WO2024078569A1 - 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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WO2024078569A1
WO2024078569A1 PCT/CN2023/124209 CN2023124209W WO2024078569A1 WO 2024078569 A1 WO2024078569 A1 WO 2024078569A1 CN 2023124209 W CN2023124209 W CN 2023124209W WO 2024078569 A1 WO2024078569 A1 WO 2024078569A1
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group
methyl
mmol
azaspiro
indazol
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PCT/CN2023/124209
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English (en)
Chinese (zh)
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仇宗兴
曹海
彭记磊
汪泽峰
张盼盼
叶成
郭泽
徐代旺
周厚江
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浙江海正药业股份有限公司
上海昂睿医药技术有限公司
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Publication of WO2024078569A1 publication Critical patent/WO2024078569A1/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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

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 microtubule ends and functions during mitosis. In late 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 early mitosis, the localization of KIF18A at the positive end of microtubules close to the kinetochore is a necessary condition for its function. The localization depends not only on the motor activity of its N-terminus, but also on the tail domain with microtubule binding ability.
  • KIF18A is also reversibly phosphorylated/dephosphorylated, 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 proliferation ability of cells both in vivo and in vitro.
  • KIF18A stabilizing microtubules at the ends of microtubules and inactivating the PI3K-Akt signal transduction pathway, which induces cell apoptosis.
  • 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 affected by the DNA copy number. Regulation, KIF18A gene knockout can inhibit the proliferation of lung adenocarcinoma cells in vivo and in vitro, induce apoptosis and G2/M phase arrest.
  • the genes that are highly expressed at the same time as KIF18A are 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 3 -C 6 cycloalkyl group, a 5- to 7-membered aryl group or a 5- to 7-membered heteroaryl group;
  • X 1 , X 2 , and X 3 are each independently selected from CR a or a N atom, and at most two atoms among X 1 , X 2 , and X 3 are N atoms at the same time;
  • R a is selected from hydrogen atom, halogen, hydroxyl, cyano, alkyl or alkoxy; wherein the alkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, alkyl or alkoxy;
  • L 1 is selected from a bond or a C 1 -C 6 alkylene group, wherein the alkylene group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or alkoxy, and wherein the one or more methylene groups of the alkylene group are optionally replaced by one or more O, S(O) r , C(O) or NR b ; wherein the “one or more methylene groups” include any one, multiple or all of the methylene groups in the C 1 -C 6 alkylene group.
  • L 2 is selected from
  • R b is selected from a hydrogen atom or an alkyl group
  • R1 is selected from hydrogen, cyano, halogen, alkyl, hydroxyl, cycloalkyl, heterocyclic, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro 8 , -C(O) OR8 , -OC(O ) R8 , -NR9R10 , -C(O) NR9R10 , -SO2NR9R10 or -NR9C ( O ) R10 ;
  • R2 are the same or different and are independently selected from halogen, hydroxy, cyano, alkyl or alkoxy; wherein the alkyl or alkoxy is optionally further substituted with 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 are the same or different and are each independently selected from cyano, halogen, alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 , -C(O)R 5 , -C(O)OR 5 , -NHC(O)R 5 , -NHC(O)OR 5 , -NR 6 R 7 , -C(O)NR 6 R 7 , -CH 2 NHC(O)OR 5 , -CH 2 NR 6 R 7 or -S(O) r R 5 ; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from RA ;
  • two R 4 and the same carbon atom to which they are attached form a -C(O)-;
  • R 8 , R 9 and R 10 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 with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;
  • 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 , 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) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein ring A is selected from:
  • a preferred embodiment of the present invention is a compound of general formula (I), (II) or (III) 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) or (III) or a stereoisomer , tautomer or a pharmaceutically acceptable salt thereof, wherein L1 is selected from a bond, -NHSO2CH2CH2- , -NHSO2CH2CH2O- , -NHSO2CH2CH2NH- , -SO2NHCH2CH2- , -SO2-, -CH2SO2- , -NHSO2- , -SO2NH-, -NHC(CH3)2CH2-, -C ( O) NHCH2CH2- , -C (O)NHC( CH3 ) 2CH2- , -C(O)N( CH3 ) CH2CH2- , -C ( CH3 )(OH)CH2- , -NHSO2CH ( CH3 ) CH2- , -SO2NHC ( CH3 ) 2CH2- , - ... -, -C(O)NH-
  • a preferred embodiment of the present invention is a compound of the general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R1 is selected from a hydrogen atom, a hydroxyl group, an alkyl group, a heterocyclic group, a cycloalkyl group or a heteroaryl group, wherein the alkyl group, the heterocyclic group, the cycloalkyl group or the heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group or an alkyl group.
