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WO2024149189A1 - Dérivé d'amide aromatique, son procédé de préparation et son utilisation - Google Patents

Dérivé d'amide aromatique, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2024149189A1
WO2024149189A1 PCT/CN2024/071077 CN2024071077W WO2024149189A1 WO 2024149189 A1 WO2024149189 A1 WO 2024149189A1 CN 2024071077 W CN2024071077 W CN 2024071077W WO 2024149189 A1 WO2024149189 A1 WO 2024149189A1
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group
mmol
alkyl
cycloalkyl
benzo
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Chinese (zh)
Inventor
仇宗兴
叶成
徐代旺
徐肖杰
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Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
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Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
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Priority to CN202480006084.1A priority Critical patent/CN120418237A/zh
Publication of WO2024149189A1 publication Critical patent/WO2024149189A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to an aromatic amide derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and use of the derivative as a therapeutic agent, in particular as a KIF18A inhibitor.
  • Kinesin molecules are motor proteins that use microtubules as tracks and play an important role in organelle migration, tissue and organ development, signal transduction, mitosis, meiosis and other processes.
  • Various microtubule-associated proteins (MAPs) of the kinesin-8 family of kinesins regulate the dynamic instability of microtubules by affecting the polymerization and depolymerization of microtubules.
  • KIF18A is a member of the kinesin-8 family. It can move toward the positive pole using microtubules as tracks and tends to bind to longer microtubules. Its activity is length-dependent and affects the length of the spindle, which can ensure the timely and smooth completion of the alignment of sister chromosomes. Its functions in different species are very similar and conservative.
  • KIF18A is a molecular motor protein that moves toward the positive end of microtubules using microtubules as tracks. It regulates the midplate assembly of chromosomes by affecting the dynamic instability of the microtubule ends and functions during mitosis. In the late stage of mitosis, the protein is ubiquitinated and degraded to ensure the precise separation of chromosomes during mitosis and promote the smooth completion of mitosis and cytokinesis. In the early stage of mitosis, the localization of KIF18A at the positive end of microtubules close to the kinetochore is a necessary condition for its function.
  • KIF18A is also modified by reversible protein phosphorylation/dephosphorylation, but there is still a lack of systematic research on how the post-translational modification of this protein regulates the function of KIF18A.
  • Estrogen receptor ER ⁇ can bind to KIF18A and promote its transcription, but it is still unclear whether KIF18A is also regulated by other transcription factors. Therefore, the research on the gene transcription regulation mechanism of KIF18A needs to be deepened. During meiosis, cells lacking KIF18A will be unable to complete meiosis, which will lead to sperm formation disorders and testicular dysplasia in male animals.
  • KIF18A protein is highly expressed in a variety of cancers, including but not limited to hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, etc., which indicates that KIF18A is closely related to the occurrence and development of tumors and can become a target for molecular diagnosis and treatment of a variety of tumors.
  • the expression of KIF18A is related to the development of clinical colorectal cancer.
  • KIF18A can induce Akt phosphorylation, and knocking out KIF18A in mice can significantly promote cell apoptosis. It is speculated that KIF18A can promote the occurrence and development of colorectal cancer by activating the PI3K-Akt signaling pathway. KIF18A is also highly expressed in human breast cancer cells, and its overexpression is related to the grade, migration and prognosis of breast tumors. Studies on breast cancer cells have found that overexpression of KIF18A can lead to the production of multinucleated cells, while low expression can significantly reduce the ability of cell proliferation both in vivo and in vitro.
  • KIF18A is upregulated at both the transcriptional and translational levels in lung adenocarcinoma, and abnormal expression of KIF18A is associated with clinical pathological malignancy.
  • KIF18 gene mutations can be observed in lung adenocarcinoma, and its expression is also regulated by DNA copy number.
  • KIF18A gene knockout can inhibit the proliferation of lung adenocarcinoma cells in vivo and in vitro, and induce cell apoptosis and G2/M phase.
  • the genes that are highly expressed together with KIF18A are all concentrated in the cell cycle signaling pathway, so in-depth research on the mechanism of action of KIF18A in tumors is of great clinical significance.
