WO2024051667A1 - Substituted triazole compound having axl inhibitory activity - Google Patents

Substituted triazole compound having axl inhibitory activity Download PDF

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Publication number
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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French (fr)
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/en

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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).

Abstract

Disclosed is a substituted triazole compound having AXL inhibitory activity represented by formula (I), which is used for treating and/or preventing AXL receptor tyrosine kinase-induced disorders.

Description

具有AXL抑制活性的取代***化合物Substituted triazole compounds with AXL inhibitory activity 技术领域Technical field
本发明属于药物领域，具体地，涉及一种具有AXL抑制活性的取代***化合物及其药物组合物。本发明还涉及使用该化合物和组合物治疗与AXL活性相关的疾病和疾病状态。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.
背景技术Background technique
AXL(也称为UFO、ARK和Tyro7或JTK11)，是受体酪氨酸激酶(RTKs)中的TAM家族成员之一。AXL最初被鉴定为一种在慢性髓细胞性白血病或慢性骨髓增生性疾病患者细胞中表达的转化基因。据报道，AXL过度表达与多种癌症有关，包括非小细胞肺癌(NSCLC)、乳腺癌、***癌、胃癌、肾细胞癌和胶质母细胞瘤。AXL的激活为细胞增殖、存活、迁移、侵袭和血管生成提供了强有力的信号。此外，AXL已越来越多地被认为是对许多已批准的酪氨酸激酶抑制剂疗法产生耐药性的关键介质。因此，AXL可以作为癌症治疗的潜在靶点。AXL (also known as UFO, ARK and Tyro7 or JTK11) is a member of the TAM family of receptor tyrosine kinases (RTKs). 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. Activation of AXL provides a powerful signal for cell proliferation, survival, migration, invasion, and angiogenesis. Furthermore, 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.
专利文献WO2008083357A1，WO2008083353A1，WO2008083354A1，WO2010005879A1，CN101622252A，CN104860930A，CN101622246A以及WO2015082887A2均披露了作为AXL抑制剂用的化合物。Patent documents WO2008083357A1, WO2008083353A1, WO2008083354A1, WO2010005879A1, CN101622252A, CN104860930A, CN101622246A and WO2015082887A2 all disclose compounds used as AXL inhibitors.
发明内容Contents of the invention
一方面，本发明提供如式I所示的化合物或其药学上可接受的盐:
In one aspect, the invention provides a compound represented by formula I or a pharmaceutically acceptable salt thereof:
其中，in,
Y选自NR3或O；Y is selected from NR 3 or O;
X选自氢、卤素、氨基、氰基、硝基、羟基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷氧基、羟基(C1-C3)烷基或C1-C3烷酰基；The -C3) alkyl or C1-C3 alkanoyl;
R1、R5和R6各自独立地选自氢、C1-C6烷基、6-10元芳基、6-10元芳基(C1-C6)烷基、-C(O)R9、-C(O)N(R7)R8或-C(＝NH)N(R7)R8；R 1 , R 5 and R 6 are each independently selected from hydrogen, C1-C6 alkyl, 6-10 membered aryl, 6-10 membered aryl (C1-C6)alkyl, -C(O)R 9 , -C(O)N(R 7 )R 8 or -C(=NH)N(R 7 )R 8 ;
R2选自-C(O)NH-R2a、6-15元芳基、3-18元杂环基或苯并(C3-C8)环烷基，其中所述的6-15元芳基、3-18元杂环基或苯并(C3-C8)环烷基任选地被酰胺基、氰基、硝基、卤素、卤代C1-C6烷基、C1-C6烷基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、3-10元杂环基或6-10元芳基取代，所述酰胺基任选地被C1-C3烷基、C3-C6环烷基或3-6元杂环基取代，其中所述的3-10元杂环基任选地被C1-C3烷基、卤素或3-8元杂环基取代，其中所述的C1-C6烷基和C1-C6烷氧基任选地被3-8元杂环基或C1-C3烷氧基取代；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-C3 alkyl, halogen or 3-8 membered heterocyclyl , wherein the C1-C6 alkyl and C1-C6 alkoxy groups are optionally substituted by 3-8 membered heterocyclic groups or C1-C3 alkoxy groups;
R2a选自6-15元芳基、3-18元杂环基或苯并(C3-C8)环烷基，其中所述的6-15元芳基、3-18元杂环基或苯并(C3-C8)环烷基任选地被氰基、硝基、卤素、卤代C1-C6烷基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、3-10元杂环基或6-10元芳基取代，其中所述的C1-C6烷基和C1-C6烷氧基任选地被3-8元杂环基或C1-C3烷氧基取代，所述3-10元杂环基任选地被C1-C3烷基或卤素取代；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;
R3选自氢、C1-C6烷基或3-10元杂环基； R 3 is selected from hydrogen, C1-C6 alkyl or 3-10 membered heterocyclyl;
R4选自-C(O)-R10或3-18元杂环基，其中所述3-18元杂环基任选地被酰胺基、C1-C6烷基、卤代C1-C6烷基、卤素、硝基、氰基、氨基、羟基、C1-C6烷氧基、卤代C1-C6烷氧基、6-10元芳基、5-7元杂环基或C3-C6环烷基取代，所述6-10元芳基或5-7元杂环基任选地被卤素、C1-C3烷基或C1-C3烷氧基取代，所述C1-C6烷基任选地被苯基、C3-C6环烷基或3-10元杂环基取代，所述酰胺基任选地被C1-C3烷基、6-8元芳基、C3-C6环烷基或3-8元杂环基取代，所述6-8元芳基、C3-C6环烷基或3-8元杂环基任选地被卤素、C1-C3烷基或C1-C3烷氧基取代；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 alkyl, 6-8 membered aryl, C3-C6 cycloalkyl or 3-8 The 6-8-membered aryl group, C3-C6 cycloalkyl group or 3-8-membered heterocyclyl group is optionally substituted by halogen, C1-C3 alkyl group or C1-C3 alkoxy group;
R10选自6-10元芳基、3-10元杂环基或C3-C8环烷基，其中所述的6-10元芳基、3-10元杂环基或C3-C8环烷基任选地被6-8元芳基、5-7元杂环基、C1-C6烷基、C1-C6烷氧基、酰胺基、卤素、硝基或氰基取代，其中所述的C1-C6烷基任选地被卤素或3-8元杂环基取代，所述的6-8元芳基或5-7元杂环基任选地被卤素、C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷基或卤代C1-C3烷氧基取代，所述的酰胺基任选地被C1-C3烷基、3-6元杂环基或苯基取代，所述的3-6元杂环基或苯基任选地被卤素、C1-C6烷基、硝基或氰基取代；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 alkoxy, halogenated C1-C3 alkyl or halogenated C1-C3 alkoxy is substituted, and the amide group is optionally substituted by C1-C3 alkyl, 3-6 membered heterocyclyl or phenyl, The 3-6 membered heterocyclic group or phenyl group is optionally substituted by halogen, C1-C6 alkyl group, nitro group or cyano group;
R7和R8独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6)烷基、卤代(C2-C6)烯基、卤代(C2-C6)炔基、羟基(C1-C6)烷基、6-10元芳基、6-10元芳(C1-C6)烷基、6-10元芳(C2-C6)烯基、6-10元芳(C2-C6)炔基、C3-C8环烷基、C3-C8环烷基(C1-C6)烷基、C3-C8环烷基(C2-C6)烯基、C3-C8环烷基(C2-C6)炔基、3-10元杂环基、3-10元杂环基(C1-C6)烷基、3-10元杂环基(C2-C6)烯基或3-10元杂环基(C2-C6)炔基，或者R7和R8同与它们均连接的共同的氮一起形成N-杂环基；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 heterocyclyl (C1-C6) alkyl, 3-10 membered heterocyclyl (C2-C6) alkenyl Or 3-10 membered heterocyclyl (C2-C6) alkynyl, or R 7 and R 8 together with the common nitrogen connected to them form N-heterocyclyl;
R9选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6)烷基、卤代(C2-C6)烯基、卤代(C2-C6)炔基、羟基(C1-C6)烷基、6-10元芳基、6-10元芳(C1-C6)烷基、6-10元芳(C2-C6)烯基、6-10元芳(C2-C6)炔基、C3-C8环烷基、C3-C8环烷基(C1-C6)烷基、C3-C8环烷基(C2-C6)烯基、C3-C8环烷基(C2-C6)炔基、3-10元杂环基、3-10元杂环基(C1-C6)烷基、3-10元杂环基(C2-C6)烯基或3-10元杂环基(C2-C6)炔基。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 (C1-C6)alkyl, 3-10-membered heterocyclyl (C2-C6)alkenyl or 3-10-membered Heterocyclyl (C2-C6)alkynyl.
在一些实施方案中，Y为NR3，R3定义如上。In some embodiments, Y is NR 3 and R 3 is as defined above.
在一些实施方案中，R3为氢或C1-C6烷基；在一些典型的实施方案中，R3为氢。In some embodiments, R3 is hydrogen or C1-C6 alkyl; in some typical embodiments, R3 is hydrogen.
在一些典型的实施方案中，Y为NH。In some typical embodiments, Y is NH.
在一些实施方案中，X选自氢或卤素。In some embodiments, X is selected from hydrogen or halogen.
在一些典型的实施方案中，X选自氢或氟。In some typical embodiments, X is selected from hydrogen or fluorine.
在一些实施方案中，R1、R5和R6均为氢。In some embodiments, R 1 , R 5 and R 6 are each hydrogen.
在一些实施方案中，R2选自-C(O)NH-R2a、6-15元芳基、3-18元杂环基或苯并(C3-C8)环烷基，其中所述的6-15元芳基、3-18元杂环基或苯并(C3-C8)环烷基任选地被酰胺基、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基或3-10元杂环基取代，其中所述的酰胺基任选地被C1-C3烷基取代，其中所述的3-10元杂环基任选地被C1-C3烷基或3-8元杂环基取代，其中所述的C1-C6烷基和C1-C6烷氧基任选地被3-8元杂环基或C1-C3烷氧基取代；In some embodiments, 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 alkoxy;
R2a为6-10元芳基，所述6-10元芳基任选地被3-10元杂环基取代，其中所述3-10元杂环基任选地被C1-C3烷基取代。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.
在一些实施方案中，R2选自 且R2任选地被酰胺基、卤素、C1-C6烷基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基或3-10元杂环基取代，其中所述3-10元杂环基任选地被C1-C3烷基或3-8元杂环基取代，其中所述的酰胺基任选地被C1-C3烷基取代，其中所述的C1-C6烷基和C1-C6烷氧基任选地被3-8元杂环基或C1-C3烷氧基取代。In some embodiments, 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.
在一些典型的实施方案中，R2选自 且R2任选地被-F、-Cl、甲基、甲氧基、 取代。In some typical embodiments, R is selected from and R 2 is optionally -F, -Cl, methyl, methoxy, replace.
在一些更为典型的实施方案中，R2选自 In some more typical embodiments, R is selected from
在一些更为典型的实施方案中，R2选自 In some more typical embodiments, R is selected from
在一些最为典型的实施方案中，R2选自 In some most typical embodiments, R is selected from
在一些实施方案中，R4选自-C(O)-R10或3-18元杂环基，其中所述的3-18元杂环基任选地被酰胺基、C1-C6烷基、C1-C6烷氧基、卤素、6-10元芳基、5-7元杂环基或C3-C6环烷基取代，所述6-10元芳基或5-7元杂环基任选地被卤素、C1-C3烷基或C1-C3烷氧基取代，所述C1-C6烷基任选地被苯基、C3-C6环烷基或3-8元杂环基取代，所述酰胺基任选地被C1-C3烷基、苯基或卤素取代的苯基取代；In some embodiments, 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;
R10选自3-10元杂环基或C3-C8环烷基，其中所述3-10元杂环基或C3-C8环烷基任选地被6-8元芳基、5-7元杂环基、C1-C6烷基、C1-C6烷氧基或酰胺基取代，其中所述的6-8元芳基或5-7元杂环基任选地被卤素或C1-C3烷基取代，所述的C1-C6烷基任选地被3-8元杂环基取代，所述酰胺基任选地被苯基或卤素取代的苯基取代。 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, and the amide group is optionally substituted by a phenyl group or a halogen-substituted phenyl group.
在一些实施方案中，R4选自-C(O)-R10或3-18元杂环基，其中所述3-18元杂环基任选地被 乙氧基、甲基、异丙基、Br、F、Cl、苯基、吡啶基、环丙基或环戊基取代，所述甲基任选地被苯基、环丙基或取代，所述苯基或吡啶基任选地被F、甲基或甲氧基取代；In some embodiments, 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;
其中R10选自3-10元杂环基或C3-C8环烷基，其中所述3-10元杂环基或C3-C8环烷基任选地被苯基、吡啶基、甲基、异丙基、乙氧基或取代，其中所述的甲基任选地被取代，所述的苯基或吡啶基任选地被卤素、甲基取代。Wherein 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.
在一些典型的实施方案中，R4选自 其中所述 任选地被F、Cl、Br、甲基、4-氟苯基、4-甲氧基苯基、 取代；In some typical embodiments, R 4 is selected from stated therein optionally F, Cl, Br, methyl, 4-fluorophenyl, 4-methoxyphenyl, replace;
其中所述任选地被甲基、异丙基、苯基、乙氧基、4-氟苯基、取代。 stated therein optionally methyl, isopropyl, phenyl, ethoxy, 4-fluorophenyl, replace.
在一些更为典型的实施方案中，R4选自 优选地，R4选自 更为优选地，R4选自 In some more typical embodiments, R4 is selected from Preferably, R 4 is selected from More preferably, R 4 is selected from
在一些实施方案中，前述式I化合物具有如式II所示的结构，
In some embodiments, the aforementioned compound of Formula I has a structure shown in Formula II,
其中R1、R2、R3、R4、R5、R6和X定义如式I所述。Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and X are defined as described in Formula I.
在一些实施方案中，前述式I化合物具有如式III所示的结构，
In some embodiments, the aforementioned compound of Formula I has a structure shown in Formula III,
其中，R3、R4、R5、R6各自定义如式I所述；W选自CH或N；Among them, R 3 , R 4 , R 5 and R 6 are each defined as described in Formula I; W is selected from CH or N;
RY1选自酰胺基、3-10元杂环基、3-10元杂环基(C1-C6)烷基或C1-C6烷氧基，其中所述的酰胺基任选地被C1-C3烷基取代，其中所述3-10元杂环基或3-10元杂环基(C1-C6)烷基任选地被C1-C6烷基或3-8元杂环基取代，所述的C1-C6烷氧基任选地被3-8元杂环基取代；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;
RY2选自氢、卤素、3-10元杂环基、3-10元杂环基(C1-C6)烷基、C1-C6烷氧基、氘代C1-C6烷氧基或卤代C1-C6烷氧基，其中所述3-10元杂环基或3-10元杂环基(C1-C6)烷基任选地被C1-C6烷基或3-8元杂环基取代，所述的C1-C6烷氧基任选地被3-8元杂环基取代；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;
和RY3选自氢、卤素、C1-C6烷氧基或卤代C1-C6烷氧基；R3、R4、R5、R6和X定义如式I所述。and 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.
在一些实施方案中，W为CH。In some embodiments, W is CH.
在一些实施方案中，RY1选自酰胺基、3-10元杂环基、3-10元杂环基亚甲基或C1-C6烷氧基，其中所述的酰胺基任选地被C1-C3烷基取代，其中所述3-10元杂环基任选地被甲基或取代，所述的C1-C6烷氧基任选地被取代。 In some embodiments, 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.
在一些更为典型的实施方案中，RY1为甲氧基、 In some more typical embodiments, R Y1 is methoxy,
在一些更为典型的实施方案中，RY1为甲氧基、 In some more typical embodiments, R Y1 is methoxy,
在一些更为典型的实施方案中，RY1为甲氧基、 In some more typical embodiments, R Y1 is methoxy,
在一些典型的实施方案中，RY2选自氢、卤素、3-10元杂环基、C1-C6烷氧基、氘代C1-C6烷氧基或或卤代C1-C6烷氧基。In some typical embodiments, R Y2 is selected from hydrogen, halogen, 3-10 membered heterocyclyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, or halogenated C1-C6 alkoxy.
在一些更为典型的实施方案中，RY2选自氢、F、Cl、甲氧基、 In some more typical embodiments, R Y2 is selected from hydrogen, F, Cl, methoxy,
在一些更为典型的实施方案中，RY2选自氢或甲氧基。In some more typical embodiments, R Y2 is selected from hydrogen or methoxy.
在一些典型的实施方案中，RY3选自氢、卤素或C1-C6烷氧基。In some typical embodiments, R Y3 is selected from hydrogen, halogen, or C1-C6 alkoxy.
在一些更为典型的实施方案中，RY3选自氢、F、Cl或甲氧基。In some more typical embodiments, R Y3 is selected from hydrogen, F, Cl, or methoxy.
在一些实施方案中，前述式I所示的化合物具有如式IV所示的结构，
In some embodiments, the compound represented by the aforementioned formula I has a structure represented by formula IV,
其中，R3、R4、R5、R6各自定义如式I所述；Rq选自C1-C6烷基或3-6元杂环基；Among them, 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选自氢、卤素或C1-C6烷氧基； Rm is selected from hydrogen, halogen or C1-C6 alkoxy;
R3、R4、R5、R6和X定义如式I所述。R 3 , R 4 , R 5 , R 6 and X are defined as described in Formula I.
在一些典型的实施方案中，Rq选自甲基或 In some typical embodiments, R q is selected from methyl or
在一些典型的实施方案中，Rm选自氢、F、Cl或甲氧基。In some typical embodiments, Rm is selected from hydrogen, F, Cl, or methoxy.
在一些实施方案中，前述式I所示的化合物具有如式V所示的结构，
In some embodiments, the compound represented by the aforementioned formula I has a structure represented by formula V,
其中，R3、R4、R5、R6和X定义如式I所述。Among them, R 3 , R 4 , R 5 , R 6 and X are defined as described in Formula I.
在一些实施方案中，前述式I所示的化合物具有如式VI所示的结构，
In some embodiments, the compound represented by the aforementioned formula I has a structure represented by formula VI,
其中，X和R2的定义如式I所述，Rv1选自氢、卤素、C1-C6烷基或C1-C6烷氧基，Rv2选自氢、卤素、C1-C6烷基或C1-C6烷氧基，Rv3选自氢、C1-C6烷基、6-10元芳基或5-7元杂环基，所述6-10元芳基或5-7元杂环基任选地被卤素、C1-C3烷基或C1-C3烷氧基取代。 Wherein , ​ -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.
在一些实施方案中，Rv1选自氢或卤素。In some embodiments, R v1 is selected from hydrogen or halogen.
在一些典型的实施方案中，Rv1选自氢、-Cl或-Br。In some typical embodiments, R v1 is selected from hydrogen, -Cl or -Br.
在一些实施方案中，Rv2选自氢或C1-C6烷基。In some embodiments, R v2 is selected from hydrogen or C1-C6 alkyl.
在一些典型的实施方案中，Rv2选自氢或甲基。In some typical embodiments, R v2 is selected from hydrogen or methyl.
在一些实施方案中，Rv3选自6-10元芳基或5-7元杂环基，所述6-10元芳基或5-7元杂环基任选地被卤素或C1-C3烷氧基取代。In some embodiments, R v3 is selected from 6-10 membered aryl or 5-7 membered heterocyclyl optionally substituted by halogen or C1-C3 Alkoxy substitution.
在一些典型的实施方案中，Rv3选自苯基或吡啶基，所述苯基或吡啶基任选地被卤素或C1-C3烷氧基取代。In some typical embodiments, R v3 is selected from phenyl or pyridyl, which is optionally substituted by halogen or C1-C3 alkoxy.
在一些更为典型的实施方案中，Rv3选自 In some more typical implementations, R v3 is selected from
在一些更为典型的实施方案中，Rv3为 In some more typical implementations, R v3 is
另一方面，本发明提供下列化合物或其药学上可接受的盐：



In another aspect, the present invention provides the following compounds or pharmaceutically acceptable salts thereof:



在一些实施方案中，本发明提供了一种药物组合物，其包含治疗有效量的式I、II、III、IV、V或式VI化合物或其药学上可接受的盐和药学上可接受的载体。In some embodiments, the invention provides 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.
在一些实施方案中，本发明提供了式I、II、III、IV、V或式VI化合物或其药学上可接受的盐，其在制备用于治疗和/或预防AXL受体酪氨酸激酶诱发的病症的药物中的应用。In some embodiments, 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.
本发明提供了一种治疗AXL受体酪氨酸激酶诱发的病症的方法，其包括向有需要的患者施用治疗有效量的式I、II、III、IV、V或式VI化合物或其药学上可接受的盐或上述的药物组合物的步骤。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.
在一些实施方案中，所述AXL受体酪氨酸激酶诱发的病症是由AXL激酶功能亢进引起、与AXL激酶功能亢进相关和/或伴随AXL激酶功能亢进的病症。In some embodiments, the AXL receptor tyrosine kinase-induced disorder is a disorder caused by, associated with, and/or accompanied by hyperfunction of AXL kinase.
在一些实施方案中，所述AXL受体酪氨酸激酶诱发的病症为癌症，所述癌症为实体瘤或血液癌症。在一些典型的实施方案中，所述AXL受体酪氨酸激酶诱发的病症为实体瘤癌症。In some embodiments, the condition induced by the AXL receptor tyrosine kinase is cancer, and the cancer is a solid tumor or a hematological cancer. In some exemplary embodiments, the AXL receptor tyrosine kinase induced disorder is a solid tumor cancer.
相关定义Related definitions
除非相反地指明，本说明书和所附权利要求中所用的下列术语具有所指明的含义：Unless stated otherwise, the following terms used in this specification and the appended claims have the meanings indicated:
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and the absence of the stated event or circumstance.
本文中的数字范围，是指给定范围中的各个整数。例如，“C1-C3”是指该基团可具有1个碳原子、2个碳原子或3个碳原子；“C1-C6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。A numerical range in this article refers to each integer in a given range. For example, "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.
术语“被……取代”是指特定基团上的任意一个或多个氢原子被取代基取代，只要特定基团的价态是正常的并且取代后的化合物是稳定的。例如，“被卤素取代”是指特定基团上的任意一个或多个氢原子被卤素取代，只要特定基 团的价态是正常的并且取代后的化合物是稳定的。The term "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. For example, "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.
术语中的是指化学键连接处。the term middle It refers to the connection point of chemical bond.
表示在环内任意位置可能存在双键。 Indicates that a double bond may exist anywhere within the ring.
术语“氰基”是指-CN基团；术语“硝基”是指-NO2基；术语“氨基”是指-NH2基团；术语“羟基”是指-OH基团；术语“卤素”是指氟、氯、溴和碘，术语“卤代”指氟代、氯代、溴代和碘代。The term "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.
术语“烷基”指饱和的脂族烃基团，包括直链的或支链的饱和烃基，所述烃基具有所示出的碳原子数。如术语“C1-C3烷基”包括C1烷基、C2烷基、C3烷基，实例包括，但不限于，甲基、乙基、正丙基、异丙基；如术语“C1-C6烷基”包括C1-C3烷基、C1烷基、C2烷基、C3烷基、C4烷基、C5烷基、C6烷基，实例包括，但不限于，甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、2-戊基、3-戊基、正己基、2-己基和3-己基等。The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight or branched chain saturated hydrocarbon groups, having the number of carbon atoms shown. For example, the term "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-hexyl and 3-hexyl, etc.
术语“烷氧基”指具有烷基-O-结构的基团，烷基是如上文所定义的烷基基团。如术语“C1-C3烷氧基”包括C1烷氧基、C2烷氧基、C3烷氧基，实例包括，但不限于，甲氧基、乙氧基、正丙基氧基、异丙基氧基；如术语“C1-C6烷氧基”包括C1-C3烷氧基、C1烷氧基、C2烷氧基、C3烷氧基、C4烷氧基、C5烷氧基、C6烷氧基，实例包括，但不限于，甲氧基、乙氧基、正丙基氧基、异丙基氧基、正丁基氧基、异丁基氧基、叔丁基氧基、正戊基氧基、2-戊基氧基、3-戊基氧基、正己基氧基、2-己基氧基和3-己基氧基等。The term "alkoxy" refers to a group having the structure alkyl-O-, alkyl being an alkyl group as defined above. For example, the term "C1-C3 alkoxy" includes C1 alkoxy, C2 alkoxy, C3 alkoxy, examples include, but are not limited to, methoxy, ethoxy, n-propyloxy, isopropyl Oxygen; such as the term "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, 2-hexyloxy and 3-hexyloxy, etc.
术语“烷酰基”是指具有RC(＝O)-结构的基团，R为饱和的脂族烃基团，包括直链的或支链的饱和烃基，例如术语“C1-C3烷酰基”实例包括但不限于例如甲酰基、乙酰基、2-甲基乙酰基、丙酰基等。The term "alkanoyl" refers to a group with an RC(=O)-structure, 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.
术语“C2-C6烯基”指具有2-6个碳原子的烯烃失去一个或两个氢原子所形成的基团，所述的烯烃可以是单烯烃、二烯烃或三烯烃，例如-CH＝CH2、-C2H4＝CH2、-CH＝C2H4，或类似基团。The term "C2-C6 alkenyl" refers to a group formed by losing one or two hydrogen atoms from an alkene having 2 to 6 carbon atoms. The alkene can be a monoolefin, a diolefin or a triene, such as -CH= CH 2 , -C 2 H 4 =CH 2 , -CH =C 2 H 4 , or similar groups.
术语“C2-C6炔基”仅由2-6个碳原子和氢原子组成的直链或支链的烃链基团，其含有至少一个三键，任选地含有至少一个双键，并且其通过单键连接至分子的其余部分，例如乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。The term "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.
术语“亚烷基”是指饱和的直链或支链的二价烃基，例如亚甲基、亚乙基、亚丙基、亚正丁基等等。The term "alkylene" refers to a saturated linear or branched divalent hydrocarbon group, such as methylene, ethylene, propylene, n-butylene, and the like.
术语“亚烯基”是指含有至少一个双键的直链或支链的二价烃基，例如亚乙烯基、亚丙烯基、亚正丁烯基等等。The term "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.
术语“亚炔基”是指含有至少一个三键的直链或支链的二价烃基，例如亚丙炔基、亚正丁炔基等等。The term "alkynylene" refers to a linear or branched divalent hydrocarbon group containing at least one triple bond, such as propynylene, n-butynylene, and the like.
术语“卤代烷基”是指被一个或多个卤素原子取代的如上文所定义的烷基基团，例如术语“卤代C1-C3烷基”包括三氟甲基、二氟甲基、三氯甲基、2,2,2-三氟乙基、1-氟甲基-2-氟乙基、3-溴-2-氟丙基、1-溴甲基-2-溴乙基等等。The term "haloalkyl" refers to an alkyl group as defined above substituted by one or more halogen atoms. For example, the term "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.
术语“卤代烷氧基”是指被一个或多个卤素原子取代的如上文所定义的烷氧基基团，例如术语“卤代C1-C6烷氧基”包括三氟甲氧基、二氟甲氧基、三氯甲氧基、2,2,2-三氟乙氧基等等。The term "haloalkoxy" refers to an alkoxy group as defined above substituted by one or more halogen atoms. For example, the term "halo C1-C6 alkoxy" includes trifluoromethoxy, difluoromethyl Oxygen, trichloromethoxy, 2,2,2-trifluoroethoxy, etc.
术语“卤代(C2-C6)烯基”是指被一个或多个卤素原子取代的如上文所定义的C2-C6烯基基团。The term "halo(C2-C6)alkenyl" refers to a C2-C6 alkenyl group as defined above substituted by one or more halogen atoms.
术语“卤代(C2-C6)炔基”是指被一个或多个卤素原子取代的如上文所定义的C2-C6炔基基团。The term "halogenated (C2-C6)alkynyl" refers to a C2-C6 alkynyl group as defined above substituted by one or more halogen atoms.
术语“羟基烷基”是指被一个或多个羟基(-OH)取代的如上文所定义的烷基基团。例如术语“羟基(C1-C3)烷基”实例包括但不限于，羟基甲基、2-羟基乙基、3-羟基丙基、2-乙基-4-羟基庚基等。The term "hydroxyalkyl" refers to an alkyl group as defined above substituted by one or more hydroxyl groups (-OH). For example, examples of the term "hydroxy(C1-C3)alkyl" include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-ethyl-4-hydroxyheptyl, and the like.
术语“芳基”是指具有共轭的π电子体系的全碳单环基团或者具有共轭的π电子体系的全碳单环与芳香碳环稠合的双环基团，其通过从母体芳香环体系的单一碳原子上除去一个氢原子而得到。例如本发明所定义的“6-10元芳基”指6-10元芳基失去一个氢原子形成的基团。实例包括但不限于苯基、萘基。The term "aryl" refers to an all-carbon monocyclic group with a conjugated π electron system or a bicyclic group in which an all-carbon monocyclic ring with a conjugated π 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. For example, 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.
术语“6-10元芳(C1-C6)烷基”是指具有通式-Rb-Rc的基团，其中Rb是如上文所定义的(C1-C6)亚烷基并且Rc是一个或多个如上文所定义的6-10元芳基基团，例如苄基、二苯基甲基等等。The term "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.
术语“6-10元芳(C2-C6)烯基”是指具有通式-Rd-Rc的基团，其中Rd是如上文所定义的C2-C6亚烯基并且Rc是一个或多个如上文所定义的6-10元芳基基团。The term "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.
术语“6-10元芳(C2-C6)炔基”是指具有通式–Re-Rc的基团，其中Re是如上文所定义的C2-C6亚炔基并且Rc是一个或多个如上文所定义的6-10元芳基基团。The term "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.
术语“环烷基”是指仅由碳和氢原子组成的稳定的饱和单环或多环烃基团，其可以包括螺环或桥环体系，具有三至十五个碳原子。例如术语“C3-C8环烷基”是指具有3-8个碳原子的环状烷基，其进一步可以为C3-C6环烷基，其实例包括但不限于，环丙基、环丁基、环戊基、环己基、环庚基和环辛基。 The term "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. For example, the term "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.
术语“C3-C8环烷基(C1-C6)烷基”是指通式–Rb-Rg的基团，其中Rb是如上文所定义的C1-C6亚烷基链并且Rg是如上文所定义的C3-C8环烷基基团。The term "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.
术语“C3-C8环烷基(C2-C6)烯基”是指通式–Rd-Rg的基团，其中Rd是如上文所定义的C2-C6亚烯基链并且Rg是如上文所定义的C3-C8环烷基基团。The term "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.
术语“C3-C8环烷基(C2-C6)炔基”是指通式–Re-Rg的基团，其中Re是如上文所定义的C2-C6亚炔基基团并且Rg是如上文所定义的C3-C8环烷基基团。The term "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.
术语“杂环基”是指包含至少一个环杂原子或杂原子团的稳定的饱和、部分不饱和或完全不饱和的非芳香的或芳香性的环基团，杂原子或杂原子团独立地选自氮、硫、氧、亚砜、砜、杂环基基团可以是单环、二环、三环或四环体系，其中两个或两个以上的环以螺环、并环或桥环形式存在。杂环为两个或以上环时，至少其中一个环中包含至少一个杂原子或杂原子团，可以是含杂原子或杂原子团的环与不含杂原子或杂原子团的环形成的二环或多环。当杂原子为氮时，氮可以作为连接点与其他基团相连。例如术语“3-18元杂环基”指包含有3-18个(例如5、6、5-7、3-8、3-10、8-10、10-14或12-18个)环原子的杂环基，进一步可以为5-7元单环杂环基、8至10元双环杂环基或10-18元三环或四环杂环基，所述“3-18元杂环基”任选地含有1、2、3、或4个作为环原子的杂原子或杂原子团，包括但不限于环氧乙烷、呋喃基、四氢呋喃基、四氢吡喃基、四氢吡咯基、四氢噻吩基、哌啶基、吗啉基、吡啶基、苯并咪唑基、 The term "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. When 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. ring. When the heteroatom is nitrogen, the nitrogen can serve as a point of attachment to other groups. For example, the term "3-18 membered heterocyclyl" refers to a ring containing 3-18 (such as 5, 6, 5-7, 3-8, 3-10, 8-10, 10-14 or 12-18) rings. The 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,
术语“杂环基(C1-C6)烷基”是指通式–Rb-Rh的基团，其中Rb是如上文所定义的C1-C6亚烷基链并且Rh是如上文所定义的杂环基，并且若所述杂环基是含氮杂环基，则所述杂环基可以在氮原子处与烷基基团连接。The term "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.
术语“杂环基(C2-C6)烯基”是指通式–Rd-Rh的基团，其中Rd是如上文所定义的C2-C6亚烯基链并且Rh是如上文所定义的杂环基，并且若所述杂环基是含氮杂环基，则所述杂环基可以在氮原子处与亚烯基链连接。The term "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. 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.
术语“杂环基(C2-C6)炔基”是指通式–Re-Rh的基团，其中Re是如上文所定义的C2-C6亚炔基链并且Rh是如上文所定义的杂环基，并且若所述杂环基是含氮杂环基，则所述杂环基可以在氮原子处与炔基基团连接。The term "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.
术语“苯并(C3-C8)环烷基”指苯环与上文中所定义的C3-C8环烷基稠合形成的基团，苯环与环烷基共用两个邻接的环碳原子，且与母核结构的连接位点位于苯环部分。实例包括，但不限于：The term "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:
等。 wait.
术语“酰胺基”是指 The term "amide" means
术语“药学上可接受的盐”是指保留了特定化合物的游离酸和碱的生物学效力而没有生物学不良作用的盐。例如酸(包括有机酸和无机酸)加成盐或碱加成盐(包括有机碱和无机碱)。The term "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. For example, acid (including organic acids and inorganic acids) addition salts or base addition salts (including organic bases and inorganic bases).
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, 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.
术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。The term "effective amount" or "therapeutically effective amount" refers to a nontoxic amount of a drug or agent that is sufficient to achieve the desired effect.
术语“药学上可接受的载体”是指对机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体。包括但不限于国家食品药品监督管理局许可的可用于人或动物的任何稀释剂、崩解剂、粘合剂、助流剂、润湿剂。 The term "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.
权利要求书和说明书中所使用的简称其含义如下：The abbreviations used in the claims and description have the following meanings:
“v/v”是指体积比；“v/v” refers to the volume ratio;
M:mol/L；mM：mmol/L；μM：μmol/L；nM：nmol/L；M: mol/L; mM: mmol/L; μM: μmol/L; nM: nmol/L;
DMB:2，4-二甲氧基苄基；DMB: 2,4-dimethoxybenzyl;
DMBNH2：2，4-二甲氧基苄胺；DMBNH 2 : 2,4-dimethoxybenzylamine;
PMBNH2:对甲氧基苄胺；PMBNH 2 : p-methoxybenzylamine;
SEB:Supplemented Enzymatic Buffer(SEB)，试剂盒中一种成分；SEB: Supplemented Enzymatic Buffer (SEB), a component in the kit;
DMF-DMA：N,N-二甲基甲酰胺二甲基缩醛；DMF-DMA: N,N-dimethylformamide dimethyl acetal;
Pd2(dba)3：三(二亚苄基丙酮)二钯；Pd 2 (dba) 3 : tris(dibenzylideneacetone)dipalladium;
rpm:转/分；min:分钟；rpm: revolution/minute; min: minute;
N或M：代表浓度，mol/L，例如“6M HCl”代表盐酸浓度是6mol/L。N or M: represents concentration, mol/L. For example, "6M HCl" represents that the concentration of hydrochloric acid is 6mol/L.
具体实施方式Detailed ways
制备例1
Preparation Example 1
a)中间体化合物M1-1的制备a) Preparation of intermediate compound M1-1
氮气保护下，将2-溴-5-甲基吡啶(6.2g)、叔丁醇钾(8.4g)、乙酸钯(336mg)、1,1'-双(二苯基膦基)二茂铁(1.66g)及二氧六环(100mL)置于250mL三口瓶中，搅拌，接着加入2-氰基乙酸叔丁酯(4.24g)，再次氮气交换。将反应液于70摄氏度下反应6小时。待原料反应完全，当反应液温度降至室温时，向其中加入乙酸(10mL)及甲醇(50mL)并搅拌5分钟，接着反应液脱溶至干。向粗品中加入乙酸乙酯(200mL)和水(100mL)搅拌，有机相脱溶至干，得标题产物5.3g。Under nitrogen protection, 2-bromo-5-methylpyridine (6.2g), potassium tert-butoxide (8.4g), palladium acetate (336mg), 1,1'-bis(diphenylphosphino)ferrocene (1.66g) and dioxane (100mL) were placed in a 250mL three-necked flask, stirred, then added tert-butyl 2-cyanoacetate (4.24g), and exchanged nitrogen again. The reaction solution was reacted at 70 degrees Celsius for 6 hours. After the reaction of the raw materials is complete, when the temperature of the reaction solution drops to room temperature, acetic acid (10 mL) and methanol (50 mL) are added and stirred for 5 minutes, and then the reaction solution is desolvated to dryness. Ethyl acetate (200 mL) and water (100 mL) were added to the crude product and stirred. The organic phase was desolvated to dryness to obtain 5.3 g of the title product.
b)中间体化合物M1-2的制备b) Preparation of intermediate compound M1-2
将M1-1(11.5g)及6M HCl(100mL)置于250mL单口瓶中，于110摄氏度搅拌5小时。待反应完全，抽滤，滤液用3N NaOH调pH至12。用二氯甲烷(50mL)洗水相，共洗三次。水相用2M HCl调pH至4。接着将水相脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物3.3g。Place M1-1 (11.5g) and 6M HCl (100mL) in a 250mL single-neck bottle and stir at 110 degrees Celsius for 5 hours. When the reaction is complete, filter with suction, and adjust the pH of the filtrate to 12 with 3N NaOH. Wash the aqueous phase with dichloromethane (50 mL) three times. Adjust the pH of the aqueous phase to 4 with 2M HCl. Then, the aqueous phase was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 3.3 g of the title product.
c)中间体化合物M1-3的制备c) Preparation of intermediate compound M1-3
将M1-3(3.25g)及乙腈(50mL)置于250mL单口瓶中(A瓶)，搅拌。待反应液溶清后，加入羰基二咪唑(5.35g)并搅拌备用。将3-乙氧基-3-氧代丙酸钾(11.23g)、无水氯化镁(6.27g)及MeCN(50mL)置于100mL单口瓶中(B瓶)搅拌。在0摄氏度下，逐滴加入三乙胺(11.62g)，滴毕后，逐渐升至室温搅拌1小时。在0摄氏度下，将A瓶反应液缓慢滴加到B瓶反应液中。滴毕后，逐渐升至室温搅拌过夜。待原料反应完全，将反应液抽滤，滤液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物600mg。 Place M1-3 (3.25g) and acetonitrile (50mL) into a 250mL single-neck bottle (Bottle A) and stir. After the reaction solution is completely dissolved, add carbonyldiimidazole (5.35g) and stir until set aside. Potassium 3-ethoxy-3-oxopropionate (11.23g), anhydrous magnesium chloride (6.27g) and MeCN (50mL) were placed in a 100mL single-neck bottle (Bottle B) and stirred. At 0 degrees Celsius, add triethylamine (11.62g) dropwise. After the addition is completed, gradually increase to room temperature and stir for 1 hour. At 0 degrees Celsius, slowly drop the reaction solution in bottle A into the reaction solution in bottle B. After the dripping is completed, gradually raise to room temperature and stir overnight. After the reaction of the raw materials is complete, the reaction solution is suction-filtered, and the filtrate is desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 600 mg of the title product.
d)中间体化合物M1-4的制备d) Preparation of intermediate compound M1-4
将M1-3(600mg)、N,N-二甲基甲酰胺二甲基缩醛(1.8g)、甲苯(100mL)置于250mL单口瓶中，并置上干燥管，搅拌。反应液于95摄氏度下搅拌8h。待反应液冷却，将反应液脱溶至干。向粗品中加入(四氢-2H-吡喃-4-基)甲胺(420mg)及乙醇(150mL)，并于84摄氏度下反应6小时。待原料反应完全，将反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物350mg。Place M1-3 (600mg), N,N-dimethylformamide dimethyl acetal (1.8g), and toluene (100mL) in a 250mL single-mouth bottle, put a drying tube in place, and stir. The reaction solution was stirred at 95 degrees Celsius for 8 hours. After the reaction liquid is cooled, the reaction liquid is desolvated to dryness. (Tetrahydro-2H-pyran-4-yl)methanamine (420 mg) and ethanol (150 mL) were added to the crude product, and the reaction was carried out at 84 degrees Celsius for 6 hours. After the reaction of the raw materials is complete, the reaction solution is desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 350 mg of the title product.
e)中间体化合物M1的制备e) Preparation of intermediate compound M1
将M1-4(350mg)、2N NaOH溶液(10.00mmol)及甲醇(5mL)置于50mL单口瓶中。反应液于室温下搅拌过夜。待原料反应完全，将反应液脱溶，向粗品中加入水(10mL)。用2M HCl调pH至5，有大量固体析出。抽滤，并将滤饼烘干，得标题化合物150mg。Place M1-4 (350mg), 2N NaOH solution (10.00mmol) and methanol (5mL) in a 50mL single-mouth bottle. The reaction was stirred at room temperature overnight. When the reaction of the raw materials is complete, the reaction solution is desolvated, and water (10 mL) is added to the crude product. Use 2M HCl to adjust the pH to 5, and a large amount of solid will precipitate. Filter with suction, and dry the filter cake to obtain 150 mg of the title compound.
制备例2
Preparation Example 2
a)中间体化合物M2-1的制备a) Preparation of intermediate compound M2-1
将1,2-二氟-4-硝基苯(795mg)、80％水合肼(400mg)及乙醇(15mL)置于25mL单口瓶中并于80摄氏度下反应。待原料反应完全，将反应液脱溶至干，接着用甲基叔丁基醚打浆，过滤。滤饼烘干，得标题产物500mg。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.
b)中间体化合物M2-2的制备b) Preparation of intermediate compound M2-2
将3，4-二甲氧基苯胺(153mg)、氰基碳亚胺二苯酯(238mg)及异丙醇(5mL)置于25mL单口瓶中并搅拌过夜。待原料反应完全，过滤。滤饼用异丙醇洗涤，并烘干，得标题产物297mg。3,4-Dimethoxyaniline (153 mg), diphenyl cyanocarboimide (238 mg) and isopropyl alcohol (5 mL) were placed in a 25 mL single-neck bottle and stirred overnight. When the reaction of the raw materials is complete, filter. The filter cake was washed with isopropyl alcohol and dried to obtain 297 mg of the title product.
c)中间体化合物M2-3的制备c) Preparation of intermediate compound M2-3
将M2-1(85mg)、M2-2(149mg)及异丙醇(5mL)置于10mL微波管中并于180摄氏度反应0.5小时。待原料反应完全，将反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物170mg。M2-1 (85 mg), M2-2 (149 mg) and isopropyl alcohol (5 mL) were placed in a 10 mL microwave tube and reacted at 180 degrees Celsius for 0.5 hours. After the reaction of the raw materials is complete, the reaction solution is desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 170 mg of the title product.
d)中间体化合物M2的制备d) Preparation of intermediate compound M2
将M2-3(160mg)、10％Pd/C(16mg)、80％水合肼(172mg)及甲醇(20mL)置于50mL单口瓶中并于室温搅拌过夜。待原料反应完全，将反应液过滤，滤液用甲醇洗涤。合并滤液，脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物147mg。M2-3 (160 mg), 10% Pd/C (16 mg), 80% hydrazine hydrate (172 mg) and methanol (20 mL) were placed in a 50 mL one-neck bottle and stirred at room temperature overnight. After the reaction of the raw materials is complete, filter the reaction solution and wash the filtrate with methanol. The filtrate was combined, desolvated to dryness, and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 147 mg of the title product.
制备例3
Preparation Example 3
a)中间体化合物M3-1的制备a) Preparation of intermediate compound M3-1
将4-(4-甲基哌嗪-1-基)苯胺(1g)、氰基碳亚胺二苯酯(1.24g)及异丙醇(10mL)置于25mL单口瓶中并搅拌过夜。待原料反应完全，过滤。滤饼用异丙醇洗涤，并烘干，得标题产物1.55g。4-(4-Methylpiperazin-1-yl)aniline (1g), diphenyl cyanocarboimide (1.24g) and isopropanol (10mL) were placed in a 25mL single-neck bottle and stirred overnight. When the reaction of the raw materials is complete, filter. The filter cake was washed with isopropanol and dried to obtain 1.55g of the title product.
b)中间体化合物M3的制备b) Preparation of intermediate compound M3
将(4-溴-2-氟苯基)盐酸肼(1.11g)、M3-1(1.55g)，三乙胺(929mg)及DMF(15mL)置于30mL微波管中并于180摄氏度反应0.5小时。待原料反应完全，将反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物1.02g。Place (4-bromo-2-fluorophenyl)hydrazine hydrochloride (1.11g), M3-1 (1.55g), triethylamine (929mg) and DMF (15mL) in a 30mL microwave tube and react at 180 degrees Celsius for 0.5 Hour. After the reaction of the raw materials is complete, the reaction solution is desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 1.02g of the title product.
MS(ESI+):446.1(M+H).MS(ESI+):446.1(M+H).
制备例4
Preparation Example 4
参照制备例3，将步骤a)中的4-(4-甲基哌嗪-1-基)苯胺替换成(S)-7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]环-2-胺进行反应得到中间体化合物M4-1，接着进行与制备例3的步骤b)相同的后续反应，获得中间体化合物M4 1.4g。Referring to Preparation Example 3, replace 4-(4-methylpiperazin-1-yl)aniline in step a) with (S)-7-(pyrrolidin-1-yl)-6,7,8,9 -Tetrahydro-5H-benzo[7]cyclo-2-amine was reacted to obtain intermediate compound M4-1, and then the same subsequent reaction as step b) of Preparation Example 3 was performed to obtain 1.4g of intermediate compound M4.
MS(ESI+):485.1(M+H).MS(ESI+):485.1(M+H).
制备例5
Preparation Example 5
参照制备例3,将步骤b)中的(4-溴-2-氟苯基)盐酸肼替换成(4-碘-苯基)盐酸肼即可，得中间体化合物M5 762mg固体。MS(ESI+):476.1(M+H).Referring to Preparation Example 3, replace (4-bromo-2-fluorophenyl)hydrazine hydrochloride in step b) with (4-iodo-phenyl)hydrazine hydrochloride to obtain 762 mg of solid intermediate compound M5. MS(ESI+):476.1(M+H).
制备例6
Preparation Example 6
a)中间体化合物M6-1的制备a) Preparation of intermediate compound M6-1
氮气保护下，将0.25M 4-氟苄基氯化镁(104mL)滴加到4-氨基-2-氯吡啶-3-甲腈(1g)的***(15mL)溶液中，并于30摄氏度下搅拌过夜。将反应液降温至零摄氏度。向反应液中滴加HCl/H2O/EtOH(1:1:2)(30mL)的混合溶液，并搅拌。接着将反应液升温至80摄氏度并反应两小时。待反应完全，将反应液冷却至室温，用饱和碳酸氢钠溶液调pH至7。用乙酸乙酯(50mL)萃取水相，共三次。合并有机相，接着用饱和氯化钠溶液洗涤。有机相用无水硫酸钠干燥。接着过滤，滤液脱溶至干，柱层析纯化(石油醚/乙酸乙酯＝2/1(V/V))，得标题产物580mg。Under nitrogen protection, 0.25M 4-fluorobenzylmagnesium chloride (104mL) was added dropwise to a solution of 4-amino-2-chloropyridine-3-carbonitrile (1g) in diethyl ether (15mL), and stirred at 30 degrees Celsius overnight. . Cool the reaction solution to zero degrees Celsius. A mixed solution of HCl/H2O/EtOH (1:1:2) (30 mL) was added dropwise to the reaction solution and stirred. Then the reaction solution was heated to 80 degrees Celsius and reacted for two hours. When the reaction is complete, cool the reaction solution to room temperature, and adjust the pH to 7 with saturated sodium bicarbonate solution. The aqueous phase was extracted three times with ethyl acetate (50 mL). The organic phases were combined and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate. Then, it was filtered, and the filtrate was desolvated to dryness and purified by column chromatography (petroleum ether/ethyl acetate = 2/1 (V/V)) to obtain 580 mg of the title product.
b)中间体化合物M6的制备b) Preparation of intermediate compound M6
将原甲酸三甲酯(324.7mg)与中间体化合物M6-1(580mg)置于100mL单口瓶中，于100摄氏度下搅拌1.5小时。接着加入4-二甲氨基吡啶(26.7mg)，继续反应过夜。待反应完全，将反应液降至室温，有大量固体析出。抽滤，滤饼用异丙醇洗涤。滤饼烘干得标题产物206mg。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.
制备例7：
Preparation Example 7:
a)中间体化合物M7-1的制备a) Preparation of intermediate compound M7-1
将2-氰基-N-(4-氟苯基)乙酰胺(1.88g)溶于无水乙醇(50mL)，依次加入哌啶(0.5mL)和乙酰丙酮(1g)，90℃搅拌3h。冷至室温，抽滤得标题产物1.98g。Dissolve 2-cyano-N-(4-fluorophenyl)acetamide (1.88g) in absolute ethanol (50mL), add piperidine (0.5mL) and acetylacetone (1g) in sequence, and stir at 90°C for 3h. Cool to room temperature and filter with suction to obtain 1.98g of the title product.
b)中间体化合物M7-2的制备b) Preparation of intermediate compound M7-2
将M7-1(1.98g)溶于DMF(30mL)，加入DMF-DMA(1.07g)，氮气保护，90℃搅拌2h。冷至室温，直接脱溶得到得标题产物2.9g。Dissolve M7-1 (1.98g) in DMF (30mL), add DMF-DMA (1.07g), protect with nitrogen, and stir at 90°C for 2 hours. Cool to room temperature and dissolve directly to obtain 2.9 g of the title product.
c)中间体化合物M7-3的制备c) Preparation of intermediate compound M7-3
将M7-2(2.9g)溶于浓硫酸(10mL)中，氮气保护，90℃搅拌2h。将反应液冷至室温，缓慢加入冰水中，用饱和碳酸钾调pH至8，用正丁醇萃取水相，分离有机相，用无水硫酸钠干燥，脱溶得到得标题产物2.20g。Dissolve M7-2 (2.9g) in concentrated sulfuric acid (10 mL), protect with nitrogen, and stir at 90°C for 2 hours. The reaction solution was cooled to room temperature, slowly added to ice water, the pH was adjusted to 8 with saturated potassium carbonate, the aqueous phase was extracted with n-butanol, the organic phase was separated, dried over anhydrous sodium sulfate, and desolvated to obtain 2.20 g of the title product.
d)中间体化合物M7的制备d) Preparation of intermediate compound M7
将M7-3(2.20g)溶于三氯氧磷(20mL)中，氮气保护，110℃搅拌2h。将反应液冷至室温，浓缩，用二氯甲烷(100mL)稀释，用饱和碳酸氢钠水溶液调pH至8，分离有机相，用无水硫酸钠干燥，脱溶，制砂，柱层析(DCM/MeOH＝50/1)得到标题产物1.3g。MS(ESI+):289.1(M+H).Dissolve M7-3 (2.20g) in phosphorus oxychloride (20 mL), protect with nitrogen, and stir at 110°C for 2 hours. Cool the reaction solution to room temperature, concentrate, dilute with dichloromethane (100 mL), adjust pH to 8 with saturated aqueous sodium bicarbonate solution, separate the organic phase, dry with anhydrous sodium sulfate, remove the solvent, make sand, and perform column chromatography ( DCM/MeOH=50/1) to obtain 1.3 g of the title product. MS(ESI+):289.1(M+H).
制备例8：
Preparation Example 8:
a)中间体化合物M8-1的制备a) Preparation of intermediate compound M8-1
将氰基乙酸(1.00g)溶于无水二氯甲烷(30mL)中，依次加入O-(7-氮杂苯并***-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐(4.91g),N,N-二异丙基乙胺(1.81g)和2-氨基-5-甲基吡啶(1.26g)，20℃搅拌16h。加水(30mL)稀释，分离有机相，用无水硫酸钠干燥，脱溶，制砂，柱层析(石油醚/乙酸乙酯＝1/1(V/V))得标题产物861mg。Dissolve cyanoacetic acid (1.00g) in anhydrous dichloromethane (30 mL), and add O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetrakis in sequence. Methylurea hexafluorophosphate (4.91g), N,N-diisopropylethylamine (1.81g) and 2-amino-5-methylpyridine (1.26g) were stirred at 20°C for 16h. Dilute with water (30 mL), separate the organic phase, dry with anhydrous sodium sulfate, remove the solution, make sand, and perform column chromatography (petroleum ether/ethyl acetate = 1/1 (V/V)) to obtain 861 mg of the title product.
b)中间体化合物M8的制备b) Preparation of intermediate compound M8
参考制备例7，将步骤a)中的2-氰基-N-(4-氟苯基)乙酰胺替换成2-氰基-N-(5-甲基吡啶-2-基)乙酰胺即可，接着进行与制备例7的步骤b)至步骤d)相同的后续反应，得到标题产物169mg。Referring to 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.
MS(ESI+):286.1(M+H).MS(ESI+):286.1(M+H).
制备例9：
Preparation Example 9:
参考制备例8，将步骤a)中的2-氨基-5-甲基吡啶替换成对甲氧基苯胺，接着进行与制备例8的步骤b)至步骤e)相同的后续反应，获得标题化合物1.1g。MS(ESI+):301.1(M+H).Referring to Preparation Example 8, replace 2-amino-5-methylpyridine in step a) with p-methoxyaniline, and then perform the same subsequent reactions as step b) to step e) in Preparation Example 8 to obtain the title compound 1.1g. MS(ESI+):301.1(M+H).
制备例10：