  • a preferred embodiment of the present invention is a compound of general formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein Selected from
  • a preferred embodiment of the present invention is a compound of general formula (I), (II) or (III) 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) or (III) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 4 is the same or different and is independently selected from halogen, alkyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 5 , -C(O)R 5 or -NR 6 R 7 ; wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more RA ;
  • two R 4 groups and the same carbon atom to which they are attached form a -C(O)-.
  • RA is selected from halogen, cyano, alkyl, cycloalkyl, heterocyclic , -OR8 , -NR9R10 , wherein the alkyl, cycloalkyl, heterocyclic is optionally further substituted by one or more substituents selected from halogen and haloalkyl;
  • R 5 is each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a halocycloalkyl group, a heterocyclic group or a haloheterocyclic group;
  • R6 and R7 are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a cycloalkyl group, a halocycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group,
  • R 8 is each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a halocycloalkyl group, a heterocyclic group or a haloheterocyclic group;
  • R9 and R10 are each independently selected from a hydrogen atom, an alkyl group, and a halogenated alkyl group.
  • two R 4 groups and the same carbon atom to which they are attached form a -C(O)-.
  • the compound described by the general formula is selected from:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective dose of a compound of general formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.
  • the present invention provides a use of a compound of general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt, 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) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a drug 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 further provides a use of a compound of general formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a drug for treating cancer.
  • the present invention provides a compound described by general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt, or its pharmaceutical composition 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.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro 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. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members.
  • the spirocycloalkyl is divided into single spiro, double spiro or multiple spirocycloalkyl, preferably single spiro and double spirocycloalkyl, preferably 4/5 members, 4/6 members, 5/5 members or 5/6 members.
  • 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- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures that share two carbon atoms that are not directly connected to each other.
  • One or more rings may contain one or more double bonds, but none of the rings has a complete A conjugated ⁇ -electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members.
  • 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 ring 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.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclic groups include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3- Azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxine.
  • “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, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoind
  • 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.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Benzyl refers to -CH2 -phenyl.
  • 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.
  • R 8 , R 9 and R 10 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 substituents selected from hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylate; 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.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • 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:
  • the compound of formula (IA) undergoes a condensation reaction with the compound (IB), and optionally further undergoes a substitution reaction to obtain a compound of formula (I)
  • L 2 is selected from
  • Y is selected from hydroxyl or chlorine
  • Ring A, X 1 , X 2 , X 3 , L 1 , R 1 to R 2 , 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-methyl-4-nitrobenzoate 3a (2.0 g, 10.25 mmol) was dissolved in 1,2-dichloroethane (10 mL), and N-bromosuccinimide (2.19 g, 12.30 mmol) and benzoyl peroxide (248.22 mg, 1.02 mmol) were added, and stirred at 100°C for 20 hours. After the reaction cooled to room temperature, it was concentrated, and ethyl acetate (5 mL) and petroleum ether (15 mL) were added. After the solid precipitated, it was filtered and the filter cake was dried to obtain methyl 2-(bromomethyl)-4-nitrobenzoate 3b (2.6 g), with a yield of 92.58%.
  • methyl 2-(bromomethyl)-4-nitrobenzoate 3b (4.10 g, 14.9 mmol) was dissolved in methanol (50 mL), triethylamine (6.06 g, 59.8 mmol) and 2,2,2-trifluoroethylamine 3c (1.78 g, 17.9 mmol, commercially available) were added in sequence, and the reaction was carried out in a sealed tank at 80 ° C for 18 hours to obtain a brown solution. The cooled reaction solution was spin-dried, then poured into water (80 mL), and extracted with ethyl acetate (40 mL ⁇ 2).
  • the combined organic phase was washed with saturated sodium chloride solution (60mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: A system) to obtain 5-amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one 3e (1.00g), with a yield of 29%.
  • methyl 2-(bromomethyl)-5-nitrobenzoate 5b (1.80 g, 6.57 mmol) was added to anhydrous methanol (20 mL), and triethylamine (1.99 g, 19.7 mmol) and 2,2,2-trifluoroethylamine 3c (1.95 g, 19.7 mmol) were added, and nitrogen was replaced three times, and the reaction was carried out at 70°C for 18 hours.
  • reaction solution was filtered, concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: A system) to obtain 6-nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one 5c (500 mg), with a yield of 29%.
