WO2024083208A1 - Inhibiteur de protéine kif18a - Google Patents

Inhibiteur de protéine kif18a Download PDF

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WO2024083208A1
WO2024083208A1 PCT/CN2023/125527 CN2023125527W WO2024083208A1 WO 2024083208 A1 WO2024083208 A1 WO 2024083208A1 CN 2023125527 W CN2023125527 W CN 2023125527W WO 2024083208 A1 WO2024083208 A1 WO 2024083208A1
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membered
mmol
ring
alkyl
methyl
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PCT/CN2023/125527
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Chinese (zh)
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温俏冬
杨欣
江珊玲
诸葛定娟
郑鹛
殷建明
吕裕斌
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杭州邦顺制药有限公司
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Publication of WO2024083208A1 publication Critical patent/WO2024083208A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines 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
    • A61K31/506—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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C07D413/14—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of pharmaceutical chemistry and relates to a KIF18A protein inhibitor, a pharmaceutical composition thereof, a preparation method thereof and use thereof in preparing, preventing and/or treating drugs for indications related to the KIF18A signaling pathway.
  • KIF18A kinesin family member 18A is a member of the Kinesin-8 family. It is a molecular motor protein that can release energy by hydrolyzing ATP and move toward the positive pole using microtubules as tracks. During mitosis, KIF18A can regulate the dynamic instability of microtubules, the dynamics of spindle microtubules and the amplitude of chromosomes. It plays a key role in the timely completion of chromosome alignment during mitosis, maintaining genome stability and successfully completing mitosis. KIF18A is lowly expressed in most normal human tissues and abnormally highly expressed in a variety of malignant tumor tissues. High expression of KIF18A is associated with malignant pathological characteristics and poor prognosis of tumor patients.
  • CIN Chromosomal instability
  • KIF18A inhibitors are expected to become anti-tumor drugs with good prospects in the treatment of various malignant tumors, but there are no KIF18A inhibitors on the market yet.
  • the KIF18A inhibitor developed by Amgen i.e. AMG650, compound 4 disclosed in CN113226473A
  • AMG650 is the only drug in the clinical stage in the world.
  • AMG650 is currently undergoing Phase I clinical research, and its safety and effectiveness have not yet been confirmed. Therefore, it is urgent to develop more safe and effective KIF18A inhibitors to meet the needs of clinical medication.
  • the first aspect of the present invention provides a compound having a structure represented by general formula (I), a deuterated substance, a stereoisomer or a pharmaceutically acceptable salt thereof:
  • X1 and X2 are each independently CH or N atom;
  • Ring A is a 5-10 membered monocyclic or bicyclic heterocyclic group, containing 1-6 heteroatoms selected from N, O, and S, and substituted by 0, 1, 2 or 3 R 3 ;
  • ring A is a 5-10 membered monocyclic or bicyclic heterocyclic group, said ring A contains 1, 2 or 3 heteroatoms selected from N, O, S, and is substituted by 0, 1, 2 or 3 R 3 ;
  • the ring A optionally has 1-2 C atoms substituted with oxo;
  • Ring B is a 5-membered, 6-membered, 7-membered or 8-membered cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from N, O and S, and the ring B is optionally substituted by 1, 2 or 3 R 4 ;
  • R 2 is -L 2 -R 7 , wherein L 2 is selected from -O-, -CO- or a covalent bond;
  • R3 is selected from halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or cyano;
  • R 4 is selected from H, R 4a or R 4b ;
  • R 4a or R 4b is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, or
  • R 4a , R 4b and the atoms to which they are connected form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group;
  • the R 5 is selected from H, R 5a or R 5b ;
  • R 5a is a 5-6 membered heteroaryl group, and is optionally substituted by 1, 2 or 3 groups selected from the following: C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 haloalkyl or C 1-3 haloalkoxy;
  • R 5b is selected from C 1-3 alkyl, C 1-3 alkoxy, which may be optionally substituted by hydroxyl or halogen;
  • the R 6 is selected from H, C 1-3 alkyl or C 3-6 cycloalkyl
  • R 7 is selected from H, R 7a or R 7b ;
  • R 7a is selected from -C 0-3 alkyl-(3-7)-membered cycloalkyl, -C 0-3 alkyl-(3-7)-membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 groups selected from the following: halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylene, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 haloalkylene;
  • R 7b is selected from C 1-6 alkyl, which is optionally substituted with 1, 2 or 3 groups selected from halogen, C 1-6 alkoxy or C 1-6 haloalkoxy.
  • the compound having the structure shown in the general formula (I) provided by the present invention may further be:
  • X1 and X2 are CH respectively;
  • the ring B is Optionally substituted by 1 or 2 R 4 ; said R 4 is selected from R 4a or R 4b ;
  • R 4a or R 4b is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, or
  • R 4a , R 4b and the atoms to which they are connected form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group;
  • the ring B, R 4a and R 4b form the following structure: Said R 4a or R 4b is independently selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, or
  • R 4a , R 4b and the atoms to which they are connected form a 3-6 membered cycloalkyl group
  • the ring B, R 4a and R 4b form the following structure:
  • the compound having the structure shown in the general formula (I) provided by the present invention may further be:
  • R 1 is -L 1 -R 5 , wherein L 1 is selected from -NR 6 -, -NR 6 SO 2 -, -NR 6 SO 2 NR 6 -, -NR 6 CONR 6 - or -N ⁇ S( ⁇ O)(—R 6 )-;
  • the R 5 is selected from H, R 5a or R 5b ;
  • the R 6 is selected from H, C 1-3 alkyl or C 3-6 cycloalkyl
  • the R 5a is selected from 5-membered heteroaryl, preferably and is optionally substituted by 1 group selected from the following: C 1-3 hydroxyalkyl, C 1-3 hydroxyalkyl or C 1-3 haloalkyl, wherein -CH 2 OH is preferred;
  • R 5a is selected from
  • the R 5b is a C 1-3 alkyl group substituted with a hydroxyl group, preferably -CH 2 -CH 2 OH;
  • R 1 is a group selected from the following structures:
  • the compound having the structure shown in the general formula (I) provided by the present invention, its deuterated substance, stereoisomer or pharmaceutically acceptable salt may further have the structure shown in the general formula (II):
  • Ring A is selected from a 5-6 membered monocyclic heteroaryl, a 6 membered monocyclic unsaturated heterocyclic group or a 9-10 membered cyclic heteroaryl group, containing 1-6 heteroatoms selected from N, O and S, and the ring A is substituted by 0, 1, 2 or 3 R 3 ;
  • ring A is selected from a 5-6 membered monocyclic heteroaryl, a 6 membered monocyclic unsaturated heterocyclic group or a 9-10 membered cyclic heteroaryl, containing 1, 2 or 3 heteroatoms selected from N, O and S, and the ring A is substituted by 0, 1, 2 or 3 R 3 ;
  • ring A is a 6-membered monocyclic unsaturated heterocyclic group, 1 to 2 C atoms are optionally substituted with oxo;
  • the R 3 is selected from halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy or 3-6 membered cycloalkyl;
  • R 2 is -L 2 -R 7 , wherein L 2 is selected from -O-, -CO- or a covalent bond;
  • R 7 is selected from H, R 7a or R 7b ;
  • R 7a is selected from -C 0-3 alkyl-(3-7)-membered cycloalkyl, -C 0-3 alkyl-(3-7)-membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 groups selected from the following: halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylene, C 1-3 haloalkyl, C 1-3 haloalkoxy or C 1-3 haloalkylene;
  • R 7a is selected from -CH 2 -(3-7)-membered cycloalkyl, -CH 2 -(3-7)-membered heterocycloalkyl, 3-7-membered cycloalkyl, 3-7-membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 groups selected from the following: halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylene , C 1-3 haloalkyl, C 1-3 haloalkoxy or C 1-3 haloalkylene;
  • R 7a is selected from 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 groups selected from the following: halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylene, C 1-3 haloalkyl, C 1-3 haloalkoxy or C 1-3 haloalkylene;
  • R 7b is selected from C 1-3 alkyl, which is optionally substituted with 1, 2 or 3 groups selected from halogen, C 1-3 alkoxy or C 1-3 haloalkoxy.
  • the compound having the structure represented by general formula (II) provided by the present invention may further be:
  • Ring A is selected from: and Ring A is substituted by 0, 1, 2 or 3 R 3 ;
  • Ring A is preferably: and Ring A is substituted with 0, 1, 2 or 3 R 3 ;
  • ring A is selected from: and Ring A is substituted by 0, 1, 2 or 3 R 3 ;
  • Ring A is further preferably: and Ring A is substituted with 0, 1, 2 or 3 R 3 ;
  • the R 3 is selected from F, Cl, methyl, ethyl, propyl, cyclopropyl, cyclopentyl, cyclohexyl, -OCH 3 , -CF 3 or -OCF 3 , preferably F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 .
  • the compound having the structure represented by general formula (II) provided by the present invention may further be:
  • R 2 is L 2 -R 7 , wherein,
  • L2 is selected from -O-, -CO- or a covalent bond
  • R 7 is selected from H, R 7a or R 7b ;
  • R 7a is selected from C 0-3 alkyl-(3-7)-membered cycloalkyl, -C 0-3 alkyl-(3-7)-membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 groups selected from the following: halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylene, C 1-3 haloalkyl, C 1-3 haloalkoxy or C 1-3 haloalkylene;
  • said R 7a is selected from
  • said R 7a is selected from
  • R 7b is selected from methyl, ethyl, n-propyl, which is optionally substituted by 1, 2 or 3 groups selected from the following: F, -OCH 3 or -OCF 3 ;
  • R 7b is selected from -CHF 2 , -CF 3 , -CH 2 -CHF 2 , -(CH 2 ) 2 -CF 3 , or -(CH 2 ) 2 -OCF 3 ;
  • R2 is a group selected from the following structures:
  • the compound having the structure represented by general formula (II) provided by the present invention may further be:
  • Ring A is a 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, and said ring A is substituted by 0, 1, 2 or 3 R 3 ;
  • the ring A is selected from and is substituted by 0, 1 or 2 R 3 ;
  • the R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • R2 is -L2 - R7 ,
  • L 2 is selected from -O-, -CO- or a covalent bond
  • R 7 is selected from R 7a or R 7b ;
  • R 7a is selected from C 0-3 alkyl-(3-7)-membered cycloalkyl, -C 0-3 alkyl-(3-7)-membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 groups selected from the following: halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylene, C 1-3 haloalkyl, C 1-3 haloalkoxy or C 1-3 haloalkylene;
  • R 7a is selected from -CH 2 -(3-7)-membered cycloalkyl, -CH 2 -(3-7)-membered heterocycloalkyl, and is optionally substituted by 1, 2 or 3 groups selected from the following: F, Cl, C 1-3 alkylene, C 1-3 haloalkylene, preferably F;
  • said R 7a is selected from
  • said R 7a is selected from
  • R 7b is selected from -CHF 2 , -CF 3 , -CH 2 -CHF 2 , -(CH 2 ) 2 -CF 3 or -(CH 2 ) 2 -OCF 3 .