  • the present invention provides a compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • Ring A is selected from a 5- to 7-membered heterocyclic group, a C 4 -C 7 cycloalkyl group, a 5- to 7-membered aryl group or a 5- to 7-membered heteroaryl group;
  • X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are each independently selected from CR a or a N atom;
  • Ra is selected from hydrogen, halogen, hydroxy, cyano, alkyl, alkoxy or heteroaryl; wherein the alkyl, alkoxy or heteroaryl is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;
  • L 1 is selected from a bond or C 1 -C 6 alkylene, wherein the alkylene is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano or alkoxy, and wherein one or more methylene groups of the alkylene are optionally replaced by one or more O, S(O) r , C(O) or NR b ;
  • L 2 is selected from
  • R b is selected from a hydrogen atom or an alkyl group
  • R2 are the same or different and are independently selected from hydrogen, halogen, hydroxyl, cyano, alkyl or alkoxy;
  • the alkyl or alkoxy group is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;
  • R 3 are each independently selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or alkoxy; R 3 is preferably a hydrogen atom;
  • R 4 is selected from a hydrogen atom, a deuterated alkyl group, a haloalkyl group, an alkyl group, an alkoxy group, a cycloalkylalkyl group, a heterocyclylalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group, wherein the cycloalkylalkyl group, the heterocyclylalkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a deuterium atom, a hydroxyl group, a halogen group, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group
  • R 4 is not selected from a hydrogen atom
  • two R 5 and the same carbon atom to which they are attached form a -C(O)-;
  • R9 , R10 and R11 are each independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more selected from hydroxyl, halogen substituted by a halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylate substituent;
  • n 0, 1 or 2; m is preferably 0;
  • n 0, 1, 2, 3 or 4;
  • r is independently 0, 1 or 2.
  • a preferred embodiment of the present invention is a compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, which is a compound of general formula (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt:
  • Ring A, R 1 , R 3 , R 4 , R 5 , L 1 and n are as defined in the general formula (I).
  • a preferred embodiment of the present invention is a compound of general formula (I) or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of general formula (IV) or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:
  • Ra is selected from C1-6 alkoxy or 5-6 membered heteroaryl
  • R4 is selected from alkyl, alkoxy, haloalkyl, deuterated alkyl or cycloalkyl, wherein the cycloalkyl is optionally further substituted with one or more deuterium atoms or halogens;
  • Ring A, R 1 , R 3 , R 5 , L 1 and n are as defined in the general formula (I).
  • a preferred embodiment of the present invention is a compound of formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein ring A is selected from:
  • a preferred embodiment of the present invention is a compound of general formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:
  • L 1 is selected from a bond or C 1 -C 6 alkylene, wherein the alkylene is optionally further substituted with one or more hydroxyl groups, and wherein the one or more methylene groups of the alkylene are optionally replaced with one or more O, S(O) r , C(O) or NR b ;
  • R b is selected from a hydrogen atom or a methyl group.
  • a preferred embodiment of the present invention is a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein L1 is selected from a bond, -NHSO2CH2CH2- , -SO2NHCH2CH2- , -SO2-, -CH2SO2- , -NHSO2- , -SO2NH- , -NHC(CH3) 2CH2-, -C (O)NHCH2CH2-, -C ( O)NHC (CH3)2CH2-, -C ( O ) N (CH3)CH2CH2-, -CH(CH3) ( OH ) CH2- , -NHSO2CH(CH3)CH2-, -SO2NHC( CH3 )2CH2-, -C(O)NHCH2CH2- , -C(O)NHC( CH3 )2CH2-, -C ( O)N( CH3 )CH2CH2-, -
  • a preferred embodiment of the present invention is a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R1 is selected from hydroxyl, alkyl, heterocyclic, cycloalkyl or heteroaryl, wherein the alkyl, heterocyclic, cycloalkyl or heteroaryl is optionally further substituted with one or more substituents selected from hydroxyl or alkyl.
  • a preferred embodiment of the present invention is a compound of general formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein for
  • a preferred embodiment of the present invention is a compound of general formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 3 is a hydrogen atom.
  • a preferred embodiment of the present invention is a compound of formula (I), (II), (III) or (IV) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R4 is selected from methyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, methoxy, isopropyl, deuterated methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl,
  • a preferred embodiment of the present invention is a compound of general formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from a hydrogen atom, a halogen, an alkyl, a cycloalkyl or a heterocyclic group; wherein the alkyl, cycloalkyl or heterocyclic group is optionally further substituted by one or more halogens; or, two R 5 and the same carbon atom to which they are connected form a -C(O)-.
  • the compound described by the general formula is selected from:
  • the present invention provides a use of a compound of general formula (I), (II), (III) or (IV) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a KIF18A inhibitor.
  • the present invention also provides a use of a compound of formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a medicament for treating a disease mediated by KIF18A, wherein the disease mediated by KIF18A is preferably cancer; wherein the disease mediated by KIF18A is selected from hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer and lung adenocarcinoma.
  • the present invention provides a compound described by general formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof, for use in preparing a drug for treating hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer and lung adenocarcinoma.
  • Alkyl when used as a group or a part of a group refers to a straight or branched aliphatic hydrocarbon group including C1 - C20 . Preferably, it is C1 - C10 alkyl, and more preferably C1 - C6 alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.
  • Alkyl can be substituted or unsubstituted.
  • Alkylene refers to a saturated C 1 -C 20 straight chain or branched aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms, preferably C 1 -C 10 alkylene, more preferably C 1 -C 6 alkylene.
  • alkylene groups include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, etc.
  • Alkylene can be substituted or unsubstituted.