  • 6-nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one 5c 500 mg, 1.92 mmol was added to anhydrous methanol (10 mL), 10% palladium carbon (102 mg, 0.961 mmol) was added to the reaction solution, hydrogen was replaced three times, and the reaction was carried out at 25°C for 2 hours.
  • the reaction solution was filtered, the filter cake was washed with anhydrous methanol (3 mL ⁇ 3), and the filtrate was collected and concentrated under reduced pressure to obtain 6-amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one 5d (400 mg), with a yield of 90.4%.
  • 6-amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one 5d 200 mg, 0.869 mmol
  • 4-bromo -2-(6-Azaspiro[2.5]octan-6-yl)benzoic acid 1e (296 mg, 0.956 mmol) was added to N,N-dimethylformamide (5 mL)
  • 1-hydroxybenzotriazole 176 mg, 1.30 mmol
  • N-methylmorphine 132 mg, 1.30 mmol
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 250 mg, 1.30 mmol
  • the reaction was carried out at 90 °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 phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure.
  • 4M hydrochloric acid
  • N, N'-carbonyldiimidazole (7.79 g, 94.9 mmol) was added to a solution of N, 2-dihydroxy-5-nitrobenzamide 6d (4.70 g, 23.7 mmol) in tetrahydrofuran (45 mL), and the mixture was stirred at 65 ° C for 1 hour to obtain a yellow suspension.
  • the reaction solution was adjusted to pH 5 with hydrochloric acid (1 M) and extracted with ethyl acetate (100 mL ⁇ 2).
  • 1,8-diazabicyclo[5.4.0]undec-7-ene (1.69 g, 11.1 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.84 g, 4.16 mmol) were added to a solution of 5-nitrobenzo[d]isoxazol-3(2H)-one 6e (500 mg, 2.78 mmol) and 4,4-difluoropiperidine hydrochloride 6f (370 mg, 3.05 mmol, commercially available) in tetrahydrofuran (30 mL), and the reaction solution was stirred at 30°C for 16 hours to form a brown suspension.
  • reaction solution was quenched with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (200 mL ⁇ 3), and the combined organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product was slurried with ethyl acetate (30 mL) to obtain 3-bromo-1-methyl-5-nitro-1H-indazole 7b (2.00 g), with a yield of 95%.
  • 2-hydroxyethane-1-sulfonamide 1g (89.6mg, 0.72mmol), cuprous iodide (68.2mg, 0.36mmol), potassium phosphate (152mg, 0.72mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (25.5mg, 0.18mmol) were added to a solution of 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 7f (200mg, 0.36mmol) in N,N-dimethylformamide (5mL), the atmosphere was replaced with nitrogen three times, and the reaction was carried out at 90°C for 16 hours.
  • reaction solution was poured into water and extracted with ethyl acetate (30 mL ⁇ 3).
  • the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 8b 300 mg, 495.49 ⁇ mol
  • tert-butyl carbamate 9a 116.09 mg, 990.98 ⁇ mol
  • dicyclohexyl(2,4,6-tri(1-methylethyl)phenyl)phosphine 47.24 mg, 5% ethanol
  • N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)-4-(vinylsulfonamido)benzamide 10a 100 mg, 171.03 ⁇ mol was dissolved in aqueous ammonia (0.4 M, 10 mL), heated to 60 °C, stirred for 18 hours, and the reaction was complete after mass spectrometry.
  • reaction solution was concentrated under reduced pressure, and the residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250 ⁇ 21.2 mm ID; 5 ⁇ m, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN), to give 4-((2-aminoethyl)sulfonamido)-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 10 (15.0 mg), yield: 10.61%.
  • N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 8b (40 mg, 66.07 ⁇ mol) and tert-butyl 3-aminosulfopyridine-1-carboxylate 11e (31.22 mg, 132.13 ⁇ mol) were dissolved in N,N-dimethylformamide (2 mL), 2-(methylamino)acetic acid (5.89 mg, 66.07 ⁇ mol) was added, and the mixture was stirred for 2 h.
  • Methyl 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoate 12a 500 mg, 1.35 mmol
  • tert-butyl 3-sulfanylazetidine-1-carboxylate 12b 509.88 mg, 2.69 mmol
  • 1,4-dioxane (2 mL) 1,4-dioxane (2 mL)
  • tris(dibenzylideneacetone)dipalladium 123.34 mg, 134.69 ⁇ mol
  • 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene 77.94 mg, 134.69 ⁇ mol
  • N,N-diisopropylethylamine 522.24 mg, 4.04 mmol
  • reaction solution was concentrated under reduced pressure and separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250 ⁇ 21.2 mm ID; 5 ⁇ m, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 4-(azetidin-3-ylsulfonyl)-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 12 (147.9 mg) with a yield of 71.78%.