Preparation Example 10:

a)中间体化合物M10-1的制备a) Preparation of intermediate compound M10-1
将5-氟吡啶-2-胺(2.24g)溶于N,N-二甲基甲酰胺(25mL)中，冰浴条件下依次加入氰基乙酸(1.72g)，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(4.18g)，N,N-二异丙基乙胺(2.42g)，逐渐升温至60℃反应2h。反应完毕，加水(80mL)，乙酸乙酯萃取两次(80mL)，有机层用水洗涤，无水硫酸钠干燥后浓缩，粗品柱层析(石油醚/乙酸乙酯＝4/1(V/V))得标题产物2.91g。Dissolve 5-fluoropyridin-2-amine (2.24g) in N,N-dimethylformamide (25mL), add cyanoacetic acid (1.72g), 2-(7-aza) in sequence under ice bath conditions Benzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.18g), N,N-diisopropylethylamine (2.42g), gradually warm to 60°C Reaction 2h. After the reaction is completed, water (80 mL) is added, and ethyl acetate is extracted twice (80 mL). The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated. The crude product is subjected to column chromatography (petroleum ether/ethyl acetate = 4/1 (V/V )) 2.91g of the title product was obtained.
b)中间体化合物M10的制备b) Preparation of intermediate compound M10
参考制备例7，将步骤a)中的2-氰基-N-(4-氟苯基)乙酰胺替换成M10-1，接着进行与制备例7的步骤b)至步骤d)相同的后续反应，获得标题化合物168mg。MS(ESI+):290.1(M+H).Referring to Preparation Example 7, replace 2-cyano-N-(4-fluorophenyl)acetamide in step a) with M10-1, and then perform the same subsequent steps as step b) to step d) in Preparation Example 7 After reaction, 168 mg of the title compound was obtained. MS(ESI+):290.1(M+H).
制备例11:
Preparation Example 11:
a)中间体化合物M11-1的制备a) Preparation of intermediate compound M11-1
将3,5-二溴-1H-1,2,4-***(1.12g)、对乙酰胺基苯硼酸(1.34g)、三氟甲磺酸铜(3.61g)、硼酸(927mg)及分子筛3g置于100mL单口瓶中，接着加入N,N-二甲基甲酰胺(50mL)，氧气置换，并于室温下搅拌过夜。待原料反应完全，过滤，接着向滤液中加入水(150mL)，用乙酸乙酯(150mL)萃取，重复三次。合并有机相，脱溶至干，柱层析纯化(二氯甲烷/甲醇＝50/1(V/V))，得标题产物1.38g。Combine 3,5-dibromo-1H-1,2,4-triazole (1.12g), p-acetamidobenzeneboronic acid (1.34g), copper triflate (3.61g), boric acid (927mg) and Place 3 g of molecular sieve in a 100 mL one-neck bottle, then add N,N-dimethylformamide (50 mL), replace with oxygen, and stir at room temperature overnight. After the reaction of the raw materials is complete, filter, then add water (150 mL) to the filtrate, and extract with ethyl acetate (150 mL), repeat three times. The organic phases were combined, desolvated to dryness, and purified by column chromatography (dichloromethane/methanol = 50/1 (V/V)) to obtain 1.38 g of the title product.
b)中间体化合物M11-2的制备b) Preparation of intermediate compound M11-2
将M11-1(891mg)、2,4-二甲氧基苄氨(499mg)、N,N-二异丙基乙基胺(642mg)及二氧六环(10mL)置于30mL微波管中，并于160摄氏度搅拌3小时。待原料反应完全，脱溶至干，柱层析纯化(二氯甲烷/甲醇＝50/1(V/V))，得标题产物804mg。Place M11-1 (891mg), 2,4-dimethoxybenzylamine (499mg), N,N-diisopropylethylamine (642mg) and dioxane (10mL) in a 30mL microwave tube , and stirred at 160 degrees Celsius for 3 hours. After the reaction of the raw materials is complete, the solution is removed to dryness and purified by column chromatography (dichloromethane/methanol=50/1 (V/V)) to obtain 804 mg of the title product.
c)中间体化合物M11-3的制备c) Preparation of intermediate compound M11-3
将M11-2(801mg)、4-(4-甲基哌嗪-1-基)苯胺(311mg)、Pd2(dba)3(164mg)、二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-联苯]-2-基)膦(289mg)、碳酸铯(1.17g)及二氧六环(20mL)置于100mL单口瓶中，氮气保护并于100摄氏度搅拌12小时。待原料反应完全，脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物250mg。 M11-2 (801mg), 4-(4-methylpiperazin-1-yl)aniline (311mg), Pd 2 (dba) 3 (164mg), dicyclohexyl (2',4',6'- Triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (289mg), cesium carbonate (1.17g) and dioxane (20mL) were placed in 100mL In a single-neck bottle, the mixture was protected with nitrogen and stirred at 100 degrees Celsius for 12 hours. After the reaction of the raw materials is complete, the solution is removed to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 250 mg of the title product.
d)中间体化合物M11的制备d) Preparation of intermediate compound M11
将M11-3(355mg)、氢氧化钠(3.2mmol,5eq)及乙醇(10mL)置于30mL微波管中，氮气保护并于150摄氏度微波反应3小时。待原料反应完全，脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物220mg。MS(ESI+):515.3(M+H).M11-3 (355 mg), sodium hydroxide (3.2 mmol, 5 eq) and ethanol (10 mL) were placed in a 30 mL microwave tube, protected by nitrogen, and reacted in the microwave at 150 degrees Celsius for 3 hours. After the reaction of the raw materials is complete, the solution is removed to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 220 mg of the title product. MS(ESI+):515.3(M+H).
制备例12：
Preparation Example 12:
a)中间体化合物M12-1的制备a) Preparation of intermediate compound M12-1
将3,4-二氟硝基苯(1g)、3,5-二溴-1H-1,2,4-***(1.68g)、碳酸钠(1.3g)及N,N-二甲基甲酰胺(30mL)置于100mL单口瓶中，氮气保护，并于75摄氏度下搅拌3小时。待原料反应完全，向反应液中加入水(150mL)，用乙酸乙酯(150mL)萃取，重复三次。合并有机相，脱溶至干，柱层析纯化(乙酸乙酯/石油醚＝1/3(V/V))，得标题产物1.37g。Combine 3,4-difluoronitrobenzene (1g), 3,5-dibromo-1H-1,2,4-triazole (1.68g), sodium carbonate (1.3g) and N,N-dimethyl Formamide (30 mL) was placed in a 100 mL single-neck bottle, protected by nitrogen, and stirred at 75 degrees Celsius for 3 hours. When the reaction of the raw materials is complete, add water (150 mL) to the reaction solution, extract with ethyl acetate (150 mL), and repeat three times. The organic phases were combined, removed to dryness, and purified by column chromatography (ethyl acetate/petroleum ether = 1/3 (V/V)) to obtain 1.37 g of the title product.
b)中间体化合物M12-2的制备b) Preparation of intermediate compound M12-2
将M12-1(1.37g)、2,4-二甲氧基苄胺(0.618g)、N,N-二异丙基乙基胺(0.95g)及二氧六环(10mL)置于30mL微波管中，并于140摄氏度搅拌1小时。待原料反应完全，脱溶至干，柱层析纯化(乙酸乙酯/石油醚＝1/3(V/V))，得标题产物1.32g。Place M12-1 (1.37g), 2,4-dimethoxybenzylamine (0.618g), N,N-diisopropylethylamine (0.95g) and dioxane (10mL) in 30mL Microwave tube and stir at 140°C for 1 hour. After the reaction of the raw materials is complete, the solution is removed to dryness and purified by column chromatography (ethyl acetate/petroleum ether=1/3 (V/V)) to obtain 1.32g of the title product.
c)中间体化合物M12-3的制备c) Preparation of intermediate compound M12-3
氮气保护下，将M12-2(515.7mg)、4-(4-甲基哌嗪-1-基)苯胺(262mg)、Pd2(dba)3(229mg)、2-二叔丁基膦基-2，4，6-三异丙基联苯(318mg)、叔丁醇钾(560mg)及甲苯(30mL)置于100mL单口瓶中，并于105下反应10小时。待原料反应完全，脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物829mg。Under nitrogen protection, mix M12-2 (515.7mg), 4-(4-methylpiperazin-1-yl)aniline (262mg), Pd 2 (dba) 3 (229mg), 2-di-tert-butylphosphine -2,4,6-triisopropylbiphenyl (318mg), potassium tert-butoxide (560mg) and toluene (30mL) were placed in a 100mL single-mouth bottle, and reacted at 105 for 10 hours. After the reaction of the raw materials is complete, the solution is removed to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 829 mg of the title product.
d)中间体化合物M12的制备d) Preparation of intermediate compound M12
将M12-3(767mg)、铁粉(611mg)、氯化铵(578mg)、乙醇(20mL)及水(10mL)置于100mL单口瓶中，氮气保护并于90摄氏度搅拌4小时。待原料反应完全，脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物645mg。MS(ESI+):533.3(M+H).M12-3 (767mg), iron powder (611mg), ammonium chloride (578mg), ethanol (20mL) and water (10mL) were placed in a 100mL single-mouth bottle, protected by nitrogen and stirred at 90 degrees Celsius for 4 hours. After the reaction of the raw materials is complete, the solution is removed to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 645 mg of the title product. MS(ESI+):533.3(M+H).
实施例Example
实施例1：
Example 1:
将M2(55mg)、M1(63mg)、1-[双(二甲氨基)亚甲基]-1H-1,2,3-***并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(183mg)及无水N,N-二甲基甲酰胺(5mL)置于25mL单口瓶中，搅拌，接着加入N,N-二异丙基乙基胺(62mg)。反应液于室温下搅拌过夜。向反应液中加入水(50mL)，接着加入乙酸乙酯(50mL)萃取，共三次。合并有机相并脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得化合物例1 30mg。M2 (55 mg), M1 (63 mg), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexaoxide Fluorophosphate (183 mg) and anhydrous N,N-dimethylformamide (5 mL) were placed in a 25 mL single-neck bottle, stirred, and then N, N-diisopropylethylamine (62 mg) was added. The reaction was stirred at room temperature overnight. Water (50 mL) was added to the reaction solution, and then ethyl acetate (50 mL) was added for extraction three times in total. The organic phases were combined and desolvated to dryness, and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 30 mg of compound example 1.
1H NMR(400MHz,DMSO-d6):δ13.27(s,1H),8.76(d,J＝2.4Hz,1H),8.69(d,J＝2.4Hz,1H),8.55(s,1H),8.51(d,J＝2.2Hz,1H),8.47(d,J＝8.1Hz,1H),8.03–7.98(m,1H),7.74-7.69(m,1H),7.53–7.46(m,2H),7.17(d,J＝2.5Hz,1H),7.09(dd,J＝8.7,2.5Hz,1H),6.79(d,J＝8.8Hz,1H),6.27(s,2H),4.21(d,J＝7.2Hz,2H),3.89–3.83(m,2H),3.67(d,J＝11.4Hz,6H),3.30-3.22(m,2H),2.36(s,3H),2.14-2.02(m,1H),1.50-1.44(m,2H),1.35-1.30(m,2H). 1 H NMR (400MHz, DMSO-d 6 ): δ13.27 (s, 1H), 8.76 (d, J = 2.4Hz, 1H), 8.69 (d, J = 2.4Hz, 1H), 8.55 (s, 1H ),8.51(d,J＝2.2Hz,1H),8.47(d,J＝8.1Hz,1H),8.03–7.98(m,1H),7.74-7.69(m,1H),7.53–7.46(m, 2H),7.17(d,J＝2.5Hz,1H),7.09(dd,J＝8.7,2.5Hz,1H),6.79(d,J＝8.8Hz,1H),6.27(s,2H),4.21( d,J＝7.2Hz,2H),3.89–3.83(m,2H),3.67(d,J＝11.4Hz,6H),3.30-3.22(m,2H),2.36(s,3H),2.14-2.02 (m,1H),1.50-1.44(m,2H),1.35-1.30(m,2H).
MS(ESI+):655.3(M+H).MS(ESI+):655.3(M+H).
实施例2：
Example 2:
a)化合物2-3的制备a) Preparation of compound 2-3
将化合物M4(363mg)、氨基甲酸叔丁酯(263mg)、三(二亚苄基丙酮)二钯(73mg)、二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-联苯]-2-基)膦(123mg)、碳酸铯(342mg)及二氧六环(20mL)置于100mL单口瓶中并于100摄氏度下反应。待原料反应完全，将反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物110mg。Compound M4 (363mg), tert-butyl carbamate (263mg), tris(dibenzylideneacetone)dipalladium (73mg), dicyclohexyl (2',4',6'-triisopropyl-3, 6-Dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (123mg), cesium carbonate (342mg) and dioxane (20mL) were placed in a 100mL single-mouth bottle and kept at 100 degrees Celsius reaction. After the reaction of the raw materials is complete, the reaction solution is desolvated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 110 mg of the title product.
b)化合物2-4的制备b) Preparation of compound 2-4
将化合物2-3(104mg)、4M二氧六环的盐酸溶液(1mL)及甲醇(5mL)置于25mL单口瓶中并于室温搅拌过夜。待原料反应完全，将反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物25mg固体。Compound 2-3 (104 mg), 4M dioxane hydrochloric acid solution (1 mL) and methanol (5 mL) were placed in a 25 mL single-neck bottle and stirred at room temperature overnight. After the reaction of the raw materials is complete, the reaction solution is desolvated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 25 mg of the title product as a solid.
c)化合物例2的制备c) Preparation of compound example 2
将化合物2-4(22mg)、(2-肟基-氰基乙酸乙酯)-N,N-二甲基-吗啉基脲六氟磷酸酯(45mg)及N,N-二甲基甲酰胺(5mL)置于25mL单口瓶中，搅拌。然后向反应液中加入N,N-二异丙基乙基胺(13mg)，反应0.5h，接着加入M1(21 mg)，反应液于室温下搅拌过夜。向反应液中加入水(50mL)，接着加入乙酸乙酯(50mL)萃取，共三次。合并有机相并脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物7.5mg。Compound 2-4 (22 mg), (2-oxime-ethyl cyanoacetate)-N,N-dimethyl-morpholinourea hexafluorophosphate (45 mg) and N,N-dimethylmethyl Amide (5 mL) was placed in a 25 mL single-neck bottle and stirred. Then N,N-diisopropylethylamine (13mg) was added to the reaction solution, reacted for 0.5h, and then M1 (21 mg), the reaction solution was stirred at room temperature overnight. Water (50 mL) was added to the reaction solution, and then ethyl acetate (50 mL) was added for extraction three times in total. The organic phases were combined, stripped to dryness, and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 7.5 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ13.27(s,1H),8.76(d,J＝2.3Hz,1H),8.69(d,J＝2.3Hz,1H),8.62(s,1H),8.53–8.44(m,2H),8.01(d,J＝12.5Hz,1H),7.71(dd,J＝8.3,2.3Hz,1H),7.53-7.46(m,2H),7.25(dd,J＝8.1,2.3Hz,1H),7.19(ds,1H),6.90(d,J＝8.2Hz,1H),6.26(s,2H),4.34-4.18(m,2H),3.89-3.82(m,2H),2.88–2.58(m,9H),2.36(s,3H),2.21–2.14(m,2H),2.03-1.98(m,1H),1.94–1.87(m,2H),1.71(br,4H),1.42-1.43(m,2H),1.45(s,2H),1.35-1.32(m,2H). 1 H NMR (400MHz, DMSO-d 6 ): δ13.27 (s, 1H), 8.76 (d, J = 2.3Hz, 1H), 8.69 (d, J = 2.3Hz, 1H), 8.62 (s, 1H ),8.53–8.44(m,2H),8.01(d,J＝12.5Hz,1H),7.71(dd,J＝8.3,2.3Hz,1H),7.53-7.46(m,2H),7.25(dd, J＝8.1,2.3Hz,1H),7.19(ds,1H),6.90(d,J＝8.2Hz,1H),6.26(s,2H),4.34-4.18(m,2H),3.89-3.82(m ,2H),2.88–2.58(m,9H),2.36(s,3H),2.21–2.14(m,2H),2.03-1.98(m,1H),1.94–1.87(m,2H),1.71(br ,4H),1.42-1.43(m,2H),1.45(s,2H),1.35-1.32(m,2H).
MS(ESI+):732.4(M+H).MS(ESI+):732.4(M+H).
实施例3：
Example 3:
a)化合物3-1的制备a) Preparation of compound 3-1
将1-((4-氟苯基)氨基甲酰基)环丙烷-1-羧酸(223mg)、氯化铵(106mg)、苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(1.04g)及N,N-二甲基甲酰胺(20mL)置于50mL单口瓶中，搅拌，接着加入N,N-二异丙基乙基胺(390mg)。反应液于室温下搅拌过夜。待原料反应完全，向其中加入水(50mL)。用1N NaOH调pH至9-10，有大量固体析出。抽滤，并将滤饼烘干，得标题产物120mg。1-((4-Fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid (223 mg), ammonium chloride (106 mg), benzotriazol-1-yloxytris(dimethylamino ) Phosphonium hexafluorophosphate (1.04g) and N,N-dimethylformamide (20mL) were placed in a 50mL single-neck bottle, stirred, and then N,N-diisopropylethylamine (390mg) was added. The reaction was stirred at room temperature overnight. When the reaction of the raw materials is complete, add water (50 mL). Use 1N NaOH to adjust the pH to 9-10, and a large amount of solid will precipitate. Filter with suction, and dry the filter cake to obtain 120 mg of the title product.
b)N-(4-(5-氨基-3-((4-(4-甲基哌嗪-1-基)苯基)氨基)-1H-1,2,4-***-1-基)-3-氟苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的制备b)N-(4-(5-amino-3-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1H-1,2,4-triazol-1-yl Preparation of )-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
将3-1(111mg)、M3(267mg)、Pd2(dba)3(46mg)、2-二叔丁基膦基-3,4,5,6-四甲基-2',4',6'-三异丙基-1,1-联苯(72mg)、碳酸铯(326mg)及叔丁醇(10mL)置于封管中，氮气保护并于96摄氏度反应24小时。将反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物20mg。3-1 (111mg), M3 (267mg), Pd 2 (dba) 3 (46mg), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4', 6'-Triisopropyl-1,1-biphenyl (72 mg), cesium carbonate (326 mg) and tert-butyl alcohol (10 mL) were placed in a sealed tube, protected by nitrogen, and reacted at 96 degrees Celsius for 24 hours. The reaction solution was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 20 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ10.44(s,1H),10.02(s,1H),8.47(s,1H),7.81(dd,J＝12.9,2.2Hz,1H),7.67-7.59(m,2H),7.51–7.41(m,2H),7.41–7.31(m,2H),7.15(t,J＝8.9Hz,2H),6.80(d,J＝8.9Hz,2H),6.18(s,2H),3.01-2.93(m,4H),2.48-2.39(m,4H),2.21(s,3H),1.56–1.40(m,4H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.44 (s, 1H), 10.02 (s, 1H), 8.47 (s, 1H), 7.81 (dd, J = 12.9, 2.2Hz, 1H), 7.67 -7.59(m,2H),7.51–7.41(m,2H),7.41–7.31(m,2H),7.15(t,J＝8.9Hz,2H),6.80(d,J＝8.9Hz,2H), 6.18(s,2H),3.01-2.93(m,4H),2.48-2.39(m,4H),2.21(s,3H),1.56–1.40(m,4H).
MS(ESI+):588.3(M+H).MS(ESI+):588.3(M+H).
实施例4：
Example 4:
a)化合物4-1的制备a) Preparation of compound 4-1
参照实施例3步骤a)将1-((4-氟苯基)氨基甲酰基)环丙烷-1-羧酸替换成M1即可，得标题产物170mg。Refer to step a) of Example 3 and replace 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid with M1 to obtain 170 mg of the title product.
b)化合物例4的制备b) Preparation of compound example 4
参照实施例3步骤d)将3-1替换成4-1即可。将反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物12mg。Refer to step d) of Example 3 and replace 3-1 with 4-1. The reaction solution was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 12 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ13.27(s,1H),8.76(d,J＝2.3Hz,1H),8.69(d,J＝2.3Hz,1H),8.56–8.43(m,3H),8.04–7.97(m,1H),7.71(dd,J＝8.2,2.3Hz,1H),7.52-7.45(m,2H),7.37(d,J＝8.8Hz,2H),6.81(s,1H),6.79(s,1H),6.24(s,2H),4.21(d,J＝7.3Hz,2H),3.90–3.82(m,2H),3.30-3.23(m,2H),2.98(s,4H),2.43(t,J＝4.9Hz,4H),2.36(s,3H),2.20(s,3H),2.10–2.04(m,1H),1.51–1.40(m,2H),1.38-1.25(m,2H). 1 H NMR (400MHz, DMSO-d 6 ): δ13.27 (s, 1H), 8.76 (d, J = 2.3Hz, 1H), 8.69 (d, J = 2.3Hz, 1H), 8.56–8.43 (m ,3H),8.04–7.97(m,1H),7.71(dd,J＝8.2,2.3Hz,1H),7.52-7.45(m,2H),7.37(d,J＝8.8Hz,2H),6.81( s,1H),6.79(s,1H),6.24(s,2H),4.21(d,J＝7.3Hz,2H),3.90–3.82(m,2H),3.30-3.23(m,2H),2.98 (s,4H),2.43(t,J＝4.9Hz,4H),2.36(s,3H),2.20(s,3H),2.10–2.04(m,1H),1.51–1.40(m,2H), 1.38-1.25(m,2H).
MS(ESI+):693.3(M+H).MS(ESI+):693.3(M+H).
实施例5：
Example 5:
a)化合物5-1的制备a) Preparation of compound 5-1
参照实施例3步骤a)将1-((4-氟苯基)氨基甲酰基)环丙烷-1-羧酸替换成3-(4-氟苯基)-1-异丙基-2,4-二氧代-1,2,3,4-四氢嘧啶-5-羧酸即可，得标题产物110mg。Refer to 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.
b)化合物例5的制备b) Preparation of compound example 5
将5-1(87.33mg)、M3(200mg)、甲磺酸基2-二环己基膦基-3,6-二甲氧基-2'-4'-6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(27mg)、2-(二环己基膦基)-3,6-二甲氧基-2'-4'-6'-三异丙基-1,1'-联苯(48mg)、碳酸钾(82.8mg)及叔丁醇(5mL)置于封管中，氮气保护并于96摄氏度反应24小时。将反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物15mg。Combine 5-1 (87.33mg), M3 (200mg), methanesulfonate 2-dicyclohexylphosphino-3,6-dimethoxy-2'-4'-6'-triisopropyl-1 ,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (27 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy 2'-4'-6'-triisopropyl-1,1'-biphenyl (48mg), potassium carbonate (82.8mg) and tert-butanol (5mL) were placed in a sealed tube, protected by nitrogen and placed in React at 96 degrees Celsius for 24 hours. The reaction solution was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 15 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ11.09(s,1H),8.69(s,1H),8.48(s,1H),7.94(dd,J＝12.6,2.1Hz,1H),7.49–7.41 (m,4H),7.36(t,J＝8.5Hz,4H),6.80(s,1H),6.78(s,1H),6.23(s,2H),4.81–4.75(m,1H),2.97(t,J＝4.9Hz,4H),2.43(t,J＝5.0Hz,4H),2.20(s,3H),1.44(s,3H),1.42(s,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ11.09 (s, 1H), 8.69 (s, 1H), 8.48 (s, 1H), 7.94 (dd, J = 12.6, 2.1Hz, 1H), 7.49 –7.41 (m,4H),7.36(t,J＝8.5Hz,4H),6.80(s,1H),6.78(s,1H),6.23(s,2H),4.81–4.75(m,1H),2.97( t,J＝4.9Hz,4H),2.43(t,J＝5.0Hz,4H),2.20(s,3H),1.44(s,3H),1.42(s,3H).
MS(ESI+):657.2(M+H).MS(ESI+):657.2(M+H).
实施例6：
Example 6:
a)化合物6-1的制备a) Preparation of compound 6-1
将M7(61mg)、M11(108mg)、正丁醇(5mL)及三氟乙酸(0.5mL)加入到10mL微波管中。氮气保护下，将反应液置于120摄氏度下微波反应2小时。反应液脱溶至干。粗品直接下一步。Add M7 (61 mg), M11 (108 mg), n-butanol (5 mL) and trifluoroacetic acid (0.5 mL) into a 10 mL microwave tube. Under nitrogen protection, the reaction solution was placed in a microwave at 120 degrees Celsius for 2 hours. The reaction solution was desolvated to dryness. Crude products go directly to the next step.
b)化合物例6的制备b) Preparation of compound example 6
将6-1及三氟乙酸(0.5mL)加入到25mL单口瓶中。氮气保护下，将反应液置于室温下反应过夜。反应液脱溶至干。接着向粗品中加入乙酸乙酯(30mL)，并用2N氢氧化钠(10mL)洗涤有机相，重复2次。有机相脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物66mg。Add 6-1 and trifluoroacetic acid (0.5 mL) to a 25 mL single-neck bottle. Under nitrogen protection, the reaction solution was left to react at room temperature overnight. The reaction solution was desolvated to dryness. Then, ethyl acetate (30 mL) was added to the crude product, and the organic phase was washed with 2N sodium hydroxide (10 mL), repeated twice. The organic phase was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 66 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ11.80(s,1H),8.51(s,1H),8.26(d,J＝5.4Hz,1H),7.92(s,1H),7.90(s,1H),7.53–7.35(m,8H),6.86(d,J＝5.5Hz,1H),6.83(s,1H),6.81(s,1H),6.63(s,1H),6.25(s,2H),2.99(t,J＝5.0Hz,4H),2.44(t,J＝5.0Hz,4H),2.21(s,3H),1.98(s,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ11.80 (s, 1H), 8.51 (s, 1H), 8.26 (d, J = 5.4Hz, 1H), 7.92 (s, 1H), 7.90 (s ,1H),7.53–7.35(m,8H),6.86(d,J＝5.5Hz,1H),6.83(s,1H),6.81(s,1H),6.63(s,1H),6.25(s, 2H),2.99(t,J＝5.0Hz,4H),2.44(t,J＝5.0Hz,4H),2.21(s,3H),1.98(s,3H).
MS(ESI+):617.3(M+H).MS(ESI+):617.3(M+H).
实施例7：
Example 7:
a)化合物例7的制备a) Preparation of compound example 7
将化合物5-1(110mg),M5(216mg),[(2-二-环己基膦基-3,6-二甲氧基-2′,4′,6′-三异丙基-1,1′-联苯基)-2-(2′-氨基-1,1′-联苯基)]甲磺酸钯(II)甲磺酸酯(36mg),二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-联苯]-2-基)膦(64mg),碳酸钾(105mg)及叔丁醇(5mL)加入到封管中。氮气保护下，将封管置于95摄氏度下反应24h。反应液脱溶至干。柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物1.1mg。Compound 5-1 (110 mg), M5 (216 mg), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1, 1′-Biphenyl)-2-(2′-amino-1,1′-biphenyl)] methanesulfonate palladium(II) mesylate (36 mg), dicyclohexyl (2',4' , 6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (64mg), potassium carbonate (105mg) and tert-butanol (5mL) were added into a sealed tube. Under nitrogen protection, place the sealed tube at 95 degrees Celsius for 24 hours. The reaction solution was desolvated to dryness. Purification by column chromatography (dichloromethane/methanol=10/1 (V/V)) gave 1.1 mg of the title product.
MS(ESI+):639.29(M+H).MS(ESI+):639.29(M+H).
实施例8：