  • Cycloalkyl refers to a non-aromatic cyclic alkyl group in which one or more of the atoms forming the ring are carbon atoms, including monocyclic, polycyclic, condensed, bridged and spirocyclic rings, preferably having a 5- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic or tricyclic ring.
  • Examples of “cycloalkyl” include, but are not limited to, cyclopropyl, cyclopentyl, and cyclobutyl. Cycloalkyl groups may be substituted or unsubstituted.
  • Spiroalkyl refers to a polycyclic group with 5 to 18 members, two or more ring structures, and the single rings share a carbon atom (called a spiro atom) with each other, and the ring contains one or more double bonds, but none of the rings has completely conjugated ⁇ electrons.
  • the aromatic system of the present invention is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl is divided into single spiro, double spiro or multiple spirocycloalkyl, preferably single spiro and double spirocycloalkyl, preferably 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan.
  • spirocycloalkyl include, but are not limited to: spiro [4.5] decyl, spiro [4.4] nonyl, spiro [3.5] nonyl, spiro [2.4] heptyl.
  • “Fused cycloalkyl” refers to a 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ -electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • fused cycloalkyl include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl or tetradecahydrophenanthryl.
  • “Bridged cycloalkyl” refers to a 5-18 membered, all-carbon polycyclic group containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron aromatic system, preferably 6-12 members, more preferably 7-10 members. Preferably 6-14 members, more preferably 7-10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s, 5s)-bicycloo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r, 5r)-bicyclo[3.3.2]decyl.
  • Heterocyclyl “heterocycloalkyl”, “heterocycle” or “heterocyclic” are used interchangeably in this application and refer to non-aromatic heterocyclic groups, wherein one or more of the atoms forming the ring are selected from nitrogen, oxygen or S(O) t (wherein t is selected from 0, 1 or 2) heteroatoms, including monocyclic, polycyclic, fused, bridged and spirocyclic rings. Preferably, it has a 5-7 membered monocyclic ring or a 7-10 membered bicyclic or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, hexahydropyrimidine,
  • the heterocyclic group may be substituted or unsubstituted.
  • “Spiro heterocyclic group” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one atom shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated ⁇ -electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t (wherein t is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon.
  • it is 6 to 14 members, more preferably 7 to 10 members.
  • the spiro alkyl group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-member/5-member or 5-member/6-member single spiral heterocyclic group.
  • spiroheterocyclyl include, but are not limited to, 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl.
  • “Fused heterocyclic group” refers to an all-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms with each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ -electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t (where t is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon.
  • it is 6 to 14 members, more preferably 7 to 10 members.
  • “Bridged heterocyclic group” refers to a 5-14-membered, 5-18-membered, polycyclic group containing two or more cyclic structures, sharing two atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ -electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t (wherein t is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon.
  • it is 6 to 14 members, more preferably 7 to 10 members.
  • bridged heterocyclic group include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl.
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be connected together in a fused manner.
  • aryl includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups.
  • the aryl group is a C 6 -C 10 aromatic group, more preferably, the aryl group is phenyl and naphthyl, and most preferably, naphthyl.
  • the aryl group may be substituted or unsubstituted.
  • Heteroaryl refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heteroaryl include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxazolyl, Cyclopentenyl, benzothiophenyl, benzimidazolyl, indolyl, isoindolyl, 1,3-di
  • Alkoxy refers to a group of (alkyl-O-), wherein alkyl is as defined herein.
  • C 1 -C 6 alkoxy is preferred, and examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Niro refers to a -NO2 radical.
  • Hydrophilicity refers to an -OH group.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • Cyano refers to -CN.
  • Carboxy refers to -C(O)OH.
  • Carboxylate refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.
  • Hydroalkyl refers to an alkyl group substituted with a hydroxy group wherein alkyl is as defined above.
  • Aminoalkyl refers to an alkyl group substituted with an amino group, wherein alkyl is as defined above.
  • Haloalkyl refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.
  • Haloalkoxy refers to an alkoxy group substituted with a halogen group, wherein alkoxy is as defined above.
  • DMSO dimethyl sulfoxide
  • BOC refers to tert-butoxycarbonyl
  • THP refers to 2-tetrahydropyranyl
  • TFA trifluoroacetic acid
  • Ts refers to p-toluenesulfonyl.
  • leaving group is an atom or functional group that leaves a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called the leaving group. Groups that are easy to accept electrons and have a strong ability to bear negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to leave other molecules.
  • Common leaving groups include but are not limited to halogens, mesyl, -OTs or -OH.
  • Substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.
  • R9 , R10 and R11 are each independently selected from hydrogen, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylate. is substituted by a substituent of a group;
  • r is selected from 0, 1 or 2;
  • 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 and atropisomers and geometric (conformation) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.
