WO2024051667A1 - Composé triazole substitué inhibiteur d'axl - Google Patents

Composé triazole substitué inhibiteur d'axl Download PDF

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WO2024051667A1
WO2024051667A1 PCT/CN2023/116897 CN2023116897W WO2024051667A1 WO 2024051667 A1 WO2024051667 A1 WO 2024051667A1 CN 2023116897 W CN2023116897 W CN 2023116897W WO 2024051667 A1 WO2024051667 A1 WO 2024051667A1
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group
alkyl
membered heterocyclyl
alkoxy
membered
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PCT/CN2023/116897
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Chinese (zh)
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马昌友
吴有智
冯海威
张位国
张林林
苗雷
赵廷丽
季晓君
吴舰
徐丹
朱春霞
田舟山
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南京正大天晴制药有限公司
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Publication of WO2024051667A1 publication Critical patent/WO2024051667A1/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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • C07D401/14—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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/12—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 three hetero rings

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to a substituted triazole compound with AXL inhibitory activity and a pharmaceutical composition thereof.
  • the present invention also relates to the use of such compounds and compositions to treat diseases and disease states associated with AXL activity.
  • AXL (also known as UFO, ARK and Tyro7 or JTK11) is a member of the TAM family of receptor tyrosine kinases (RTKs).
  • RTKs receptor tyrosine kinases
  • AXL was originally identified as a transforming gene expressed in cells from patients with chronic myelogenous leukemia or chronic myeloproliferative disorders.
  • AXL overexpression has been reported to be associated with a variety of cancers, including non-small cell lung cancer (NSCLC), breast cancer, prostate cancer, gastric cancer, renal cell carcinoma, and glioblastoma.
  • NSCLC non-small cell lung cancer
  • AXL has increasingly been recognized as a key mediator of resistance to many approved tyrosine kinase inhibitor therapies. Therefore, AXL can serve as a potential target for cancer treatment.
  • Patent documents WO2008083357A1, WO2008083353A1, WO2008083354A1, WO2010005879A1, CN101622252A, CN104860930A, CN101622246A and WO2015082887A2 all disclose compounds used as AXL inhibitors.
  • the invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof:
  • Y is selected from NR 3 or O;
  • R 2 is selected from -C(O)NH-R 2a , 6-15 membered aryl group, 3-18 membered heterocyclyl group or benzo(C3-C8) cycloalkyl group, wherein the 6-15 membered aryl group , 3-18 membered heterocyclyl or benzo (C3-C8) cycloalkyl optionally substituted by amide group, cyano group, nitro, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, C1- C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, 3-10 membered heterocyclyl or 6-10 membered aryl group, the amide group is optionally substituted by C1-C3 Alkyl, C3-C6 cycloalkyl or 3-6 membered heterocyclyl substituted, wherein the 3-10 membered heterocyclyl is optionally substituted by C1-
  • R 2a is selected from 6-15-membered aryl, 3-18-membered heterocyclyl or benzo(C3-C8) cycloalkyl, wherein the 6-15-membered aryl, 3-18-membered heterocyclyl or benzene And (C3-C8) cycloalkyl is optionally substituted by cyano, nitro, halogen, halogenated C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy , 3-10 membered heterocyclyl or 6-10 membered aryl substituted, wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by 3-8 membered heterocyclyl or C1-C3 alkoxy Substituted with a base, the 3-10 membered heterocyclic group is optionally substituted by a C1-C3 alkyl group or halogen;
  • R 3 is selected from hydrogen, C1-C6 alkyl or 3-10 membered heterocyclyl
  • R 4 is selected from -C(O)-R 10 or 3-18 membered heterocyclyl, wherein the 3-18 membered heterocyclyl is optionally replaced by amide group, C1-C6 alkyl, halogenated C1-C6 alkyl base, halogen, nitro, cyano, amino, hydroxyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, 6-10 membered aryl, 5-7 membered heterocyclyl or C3-C6 cycloalkyl substituted, the 6-10-membered aryl group or 5-7-membered heterocyclyl group is optionally substituted by halogen, C1-C3 alkyl or C1-C3 alkoxy group, the C1-C6 alkyl group is optionally substituted by Phenyl, C3-C6 cycloalkyl or 3-10 membered heterocyclyl substituted, the amide group is optionally substituted by C1-C3 al
  • R 10 is selected from a 6-10-membered aryl group, a 3-10-membered heterocyclyl group or a C3-C8 cycloalkyl group, wherein the 6-10-membered aryl group, a 3-10-membered heterocyclyl group or a C3-C8 cycloalkyl group
  • the base is optionally substituted by a 6-8-membered aryl group, a 5-7-membered heterocyclyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, an amide group, a halogen, a nitro group or a cyano group, wherein the C1 -C6 alkyl is optionally substituted by halogen or 3-8-membered heterocyclyl, and the 6-8-membered aryl or 5-7-membered heterocyclyl is optionally substituted by halogen, C1-C3 alkyl, C1- C3 al
  • R 7 and R 8 are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6)alkyl, halo(C2-C6)alkenyl, halo Generation (C2-C6) alkynyl, hydroxy (C1-C6) alkyl, 6-10-membered aryl, 6-10-membered aryl (C1-C6) alkyl, 6-10-membered aryl (C2-C6) alkenyl , 6-10 yuan aryl (C2-C6) alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl (C1-C6) alkyl, C3-C8 cycloalkyl (C2-C6) alkenyl, C3 -C8 cycloalkyl (C2-C6) alkynyl, 3-10 membered heterocyclyl, 3-10 membered hetero
  • R 9 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo(C1-C6)alkyl, halo(C2-C6)alkenyl, halo(C2-C6) )alkynyl, hydroxy (C1-C6) alkyl, 6-10-membered aryl, 6-10-membered aryl (C1-C6) alkyl, 6-10-membered aryl (C2-C6) alkenyl, 6-10-membered Aryl (C2-C6) alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl (C1-C6) alkyl, C3-C8 cycloalkyl (C2-C6) alkenyl, C3-C8 cycloalkyl (C2-C6)alkynyl, 3-10-membered heterocyclyl, 3-10-membered heterocyclyl (
  • Y is NR 3 and R 3 is as defined above.