Example 8:

a)化合物8-1的制备a) Preparation of compound 8-1
将4-甲基-2-氧代-1,2-二氢吡啶-3-甲腈(460mg)、对氟碘苯(839mg)、碘化亚铜(720mg)、磷酸钾(873mg)、N,N'-二甲基乙二胺(333mg)及二氧六环(6mL)置于封管中，氮气保护并于105摄氏度搅拌24小时。待原料反应完全，脱溶，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物230mg。Combine 4-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (460mg), p-fluoriodobenzene (839mg), copper iodide (720mg), potassium phosphate (873mg), N , N'-dimethylethylenediamine (333mg) and dioxane (6mL) were placed in a sealed tube, protected by nitrogen and stirred at 105 degrees Celsius for 24 hours. After the reaction of the raw materials is complete, the solution is removed and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 230 mg of the title product.
b)化合物8-2的制备b) Preparation of compound 8-2
将8-1(210mg)及N,N-二甲基甲酰胺二甲基缩醛(10mL)置于50mL单口瓶中于105摄氏度下反应4h。待原料反应完全，待原料反应完全，脱溶，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物279mg。Place 8-1 (210 mg) and N,N-dimethylformamide dimethyl acetal (10 mL) in a 50 mL single-mouth bottle and react at 105 degrees Celsius for 4 hours. After the reaction of the raw materials is complete, the solution is removed and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 279 mg of the title product.
c)化合物8-3的制备c) Preparation of compound 8-3
将8-2(269mg)及H2SO4(5mL)置于25mL单口瓶中，于110摄氏度下反应。待原料反应完全，将反应液加入碳酸氢钠饱和的冰水溶液中并搅拌。用2M氢氧化钠调pH至7，有大量固体析出。抽滤，滤饼用水洗涤。所得滤饼烘干，得240mg。Place 8-2 (269 mg) and H 2 SO 4 (5 mL) in a 25 mL single-neck bottle, and react at 110 degrees Celsius. When the reaction of the raw materials is complete, add the reaction solution to a saturated ice-water solution of sodium bicarbonate and stir. Use 2M sodium hydroxide to adjust the pH to 7, and a large amount of solid will precipitate. Suction filter and wash the filter cake with water. The obtained filter cake was dried to obtain 240 mg.
d)化合物8-4的制备d) Preparation of compound 8-4
氮气保护下，将8-3(250mg)及POCl3(6mL)置于25mL单口瓶中并搅拌。反应液加热至105摄氏度下反应1h。待原料反应完全，反应液降至室温，接着脱溶至干。向粗品中加入乙酸乙酯(50mL)，接着用饱和碳酸氢钠溶液洗涤2次。有机层脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物58mg。Under nitrogen protection, place 8-3 (250 mg) and POCl 3 (6 mL) in a 25 mL single-neck bottle and stir. The reaction solution was heated to 105 degrees Celsius and reacted for 1 hour. After the reaction of the raw materials is complete, the reaction solution is lowered to room temperature, and then desolvated to dryness. Ethyl acetate (50 mL) was added to the crude product, followed by washing twice with saturated sodium bicarbonate solution. The organic layer was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 58 mg of the title product.
e)化合物例8的制备e) Preparation of compound example 8
将8-4(22mg),M11(40mg),三氟乙酸(0.5mL)及正丁醇(5mL)加入到微波管中。氮气保护下，将微波管置于120摄氏度下反应。1小时后，停止反应。反应液脱溶至干。向反应液中加入三氟乙酸(5mL)，搅拌过夜。反应液脱溶至干。接着向粗品中加入乙酸乙酯(30mL)，并用2N氢氧化钠(10mL)洗涤有机相，重复2次。有机相脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物26mg。Add 8-4 (22 mg), M11 (40 mg), trifluoroacetic acid (0.5 mL) and n-butanol (5 mL) into the microwave tube. Under nitrogen protection, place the microwave tube at 120 degrees Celsius for reaction. After 1 hour, the reaction was stopped. The reaction solution was desolvated to dryness. Trifluoroacetic acid (5 mL) was added to the reaction solution and stirred overnight. The reaction solution was desolvated to dryness. Then, ethyl acetate (30 mL) was added to the crude product, and the organic phase was washed with 2N sodium hydroxide (10 mL), repeated twice. The organic phase was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 26 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ11.89(s,1H),8.53(s,1H),8.31(d,J＝5.4Hz,1H),7.96–7.90(m,2H),7.70(d,J＝7.2Hz,1H),7.63–7.56(m,2H),7.53–7.47(m,2H),7.45-7.37(m,4H),6.98(d,J＝5.5Hz,1H),6.86–6.80(m,2H),6.69(d,J＝7.3Hz,1H),6.27(s,2H),3.00(t,J＝4.9Hz,4H),2.48(t,J＝4.9Hz,4H),2.23(s,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ11.89 (s, 1H), 8.53 (s, 1H), 8.31 (d, J = 5.4Hz, 1H), 7.96–7.90 (m, 2H), 7.70 (d,J＝7.2Hz,1H),7.63–7.56(m,2H),7.53–7.47(m,2H),7.45-7.37(m,4H),6.98(d,J＝5.5Hz,1H), 6.86–6.80(m,2H),6.69(d,J＝7.3Hz,1H),6.27(s,2H),3.00(t,J＝4.9Hz,4H),2.48(t,J＝4.9Hz,4H ),2.23(s,3H).
MS(ESI+):603.2(M+H).MS(ESI+):603.2(M+H).
实施例9：
Example 9:
a)化合物9-1的制备a) Preparation of compound 9-1
氮气保护下，将8-3(250mg)及POCl3(6mL)置于25mL单口瓶中并搅拌。反应液加热至105摄氏度下反应1h。待原料反应完全，反应液降至室温，接着脱溶至干。向粗品中加入乙酸乙酯(50mL)，接着用饱和碳酸氢钠溶液洗涤2次。有机层脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物58mg。Under nitrogen protection, place 8-3 (250 mg) and POCl 3 (6 mL) in a 25 mL single-neck bottle and stir. The reaction solution was heated to 105 degrees Celsius and reacted for 1 hour. After the reaction of the raw materials is complete, the reaction solution is lowered to room temperature, and then desolvated to dryness. Ethyl acetate (50 mL) was added to the crude product, followed by washing twice with saturated sodium bicarbonate solution. The organic layer was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 58 mg of the title product.
b)化合物例9的制备b) Preparation of compound example 9
将9-1(24mg),M11(40mg),三氟乙酸(0.5mL)及正丁醇(5mL)加入到微波管中。氮气保护下，将微波管置于120摄氏度下反应。1小时后，停止反应。反应液脱溶至干。向反应液中加入三氟乙酸(5mL)，搅拌过夜。反应液脱溶至干。接着向粗品中加入乙酸乙酯(30mL)，并用2N氢氧化钠(10mL)洗涤有机相，重复2次。有机相脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物15.58mg。Add 9-1 (24 mg), M11 (40 mg), trifluoroacetic acid (0.5 mL) and n-butanol (5 mL) into the microwave tube. Under nitrogen protection, place the microwave tube at 120 degrees Celsius for reaction. After 1 hour, the reaction was stopped. The reaction solution was desolvated to dryness. Trifluoroacetic acid (5 mL) was added to the reaction solution and stirred overnight. The reaction solution was desolvated to dryness. Then, ethyl acetate (30 mL) was added to the crude product, and the organic phase was washed with 2N sodium hydroxide (10 mL), repeated twice. The organic phase was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 15.58 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ11.93(s,1H),8.54(s,1H),8.49(d,J＝5.5Hz,1H),8.16(s,1H),7.94–7.88(m,2H),7.66–7.60(m,2H),7.54–7.49(m,2H),7.42(dt,J＝8.8,4.3Hz,4H),7.08(d,J＝5.5Hz,1H),6.85–6.79(m,2H),6.29(s,2H),2.99(t,J＝4.9Hz,4H),2.44(t,J＝5.0Hz,4H),2.21(s,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ11.93 (s, 1H), 8.54 (s, 1H), 8.49 (d, J = 5.5Hz, 1H), 8.16 (s, 1H), 7.94–7.88 (m,2H),7.66–7.60(m,2H),7.54–7.49(m,2H),7.42(dt,J＝8.8,4.3Hz,4H),7.08(d,J＝5.5Hz,1H), 6.85–6.79(m,2H),6.29(s,2H),2.99(t,J＝4.9Hz,4H),2.44(t,J＝5.0Hz,4H),2.21(s,3H).
MS(ESI+):637.2(M+H).MS(ESI+):637.2(M+H).
实施例10：
Example 10:
a)化合物10-1的制备a) Preparation of compound 10-1
将2-氰基-N-(4-氟苯基)乙酰胺(1.88g)、1-环丙基丁烷-1,3-二酮(1.26g)、六氢哌啶(0.5mL)及EtOH(50mL)置于100mL单口瓶中搅拌。将反应也升温至85摄氏度，反应10小时。待原料反应完全，脱溶至干。柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物1.4g。Combine 2-cyano-N-(4-fluorophenyl)acetamide (1.88g), 1-cyclopropylbutane-1,3-dione (1.26g), hexahydropiperidine (0.5mL) and EtOH (50 mL) was placed in a 100 mL one-neck bottle and stirred. The reaction temperature was also raised to 85 degrees Celsius and the reaction was carried out for 10 hours. When the reaction of the raw materials is complete, remove the solvent to dryness. Purification by column chromatography (dichloromethane/methanol=10/1 (V/V)) gave 1.4 g of the title product.
b)化合物10-2的制备b) Preparation of compound 10-2
将10-1(41.3g)、N,N-二甲基甲酰胺二甲基缩醛(2.88g)及N,N-二甲基甲酰胺(10mL)置于25mL单口瓶中，氮气保护并搅拌。将反应液加热至100摄氏度反应1h。待原料反应完全，将反应液脱溶至干，得1.8g粗品，直接进行下一步。Place 10-1 (41.3g), N,N-dimethylformamide dimethyl acetal (2.88g) and N,N-dimethylformamide (10mL) in a 25mL single-neck bottle, protect with nitrogen and Stir. The reaction solution was heated to 100 degrees Celsius and reacted for 1 hour. When the reaction of the raw materials is complete, the reaction solution is desolvated to dryness to obtain 1.8g of crude product, which can be directly carried out to the next step.
c)化合物10-3的制备c) Preparation of compound 10-3
将10-2(1.8g)及硫酸(5mL)置于25mL单口瓶中，于110摄氏度下反应。待原料反应完全，将反应液加入碳酸 氢钠饱和的冰水溶液中并搅拌。用2M氢氧化钠调pH至7，有大量固体析出。抽滤，滤饼用水洗涤。所得滤饼烘干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物74mg。Place 10-2 (1.8g) and sulfuric acid (5mL) in a 25mL single-neck bottle and react at 110 degrees Celsius. When the reaction of the raw materials is complete, add carbonic acid to the reaction solution into an ice-water solution saturated with sodium hydride and stir. Use 2M sodium hydroxide to adjust the pH to 7, and a large amount of solid will precipitate. Suction filter and wash the filter cake with water. The obtained filter cake was dried and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 74 mg of the title product.
d)化合物10-4的制备d) Preparation of compound 10-4
氮气保护下，将10-3(74mg)及三氯氧磷(6mL)置于25mL单口瓶中并搅拌。反应液加热至105摄氏度下反应1h。待原料反应完全，反应液降至室温，接着脱溶至干。向粗品中加入乙酸乙酯(50mL)，接着用饱和碳酸氢钠溶液洗涤2次。有机层脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物100mg。Under nitrogen protection, place 10-3 (74 mg) and phosphorus oxychloride (6 mL) in a 25 mL single-neck bottle and stir. The reaction solution was heated to 105 degrees Celsius and reacted for 1 hour. After the reaction of the raw materials is complete, the reaction solution is lowered to room temperature, and then desolvated to dryness. Ethyl acetate (50 mL) was added to the crude product, followed by washing twice with saturated sodium bicarbonate solution. The organic layer was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 100 mg of the title product.
e)化合物10-5的制备e) Preparation of compound 10-5
将10-4(31.5mg),M11(51.4mg),三氟乙酸(0.1mL)及叔丁醇(6mL)加入到微波管中。氮气保护下，将微波管置于120摄氏度下微波反应1h。反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物50mg。Add 10-4 (31.5 mg), M11 (51.4 mg), trifluoroacetic acid (0.1 mL) and tert-butanol (6 mL) into the microwave tube. Under nitrogen protection, place the microwave tube at 120 degrees Celsius for microwave reaction for 1 hour. The reaction solution was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 50 mg of the title product.
f)化合物例10的制备f) Preparation of compound example 10
将10-5(50mg)及三氟乙酸(10mL)置入25mL单口瓶中。将反应液置于室温下搅拌过夜。反应液脱溶至干。接着向粗品中加入乙酸乙酯(30mL)，并用2N氢氧化钠(10mL)洗涤有机相，重复2次。有机相脱溶至干柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物18mg。Place 10-5 (50 mg) and trifluoroacetic acid (10 mL) into a 25 mL single-neck bottle. The reaction solution was left to stir at room temperature overnight. The reaction solution was desolvated to dryness. Then, ethyl acetate (30 mL) was added to the crude product, and the organic phase was washed with 2N sodium hydroxide (10 mL), repeated twice. The organic phase was desolvated and purified by dry column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 18 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ11.86(s,1H),8.53(s,1H),8.30–8.27(m,2H),7.98-7.92(m,2H),7.55-7.50(m,2H),7.45-7.41(m,2H),7.28–7.20(m,2H),6.87(d,J＝5.4Hz,1H),6.85–6.81(m,2H),6.64(s,1H),6.28(s,2H),3.10-3.05(m,2H),3.02-2.99(m,4H),2.76–2.70(m,1H),2.48-2.42(m,4H),2.22(s,3H),1.23(d,J＝6.9Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ11.86(s,1H),8.53(s,1H),8.30–8.27(m,2H),7.98-7.92(m,2H),7.55-7.50( m,2H),7.45-7.41(m,2H),7.28–7.20(m,2H),6.87(d,J＝5.4Hz,1H),6.85–6.81(m,2H),6.64(s,1H) ,6.28(s,2H),3.10-3.05(m,2H),3.02-2.99(m,4H),2.76–2.70(m,1H),2.48-2.42(m,4H),2.22(s,3H) ,1.23(d,J＝6.9Hz,3H).
MS(ESI+):643.3(M+H).MS(ESI+):643.3(M+H).
实施例11:
Example 11:
a)化合物11-1的制备a) Preparation of compound 11-1
将4-氯嘧啶-5-甲酸乙酯(186.6mg)、(2,4-二甲氧基苯基)甲胺(167.2mg)、N,N-二异丙基乙基胺(258mg)及二氧六环(5mL)置于10mL微波管中。反应液于80摄氏度下微波反应1h。将反应脱溶至干，有机相脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物287mg。4-Chloropyrimidine-5-carboxylic acid ethyl ester (186.6mg), (2,4-dimethoxyphenyl)methanamine (167.2mg), N,N-diisopropylethylamine (258mg) and Dioxane (5 mL) was placed in a 10 mL microwave tube. The reaction solution was microwaved at 80 degrees Celsius for 1 hour. The reaction was desolvated to dryness, the organic phase was desolvated to dryness, and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 287 mg of the title product.
b)化合物11-2的制备b) Preparation of compound 11-2
将11-1(287mg)、四氢呋喃(10mL)及2N氢氧化锂(4.5mL)置于25mL单口瓶中并搅拌过夜。待原料反应完全，当溶液pH调至5时，将反应液脱溶至干。接着加入2mL水，将溶液pH调至2，有大量固体析出，抽滤。所 得滤饼烘干得250mg固体。11-1 (287 mg), tetrahydrofuran (10 mL) and 2N lithium hydroxide (4.5 mL) were placed in a 25 mL single-neck bottle and stirred overnight. When the reaction of the raw materials is complete and the pH of the solution is adjusted to 5, the reaction solution is desolvated to dryness. Then add 2 mL of water to adjust the pH of the solution to 2. A large amount of solid will precipitate and filter. Place The filter cake was dried to obtain 250 mg solid.
c)化合物11-3的制备c) Preparation of compound 11-3
将11-2(250mg)、对氟苯胺(111)、1-[双(二甲氨基)亚甲基]-1H-1,2,3-***并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(661mg)、N,N-二异丙基乙基胺(225mg)及N,N-二甲基甲酰胺(10mL)置于25mL单口瓶中并搅拌1h。待原料反应完全，将反应液加入水(30mL)中，接着用乙酸乙酯(30mL)萃取2次，合并有机层。依次用水，饱和食盐水洗涤有机相。有机相脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物330mg。Combine 11-2 (250mg), p-fluoroaniline (111), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3 -Oxide hexafluorophosphate (661mg), N,N-diisopropylethylamine (225mg) and N,N-dimethylformamide (10mL) were placed in a 25mL single-neck bottle and stirred for 1 hour. After the reaction of the raw materials is complete, the reaction solution is added to water (30 mL), and then extracted twice with ethyl acetate (30 mL), and the organic layers are combined. Wash the organic phase with water and saturated brine in sequence. The organic phase was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 330 mg of the title product.
d)化合物11-4的制备d) Preparation of compound 11-4
将11-3(41mg)及TFA(10mL)置于25mL单口瓶中并于70摄氏度下搅拌1h。待原料反应完全，将反应液脱溶至干,柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物22mg。11-3 (41 mg) and TFA (10 mL) were placed in a 25 mL single-neck bottle and stirred at 70 degrees Celsius for 1 h. After the reaction of the raw materials is complete, the reaction solution is desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 22 mg of the title product.
e)化合物例11的制备e) Preparation of compound example 11
将11-4(15mg),M3(25mg),Pd2(dba)3(6mg),二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-联苯]-2-基)膦(10mg),碳酸铯(36mg)及二氧六环(5mL)加入到微波管中。氮气保护下，将微波管置于120摄氏度下反应。2小时后，停止反应。反应液脱溶至干。柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物10mg。11-4 (15mg), M3 (25mg), Pd 2 (dba) 3 (6mg), dicyclohexyl (2',4',6'-triisopropyl-3,6-dimethoxy- [1,1'-Biphenyl]-2-yl)phosphine (10 mg), cesium carbonate (36 mg) and dioxane (5 mL) were added to the microwave tube. Under nitrogen protection, place the microwave tube at 120 degrees Celsius for reaction. After 2 hours, the reaction was stopped. The reaction solution was desolvated to dryness. Purification by column chromatography (dichloromethane/methanol=20/1 (V/V)) gave 10 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ10.71(s,1H),10.66(s,1H),9.02(s,1H),8.84(s,1H),8.48(s,1H),8.06(d,J＝12.4Hz,1H),7.79–7.74(m,2H),7.57-7.52(m,1H),7.51-7.46(m,1H),7.37(d,J＝9.0Hz,2H),7.25(t,J＝8.7Hz,2H),6.80(d,J＝9.1Hz,2H),6.23(s,2H),2.97(t,J＝5.0Hz,4H),2.43(t,J＝5.0Hz,4H),2.20(s,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.71(s,1H),10.66(s,1H),9.02(s,1H),8.84(s,1H),8.48(s,1H),8.06 (d,J＝12.4Hz,1H),7.79–7.74(m,2H),7.57-7.52(m,1H),7.51-7.46(m,1H),7.37(d,J＝9.0Hz,2H), 7.25(t,J＝8.7Hz,2H),6.80(d,J＝9.1Hz,2H),6.23(s,2H),2.97(t,J＝5.0Hz,4H),2.43(t,J＝5.0 Hz,4H),2.20(s,3H).
MS(ESI+):598.3(M+H).MS(ESI+):598.3(M+H).
实施例12：
Example 12:
a)化合物12-1的制备a) Preparation of compound 12-1
氮气保护下，将2-氯-4-氟烟酸(176mg)、对氟苯肼盐酸盐(163mg)及四氢呋喃(20mL)置于100mL三口瓶中搅拌。当反应液降温至-5摄氏度时，滴加1M二(三甲基硅基)氨基锂(4mL)至反应液中。滴毕后，在室温下搅拌过夜。待原料反应完全，向反应液中加入氯化铵饱和溶液淬灭。接着向反应液中加入乙酸乙酯(50mL)和H2O(50mL)萃取。水相用乙酸乙酯(20mL)萃取两次。合并有机相，脱溶，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物73mg。Under nitrogen protection, place 2-chloro-4-fluoronicotinic acid (176 mg), p-fluorophenylhydrazine hydrochloride (163 mg) and tetrahydrofuran (20 mL) in a 100 mL three-necked flask and stir. When the reaction solution cooled to -5 degrees Celsius, 1M lithium bis(trimethylsilyl)amide (4 mL) was added dropwise to the reaction solution. After the dripping is completed, stir at room temperature overnight. After the reaction of the raw materials is complete, add a saturated solution of ammonium chloride to the reaction solution to quench. Then, ethyl acetate (50 mL) and H 2 O (50 mL) were added to the reaction liquid for extraction. The aqueous phase was extracted twice with ethyl acetate (20 mL). The organic phases were combined, desolvated, and purified by column chromatography (dichloromethane/methanol = 20/1 (V/V)) to obtain 73 mg of the title product.
b)化合物12-2的制备b) Preparation of compound 12-2
氮气保护下，将12-1(60mg)及N,N-二甲基甲酰胺(6mL)置于10mL单口瓶中并搅拌。-10摄氏度下，向反应液中加入60％NaH(19mg)，保温搅拌10min。接着向反应液中滴加碘甲烷(39mg)，然后将反应液置于室温下搅拌过夜。待原料反应完全，向反应液中加入乙酸乙酯(50mL)和H2O(50mL)萃取。有机层脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物48mg。Under nitrogen protection, place 12-1 (60 mg) and N,N-dimethylformamide (6 mL) in a 10 mL single-neck bottle and stir. At -10 degrees Celsius, add 60% NaH (19 mg) to the reaction solution and keep stirring for 10 minutes. Next, methyl iodide (39 mg) was added dropwise to the reaction solution, and the reaction solution was left to stir at room temperature overnight. After the reaction of the raw materials is complete, add ethyl acetate (50 mL) and H 2 O (50 mL) to the reaction solution for extraction. The organic layer was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 48 mg of the title product.
c)化合物12-3的制备 c) Preparation of compound 12-3
将12-2(31mg),M11(51.4mg),Pd2(dba)3(10mg),2,2'-双二苯膦基-1,1'-联萘(19mg),叔丁醇钾(23mg)及甲苯(6mL)加入到封管中。氮气保护下，将封管置于100摄氏度下反应。24小时后，停止反应。反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物70mg。Combine 12-2 (31mg), M11 (51.4mg), Pd 2 (dba) 3 (10mg), 2,2'-bisdiphenylphosphino-1,1'-binaphthyl (19mg), potassium tert-butoxide (23 mg) and toluene (6 mL) were added to the sealed tube. Under nitrogen protection, place the sealed tube at 100 degrees Celsius for reaction. After 24 hours, the reaction was stopped. The reaction solution was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 70 mg of the title product.
d)化合物例12的制备d) Preparation of compound example 12
将12-3(67mg)及三氟乙酸(10mL)置入25mL单口瓶中。将反应液置于室温下搅拌过夜。反应液脱溶至干。接着向粗品中加入乙酸乙酯(30mL)，并用2N氢氧化钠(10mL)洗涤有机相，重复2次。有机相脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物34mg。Place 12-3 (67 mg) and trifluoroacetic acid (10 mL) into a 25 mL single-neck bottle. The reaction solution was left to stir at room temperature overnight. The reaction solution was desolvated to dryness. Then, ethyl acetate (30 mL) was added to the crude product, and the organic phase was washed with 2N sodium hydroxide (10 mL), repeated twice. The organic phase was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 34 mg of the title product.
MS(ESI+):606(M+H).MS(ESI+):606(M+H).
实施例13：
Example 13:
a)化合物13-1的制备a) Preparation of compound 13-1
将2-氯-3-碘吡啶-4-胺(3g)、1-(乙烯基氧基)丁烷(1.4g)、醋酸钯(262mg)、三(邻甲苯)膦(1.07g)、三乙胺(2.53g)及乙腈(40mL)置于100mL单口瓶中，氮气保护并于85摄氏度下反应5小时。待原料反应完全，硅藻土过滤，滤液脱溶至干。向粗品中加入四氢呋喃(50mL)及3M HCl(9mL)，搅拌过夜。待原料反应完全，用2N NaOH调pH至9，接着水相用乙酸乙酯(50mL)萃取，合并有机相，依次用饱和氯化钠溶液洗涤、无水硫酸钠干燥。有机相脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物2.04g。2-Chloro-3-iodopyridin-4-amine (3g), 1-(vinyloxy)butane (1.4g), palladium acetate (262mg), tris(o-toluene)phosphine (1.07g), tris Ethylamine (2.53g) and acetonitrile (40mL) were placed in a 100mL single-neck bottle, protected by nitrogen, and reacted at 85 degrees Celsius for 5 hours. After the reaction of the raw materials is complete, filter through diatomaceous earth and desolubilize the filtrate to dryness. Tetrahydrofuran (50 mL) and 3M HCl (9 mL) were added to the crude product, and stirred overnight. After the reaction of the raw materials is complete, adjust the pH to 9 with 2N NaOH, then extract the aqueous phase with ethyl acetate (50 mL), combine the organic phases, wash with saturated sodium chloride solution, and dry with anhydrous sodium sulfate. The organic phase was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 2.04 g of the title product.
b)化合物13-2的制备b) Preparation of compound 13-2
将13-1(2.04g)、N,N-二甲基甲酰胺二甲基缩醛(1.72g)及甲苯(50mL)置于100mL单口瓶中，氮气保护并于95摄氏度搅拌5小时。原料消失，则将反应液脱溶至干，向粗品中加入甲醇(30mL)及5.4M甲醇钠(2.3mL)，并于65摄氏度下反应2小时。待原料反应完全，反应液降至室温，滴加醋酸至中性。反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物1.47g。Place 13-1 (2.04g), N,N-dimethylformamide dimethyl acetal (1.72g) and toluene (50mL) in a 100mL single-mouth bottle, protect with nitrogen and stir at 95 degrees Celsius for 5 hours. If the raw materials disappear, desolve the reaction solution to dryness, add methanol (30 mL) and 5.4 M sodium methoxide (2.3 mL) to the crude product, and react at 65 degrees Celsius for 2 hours. When the reaction of the raw materials is complete, the reaction solution is brought to room temperature, and acetic acid is added dropwise until neutral. The reaction solution was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 1.47g of the title product.
c)化合物13-3的制备c) Preparation of compound 13-3
将13-2(1.27g)及N,N-二甲基甲酰胺(10mL)置于50mL单口瓶中搅拌，接着分次加入N-碘代丁二酰亚胺(1.58 g)，并室温搅拌过夜。待原料反应完全，直接过滤，滤饼用甲叔醚洗涤，抽干得标题产物1.29g。Place 13-2 (1.27g) and N,N-dimethylformamide (10mL) in a 50mL single-neck bottle and stir, then add N-iodosuccinimide (1.58 g) and stir at room temperature overnight. After the reaction of the raw materials is complete, filter directly, wash the filter cake with methyl tertiary ether, and drain to obtain 1.29g of the title product.
d)化合物13-4的制备d) Preparation of compound 13-4
将13-3(306mg)、环丙基硼酸(172mg)、醋酸铜(272mg)、2,2'-联吡啶(234mg)、碳酸钠(212mg)及1,2-二氯乙烷(30mL)置于100mL单口瓶中，接着加入分子筛。反应经氧气置换后，于70摄氏度下过夜反应。待反应液冷却至室温，反应液经硅藻土抽滤，接着滤液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物44mg。Combine 13-3 (306mg), cyclopropylboronic acid (172mg), copper acetate (272mg), 2,2'-bipyridine (234mg), sodium carbonate (212mg) and 1,2-dichloroethane (30mL). Place it in a 100mL single-neck bottle, then add molecular sieve. After the reaction was replaced with oxygen, the reaction was carried out overnight at 70 degrees Celsius. After the reaction solution was cooled to room temperature, the reaction solution was suction-filtered through diatomaceous earth, and then the filtrate was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 44 mg of the title product.
e)化合物13-5的制备e) Preparation of compound 13-5
将13-4(20mg)、M12(31mg)、正丁醇(5mL)及三氟乙酸(0.5mL)加入到25mL单口瓶中。氮气保护下，将反应液置于50摄氏度下反应5h。反应液脱溶至干。柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物57mg。Add 13-4 (20 mg), M12 (31 mg), n-butanol (5 mL) and trifluoroacetic acid (0.5 mL) into a 25 mL single-mouth bottle. Under nitrogen protection, the reaction solution was placed at 50 degrees Celsius for 5 hours. The reaction solution was desolvated to dryness. Purification by column chromatography (dichloromethane/methanol=20/1 (V/V)) gave 57 mg of the title product.
f)化合物13-6的制备f) Preparation of compound 13-6
将13-5(57mg)、对氟苯硼酸(28mg)、四三苯基膦钯(8mg)、碳酸钠(15mg)二氧六环(5mL)及水(0.5mL)加入到28mL封管中。氮气保护下，将反应液置于80摄氏度下反应过夜。反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物48mg。Add 13-5 (57 mg), p-fluorophenylboronic acid (28 mg), tetrakis triphenylphosphine palladium (8 mg), sodium carbonate (15 mg), dioxane (5 mL) and water (0.5 mL) into a 28 mL sealed tube. . Under nitrogen protection, the reaction solution was placed at 80 degrees Celsius to react overnight. The reaction solution was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 48 mg of the title product.
g)化合物例13的制备g) Preparation of compound example 13
将13-6(48mg)及三氟乙酸(5mL)加入到25mL单口瓶中。氮气保护下，将反应液置于50摄氏度下反应5h。反应液脱溶至干。接着向粗品中加入乙酸乙酯(30mL)，并用2N氢氧化钠(10mL)洗涤有机相，重复2次。有机相脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物7.8mg。Add 13-6 (48 mg) and trifluoroacetic acid (5 mL) to a 25 mL single-neck bottle. Under nitrogen protection, the reaction solution was placed at 50 degrees Celsius for 5 hours. The reaction solution was desolvated to dryness. Then, ethyl acetate (30 mL) was added to the crude product, and the organic phase was washed with 2N sodium hydroxide (10 mL), repeated twice. The organic phase was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 7.8 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ13.45(s,1H),8.48(s,1H),8.40–8.34(m,3H),7.77–7.70(m,2H),7.51–7.35(m,5H),7.31–7.25(m,2H),6.83–6.78(m,2H),6.20(s,2H),3.63–3.57(m,1H),2.98(t,J＝5.0Hz,4H),2.44(d,J＝4.9Hz,4H),2.21(s,3H),1.27–1.16(m,4H). 1 H NMR (400MHz, DMSO-d 6 ): δ13.45(s,1H),8.48(s,1H),8.40–8.34(m,3H),7.77–7.70(m,2H),7.51–7.35( m,5H),7.31–7.25(m,2H),6.83–6.78(m,2H),6.20(s,2H),3.63–3.57(m,1H),2.98(t,J＝5.0Hz,4H) ,2.44(d,J＝4.9Hz,4H),2.21(s,3H),1.27–1.16(m,4H).
MS(ESI+):661.2(M+H).MS(ESI+):661.2(M+H).
实施例14：
Example 14:
a)化合物14-1的制备a) Preparation of compound 14-1
将2-氯-4-氟烟酸(1.0g)、4-氟苯胺(0.62g)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸(3.19g)及N,N- 二甲基甲酰胺(15mL)置于50mL单口瓶中，并于室温搅拌。接着向反应液中加入二异丙基乙基胺(1.44g)并于室温下反应5小时。向反应液中加入45mL水及50mL乙酸乙酯萃取。水相接着用乙酸乙酯(50mL)萃取一次。合并有机相，依次用饱和氯化钠溶液洗涤、无水硫酸钠干燥。有机相脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物1.5g。Combine 2-chloro-4-fluoronicotinic acid (1.0g), 4-fluoroaniline (0.62g), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (3.19g) and N,N- Dimethylformamide (15 mL) was placed in a 50 mL one-neck bottle and stirred at room temperature. Then, diisopropylethylamine (1.44g) was added to the reaction solution and the reaction was carried out at room temperature for 5 hours. 45 mL of water and 50 mL of ethyl acetate were added to the reaction solution for extraction. 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. The organic phase was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 1.5 g of the title product.
b)化合物14-2的制备b) Preparation of compound 14-2
将14-1(600mg)、对甲氧基苄胺(368mg)及四氢呋喃(20mL)置于100mL三口瓶中，氮气保护并于-10摄氏度下搅拌。接着像反应液中滴加1M双(三甲基硅基)氨基锂(4.48mL)。滴毕后，反应液置于室温下反应。待原料消失，向反应液中加入饱和氯化铵溶液淬灭。反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物700mg。Place 14-1 (600 mg), p-methoxybenzylamine (368 mg) and tetrahydrofuran (20 mL) in a 100 mL three-necked flask, protect with nitrogen and stir at -10 degrees Celsius. Then, 1M lithium bis(trimethylsilyl)amide (4.48 mL) was added dropwise to the reaction solution. After the dropping is completed, the reaction solution is allowed to react at room temperature. When the raw materials disappear, add saturated ammonium chloride solution to the reaction solution to quench. The reaction solution was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 700 mg of the title product.
c)化合物14-3的制备c) Preparation of compound 14-3
将14-2(690mg)及三氟乙酸(10mL)置于50mL单口瓶中，并于55摄氏度下搅拌。待原料反应完全，反应液脱溶至干。接着用2N氢氧化钠溶液调pH至9，乙酸乙酯萃取(30mL)。有机相脱溶至干，接着加入3mL二氯甲烷打浆。过滤，滤饼烘干得标题产物467mg。14-2 (690 mg) and trifluoroacetic acid (10 mL) were placed in a 50 mL single-neck bottle and stirred at 55 degrees Celsius. When the reaction of the raw materials is complete, the reaction solution is desolvated to dryness. Then adjust the pH to 9 with 2N sodium hydroxide solution, and extract with ethyl acetate (30 mL). The organic phase was desolvated to dryness, and then 3 mL of methylene chloride was added to make a pulp. Filter and dry the filter cake to obtain 467 mg of the title product.
d)化合物14-4的制备d) Preparation of compound 14-4
将14-3(100mg)、二甲氨基吡啶(15mg)、二异丙基乙基胺(103mg)及N,N-二甲基甲酰胺(10mL)置于封管中搅拌。滴加乙酰氯(4mmol,10eq)，并于室温下搅拌2分钟。将反应液置于60摄氏度下反应0.5小时。待反应液冷却至室温，将反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物86mgPlace 14-3 (100 mg), dimethylaminopyridine (15 mg), diisopropylethylamine (103 mg) and N,N-dimethylformamide (10 mL) in a sealed tube and stir. Acetyl chloride (4 mmol, 10 eq) was added dropwise and stirred at room temperature for 2 minutes. The reaction solution was placed at 60 degrees Celsius for 0.5 hours. After the reaction solution is cooled to room temperature, the reaction solution is desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 86 mg of the title product.
e)化合物14-5的制备e) Preparation of compound 14-5
将14-4(85mg)及三氯氧磷(5mL)加入到封管中。氮气保护下，将反应液置于100摄氏度下反应2h。反应液脱溶至干。柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物48mg。Add 14-4 (85 mg) and phosphorus oxychloride (5 mL) to the sealed tube. Under nitrogen protection, the reaction solution was placed at 100 degrees Celsius for 2 hours. The reaction solution was desolvated to dryness. Purification by column chromatography (dichloromethane/methanol=20/1 (V/V)) gave 48 mg of the title product.
f)化合物14-6的制备f) Preparation of compound 14-6
将14-5(49mg)、M11(75mg)、三二亚苄基丙酮二钯(13mg)、1,1'-联萘-2,2'-双二苯膦(26mg)、叔丁醇钾(32mg)及甲苯(10mL)加入到30mL微波管中。氮气保护下，将反应液置于130摄氏度下微波反应3小时。反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物38mg。Combine 14-5 (49mg), M11 (75mg), tridibenzylideneacetone dipalladium (13mg), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (26mg), potassium tert-butoxide (32 mg) and toluene (10 mL) were added to a 30 mL microwave tube. Under nitrogen protection, the reaction solution was placed in a microwave at 130 degrees Celsius for 3 hours. The reaction solution was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 38 mg of the title product.
g)化合物例14的制备g) Preparation of compound example 14
将14-6(0.06mmol,1eq)及三氟乙酸(5mL)加入到25mL单口瓶中。氮气保护下，将反应液置于50摄氏度下反应5h。反应液脱溶至干。接着向粗品中加入乙酸乙酯(30mL)，并用2N氢氧化钠(10mL)洗涤有机相，重复2次。有机相脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物12.7mg。Add 14-6 (0.06mmol, 1eq) and trifluoroacetic acid (5mL) into a 25mL single-neck bottle. Under nitrogen protection, the reaction solution was placed at 50 degrees Celsius for 5 hours. The reaction solution was desolvated to dryness. Then, ethyl acetate (30 mL) was added to the crude product, and the organic phase was washed with 2N sodium hydroxide (10 mL), repeated twice. The organic phase was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 12.7 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ11.32(s,1H),8.51–8.46(m,2H),8.28(dd,J＝13.2,2.3Hz,1H),7.65–7.60(m,2H),7.52(dd,J＝8.9,2.2Hz,1H),7.49–7.42(m,3H),7.39–7.33(m,2H),7.01(d,J＝5.6Hz,1H),6.82–6.77(m,2H),6.20(s,2H),3.00–2.94(m,4H),2.45–2.42(m,4H),2.20(s,3H),2.18(s,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ11.32 (s, 1H), 8.51–8.46 (m, 2H), 8.28 (dd, J = 13.2, 2.3Hz, 1H), 7.65–7.60 (m, 2H),7.52(dd,J＝8.9,2.2Hz,1H),7.49–7.42(m,3H),7.39–7.33(m,2H),7.01(d,J＝5.6Hz,1H),6.82–6.77 (m,2H),6.20(s,2H),3.00–2.94(m,4H),2.45–2.42(m,4H),2.20(s,3H),2.18(s,3H).
MS(ESI+):636.3(M+H).MS(ESI+):636.3(M+H).
实施例15：