  • structures depicted herein also encompass all isomeric (e.g., diastereoisomers, enantiomers, and atropisomers and geometric (conformational) isomeric forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereoisomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (conformational) isomeric mixtures of the compounds of the invention are within the scope of the invention.
  • “Pharmaceutically acceptable salts” refer to salts of the above compounds that can retain their original biological activity and are suitable for medical use.
  • Pharmaceutically acceptable salts of the compounds represented by general formula (I) may be metal salts or amine salts formed with suitable acids.
  • the present invention adopts the following technical solution:
  • the present invention provides a method for preparing a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, the method comprising:
  • L 2 is selected from
  • Y is selected from hydroxyl or chlorine
  • Ring A, X 1 to X 6 , L 1 , R 1 to R 5 , m and n are as defined in the general formula (I).
  • the mass spectrum is obtained by LC/MS, and the ionization method can be ESI or APCI.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.
  • CD 3 OD deuterated methanol.
  • Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1L.
  • the solution in the reaction refers to an aqueous solution.
  • the compound is purified by silica gel column chromatography and reverse phase column chromatography, wherein the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: ethyl acetate; D: trifluoroacetic acid aqueous solution and acetonitrile system.
  • the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine, can also be added for adjustment.
  • methyl 2-(bromomethyl)-6-nitrobenzoate 1a 300 mg, 1.09 mmol, prepared by the known method "Patent WO2021126973A1" was added to methanol (8 mL), triethylamine (443 mg, 4.38 mmol) and 3,3-difluorocyclobutyl-1-amine 1b (314 mg, 2.19 mmol, commercially available) were added to the above reaction solution, nitrogen was replaced three times, and the reaction was carried out at 70 ° C for 18 hours.
  • the reaction was carried out at 100°C for 18 hours.
  • the mixture was poured into water (10 mL), and the mixture was extracted with ethyl acetate (10 mL ⁇ 3).
  • the organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure.
  • Zinc powder (845 mg, 12.9 mmol) and ammonium chloride (346 mg, 6.46 mmol) were added to a methanol (5 mL) solution of 2-(cyclopropylmethyl)-7-nitroisoindolin-1-one 2b (300 mg, 1.29 mmol) at 25°C and reacted at 65°C for 6 hours.
  • the mixture was filtered and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to give 7-amino-2-(cyclopropylmethyl)isoindolin-1-one 2c (150 mg) in a yield of 57%.
  • the reaction was carried out at 100 °C for 18 hours.
  • the mixture was poured into water (10 mL), and the mixture was extracted with ethyl acetate (10 mL ⁇ 3).
  • the organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure.
  • methyl 2-(bromomethyl)-6-nitrobenzoate 1a 500 mg, 1.82 mmol was added to methanol (10 mL), triethylamine (554 mg, 5.47 mmol) and (3,3-difluorocyclobutyl)methylamine hydrochloride 4a (332 mg, 2.74 mmol) were added to the above reaction solution, nitrogen was replaced three times, and the reaction was carried out at 70°C for 18 hours.
  • the reaction was carried out at 100 °C for 18 hours.
  • the mixture was poured into water (10 mL), and the mixture was extracted with ethyl acetate (10 mL ⁇ 3).
  • the organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure.
  • reaction solution was poured into water and extracted with ethyl acetate (50 mL ⁇ 3). The extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-7-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 5f (180 mg) with a yield of 41%.
  • 2-hydroxyethane-1-sulfonamide 1g (80.7mg, 0.64mmol), cuprous iodide (61.4mg, 0.32mmol), potassium phosphate (137mg, 0.64mmol) and trans-N,N'-dimethyl-1,2-cyclohexanediamine (22.9mg, 0.16mmol) were added to a solution of 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-7-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 5f (180mg, 0.32mmol) in N,N-dimethylformamide (5mL), the atmosphere was replaced with nitrogen three times, and the reaction was carried out at 100°C for 16 hours.
  • reaction solution was poured into water and extracted with ethyl acetate (50 mL ⁇ 3). The extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • ethyl glyoxylate (1.64 g, 16.0 mmol) was added to a solution of 3-bromobenzene-1,2-diamine 7a (2.00 g, 10.69 mmol) in ethanol (20 mL), and the mixture was reacted at 80°C for 18 hours.
  • the mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL ⁇ 3), and the combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography (eluent: System A) to obtain 5-bromoquinoxaline-2(1H)-one 7b (2.20 g) with a yield of 91%.
  • Phosphorus oxychloride (8.18 g, 53.3 mmol) was added to a solution of 5-bromoquinoxaline-2(1H)-one 7b (2.00 g, 8.89 mmol) in acetonitrile (20 mL) at 25°C, and the mixture was reacted at 90°C for 3 hours.
  • the mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL ⁇ 3), the combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography (eluent: System A) to obtain 5-bromo-2-chloroquinoxaline 7c (260 mg) with a yield of 12%.