  • R3 is hydrogen or C1-C6 alkyl; in some typical embodiments, R3 is hydrogen.
  • Y is NH
  • X is selected from hydrogen or halogen.
  • X is selected from hydrogen or fluorine.
  • R 1 , R 5 and R 6 are each hydrogen.
  • R 2 is selected from -C(O)NH-R 2a , 6-15 membered aryl, 3-18 membered heterocyclyl, or benzo(C3-C8)cycloalkyl, wherein 6-15-membered aryl, 3-18-membered heterocyclyl or benzo (C3-C8) cycloalkyl is optionally substituted by amide group, halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1 -C6 alkoxy or 3-10 membered heterocyclyl substituted, wherein the amide group is optionally substituted by C1-C3 alkyl, wherein the 3-10 membered heterocyclyl is optionally substituted by C1-C3 Alkyl or 3-8 membered heterocyclyl substituted, wherein the C1-C6 alkyl and C1-C6 alkoxy groups are optionally substituted by 3-8 membered heterocyclyl or C1-C3 al
  • R 2a is a 6-10 membered aryl group, the 6-10 membered aryl group is optionally substituted by a 3-10 membered heterocyclyl group, wherein the 3-10 membered heterocyclyl group is optionally substituted by a C1-C3 alkyl group replace.
  • R is selected from And R 2 is optionally substituted by amide group, halogen, C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy or 3-10 membered heterocyclyl Substituted, wherein the 3-10 membered heterocyclyl group is optionally substituted by a C1-C3 alkyl group or a 3-8 membered heterocyclyl group, wherein the amide group is optionally substituted by a C1-C3 alkyl group, wherein the The above-mentioned C1-C6 alkyl and C1-C6 alkoxy groups are optionally substituted by 3-8 membered heterocyclic groups or C1-C3 alkoxy groups.
  • R is selected from and R 2 is optionally -F, -Cl, methyl, methoxy, replace.
  • R is selected from
  • R is selected from
  • R is selected from
  • R 4 is selected from -C(O)-R 10 or 3-18 membered heterocyclyl, wherein the 3-18 membered heterocyclyl is optionally replaced by amide, C1-C6 alkyl , C1-C6 alkoxy, halogen, 6-10 membered aryl, 5-7 membered heterocyclyl or C3-C6 cycloalkyl substitution, the 6-10 membered aryl or 5-7 membered heterocyclyl is optional optionally substituted by halogen, C1-C3 alkyl or C1-C3 alkoxy, the C1-C6 alkyl is optionally substituted by phenyl, C3-C6 cycloalkyl or 3-8 membered heterocyclyl, so
  • the amide group is optionally substituted by C1-C3 alkyl, phenyl or halogen-substituted phenyl;
  • R 10 is selected from 3-10 membered heterocyclyl or C3-C8 cycloalkyl, wherein the 3-10 membered heterocyclyl or C3-C8 cycloalkyl is optionally replaced by 6-8 membered aryl, 5-7 6-membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy or amide substituted, wherein the 6-8-membered aryl or 5-7-membered heterocyclyl is optionally substituted by halogen or C1-C3 alkyl
  • the C1-C6 alkyl group is optionally substituted by a 3-8 membered heterocyclyl group
  • the amide group is optionally substituted by a phenyl group or a halogen-substituted phenyl group.
  • R4 is selected from -C(O) -R10 or 3-18 membered heterocyclyl, wherein the 3-18 membered heterocyclyl is optionally replaced by Ethoxy, methyl, isopropyl, Br, F, Cl, phenyl, pyridyl, cyclopropyl or cyclopentyl, the methyl optionally being substituted by phenyl, cyclopropyl or Substituted, the phenyl or pyridyl is optionally substituted by F, methyl or methoxy;
  • R 10 is selected from 3-10 membered heterocyclyl or C3-C8 cycloalkyl, wherein the 3-10 membered heterocyclyl or C3-C8 cycloalkyl is optionally replaced by phenyl, pyridyl, methyl, isopropyl, ethoxy or substituted, wherein said methyl group is optionally replaced by Substituted, the phenyl or pyridyl group is optionally substituted by halogen or methyl.
  • R 4 is selected from stated therein optionally F, Cl, Br, methyl, 4-fluorophenyl, 4-methoxyphenyl, replace;
  • R4 is selected from Preferably, R 4 is selected from More preferably, R 4 is selected from
  • the aforementioned compound of Formula I has a structure shown in Formula II,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and X are defined as described in Formula I.