  • R 2 is selected from:
  • the compound having the structure shown in the general formula (II) provided by the present invention, its deuterated substance, stereoisomer or pharmaceutically acceptable salt may further have the structure shown in the general formula (III):
  • R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • n is selected from 0, 1 or 2;
  • R 2 is -L 2 -R 7 , wherein L 2 is selected from -O-, -CO- or a covalent bond;
  • R 7 is selected from R 7a ;
  • R 7a is selected from C 0-3 alkyl-(3-7)-membered cycloalkyl, -C 0-3 alkyl-(3-7)-membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 groups selected from the following: halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylene, C 1-3 haloalkyl, C 1-3 haloalkoxy or C 1-3 haloalkylene;
  • R 7a is selected from -CH 2 -(3-7)-membered cycloalkyl, -CH 2 -(3-7)-membered heterocycloalkyl, and is optionally substituted with 1, 2 or 3 F;
  • said R 7a is selected from
  • R 2 is selected from:
  • the compound having the structure shown in the general formula (II) provided by the present invention, its deuterated substance, stereoisomer or pharmaceutically acceptable salt may further have the structure shown in the general formula (III):
  • R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • n is selected from 0, 1 or 2;
  • R2 is -L2 - R7 ,
  • L 2 is selected from -O-, -CO- or a covalent bond
  • R 7 is selected from R 7a ;
  • R 7a is selected from and is optionally substituted with 1, 2 or 3 F;
  • said R 7a is selected from:
  • the compound having the structure represented by general formula (II) provided by the present invention may further be:
  • Ring A is a 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O or S, and said ring A is substituted by 0, 1, 2 or 3 R 3 ;
  • the ring A is and is substituted by 0, 1 or 2 R 3 ;
  • the R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • R2 is -L2 - R7 ,
  • L 2 is selected from -O-, -CO- or a covalent bond
  • R 7 is selected from R 7a ;
  • R 7a is selected from
  • the compound having the structure shown in the general formula (II) provided by the present invention, its deuterated product, stereoisomer or pharmaceutically acceptable salt may further have the structure shown in the general formula (IV):
  • R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • n is selected from 0, 1 or 2;
  • R2 is -L2 - R7 ,
  • L 2 is selected from -O-, -CO-, a covalent bond
  • R 7 is selected from R 7a ;
  • R 7a is selected from
  • the compound having the structure represented by general formula (II) provided by the present invention may further be:
  • Ring A is a 6-membered unsaturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O or S, and 1-2 C atoms of Ring A are oxo-substituted; Ring A is substituted by 0, 1, 2 or 3 R 3 ;
  • the ring A is selected from: and is substituted by 0, 1, 2 or 3 R 3 ;
  • R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • R2 is -L2 - R7 ,
  • L 2 is selected from -O-, -CO- or a covalent bond
  • R 7 is selected from R 7a ;
  • R 7a is selected from and is optionally substituted by 1, 2 or 3 groups selected from the following: F, Cl, C 1-3 alkylene, C 1-3 haloalkylene, preferably F;
  • said R 7a is selected from
  • R 2 is selected from
  • the compound having the structure shown in the general formula (II) provided by the present invention, its deuterated substance, stereoisomer or pharmaceutically acceptable salt may further have the structure shown in the general formula (V):
  • Z 1 is selected from N, CH or CR 3 ;
  • Z 2 is selected from NH or NR 3 ;
  • R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • R2 is -L2 - R7 ,
  • L 2 is selected from -O-, -CO- or a covalent bond
  • R 7 is selected from R 7a ;
  • R 7a is selected from and is optionally substituted with 1, 2 or 3 F;
  • R 7a is selected from
  • R 2 is selected from
  • the compound having the structure represented by general formula (II) provided by the present invention may further be:
  • Ring A is a 9-10 membered heteroaryl ring containing 1-6 heteroatoms selected from N, O, and S, and the ring A is substituted by 0, 1, 2 or 3 R 3 ;
  • the compound provided by the present invention may further have a structure represented by general formula (I):
  • X1 and X2 are independently CH or N atoms, preferably CH;
  • Ring A is a 5-10 membered bicyclic heterocyclic group, preferably an 8-, 9- or 10-membered bicyclic heterocyclic group; the ring A contains 1-6 heteroatoms selected from N, O, S, preferably 2-4, and is substituted by 0, 1, 2 or 3 R 3 ;
  • R3 is selected from halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl or cyano;
  • the ring A optionally has 1-2 C atoms substituted with oxo;
  • R 2 is -L 2 -R 7 , wherein L 2 is selected from -O-, -CO- or a covalent bond;
  • R 7 is selected from H, R 7a or R 7b ;
  • R 7a is selected from -C 0-3 alkyl-(3-7)-membered cycloalkyl, -C 0-3 alkyl-(3-7)-membered heterocycloalkyl, preferably 3-7-membered cycloalkyl, 4-7-membered heterocycloalkyl, -CH 2 -(3-7)-membered cycloalkyl, -CH 2 -(4-7)-membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 groups selected from the following: halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylene, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 haloalkylene;
  • R 7b is selected from C 1-6 alkyl, which is optionally substituted with 1, 2 or 3 groups selected from halogen, C 1-6 alkoxy or C 1-6 haloalkoxy.
  • Ring B is a 5-membered, 6-membered, 7-membered or 8-membered cycloalkyl or heterocycloalkyl, wherein the heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from N, O and S, and the ring B is optionally substituted by 1, 2, 3 or 4 R 4 ;
  • R 4 is selected from H, R 4a or R 4b ;
  • R 4a or R 4b is independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, or
  • R 4a , R 4b and the atoms to which they are connected form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group;
  • the R 5 is selected from H, R 5a or R 5b ;
  • R 5a is a 5-6 membered heteroaryl group, and is optionally substituted by 1, 2 or 3 groups selected from the following: C 1-3 alkyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 1-3 haloalkyl or C 1-3 haloalkoxy;
  • the R 5b is selected from C 1-3 alkyl, C 1-3 alkoxy, which may be optionally substituted by hydroxyl or halogen;
  • the R 6 is selected from H, C 1-3 alkyl or C 3-6 cycloalkyl.
  • the ring A is selected from an 8-membered, 9-membered or 10-membered bicyclic heterocyclic group, an 8-membered, 9-membered or 10-membered bicyclic heteroaryl group, contains 2-4 heteroatoms selected from N, O, and S, and is substituted by 0, 1, 2 or 3 R3;
  • R3 is selected from halogen, C1-3 alkyl, C1-3 alkoxy, 3-6-membered cycloalkyl, C1-3 haloalkyl, C1-3 haloalkoxy or cyano; when the ring A is an 8-membered, 9-membered or 10-membered bicyclic heterocyclic group, 1-2 C atoms are optionally substituted by oxo;
  • the ring A is an 8-membered, 9-membered or 10-membered bicyclic heteroaryl group containing 2-4 N atoms and substituted by 0, 1, 2 or 3 R 3 ;
  • R 3 is selected from halogen, 3-5-membered cycloalkyl, C 1-3 alkyl, C 1-3 haloalkyl or cyano.
  • Ring A is selected from
  • Ring A is preferred
  • Ring A is more preferably
  • Ring A is further preferably
  • Ring A is optionally substituted with 0, 1 or 2 R 3 ;
  • R 3 is selected from halogen, 3-5 membered cycloalkyl, C 1-3 alkyl, C 1-3 haloalkyl or cyano, preferably F, methyl, trifluoromethyl or cyano.
  • R 2 is -L 2 -R 7 , wherein L 2 is selected from -O-, -CO- or a covalent bond;
  • R 7 is selected from H, R 7a or R 7b ;
  • R 7a is selected from 3-6 membered cycloalkyl, 4-7 membered heterocycloalkyl, -CH 2 -(3-6) membered cycloalkyl, -CH 2 -(4-7) membered heterocycloalkyl, more preferably 3-6 membered cycloalkyl, 4-7 membered azacycloalkyl, -CH 2 -(3-6) membered cycloalkyl, -CH 2 -(4-7) membered azacycloalkyl;
  • R 7a is further preferably More preferred
  • R 7b is selected from C 1-6 alkyl, more preferably C 1-3 alkyl, further preferably methyl, ethyl, n-propyl, isopropyl;
  • R 7b is optionally substituted by 1, 2 or 3 groups selected from the following: halogen, C 1-6 alkoxy or C 1-6 haloalkoxy, more preferably halogen, C 1-3 alkoxy or C 1-3 haloalkoxy, further preferably F, methoxy, trifluoromethoxy, and even more preferably F.