  • the mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL ⁇ 3), the extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • 8-bromo-2-chloroquinoxaline 8a 300 mg, 1.23 mmol, prepared by the known method "WO2013130660A1" was added to dimethyl sulfoxide (8 mL), 3,3-difluoroazetidine hydrochloride (160 mg, 1.23 mmol) and potassium carbonate (341 mg, 2.46 mmol) were added to the above reaction solution, nitrogen was replaced three times, and the reaction was carried out at 65 ° C for 18 hours.
  • the mixture was poured into water (10 mL), the mixture was extracted with ethyl acetate (10 mL ⁇ 3), the organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography (eluent: A system) to obtain 8-bromo-2-(3,3-difluoroazetidine-1-yl)quinoxaline 8b (300 mg), with a yield of 81.14%.
  • 8-bromo-2-(3,3-difluoroazetidin-1-yl)quinoxaline 8b 300 mg, 1.00 mmol
  • tert-butyl carbamate 129 mg, 1.10 mmol
  • 1,4-dioxane 5 mL
  • 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl 71.5 mg, 0.150 mmol
  • triphenylphosphine 129 mg, 1.10 mmol
  • cesium carbonate 977 mg, 3.00 mmol
  • tert-butyl (3-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)carbamate 8c (100 mg, 0.297mmol) was added to dichloromethane (2mL), and a solution of hydrogen chloride in 1,4-dioxane (4M, 2mL) was added to the above reaction solution, and the reaction was carried out at 25°C for 18 hours. The mixture was concentrated under reduced pressure to obtain 3-(3,3-difluoroazetidin-1-yl)quinoxaline-5-amine 8d (60mg, 0.254mmol, 85.43% yield).
  • the reaction was carried out at 100°C for 18 hours.
  • the mixture was poured into water (10 mL), and the mixture was extracted with ethyl acetate (10 mL ⁇ 3).
  • the organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • 2-chloro-4-nitro-1H-benzo[d]imidazole 9a (40.0 mg, 0.202 mmol, prepared by the known method "WO2013104577A1") and 4,4-difluoropiperidine (245 mg, 2.02 mmol) were mixed and reacted at 100°C for 18 hours.
  • the mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL ⁇ 3), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Phosphorus oxychloride (10 mL) was added to 4-bromo-1,3-dihydro-2H-benzo[d]imidazole-2-one 10a (1.00 g, 4.69 mmol, prepared by the known method "WO2009111260A1"), and the reaction was carried out at 90°C for 3 hours after nitrogen substitution three times.
  • Phosphorus oxychloride was removed under reduced pressure and slowly added dropwise to water (50 mL) under stirring to quench, and the obtained product was poured into water (50 mL), extracted with ethyl acetate (60 mL ⁇ 2), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4-bromo-2-chloro-1H-benzo[d]imidazole 10b (1.00 g), with a yield of 92.03%.
  • reaction solution was diluted with water (150 mL), extracted with ethyl acetate (60 mL ⁇ 2), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography (eluent: System A) to obtain 4-bromo-2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazole 10d (520.00 mg), yield: 41.49%; 7-bromo-2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazole 10d (520.00 mg), yield: 41.49%; pyridine-1-yl)-1-methyl-1H-benzo[d]imidazole 10e (400.00 mg), yield: 31.92%.
  • reaction solution was diluted with water (40 mL), extracted with ethyl acetate (40 mL ⁇ 2), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-yl)carbamate 10f (480 mg), yield: 83%.
  • 2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-amine 10g (100mg, 0.38mmol) was dissolved in N,N-dimethylformamide (1mL), and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 5e (116mg, 0.38mmol), N,N-diisopropylethylamine (194mg, 1.50mmol) and (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (293.69mg, 0.56mmol) were added in sequence.
  • reaction solution was diluted with water (40 mL), extracted with ethyl acetate (40 mL ⁇ 2), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-7-yl)carbamate 11a (280 mg), yield: 63%.
  • 1-bromo-3-fluoro-2-nitrobenzene 12a (5.00 g, 22.7 mmol, commercially available) was added to 1,2-dichloroethane (50 mL), and cyclopropylamine (3.89 g, 68.2 mmol) was added to the above reaction solution, replaced with nitrogen three times, and reacted at 80°C for 18 hours.
  • the mixture was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: A system) to obtain 3-bromo-N-cyclopropyl-2-nitroaniline 12b (5.50 g), with a yield of 94.13%.
  • 3-bromo-N-cyclopropyl-2-nitroaniline 12b (5.50 g, 21.4 mmol) was added to a mixed solvent of ethanol (30 mL), tetrahydrofuran (30 mL) and water (15 mL), iron powder (7.17 g, 128 mmol) and ammonium chloride (11.4 g, 214 mmol) were added to the above reaction solution, nitrogen was replaced three times, and the reaction was carried out at 60°C for 2 hours. After the mixture was cooled to room temperature, ethyl acetate (30 mL) and diatomaceous earth (10 g) were added to the solution and stirred for 1 hour.