  • 3-Bromo-5-nitroindazole 7a 500 mg, 2.07 mmol
  • 4-methylbenzenesulfonic acid 35.57 mg, 206.59 ⁇ mol
  • dichloromethane 10 mL
  • 3,4-dihydro-2H-pyran 208.53 mg, 2.48 mmol
  • Water (20 mL) was added, and ethyl acetate (30 mL ⁇ 2) was used for extraction.
  • the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • reaction solution was concentrated under reduced pressure and separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250 ⁇ 21.2 mm ID; 5 ⁇ m, 20 mL/min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give N-(1-cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 13 (48.2 mg) with a yield of 47.40%.
  • N-(3-(4,4-difluoropiperidin-1-yl)-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 14b (40 mg, 59.21 ⁇ mol) and ethanesulfonamide 8c (6.46 mg, 59.21 ⁇ mol) were added to a solution of cuprous iodide (5.64 mg, 29.61 ⁇ mol), sarcosine (5.28 mg, 59.21 ⁇ mol) and potassium phosphate (62.84 mg, 296.06 ⁇ mol) in N,N-dimethylformamide (1 mL).
  • the mixture was stirred at 100 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • N-(3-(4,4-difluoropiperidin-1-yl)-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 14c (30 mg, 45.68 ⁇ mol) was added to a solution of hydrogen chloride in ethyl acetate (1 mL, 4 M) at room temperature and stirred at room temperature for 1 hour. The reaction was completed.
  • reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL ⁇ 3), and the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography (eluent: A system) to give 1-methyl-5-nitro-N-(2,2,2-trifluoroethyl)-1H-indazol-3-amine 15b (235 mg) in a yield of 73.15%.
  • reaction solution was poured into water (20 mL), extracted with ethyl acetate (20 mL ⁇ 3), and the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography (eluent: A system) to give N,1-dimethyl-5-nitro-N-(2,2,2-trifluoroethyl)-1H-indazol-3-amine 15c (220 mg) in a yield of 97.35%.
  • N,1-dimethyl-5-nitro-N-(2,2,2-trifluoroethyl)-1H-indazole-3-amine 15c 120 mg, 416.34 ⁇ mol was dissolved in methanol (10 mL), palladium carbon (10%) (4.43 mg, 41.63 ⁇ mol) was added, and stirred at room temperature for 4 hours. Mass spectrometry showed that the reaction was complete. Filter and concentrate under reduced pressure to obtain N3,1-dimethyl-N3-(2,2,2-trifluoroethyl)-1H-indazole-3,5-diamine 15d (100 mg), yield: 93.01%.
  • N3,1-dimethyl-N3-(2,2,2-trifluoroethyl)-1H-indazole-3,5-diamine 15d (99.41 mg, 384.95 ⁇ mol) and 2-(6-azaspiro[2.5]octan-6-yl)-4-iodo-benzoic acid 8a (125.00 mg, 349.96 ⁇ mol) were dissolved in acetonitrile (5 mL), 1-methylimidazole (87.26 mg, 1.05 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (294.57 mg, 1.05 mmol) were added, and the mixture was stirred at room temperature for 1 hour.
  • 6-nitro-1H-indazole 17a 500 mg, 3.06 mmol, commercially available was added to N,N-dimethylformamide (10 mL), cesium carbonate (2.00 g, 6.13 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate 1b (1.07 g, 4.60 mmol, commercially available) were added to the above reaction solution, nitrogen was replaced three times, and the reaction was carried out at 25°C for 18 hours. The mixture was poured into water (20 mL), and the mixture was extracted with ethyl acetate (20 mL ⁇ 3).
  • 1-(2,2,2-trifluoroethyl)-1H-indazol-6-amine 17c 100 mg, 0.465 mmol
  • 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 6i 164.71 mg, 0.465 mmol
  • N,N-dimethylformamide 5 mL
  • O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 353 mg, 0.929 mmol
  • N,N-diisopropylethylamine 180 mg, 1.39 mmol
  • 6-bromo-1H-indazole 18a (1.00 g, 5.08 mmol, commercially available) and 4,4-difluorocyclohexane-1-ol 18b (760 mg, 5.58 mmol, commercially available) were added to tetrahydrofuran (10 mL), followed by diisopropyl azodicarboxylate (1.54 g, 7.61 mmol) and triphenylphosphine (2.00 g, 7.61 mmol), nitrogen replacement three times, and reaction at 25°C for 18 hours.