  • Ring B is Optionally substituted with 1, 2, 3 or 4 R 4 ;
  • R 4 is selected from H, R 4a or R 4b ;
  • R 4a or R 4b is independently selected from halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, or
  • R 4a , R 4b and the atoms to which they are connected form a 3-6 membered cycloalkyl group or a 3-6 membered heterocycloalkyl group;
  • ring B is Optionally substituted with 1 or 2 R 4 , R 4 is selected from H or R 4a , R 4a is independently selected from halogen, hydroxy, cyano, C 1-3 alkyl, C 1-3 alkoxy, preferably F, hydroxy, cyano, methyl, methoxy;
  • ring B is Best More preferred
  • R 1 is -L 1 -R 5 , wherein L 1 is selected from -NR 6 SO 2 -, -NR 6 SO 2 NR 6 -, -NR 6 CO- or -NR 6 CONR 6 -;
  • the R 5 is selected from R 5b ;
  • R 5b is selected from C 1-3 alkyl, which may be optionally substituted by hydroxyl or halogen;
  • the R 6 is selected from H, C 1-3 alkyl
  • R 1 is -L 1 -R 5 , wherein L 1 is selected from -NHSO 2 -; said R 5 is selected from R 5b ; said R 5b is selected from methyl, ethyl, n-propyl, which may be optionally substituted by hydroxyl, halogen;
  • R1 is
  • the compound provided by the present invention may further have a structure represented by general formula (X):
  • the ring A is selected from 8-membered, 9-membered or 10-membered bicyclic heterocyclic group, 8-membered, 9-membered or 10-membered bicyclic heteroaryl group, contains 2-4 heteroatoms selected from N, O, S, and is substituted by 0, 1, 2 or 3 R3; when the ring A is 8-membered, 9-membered or 10-membered bicyclic heterocyclic group, 1-2 C atoms are optionally substituted by oxo;
  • Ring A is preferred Wherein the * end is connected to R 2 , and the # end is connected to an amide group;
  • Ring A is more preferably Wherein the * end is connected to R 2 , and the # end is connected to an amide group;
  • Ring A is an 8-, 9- or 10-membered bicyclic heteroaryl group containing 2-4 N atoms and substituted by 0, 1, 2 or 3 R 3 ;
  • Ring A is more preferably Wherein the * end is connected to R 2 , and the # end is connected to an amide group;
  • Ring A is more preferably Wherein the * end is connected to R 2 , and the # end is connected to an amide group;
  • R3 is selected from halogen, C1-3 alkyl, 3-5 membered cycloalkyl, C1-3 haloalkyl or cyano, preferably F, methyl, trifluoromethyl or cyano;
  • R 2 is -L 2 -R 7 , wherein L 2 is selected from -O-, -CO- or a covalent bond;
  • R 7 is selected from H, R 7a or R 7b ;
  • R 7a is selected from 3-6 membered cycloalkyl, 4-7 membered azacycloalkyl, -CH 2 -(3-6) membered cycloalkyl, -CH 2 -(4-7) membered azacycloalkyl, which is optionally substituted by 1 or 2 groups selected from the following: halogen, C 1-3 alkyl, C 1-3 alkylene, C 1-3 haloalkyl or C 1-3 haloalkylene;
  • R 7b is selected from C 1-3 alkyl, which is optionally substituted by 1, 2 or 3 groups selected from halogen, C 1-3 alkoxy or C 1-3 haloalkoxy;
  • R 7b is preferably methyl, n-propyl, isopropyl, which is optionally substituted by 1, 2 or 3 groups selected from the following: halogen, C 1-3 alkoxy or C 1-3 haloalkoxy, more preferably F, methoxy, trifluoromethoxy, further preferably F.
  • R 4 is selected from halogen, hydroxy, cyano, C 1-3 alkyl, C 1-3 alkoxy, preferably F, hydroxy, cyano, methyl, methoxy;
  • n is selected from 0, 1 or 2.
  • the ring A has a structure represented by the general formula (VI-1) and is substituted by 0, 1, 2 or 3 R 3 :
  • Z3 is selected from N or CH
  • Z 4 is selected from N or C
  • Ring A1 is a parallel 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;
  • the ring A is selected from: and is substituted by 0, 1, 2 or 3 R 3 ;
  • R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • R2 is -L2 - R7 ,
  • L 2 is selected from -O-, -CO- or a covalent bond
  • R 7 is selected from R 7a or R 7b ;
  • R 7a is selected from C 0-3 alkyl-(3-7)-membered cycloalkyl, -C 0-3 alkyl-(3-7)-membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 groups selected from the following: halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylene, C 1-3 haloalkyl, C 1-3 haloalkoxy or C 1-3 haloalkylene;
  • R 7a is selected from -CH 2 -(3-7)-membered cycloalkyl, -CH 2 -(3-7)-membered heterocycloalkyl, 3-7-membered paracycloalkyl, 3-7-membered paraheterocycloalkyl, and is optionally substituted by 1, 2 or 3 groups selected from the following: F, Cl, C 1-3 alkylene, C 1-3 haloalkylene, preferably F;
  • R 7a is selected from
  • R 7b is selected from -CHF 2 , -CF 3 , -CH 2 -CHF 2 , -(CH 2 ) 2 -CF 3 or -(CH 2 ) 2 -OCF 3 ;
  • R 2 is selected from
  • the compound having the structure represented by the general formula (II) provided by the present invention, its deuterated product, stereoisomer or pharmaceutically acceptable salt may further be: the ring A is selected from: and is substituted by 0, 1, 2 or 3 R 3 ;
  • R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • R2 is -L2 - R7 ,
  • L 2 is selected from -O-, -CO- or a covalent bond
  • R 7 is selected from R 7a or R 7b ;
  • R 7a is selected from and is optionally substituted by 1, 2 or 3 groups selected from the following: F, Cl, C 1-3 alkylene, C 1-3 haloalkylene, preferably F;
  • said R 7a is selected from
  • R 7b is selected from -CHF 2 , -CF 3 , -CH 2 -CHF 2 , -(CH 2 ) 2 -CF 3 or -(CH 2 ) 2 -OCF 3 .
  • the compound having the structure shown in the general formula (II) provided by the present invention, its deuterated product, stereoisomer or pharmaceutically acceptable salt may further have the structure shown in the general formula (VI-1a):
  • Z 3 is N or CH
  • the R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • x and y are independently selected from 0, 1 or 2;
  • R 2 is -L 2 -R 7 , wherein L 2 is selected from -O-, -CO- or a covalent bond;
  • R 7 is selected from R 7a ;
  • R 7a is selected from C 0-3 alkyl-(3-7)-membered cycloalkyl, -C 0-3 alkyl-(3-7)-membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 groups selected from the following: halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylene, C 1-3 haloalkyl, C 1-3 haloalkoxy or C 1-3 haloalkylene;
  • R 7a is selected from -CH 2 -(3-7)-membered cycloalkyl, -CH 2 -(3-7)-membered heterocycloalkyl, 3-7-membered paracycloalkyl, 3-7-membered paraheterocycloalkyl, which is optionally substituted with 1, 2 or 3 F;
  • R 7a is selected from
  • R 2 is selected from
  • the compound having the structure shown in the general formula (II) provided by the present invention, its deuterated product, stereoisomer or pharmaceutically acceptable salt may further have the structure shown in the general formula (VI-1a):
  • Z 3 is N or CH
  • the R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • x and y are independently selected from 0, 1 or 2;
  • R 2 is -L 2 -R 7 , wherein L 2 is selected from -O-, -CO- or a covalent bond;
  • R 7 is selected from R 7a ;
  • R 7a is selected from which is optionally substituted with 1, 2 or 3 F;
  • R 7a is selected from
  • the compound having the structure shown in the general formula (II) provided by the present invention, its deuterated product, stereoisomer or pharmaceutically acceptable salt may further have the structure shown in the general formula (VI-1a):
  • Z 3 is N or CH
  • the R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • x and y are independently selected from 0, 1 or 2;
  • R 2 is -L 2 -R 7 , wherein L 2 is selected from -O-, -CO- or a covalent bond;
  • R 7 is selected from R 7a ;
  • R 7a is selected from which is optionally substituted with 1, 2 or 3 F;
  • R 7a is selected from
  • the compound having the structure represented by general formula (II) provided by the present invention may further be:
  • Ring A is a 9-10-membered heteroaryl ring, containing 1-6 heteroatoms selected from N, O, and S, and substituted by 0, 1, 2 or 3 R 3 ;
  • the ring A has a structure represented by the general formula (VI-2) and is substituted by 0, 1, 2 or 3 R 3 :
  • Z 5 is selected from N or CH
  • Ring A2 is a 5-6-membered heteroaryl group connected in parallel, containing 1, 2 or 3 heteroatoms selected from N, O and S;
  • ring A is selected from: and is substituted by 0, 1, 2 or 3 R 3 ,
  • R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • R2 is -L2 - R7 ,
  • L 2 is selected from -O-, -CO- or a covalent bond
  • R 7 is selected from R 7a or R 7b ;
  • R 7a is selected from C 0-3 alkyl-(3-7)-membered cycloalkyl, -C 0-3 alkyl-(3-7)-membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 groups selected from the following: halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylene, C 1-3 haloalkyl, C 1-3 haloalkoxy or C 1-3 haloalkylene;
  • R 7a is selected from -CH 2 -(3-7)-membered cycloalkyl, -CH 2 -(3-7)-membered heterocycloalkyl, and is optionally substituted by 1, 2 or 3 groups selected from the following: F, Cl, C 1-3 alkylene, C 1-3 haloalkylene, preferably F;
  • said R 7a is selected from
  • R 7b is selected from -CHF 2 , -CF 3 , -CH 2 -CHF 2 , -(CH 2 ) 2 -CF 3 or -(CH 2 ) 2 -OCF 3 .
  • the compound having the structure represented by the general formula (II) provided by the present invention, its deuterated substance, stereoisomer or pharmaceutically acceptable salt may further be: Ring A is selected from: and is substituted by 0, 1, 2 or 3 R 3 ;
  • R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • R2 is -L2 - R7 ,
  • L 2 is selected from -O-, -CO- or a covalent bond
  • R 7 is selected from R 7a or R 7b ;
  • R 7a is selected from and is optionally substituted by 1, 2 or 3 groups selected from the following: F, Cl, C 1-3 alkylene, C 1-3 haloalkylene, preferably F;
  • said R 7a is selected from
  • R 7b is selected from -CHF 2 , -CF 3 , -CH 2 -CHF 2 , -(CH 2 ) 2 -CF 3 or -(CH 2 ) 2 -OCF 3 .