Example 15:

a)化合物15-1的制备a) Preparation of compound 15-1
参照制备例12的制备方法制备，将步骤c)中的4-(4-甲基哌嗪-1-基)苯胺替换成1-(1-甲基哌啶-4-基)-1H-吡唑-4-胺即可，得标题产物100mg。Prepare according to the preparation method of Preparation Example 12, replacing 4-(4-methylpiperazin-1-yl)aniline in step c) with 1-(1-methylpiperidin-4-yl)-1H-pyridine Azole-4-amine is sufficient to obtain 100 mg of the title product.
b)化合物15-2的制备b) Preparation of compound 15-2
参照制备例12的制备方法制备，将步骤d)中的M12-3替换成15-1即可，得标题产物34mg。Prepare according to the preparation method of Preparation Example 12, replace M12-3 in step d) with 15-1 to obtain 34 mg of the title product.
c)化合物15-3的制备c) Preparation of compound 15-3
将15-2(28mg)、M7(39mg)、三二亚苄基丙酮二钯(6mg)、叔丁醇钠(11mg)、1,3-二(二苯基膦)丙烷(8mg)及二氧六环(4mL)加入到30mL微波管中。氮气保护下，将反应液置于140摄氏度下微波反应3h。反应液脱溶至干。柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物41mg。Combine 15-2 (28mg), M7 (39mg), tridibenzylideneacetone dipalladium (6mg), sodium tert-butoxide (11mg), 1,3-bis(diphenylphosphine)propane (8mg) and di Oxyhexanes (4 mL) was added to the 30 mL microwave tube. Under nitrogen protection, the reaction solution was placed in a microwave at 140 degrees Celsius for 3 hours. The reaction solution was desolvated to dryness. Purification by column chromatography (dichloromethane/methanol=10/1 (V/V)) gave 41 mg of the title product.
d)化合物例15的制备d) Preparation of compound example 15
将15-3(41mg)及三氟乙酸(5mL)加入到25mL单口瓶中。氮气保护下，将反应液置于50摄氏度下反应5h。反应液脱溶至干。接着向粗品中加入乙酸乙酯(30mL)，并用2N氢氧化钠(10mL)洗涤有机相，重复2次。有机相脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物11.27mg。Add 15-3 (41 mg) and trifluoroacetic acid (5 mL) to a 25 mL single-neck bottle. Under nitrogen protection, the reaction solution was placed at 50 degrees Celsius for 5 hours. The reaction solution was desolvated to dryness. Then, ethyl acetate (30 mL) was added to the crude product, and the organic phase was washed with 2N sodium hydroxide (10 mL), repeated twice. The organic phase was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 11.27 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ12.01(s,1H),8.41(s,1H),8.33(d,J＝5.5Hz,1H),7.60(s,1H),7.53–7.36(m,7H),7.28(s,1H),6.95(d,J＝5.5Hz,1H),6.68(s,1H),6.13(s,2H),4.01–3.93(m,1H),2.81(d,J＝11.0Hz,2H),2.17(s,3H),2.00(s,3H),1.99–1.95(m,2H),1.91–1.82(m,4H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.01 (s, 1H), 8.41 (s, 1H), 8.33 (d, J = 5.5Hz, 1H), 7.60 (s, 1H), 7.53–7.36 (m,7H),7.28(s,1H),6.95(d,J＝5.5Hz,1H),6.68(s,1H),6.13(s,2H),4.01–3.93(m,1H),2.81( d,J＝11.0Hz,2H),2.17(s,3H),2.00(s,3H),1.99–1.95(m,2H),1.91–1.82(m,4H).
MS(ESI+):624.3(M+H).MS(ESI+):624.3(M+H).
实施例16：
 Example 16:
a)化合物16-1的制备 a) Preparation of compound 16-1
向反应瓶中加入8-氯-2-(4-氟苯基)-3-甲基-2,7-萘啶-1(2H)-酮(2.88g)，N-溴代丁二酰亚胺(1.99g)，偶氮二异丁腈(0.5g)，四氯化碳(30mL)，于50℃下反应。3小时后停止反应，用二氯甲烷-甲醇梯度洗脱，得标题产物0.8g固体。Add 8-chloro-2-(4-fluorophenyl)-3-methyl-2,7-naphthyridin-1(2H)-one (2.88g), N-bromosuccinimide to the reaction flask. Amine (1.99g), azobisisobutyronitrile (0.5g), carbon tetrachloride (30mL) were reacted at 50°C. The reaction was stopped after 3 hours and eluted with dichloromethane-methanol gradient to obtain 0.8 g of the title product as a solid.
b)化合物16-2的制备b) Preparation of compound 16-2
将16-1(44mg)、M12(53mg)、三二亚苄基丙酮二钯(10mg)、1,3-双(二苯基膦)丙烷(20mg)、叔丁醇钠(20mg)及甲苯(10mL)置于10mL单口瓶中，并于105摄氏度下反应10小时。待原料反应完全，脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物100mg固体。Combine 16-1 (44mg), M12 (53mg), tridibenzylideneacetone dipalladium (10mg), 1,3-bis(diphenylphosphine)propane (20mg), sodium tert-butoxide (20mg) and toluene (10 mL) was placed in a 10 mL single-neck bottle and reacted at 105 degrees Celsius for 10 hours. After the reaction of the raw materials is complete, the solution is removed to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 100 mg of the title product as a solid.
c)化合物例16的制备c) Preparation of compound example 16
参考实施例15的制备方法制备，将步骤d)中的15-3替换成16-2即可。反应液脱溶至干，脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物7.9mg。Prepare according to the preparation method of Example 15, just replace 15-3 in step d) with 16-2. The reaction solution was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 7.9 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ12.15(s,1H),8.51(d,J＝5.7Hz,1H),8.48(s,1H),8.31–8.24(m,2H),7.57–7.39(m,7H),7.37(d,J＝2.1Hz,1H),7.35(d,J＝2.3Hz,1H),7.23(d,J＝5.7Hz,1H),6.83–6.78(m,2H),6.20(s,2H),2.97(t,J＝4.9Hz,4H),2.43(t,J＝5.0Hz,4H),2.24(s,3H),2.21(s,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.15 (s, 1H), 8.51 (d, J = 5.7Hz, 1H), 8.48 (s, 1H), 8.31–8.24 (m, 2H), 7.57 –7.39(m,7H),7.37(d,J＝2.1Hz,1H),7.35(d,J＝2.3Hz,1H),7.23(d,J＝5.7Hz,1H),6.83–6.78(m, 2H),6.20(s,2H),2.97(t,J＝4.9Hz,4H),2.43(t,J＝5.0Hz,4H),2.24(s,3H),2.21(s,3H).
MS(ESI+):713.1(M+H).MS(ESI+):713.1(M+H).
实施例17：
Example 17:
a)化合物17-1的制备a) Preparation of compound 17-1
将M12(58mg),M7(40mg),三氟乙酸(0.5mL)及正丁醇(5mL)加入到微波管中。氮气保护下，将微波管置于120摄氏度下反应。1小时后，停止反应。反应液脱溶至干。接着向粗品中加入乙酸乙酯(30mL)，并用2N氢氧化钠(10mL)洗涤有机相，重复2次。有机相脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物55mg。Add M12 (58mg), M7 (40mg), trifluoroacetic acid (0.5mL) and n-butanol (5mL) into the microwave tube. Under nitrogen protection, place the microwave tube at 120 degrees Celsius for reaction. After 1 hour, the reaction was stopped. The reaction solution was desolvated to dryness. Then, ethyl acetate (30 mL) was added to the crude product, and the organic phase was washed with 2N sodium hydroxide (10 mL), repeated twice. The organic phase was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 55 mg of the title product.
b)化合物例17的制备b) Preparation of compound example 17
将17-1(55mg)及三氟乙酸(5mL)加入到25mL单口瓶中。氮气保护下，将反应液置于50摄氏度下反应。1小时后，停止反应。反应液脱溶至干。接着向粗品中加入乙酸乙酯(30mL)，并用2N氢氧化钠(10mL)洗涤有机相，重复2次。有机相脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物38mg。Add 17-1 (55 mg) and trifluoroacetic acid (5 mL) to a 25 mL single-neck bottle. Under nitrogen protection, the reaction solution was placed at 50 degrees Celsius for reaction. After 1 hour, the reaction was stopped. The reaction solution was desolvated to dryness. Then, ethyl acetate (30 mL) was added to the crude product, and the organic phase was washed with 2N sodium hydroxide (10 mL), repeated twice. The organic phase was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 38 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ12.02(s,1H),8.48(s,1H),8.33(d,J＝5.5Hz,1H),8.29(dd,J＝13.4,2.3Hz,1H),7.52–7.34(m,8H),6.95(d,J＝5.5Hz,1H),6.83–6.77(m,2H),6.67(d,J＝1.0Hz,1H),6.18(s,2H),2.99(t,J＝5.0Hz,4H),2.48(s,4H),2.24(s,3H),2.03–1.95(m,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.02 (s, 1H), 8.48 (s, 1H), 8.33 (d, J = 5.5Hz, 1H), 8.29 (dd, J = 13.4, 2.3Hz ,1H),7.52–7.34(m,8H),6.95(d,J＝5.5Hz,1H),6.83–6.77(m,2H),6.67(d,J＝1.0Hz,1H),6.18(s, 2H),2.99(t,J＝5.0Hz,4H),2.48(s,4H),2.24(s,3H),2.03–1.95(m,3H).
MS(ESI+):635.3(M+H).MS(ESI+):635.3(M+H).
实施例18：
Example 18:
a)化合物18-1的制备a) Preparation of compound 18-1
将M8(25mg)，M12(45mg)，三(二亚苄基丙酮)二钯(15mg)，1,1'-联萘-2,2'-双二苯膦(20mg)，叔丁醇钾(12mg)溶于甲苯(3mL)，并用氮气保护，80℃搅拌3h。将反应液直接脱溶,柱层析(二氯甲烷/甲醇＝10/1(V/V))得到标题产 物66mg。Combine M8 (25mg), M12 (45mg), tris(dibenzylideneacetone)dipalladium (15mg), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (20mg), potassium tert-butoxide (12mg) was dissolved in toluene (3mL), protected with nitrogen, and stirred at 80°C for 3h. The reaction solution was directly desolvated and subjected to column chromatography (dichloromethane/methanol = 10/1 (V/V)) to obtain the title product. substance 66mg.
MS(ESI+):782.4(M+H).MS(ESI+):782.4(M+H).
b)化合物例18的制备b) Preparation of compound example 18
将16-1(50mg)溶于三氟乙酸(0.5mL)中，50℃搅拌16h。将反应液冷至室温，浓缩，用二氯甲烷(10mL)稀释，用1N氢氧化钠水溶液洗涤3次，分离有机相，用无水硫酸钠干燥，脱溶，柱层析(二氯甲烷/甲醇＝10/1(V/V))得到标题产物30mg。Dissolve 16-1 (50 mg) in trifluoroacetic acid (0.5 mL) and stir at 50°C for 16 h. The reaction solution was cooled to room temperature, concentrated, diluted with dichloromethane (10 mL), washed three times with 1N sodium hydroxide aqueous solution, separated the organic phase, dried over anhydrous sodium sulfate, removed, and column chromatographed (dichloromethane/ Methanol = 10/1 (V/V)) to obtain 30 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ11.95(brs,1H),8.53-8.47(m,2H),8.36-8.27(m,2H),7.94-7.91(m,1H),7.54(d,J＝8.0Hz,1H),7.48-7.35(m,4H),6.96(d,J＝4.0Hz,1H),6.80(d,J＝4.0Hz,2H),6.67(brs,1H),6.18(brs,2H),2.99-2.96(m,4H),2.44-2.42(m,7H),2.20(s,3H),1.98(s,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ11.95(brs,1H),8.53-8.47(m,2H),8.36-8.27(m,2H),7.94-7.91(m,1H),7.54( d,J＝8.0Hz,1H),7.48-7.35(m,4H),6.96(d,J＝4.0Hz,1H),6.80(d,J＝4.0Hz,2H),6.67(brs,1H), 6.18(brs,2H),2.99-2.96(m,4H),2.44-2.42(m,7H),2.20(s,3H),1.98(s,3H).
MS(ESI+):632.3(M+H).MS(ESI+):632.3(M+H).
实施例19：
Example 19:
a)化合物19-1的制备a) Preparation of compound 19-1
参照实施例18中步骤a)的方法，将其中的M8替换成M9，制备得到标题产物215mg。Referring to the method of step a) in Example 18, replacing M8 with M9, 215 mg of the title product was prepared.
MS(ESI+):797.36(M+H).MS(ESI+):797.36(M+H).
b)化合物例19的制备b) Preparation of compound example 19
参照实施例18中步骤b)的方法，将其中的18-1替换成19-1，制备得到标题产物11mg。Referring to the method of step b) in Example 18, replacing 18-1 with 19-1, 11 mg of the title product was prepared.
1H NMR(400MHz,DMSO-d6):δ12.11(s,1H),8.47(s,1H),8.33–8.28(m,3H),7.48–7.31(m,5H),7.14–7.09(m,2H),6.94(d,J＝4Hz,1H),6.80(d,J＝8Hz,2H),6.66(s,1H),6.18(s,2H),3.85(s,3H),2.99-2.96(m,4H),2.42-2.44(m,4H),2.21(s,3H),2.01(s,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.11(s,1H),8.47(s,1H),8.33–8.28(m,3H),7.48–7.31(m,5H),7.14–7.09( m,2H),6.94(d,J＝4Hz,1H),6.80(d,J＝8Hz,2H),6.66(s,1H),6.18(s,2H),3.85(s,3H),2.99- 2.96(m,4H),2.42-2.44(m,4H),2.21(s,3H),2.01(s,3H).
MS(ESI+):647.29(M+H).MS(ESI+):647.29(M+H).
实施例20：
Example 20:
a)化合物20-1的制备a) Preparation of compound 20-1
将M6(30mg)、M11(52mg)及正丁醇(3mL)置于封管中，接着加入三氟乙酸(0.12mL),并于室温搅拌5分钟。接着将反应液置于80摄氏度油浴下反应2小时。反应液脱溶至干得标题产物粗品30mg。M6 (30 mg), M11 (52 mg) and n-butanol (3 mL) were placed in a sealed tube, then trifluoroacetic acid (0.12 mL) was added, and stirred at room temperature for 5 minutes. Then, the reaction solution was placed in an 80°C oil bath for 2 hours. The reaction solution was desolvated to dryness to obtain 30 mg of crude title product.
b)化合物例20的制备。b) Preparation of compound example 20.
将20-1(30mg)与三氟乙酸(3mL)置于10mL单口瓶中。反应液在氮气保护下于120摄氏度反应2小时。接着将反应液脱溶至干。所得粗品采用反相高效液相色谱法纯化(柱：Xselect CSH C18 OBD柱，30×150mm填料粒径5μm；流动相A:0.05％三氟乙酸水溶液，流动相B:乙腈；流速：60mL/min；梯度：5％B～25％B，8min；检测波长：220nm；目标化合物保留时间:6.98min)，得到了标题产物17.8mg。 Place 20-1 (30 mg) and trifluoroacetic acid (3 mL) in a 10 mL single-neck bottle. The reaction solution was reacted at 120 degrees Celsius for 2 hours under nitrogen protection. The reaction solution was then desolvated to dryness. 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 μm; mobile phase A: 0.05% trifluoroacetic acid aqueous solution, mobile phase B: acetonitrile; flow rate: 60mL/min ; Gradient: 5% B ~ 25% B, 8 min; detection wavelength: 220 nm; target compound retention time: 6.98 min), and 17.8 mg of the title product was obtained.
1H NMR:(400MHz,DMSO-d6):δ13.03(s,1H),12.38(s,1H),8.55(s,1H),8.40–8.04(m,2H),8.01–7.83(m,2H),7.82–7.63(m,2H),7.59–7.47(m,2H),7.47–7.37(m,2H),7.32–7.19(m,2H),6.95–6.71(m,3H),6.26(s,2H),3.09(s,3H),2.78(s,4H)，2.48(s,4H). 1 H NMR: (400MHz, DMSO-d 6 ): δ13.03(s,1H),12.38(s,1H),8.55(s,1H),8.40–8.04(m,2H),8.01–7.83(m ,2H),7.82–7.63(m,2H),7.59–7.47(m,2H),7.47–7.37(m,2H),7.32–7.19(m,2H),6.95–6.71(m,3H),6.26 (s,2H),3.09(s,3H),2.78(s,4H),2.48(s,4H).
MS(ESI+):603(M+H).MS(ESI+):603(M+H).
实施例21：
Example 21:
a)化合物21-1的制备a) Preparation of compound 21-1
将M6(50mg)、碳酸铯(177.93mg)及四氢呋喃(5mL)置于封管中，并于室温下搅拌。向反应液中加入2-碘丙烷(309.44mg)，然后氮气保护。将反应液加热至80摄氏度下反应2小时。待原料反应完全，将反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物24mg。M6 (50 mg), cesium carbonate (177.93 mg) and tetrahydrofuran (5 mL) were placed in a sealed tube and stirred at room temperature. 2-iodopropane (309.44 mg) was added to the reaction solution, and then nitrogen was protected. The reaction solution was heated to 80 degrees Celsius and reacted for 2 hours. After the reaction of the raw materials is complete, the reaction solution is desolvated to dryness and purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 24 mg of the title product.
b)化合物21-2的制备b) Preparation of compound 21-2
参照实施例20的制备方法制备，将步骤a)中的M6替换成21-1即可。得标题产物19mg。Prepare according to the preparation method of Example 20, just replace M6 in step a) with 21-1. 19 mg of the title product was obtained.
c)化合物例21的制备c) Preparation of compound example 21
参照实施例20的制备方法制备，将步骤b)中的20-1替换成21-2即可。接着将反应液脱溶至干。所得粗品采用反相高效液相色谱法纯化(柱：Xselect CSH C18 OBD柱，30×150mm填料粒径5μm；流动相A:0.05％三氟乙酸水溶液，流动相B:乙腈；流速：60mL/min；梯度：5％B～40％B，8min；检测波长：220nm；目标化合物保留时间:5.78min)，得到了标题产物1.8mg。Prepare according to the preparation method of Example 20, just replace 20-1 in step b) with 21-2. The reaction solution was then desolvated to dryness. 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 μm; mobile phase A: 0.05% trifluoroacetic acid aqueous solution, mobile phase B: acetonitrile; flow rate: 60mL/min ; Gradient: 5% B ~ 40% B, 8 min; detection wavelength: 220 nm; target compound retention time: 5.78 min), and 1.8 mg of the title product was obtained.
1H NMR(400MHz,DMSO-d6):δ13.45(s,1H),9.48(s,1H),8.65(s,1H),8.28–8.19(m,1H),8.02–7.92(m,2H),7.72(ddd,J＝8.9,5.6,2.7Hz,2H),7.56–7.41(m,4H),7.33–7.23(m,2H),7.15(d,J＝6.7Hz,1H),6.95–6.86(m,2H),6.31(s,2H),5.04–4.98(m,1H),3.64(d,J＝13.0Hz,2H),3.49(s,2H),3.18(s,2H),2.86(d,J＝4.7Hz,5H),1.53(d,J＝6.6Hz,6H). 1 H NMR (400MHz, DMSO-d 6 ): δ13.45(s,1H),9.48(s,1H),8.65(s,1H),8.28–8.19(m,1H),8.02–7.92(m, 2H),7.72(ddd,J＝8.9,5.6,2.7Hz,2H),7.56–7.41(m,4H),7.33–7.23(m,2H),7.15(d,J＝6.7Hz,1H),6.95 –6.86(m,2H),6.31(s,2H),5.04–4.98(m,1H),3.64(d,J＝13.0Hz,2H),3.49(s,2H),3.18(s,2H), 2.86(d,J＝4.7Hz,5H), 1.53(d,J＝6.6Hz,6H).
MS(ESI+):645(M+H).MS(ESI+):645(M+H).
实施例22：