  • Trifluoroacetic anhydride (277.45 mg, 1.32 mmol) was added to a solution of 3-bromo-N1-cyclopropylbenzene-1,2-diamine 12c (300 mg, 1.32 mmol), pyridine (418 mg, 5.28 mmol) and 4-dimethylaminopyridine (32.3 mg, 0.264 mmol) in tetrahydrofuran (3 mL), and the mixture was stirred at 70°C for 2 hours to form a yellow solution.
  • N-(2-bromo-6-(cyclopropylamino)phenyl)-3,3,3-trifluoropropionamide 13a (1.3 g, 3.86 mmol) was added to acetic acid (5 mL), replaced with nitrogen three times, and reacted at 65°C for 18 hours. The mixture was filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: A system) to obtain 4-bromo-1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole 13b (1.0 g), yield: 81.27%.
  • tert-butyl (1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-yl)carbamate 13c 350 mg, 0.985 mmol was added to dichloromethane (5 mL), and a solution of hydrogen chloride in dioxane (4 M, 2.5 mL) was added to the reaction solution, and the reaction was carried out at 25°C for 18 hours. The mixture was concentrated to dryness under reduced pressure to give 1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-amine 13d (250 mg), with a yield of 99.45%.
  • the reaction was carried out at 70°C for 18 hours.
  • the mixture was poured into water (10 mL), and the mixture was extracted with ethyl acetate (10 mL ⁇ 3).
  • the organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure.
  • the reaction was carried out at 90 °C for 18 hours.
  • the mixture was poured into water (30 mL), extracted with ethyl acetate (20 mL ⁇ 2), the organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Example 14 was synthesized according to the synthesis method of Example 12 of the present invention.
  • the structure and characterization data of Example 14 are shown in the following table:
  • the reaction mixture was cooled to room temperature, poured into 200 mL of ice water, adjusted to pH 6 with 2M dilute hydrochloric acid, extracted with dichloromethane (200 mL ⁇ 3), and the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated.
  • the crude product was purified by silica gel column chromatography (eluent: System A) to obtain 4-(ethylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 15c (0.75 g). Yield: 79.16%.
  • N-(2-amino-3-nitrophenyl)cyclopropanecarboxamide 15e (500 mg, 2.26 mmol) was dissolved in acetic acid (5 mL), heated to 100°C and stirred for 1 hour. The mixture was concentrated under reduced pressure to give 2-cyclopropyl-4-nitro-1H-benzo[d]imidazole 15f (450 mg). Yield: 97%.
  • Examples 16-21 were synthesized according to the synthesis method of Example 15 of the present invention.
  • the structures and characterization data of Examples 16-21 are shown in the following table:
  • 3-methoxybenzene-1,2-diamine 22a (850 mg, 6.15 mmol, commercially available) was dissolved in trifluoroacetic acid (7.01 g, 61.5 mmol), replaced with nitrogen three times, heated to 70°C and stirred for 5 hours under nitrogen protection.
  • the cooled reaction solution was poured into 100 mL of water, extracted with ethyl acetate (50 mL ⁇ 2), washed with saturated sodium chloride solution (50 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure.
  • Examples 23-32 were synthesized according to the synthesis method of Example 22 of the present invention.
  • the structures and characterization data of Examples 23-32 are shown in the following table:
  • the reaction solution was put into water and extracted with ethyl acetate (1 mL ⁇ 3). The extracts were combined, washed with saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product was purified by preparative high performance liquid chromatography (separation column AKZONOBEL Kromasil; 250 ⁇ 21.2 mm ID; 5 ⁇ m, 20 mL/min; mobile phase A: 0.05% ammonium bicarbonate + H 2 O, mobile phase B: CH 3 CN) to obtain N-(2,7-dimethoxy-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 33 (16.4 mg). Yield: 24%.
  • 2-Amino-6-bromophenol 34a (1.00 g, 5.32 mmol) and 2,2-difluorocyclopropane-1-carboxylic acid (844 mg, 6.91 mmol) were added to carbon tetrachloride (20 mL), triethylamine (1.61 g, 16.0 mmol) and triphenylphosphine (4.86 g, 16.0 mmol) were added, and the resulting mixture was stirred at 80 ° C under nitrogen protection for 16 hours.
  • 3-Bromo-6-nitrobenzene-1,2-diamine 49b (700 mg, 3.02 mmol) and cyclopropylcarbonyl chloride (473 mg, 4.53 mmol) were added to acetonitrile (8 mL) at 0°C, triethylamine (305.27 mg, 3.02 mmol) was added, and the mixture was stirred at 0°C for 2 hours.
  • the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL ⁇ 2).