  • the compound having the structure shown in the general formula (II) provided by the present invention, its deuterated product, stereoisomer or pharmaceutically acceptable salt may further have the structure shown in the general formula (VI-2a):
  • R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF;
  • x is selected from 0 or 1;
  • y is selected from 0, 1, 2 or 3;
  • R 2 is -L 2 -R 7 , wherein L 2 is selected from -O-, -CO- or a covalent bond;
  • R 7 is selected from R 7a or R 7b ;
  • R 7a is selected from C 0-3 alkyl-(3-7)-membered cycloalkyl, -C 0-3 alkyl-(3-7)-membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 groups selected from the following: halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylene, C 1-3 haloalkyl, C 1-3 haloalkoxy or C 1-3 haloalkylene;
  • R 7a is selected from -CH 2 -(3-7)-membered cycloalkyl, -CH 2 -(3-7)-membered heterocycloalkyl, and is optionally substituted by 1, 2 or 3 groups selected from the following: F, Cl, C 1-3 alkylene, C 1-3 haloalkylene, preferably F;
  • said R 7a is selected from
  • R 7b is selected from -CHF 2 , -CF 3 , -CH 2 -CHF 2 , -(CH 2 ) 2 -CF 3 or -(CH 2 ) 2 -OCF 3 ;
  • R 2 is selected from -CF 3 and -CHF 2 .
  • the compound having the structure shown in the general formula (II) provided by the present invention, its deuterated substance, stereoisomer or pharmaceutically acceptable salt may further have the structure shown in the general formula (VI-2a):
  • R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF;
  • x is selected from 0 or 1;
  • y is selected from 0, 1, 2 or 3;
  • R 2 is -L 2 -R 7 , wherein L 2 is selected from -O-, -CO- or a covalent bond;
  • R 7 is selected from R 7b ;
  • R 7b is selected from -CHF 2 , -CF 3 , -CH 2 -CHF 2 , -(CH 2 ) 2 -CF 3 or -(CH 2 ) 2 -OCF 3 ;
  • R 2 is selected from -CF 3 and -CHF 2 .
  • the compound having the structure represented by general formula (II) provided by the present invention may further be:
  • Ring A is a 9-10-membered cyclic heteroaryl group, containing 1, 2 or 3 heteroatoms selected from N, O and S, and substituted by 0, 1, 2 or 3 R 3 ;
  • the ring A has a structure represented by the general formula (VI-3) and is substituted by 0, 1, 2 or 3 R 3 :
  • Ring A 3 is a parallel 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S;
  • the ring A is substituted by 0, 1, 2 or 3 R 3 ;
  • ring A is the following structure: or a group substituted by 0, 1, 2 or 3 R 3 :
  • R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • R2 is -L2 - R7 ,
  • L 2 is selected from -O-, -CO- or a covalent bond
  • R 7 is selected from R 7a or R 7b ;
  • R 7a is selected from and is optionally substituted by 1, 2 or 3 groups selected from the following: F, Cl, C 1-3 alkylene, C 1-3 haloalkylene, preferably F;
  • R 7a is selected from
  • R 7b is selected from -CHF 2 , -CF 3 , -CH 2 -CHF 2 , -(CH 2 ) 2 -CF 3 or -(CH 2 ) 2 -OCF 3 .
  • the compound having the structure shown in the general formula (II) provided by the present invention, its deuterated product, stereoisomer or pharmaceutically acceptable salt may further have the structure shown in the general formula (VI-3a):
  • R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • x and y are independently selected from 0, 1 or 2;
  • R2 is -L2 - R7 ,
  • L 2 is selected from -O-, -CO- or a covalent bond
  • R 7 is selected from R 7a or R 7b ;
  • R 7a is selected from and is optionally substituted by 1, 2 or 3 groups selected from the following: F, Cl, C 1-3 alkylene, C 1-3 haloalkylene, preferably F;
  • said R 7a is selected from
  • R 7b is selected from -CHF 2 , -CF 3 , -CH 2 -CHF 2 , -(CH 2 ) 2 -CF 3 or -(CH 2 ) 2 -OCF 3 .
  • the compound having the structure represented by general formula (II) provided by the present invention may further be:
  • Ring A is a 9-10 membered heteroaryl ring containing 1-6 heteroatoms selected from N, O, and S, and the ring A is substituted by 0, 1, 2 or 3 R 3 ;
  • the ring A has a structure represented by the general formula (VI-4) and is substituted by 0, 1, 2 or 3 R 3 :
  • Z6 and Z7 are independently selected from N or CH;
  • R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • R2 is -L2 - R7 ,
  • L 2 is selected from -O-, -CO- or a covalent bond
  • R 7 is selected from R 7a or R 7b ;
  • R 7a is selected from C 0-3 alkyl-(3-7)-membered cycloalkyl, -C 0-3 alkyl-(3-7)-membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 groups selected from the following: halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylene, C 1-3 haloalkyl, C 1-3 haloalkoxy or C 1-3 haloalkylene;
  • R 7a is selected from -CH 2 -(3-7)-membered cycloalkyl, -CH 2 -(3-7)-membered heterocycloalkyl, 3-7-membered paracycloalkyl, 3-7-membered paraheterocycloalkyl, and is optionally substituted by 1, 2 or 3 groups selected from the following: F, Cl, C 1-3 alkylene, C 1-3 haloalkylene, preferably F;
  • said R 7a is selected from
  • R 7b is selected from -CHF 2 , -CF 3 , -CH 2 -CHF 2 , -(CH 2 ) 2 -CF 3 or -(CH 2 ) 2 -OCF 3 .
  • the compound having the structure shown in the general formula (II) provided by the present invention, its deuterated substance, stereoisomer or pharmaceutically acceptable salt may further have the structure shown in the general formula (VI-4a):
  • Z 6 is selected from N or CH
  • R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • n is selected from 0, 1 or 2;
  • R2 is -L2 - R7 ,
  • L 2 is selected from -O-, -CO- or a covalent bond
  • R 7 is selected from R 7a or R 7b ;
  • R 7a is selected from -CH 2 -(3-7)-membered cycloalkyl, -CH 2 -(3-7)-membered heterocycloalkyl, and is optionally substituted by 1, 2 or 3 groups selected from the following: F, Cl, C 1-3 alkylene, C 1-3 haloalkylene, preferably F;
  • said R 7a is selected from
  • said R 7a is selected from
  • R 7b is selected from -CHF 2 , -CF 3 , -CH 2 -CHF 2 , -(CH 2 ) 2 -CF 3 or -(CH 2 ) 2 -OCF 3 .
  • the compound having the structure shown in the general formula (I) provided by the present invention, its deuterated substance, stereoisomer or pharmaceutically acceptable salt may further have the structure shown in the general formula (IX):
  • the R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • x and y are independently selected from 0, 1 or 2;
  • R 2 is -L 2 -R 7 , wherein L 2 is selected from -O-, -CO- or a covalent bond;
  • R 7 is selected from R 7a or R 7b ;
  • R 7a is selected from C 0-3 alkyl-(3-7)-membered cycloalkyl, -C 0-3 alkyl-(3-7)-membered heterocycloalkyl, which is optionally substituted by 1, 2 or 3 groups selected from the following: halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylene, C 1-3 haloalkyl, C 1-3 haloalkoxy or C 1-3 haloalkylene;
  • R 7a is selected from -CH 2 -(3-7)-membered cycloalkyl, -CH 2 -(3-7)-membered heterocycloalkyl, and is optionally substituted by 1, 2 or 3 groups selected from the following: F, Cl, C 1-3 alkylene, C 1-3 haloalkylene, preferably F;
  • said R 7a is selected from
  • R 7b is selected from -CHF 2 , -CF 3 , -CH 2 -CHF 2 , -(CH 2 ) 2 -CF 3 or -(CH 2 ) 2 -OCF 3 .
  • the compound having the structure shown in the general formula (I) provided by the present invention, its deuterated substance, stereoisomer or pharmaceutically acceptable salt may further have the structure shown in the general formula (VII):
  • R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • n is selected from 0, 1 or 2;
  • R 1 is -L 1 -R 5 , wherein L 1 is selected from -NR 6 -, -NR 6 SO 2 NR 6 - or -NR 6 CONR 6 -;
  • R6 is selected from H, C1-3 alkyl or C3-6 cycloalkyl
  • the R 5 is selected from R 5a or R 5b ,
  • the R 5a is selected from and is optionally substituted by C 1-3 hydroxyalkyl, preferably by -CH 2 OH;
  • R 5a is selected from
  • the R 5b is a C 1-3 alkyl group substituted with a hydroxyl group, preferably -CH 2 -CH 2 OH;
  • R 1 is a group selected from the following structures:
  • R 2 is L 2 -R 7 , wherein,
  • L 2 is selected from -O-, -CO-, a covalent bond
  • R 7 is selected from R 7a ;
  • R 7a is selected from It is optionally substituted by 1, 2 or 3 groups selected from the following: F, Cl, C 1-3 alkylene, C 1-3 haloalkylene, preferably F;
  • said R 7a is selected from
  • R 2 is selected from
  • the compound having the structure shown in the general formula (I) provided by the present invention, its deuterated substance, stereoisomer or pharmaceutically acceptable salt may further have the structure shown in the general formula (VIII):
  • the R 3 is selected from F, methyl, ethyl, cyclopropyl, -OCH 3 , -CF 3 or -OCF 3 ;
  • n is selected from 0, 1 or 2;
  • R 1 is -L 1 -R 5 , wherein L 1 is selected from -NR 6 SO 2 -;
  • the R 6 is selected from H, C 1-3 alkyl or C 3-6 cycloalkyl
  • the R 5 is selected from R 5b .
  • the R 5b is a C 1-3 alkyl group substituted with a hydroxyl group, preferably -CH 2 -CH 2 OH;
  • the R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoe
  • R 2 is L 2 -R 7 , wherein,
  • L 2 is selected from -O-, -CO-, a covalent bond
  • R 7 is selected from R 7a ;
  • R 7a is selected from It is optionally substituted by 1, 2 or 3 groups selected from the following: F, Cl, C 1-3 alkylene, C 1-3 haloalkylene, preferably F;
  • R2 is
  • the compound having the structure represented by the general formula (I) provided by the present invention, its deuterated substance, stereoisomer or pharmaceutically acceptable salt may further include any one of the following:
  • the second aspect of the present invention provides a pharmaceutical composition, which contains any one of the aforementioned compounds, deuterated substances, stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier thereof.
  • the third aspect of the present invention provides use of any of the aforementioned compounds, deuterated products, stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of drugs for treating and/or preventing KIF18A-related diseases.
  • the KIF18A-related disease is selected from advanced or metastatic solid tumors associated with p53 gene mutation, or accompanied by abnormal expression of one or more other genes, and the abnormal expression of other genes is selected from RB deletion, BRCA1 mutation/inactivation, and CCNE amplification.