Example 22:

a)化合物22-1的制备a) Preparation of compound 22-1
在氮气保护下将M12-2(500mg)、(7S)-7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]环烯-2-胺(382.02mg)、碳酸铯(720.46mg)、甲磺酸(2-二环己基膦基-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2-氨基-1,1'-联苯-2-基)钯(II)(100.22mg)和二氧六环(5mL)置于封管中，于80℃搅拌3小时。反应液脱溶，柱层析纯化(二氯甲烷/甲醇＝1/10(V/V))，得标题产物500mg。M12-2 (500mg), (7S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]cycloene-2- Amine (382.02mg), cesium carbonate (720.46mg), methanesulfonic acid (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1, 1'-Biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (100.22mg) and dioxane (5mL) were placed in a sealed tube and stirred at 80°C for 3 Hour. The reaction solution was desolvated and purified by column chromatography (dichloromethane/methanol=1/10 (V/V)) to obtain 500 mg of the title product.
b)化合物22-2的制备b) Preparation of compound 22-2
将22-1(470mg)、铁粉(46.41mg)和醋酸(5mL)置于25mL单口瓶中。将反应液进行氮气置换，然后于35摄氏度下反应过夜。待反应完全，将反应液浓缩至干，接着用饱和碳酸氢钠调pH至8。用乙酸乙酯萃取(3x30mL)。合并有机相，依次用饱和食盐水洗，无水硫酸钠干燥。滤液脱溶至干，得目标产物300mg。Place 22-1 (470mg), iron powder (46.41mg) and acetic acid (5mL) in a 25mL single-neck bottle. The reaction solution was replaced with nitrogen, and then reacted at 35 degrees Celsius overnight. When the reaction is complete, the reaction solution is concentrated to dryness, and then the pH is adjusted to 8 with saturated sodium bicarbonate. Extract with ethyl acetate (3x30 mL). The organic phases were combined, washed with saturated brine in sequence, and dried over anhydrous sodium sulfate. The filtrate was desolvated to dryness to obtain 300 mg of the target product.
c)化合物22-3的制备c) Preparation of compound 22-3
氮气保护下，将22-2(40mg)，1,1'-联萘-2,2'-双二苯膦(8.71mg)、叔丁醇钾(23.55mg)、三(二亚苄基丙酮)二钯(1.64mg)、M7(24mg)及甲苯(5mL)置于封管中。反应液于80摄氏度下反应2小时。待反应完全，反应液脱溶至干，柱层析纯化(甲醇/二氯甲烷＝1/5(V/V))，得标题产物44mg。Under nitrogen protection, combine 22-2 (40mg), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (8.71mg), potassium tert-butoxide (23.55mg), tris(dibenzylideneacetone) ) Dipalladium (1.64mg), M7 (24mg) and toluene (5mL) were placed in a sealed tube. The reaction solution was reacted at 80 degrees Celsius for 2 hours. When the reaction is complete, the reaction solution is desolvated to dryness and purified by column chromatography (methanol/dichloromethane=1/5 (V/V)) to obtain 44 mg of the title product.
d)化合物例22的制备d) Preparation of compound example 22
参照实施例20的制备方法制备，将步骤b)中的20-1替换成22-3即可。接着将反应液脱溶至干。所得粗品采用反相高效液相色谱法纯化(柱：Xselect CSH C18 OBD柱，30×150mm填料粒径5μm；流动相A:0.05％三氟乙酸水溶液，流动相B:乙腈；流速：60mL/min；梯度：15％B～55％B，10min；检测波长：220nm；目标化合物保留时间:7.2min)，得到了标题产物14.7mg。Prepare according to the preparation method of Example 20, and replace 20-1 in step b) with 22-3. The reaction solution was then desolvated to dryness. 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 μm; mobile phase A: 0.05% trifluoroacetic acid aqueous solution, mobile phase B: acetonitrile; flow rate: 60mL/min ; Gradient: 15% B ~ 55% B, 10 min; detection wavelength: 220 nm; target compound retention time: 7.2 min), and 14.7 mg of the title product was obtained.
1H NMR:(400MHz,DMSO-d6):δ12.03(s,1H),8.68(s,1H),8.37–8.26(m,2H),7.55–7.47(m,3H),7.41(dt,J＝11.8,8.6Hz,3H),7.31–7.20(m,2H),6.95(dd,J＝7.1,5.6Hz,2H),6.68(s,1H),6.23(s,2H),3.13(s,4H),2.80–2.59(m,5H),2.20(s,2H),1.99(s,3H),1.85(s,4H),1.38(s,2H). 1 H NMR: (400MHz, DMSO-d 6 ): δ12.03(s,1H),8.68(s,1H),8.37–8.26(m,2H),7.55–7.47(m,3H),7.41(dt ,J＝11.8,8.6Hz,3H),7.31–7.20(m,2H),6.95(dd,J＝7.1,5.6Hz,2H),6.68(s,1H),6.23(s,2H),3.13( s,4H),2.80–2.59(m,5H),2.20(s,2H),1.99(s,3H),1.85(s,4H),1.38(s,2H).
MS(ESI+):674.4(M+H).MS(ESI+):674.4(M+H).
实施例23：
Example 23:
a)化合物23-1的制备a) Preparation of compound 23-1
参考实施例22中的制备方法制备，将步骤c)中的M7替换成21-1即可，得标题产物20mg。Prepare by referring to the preparation method in Example 22. Just replace M7 in step c) with 21-1 to obtain 20 mg of the title product.
b)化合物例23的制备b) Preparation of compound example 23
参考实施例20的制备方法制备，将步骤b)中的20-1替换成23-1即可。接着将反应液脱溶至干。所得粗品采用反相高效液相色谱法纯化(柱：XBridge Prep OBD C18柱，30×150mm填料粒径5μm；流动相A:10mmol/L碳酸氢 铵水溶液，流动相B:乙腈；流速：60mL/min；梯度：25％B～66％B，10min；检测波长：220nm；目标化合物保留时间:9.32min)，得到了标题产物得标题产物5.1mg。Prepare according to the preparation method of Example 20, just replace 20-1 in step b) with 23-1. 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 μm; mobile phase A: 10mmol/L hydrogen carbonate Ammonium aqueous solution, mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 25% B ~ 66% B, 10 min; detection wavelength: 220 nm; target compound retention time: 9.32 min), the title product was obtained and 5.1 mg of the title product was obtained .
1H NMR:(400MHz,DMSO-d6):δ13.69(s,1H),8.61(s,1H),8.39–8.22(m,3H),7.77–7.69(m,2H),7.52–7.39(m,2H),7.33–7.22(m,4H),7.19(d,J＝2.3Hz,1H),6.89(d,J＝8.2Hz,1H),6.22(s,2H),5.03(q,J＝6.8Hz,1H),3.69(d,J＝3.9Hz,1H),3.31(s,5H),2.80(d,J＝10.8Hz,1H),2.59(s,3H),1.90(s,2H),1.69(s,4H),1.54(d,J＝6.5Hz,6H),1.23(s,1H). 1 H NMR: (400MHz, DMSO-d 6 ): δ13.69(s,1H),8.61(s,1H),8.39–8.22(m,3H),7.77–7.69(m,2H),7.52–7.39 (m,2H),7.33–7.22(m,4H),7.19(d,J＝2.3Hz,1H),6.89(d,J＝8.2Hz,1H),6.22(s,2H),5.03(q, J＝6.8Hz,1H),3.69(d,J＝3.9Hz,1H),3.31(s,5H),2.80(d,J＝10.8Hz,1H),2.59(s,3H),1.90(s, 2H), 1.69 (s, 4H), 1.54 (d, J = 6.5Hz, 6H), 1.23 (s, 1H).
MS(ESI+):702.0(M+H).MS(ESI+):702.0(M+H).
实施例24：
Example 24:
a)化合物24-1的制备a) Preparation of compound 24-1
将(S)-(1,4-二恶烷-2-基)甲醇(1g)、2-甲氧基-4-硝基苯酚(1.72g)、三苯基膦(3.77g)及四氢呋喃(20mL)置于50mL三口瓶中，0摄氏度下搅拌。氮气保护下，滴加偶氮二甲酸二乙酯(2.91g)。滴毕后，反应液于室温下反应过夜。待原料反应完全，反应液脱溶至干，柱层析纯化(石油醚/乙酸乙酯＝1/1(V/V))，得标题产物2.20g。Combine (S)-(1,4-dioxan-2-yl)methanol (1g), 2-methoxy-4-nitrophenol (1.72g), triphenylphosphine (3.77g) and tetrahydrofuran ( 20mL) into a 50mL three-necked flask and stir at 0 degrees Celsius. Under nitrogen protection, diethyl azodicarboxylate (2.91g) was added dropwise. After the dropping was completed, the reaction solution was allowed to react at room temperature overnight. After the reaction of the raw materials is complete, the reaction solution is desolvated to dryness and purified by column chromatography (petroleum ether/ethyl acetate = 1/1 (V/V)) to obtain 2.20 g of the title product.
b)化合物24-2的制备b) Preparation of compound 24-2
将24-1(2.20g)、甲醇(40mL)及5％钯碳(0.245g)置于100mL单口瓶中，接着在氢气条件下搅拌2小时。待原料消失，过滤。滤液脱溶至干的标题产物1.53g。24-1 (2.20g), methanol (40mL) and 5% palladium on carbon (0.245g) were placed in a 100mL single-neck bottle, and then stirred under hydrogen conditions for 2 hours. When the raw materials disappear, filter. The filtrate was desolvated to 1.53 g of dry title product.
c)化合物24-3的制备c) Preparation of compound 24-3
参考实施例22的制备方法，将步骤a)中的(7S)-7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]环烯-2-胺替换成(R)-4-((1,4-二恶烷-2-基)甲氧基)-3-甲氧基苯胺即可，得标题产物500mg。Referring to the preparation method of Example 22, (7S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]cycloene- The 2-amine can be replaced by (R)-4-((1,4-dioxan-2-yl)methoxy)-3-methoxyaniline to obtain 500 mg of the title product.
d)化合物24-4的制备d) Preparation of compound 24-4
参考实施例22的制备方法，将步骤b)中的22-1替换成24-3即可，得标题产物470mg。 Referring to the preparation method of Example 22, just replace 22-1 in step b) with 24-3 to obtain 470 mg of the title product.
e)化合物24-5的制备e) Preparation of compound 24-5
参考实施例22的制备方法，将步骤c)中的22-2替换成24-4即可，得标题产物25mg。Referring to the preparation method of Example 22, just replace 22-2 in step c) with 24-4 to obtain 25 mg of the title product.
f)–化合物例24的制备f) – Preparation of compound example 24
参考实施例22的制备方法，将步骤d)22-3替换成24-5即可。接着将反应液脱溶至干。所得粗品采用反相高效液相色谱法纯化(柱：XBridge Prep OBD C18柱，30×150mm填料粒径5μm；流动相A:10mmol/L HCl水溶液，流动相B:乙腈；流速：60mL/min；梯度：10％B～62％B，10min；检测波长：220nm；目标化合物保留时间:7.75min)，得到了标题产物5.3mg。Referring to the preparation method of Example 22, 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 μm; 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.
1H NMR:(400MHz,DMSO-d6):δ12.03(s,1H),8.58(s,1H),8.37–8.21(m,2H),7.55–7.32(m,6H),7.16(d,J＝2.5Hz,1H),7.05(dd,J＝8.7,2.5Hz,1H),6.95(d,J＝5.5Hz,1H),6.79(d,J＝8.8Hz,1H),6.68(s,1H),6.22(s,2H),3.87–3.71(m,5H),3.69(s,3H),3.67–3.61(m,2H),3.58(dd,J＝11.4,2.5Hz,1H),3.47(td,J＝10.7,10.2,2.8Hz,1H),1.99(s,3H). 1 H NMR: (400MHz, DMSO-d 6 ): δ12.03(s,1H),8.58(s,1H),8.37–8.21(m,2H),7.55–7.32(m,6H),7.16(d ,J＝2.5Hz,1H),7.05(dd,J＝8.7,2.5Hz,1H),6.95(d,J＝5.5Hz,1H),6.79(d,J＝8.8Hz,1H),6.68(s ,1H),6.22(s,2H),3.87–3.71(m,5H),3.69(s,3H),3.67–3.61(m,2H),3.58(dd,J＝11.4,2.5Hz,1H), 3.47(td,J＝10.7,10.2,2.8Hz,1H),1.99(s,3H).
MS(ESI+):683.4(M+H).MS(ESI+):683.4(M+H).
实施例25：
Example 25:
a)化合物25-1的制备a) Preparation of compound 25-1
氮气保护下，将2-氯4-氟-1-硝基苯(1g)、碳酸钾(1.57g)、1-甲基哌嗪(0.68g)及N,N-二甲基甲酰胺(10mL)置于25mL单口瓶中。反应液于100摄氏度下反应1小时。待反应液冷却至室温，向反应液中加入40mL水，搅拌，有 大量固体析出。过滤，滤饼用少量水洗涤，干燥。得标题产物1.2g。Under nitrogen protection, add 2-chloro4-fluoro-1-nitrobenzene (1g), potassium carbonate (1.57g), 1-methylpiperazine (0.68g) and N,N-dimethylformamide (10mL ) into a 25mL single-neck bottle. The reaction solution was reacted at 100 degrees Celsius for 1 hour. After the reaction solution cools to room temperature, add 40 mL of water to the reaction solution, stir, and A large amount of solids precipitated. Filter, wash the filter cake with a small amount of water and dry. 1.2g of the title product was obtained.
b)化合物25-2的制备b) Preparation of compound 25-2
参考实施例22的制备方法，将步骤b)中的22-1替换成1-(3-氯-4-硝基苯基)-4-甲基哌嗪即可。得标题产物0.91g。Referring to the preparation method of Example 22, replace 22-1 in step b) with 1-(3-chloro-4-nitrophenyl)-4-methylpiperazine. 0.91g of the title product was obtained.
c)化合物25-3的制备c) Preparation of compound 25-3
参考实施例22的制备方法，将步骤a)中的(7S)-7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]环烯-2-胺替换成2-氯-4-(4-甲基哌嗪-1-基)苯胺即可。得标题产物120mg。Referring to the preparation method of Example 22, (7S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]cycloene- Just replace 2-amine with 2-chloro-4-(4-methylpiperazin-1-yl)aniline. 120 mg of the title product was obtained.
d)化合物25-4的制备d) Preparation of compound 25-4
参考实施例22的制备方法，将步骤b)中的22-1替换成25-3即可。得标题产物130mg。Referring to the preparation method of Example 22, just replace 22-1 in step b) with 25-3. 130 mg of the title product was obtained.
e)化合物25-5的制备e) Preparation of compound 25-5
参考实施例22的制备方法，将步骤c)中的22-2替换成25-4即可。得标题产物20mg。Referring to the preparation method of Example 22, just replace 22-2 in step c) with 25-4. 20 mg of the title product was obtained.
f)化合物例25的制备f) Preparation of compound example 25
参考实施例22的制备方法，将步骤d)中的20-1替换成25-5即可。接着将反应液脱溶至干。所得粗品采用反相高效液相色谱法纯化(柱：XSelect CSH Fluoro Phenyl柱，30×150mm填料粒径5μm；流动相A:0.1％三氟乙酸水溶液，流动相B:乙腈；流速：60mL/min；梯度：5％B～45％B，8min；检测波长：220nm；目标化合物保留时间:7.32min)，得到了标题产物得标题产物10.1mg。Referring to the preparation method of Example 22, just replace 20-1 in step d) with 25-5. The reaction solution was then desolvated to dryness. The crude product obtained was purified by reversed-phase high performance liquid chromatography (column: XSelect CSH Fluoro Phenyl column, 30×150mm packing particle size 5μm; mobile phase A: 0.1% trifluoroacetic acid aqueous solution, mobile phase B: acetonitrile; flow rate: 60mL/min ; Gradient: 5% B to 45% B, 8 min; detection wavelength: 220 nm; target compound retention time: 7.32 min), and the title product was obtained, and 10.1 mg of the title product was obtained.
1H NMR:(400MHz,DMSO-d6):δ12.03(s,1H),8.33(d,J＝5.5Hz,1H),8.30(dd,J＝13.4,2.3Hz,1H),7.88(d,J＝9.0Hz,1H),7.53–7.45(m,3H),7.41(dt,J＝15.5,8.7Hz,3H),7.20(s,1H),6.96(dd,J＝6.0,4.1Hz,2H),6.89(dd,J＝9.1,2.8Hz,1H),6.68(d,J＝1.0Hz,1H),6.29(s,2H),3.08(s,4H),2.51(s,4H),2.39–2.26(m,3H),2.05–1.95(m,3H). 1 H NMR: (400MHz, DMSO-d 6 ): δ12.03 (s, 1H), 8.33 (d, J = 5.5Hz, 1H), 8.30 (dd, J = 13.4, 2.3Hz, 1H), 7.88 ( d,J＝9.0Hz,1H),7.53–7.45(m,3H),7.41(dt,J＝15.5,8.7Hz,3H),7.20(s,1H),6.96(dd,J＝6.0,4.1Hz ,2H),6.89(dd,J＝9.1,2.8Hz,1H),6.68(d,J＝1.0Hz,1H),6.29(s,2H),3.08(s,4H),2.51(s,4H) ,2.39–2.26(m,3H),2.05–1.95(m,3H).
MS(ESI+):669.1(M+H).MS(ESI+):669.1(M+H).
实施例26：
Example 26:
a)化合物26-1的制备a) Preparation of compound 26-1
将1-(溴甲基)-4-硝基苯(200mg)和4-甲基-1,4-氮杂膦4-氧化物(123mg)溶于无水N,N-二甲基甲酰胺(2mL)中，加入N,N-二异丙基乙胺(359mg)，氮气保护，20℃搅拌12h。将反应液直接脱溶，制砂，柱层析(二氯甲烷/甲醇＝100/0-100/10(V/V))得标题产物120mg。Dissolve 1-(bromomethyl)-4-nitrobenzene (200 mg) and 4-methyl-1,4-azaphosphine 4-oxide (123 mg) in anhydrous N,N-dimethylformamide (2mL), add N,N-diisopropylethylamine (359mg), protect with nitrogen, and stir at 20°C for 12h. The reaction solution was directly desolvated, sand was made, and column chromatography (dichloromethane/methanol=100/0-100/10 (V/V)) was performed to obtain 120 mg of the title product.
MS(ESI+):269.1(M+H).MS(ESI+):269.1(M+H).
b)化合物26-2的制备b) Preparation of compound 26-2
将26-1(120mg)溶于无水甲醇(2mL)，加入Pd/C(24mg)并通氢气，20℃搅拌12h。将反应液过滤并用甲醇洗涤3次，脱溶得到标题产物100mg。Dissolve 26-1 (120 mg) in anhydrous methanol (2 mL), add Pd/C (24 mg), vent hydrogen gas, and stir at 20°C for 12 h. The reaction solution was filtered and washed three times with methanol to obtain 100 mg of the title product.
MS(ESI+):239.1(M+H).MS(ESI+):239.1(M+H).
c)化合物26-3的制备c) Preparation of compound 26-3
将26-2(100mg)和3-溴-N-(2,4-二甲氧基苄基)-1-(2-氟-4-硝基苯基)-1H-1,2,4-***-5-胺(105mg)溶于无水1,4-二氧六环(5mL)，加入碳酸铯(144mg)和[(2-二环己基膦基-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)-2-(2'-氨基-1,1'-联苯)]钯(二)甲磺酸盐(18mg)。氮气保护下，80℃搅拌3h。冷至室温，直接脱溶，制砂，柱层析(二氯甲烷/甲醇＝100/0-100/10(V/V))得到标题产物130mg。Combine 26-2 (100 mg) and 3-bromo-N-(2,4-dimethoxybenzyl)-1-(2-fluoro-4-nitrophenyl)-1H-1,2,4- Triazole-5-amine (105mg) was dissolved in anhydrous 1,4-dioxane (5mL), cesium carbonate (144mg) and [(2-dicyclohexylphosphino-3,6-dimethoxy) were added -2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(di)methanesulfonate( 18mg). Under nitrogen protection, stir at 80°C for 3 hours. Cool to room temperature, directly remove the solution, make sand, and perform column chromatography (dichloromethane/methanol=100/0-100/10 (V/V)) to obtain 130 mg of the title product.
MS(ESI+):610.1(M+H).MS(ESI+):610.1(M+H).
d)化合物26-4的制备d) Preparation of compound 26-4
将26-3(130mg)溶于冰醋酸(2mL)中，加入铁粉(119mg)，氮气保护，50℃搅拌2h。将反应液过滤，滤液脱溶，所得粗品采用反相高效液相色谱法纯化(反相柱，Irregular C18,40-63μm,60A；流动相：水(10mmol/L NH4HCO3)/MeCN＝100/0-0/100,15min)得标题产物60mg。Dissolve 26-3 (130 mg) in glacial acetic acid (2 mL), add iron powder (119 mg), protect with nitrogen, and stir at 50°C for 2 hours. The reaction solution was filtered, the filtrate was desolvated, and the crude product was purified by reversed-phase high performance liquid chromatography (reversed-phase column, Irregular C18, 40-63μm, 60A; mobile phase: water (10mmol/L NH 4 HCO 3 )/MeCN＝ 100/0-0/100,15min) to obtain 60 mg of the title product.
MS(ESI+):580.1(M+H).MS(ESI+):580.1(M+H).
e)化合物26-5的制备e) Preparation of compound 26-5
将26-4(60mg)，M7(45mg)，三(二亚苄基丙酮)二钯(9mg)，1,1'-联萘-2,2'-双二苯膦(13mg)，叔丁醇钾(23mg)溶于甲苯(2mL)，并用氮气保护，80℃搅拌2h。将反应液冷至室温，直接脱溶，制砂，柱层析(二氯甲烷/甲醇＝100/0-100/10(V/V))得到标题产物60mg。26-4 (60mg), M7 (45mg), tris(dibenzylideneacetone)dipalladium (9mg), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (13mg), tert-butyl Potassium alkoxide (23 mg) was dissolved in toluene (2 mL), protected with nitrogen, and stirred at 80°C for 2 h. The reaction solution was cooled to room temperature, directly desolvated, sand was made, and column chromatography (dichloromethane/methanol=100/0-100/10 (V/V)) was performed to obtain 60 mg of the title product.
MS(ESI+):832.1(M+H).MS(ESI+):832.1(M+H).
f)化合物例26的制备f) Preparation of compound example 26
将26-5(60mg)溶于正丁醇(1mL)和三氟乙酸(2mL)中，氮气保护，110℃搅拌2h。将反应液冷至室温，浓缩，所得粗品采用反相高效液相色谱法纯化(柱：Kinetex EVO prep C18，30×150mm，填料粒径5μm；流动相A:水溶液(10mmol/L NH4HCO3)，流动相B:乙腈；流速：60mL/min；梯度：20％B～53％B，8min；检测波长：220nm；目标化合物保留时间:7.00min)得到标题产物16.7mg。Dissolve 26-5 (60 mg) in n-butanol (1 mL) and trifluoroacetic acid (2 mL), protect with nitrogen, and stir at 110°C for 2 h. 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 μm; mobile phase A: aqueous solution (10mmol/L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 20% B to 53% B, 8 min; detection wavelength: 220 nm; target compound retention time: 7.00 min) to obtain 16.7 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ12.03(s,1H),8.77(s,1H),8.37-8.25(m,2H),7.54-7.33(m,8H),7.09(d,J＝8.0Hz,2H),6.95(d,J＝4.0Hz,1H),6.68(s,1H),6.22(s,2H),3.44(s,4H),2.74-2.78(m,2H),2.00(s,3H),1.77(s,4H),1.39(d,J＝12Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.03(s,1H),8.77(s,1H),8.37-8.25(m,2H),7.54-7.33(m,8H),7.09(d, J＝8.0Hz,2H),6.95(d,J＝4.0Hz,1H),6.68(s,1H),6.22(s,2H),3.44(s,4H),2.74-2.78(m,2H), 2.00(s,3H),1.77(s,4H),1.39(d,J＝12Hz,3H).
MS(ESI+):682.4(M+H).MS(ESI+):682.4(M+H).
实施例27：