  • the aforementioned compound of Formula I has a structure shown in Formula III,
  • R 3 , R 4 , R 5 and R 6 are each defined as described in Formula I; W is selected from CH or N;
  • R Y1 is selected from amide group, 3-10 membered heterocyclyl group, 3-10 membered heterocyclyl (C1-C6) alkyl group or C1-C6 alkoxy group, wherein the amide group is optionally replaced by C1-C3 Alkyl substitution, wherein the 3-10 membered heterocyclyl or 3-10 membered heterocyclyl (C1-C6) alkyl is optionally substituted by a C1-C6 alkyl or 3-8 membered heterocyclyl, the The C1-C6 alkoxy group is optionally substituted by a 3-8 membered heterocyclyl group;
  • R Y2 is selected from hydrogen, halogen, 3-10 membered heterocyclyl, 3-10 membered heterocyclyl (C1-C6) alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy or halogenated C1 -C6 alkoxy, wherein the 3-10 membered heterocyclyl or 3-10 membered heterocyclyl (C1-C6)alkyl is optionally substituted by C1-C6 alkyl or 3-8 membered heterocyclyl, The C1-C6 alkoxy group is optionally substituted by a 3-8 membered heterocyclyl group;
  • R Y3 are selected from hydrogen, halogen, C1-C6 alkoxy or halogenated C1-C6 alkoxy; R 3 , R 4 , R 5 , R 6 and X are defined as described in Formula I.
  • W is CH.
  • R Y1 is selected from amide, 3-10 membered heterocyclyl, 3-10 membered heterocyclylmethylene, or C1-C6 alkoxy, wherein the amide group is optionally replaced by C1 -C3 alkyl substituted, wherein the 3-10 membered heterocyclyl is optionally substituted by methyl or Substituted, the C1-C6 alkoxy group is optionally replaced by replace.
  • R Y1 is methoxy
  • R Y1 is methoxy
  • R Y1 is methoxy
  • R Y2 is selected from hydrogen, halogen, 3-10 membered heterocyclyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, or halogenated C1-C6 alkoxy.
  • R Y2 is selected from hydrogen, F, Cl, methoxy
  • R Y2 is selected from hydrogen or methoxy.
  • R Y3 is selected from hydrogen, halogen, or C1-C6 alkoxy.
  • R Y3 is selected from hydrogen, F, Cl, or methoxy.
  • the compound represented by the aforementioned formula I has a structure represented by formula IV,
  • R 3 , R 4 , R 5 and R 6 are each defined as described in Formula I;
  • R q is selected from C1-C6 alkyl or 3-6 membered heterocyclyl;
  • Rm is selected from hydrogen, halogen or C1-C6 alkoxy
  • R 3 , R 4 , R 5 , R 6 and X are defined as described in Formula I.
  • R q is selected from methyl or
  • Rm is selected from hydrogen, F, Cl, or methoxy.
  • the compound represented by the aforementioned formula I has a structure represented by formula V,
  • R 3 , R 4 , R 5 , R 6 and X are defined as described in Formula I.
  • the compound represented by the aforementioned formula I has a structure represented by formula VI,
  • -C6 alkoxy group, R v3 is selected from hydrogen, C1-C6 alkyl group, 6-10-membered aryl group or 5-7-membered heterocyclyl group, the 6-10-membered aryl group or 5-7-membered heterocyclyl group can be any Optionally substituted by halogen, C1-C3 alkyl or C1-C3 alkoxy.
  • R v1 is selected from hydrogen or halogen.
  • R v1 is selected from hydrogen, -Cl or -Br.
  • R v2 is selected from hydrogen or C1-C6 alkyl.
  • R v2 is selected from hydrogen or methyl.
  • R v3 is selected from 6-10 membered aryl or 5-7 membered heterocyclyl optionally substituted by halogen or C1-C3 Alkoxy substitution.
  • R v3 is selected from phenyl or pyridyl, which is optionally substituted by halogen or C1-C3 alkoxy.
  • R v3 is selected from
  • R v3 is
  • the present invention provides the following compounds or pharmaceutically acceptable salts thereof:
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, II, III, IV, V or Formula VI, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention provides compounds of Formula I, II, III, IV, V or Formula VI, or pharmaceutically acceptable salts thereof, for use in the treatment and/or prevention of AXL receptor tyrosine kinase.
  • Use of drugs to induce disease are known in the art.
  • the present invention provides a method for treating AXL receptor tyrosine kinase-induced disorders, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, II, III, IV, V or Formula VI or a pharmaceutical agent thereof. Acceptable salts or steps of the pharmaceutical compositions described above.
  • the AXL receptor tyrosine kinase-induced disorder is a disorder caused by, associated with, and/or accompanied by hyperfunction of AXL kinase.
  • the condition induced by the AXL receptor tyrosine kinase is cancer, and the cancer is a solid tumor or a hematological cancer.
  • the AXL receptor tyrosine kinase induced disorder is a solid tumor cancer.
  • C1-C3 means that the group can have 1 carbon atom, 2 carbon atoms, or 3 carbon atoms
  • C1-C6 means that the group can have 1 carbon atom, 2 carbon atoms , 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • substituted by means that any one or more hydrogen atoms on a specific group are replaced by a substituent, as long as the valence state of the specific group is normal and the substituted compound is stable.
  • substituted by halogen means that any one or more hydrogen atoms on a specific group are replaced by halogen, as long as the specific group The valence state of the group is normal and the substituted compound is stable.
  • middle It refers to the connection point of chemical bond.
  • cyano refers to the -CN group; the term “nitro” refers to the -NO group; the term “amino” refers to the -NH group; the term “ hydroxy " refers to the -OH group; the term “halogen” ” refers to fluorine, chlorine, bromine and iodine, and the term “halo” refers to fluoro, chlorine, bromo and iodine.
  • alkyl refers to a saturated aliphatic hydrocarbon group, including straight or branched chain saturated hydrocarbon groups, having the number of carbon atoms shown.
  • C1-C3 alkyl includes C1 alkyl, C2 alkyl, C3 alkyl, examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl; such as the term “C1-C6 alkyl” "Basic” includes C1-C3 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, examples include, but are not limited to, methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-he
  • alkoxy refers to a group having the structure alkyl-O-, alkyl being an alkyl group as defined above.
