
  • the intravenous injection was a clear solution
  • the oral dosage was a clear solution or a homogeneous suspension.
  • the plasma drug concentration-time curve was drawn according to the test concentration, and the pharmacokinetic parameters including half-life (T1/2), area under the concentration-time curve (AUC0-t), clearance (CL), steady-state volume of distribution (Vss), and bioavailability (F) were calculated using WinNonlin software according to the non-compartmental model.
  • Electrophysiological experiments were performed using a manual patch-clamp system (HEKA EPC-10 signal amplifier and digital converter, HEKA Electronics, Germany) for whole-cell current recording.
  • the specific testing method is described as follows: A circular slide with CHO hERG cells grown on its surface was placed in an electrophysiological recording chamber under an inverted microscope. Extracellular fluid was continuously perfused into the recording chamber (approximately 1 ml per minute). Conventional whole-cell patch-clamp current recording techniques were used. Unless otherwise specified, experiments were performed at room temperature ( ⁇ 25°C). Cells were clamped at -80 mV.
  • the clamping voltage was depolarized to +30 mV to activate hERG potassium channels, and then clamped back to -50 mV after 5 seconds to eliminate inactivation and generate tail current.
  • the peak tail current was used as the hERG current magnitude.
  • the dose response curve of the test compound was plotted with % hERG inhibition as the vertical axis and the concentration of the test compound as the horizontal axis, and IC50 was calculated.
  • the compounds of the present invention have excellent KIF18A inhibitory activity and in vivo anti-tumor efficacy.
  • the compounds of the present invention have better physicochemical properties (such as solubility, physical and/or chemical stability), improved pharmacokinetic properties (such as improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (such as reduced cardiotoxicity and/or fewer side effects), less prone to drug resistance, and other excellent properties.

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Abstract

L'invention concerne un composé représenté par la formule (I). Le composé peut moduler une protéine KIF18A, influant ainsi sur un cycle cellulaire et un processus de prolifération cellulaire pour traiter des cancers et des maladies associées au cancer. L'invention concerne en outre une composition pharmaceutique comprenant le composé et une méthode de traitement d'états associés à l'activité de KIF18A.
PCT/CN2025/085858 2024-03-29 2025-03-28 Composé tricyclique et son utilisation Pending WO2025201531A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103038233A (zh) * 2010-05-07 2013-04-10 吉利德康涅狄格有限公司 吡啶酮和氮杂吡啶酮化合物及使用方法
CN108299419A (zh) * 2017-01-11 2018-07-20 南京圣和药业股份有限公司 一种新型egfr激酶抑制剂的几种新晶型及其制备方法
CN114302880A (zh) * 2019-08-02 2022-04-08 美国安进公司 Kif18a抑制剂
WO2023174175A1 (fr) * 2022-03-17 2023-09-21 微境生物医药科技(上海)有限公司 Inhibiteur de kif18a
WO2023217230A1 (fr) * 2022-05-13 2023-11-16 上海湃隆生物科技有限公司 Inhibiteur de kinésine kif18a et son utilisation
WO2024114787A1 (fr) * 2022-12-02 2024-06-06 深圳众格生物科技有限公司 Composé amide ou urée

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103038233A (zh) * 2010-05-07 2013-04-10 吉利德康涅狄格有限公司 吡啶酮和氮杂吡啶酮化合物及使用方法
CN108299419A (zh) * 2017-01-11 2018-07-20 南京圣和药业股份有限公司 一种新型egfr激酶抑制剂的几种新晶型及其制备方法
CN114302880A (zh) * 2019-08-02 2022-04-08 美国安进公司 Kif18a抑制剂
WO2023174175A1 (fr) * 2022-03-17 2023-09-21 微境生物医药科技(上海)有限公司 Inhibiteur de kif18a
WO2023217230A1 (fr) * 2022-05-13 2023-11-16 上海湃隆生物科技有限公司 Inhibiteur de kinésine kif18a et son utilisation
WO2024114787A1 (fr) * 2022-12-02 2024-06-06 深圳众格生物科技有限公司 Composé amide ou urée

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