  • 6-bromo-1-(4,4-difluorocyclohexyl)-1H-indazole 18c 300 mg, 0.952 mmol
  • tert-butyl carbamate 123 mg, 1.05 mmol
  • 1,4-dioxane 8 mL
  • tris(dibenzylideneacetone)dipalladium 87.2 mg, 0.0952 mmol
  • cesium carbonate 930 mg, 2.86 mmol
  • 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl 68.1 mg, 0.143 mmol
  • tert-butyl (1-(4,4-difluorocyclohexyl)-1H-indazol-6-yl)carbamate 18d 200 mg, 569.17 ⁇ mol was added to dichloromethane (5 mL), followed by hydrochloric acid (1,4-dioxane solution, 4 M) (2.5 mL), and reacted at 25° C. for 18 hours. The mixture was concentrated under reduced pressure to give 1-(4,4-difluorocyclohexyl)-1H-indazol-6-amine 18e (140 mg), with a yield of 97.89%.
  • 1-(4,4-difluorocyclohexyl)-1H-indazol-6-amine 18e 180 mg, 716.35 ⁇ mol
  • 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 1e (244.42 mg, 787.98 ⁇ mol) were added to N,N-dimethylformamide (5 mL), followed by (7-azabenzotriazole-1-oxy)tripyrrolphosphonium hexafluorophosphate (746.98 mg, 1.43 mmol) and N,N-diisopropylethylamine (277.74 mg, 2.15 mmol), and the atmosphere was replaced with nitrogen three times, and the reaction was carried out at 70°C for 18 hours.
  • Example 19 was synthesized according to the synthesis method of Example 18 of the present invention.
  • the spectrum parameters of Example 19 are shown in the following table:
  • diethylaminosulfur trifluoride (1.97 g, 12.22 mmol) was added dropwise to a solution of 5-bromo-1H-indazole-3-carboxaldehyde 20a (1.1 g, 4.89 mmol) in dichloromethane (20 mL), and stirred at room temperature for 4 hours.
  • reaction solution was quenched with saturated aqueous sodium carbonate solution (20 mL), extracted with dichloromethane (20 mL ⁇ 3), and the combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5-bromo-3-(difluoromethyl)-1H-indazole 20b (0.8 g), with a yield of 66%.
  • reaction solution was quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL ⁇ 3), and the combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product was purified by silica gel column chromatography (eluent: A system) to obtain 5-bromo-3-(difluoromethyl)-1-methyl-1H-indazole 20c (632 mg), yield: 75%.
  • 5-bromo-3-(difluoromethyl)-1-methyl-1H-indazole 20c 158 mg, 605.21 ⁇ mol
  • tert-butyl carbamate 158 mg, 605.21 ⁇ mol
  • cuprous iodide 57.63 mg, 302.61 ⁇ mol
  • potassium phosphate trihydrate 483.52 mg, 1.82 mmol
  • racemic-(1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (86.09 mg, 605.21 ⁇ mol) were added to N,N-dimethylformamide (3 mL), replaced with nitrogen three times, and reacted at 100 °C for 16 hours.
  • reaction solution was poured into water and extracted with ethyl acetate (10 mL ⁇ 3).
  • the combined organic phase was washed with saturated sodium chloride solution (10 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 obtain tert-butyl (3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)carbamate 20d (110 mg) with a yield of 61%.
  • N-(3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 20f (40 mg, 74.58 ⁇ mol), 2-hydroxyethane-1-sulfonamide 1 g (10.27 mg, 82.04 ⁇ mol), 2-(methylamino)acetic acid (9.97 mg, 111.87 ⁇ mol), cuprous iodide (4.26 mg, 22.37 ⁇ mol) and potassium phosphate trihydrate (99.30 mg, 372.89 ⁇ mol) were added to N,N-dimethylformamide (2 mL) solution, replaced with nitrogen three times, and reacted at 90 ° C for 16 hours.
  • reaction solution was poured into water and extracted with ethyl acetate (10 mL ⁇ 3).
  • the combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250 ⁇ 21.2 mm ID; 5 ⁇ m, 20 mL/min; mobile phase A: 0.05% NH 4 HCO 3 +H 2 O, mobile phase B: CH 3 CN) to give N-(3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 20 (6 mg) in a yield of 14.82%.
  • N-(3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 20f (40 mg, 74.58 ⁇ mol), ethanesulfonamide 8c (8.95 mg, 82.04 ⁇ mol), 2-(methylamino)acetic acid (9.97 mg, 111.87 ⁇ mol), cuprous iodide (4.26 mg, 22.37 ⁇ mol) and potassium phosphate trihydrate (99.30 mg, 372.89 ⁇ mol) were added to N,N-dimethylformamide (2 mL), replaced with nitrogen three times, and reacted at 90 °C for 16 hours.