  • C1-C3 alkoxy includes C1 alkoxy, C2 alkoxy, C3 alkoxy, examples include, but are not limited to, methoxy, ethoxy, n-propyloxy, isopropyl Oxygen;
  • C1-C6 alkoxy includes C1-C3 alkoxy, C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy, C6 alkoxy , examples include, but are not limited to, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, n-pentyloxy base, 2-pentyloxy, 3-pentyloxy, n-hexyloxy
  • R is a saturated aliphatic hydrocarbon group, including linear or branched saturated hydrocarbon groups, for example, examples of the term “C1-C3 alkanoyl” include However, it is not limited to, for example, formyl, acetyl, 2-methylacetyl, propionyl, etc.
  • C2-C6 alkenyl refers to a group formed by losing one or two hydrogen atoms from an alkene having 2 to 6 carbon atoms.
  • C2-C6 alkynyl refers to a straight or branched hydrocarbon chain group consisting only of 2 to 6 carbon atoms and hydrogen atoms, which contains at least one triple bond, optionally at least one double bond, and which Attached to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.
  • alkylene refers to a saturated linear or branched divalent hydrocarbon group, such as methylene, ethylene, propylene, n-butylene, and the like.
  • alkenylene refers to a linear or branched divalent hydrocarbon group containing at least one double bond, such as vinylene, propenylene, n-butenylene, and the like.
  • alkynylene refers to a linear or branched divalent hydrocarbon group containing at least one triple bond, such as propynylene, n-butynylene, and the like.
  • haloalkyl refers to an alkyl group as defined above substituted by one or more halogen atoms.
  • halo C1-C3 alkyl includes trifluoromethyl, difluoromethyl, trichloro Methyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, etc.
  • haloalkoxy refers to an alkoxy group as defined above substituted by one or more halogen atoms.
  • halo C1-C6 alkoxy includes trifluoromethoxy, difluoromethyl Oxygen, trichloromethoxy, 2,2,2-trifluoroethoxy, etc.
  • halo(C2-C6)alkenyl refers to a C2-C6 alkenyl group as defined above substituted by one or more halogen atoms.
  • halogenated (C2-C6)alkynyl refers to a C2-C6 alkynyl group as defined above substituted by one or more halogen atoms.
  • hydroxyalkyl refers to an alkyl group as defined above substituted by one or more hydroxyl groups (-OH).
  • hydroxy(C1-C3)alkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyheptyl, and the like.
  • aryl refers to an all-carbon monocyclic group with a conjugated ⁇ electron system or a bicyclic group in which an all-carbon monocyclic ring with a conjugated ⁇ electron system is fused with an aromatic carbocyclic ring, which is obtained by converting the parent aromatic It is obtained by removing one hydrogen atom from a single carbon atom of the ring system.
  • the "6-10-membered aryl group” defined in the present invention refers to a group formed by losing one hydrogen atom from a 6-10-membered aryl group. Examples include, but are not limited to, phenyl, naphthyl.
  • 6-10 membered aryl(C1-C6)alkyl refers to a group having the general formula -Rb - Rc , wherein Rb is (C1-C6)alkylene as defined above and Rc Is one or more 6-10 membered aryl groups as defined above, such as benzyl, diphenylmethyl, etc.
  • 6-10 membered aryl(C2-C6)alkenyl refers to a group having the general formula -Rd - Rc , wherein Rd is a C2-C6alkenylene group as defined above and Rc is a or a plurality of 6-10 membered aryl groups as defined above.
  • 6-10 membered aryl(C2-C6)alkynyl refers to a group having the general formula -Re - Rc , wherein Re is a C2-C6 alkynylene as defined above and Rc is a or a plurality of 6-10 membered aryl groups as defined above.
  • cycloalkyl refers to a stable saturated monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, which may include spiro or bridged ring systems, having from three to fifteen carbon atoms.
  • C3-C8 cycloalkyl refers to a cyclic alkyl group with 3-8 carbon atoms, which may further be a C3-C6 cycloalkyl group, examples of which include, but are not limited to, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • C3-C8 cycloalkyl(C1-C6)alkyl refers to a group of the general formula -Rb - Rg , where Rb is a C1-C6 alkylene chain as defined above and Rg is C3-C8 cycloalkyl group as defined above.
  • C3-C8 cycloalkyl(C2-C6)alkenyl refers to a group of the general formula -Rd - Rg , where Rd is a C2-C6 alkenylene chain as defined above and Rg is C3-C8 cycloalkyl group as defined above.
  • C3-C8 cycloalkyl(C2-C6)alkynyl refers to a group of the general formula -R e -R g , wherein R e is a C2-C6 alkynylene group as defined above and R g is a C3-C8 cycloalkyl group as defined above.
  • heterocyclyl refers to a stable saturated, partially unsaturated or fully unsaturated non-aromatic or aromatic ring group containing at least one ring heteroatom or heteroatom group independently selected from Nitrogen, sulfur, oxygen, sulfoxide, sulfone,
  • the heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, in which two or more rings exist in the form of spiro, joined or bridged rings.
  • the heterocycle is two or more rings, at least one of the rings contains at least one heteroatom or heteroatom group, which can be two or more rings formed by a ring containing heteroatoms or heteroatom groups and a ring that does not contain heteroatoms or heteroatom groups.
  • heteroatom when the heteroatom is nitrogen, the nitrogen can serve as a point of attachment to other groups.
  • heterocyclic group of the atom can further be a 5-7 membered monocyclic heterocyclic group, an 8-10 membered bicyclic heterocyclic group or a 10-18 membered tricyclic or tetracyclic heterocyclic group.