  • N-(2-amino-6-bromo-3-nitrobenzene)cyclopropanecarboxamide 49c (900 mg, 3.00 mmol) was dissolved in acetic acid (13 mL), heated to 100°C and stirred for 6 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the crude product was added to ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure.
  • N-(2-amino-3-fluorophenyl)cyclopropanecarboxamide 50b (769 mg, 3.96 mmol) was dissolved in acetic acid (20 mL) and stirred at 100°C for 2 hours.
  • the reaction solution was concentrated to dryness and then poured into a saturated sodium bicarbonate solution (70 mL), extracted with ethyl acetate (100 mL ⁇ 2), and the combined organic phase was washed with a saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure.
  • the crude product was purified by silica gel column chromatography (eluent: A system) to obtain 2-cyclopropyl-7-fluoro-1H-benzo[d]imidazole 50c (583 mg). Yield: 83%.
  • Test Example 1 Determination of the inhibitory effect of the compounds of the present invention on OVCAR-3 cell proliferation
  • OVCAR-3 cells (containing the TP53 R248Q mutation) were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100 U penicillin, and 100 ⁇ g/mL streptomycin. Cell viability was measured by The assay was performed using the Luminescent Cell Viability Assay Kit (Promega, Catalog No. G7573).
  • test compound was first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with culture medium to prepare the test sample, and the final concentration of the compound ranged from 1000nM to 0.015nM.
  • Cells in the logarithmic growth phase were seeded into a 96-well cell culture plate at a density of 1000 cells per well, cultured overnight in a 37°C, 5% CO2 incubator, and then the test compound was added and continued to be cultured for 72 hours.
  • the compound of the present invention has a good inhibitory effect on the proliferation of OVCAR-3 cells with IC 50 ⁇ 50nM.
  • AMG 650 prepared according to the patent publication WO2020132648A1, Example 4 is as follows:
  • Test Example 2 Determination of the inhibitory effect of the compounds of the present invention on HT-29 cell proliferation
  • HT-29 cells (containing the TP53R273H mutation) were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in McCoy's 5A medium containing 10% fetal bovine serum, 100 U penicillin, and 100 ⁇ g/mL streptomycin. Cell viability was measured by The assay was performed using the Luminescent Cell Viability Assay Kit (Promega, Catalog No. G7573).
  • test compound was first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with culture medium to prepare the test sample, and the final concentration of the compound ranged from 1000nM to 0.015nM.
  • Cells in the logarithmic growth phase were inoculated into a 96-well cell culture plate at a density of 1000 cells per well, cultured overnight in a 37°C, 5% CO2 incubator, and then the test compound was added and continued to be cultured for 120 hours.
  • the compounds of the present invention have a good inhibitory effect on HT-29 cell proliferation with IC 50 ⁇ 50nM.
  • Test Example 3 Test of the Inhibition of KIF18A Enzyme Activity by the Compounds of the Invention
  • the following method is used to determine the degree of inhibition of the compound of the present invention on the recombinant human KIF18A enzyme activity under in vitro conditions.
  • This method uses the ADP-Glo TM Kinase Assay kit (Cat. No. V9102) from Promega.
  • ADP-Glo TM Kinase Assay kit Cat. No. V9102
  • the kit instructions please refer to the kit instructions.
  • test compound is first dissolved in DMSO to prepare a storage solution, and then gradiently diluted using reaction buffer A (15mM Tris, pH 7.5, 10mM MgCl2, 0.01% Pluronic F-68).
  • reaction buffer A 15mM Tris, pH 7.5, 10mM MgCl2, 0.01% Pluronic F-68.
  • the final concentration range of the test compound in the reaction system is 10000nM to 0.15nM
  • reaction buffer B (15mM Tris, pH 7.5, 10mM MgCl2, 0.01% Pluronic F-68, 37.5ug/ml tubulin, 1.25uM paclitaxel) is used to prepare KIF18A protein and ATP working solution.
  • the reaction was carried out in a 384-well microplate.
  • the compound and recombinant human KIF18A protein (final concentration 100nM, entrusted to GenScript for expression) were added to the wells and incubated at room temperature for 20 minutes.
  • ATP solution from ADP-Glo TM Kinase Assay kit component V915A, final concentration 60uM was added to the reaction solution and incubated at room temperature for 20 minutes.
  • 5 ⁇ L ADP-Glo Reagent was added to the reaction system and incubated at room temperature for 50 minutes.
  • 10 ⁇ L Kinase Detection Reagent was added to the reaction system and incubated at room temperature for 30 minutes.
  • the chemiluminescence intensity value of each well was measured in the ELISA reader in Luminescence mode.
  • the percentage inhibition rate of the compound at each concentration was calculated by comparing the luminescence intensity ratio with the control group (0.1% DMSO), and the IC 50 value of the compound was obtained by nonlinear regression analysis of the compound concentration logarithm-inhibition rate by GraphPad Prism 5 software, as shown in Table 3.