  • the KIF18A-related disease is selected from colon cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, peritoneal cancer, fallopian tube cancer, endometrial cancer and ovarian cancer, etc.; preferably triple-negative breast cancer (TNBC), platinum-resistant high-grade serous ovarian cancer (HGSOC), primary peritoneal cancer, fallopian tube cancer or serous endometrial cancer.
  • TNBC triple-negative breast cancer
  • HOSOC platinum-resistant high-grade serous ovarian cancer
  • primary peritoneal cancer fallopian tube cancer or serous endometrial cancer.
  • the compound provided by the present invention has good inhibitory activity against KIF18A, and has stronger cell inhibitory activity and lower toxic side effects than the KIF18A inhibitor AMG650, and has strong animal efficacy, good pharmacokinetic properties, and high bioavailability, and is an ideal KIF18A inhibitor; at the same time, methyl or halogen (such as F) substitution on the bicyclic ring can significantly
  • the pharmacokinetic properties of the compound can be improved, especially the clearance rate can be reduced, Cmax (maximum blood drug concentration) can be increased, and the exposure can be increased.
  • the compounds of the present invention are ideal high-activity KIF18A inhibitors, and can be used to treat and/or prevent clinical diseases including colon cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, peritoneal cancer, fallopian tube, endometrial cancer, ovarian cancer and other solid tumors.
  • substituted or “substituted” means that any one or more hydrogen atoms on any atom in a group or fragment are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • optionally substituted means that it may be substituted or not substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical feasibility.
  • ring A when ring A is a 6-membered monocyclic unsaturated heterocyclic group, ring A contains 0, 1, 2 or 3 heteroatoms selected from N, O, and S, and 1-2 C atoms are optionally oxo-substituted", then ring A at least comprises the following structure:
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CR a R b ) 0 -, it means that the linking group is a single bond/chemical bond.
  • one of the variables is selected from covalent bond/chemical bond/single bond, it means that the two groups connected are directly connected.
  • L 2 in AL 2 -R 7 represents a covalent bond, it means that the structure is actually AR 7 .
  • a substituent When a substituent is vacant, it means that the substituent does not exist.
  • X in AX it means that the structure is actually A; for example,
  • n When n is 0, it means that the hydrogen atoms on the ring are not replaced by R 3 .
  • the linking group L 1 is -MW-.
  • -MW- can connect the ring A and R 1 in the same direction as the reading order from left to right to form the ring AMWR 1 , or can connect the ring A and R 1 in the opposite direction to the reading order from left to right to form the ring AWMR 1 .
  • Combinations of the linking groups, substituents and/or variants thereof are permitted only if such combinations will produce stable compounds.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • connection mode of the chemical bond is non-positional and there is an H atom at the connectable site
  • the chemical bond connecting the site to other groups can be represented by a straight solid bond.
  • the straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in the group indicates that the two ends of the carbon atom in the group are connected to other groups;
  • the dotted lines in the figure indicate that the 1- and 4-carbon atoms in the phenyl group are connected to other groups; It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.
  • the attachment site of the group or fragment is located on the ring connected by the dotted line.
  • any connection site on the nitrogen-containing spiro ring of the group can be connected to other groups through one chemical bond, including at least These 3 connection methods; Indicates that the group includes at least These 6 connection methods; Indicates that the group includes at least: These 8 connection methods.
  • double bonds and single bonds have no limiting meaning.
  • All refer to a benzene ring or a phenyl group, wherein the double bond or Specifically refers to the large ⁇ bond delocalized in the plane of the benzene ring;
  • Z 3 is selected from N or CH;
  • Z 4 is selected from N or C;
  • ring A1 is a parallel 5-6 membered heteroaryl group
  • non-limiting examples of the structure include: These groups are included even if the parallel six-membered rings contain only two double bonds, or the parallel five-membered rings contain only one double bond, where the double bond represents a large ⁇ bond delocalized on the annular aromatic ring.
  • the numerical intervals used herein include the endpoint values and any values between the endpoint values.
  • “0-3” may include 0, 1, 2 or 3
  • “1-3” may include 1, 2 or 3.
  • C 1-n includes C 1-2 , C 1-3 , ... C 1-n .
  • a “C 1-6 " group means that there are 1-6 carbon atoms in the portion, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • C 1-4 alkyl refers to an alkyl group containing 1-4 carbon atoms, i.e., the alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Numerical ranges herein, such as “1-6” refer to each integer in the given range.
  • the ring atom refers to the non-hydrogen atom in the ring group that is used to form the ring.
  • the linking atoms in are 3 carbon atoms;
  • the atoms in the middle ring are three carbon atoms and one oxygen atom;
  • the atoms in the middle chain are 1 N atom and 5 carbon atoms;
  • the atoms in the middle chain are 8 carbon atoms and 1 nitrogen atom.
  • nm yuan refers to the number of annular atoms in a cyclic group.
  • a “5-10 yuan” group refers to a group having 5-10 annular atoms, i.e., the group comprises 5 annular atoms, 6 annular atoms, 7 annular atoms, 8 annular atoms, 9 annular atoms, or 10 annular atoms.
  • hydrocarbon group used herein alone or in combination refers to an atomic group consisting only of carbon and hydrogen elements, including saturated, unsaturated or aromatic hydrocarbon groups, such as alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl. Unless specifically stated, the “hydrocarbon group” can be straight chain, branched or cyclic.
  • alkyl used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched saturated aliphatic hydrocarbon. In the absence of a specified number of carbon atoms, the “alkyl” herein preferably has 1-6 carbon atoms, or has 1-5 carbon atoms, or has 1-4 carbon atoms, or has 1-3 carbon atoms.
  • Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, and the like.
  • alkyl refers to an alkyl group that can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, and the alkyl group herein also includes the case where no numerical range is specified.
  • the alkyl group may be optionally substituted or unsubstituted.
  • Alkyl as used herein in combination refers to an alkyl group attached to another group, for example, an alkyl group in an alkoxy group, and has the same definition as when used alone.
  • alkylene refers to a saturated aliphatic divalent hydrocarbon group derived from a straight or branched saturated aliphatic hydrocarbon group by removing two hydrogen atoms, wherein the two hydrogen atoms removed may be attached to the same carbon atom, and the formed divalent hydrocarbon group may be attached to the same atom.
  • alkylene groups include -CH2- (i.e., methylene), -CH2- CH2- ( i.e.
  • alkylene group may be optionally substituted or unsubstituted.
  • alkoxy or "-O-alkyl” as used herein, alone or in combination, is represented as "alkyl-O-".
  • alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
  • C1-6 alkoxy means that the alkyl in "alkyl-O-" is an alkyl having 1 to 6 carbon atoms.
  • Alkoxy may be optionally substituted or unsubstituted.
  • hydroxyalkyl as used herein alone or in combination is an alkyl group substituted by a hydroxy group.
  • C 1-3 hydroxyalkyl refers to an alkyl group containing 1 to 3 carbon atoms substituted by a hydroxy group, including hydroxymethyl, hydroxyethyl, and hydroxypropyl.
  • the hydroxy group may be substituted on any carbon atom of the hydroxyalkyl group, and the present application preferably substitutes on the terminal carbon atom.
  • the hydroxyalkyl group may be optionally substituted or unsubstituted.
  • cyclyl or "ring” used herein alone or in combination refers to any organic compound having a cyclic structure, wherein the cyclyl may be saturated or unsaturated and may include one or more heteroatoms such as N, O or S in its carbon skeleton.
  • cyclyls include carbocyclyls and heterocyclyls as discussed below, specifically cycloalkyls, cycloalkenyls, heterocycloalkyls, unsaturated heterocyclyls, aryls and heteroaryls.
  • any of the rings may be selected from cycloalkyls, cycloalkenyls, heterocycloalkyls, unsaturated heterocyclyls, aryls or heteroaryls; when one or more of the rings are aryls, the remaining rings may be aryls, or may be cycloalkyls, heterocycloalkyls, or unsaturated heterocyclyls that are not aromatic.
  • the number of rings in the cyclyl may be monocyclic, bicyclic or polycyclic.
  • bicyclic or polycyclic cyclyls may be divided into spirocyclics, bridged rings (including cyclic or condensed rings) according to different connection methods.
  • the cyclic group is a 3-15-membered cyclic group, which means it contains 3 to 12 ring atoms, and is preferably a 5-10-membered cyclic group.
  • spiro refers to a cyclyl with two or more cyclic structures and one atom (called spiro atom) shared between the monocyclic rings. It is preferably 5-8 yuan, more preferably 7-8 yuan. According to the number of spiro atoms shared between the rings, the spiro ring is divided into a single spiro, a double spiro or a multi-spiro cyclyl, and it is preferably a single spiro, preferably a 3-yuan/5-yuan or a 3-yuan/6-yuan spiro cyclyl. Its non-limiting examples include, but are not limited to, 6-azaspiro [2.5] octane-6-yl.
  • bridged ring refers to a polycyclic ring group containing two or more ring structures and sharing two or more atoms.
  • parallel ring or “condensed ring” is a special bridged ring, which refers to a polycyclic ring group containing two or more ring structures and sharing two or more atoms.
  • the bicyclic or polycyclic ring group that shares a pair of atoms is preferably 9-10-membered, more preferably 9-membered.
  • the number of constituent rings it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged ring group, preferably a bicyclic, more preferably a 5-membered/6-membered bicyclic and bridging ring group.
  • spiro and bridged rings may also be applied to cycloalkyl, heterocycloalkyl, and unsaturated heterocyclic groups discussed below, including spiroalkyl, spirocycloalkenyl, spiroheterocycloalkyl, spiroheterocycloalkenyl, bridged cycloalkyl, bridged cycloalkenyl, bridged heterocycloalkyl, and bridged heterocycloalkenyl.
  • Condensed rings include condensed cycloalkyl, condensed cycloalkenyl, condensed heterocycloalkyl, condensed heterocycloalkenyl, condensed ring aryl, and condensed ring heteroaryl.
  • the above terms are defined similarly to spiro, bridged, fused, or condensed rings.
  • heterocyclyl used herein alone or in combination includes alicyclic and heteroaryl groups, wherein one or more (such as one, two, three or four) of the annular atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, etc., including monocyclic, condensed, bridged and spirocyclic rings.