  • the "3-18 membered heterocyclic group""Basic optionally contains 1, 2, 3, or 4 heteroatoms or heteroatom groups as ring atoms, including but not limited to ethylene oxide, furyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydropyrrolyl , tetrahydrothiophenyl, piperidinyl, morpholinyl, pyridyl, benzimidazolyl,
  • heterocyclyl(C1-C6)alkyl refers to a group of the general formula -Rb - Rh , wherein Rb is a C1-C6 alkylene chain as defined above and Rh is as defined above Heterocyclyl group as defined, and if the heterocyclyl group is a nitrogen-containing heterocyclyl group, the heterocyclyl group may be connected to an alkyl group at the nitrogen atom.
  • heterocyclyl(C2-C6)alkenyl refers to a group of the general formula -Rd - Rh , wherein Rd is a C2-C6 alkenylene chain as defined above and Rh is a C2-C6 alkenylene chain as defined above.
  • Rd is a C2-C6 alkenylene chain as defined above
  • Rh is a C2-C6 alkenylene chain as defined above.
  • a defined heterocyclyl group and if the heterocyclyl group is a nitrogen-containing heterocyclyl group, the heterocyclyl group may be connected to an alkenylene chain at the nitrogen atom.
  • heterocyclyl(C2-C6)alkynyl refers to a group of the general formula -Re - Rh , wherein Re is a C2-C6 alkynylene chain as defined above and Rh is as defined above Heterocyclyl as defined, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be linked to an alkynyl group at the nitrogen atom.
  • benzo(C3-C8)cycloalkyl refers to a group formed by fusion of a benzene ring and a C3-C8 cycloalkyl group as defined above.
  • the benzene ring and the cycloalkyl group share two adjacent ring carbon atoms, And the connection site with the parent core structure is located in the benzene ring part. Examples include, but are not limited to:
  • pharmaceutically acceptable salt refers to a salt that retains the biological potency of the free acid and base of a particular compound without adverse biological effects.
  • acid including organic acids and inorganic acids
  • base addition salts including organic bases and inorganic bases.
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • ⁇ ективное amount refers to a nontoxic amount of a drug or agent that is sufficient to achieve the desired effect.
  • pharmaceutically acceptable carrier refers to those carriers that have no obvious irritating effect on the body and do not impair the biological activity and performance of the active compound. Including but not limited to any diluent, disintegrant, binder, glidant, and wetting agent approved by the State Food and Drug Administration for use on humans or animals.
  • v/v refers to the volume ratio
  • SEB Supplemented Enzymatic Buffer (SEB), a component in the kit;
  • DMF-DMA N,N-dimethylformamide dimethyl acetal
  • Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium
  • N or M represents concentration, mol/L.
  • concentration mol/L.
  • concentration of hydrochloric acid 6mol/L.
  • 1,2-Difluoro-4-nitrobenzene (795 mg), 80% hydrazine hydrate (400 mg) and ethanol (15 mL) were placed in a 25 mL single-mouth bottle and reacted at 80 degrees Celsius. After the reaction of the raw materials is complete, the reaction solution is desolvated to dryness, then slurried with methyl tert-butyl ether, and filtered. The filter cake was dried to obtain 500 mg of the title product.
  • Trimethyl orthoformate (324.7 mg) and intermediate compound M6-1 (580 mg) were placed in a 100 mL single-neck bottle, and stirred at 100 degrees Celsius for 1.5 hours. Then 4-dimethylaminopyridine (26.7 mg) was added, and the reaction was continued overnight. When the reaction is complete, the reaction solution is lowered to room temperature, and a large amount of solid precipitates. Filter with suction, and wash the filter cake with isopropyl alcohol. The filter cake was dried to obtain 206 mg of the title product.
  • Preparation Example 7 replace 2-cyano-N-(4-fluorophenyl)acetamide in step a) with 2-cyano-N-(5-methylpyridin-2-yl)acetamide. That is Yes, the same subsequent reaction as step b) to step d) in Preparation Example 7 was carried out to obtain 169 mg of the title product.
  • step a) of Example 3 to replace 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid with 3-(4-fluorophenyl)-1-isopropyl-2,4 -Dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid is sufficient to obtain 110 mg of the title product.
  • the aqueous phase was extracted twice with ethyl acetate (20 mL).
  • the aqueous phase was then extracted once with ethyl acetate (50 mL).
  • the organic phases were combined, washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate.
  • step b) in Example 18 Referring to the method of step b) in Example 18, replacing 18-1 with 19-1, 11 mg of the title product was prepared.
  • step d) 22-3 just replace step d) 22-3 with 24-5.
  • the reaction solution was then desolvated to dryness.
  • the crude product obtained was purified by reversed-phase high performance liquid chromatography (column: XBridge Prep OBD C18 column, 30 ⁇ 150mm packing particle size 5 ⁇ m; mobile phase A: 10mmol/L HCl aqueous solution, mobile phase B: acetonitrile; flow rate: 60mL/min; Gradient: 10% B ⁇ 62% B, 10 min; detection wavelength: 220 nm; target compound retention time: 7.75 min), and 5.3 mg of the title product was obtained.
  • Example 26 just replace 26-5 in step f) with 27-3.
  • the crude product obtained was purified by reversed-phase high performance liquid chromatography (column: XBridge Prep OBD C18, 30 ⁇ 150mm, packing particle size 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate :100mL/min; Gradient: 25%B ⁇ 65%B, 40min; Detection wavelength: 220nm; Target compound retention time: 35min) to obtain 3 mg of the title product.