  • the compounds of the present invention have a significant inhibitory effect on KIF18A enzyme activity with an IC 50 of ⁇ 200 nM.
  • Test Example 4 Pharmacokinetics of the Compounds of the Invention in Mice
  • ICR mice were used as test animals, and the drug concentrations in plasma at different times after oral administration of the control compound AMG650 and the compound 22 of the present invention were determined by LC/MS/MS to study the pharmacokinetic characteristics of the compound of the present invention in mice.
  • ICR mice male, 27.2-30.5 g, were purchased from Weitonglihua Laboratory Animal Technology Co., Ltd.
  • mice were fasted overnight and then intragastrically administered with each test compound injection group (9 mice per group) (PO, compound dosage was 10 mg/kg, administration volume was 10 mL/kg), and food was allowed to be consumed 4 hours after administration.
  • PO mice per group
  • the content of the test compound in mouse plasma after oral administration was determined by LC-MS/MS.

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Abstract

L'invention concerne un dérivé d'amide aromatique, son procédé de préparation et une utilisation d'une composition pharmaceutique contenant le dérivé en médecine. Spécifiquement, l'invention concerne un dérivé d'amide aromatique tel que représenté par la formule générale (I), son procédé de préparation, un sel pharmaceutiquement acceptable de celui-ci, et une utilisation de celui-ci en tant qu'agents thérapeutiques, en particulier des inhibiteurs de KIF18A, les définitions des substituants dans la formule générale (I) étant les mêmes que les définitions dans la description.
PCT/CN2024/071077 2023-01-09 2024-01-08 Dérivé d'amide aromatique, son procédé de préparation et son utilisation Ceased WO2024149189A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025036479A1 (fr) * 2023-08-16 2025-02-20 上海湃隆生物科技有限公司 Inhibiteur de kinésine kif18a et son utilisation
WO2025157274A1 (fr) * 2024-01-25 2025-07-31 海南先声再明医药股份有限公司 Composés amides substitués par un cycle, composition et utilisation associées
US12391709B2 (en) 2022-08-18 2025-08-19 Accent Therapeutics, Inc. Inhibitors of KIF18A and uses thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114302880A (zh) * 2019-08-02 2022-04-08 美国安进公司 Kif18a抑制剂
CN114391012A (zh) * 2019-08-02 2022-04-22 美国安进公司 作为kif18a抑制剂的吡啶衍生物
WO2023174175A1 (fr) * 2022-03-17 2023-09-21 微境生物医药科技(上海)有限公司 Inhibiteur de kif18a
WO2023217233A1 (fr) * 2022-05-13 2023-11-16 上海湃隆生物科技有限公司 Inhibiteur de kinésine kif18a et son utilisation
CN117209472A (zh) * 2022-06-10 2023-12-12 武汉人福创新药物研发中心有限公司 Kif18a抑制剂
WO2024002328A1 (fr) * 2022-06-30 2024-01-04 勤浩医药（苏州）有限公司 Composé contenant de l'azote et son utilisation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114302880A (zh) * 2019-08-02 2022-04-08 美国安进公司 Kif18a抑制剂
CN114391012A (zh) * 2019-08-02 2022-04-22 美国安进公司 作为kif18a抑制剂的吡啶衍生物
WO2023174175A1 (fr) * 2022-03-17 2023-09-21 微境生物医药科技(上海)有限公司 Inhibiteur de kif18a
WO2023217233A1 (fr) * 2022-05-13 2023-11-16 上海湃隆生物科技有限公司 Inhibiteur de kinésine kif18a et son utilisation
WO2023217230A1 (fr) * 2022-05-13 2023-11-16 上海湃隆生物科技有限公司 Inhibiteur de kinésine kif18a et son utilisation
CN117209472A (zh) * 2022-06-10 2023-12-12 武汉人福创新药物研发中心有限公司 Kif18a抑制剂
WO2024002328A1 (fr) * 2022-06-30 2024-01-04 勤浩医药（苏州）有限公司 Composé contenant de l'azote et son utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TAMAYO, N. A. ET AL.: "Targeting the Mitotic Kinesin KIF18A in Chromosomally Unstable Cancers: Hit Optimization Toward an In Vivo Chemical Probe", JOURNAL OF MEDICINAL CHEMISTRY, vol. 65, 14 March 2022 (2022-03-14), pages 4972 - 4990, XP093064019, DOI: 10.1021/acs.jmedchem.1c02030 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12391709B2 (en) 2022-08-18 2025-08-19 Accent Therapeutics, Inc. Inhibitors of KIF18A and uses thereof
WO2025036479A1 (fr) * 2023-08-16 2025-02-20 上海湃隆生物科技有限公司 Inhibiteur de kinésine kif18a et son utilisation
WO2025157274A1 (fr) * 2024-01-25 2025-07-31 海南先声再明医药股份有限公司 Composés amides substitués par un cycle, composition et utilisation associées

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