  • heterocyclic groups include heterocycloalkyl, unsaturated heterocyclic and heteroaryl groups as discussed below. 5-10 membered monocyclic or bicyclic heterocyclic groups are preferred herein, which may contain 1, 2 or 3 annular atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include azetidinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, oxathiolanyl, piperidinyl, 2-oxo-piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, piperazin-2-one, dioxanyl, morpholinyl and thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, etc.
  • the heterocyclyl group may be optionally substituted or unsubstituted.
  • cycloalkyl refers to a saturated monocyclic, bicyclic or polycyclic carbocyclic ring, which may be a spirocyclic or bridged ring.
  • the cycloalkyl is 5-8 members.
  • monocyclic cycloalkyls include, but are not limited to, cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc., which may be optionally substituted or unsubstituted.
  • spiro refers to a full-carbon polycyclic group with two or more cyclic structures and one carbon atom (called spiro atom) shared between the single rings. It is preferably 5 to 8 members, more preferably 8 members. According to the number of spiro atoms shared between the rings, the spiro ring is divided into a single spiro, a double spiro or a multi-spiro cycloalkyl, and it is preferably a single spiro cycloalkyl, preferably a 3-membered/6-membered spiro cycloalkyl.
  • cycloalkyl refers to an all-carbon polycyclic group containing two or more cyclic structures and sharing a pair of carbon atoms. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl.
  • heterocycloalkyl used herein alone or in combination refers to a saturated monocyclic, bicyclic or polycyclic, wherein one or more (such as one, two, three or four) annular atoms are saturated heterocyclic radicals of heteroatoms, which can be spirocyclic or bridged rings.
  • Non-limiting examples of monocyclic heterocycloalkyls include but are not limited to propylene oxide, thiirane, aziridine, azetidine, oxetane, thiamine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, oxazolidine, thiazolidine, imidazolidine, tetrahydropyran, piperidine, dioxane, azepane.
  • aryl used herein, alone or in combination, refers to an aromatic hydrocarbon ring.
  • aryl includes monocyclic aromatic hydrocarbons, annular aromatic hydrocarbons or polycyclic condensed ring aromatic hydrocarbons, wherein all condensed ring systems (excluding any ring system that is a part of an optional substituent or formed by an optional substituent) are aromatic. Examples of aryl groups/parts include phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless otherwise indicated, the term “aryl” does not include “heteroaryl”.
  • heteroaryl refers to a 5-10 membered (preferably 5-6 membered) monocyclic, bicyclic or tricyclic ring system, wherein at least one ring is aromatic, and at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and the heteroaryl has one or more attachment points to the rest of the molecule.
  • the "heteroaryl” of the bicyclic or tricyclic ring system if it contains a saturated or unsaturated heterocycloalkyl.
  • heteroaryl include furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, and the like; and also include, but are not limited to, the following bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indolyl, oxoindolyl, indolinyl, imidazopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, quinolyl, isoquinolyl, quinazolinyl, indazole, 1,8-naphthyridine, benzo[d]isoxazole, benzo[ d]thiazole, pyrrolo[3,2-b]pyridine, fur
  • unsaturated heterocyclic group used herein alone or in combination refers to a monocyclic, bicyclic or polycyclic group having one or more unsaturated double bonds and not having aromaticity, wherein one or more (such as one, two, three or four) of the atoms in the ring are heteroatoms, which may be a spirocyclic or bridged ring.
  • it is a monocyclic 6-membered unsaturated heterocyclic group, wherein 1-2 C atoms of the unsaturated heterocyclic group may be oxo-substituted
  • heterocycloalkenyl groups include but are not limited to the following
  • cyano as used herein, alone or in combination, refers to -CN.
  • substituted or “substituted by” means that one or more hydrogen atoms on a particular atom are replaced by a designated group (such as halogen, alkyl, etc.), and if the normal valence of the designated atom is not exceeded under the existing circumstances, the substitution results in a stable compound.
  • a designated group such as halogen, alkyl, etc.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.
  • composition refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component, including but not limited to a carrier, stabilizer, diluent, dispersant, suspending agent, thickener and/or excipient.
  • carrier refers to relatively nontoxic chemical compounds or agents that facilitate the introduction of a compound into cells or tissues.
  • stereoisomer as used herein includes, but is not limited to, enantiomers, cis-trans isomers, and the like.
  • enantiomer refers to the isomerism caused by the different spatial configuration of atoms or atomic groups (groups) in compounds with the same molecular formula, and two compounds that are enantiomers are mirror images of each other and cannot overlap.
  • cis-trans isomer generally refers to the stereoisomerism of diastereoisomers that occur in compound molecules due to the restriction factor of free rotation, which makes each group arranged in space differently.
  • Organic molecules containing such isomers such as olefins, azo compounds, alicyclic hydrocarbons, etc. are regarded as cis-trans isomerism.
  • cis-trans isomerism is mainly embodied in the form of alicyclic hydrocarbons.
  • cis-trans isomerism will occur when cyclohexane is replaced by two substituents, and when the two substituents are replaced on the same side of the ring, they are "cis” isomers, and on different sides, they are "trans” isomers.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, hindered isomers and geometric (conformation) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.
  • the structure described in the present invention also includes all isomers of the structure (e.g., diastereomers, enantiomers, cis-trans isomers, steric isomers, geometric (conformation) isomer forms), for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, cis-trans isomers of aliphatic cyclic hydrocarbons, steric isomers of biphenyl structures (see “Basic Organic Chemistry” (Second Edition), Volume 1, Xing Qiyi et al., p104-105); PAC, 1996, 68, 2193.
  • isomers of the structure e.g., diastereomers, enantiomers, cis-trans isomers, steric isomers, geometric (conformation) isomer forms
  • R and S configurations of each asymmetric center Z
  • (E) double bond isomers cis-trans isomers of alipha
  • Preparative Pre-HPLC conditions instrument: GILSON-GX281; wavelength: 220 nm & 254 nm; column model: Waters X-bridge (30 ⁇ 100 mm, 10 ⁇ m) or Luna C18 (30 ⁇ 75 mm, 3 ⁇ m) or Luna C18 (30 ⁇ 75 mm, 3 ⁇ m); mobile phase: A: 10 mM ammonium bicarbonate or H 2 O (0.1% formic acid) or H 2 O (0.1% trifluoroacetic acid), B: acetonitrile; running time: 15 min; flow rate: 25 mL/min.
  • Reverse phase column purification used a C18 reverse phase silica column (Spherical C18, 40-60 ⁇ m, 40g-120g) with water/acetonitrile (95/5 ⁇ 30/70) as the mobile phase.
  • 5-(4,4-difluoropiperidin-1-yl)-1,3,4-thiadiazole-2-amine (900 mg, 4.1 mmol) was dissolved in N,N-dimethylformamide (20 mL), and intermediate 1 (732 mg, 2.05 mmol), N,N-diisopropylethylamine (543 mg, 4.20 mmol) and HATU (2.3 g, 6.15 mmol) were added. The mixture was heated to 50 °C under nitrogen protection for 18 hours.
  • N-(5-(4,4-difluoropiperidin-1-yl)-1,3,4-thiadiazol-2-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 70 mg, 0.13 mmol was dissolved in 1,4-dioxane (5 mL), and 2-hydroxyethanesulfonamide (33 mg, 0.26 mmol), Xphos (25 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium (27 mg, 0.03 mmol) and cesium carbonate (85 mg, 0.26 mmol) were added in sequence. The mixture was heated to 100 ° C and stirred for 4 hours under nitrogen protection.
  • N-(1-(4,4-difluorocyclohexyl)-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 100 mg, 0.19 mmol was dissolved in 1,4-dioxane (5 mL), and 2-hydroxyethanesulfonamide (48 mg, 0.38 mmol), Xphos (40 mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol) and cesium carbonate (124 mg, 0.32 mmol) were added in sequence. The mixture was heated to 100 ° C and stirred for 4 hours under nitrogen protection.
  • 4,4-Difluorocyclohexyl methanesulfonate (678 mg, 6.0 mmol) was dissolved in N,N-dimethylformamide (20 mL), 4-nitro-1H-pyrazole (1.28 g, 6.0 mmol) and cesium carbonate (5.83 g, 18.0 mmol) were added, and the mixture was stirred at 100 ° C for 3 hours.
  • the reaction solution was cooled to room temperature, water (80 mL) was added, and the aqueous phase was extracted with ethyl acetate (80 mL x 4). The organic phase was washed with saturated sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • 1-(4,4-difluorocyclohexyl)-1H-pyrazole-4-amine (201 mg, 1 mmol) was dissolved in N,N-dimethylformamide (10 mL), and intermediate 1 (178.5 mg, 0.5 mmol), N,N-diisopropylethylamine (322.5 mg, 2.5 mmol) and HATU (578 mg, 1.5 mmol) were added. The mixture was heated to 50 °C and stirred for 4 hours under nitrogen protection.
  • N-(1-(4,4-difluorocyclohexyl)-1H-pyrazol-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 100 mg, 0.19 mmol was dissolved in 1,4-dioxane solution (5 mL), and 2-hydroxyethanesulfonamide (48 mg, 0.38 mmol), Xphos (40 mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol) and cesium carbonate (124 mg, 0.32 mmol) were added. The mixture was heated to 100 ° C and stirred for 4 hours under nitrogen protection.
  • N-(5-((4,4-difluorocyclohexyl)oxy)-1,3,4-thiadiazol-2-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 80 mg, 0.14 mmol
  • 2-hydroxyethanesulfonamide 34.8 mg, 0.28 mmol
  • 1,4-dioxane 3 mL
  • tris(dibenzylideneacetone)dipalladium 26 mg, 0.03 mmol
  • Xphos 28 mg, 0.06 mmol
  • cesium carbonate 92 mg, 0.28 mmol
  • N-(5-(3,3-difluorocyclobutyloxy)-1,3,4-thiadiazol-2-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 100 mg, 0.18 mmol was dissolved in 1,4-dioxane solution (5 mL), and 2-hydroxyethanesulfonamide (23 mg, 0.18 mmol), Xphos (43 mg, 0.09 mmol), tris(dibenzylideneacetone)dipalladium (83 mg, 0.09 mmol) and cesium carbonate (178 mg, 0.54 mmol) were added in sequence.