  • reversed-phase high performance liquid chromatography columnumn: XBridge Prep OBD C18, 30 ⁇ 150mm, packing particle size 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate :100mL/min; Gradient: 25%B ⁇ 65%B, 40min; Detection wavelength: 220nm; Target
  • step c was replaced with 2-methoxy-4-(4-methylpiperazin-1-yl)aniline to obtain 160 mg of the title product.
  • Example 26 replace 26-5 in step f) with 28-3.
  • the crude product obtained is purified by reversed-phase high performance liquid chromatography (column: XBridge Prep OBD C18, 30 ⁇ 150mm, packing particles Diameter 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L HCl), mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 10%B ⁇ 62%B, 8min; detection wavelength: 220nm; target compound retention time: 7.75 min), 4.1 mg of the title product was obtained.
  • reversed-phase high performance liquid chromatography columnumn: XBridge Prep OBD C18, 30 ⁇ 150mm, packing particles Diameter 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L HCl), mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 10%B ⁇ 62%B, 8min; detection wavelength: 220nm; target compound retention time: 7.75 min
  • Example 26 replace 26-5 in step f) with 29-3.
  • the crude product obtained is purified by reversed-phase high performance liquid chromatography (column: XSelect CSH Fluoro Phenyl, 30 ⁇ 150mm, packing particles Diameter 5 ⁇ m; mobile phase A: aqueous solution (0.1% FA), mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 5%B ⁇ 50%B, 8min; detection wavelength: 220nm; target compound retention time: 6.25min ), 6.9 mg of the title product was obtained.
  • reversed-phase high performance liquid chromatography columnumn: XSelect CSH Fluoro Phenyl, 30 ⁇ 150mm, packing particles Diameter 5 ⁇ m; mobile phase A: aqueous solution (0.1% FA), mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 5%B ⁇ 50%B, 8min; detection wavelength: 220nm; target compound retention time: 6.25min ), 6.9 mg
  • Acetonitrile (15mL), potassium carbonate (3.92g), 4-fluoronitrobenzene (2g), and 1-(oxetan-3-yl)piperazine (2.02g) were placed in a sealed tube. Reaction was carried out overnight at 100°C. When the raw materials disappear, add water (10 mL) to the reaction solution. Extract three times with dichloromethane (20 mL). The combined organic phases were extracted with n-hexane (3 mL) and dried over anhydrous sodium sulfate. Filter, and the filtrate is desolvated to dryness to obtain 3.6 g of the title product.
  • Example 26 just replace 26-5 in step f) with 31-3.
  • the reaction solution was cooled to room temperature and concentrated, and the crude product was purified by reversed-phase high performance liquid chromatography (column: XBridge Shield RP18 OBD, 30 ⁇ 150mm, filler particle size 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 20% B to 60% B, 10 min; detection wavelength: 220 nm; target compound retention time: 9.53 min) to obtain 15.7 mg of the title product.
  • reversed-phase high performance liquid chromatography columnumn: XBridge Shield RP18 OBD, 30 ⁇ 150mm, filler particle size 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 20% B to 60% B, 10
  • Example 26 just replace 26-5 in step f) with 32-2.
  • the reaction solution was cooled to room temperature, concentrated, and the crude product was purified by reversed-phase high performance liquid chromatography (column: Xselect CSH C18 OBD, 30 ⁇ 150 mm, filler particle size 5 ⁇ m; mobile phase A: aqueous solution (0.1% trifluoroacetic acid), Mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 5% B to 40% B, 10 min; detection wavelength: 220 nm; target compound retention time: 8.62 min) to obtain 19.1 mg of the title product.
  • reversed-phase high performance liquid chromatography columnumn: Xselect CSH C18 OBD, 30 ⁇ 150 mm, filler particle size 5 ⁇ m; mobile phase A: aqueous solution (0.1% trifluoroacetic acid), Mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 5% B to 40% B
  • step f just replace 30-5 in step f) with 33-5.
  • the reaction solution was cooled to room temperature and concentrated, and the crude product was purified by reversed-phase high performance liquid chromatography (column: Kinetex EVO prep C18, 30 ⁇ 150mm, filler particle size 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 25% B to 60% B, 7.88 min; detection wavelength: 220 nm; target compound retention time: 7.75 min) to obtain 9.6 mg of the title product.
  • reversed-phase high performance liquid chromatography columnumn: Kinetex EVO prep C18, 30 ⁇ 150mm, filler particle size 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 25% B to 60% B, 7.88 min; detection
  • N-(4-aminophenyl)acetamide 150mg
  • hydrochloric acid solution 2M, 5mL
  • sodium nitrite 73mg
  • Tin dichloride 380 mg was added dropwise, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the product was filtered with suction, the filter cake was washed with water, and 142 mg of the title product was obtained after drying the filter cake.
  • Example 26 replace 26-5 in step f) with 47-6.
  • the crude product obtained was purified by reversed-phase high performance liquid chromatography (column: XBridge Prep OBD C18, 30 ⁇ 150mm, packing particle size 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L HCOOH), mobile phase B: acetonitrile; flow rate: 60mL/ min; gradient: 10% B to 62% B, 8 min; detection wavelength: 220 nm; target compound retention time: 7.75 min) to obtain 17.5 mg of the title product.