  • reaction solution was poured into water and extracted with ethyl acetate (10 mL ⁇ 3).
  • the combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250 ⁇ 21.2 mm ID; 5 ⁇ m, 20 mL/min; mobile phase A: 0.05% NH4HCO3 + H2O , mobile phase B: CH3CN ) to give N-(3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 21 (13 mg) with a yield of 31.0%.
  • 2-(6-azaspiro[2.5]octan-6-yl)-4-iodo-benzoic acid 8a 300 mg, 839.90 ⁇ mol
  • 3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-amine 22d 65.59 mg, 279.97 ⁇ mol
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (161.01 mg, 839.90 ⁇ mol) and 1-hydroxybenzotriazole (113.49 mg, 839.90 ⁇ mol) in N,N-dimethylformamide (4 mL) solvent, and the mixture was stirred at room temperature for 16 hours.
  • N-(3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 22e (200.00 mg, 338.16 ⁇ mol) and 2-hydroxyethane-1-sulfonamide 1 g (84.64 mg, 676.32 ⁇ mol) were added to 2-(methylamino)acetic acid (30.13 mg, 338.16 ⁇ mol), and iodinated.
  • 5-bromo-1-methyl-indazole-3-carboxaldehyde 23a 100 mg, 418.29 ⁇ mol
  • 4,4-difluoropiperidine 101.33 mg, 836.58 ⁇ mol
  • acetic acid 2.51 mg, 41.83 ⁇ mol
  • sodium cyanoborohydride 105.14 mg, 1.67 mmol
  • the reaction solution was poured into water and extracted with ethyl acetate (30 mL ⁇ 3).
  • 2-(6-azaspiro[2.5]octan-6-yl)-4-iodo-benzoic acid 8a 50 mg, 139.98 ⁇ mol
  • 3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-amine 23d 39.24 mg, 139.98 ⁇ mol
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 53.67 mg, 279.97 ⁇ mol
  • 1-hydroxybenzotriazole 37.83 mg, 279.97 ⁇ mol
  • N-(3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 23e 70 mg, 113.00 ⁇ mol
  • 2-hydroxyethane-1-sulfonamide 1 g 42.42 mg, 338.99 ⁇ mol
  • 2-(methylamino)acetic acid (20.13 mg, 225.99 ⁇ mol)
  • cuprous iodide 43.
  • N-(3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 22e 100 mg, 169.08 ⁇ mol
  • ethanesulfonamide 8c 36.91 mg, 338.16 ⁇ mol
  • 2-(methylamino)acetic acid (30.13 mg, 338.16 ⁇ mol)
  • cuprous iodide 64.40 mg, 338.16 ⁇ mol
  • potassium phosphate 71.78 mg, 338.16 ⁇ mol
  • reaction mixture was stirred for 16 hours.
  • the reaction solution was put into water and extracted with ethyl acetate (30 mL ⁇ 3).
  • the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Examples 25-27 were synthesized according to the synthesis method of Examples 22-24 of the present invention.
  • the spectrum parameters of Examples 25-27 are shown in the following table:
  • tert-butyl (2,2-difluoroethyl)((1-methyl-5-nitro-1H-indazol-3-yl)methyl)carbamate 28b (170 mg, 459.02 ⁇ mol) and iron powder (51.27 mg, 918.05 ⁇ mol) were added to a mixed solution of ammonium chloride (49.11 mg, 918.05 ⁇ mol) in ethanol (2 mL) and water (1 mL), and stirred at 75°C for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate (30 mL ⁇ 3).
  • tert-butyl (2,2-difluoroethyl)((5-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-1-methyl-1H-indazol-3-yl)methyl)carbamate 28d (170 mg, 250.17 ⁇ mol) and ethanesulfonamide 8c (54.61 mg, 500.34 ⁇ mol) were added to sarcosine (22.29 mg, 250.17 ⁇ mol), cuprous iodide (23.82 mg, 125.09 ⁇ mol) and Potassium phosphate (265.52 mg, 1.25 mmol) in N,N-dimethylformamide (1 mL) solution was replaced with nitrogen three times and stirred at 100 ° C for 16 hours.
  • tert-butyl (2,2-difluoroethyl)((5-(4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-1-methyl-1H-indazol-3-yl)methyl)carbamate 28e (108 mg, 163.44 ⁇ mol) was added to a solution of hydrogen chloride in ethyl acetate (1 mL, 4 M) and stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate (30 mL ⁇ 3).