  • N-(1-(4,4-difluorocyclohexyl)-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (20 mg, 0.034 mmol) was dissolved in 1,4-dioxane solution (5 mL), and 2-hydroxyethanesulfonamide (9 mg, 0.068 mmol), Xphos (7 mg, 0.014 mmol), tris(dibenzylideneacetone)dipalladium (6 mg, 0.007 mmol) and cesium carbonate (22 mg, 0.068 mmol) were added in sequence.
  • N-(5-(4,4-difluoropiperidin-1-yl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (116 mg, 0.2 mmol) was dissolved in 1,4-dioxane (4 mL), and 2-hydroxyethanesulfonamide (50 mg, 0.4 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol), Xphos (19 mg, 0.04 mmol) and cesium carbonate (130 mg, 0.4 mmol) were added in sequence.
  • 3,5-Dibromo-1-methylpyrazine-2(1H)-one (3.0 g, 11.1 mmol) was dissolved in 1,4-dioxane (20 mL), and 4,4-difluoropiperidine hydrochloride (1.7 g, 11.1 mmol), tris(dibenzylideneacetone)dipalladium (1.1 g, 1.1 mmol), Xphos (1.2 g, 2.2 mmol) and cesium carbonate (11.5 g, 33.6 mmol) were added in sequence. The mixture was heated to 110°C under nitrogen protection for 12 hours.
  • N-(6-(4,4-difluoropiperidin-1-yl)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 70.0 mg, 0.12 mmol was dissolved in 1,4-dioxane (5 mL), and 2-hydroxyethanesulfonamide (18.0 mg, 0.14 mmol), tris(dibenzylideneacetone)dipalladium (27.7 mg, 0.03 mmol), Xphos (28.8 mg, 0.06 mmol) and cesium carbonate (117.3 mg, 0.36 mmol) were added in sequence.
  • N-(1-(4,4-difluorocyclohexyl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 150 mg, 0.26 mmol was dissolved in 1,4-dioxane solution (5 mL), and 2-hydroxyethanesulfonamide (65 mg, 0.52 mmol), Xphos (50 mg, 0.104 mmol), tris(dibenzylideneacetone)dipalladium (48 mg, 0.052 mmol) and cesium carbonate (170 mg, 0.52 mmol) were added in sequence.
  • N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (10 mg, 0.02 mmol) was dissolved in dioxane (5 mL), and 2-hydroxyethanesulfonamide (5 mg, 0.04 mmol), Xphos (1 mg, 0.002 mmol), tris(dibenzylideneacetone)dipalladium (1 mg, 0.001 mmol) and cesium carbonate (13 mg, 0.04 mmol) were added in sequence. The mixture was heated to 100 °C under nitrogen protection and stirred overnight.
  • N-(8-(4,4-difluoropiperidin-1-yl)imidazo[1,2-a]pyrazine-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (10 mg, 0.017 mmol) was dissolved in 1,4-dioxane solution (5 mL), and 2-hydroxyethanesulfonamide (4 mg, 0.034 mmol), Xphos (3 mg, 0.007 mmol), tris(dibenzylideneacetone)dipalladium (3 mg, 0.003 mmol) and cesium carbonate (11 mg, 0.034 mmol) were added in sequence.
  • 6-Nitro-1H-indazole (5 g, 30.68 mmol) was dissolved in 1-methyl-2-pyrrolidone (200 mL), and sodium 2-chloro-2,2-difluoroacetate (9.32 g, 61.35 mmol) and sodium hydride (2.21 g, 92.03 mmol) were added. The mixture was heated to 100 °C for 1 hour. The reaction solution was cooled to room temperature, poured into ice water, and extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • N-(1-(difluoromethyl)-1H-indazol-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 100 mg, 0.18 mmol was dissolved in 1,4-dioxane (3 mL), and 2-hydroxyethanesulfonamide (43.71 mg, 0.35 mmol), tris(dibenzylideneacetone)dipalladium (33 mg, 0.04 mmol), Xphos (36 mg, 0.07 mmol) and cesium carbonate (115 mg, 0.35 mmol) were added in sequence. The mixture was heated to 100 ° C under a nitrogen atmosphere and reacted overnight.
  • N-(2-(4-(difluoromethylene)piperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (90 mg, 0.16 mmol) was dissolved in 1,4-dioxane (5 mL), and 2-hydroxyethanesulfonamide (39 mg, 0.32 mmol), Xphos (8 mg, 0.016 mmol), tris(dibenzylideneacetone)dipalladium (7 mg, 0.008 mmol) and cesium carbonate (104 mg, 0.32 mmol) were added in sequence. The mixture was heated to 100 ° C and stirred overnight under nitrogen protection.
  • N-(2-(3-(difluoromethylene)piperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (84 mg, 0.15 mmol) was dissolved in 1,4-dioxane (10 mL), and 2-hydroxyethanesulfonamide (37 mg, 0.3 mmol), tris(dibenzylideneacetone)dipalladium (14 mg, 0.015 mmol), Xphos (14 mg, 0.03 mmol) and cesium carbonate (96 mg, 0.3 mmol) were added in sequence.
  • N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (1.1 g, 2.0 mmol) and tert-butyl carbamate (469 mg, 4.0 mmol) were dissolved in 1,4-dioxane (20 mL), and Xphos (191 mg, 0.4 mmol), tris(dibenzylideneacetone)dipalladium (183 mg, 0.2 mmol) and cesium carbonate (1.3 g, 4.0 mmol) were added in sequence. The mixture was heated to 85 ° C and stirred for 4 hours under nitrogen protection.
  • N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (28 mg, 0.05 mmol, step 2 of Example 19) was dissolved in 1,4-dioxane (3 mL), and (4-amino-1,2,5-oxadiazol-3-yl)methanol (6.5 mg, 0.06 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethoxyanthracene (3 mg, 5 umol), tris(dibenzylideneacetone)dipalladium (2.5 mg, 2.5 umol) and cesium carbonate (48.75 mg, 0.15 mmol) were added in sequence.
  • tert-butyl nitrite 441 mg, 3.86 mml
  • copper bromide 441 mg, 1.93 mmol
  • a solution of ethyl 4-amino-3-(6-azaspiro[2.5]octan-6-yl)benzoate in acetonitrile (20 mL) was stirred at room temperature for 16 hours under nitrogen protection.
  • the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (2 x 50 mL). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • N-(8-(4,4-difluoropiperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 60 mg, 0.1 mmol was dissolved in 1,4-dioxane (5 mL), and 2-hydroxyethanesulfonamide (25 mg, 0.2 mmol), Xphos (5 mg, 0.01 mmol), tris(dibenzylideneacetone)dipalladium (5 mg, 0.005 mmol) and cesium carbonate (65 mg, 0.2 mmol) were added in sequence.
  • N-(3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (76 mg, 0.14 mmol) was dissolved in 1,4-dioxane (5 mL), and 2-hydroxyethanesulfonamide (35 mg, 0.28 mmol), tris(dibenzylideneacetone)dipalladium (13 mg, 0.014 mmol), XPhos (14 mg, 0.03 mmol) and cesium carbonate (137 mg, 0.42 mmol) were added. The mixture was heated to 90°C under nitrogen protection for 16 hours.
  • 3-iodo-5-nitroindazole (2.32 g, 8 mmol) was dissolved in N,N-dimethylformamide (40 mL), sodium hydride (380 mg, 16 mmol) was slowly added, and the mixture was stirred at room temperature for 10 minutes. Methyl iodide (1.36 g, 9.6 mmol) was then added, and the reaction solution was kept at 30°C overnight. Water (200 mL) was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (100 mL x 2).
  • 3-iodo-1-methyl-5-nitro-1H-indoleazole (480 mg, 1.6 mmol) was dissolved in 1,4-dioxane (15 mL), and 3,3-difluoroazetidine (250 mg, 1.92 mmol), XantPhos (92 mg, 0.16 mmol), tris(dibenzylideneacetone)dipalladium (73 mg, 0.08 mmol) and cesium carbonate (1.56 g, 4.8 mmol) were added. The mixture was heated to 100 ° C under nitrogen protection and stirred overnight.
  • N-(3-(3,3-difluoroazetidine-1-yl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 50 mg, 0.21 mmol was dissolved in 1,4-dioxane solution (3 mL), and 2-hydroxyethanesulfonamide (78 mg, 0.62 mmol), Xphos (21 mg, 0.04 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.02 mmol) and cesium carbonate (200 mg, 0.62 mmol) were added. The mixture was heated to 100 ° C under nitrogen protection and stirred overnight.
  • 3-iodo-5-nitroindazole (2.32 g, 8 mmol) was dissolved in N,N-dimethylformamide (40 mL), sodium hydride (380 mg, 16 mmol) was slowly added, and the mixture was stirred at room temperature for 10 minutes. Methyl iodide (1.36 g, 9.6 mmol) was then added, and the mixture was stirred at 30°C overnight. Water (200 mL) was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (100 mL x 2).
  • 3-iodo-1-methyl-5-nitro-1H-indoleazole (1.0 g, 3.3 mmol) and cyclopropylboronic acid (344 mg, 4.0 mmol) were dissolved in a mixed solvent of 1,4-dioxane/water (10 mL/1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (270 mg, 0.33 mmol) and cesium carbonate (911 mg, 6.6 mmol) were added in sequence. The mixture was heated to 100°C and stirred overnight under nitrogen protection.
  • N-(3-cyclopropyl-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octyl-6-yl)benzamide 50 mg, 0.1 mmol was dissolved in 1,4-dioxane (5 mL), 2-hydroxyethanesulfonamide (25 mg, 0.2 mmol), Xphos (19 mg, 0.04 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol) and cesium carbonate (65 mg, 0.2 mmol) were added in sequence, and the mixture was heated to 90°C and stirred overnight under nitrogen protection.
  • N-(1-(4,4-difluorocyclohexyl)-1H-indazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 150 mg, 0.25 mmol was dissolved in 1,4-dioxane (10 mL), and 2-hydroxyethanesulfonamide (50 mg, 0.8 mmol), tris(dibenzylideneacetone)dipalladium (37 mg, 0.04 mmol), Xphos (38 mg, 0.08 mmol) and cesium carbonate (391 mg, 1.2 mmol) were added in sequence. The mixture was heated to 100 ° C under nitrogen protection for 3 hours.