  • reversed-phase high performance liquid chromatography columnumn: XBridge Prep OBD C18, 30 ⁇ 150mm, packing particle size 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L HCOOH), mobile phase B: acetonitrile; flow rate: 60mL/ min; gradient: 10% B to 62% B, 8 min; detection wavelength: 220 nm; target compound retention time: 7.75 min
  • the crude product obtained was purified by reversed-phase high performance liquid chromatography (column: Xselect CSH C18 OBD column, 30 ⁇ 150mm packing particle size 5 ⁇ m; mobile phase A: aqueous solution (10mmol/L HCOOH), mobile phase B: acetonitrile; flow rate: 60mL/ min; gradient: 10% B to 62% B, 8 min; detection wavelength: 220 nm; target compound retention time: 7.75 min), and 34.1 mg of the title product was obtained.
  • the obtained crude product (250 mg crude product) was purified by reversed-phase high performance liquid chromatography (column: Xselect CSH C18 OBD column, 30 ⁇ 150mm packing particle size 5 ⁇ m; mobile phase A: 0.05% trifluoroacetic acid aqueous solution, mobile phase B: acetonitrile; flow rate : 60 mL/min; gradient: 10% B to 40% B, 10 min; detection wavelength: 220 nm; target compound retention time: 9.18 min), and 100 mg of the mixture was obtained (Example 50 and Example 53).
  • Embodiment 50 is purified by reversed-phase chiral high performance liquid chromatography (column: CHIRALPAK IA C18 column, 2 ⁇ 25mm packing particle size 5 ⁇ m; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B : ethanol; flow rate: 20 mL/min; gradient: 50% B ⁇ 50% B, 22 min; detection wavelength: 256/220 nm; target compound retention time: 9.08 min), and 29.3 mg of the title compound was obtained.
  • the crude product obtained was purified by reversed-phase high performance liquid chromatography (column: Kinetex EVO C18 column, 21.2 ⁇ 150mm packing particle size 5 ⁇ m; mobile phase A: 10mmol/L ammonium bicarbonate solution, mobile phase B: acetonitrile; flow rate: 60mL/min ; Gradient: 20% B ⁇ 50% B, 10 min; detection wavelength: 220 nm; target compound retention time: 10.15 min), and 7.1 mg of the title product was obtained.
  • the obtained crude product (250 mg crude product) was purified by reversed-phase high performance liquid chromatography (column: Xselect CSH C18 OBD column, 30 ⁇ 150mm packing particle size 5 ⁇ m; mobile phase A: 0.05% trifluoroacetic acid aqueous solution, mobile phase B: acetonitrile; flow rate : 60 mL/min; gradient: 10% B to 40% B, 10 min; detection wavelength: 220 nm; target compound retention time: 9.18 min), and 100 mg of the mixture was obtained (Example 50 and Example 53).
  • Embodiment 53 is purified by reversed-phase chiral high performance liquid chromatography (column: CHIRALPAK IA C18 column, 2 ⁇ 25mm packing particle size 5 ⁇ m; mobile phase A: methyl tert-butyl ether (0.1% diethylamine), mobile phase B : ethanol; flow rate: 20 mL/min; gradient: 50% B ⁇ 50% B, 22 min; detection wavelength: 256/220 nm; target compound retention time: 19.32 min), and 36 mg of the title compound was obtained.
  • Example 50 replace 5-nitro-1H-benzo[d]imidazole in step a) with 6-nitro-2H-indazole to obtain 800 mg of the title product.
  • the crude product obtained was purified by reversed-phase high performance liquid chromatography (column: Kinetex EVO prep C18 column, 30 ⁇ 150mm packing particle size 5 ⁇ m; mobile phase A: water (10mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 20% B to 60% B, 10 min; detection wavelength: 220 nm; target compound retention time: 9.68 min), and 16.4 mg of the title product was obtained.
  • the positive drug BGB-324 used in the activity test was purchased from Hubei Kele Fine Chemical Co., Ltd.
  • ATP, substrate preparation and sample addition Use 1 ⁇ enzyme buffer to prepare ATP (Sigma, A7699) working solution for AXL, Mer and Tyro3 kinase reactions in sequence: dilute sequentially from 10mM to 75 ⁇ M (5 ⁇ , final concentration 15 ⁇ M) , 50 ⁇ M (5 ⁇ , final concentration 10 ⁇ M), 2 ⁇ M (5 ⁇ , final concentration 0.4 ⁇ M), use 1 ⁇ enzyme buffer to dilute the substrate TK Substrate-biotin (Cisbio, 61TK0BLC) from 500 ⁇ M to 5 ⁇ M (5 ⁇ , final concentration The concentration is 1 ⁇ M); mix ATP and substrate in equal volumes, and add 4 ⁇ L to each well using a BioTek automatic dispenser; centrifuge at 2500 rpm for 30 seconds, and react at 25°C for 45 min (AXL kinase reaction time) and 45 min (Mer kinase reaction time), respectively. 30min (Tyro3 kinase reaction time);
  • Detection reagent preparation and sample addition Use detection buffer (Cisbio, 62SDBRDF) to dilute Streptavidin-XL665 (Cisbio, 610SAXLG) from 16.67 ⁇ M to 250nM (4 ⁇ , final concentration is 62.5nM); use detection buffer to dilute TK Antibody-Cryptate (Cisbio) was diluted from 100 ⁇ to 1 ⁇ ; mix Streptavidin-XL665 and TK Antibody-Cryptate in equal volumes, add 10 ⁇ L to each well using a BioTek automatic liquid dispenser, centrifuge at 2500 rpm for 30 s, and react at 25°C for 1 hour. After the reaction, the HTRF module of a multifunctional plate reader (PerkinElmer, Envision) was used for detection;
  • Inhibition rate (%) (Ratio negative control group - Ratio compound group)/(Ratio negative control group - Ratio blank control group) ⁇ 100%
  • the experimental results are shown in Table 1.