  • N-(3-(((2,2-difluoroethyl)amino)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 28 (15 mg, 26.75 ⁇ mol) was added to a solution of paraformaldehyde (2.41 mg, 80.26 ⁇ mol) in methanol (0.5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate (30 mL ⁇ 3).
  • Examples 30-34 were synthesized according to the synthesis method of Example 7 of the present invention.
  • the spectrum parameters of Examples 30-34 are shown in the following table:
  • Nitric acid (1.04 g, 16.53 mmol) was added to a solution of 1-(1-methyl-1H-indazol-3-yl)ethan-1-one 35a (1 g, 5.74 mmol, commercially available) in trifluoroacetic acid (9 mL), and the resulting mixture was stirred at 25°C for 5 hours.
  • the reaction mixture was added to water (50 mL), and the pH was adjusted to 7 with a saturated sodium bicarbonate solution, and extracted with ethyl acetate (100 mL ⁇ 2).
  • the obtained product was purified by SFC (Column: Chiralpak AD-3 50 ID,3um Mobile phase:A:CO2B:Methanol(0.05%DEA)Gradient:from 5%to 40%of B in 4min and from 40%to 5%of B in 0.2min,then hold 5%of B for1.8minFlow rate:3mL/minColumn temp.:35 1500psi) to obtain a single configuration compound (shorter retention time) and a single configuration compound (longer retention time).
  • Example 37 was synthesized according to the synthesis method of Examples 35-36 of the present invention.
  • the spectrum parameters of Example 37 are shown in the following table:
  • methylhydrazine sulfate (2.17 g, 15.1 mmol) and triethylamine (3.05 g, 30.1 mmol) were added to an ethanol (40 mL) solution of methyl 2-fluoro-5-nitrobenzoate 38a (2 g, 10 mmol).
  • the reaction solution was reacted at 80°C for 16 hours.
  • the reaction solution was put into water and extracted three times with ethyl acetate (150 mL).
  • the combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the reaction mixture was reacted at 60°C for 16 hours.
  • the reaction solution was poured into water and extracted three times with ethyl acetate (50 mL).
  • the combined organic phase was washed with saturated sodium chloride solution (30 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-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 38e (300 mg) in a yield of 68%.
  • ethanesulfonamide 8c (24.4 mg, 0.22 mmol), cuprous iodide (28.4 mg, 0.15 mmol), potassium phosphate (63.2 mg, 0.3 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (10.6 mg, 0.07 mmol) were added to a solution of 4-bromo-N-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 38e (80 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL), 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 three times with ethyl acetate (50 mL).
  • the combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250 ⁇ 21.2 mm ID; 5 ⁇ m, 20 mL/min; mobile phase A: 0.05% TFA+ H2O , mobile phase B: CH3CN ) to obtain 4-(ethylsulfonamido)-N-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 38 (19.7 mg) in a yield of 23%.
  • 1-methyl-5-nitro-1,2-dihydro-3H-indazol-3-one 38b 200 mg, 1.04 mmol
  • triphenylphosphine 473 mg, 1.55 mmol
  • 3,3-difluorocyclobutanol 39a 168 mg, 1.55 mmol, commercially available
  • diethyl azodicarboxylate 270 mg, 1.55 mmol
  • reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: A system) to obtain 3-(3,3-difluorocyclobutyloxy)-1-methyl-5-nitro-1H-indazole 39b (210 mg) with a yield of 72%.
  • reaction mixture was reacted at 25°C for 16 hours.
  • the reaction solution was poured into water and extracted three times with ethyl acetate (30 mL).
  • the combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Examples 40-42 were synthesized according to the synthesis method of Example 39 of the present invention.
  • the spectrum parameters of Examples 40-42 are shown in the following table:
  • tert-butyl bromoacetate 43a (1.50 g, 7.71 mmol), sodium hydroxide (3.08 g, 77.1 mmol) and tetrabutylammonium hydrogen sulfate (262 mg, 0.771 mmol) were added to a mixed solution of 3,3-difluorocyclobutanol 39a (1.00 g, 9.25 mmol) in toluene (15 mL) and water (7 mL). The mixture was reacted at 25°C for 4 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL).
  • dimethylhydroxylamine hydrochloride 330 mg, 5.40 mmol
  • N,N'-carbonyldiimidazole 777 mg, 5.40 mmol
  • the mixture was reacted at 25°C for 3 hours.
  • the mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL).