  • Methyl (3,3-difluorocyclobutyl) methanesulfonate (1.0 g, 4.6 mmol) and 3-nitro-1H-pyrazole (520 mg, 4.6 mmol) were dissolved in dimethyl sulfoxide (8 mL), cesium carbonate (4.48 g, 13.8 mmol) was added, and the mixture was heated to 100 ° C and stirred overnight under nitrogen protection.
  • Water (30 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (40 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • N-(1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (58 mg, 0.11 mmol) was dissolved in 1,4-dioxane (5 mL), and 2-hydroxyethanesulfonamide (42 mg, 0.33 mmol), cesium carbonate (108 mg, 0.33 mmol), tris(dibenzylideneacetone)dipalladium (11 mg, 0.011 mmol) and Xphos (11 mg, 0.022 mmol) were added in sequence.
  • tert-butyl (tert-butyloxycarbonyl)(8-(3,3-difluoroazetidine-1-yl)imidazo[1,2-a]pyridin-6-yl)carbamate 260 mg, 0.5 mmol
  • dichloromethane 3 mL
  • trifluoroacetic acid 3 mL
  • the reaction solution is concentrated, sodium bicarbonate solution (30 mL) is added, and the aqueous phase is extracted with dichloromethane (20 ml x 3).
  • the organic phases are combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (174 mg, yellow solid), yield: 100%.
  • N-(8-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl]benzamide 100 mg, 0.18 mmol was dissolved in 1,4-dioxane (8 mL), and 2-hydroxyethanesulfonamide (113 mg, 0.9 mmol), Xphos (36 mg, 0.072 mmol), tris(dibenzylideneacetone)dipalladium (50 mg, 0.054 mmol) and cesium carbonate (234 mg, 0.72 mmol) were added in sequence.
  • Example 28 Referring to the synthesis method of Example 28, using (8-bromoimidazo[1,2-a]pyridin-6-yl)(tert-butoxycarbonyl)carbamic acid tert-butyl ester (Step 3 of Example 11) and 3,3-difluoropyrrolidine hydrochloride as starting materials, the title compound (3.3 mg, white solid) was obtained through similar steps. MS (ESI): m/z 575.1 [M+H] + .
  • N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 430 mg, 0.76 mmol, step 2 of Example 19
  • diboronic acid pinacol ester 231 mg, 0.91 mmol
  • PdCl 2 (dppf) 57 mg, 0.07 mmol
  • potassium acetate 149 mg, 1.52 mmol
  • N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (150 mg, 0.26 mmol) was dissolved in a mixed solvent of tetrahydrofuran/water (8 mL/2 mL), sodium periodate (170 mg, 0.79 mmol) was added, stirred at room temperature for half an hour, and then 1M aqueous hydrochloric acid solution (0.26 mL) was added and stirred at room temperature overnight.
  • N-(1-((4,4-difluorocyclohexyl)methyl)-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 100 mg, 0.18 mmol was dissolved in 1,4-dioxane (5 mL), and 2-hydroxyethanesulfonamide (34 mg, 0.27 mmol), cesium carbonate (176 mg, 0.54 mmol), tris(dibenzylideneacetone)dipalladium (16 mg, 0.018 mmol) and Xphos (18 mg, 0.036 mmol) were added. The mixture was heated to 100 ° C and stirred overnight under nitrogen protection.
  • N-(1-(Cyclopropylmethyl)-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 100 mg, 0.2 mmol
  • 2-hydroxyethanesulfonamide 53 mg, 0.2 mmol
  • 1,4-dioxane 5 mL
  • Xphos 10 mg, 0.02 mmol
  • tris(dibenzylideneacetone)dipalladium 10 mg, 0.01 mmol
  • cesium carbonate 136 mg, 0.4 mmol
  • N-(1-cyclopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 150 mg, 0.28 mmol
  • 2-hydroxyethanesulfonamide 85 mg, 0.68 mmol
  • Xphos 67 mg, 0.14 mmol
  • tris(dibenzylideneacetone)dipalladium 64 mg, 0.07 mmol
  • cesium carbonate 222 mg, 0.68 mmol
  • N-(3-(4,4-difluorocyclohexyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 100 mg, 0.16 mmol was dissolved in 1,4-dioxane solution (5 mL), and 2-hydroxyethanesulfonamide (40 mg, 0.32 mmol), Xphos (31 mg, 0.064 mmol), tris(dibenzylideneacetone)dipalladium (29 mg, 0.032 mmol) and cesium carbonate (104 mg, 0.32 mmol) were added in sequence.
  • Methyl (3,3-difluorocyclobutyl) methanesulfonate (300 mg, 1.5 mmol, step 1 of Example 27) and 3-nitro-1H-indazole (270 mg, 1.6 mmol) were dissolved in N,N-dimethylformamide (10 mL), cesium carbonate (1.5 g, 4.5 mmol) was added, and the mixture was heated to 100 ° C and stirred overnight under nitrogen protection. Water (30 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (30 mL x 3).
  • N-(1-((3,3-difluorocyclobutyl)methyl)-1H-indazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 160 mg, 0.28 mmol was dissolved in 1,4-dioxane (5 mL), and 2-hydroxyethanesulfonamide (35 mg, 0.28 mmol), cesium carbonate (273 mg, 0.84 mmol), tris(dibenzylideneacetone)dipalladium (13 mg, 0.014 mmol) and Xphos (14 mg, 0.028 mmol) were added in sequence. The mixture was heated to 100°C and stirred overnight under nitrogen protection.
  • N-(1-((3,3-difluorocyclobutyl)methyl)-5-methyl-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 200 mg, 0.37 mmol was dissolved in 1,4-dioxane (8 mL), and 2-hydroxyethanesulfonamide (139 mg, 1.11 mmol), Xphos (37 mg, 0.075 mmol), tris(dibenzylideneacetone)dipalladium (34 mg, 0.037 mmol) and cesium carbonate (361 mg, 1.11 mmol) were added in sequence.
  • N-(8-cyclopropylimidazo[1,2-a]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 200 mg, 0.39 mmol was dissolved in 1,4-dioxane (10 mL), and 2-hydroxyethanesulfonamide (59 mg, 0.47 mmol), Xphos (9 mg, 0.02 mmol), tris(dibenzylideneacetone)dipalladium (36 mg, 0.04 mmol) and cesium carbonate (382 mg, 1.17 mmol) were added in sequence. The mixture was heated to 100 °C under nitrogen protection and stirred overnight.

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Abstract

La présente invention concerne un composé ayant une structure telle que représentée par la formule générale (I) ; une substance deutérée, un stéréoisomère ou un sel pharmaceutiquement acceptable de celui-ci ; une composition pharmaceutique le contenant ; et une utilisation associée. Le composé selon la présente invention a un bon effet d'inhibition de la protéine KIF18A, et peut être utilisé pour traiter et/ou prévenir le cancer du côlon avancé ou métastatique, le cancer du sein, le cancer du poumon, le cancer du pancréas, le cancer de la prostate, le cancer de la vessie, le cancer de la tête, le cancer du cou, le cancer du col de l'utérus, le cancer péritonéal, le cancer de la trompe de Fallope, le cancer de l'ovaire ou le cancer de l'endomètre.
PCT/CN2023/125527 2022-10-21 2023-10-20 Inhibiteur de protéine kif18a WO2024083208A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2020132651A1 (fr) * 2018-12-20 2020-06-25 Amgen Inc. Inhibiteurs de kif18a
WO2020132653A1 (fr) * 2018-12-20 2020-06-25 Amgen Inc. Amides d'hétéroaryle utiles en tant qu'inhibiteurs de kif18a
WO2020132648A1 (fr) * 2018-12-20 2020-06-25 Amgen Inc. Inhibiteurs de kif18a
WO2021026098A1 (fr) * 2019-08-02 2021-02-11 Amgen Inc. Inhibiteurs de kif18a
WO2021026099A1 (fr) * 2019-08-02 2021-02-11 Amgen Inc. Inhibiteurs de kif18a
WO2021026100A1 (fr) * 2019-08-02 2021-02-11 Amgen Inc. Dérivés de pyridine en tant qu'inhibiteurs de kif18a
WO2021211549A1 (fr) * 2020-04-14 2021-10-21 Amgen Inc. Inhibiteurs de kif18a pour le traitement des maladies néoplasiques
WO2022268230A1 (fr) * 2021-06-25 2022-12-29 杭州英创医药科技有限公司 Composé destiné à être utilisé en tant qu'inhibiteur de kif18a
CN115785068A (zh) * 2021-09-10 2023-03-14 微境生物医药科技(上海)有限公司 Kif18a抑制剂
WO2023041055A1 (fr) * 2021-09-16 2023-03-23 微境生物医药科技(上海)有限公司 Inhibiteur de kif18a
WO2023088441A1 (fr) * 2021-11-19 2023-05-25 微境生物医药科技(上海)有限公司 Inhibiteur de kif18a
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

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020132651A1 (fr) * 2018-12-20 2020-06-25 Amgen Inc. Inhibiteurs de kif18a
WO2020132653A1 (fr) * 2018-12-20 2020-06-25 Amgen Inc. Amides d'hétéroaryle utiles en tant qu'inhibiteurs de kif18a
WO2020132648A1 (fr) * 2018-12-20 2020-06-25 Amgen Inc. Inhibiteurs de kif18a
WO2021026098A1 (fr) * 2019-08-02 2021-02-11 Amgen Inc. Inhibiteurs de kif18a
WO2021026099A1 (fr) * 2019-08-02 2021-02-11 Amgen Inc. Inhibiteurs de kif18a
WO2021026100A1 (fr) * 2019-08-02 2021-02-11 Amgen Inc. Dérivés de pyridine en tant qu'inhibiteurs de kif18a
WO2021211549A1 (fr) * 2020-04-14 2021-10-21 Amgen Inc. Inhibiteurs de kif18a pour le traitement des maladies néoplasiques
WO2022268230A1 (fr) * 2021-06-25 2022-12-29 杭州英创医药科技有限公司 Composé destiné à être utilisé en tant qu'inhibiteur de kif18a
CN115785068A (zh) * 2021-09-10 2023-03-14 微境生物医药科技(上海)有限公司 Kif18a抑制剂
WO2023041055A1 (fr) * 2021-09-16 2023-03-23 微境生物医药科技(上海)有限公司 Inhibiteur de kif18a
WO2023088441A1 (fr) * 2021-11-19 2023-05-25 微境生物医药科技(上海)有限公司 Inhibiteur de kif18a
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

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