  • Ba/F3 (mouse-derived B lymphocytes, culture medium: RPMI1640+10% FBS+IL-3 (10ng/ml)), purchased from Peking Union Cell Resource Center.
  • Ba/F3-TEL-AXL (mouse-derived B lymphocytes stably expressing TEL-AXL, culture medium: RPMI1640+10% FBS), self-built from Nanjing Zhengda Tianqing Pharmaceutical Co., Ltd., cells were placed at 37°C, 5% Culture in a CO 2 incubator. The above cells in the logarithmic growth phase were plated in a 96-well plate at a cell density of 3000 cells/well/150 ⁇ L, and a blank control group was set at the same time.
  • DMSO dimethyl sulfoxide
  • Test substance signal value mean fluorescence signal value of cells + culture medium + compound group
  • Signal value of blank group mean fluorescence signal value of culture medium group (containing 0.3% DMSO);
  • Signal value of negative control group mean fluorescence signal value of cells + culture medium group (containing 0.3% DMSO).

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Abstract

L'invention concerne un composé triazole substitué inhibiteur d'AXL représenté par la formule (I), qui est utilisé pour traiter et/ou prévenir des troubles induits par le récepteur tyrosine kinase AXL.
PCT/CN2023/116897 2022-09-05 2023-09-05 Composé triazole substitué inhibiteur d'axl WO2024051667A1 (fr)

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Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004046120A2 (fr) * 2002-11-15 2004-06-03 Vertex Pharmaceuticals Incorporated Diaminotriazoles convenant comme inhibiteurs de proteine kinases
WO2007030680A2 (fr) * 2005-09-07 2007-03-15 Rigel Pharmaceuticals, Inc. Derives de triazole utiles comme inhibiteurs d'axl
WO2008083353A1 (fr) * 2006-12-29 2008-07-10 Rigel Pharmaceuticals, Inc. Triazoles à substitution aryle bicycliques et hétéroaryle bicycliques utiles en tant qu'inhibiteurs axl
WO2008083357A1 (fr) * 2006-12-29 2008-07-10 Rigel Pharmaceuticals, Inc. Triazoles substitués par aryle bicyclique ponté et hétéroaryle bicyclique ponté utilisés comme inhibiteurs d'axl
WO2008083367A2 (fr) * 2006-12-29 2008-07-10 Rigel Pharmaceuticals, Inc. Triazoles substitués par hétéroaryle polycyclique utiles comme inhibiteurs de axl
WO2008083354A1 (fr) * 2006-12-29 2008-07-10 Rigel Pharmaceuticals, Inc. Triazoles substitués par n3-hétéroaryle et triazoles substitués par n5-hétéroaryle utiles comme inhibiteurs de axl
WO2008083356A1 (fr) * 2006-12-29 2008-07-10 Rigel Pharmaceuticals, Inc. Triazoles substitués utilisés comme inhibiteurs d'axl
WO2009054864A1 (fr) * 2007-10-26 2009-04-30 Rigel Pharmaceuticals, Inc. Triazoles substitués par aryle polycyclique et triazoles substitués par hétéroaryle polycyclique utiles comme inhibiteurs d'axl
WO2010005876A2 (fr) * 2008-07-09 2010-01-14 Rigel Pharmaceuticals, Inc. Triazoles à substitution hétéroaryle polycycliques utiles en tant qu’inhibiteurs d’axl
WO2016197009A1 (fr) * 2015-06-05 2016-12-08 Vertex Pharmaceuticals Incorporated Triazoles pour le traitement de maladies liées à la démyélinisation

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004046120A2 (fr) * 2002-11-15 2004-06-03 Vertex Pharmaceuticals Incorporated Diaminotriazoles convenant comme inhibiteurs de proteine kinases
WO2007030680A2 (fr) * 2005-09-07 2007-03-15 Rigel Pharmaceuticals, Inc. Derives de triazole utiles comme inhibiteurs d'axl
WO2008083353A1 (fr) * 2006-12-29 2008-07-10 Rigel Pharmaceuticals, Inc. Triazoles à substitution aryle bicycliques et hétéroaryle bicycliques utiles en tant qu'inhibiteurs axl
WO2008083357A1 (fr) * 2006-12-29 2008-07-10 Rigel Pharmaceuticals, Inc. Triazoles substitués par aryle bicyclique ponté et hétéroaryle bicyclique ponté utilisés comme inhibiteurs d'axl
WO2008083367A2 (fr) * 2006-12-29 2008-07-10 Rigel Pharmaceuticals, Inc. Triazoles substitués par hétéroaryle polycyclique utiles comme inhibiteurs de axl
WO2008083354A1 (fr) * 2006-12-29 2008-07-10 Rigel Pharmaceuticals, Inc. Triazoles substitués par n3-hétéroaryle et triazoles substitués par n5-hétéroaryle utiles comme inhibiteurs de axl
WO2008083356A1 (fr) * 2006-12-29 2008-07-10 Rigel Pharmaceuticals, Inc. Triazoles substitués utilisés comme inhibiteurs d'axl
WO2009054864A1 (fr) * 2007-10-26 2009-04-30 Rigel Pharmaceuticals, Inc. Triazoles substitués par aryle polycyclique et triazoles substitués par hétéroaryle polycyclique utiles comme inhibiteurs d'axl
WO2010005876A2 (fr) * 2008-07-09 2010-01-14 Rigel Pharmaceuticals, Inc. Triazoles à substitution hétéroaryle polycycliques utiles en tant qu’inhibiteurs d’axl
WO2016197009A1 (fr) * 2015-06-05 2016-12-08 Vertex Pharmaceuticals Incorporated Triazoles pour le traitement de maladies liées à la démyélinisation

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