  • methylhydrazine (171 mg, 3.71 mmol), p-toluenesulfonic acid monohydrate (10.7 mg, 0.0619 mmol) and triethylamine (626 mg, 6.19 mmol) were added to a solution of 1-(5-bromo-2-fluorophenyl)-2-(3,3-difluorocyclobutyloxy)ethan-1-one 43f (200 mg, 0.619 mmol) in N-methylpyrrolidone (10 mL). The mixture was reacted under microwave at 150°C for 1 hour. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL ⁇ 3).
  • tert-butyl carbamate 106 mg, 0.906 mmol
  • cesium carbonate 443 mg, 1.36 mmol
  • tris(dibenzylideneacetone)dipalladium 41.5 mg, 0.0453 mmol
  • 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl 64.8 mg, 0.136 mmol
  • 43 g 150 mg, 0.453 mmol
  • 5-bromo-3-((3,3-difluorocyclobutyloxy)methyl)-1-methyl-1H-indazole in 1,4-dioxane 5 mL
  • Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl (3-((3,3-difluorocyclobutyloxy)methyl)-1-methyl-1H-indazol-5-yl)carbamate 43h (150 mg, 0.408 mmol) in dichloromethane (4 mL) at 25°C and reacted for 2 hours at 25°C. The mixture was concentrated under reduced pressure to give the crude product 3-((3,3-difluorocyclobutyloxy)methyl)-1-methyl-1H-indazol-5-amine 43i (109 mg). MS m/z(ESI):268.0[M+1]
  • lithium hydroxide monohydrate (233.92 mg, 5.57 mmol) was added to a mixed solution of 5-bromo-1-methyl-1H-indazole-3-carboxylic acid methyl ester 44a (500 mg, 1.86 mmol, commercially available) in water (5 mL), tetrahydrofuran (5 mL) and methanol (5 mL), and the reaction solution was reacted at 25°C for 16 hours.
  • the reaction solution was adjusted to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate (50 mL ⁇ 2).
  • reaction solution was poured into water and extracted three times with ethyl acetate (50 mL). The extracts were combined, and the combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the product was purified by silica gel column chromatography (eluent: System A) to give (5-bromo-1-methyl-1H-indazol-3-yl)(3,3-difluoroazetidine-1-yl)methanone 44c (550 mg) in a yield of 94%.
  • Trisdibenzylideneacetone dipalladium (139 mg, 0.15 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (87.6 mg, 0.15 mmol) and cesium carbonate (987 mg, 3.03 mmol) were added to (5-bromo-1-methyl-1H-indazol-3-yl)(3,3-difluoroazetidin-1-yl)methanone 44c (500 mg, 1.51 mmol) and tert-butyl carbamate (266 mg, 2.27 mmol) in dioxane (20 mL) at room temperature.
  • tert-butyl (3-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indazol-5-yl)carbamate 44d (230 mg, 0.63 mmol) was added to a solution of hydrochloric acid in dioxane (5 mL, 4 M). The reaction solution was reacted at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain (5-amino-1-methyl-1H-indazol-3-yl)(3,3-difluoroazetidine-1-yl)methanone 44e (180 mg), and the crude product was used directly in the next step.
  • reaction mixture was reacted at 25°C for 16 hours.
  • the reaction solution was poured into water and extracted three times with ethyl acetate (3 mL).
  • the combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.

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Abstract

La présente invention concerne un dérivé d'amide aromatique, son procédé de préparation et une utilisation d'une composition pharmaceutique le comprenant en médecine. Plus particulièrement, la présente invention concerne un dérivé d'amide aromatique représenté par la formule générale (I), son procédé de préparation, un sel pharmaceutiquement acceptable de celui-ci, et son utilisation en tant qu'agent thérapeutique, en particulier, en tant qu'inhibiteur de KIF18A, les définitions des substituants dans la formule générale (I) étant les mêmes que celles dans la description.
PCT/CN2023/124209 2022-10-13 2023-10-12 Dérivé d'amide aromatique, son procédé de préparation et son utilisation WO2024078569A1 (fr)

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Citations (4)

* 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
WO2021211549A1 (fr) * 2020-04-14 2021-10-21 Amgen Inc. Inhibiteurs de kif18a pour le traitement des maladies néoplasiques
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

Patent Citations (4)

* 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
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
WO2021211549A1 (fr) * 2020-04-14 2021-10-21 Amgen Inc. Inhibiteurs de kif18a pour le traitement des maladies néoplasiques

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", J. MED. CHEM., vol. 65, no. 6, 14 March 2022 (2022-03-14), XP093064019, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.1c02030 *

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