Example 27:

a)化合物27-1的制备a) Preparation of compound 27-1
参照实施例26的制备方法，将步骤c)中的26-2替换成2-氟-4-(4-甲基哌嗪-1-基)苯胺，得到标题产物230mg。Referring to the preparation method of Example 26, 26-2 in step c) was replaced with 2-fluoro-4-(4-methylpiperazin-1-yl)aniline to obtain 230 mg of the title product.
b)化合物27-2的制备b) Preparation of compound 27-2
参照实施例26的制备方法，将步骤d)中的26-3替换成27-1即可，得到标题产物100mg。Referring to the preparation method of Example 26, just replace 26-3 in step d) with 27-1 to obtain 100 mg of the title product.
MS(ESI+):551.2(M+H).MS(ESI+):551.2(M+H).
c)化合物27-3的制备c) Preparation of compound 27-3
参照实施例26的制备方法，将步骤e)中的26-4替换成27-2即可，方法制备得到标题产物24mg。Referring to the preparation method of Example 26, just replace 26-4 in step e) with 27-2, and prepare 24 mg of the title product.
MS(ESI+):803.2(M+H).MS(ESI+):803.2(M+H).
d)化合物27-4的制备d) Preparation of compound 27-4
参照实施例26的制备方法，将步骤f)中的26-5替换成27-3即可。所得粗品通过反相高效液相色谱法纯化(柱：XBridge Prep OBD C18，30×150mm，填料粒径5μm；流动相A:水溶液(10mmol/L NH4HCO3)，流动相B:乙腈；流速：100mL/min；梯度：25％B～65％B，40min；检测波长：220nm；目标化合物保留时间:35min)得到标题产物3mg。Referring to the preparation method of 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 μm; 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.
1H NMR(400MHz,DMSO-d6):δ12.03(s,1H),8.35-8.26(m,2H),7.82-7.73(m,2H),7.52-7.42(m,4H),7.42-7.38(m,1H),7.36(d,J＝8.0Hz,1H),6.95(d,J＝4.0Hz,1H),6.76(dd,J＝14.0,2.0Hz,1H),6.70-6.62(m,2H),6.22(s,2H),3.30(s,4H),3.05(s,4H),2.25(s,3H),1.99(s,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.03(s,1H),8.35-8.26(m,2H),7.82-7.73(m,2H),7.52-7.42(m,4H),7.42- 7.38(m,1H),7.36(d,J＝8.0Hz,1H),6.95(d,J＝4.0Hz,1H),6.76(dd,J＝14.0,2.0Hz,1H),6.70-6.62(m ,2H),6.22(s,2H),3.30(s,4H),3.05(s,4H),2.25(s,3H),1.99(s,3H).
MS(ESI+):652.7(M+H).MS(ESI+):652.7(M+H).
实施例28：
Example 28:
a)化合物28-1的制备a) Preparation of compound 28-1
参照实施例26的制备方法，将步骤c中的26-2替换成2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺，得到标题产物160mg。Referring to the preparation method of Example 26, 26-2 in step c was replaced with 2-methoxy-4-(4-methylpiperazin-1-yl)aniline to obtain 160 mg of the title product.
MS(ESI+):593.2,(M+H).MS(ESI+):593.2,(M+H).
b)化合物28-2的制备b) Preparation of compound 28-2
参照实施例26的制备方法，将步骤d)中的26-3替换成28-1即可，得到标题产物137mg。Referring to the preparation method of Example 26, just replace 26-3 in step d) with 28-1 to obtain 137 mg of the title product.
MS(ESI+):563.2,(M+H).MS(ESI+):563.2,(M+H).
c)化合物28-3的制备c) Preparation of compound 28-3
参照实施例26的制备方法，将步骤e)中的26-4替换成28-2即可，得到标题产物25mg。Referring to the preparation method of Example 26, just replace 26-4 in step e) with 28-2 to obtain 25 mg of the title product.
MS(ESI+):815.2,(M+H).MS(ESI+):815.2,(M+H).
d)化合物例28的制备d) Preparation of compound example 28
参照实施例26的制备方法，将步骤f)中的26-5替换成28-3即可，所得粗品通过反相高效液相色谱法纯化(柱：XBridge Prep OBD C18，30×150mm，填料粒径5μm；流动相A:水溶液(10mmol/L HCl)，流动相B:乙腈；流速：60mL/min；梯度：10％B～62％B，8min；检测波长：220nm；目标化合物保留时间:7.75min)，得到标题产物4.1mg。Referring to the preparation method of 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 5μm; 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.
1H NMR(400MHz,DMSO-d6):δ12.03(s,1H),8.33(d,J＝4.0Hz,1H),8.30(dd,J＝12.0,2.0Hz,1H),7.78(d,J＝8.0Hz,1H),7.54-7.36(m,6H),6.95(d,J＝4.0Hz,1H),6.76(s,1H),6.70-6.65(m,1H),6.61(d,J＝2.0Hz,1H),6.42(dd,J＝8.0,2.0Hz,1H),6.25(s,2H),3.84(s,3H),3.05(s,4H),2.53(s,4H),2.28(s,3H),2.02-1.96(m,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.03 (s, 1H), 8.33 (d, J = 4.0Hz, 1H), 8.30 (dd, J = 12.0, 2.0Hz, 1H), 7.78 (d ,J＝8.0Hz,1H),7.54-7.36(m,6H),6.95(d,J＝4.0Hz,1H),6.76(s,1H),6.70-6.65(m,1H),6.61(d, J＝2.0Hz,1H),6.42(dd,J＝8.0,2.0Hz,1H),6.25(s,2H),3.84(s,3H),3.05(s,4H),2.53(s,4H), 2.28(s,3H),2.02-1.96(m,3H).
MS(ESI+):665.0,(M+H).MS(ESI+):665.0,(M+H).
实施例29：
Example 29:
a)化合物29-1的制备a) Preparation of compound 29-1
参照实施例26的制备方法，将步骤c)中的26-2替换成3-甲氧基-4-(4-甲基哌嗪-1-基)苯胺即可，得到标题产物180mg。Referring to the preparation method of Example 26, replace 26-2 in step c) with 3-methoxy-4-(4-methylpiperazin-1-yl)aniline to obtain 180 mg of the title product.
MS(ESI+):593.2(M+H).MS(ESI+):593.2(M+H).
b)化合物29-2的制备b) Preparation of compound 29-2
参照实施例26的制备方法，将步骤d)中的26-3替换成29-1即可，得到标题产物160mg。Referring to the preparation method of Example 26, just replace 26-3 in step d) with 29-1 to obtain 160 mg of the title product.
MS(ESI+):563.2(M+H).MS(ESI+):563.2(M+H).
c)化合物29-3的制备c) Preparation of compound 29-3
参照实施例26的制备方法，将步骤e)中的26-4替换成29-2即可，得到标题产物20mg。Referring to the preparation method of Example 26, just replace 26-4 in step e) with 29-2 to obtain 20 mg of the title product.
MS(ESI+):815.2(M+H). MS(ESI+):815.2(M+H).
d)化合物例29的制备d) Preparation of compound example 29
参照实施例26的制备方法，将步骤f)中的26-5替换成29-3即可，所得粗品通过反相高效液相色谱法纯化(柱：XSelect CSH Fluoro Phenyl，30×150mm，填料粒径5μm；流动相A:水溶液(0.1％FA)，流动相B:乙腈；流速：60mL/min；梯度：5％B～50％B，8min；检测波长：220nm；目标化合物保留时间:6.25min)，得到标题产物6.9mg。Referring to the preparation method of 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 5μm; 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.
1H NMR(400MHz,DMSO-d6):δ12.03(s,1H),8.68(s,1H),8.33(d,J＝4.0Hz,1H),8.29(dd,J＝12.0,2.0Hz,1H),7.52-7.47(m,3H),7.42(q,J＝8.0Hz,3H),7.19(d,J＝2.0Hz,1H),7.10(dd,J＝8.0,2.0Hz,1H),6.96(d,J＝4.0Hz,1H),6.80(d,J＝8.0Hz,1H),6.68(s,1H),6.28(s,2H),3.72(s,3H),3.47-3.44(m,2H),3.34(d,J＝12.0Hz,2H),3.18-3.15(m,2H),2.88-2.80(m,5H),2.06-1.96(m,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.03 (s, 1H), 8.68 (s, 1H), 8.33 (d, J = 4.0Hz, 1H), 8.29 (dd, J = 12.0, 2.0Hz ,1H),7.52-7.47(m,3H),7.42(q,J＝8.0Hz,3H),7.19(d,J＝2.0Hz,1H),7.10(dd,J＝8.0,2.0Hz,1H) ,6.96(d,J＝4.0Hz,1H),6.80(d,J＝8.0Hz,1H),6.68(s,1H),6.28(s,2H),3.72(s,3H),3.47-3.44( m,2H),3.34(d,J=12.0Hz,2H),3.18-3.15(m,2H),2.88-2.80(m,5H),2.06-1.96(m,3H).
MS(ESI+):665.0(M+H).MS(ESI+):665.0(M+H).
实施例30：
Example 30:
a)化合物30-1的制备a) Preparation of compound 30-1
将乙腈(15mL)、碳酸钾(3.92g)、4-氟硝基苯(2g)、和1-(氧杂环丁烷-3-基)哌嗪(2.02g)置于封管中，于100摄氏度下反应过夜。待原料消失，向反应液中加入水(10mL)。用二氯甲烷(20mL)萃取，共三次。合并的有机相依次用正己烷(3mL)萃取，及无水硫酸钠干燥。过滤，滤液脱溶至干，得标题产物3.6g。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.
b)化合物30-2的制备b) Preparation of compound 30-2
参考实施例26的制备方法，将步骤b)中的26-1替换成30-1即可，得标题产物1.6g。Referring to the preparation method of Example 26, just replace 26-1 in step b) with 30-1 to obtain 1.6 g of the title product.
c)化合物30-3的制备c) Preparation of compound 30-3
参考实施例26的制备方法，将步骤c)中的26-2替换成30-2即可，得标题产物160mg。Referring to the preparation method of Example 26, just replace 26-2 in step c) with 30-2 to obtain 160 mg of the title product.
d)化合物30-4的制备d) Preparation of compound 30-4
参考实施例26的制备方法，将步骤d)中的26-3替换成30-3即可，得标题产物110mg。Referring to the preparation method of Example 26, just replace 26-3 in step d) with 30-3 to obtain 110 mg of the title product.
e)化合物30-5的制备e) Preparation of compound 30-5
参考实施例26的制备方法，将步骤e)中的26-4替换成30-4即可，得标题产物104mg。Referring to the preparation method of Example 26, just replace 26-4 in step e) with 30-4 to obtain 104 mg of the title product.
f)化合物例30的制备f) Preparation of compound example 30
参考实施例26的制备方法，将步骤f)中的26-5替换成30-5即可。将反应液冷至室温，浓缩，所得粗品采用反相高效液相色谱法纯化(柱：XBridge Prep OBD C18，30×150mm，填料粒径5μm；流动相A:水溶液(10mmol/L NH4HCO3)，流动相B:乙腈；流速：60mL/min；梯度：10％B～62％B，8min；检测波长：220nm；目标化合物保留时间:7.75min)得到标题产物11.7mg。Referring to the preparation method of Example 26, just replace 26-5 in step f) with 30-5. The reaction solution was cooled to room temperature and concentrated, and the crude product was purified by reversed-phase high performance liquid chromatography (column : ), mobile phase B: acetonitrile; flow rate: 60 mL/min; gradient: 10% B to 62% B, 8 min; detection wavelength: 220 nm; target compound retention time: 7.75 min) to obtain 11.7 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ12.05(s,1H),9.37(s,1H),8.40–8.23(m,2H),7.73–7.61(m,4H),7.54–7.47(m,3H),7.42(td,J＝8.7,5.8Hz,3H),6.96(d,J＝5.5Hz,1H),6.69(s,1H),6.38(s,2H),5.04(s,1H),3.84(t,J＝10.6Hz,1H),3.79–3.51(m,6H),3.45(t,J＝9.6Hz,2H),3.21(d,J＝7.2Hz,2H),3.03(s,1H),2.00(s,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.05(s,1H),9.37(s,1H),8.40–8.23(m,2H),7.73–7.61(m,4H),7.54–7.47( m,3H),7.42(td,J＝8.7,5.8Hz,3H),6.96(d,J＝5.5Hz,1H),6.69(s,1H),6.38(s,2H),5.04(s,1H ),3.84(t,J＝10.6Hz,1H),3.79–3.51(m,6H),3.45(t,J＝9.6Hz,2H),3.21(d,J＝7.2Hz,2H),3.03(s ,1H),2.00(s,3H).
MS(ESI+):677(M+H).MS(ESI+):677(M+H).
实施例31：
Example 31:
a)化合物31-1的制备a) Preparation of compound 31-1
参考实施例26的制备方法，将步骤c)中的26-2替换成6-(4-甲基哌嗪-1-基)吡啶-3-胺即可，得到标题产物240mg。Referring to the preparation method of Example 26, replace 26-2 in step c) with 6-(4-methylpiperazin-1-yl)pyridin-3-amine to obtain 240 mg of the title product.
b)–化合物31-2的制备b) – Preparation of compound 31-2
参考实施例26的制备方法，将步骤d)中的26-3替换成31-1即可，得到标题产物200mg。Referring to the preparation method of Example 26, just replace 26-3 in step d) with 31-1 to obtain 200 mg of the title product.
c)化合物31-3的制备c) Preparation of compound 31-3
参考实施例26的制备方法，将步骤e)中的26-4替换成31-2即可，得到标题产物50mg。Referring to the preparation method of Example 26, just replace 26-4 in step e) with 31-2 to obtain 50 mg of the title product.
d)化合物例31的制备d) Preparation of compound example 31
参考实施例26的制备方法，将步骤f)中的26-5替换成31-3即可。将反应液冷至室温，浓缩，所得粗品采用反相高效液相色谱法纯化(柱：XBridge Shield RP18 OBD，30×150mm，填料粒径5μm；流动相A:水溶液(10mmol/L NH4HCO3)，流动相B:乙腈；流速：60mL/min；梯度：20％B～60％B，10min；检测波长：220nm；目标化合物保留时间:9.53min)得到标题产物15.7mg。Referring to the preparation method of 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 μm; 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.
1H NMR(400MHz,DMSO-d6):δ12.03(s,1H),8.52(s,1H),8.33(d,J＝5.5Hz,1H),8.32–8.26(m,2H),7.76(dd,J＝9.1,2.8Hz,1H),7.52–7.38(m,6H),6.95(d,J＝5.6Hz,1H),6.74(d,J＝9.1Hz,1H),6.68(d,J＝1.0Hz,1H),6.23(s,2H),3.29(d,J＝10.2Hz,4H),2.38(t,J＝5.0Hz,4H),2.19(s,3H),2.02–1.96(m,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.03 (s, 1H), 8.52 (s, 1H), 8.33 (d, J = 5.5Hz, 1H), 8.32–8.26 (m, 2H), 7.76 (dd,J＝9.1,2.8Hz,1H),7.52–7.38(m,6H),6.95(d,J＝5.6Hz,1H),6.74(d,J＝9.1Hz,1H),6.68(d, J＝1.0Hz,1H),6.23(s,2H),3.29(d,J＝10.2Hz,4H),2.38(t,J＝5.0Hz,4H),2.19(s,3H),2.02–1.96( m,3H).
MS(ESI+):636(M+H).MS(ESI+):636(M+H).
实施例32：
Example 32:
a)化合物32-1的制备a) Preparation of compound 32-1
氮气保护下，将M6(280mg)及N,N-二甲基甲酰胺(6mL)置于25mL三口瓶中。0摄氏度下，向反应液中加入钠氢(49mg)，并搅拌十分钟。向反应液中滴加4-(溴甲基)恶烷(1.83g),滴毕后将反应液置于80摄氏度下反应7小时。将反应液冷却至室温，接着直接脱溶至干，柱层析(二氯甲烷/甲醇＝100/0-100/10(V/V))得到标题产物200mg。Under nitrogen protection, place M6 (280mg) and N,N-dimethylformamide (6mL) in a 25mL three-necked flask. At 0 degrees Celsius, sodium hydrogen (49 mg) was added to the reaction solution and stirred for ten minutes. 4-(Bromomethyl)oxane (1.83g) was added dropwise to the reaction solution. After the dripping was completed, the reaction solution was placed at 80 degrees Celsius for 7 hours. The reaction solution was cooled to room temperature, then directly desolvated to dryness, and column chromatography (dichloromethane/methanol=100/0-100/10 (V/V)) was performed to obtain 200 mg of the title product.
b)化合物32-2的制备b) Preparation of compound 32-2
参考实施例31的制备方法，将步骤c)中的M7替换成M12即可。得标题产物60mg。Referring to the preparation method of Example 31, just replace M7 in step c) with M12. 60 mg of the title product was obtained.
c)化合物例32制备c) Preparation of Compound Example 32
参考实施例26的制备方法，将步骤f)中的26-5替换成32-2即可。将反应液冷至室温，浓缩，所得粗品采用反相高效液相色谱法纯化(柱：Xselect CSH C18 OBD，30×150mm，填料粒径5μm；流动相A:水溶液(0.1％三氟乙酸)，流动相B:乙腈；流速：60mL/min；梯度：5％B～40％B，10min；检测波长：220nm；目标化合物保留时间:8.62min)得到标题产物19.1mg。Referring to the preparation method of 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 μm; 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.
1H NMR(400MHz,DMSO-d6):δ13.57(s,1H),9.47(s,1H),8.61(s,1H),8.40–8.27(m,3H),7.76–7.67(m,2H),7.48(dd,J＝8.9,2.2Hz,1H),7.42(d,J＝8.7Hz,2H),7.29(t,J＝8.8Hz,2H),7.17(d,J＝6.4Hz,1H),6.88(d,J＝8.9Hz,2H),6.26(s,2H),4.22(d,J＝7.4Hz,2H),3.85(d,J＝11.2Hz,2H),3.62(d,J＝13.0Hz,2H),3.50(s,2H),3.23(t,J＝11.7Hz,2H),3.16(d,J＝10.8Hz,2H),2.88–2.82(m,5H),2.13(s,1H),1.50(d,J＝12.5Hz,2H),1.39(d,J＝12.3Hz,2H). 1 H NMR (400MHz, DMSO-d 6 ): δ13.57(s,1H),9.47(s,1H),8.61(s,1H),8.40–8.27(m,3H),7.76–7.67(m, 2H),7.48(dd,J＝8.9,2.2Hz,1H),7.42(d,J＝8.7Hz,2H),7.29(t,J＝8.8Hz,2H),7.17(d,J＝6.4Hz, 1H),6.88(d,J＝8.9Hz,2H),6.26(s,2H),4.22(d,J＝7.4Hz,2H),3.85(d,J＝11.2Hz,2H),3.62(d, J＝13.0Hz,2H),3.50(s,2H),3.23(t,J＝11.7Hz,2H),3.16(d,J＝10.8Hz,2H),2.88–2.82(m,5H),2.13( s,1H),1.50(d,J＝12.5Hz,2H),1.39(d,J＝12.3Hz,2H).
MS(ESI+):719.1(M+H).MS(ESI+):719.1(M+H).
实施例33：

Example 33:

a)化合物33-1的制备a) Preparation of compound 33-1
参考实施例30的制备方法，将步骤a)中的1-(氧杂环丁烷-3-基)哌嗪替换成3-甲基-3,8-二氮杂双环[3.2.1]辛烷盐酸盐即可，得标题产物570mg。Referring to the preparation method of Example 30, 1-(oxetan-3-yl)piperazine in step a) is replaced with 3-methyl-3,8-diazabicyclo[3.2.1]octane alkane hydrochloride to obtain 570 mg of the title product.
b)化合物33-2的制备b) Preparation of compound 33-2
参考实施例30的制备方法，将步骤b)中的30-1替换成33-1即可，得标题产物400mg。Referring to the preparation method of Example 30, just replace 30-1 in step b) with 33-1 to obtain 400 mg of the title product.
c)化合物33-3的制备c) Preparation of compound 33-3
参考实施例30的制备方法，将步骤c)中的30-2替换成33-2即可，得标题产物200mg。Referring to the preparation method of Example 30, just replace 30-2 in step c) with 33-2 to obtain 200 mg of the title product.
d)化合物33-4的制备d) Preparation of compound 33-4
参考实施例30的制备方法，将步骤d)中的30-3替换成33-3即可，得标题产物170mg。Referring to the preparation method of Example 30, just replace 30-3 in step d) with 33-3 to obtain 170 mg of the title product.
e)化合物33-5的制备e) Preparation of compound 33-5
参考实施例30的制备方法，将步骤e)中的30-4替换成33-4即可，得标题产物50mg。Referring to the preparation method of Example 30, just replace 30-4 in step e) with 33-4 to obtain 50 mg of the title product.
f)化合物例33的制备f) Preparation of compound example 33
参考实施例30的制备方法，将步骤f)中的30-5替换成33-5即可。将反应液冷至室温，浓缩，所得粗品采用反相高效液相色谱法纯化(柱：Kinetex EVO prep C18，30×150mm，填料粒径5μm；流动相A:水溶液(10mmol/L NH4HCO3)，流动相B:乙腈；流速：60mL/min；梯度：25％B～60％B，7.88min；检测波长：220nm；目标化合物保留时间:7.75min)得到标题产物9.6mg。Referring to the preparation method of Example 30, 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 μm; 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.
1H NMR(400MHz,DMSO-d6):δ12.02(s,1H),δ10.31(s,1H),8.40(s,1H),8.33(d,J＝5.4Hz,1H),8.30(dd,J＝13.5,2.4Hz,1H),7.50(dt,J＝7.9,4.0Hz,2H),7.45(q,J＝2.3Hz,1H),7.44–7.37(m,2H),7.36(d,J＝3.2Hz,1H),7.33(s,1H),6.95(d,J＝5.5Hz,1H),6.73(s,1H),6.71(s,1H),6.68(s,1H),6.17(s,2H),4.14(s,2H),3.91–3.69(m,2H),3.33(s,2H),2.26(s,2H),1.99(s,3H),1.86(s,3H),1.16(q,J＝7.0Hz,2H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.02 (s, 1H), δ10.31 (s, 1H), 8.40 (s, 1H), 8.33 (d, J = 5.4Hz, 1H), 8.30 (dd,J＝13.5,2.4Hz,1H),7.50(dt,J＝7.9,4.0Hz,2H),7.45(q,J＝2.3Hz,1H),7.44–7.37(m,2H),7.36( d,J＝3.2Hz,1H),7.33(s,1H),6.95(d,J＝5.5Hz,1H),6.73(s,1H),6.71(s,1H),6.68(s,1H), 6.17(s,2H),4.14(s,2H),3.91–3.69(m,2H),3.33(s,2H),2.26(s,2H),1.99(s,3H),1.86(s,3H) ,1.16(q,J＝7.0Hz,2H).
MS(ESI+):660.7(M+H).MS(ESI+):660.7(M+H).
实施例34：
Example 34:
a)化合物34-1的制备a) Preparation of compound 34-1
依次向反应瓶中加入1-(4-氟苯基)-6-甲基-2-氧代-1,2-二氢吡啶-3-羧酸(150mg)，N,N-二甲基甲酰胺(5mL)，羰基二咪唑(210mg)，65℃下反应2h。冷却至室温，加入饱和氨水溶液(1mL)，室温反应1h。反应完毕加水20mL，乙酸乙酯萃取(5mL*3)，合并有机层，干燥后浓缩至干，得标题产物85mg。Add 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (150 mg) and N,N-dimethylmethyl to the reaction bottle in sequence. Amide (5mL), carbonyldiimidazole (210mg), react at 65°C for 2h. Cool to room temperature, add saturated ammonia solution (1 mL), and react at room temperature for 1 hour. After the reaction, add 20 mL of water, extract with ethyl acetate (5 mL*3), combine the organic layers, dry and concentrate to dryness to obtain 85 mg of the title product.
b)化合物例34的制备b) Preparation of compound example 34
依次向反应瓶中加入M4.cn(58mg)，34-1(55mg)，二氧六环(5mL)，碳酸铯(78mg)，碘化亚铜(2.3mg)，N,N’-二甲基乙胺(1.5mg)，氮气置换5次，400W微波160℃下反应2h。反应完毕反应液浓缩至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物7.0mg。 Add M4.cn (58mg), 34-1 (55mg), dioxane (5mL), cesium carbonate (78mg), copper iodide (2.3mg), and N,N'-dimethyl to the reaction bottle in sequence. Ethylamine (1.5 mg), replaced with nitrogen 5 times, reacted under 400W microwave at 160°C for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 7.0 mg of the title product.
MS(ESI+):636.3(M+H).MS(ESI+):636.3(M+H).
实施例35：
Example 35:
a)化合物35-1的制备a) Preparation of compound 35-1
依次向反应瓶中加入1-(4-氟苯基)-6-甲基-2-氧代-1,2-二氢吡啶-3-羧酸(200mg)，N,N-二甲基甲酰胺(5mL)，羰基二咪唑(262mg)，65℃下反应2h。冷却至室温，加入饱和氨水溶液(1mL)，室温反应1h。反应完毕加水20mL，乙酸乙酯萃取(5mL*3)，合并有机层，干燥后浓缩至干，得标题产物195mg。Add 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (200mg) and N,N-dimethylmethyl to the reaction bottle in sequence. Amide (5mL), carbonyldiimidazole (262mg), react at 65°C for 2h. Cool to room temperature, add saturated ammonia solution (1 mL), and react at room temperature for 1 hour. After the reaction, add 20 mL of water, extract with ethyl acetate (5 mL*3), combine the organic layers, dry and concentrate to dryness to obtain 195 mg of the title product.
b)–化合物例35的制备b) - Preparation of compound example 35
依次向反应瓶中加入M4(118mg)，35-1(60mg)，二氧六环(10mL)，碳酸铯(156mg)，碘化亚铜(3.5mg)，N,N’-二甲基乙胺(1.5mg)，氮气置换5次，400W微波160℃下反应2h。反应完毕反应液浓缩至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物5.2mg。Add M4 (118mg), 35-1 (60mg), dioxane (10mL), cesium carbonate (156mg), copper iodide (3.5mg), and N,N'-dimethylethane to the reaction flask in sequence. Amine (1.5 mg), replaced with nitrogen 5 times, reacted under 400W microwave at 160°C for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 5.2 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ12.14(s,1H),8.60(s,1H),8.52(d,J＝7.6Hz,1H),8.30(s,1H),8.01–7.94(m,1H),7.53–7.49(m,2H),7.46(d,J＝8.0Hz,4H),7.24(dd,J＝8.2,2.3Hz,1H),7.17(d,J＝2.3Hz,1H),6.90(d,J＝8.2Hz,1H),6.73(d,J＝7.7Hz,1H),6.24(s,2H),2.80(s,5H),2.09(s,3H),1.96–1.80(m,4H),1.69(br,4H),1.47(br,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.14 (s, 1H), 8.60 (s, 1H), 8.52 (d, J = 7.6Hz, 1H), 8.30 (s, 1H), 8.01–7.94 (m,1H),7.53–7.49(m,2H),7.46(d,J＝8.0Hz,4H),7.24(dd,J＝8.2,2.3Hz,1H),7.17(d,J＝2.3Hz, 1H),6.90(d,J＝8.2Hz,1H),6.73(d,J＝7.7Hz,1H),6.24(s,2H),2.80(s,5H),2.09(s,3H),1.96– 1.80(m,4H),1.69(br,4H),1.47(br,3H).
MS(ESI+):651.2(M+H).MS(ESI+):651.2(M+H).
实施例36：
Example 36:
a)化合物36-1的制备a) Preparation of compound 36-1
依次向反应瓶中加入环丁烷-1,1-二羧酸(144mg)，二氯甲烷(5mL)，羰基二咪唑(262mg)，4-氟苯胺(111mg)，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(570mg)，N,N-二异丙基乙胺(258mg)，室温下反应2h。反应完毕，反应液浓缩至干，得标题产物180mg。Add cyclobutane-1,1-dicarboxylic acid (144mg), dichloromethane (5mL), carbonyldiimidazole (262mg), 4-fluoroaniline (111mg), 2-(7-aza) to the reaction bottle in sequence. Benzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (570mg), N,N-diisopropylethylamine (258mg), react at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness to obtain 180 mg of the title product.
b)化合物36-2的制备b) Preparation of compound 36-2
依次向反应瓶中加入36-1(50mg)，N,N-二甲基甲酰胺(5mL)，羰基二咪唑(68mg)，65℃下反应2h。冷却至室温，加入饱和氨水溶液(1mL)，室温反应1h。反应完毕加水20mL，乙酸乙酯萃取(5mL*3)，合并有机层，干燥后浓缩至干，得标题产物45mg。Add 36-1 (50 mg), N,N-dimethylformamide (5 mL), and carbonyldiimidazole (68 mg) to the reaction bottle in sequence, and react at 65°C for 2 hours. Cool to room temperature, add saturated ammonia solution (1 mL), and react at room temperature for 1 hour. After the reaction, add 20 mL of water, extract with ethyl acetate (5 mL*3), combine the organic layers, dry and concentrate to dryness to obtain 45 mg of the title product.
c)化合物例36的制备 c) Preparation of compound example 36
依次向反应瓶中加入M4(33mg)，36-2(45mg)，二氧六环(5mL)，碳酸铯(91mg)，碘化亚铜(2.0mg)，N,N’-二甲基乙胺(0.88mg)，氮气置换5次，400W微波160℃下反应2h。反应完毕反应液浓缩至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物4.2mg。Add M4 (33 mg), 36-2 (45 mg), dioxane (5 mL), cesium carbonate (91 mg), copper iodide (2.0 mg), and N, N'-dimethylethane to the reaction flask in sequence. Amine (0.88 mg), replaced with nitrogen 5 times, reacted under 400W microwave at 160°C for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 4.2 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ10.05(s,1H),9.76(s,1H),8.59(s,1H),8.36(s,1H),7.86(d,J＝12.7Hz,1H),7.69(dd,J＝9.0,5.0Hz,2H),7.58(d,J＝9.0Hz,1H),7.44(t,J＝8.8Hz,2H),7.19–7.12(m,3H),6.88(d,J＝8.1Hz,1H),6.20(s,2H),2.82(s,5H),2.04-1.96(m,4H),194–1.81(m,6H),1.68(br,4H),1.52–1.42(m,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.05 (s, 1H), 9.76 (s, 1H), 8.59 (s, 1H), 8.36 (s, 1H), 7.86 (d, J = 12.7Hz ,1H),7.69(dd,J＝9.0,5.0Hz,2H),7.58(d,J＝9.0Hz,1H),7.44(t,J＝8.8Hz,2H),7.19–7.12(m,3H) ,6.88(d,J＝8.1Hz,1H),6.20(s,2H),2.82(s,5H),2.04-1.96(m,4H),194–1.81(m,6H),1.68(br,4H ),1.52–1.42(m,3H).
MS(ESI+):641.3(M+H).MS(ESI+):641.3(M+H).
实施例37：
Example 37:
a)化合物37-1的制备a) Preparation of compound 37-1
依次向反应瓶中加入1-甲基-2-氧代-1,2-二氢吡啶-3-羧酸(153mg)，N,N-二甲基甲酰胺(5mL)，羰基二咪唑(324mg)，65℃下反应2h。冷却至室温，加入饱和氨水溶液(1mL)，室温反应1h。反应完毕加水20mL，乙酸乙酯萃取(5mL*3)，合并有机层，干燥后浓缩至干，粗品柱层析纯化(二氯甲烷/甲醇＝5/1(V/V))，得标题产物135mg。Add 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (153mg), N,N-dimethylformamide (5mL), and carbonyldiimidazole (324mg) to the reaction bottle in sequence. ), react at 65°C for 2 hours. Cool to room temperature, add saturated ammonia solution (1 mL), and react at room temperature for 1 hour. After the reaction, add 20 mL of water, extract with ethyl acetate (5 mL*3), combine the organic layers, dry and concentrate to dryness, and purify the crude product by column chromatography (dichloromethane/methanol = 5/1 (V/V)) to obtain the title product 135mg.
b)化合物例37的制备b) Preparation of compound example 37
依次向反应瓶中加入M3(395mg)，37-1(135mg)，二氧六环(5mL)，碳酸铯(652mg)，碘化亚铜(15mg)，N,N’-二甲基乙胺(6.0mg)，氮气置换5次，400W微波160℃下反应2h。反应完毕反应液浓缩至干，柱层析纯化(二氯甲烷/甲醇＝5/1(V/V))，得标题产物20mg。Add M3 (395mg), 37-1 (135mg), dioxane (5mL), cesium carbonate (652mg), copper iodide (15mg), and N,N'-dimethylethylamine to the reaction bottle in sequence. (6.0 mg), replaced with nitrogen 5 times, and reacted under 400W microwave at 160°C for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness and purified by column chromatography (dichloromethane/methanol=5/1 (V/V)) to obtain 20 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ12.47(s,1H),8.50(s,1H),8.48(d,J＝2.2Hz,1H),8.32(s,1H),8.20(dd,J＝6.6,2.2Hz,1H),8.02–7.97(m,1H),7.48(s,1H),7.37(d,J＝9.0Hz,2H),6.81(d,J＝9.0Hz,2H),6.67–6.62(m,1H),6.24(s,2H),3.66(s,3H),2.98(t,J＝5.1Hz,4H),2.44(t,J＝4.9Hz,4H),2.21(s,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.47 (s, 1H), 8.50 (s, 1H), 8.48 (d, J = 2.2Hz, 1H), 8.32 (s, 1H), 8.20 (dd ,J＝6.6,2.2Hz,1H),8.02–7.97(m,1H),7.48(s,1H),7.37(d,J＝9.0Hz,2H),6.81(d,J＝9.0Hz,2H) ,6.67–6.62(m,1H),6.24(s,2H),3.66(s,3H),2.98(t,J＝5.1Hz,4H),2.44(t,J＝4.9Hz,4H),2.21( s,3H).
MS(ESI+):518.2(M+H).MS(ESI+):518.2(M+H).
实施例38：
Example 38:
a)化合物38-1的制备a) Preparation of compound 38-1
依次向反应瓶中加入4-乙氧基-1-(4-氟苯基)-2-氧代-1,2-二氢吡啶-3-羧酸(28mg)，N,N-二甲基甲酰胺(5mL)，羰基二咪唑(32mg)，65℃下反应2h。冷却至室温，加入饱和氨水溶液(1mL)，室温反应1h。反应完毕加水20mL，乙酸乙酯萃取(5mL*3)，合并有机层，干燥后浓缩至干，粗品柱层析纯化(二氯甲烷/甲醇＝5/1(V/V))，得标题产物15mg。Add 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (28mg) and N,N-dimethyl to the reaction bottle in sequence. Formamide (5mL), carbonyldiimidazole (32mg), react at 65°C for 2h. Cool to room temperature, add saturated ammonia solution (1 mL), and react at room temperature for 1 hour. After the reaction, add 20 mL of water, extract with ethyl acetate (5 mL*3), combine the organic layers, dry and concentrate to dryness, and purify the crude product by column chromatography (dichloromethane/methanol = 5/1 (V/V)) to obtain the title product 15mg.
b)–化合物例38的制备b) - Preparation of compound example 38
依次向反应瓶中加入M4(26mg)，38-1(15mg)，二氧六环(5mL)，碳酸铯(52mg)，碘化亚铜(1mg)，N,N’-二甲基 乙胺(0.7mg)，氮气置换5次，400W微波160℃下反应2h。反应完毕反应液浓缩至干，粗品柱层析纯化(二氯甲烷/甲醇＝5/1(V/V))，得标题产物0.72mg。Add M4 (26 mg), 38-1 (15 mg), dioxane (5 mL), cesium carbonate (52 mg), copper iodide (1 mg), and N, N'-dimethyl to the reaction flask in sequence. Ethylamine (0.7 mg), replaced with nitrogen 5 times, reacted under 400W microwave at 160°C for 2 hours. After the reaction, the reaction solution was concentrated to dryness, and the crude product was purified by column chromatography (dichloromethane/methanol=5/1 (V/V)) to obtain 0.72 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ10.64(s,1H),8.60(s,1H),7.91–7.82(m,2H),7.50–7.42(m,4H),7.37(t,J＝8.8Hz,2H),7.23(dd,J＝8.0,2.3Hz,1H),7.19(d,J＝2.4Hz,1H),6.89(d,J＝8.1Hz,1H),6.52(d,J＝7.9Hz,1H),6.23(s,2H),4.26(q,J＝7.0Hz,2H),2.90–2.73(m,4H),2.59(s,4H),2.18(t,J＝8.1Hz,1H),1.91(dt,J＝15.3,7.6Hz,4H),1.69(d,J＝5.6Hz,4H),1.30(t,J＝7.0Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ10.64(s,1H),8.60(s,1H),7.91–7.82(m,2H),7.50–7.42(m,4H),7.37(t, J＝8.8Hz,2H),7.23(dd,J＝8.0,2.3Hz,1H),7.19(d,J＝2.4Hz,1H),6.89(d,J＝8.1Hz,1H),6.52(d, J＝7.9Hz,1H),6.23(s,2H),4.26(q,J＝7.0Hz,2H),2.90–2.73(m,4H),2.59(s,4H),2.18(t,J＝8.1 Hz,1H),1.91(dt,J＝15.3,7.6Hz,4H),1.69(d,J＝5.6Hz,4H),1.30(t,J＝7.0Hz,3H).
MS(ESI+):681.3(M+H).MS(ESI+):681.3(M+H).
实施例39：
Example 39:
a)化合物39-1的制备a) Preparation of compound 39-1
依次向反应瓶中加入(1R，2R)-环丙烷-1,2-二甲酸二乙酯(376mg)，甲醇(8mL)，氢氧化钠(2M，4mL)，室温反应过夜。反应完毕，1M盐酸溶液调节pH至4-5，检验旋蒸除去溶剂，粗品用丙酮溶解，抽滤除去固体，母液浓缩至干，得标题产物反应液浓缩至干，得标题产物218mg。Add (1R, 2R)-cyclopropane-1,2-dicarboxylic acid diethyl ester (376 mg), methanol (8 mL), and sodium hydroxide (2 M, 4 mL) to the reaction bottle in sequence, and react at room temperature overnight. After the reaction is completed, adjust the pH to 4-5 with 1M hydrochloric acid solution, remove the solvent by rotary evaporation, dissolve the crude product in acetone, remove the solid by suction filtration, and concentrate the mother liquor to dryness to obtain the title product. The reaction solution is concentrated to dryness to obtain 218 mg of the title product.
b)化合物39-2的制备b) Preparation of compound 39-2
向反应瓶中依次加入39-1(200mg)，4-氟苯胺(85mg)，2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(760mg)，N,N-二异丙基乙胺(258mg)，室温下反应2h。反应完毕，减压旋蒸除去溶剂，粗品柱层析纯化(二氯甲烷/甲醇＝50/1(V/V))得标题产物125mg。Add 39-1 (200mg), 4-fluoroaniline (85mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea to the reaction bottle. Fluorophosphate (760mg), N,N-diisopropylethylamine (258mg), react at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/methanol=50/1 (V/V)) to obtain 125 mg of the title product.
c)化合物39-3的制备c) Preparation of compound 39-3
依次向反应瓶中加入39-2(100mg)，N,N-二甲基甲酰胺(5mL)，羰基二咪唑(145mg)，65℃下反应2h。冷却至室温，加入饱和氨水溶液(1mL)，室温反应1h。反应完毕加水20mL，乙酸乙酯萃取(5mL*3)，合并有机层，干燥后浓缩至干，得标题产物72mg。Add 39-2 (100 mg), N,N-dimethylformamide (5 mL), and carbonyldiimidazole (145 mg) to the reaction bottle in sequence, and react at 65°C for 2 hours. Cool to room temperature, add saturated ammonia solution (1 mL), and react at room temperature for 1 hour. After the reaction, add 20 mL of water, extract with ethyl acetate (5 mL*3), combine the organic layers, dry and concentrate to dryness to obtain 72 mg of the title product.
d)化合物例39的制备d) Preparation of compound example 39
依次向反应瓶中加入39-3(45mg)，M3(90mg)，二氧六环(5mL)，碳酸铯(130mg)，碘化亚铜(3.0mg)，N,N’-二甲基乙胺(1.0mg)，氮气置换5次，400W微波160℃下反应2h。反应完毕反应液浓缩至干，粗品柱层析纯化(二氯甲烷/甲醇＝5/1(V/V))，得标题产物7.2mg。Add 39-3 (45mg), M3 (90mg), dioxane (5mL), cesium carbonate (130mg), copper iodide (3.0mg), and N,N'-dimethylethane to the reaction flask in sequence. Amine (1.0 mg), replaced with nitrogen 5 times, reacted under 400W microwave at 160°C for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness, and the crude product was purified by column chromatography (dichloromethane/methanol=5/1 (V/V)) to obtain 7.2 mg of the title product.
MS(ESI+):588.3(M+H).MS(ESI+):588.3(M+H).
1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),10.02(s,1H),8.47(s,1H),7.81(dd,J＝12.9,2.2Hz,1H),7.67-7.59(m,2H),7.51–7.41(m,2H),7.41–7.31(m,2H),7.15(t,J＝8.9Hz,2H),6.80(d,J＝8.9Hz,2H),6.18(s,2H),3.01-2.93(m,4H),2.48-2.39(m,4H),2.21(s,3H),1.56–1.40(m,4H). 1 H NMR (400MHz, DMSO-d 6) δ10.44(s,1H),10.02(s,1H),8.47(s,1H),7.81(dd,J＝12.9,2.2Hz,1H),7.67- 7.59(m,2H),7.51–7.41(m,2H),7.41–7.31(m,2H),7.15(t,J＝8.9Hz,2H),6.80(d,J＝8.9Hz,2H),6.18 (s,2H),3.01-2.93(m,4H),2.48-2.39(m,4H),2.21(s,3H),1.56–1.40(m,4H).
实施例40：
Example 40:
a)化合物40-1的制备a) Preparation of compound 40-1
依次向反应瓶中加入4-(4-甲基哌嗪-1-基)苯胺(191mg)，N,N'-羰基二咪唑(178mg)，二氧六环(5mL)，室温下反应2h。反应完毕，减压旋蒸除去溶剂，得标题产物208mg。Add 4-(4-methylpiperazin-1-yl)aniline (191mg), N,N'-carbonyldiimidazole (178mg), and dioxane (5mL) to the reaction bottle in sequence, and react at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain 208 mg of the title product.
b)化合物40-2的制备b) Preparation of compound 40-2
0℃下，依次向反应瓶中加入N-(4-氨基苯基)乙酰胺(150mg)，盐酸溶液(2M，5mL)，亚硝酸钠(73mg)，在0-5℃下反应40min。滴加二氯化锡(380mg)，室温下反应2h。反应完毕，抽滤，滤饼用水洗涤，滤饼干燥后得标题产物142mg。At 0°C, add N-(4-aminophenyl)acetamide (150mg), hydrochloric acid solution (2M, 5mL), and sodium nitrite (73mg) to the reaction bottle in sequence, and react at 0-5°C for 40 minutes. 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.
c)化合物40-3的制备c) Preparation of compound 40-3
依次向反应瓶中加入40-2(142mg)，氰基胍(75mg)，水(10mL)，400W微波100℃下反应3h。反应完毕，减压旋蒸除去溶剂，粗品柱层析纯化(二氯甲烷/甲醇＝50/1(V/V))，得标题产物114mg。Add 40-2 (142 mg), cyanoguanidine (75 mg), and water (10 mL) to the reaction bottle in sequence, and react under 400W microwave at 100°C for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/methanol=50/1 (V/V)) to obtain 114 mg of the title product.
d)化合物40-4的制备d) Preparation of compound 40-4
依次向反应瓶中加入40-3(114mg)，甲苯(5mL)，40-1(58mg)，室温下反应3h。反应完毕，减压旋蒸除去溶剂，粗品柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物137mg。Add 40-3 (114 mg), toluene (5 mL), and 40-1 (58 mg) to the reaction bottle in sequence, and react at room temperature for 3 hours. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 137 mg of the title product.
e)化合物40-5的制备e) Preparation of compound 40-5
依次向反应瓶中加入40-4(114mg)，盐酸乙醇溶液(4M，5mL)，室温反应过夜。反应完毕，减压旋蒸除去溶剂，粗品用二氯甲烷溶解，饱和碳酸氢钠溶液洗涤，有机层干燥后浓缩，粗品柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物85mg。Add 40-4 (114mg) and hydrochloric acid ethanol solution (4M, 5mL) to the reaction bottle in sequence, and react at room temperature overnight. After the reaction is completed, the solvent is evaporated under reduced pressure, the crude product is dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, the organic layer is dried and concentrated, and the crude product is purified by column chromatography (dichloromethane/methanol=20/1 (V/V) ), 85 mg of the title product was obtained.
f)化合物例40的制备f) Preparation of compound example 40
依次向反应瓶中加入40-5(25mg)，M7(13mg)，三(二亚苄基丙酮)二钯(8mg)，2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三-I-丙基-11'-联苯(11mg)，碳酸铯(62mg)，二氧六环(5mL),氮气置换5次，100℃下反应5h。反应完毕，抽滤除去固体，母液减压浓缩除去溶剂，粗品柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物4.47mg。Add 40-5 (25mg), M7 (13mg), tris(dibenzylideneacetone)dipalladium (8mg), 2-(dicyclohexylphosphine)-3,6-dimethoxy- 2'-4'-6'-tri-I-propyl-11'-biphenyl (11 mg), cesium carbonate (62 mg), dioxane (5 mL), nitrogen replacement 5 times, reaction at 100°C for 5 hours. After the reaction was completed, the solid was removed by suction filtration, the mother liquor was concentrated under reduced pressure to remove the solvent, and the crude product was purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 4.47 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ11.87(s,1H),8.40(s,1H),8.28(d,J＝5.4Hz,1H),8.00–7.92(m,3H),7.52–7.40(m,8H),7.34(d,J＝8.7Hz,2H),6.90–6.87(m,2H),6.65(s,2H),3.06(t,J＝4.9Hz,4H),2.45(s,4H),2.22(s,3H),1.99(s,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ11.87 (s, 1H), 8.40 (s, 1H), 8.28 (d, J = 5.4Hz, 1H), 8.00–7.92 (m, 3H), 7.52 –7.40(m,8H),7.34(d,J＝8.7Hz,2H),6.90–6.87(m,2H),6.65(s,2H),3.06(t,J＝4.9Hz,4H),2.45( s,4H),2.22(s,3H),1.99(s,3H).
MS(ESI+):660.3(M+H).MS(ESI+):660.3(M+H).
实施例41：
Example 41:
a)化合物41-1的制备a) Preparation of compound 41-1
依次向反应瓶中加入M12(64mg)，M8(35mg)，正丁醇(5mL)，三氟乙酸(0.1mL)，400W微波120℃下反应3h。反应完毕，减压旋蒸除去溶剂，粗品柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物84mg。Add M12 (64 mg), M8 (35 mg), n-butanol (5 mL), and trifluoroacetic acid (0.1 mL) to the reaction bottle in sequence, and react under 400W microwave at 120°C for 3 hours. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 84 mg of the title product.
b)化合物例41的制备b) Preparation of compound example 41
依次向反应瓶中加入41-1(84mg)，三氟乙酸(5mL)，室温下反应过夜。反应完毕，减压旋蒸除去溶剂，粗品用二氯甲烷溶解，2M氢氧化钠溶液洗涤，分液，有机层干燥浓缩，粗品柱层析纯化(二氯甲烷/甲醇＝5/1(V/V))，得标题产物26.8mg。Add 41-1 (84 mg) and trifluoroacetic acid (5 mL) to the reaction bottle in sequence, and react at room temperature overnight. After the reaction is completed, the solvent is removed by rotary evaporation under reduced pressure. The crude product is dissolved in dichloromethane, washed with 2M sodium hydroxide solution, separated, the organic layer is dried and concentrated, and the crude product is purified by column chromatography (dichloromethane/methanol=5/1 (V/ V)), 26.8 mg of the title product was obtained.
1H NMR(400MHz,DMSO-d6):δ11.87(s,1H),8.73(d,J＝3.0Hz,1H),8.51(s,1H),8.36(d,J＝5.5Hz,1H),8.29(dd,J＝13.3,2.3Hz,1H),8.09(td,J＝8.4,3.1Hz,1H),7.79(dd,J＝8.7,4.1Hz,1H),7.48(dd,J＝8.8,2.3Hz,1H),7.45–7.35(m,3H),6.98(d,J＝5.5Hz,1H),6.87–6.79(m,2H),6.69(s,1H),6.20(s,2H),3.08–2.99(m,4H),2.64(s,4H),2.36(s,3H),1.99(s,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ11.87 (s, 1H), 8.73 (d, J = 3.0Hz, 1H), 8.51 (s, 1H), 8.36 (d, J = 5.5Hz, 1H ),8.29(dd,J＝13.3,2.3Hz,1H),8.09(td,J＝8.4,3.1Hz,1H),7.79(dd,J＝8.7,4.1Hz,1H),7.48(dd,J＝ 8.8,2.3Hz,1H),7.45–7.35(m,3H),6.98(d,J＝5.5Hz,1H),6.87–6.79(m,2H),6.69(s,1H),6.20(s,2H ),3.08–2.99(m,4H),2.64(s,4H),2.36(s,3H),1.99(s,3H).
MS(ESI+):636.3(M+H).MS(ESI+):636.3(M+H).
实施例42：
Example 42:
a)化合物42-1的制备a) Preparation of compound 42-1
依次向反应瓶中加入22-1(30mg)，M10(16mg)，正丁醇(3mL)，三氟乙酸(0.1mL)85℃下反应4h。反应完毕，减压旋蒸除去溶剂，粗品柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物35mg。Add 22-1 (30 mg), M10 (16 mg), n-butanol (3 mL), and trifluoroacetic acid (0.1 mL) to the reaction bottle in sequence and react at 85°C for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 35 mg of the title product.
b)化合物例42的制备b) Preparation of compound example 42
依次向反应瓶中加入42-1(35mg)，三氟乙酸(5mL)，室温下反应过夜。反应完毕，减压旋蒸除去溶剂，粗品用二氯甲烷溶解，2M氢氧化钠溶液洗涤，分液，有机层干燥浓缩，粗品柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物10.1mg。Add 42-1 (35 mg) and trifluoroacetic acid (5 mL) to the reaction bottle in sequence, and react at room temperature overnight. After the reaction is completed, the solvent is evaporated under reduced pressure, the crude product is dissolved in dichloromethane, washed with 2M sodium hydroxide solution, separated, the organic layer is dried and concentrated, and the crude product is purified by column chromatography (dichloromethane/methanol=10/1 (V/ V)), 10.1 mg of the title product was obtained.
1H NMR(400MHz,DMSO-d6):δ11.87(s,1H),8.73(d,J＝3.0Hz,1H),8.36(d,J＝5.5Hz,1H),8.31(d,J＝2.4Hz,1H),7.79(dd,J＝8.7,4.1Hz,2H),7.49(d,J＝8.8Hz,1H),7.41(t,J＝8.7Hz,2H),7.28(d,J＝7.9Hz,1H),7.23(s,2H),6.98(d,J＝5.5Hz,1H),6.70(s,1H),6.23(s,2H),3.13(s,4H),2.80–2.59(m,5H),2.20(s,2H),1.99(s,3H),1.85(s,4H),1.38(s,2H). 1 H NMR (400MHz, DMSO-d 6 ): δ11.87 (s, 1H), 8.73 (d, J = 3.0Hz, 1H), 8.36 (d, J = 5.5Hz, 1H), 8.31 (d, J ＝2.4Hz,1H),7.79(dd,J＝8.7,4.1Hz,2H),7.49(d,J＝8.8Hz,1H),7.41(t,J＝8.7Hz,2H),7.28(d,J ＝7.9Hz,1H),7.23(s,2H),6.98(d,J＝5.5Hz,1H),6.70(s,1H),6.23(s,2H),3.13(s,4H),2.80–2.59 (m,5H),2.20(s,2H),1.99(s,3H),1.85(s,4H),1.38(s,2H).
MS(ESI+):675.3(M+H).MS(ESI+):675.3(M+H).
实施例43：
Example 43:
a)化合物43-1的制备a) Preparation of compound 43-1
依次向反应瓶中加入44-1(21mg)，(溴甲基)环丙烷(4.5mg)，碳酸钾(7.5mg)，N,N-二甲基甲酰胺(5mL)，55℃下反应4h。反应完毕，减压旋蒸除去溶剂，粗品柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物26mg。Add 44-1 (21 mg), (bromomethyl)cyclopropane (4.5 mg), potassium carbonate (7.5 mg), and N, N-dimethylformamide (5 mL) to the reaction bottle in sequence, and react at 55°C for 4 hours. . After the reaction was completed, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 26 mg of the title product.
b)化合物例43的制备b) Preparation of compound example 43
依次向反应瓶中加入43-1(26mg)，三氟乙酸(5mL)，室温下反应过夜。反应完毕，减压旋蒸除去溶剂，粗品用二氯甲烷溶解，2M氢氧化钠溶液洗涤，分液，有机层干燥浓缩，粗品柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物3.25mg。Add 43-1 (26 mg) and trifluoroacetic acid (5 mL) to the reaction bottle in sequence, and react at room temperature overnight. After the reaction is completed, the solvent is evaporated under reduced pressure, the crude product is dissolved in dichloromethane, washed with 2M sodium hydroxide solution, separated, the organic layer is dried and concentrated, and the crude product is purified by column chromatography (dichloromethane/methanol=10/1 (V/ V)), 3.25 mg of the title product was obtained.
1H NMR(400MHz,DMSO-d6):δ13.59(s,1H),8.48(s,1H),8.39(s,1H),8.35–8.32(m,1H),7.76–7.72(m,2H),7.50–7.43(m,2H),7.40–7.35(m,2H),7.33–7.27(m,2H),7.21(d,J＝6.3Hz,2H),6.85–6.78(m,2H),6.20(s,2H),4.21(d,J＝7.1Hz,2H),2.98(t,J＝4.9Hz,4H),2.44(t,J＝5.0Hz,4H),2.21(s,3H),0.85(d,J＝7.0Hz,1H),0.58–0.51(m,4H). 1 H NMR (400MHz, DMSO-d 6 ): δ13.59(s,1H),8.48(s,1H),8.39(s,1H),8.35–8.32(m,1H),7.76–7.72(m, 2H),7.50–7.43(m,2H),7.40–7.35(m,2H),7.33–7.27(m,2H),7.21(d,J＝6.3Hz,2H),6.85–6.78(m,2H) ,6.20(s,2H),4.21(d,J＝7.1Hz,2H),2.98(t,J＝4.9Hz,4H),2.44(t,J＝5.0Hz,4H),2.21(s,3H) ,0.85(d,J＝7.0Hz,1H),0.58–0.51(m,4H).
MS(ESI+):675.3(M+H).MS(ESI+):675.3(M+H).
实施例44：
Example 44:
a)化合物44-1的制备a) Preparation of compound 44-1
依次向反应瓶中加入M12(45mg)，M6(48mg)，正丁醇(5mL)，三氟乙酸(0.1mL)，85℃下反应3h。反应完毕，减压旋蒸除去溶剂，粗品用二氯甲烷溶解，2M氢氧化钠溶液洗涤，分液，有机层干燥浓缩，粗品层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物47mg。 Add M12 (45 mg), M6 (48 mg), n-butanol (5 mL), and trifluoroacetic acid (0.1 mL) to the reaction bottle in sequence, and react at 85°C for 3 hours. After the reaction is completed, the solvent is evaporated under reduced pressure, the crude product is dissolved in dichloromethane, washed with 2M sodium hydroxide solution, separated, the organic layer is dried and concentrated, and the crude product is purified by chromatography (dichloromethane/methanol=20/1 (V/V )), 47 mg of the title product was obtained.
b)化合物44-2的制备b) Preparation of compound 44-2
依次向反应瓶中加入44-1(47mg)，溴代环戊烷(0.2mL)，N,N-二甲基甲酰胺(5mL)，碳酸钾(22mg)，85℃下反应3h。反应完毕，减压旋蒸除去溶剂，粗品层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物28mg。Add 44-1 (47 mg), bromocyclopentane (0.2 mL), N, N-dimethylformamide (5 mL), and potassium carbonate (22 mg) to the reaction bottle in sequence, and react at 85°C for 3 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the crude product was purified by chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 28 mg of the title product.
c)化合物例44的制备c) Preparation of compound example 44
依次向反应瓶中加入44-2(28mg)，三氟乙酸(5mL)，室温下反应过夜。反应完毕，减压旋蒸除去溶剂，粗品用二氯甲烷溶解，2M氢氧化钠溶液洗涤，分液，有机层干燥浓缩，粗品层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物2.46mg。Add 44-2 (28 mg) and trifluoroacetic acid (5 mL) to the reaction bottle in sequence, and react at room temperature overnight. After the reaction is completed, the solvent is evaporated under reduced pressure, the crude product is dissolved in dichloromethane, washed with 2M sodium hydroxide solution, separated, the organic layer is dried and concentrated, and the crude product is purified by chromatography (dichloromethane/methanol=20/1 (V/V )), 2.46 mg of the title product was obtained.
1H NMR(400MHz,DMSO-d6):δ13.66(s,1H),8.48(s,1H),8.36–8.31(m,2H),8.21(s,1H),8.14(s,1H),7.76–7.71(m,2H),7.49–7.42(m,2H),7.39–7.35(m,2H),7.31–7.26(m,3H),6.83–6.78(m,2H),6.20(s,2H),2.98(t,J＝4.9Hz,4H),2.45(d,J＝5.1Hz,4H),2.22(s,3H),2.00(dt,J＝13.3,7.3Hz,4H),1.86(d,J＝7.8Hz,4H). 1 H NMR (400MHz, DMSO-d 6 ): δ13.66(s,1H),8.48(s,1H),8.36–8.31(m,2H),8.21(s,1H),8.14(s,1H) ,7.76–7.71(m,2H),7.49–7.42(m,2H),7.39–7.35(m,2H),7.31–7.26(m,3H),6.83–6.78(m,2H),6.20(s, 2H),2.98(t,J＝4.9Hz,4H),2.45(d,J＝5.1Hz,4H),2.22(s,3H),2.00(dt,J＝13.3,7.3Hz,4H),1.86( d,J＝7.8Hz,4H).
MS(ESI+):689.3(M+H).MS(ESI+):689.3(M+H).
实施例45：
Example 45:
a)化合物45-1的制备a) Preparation of compound 45-1
依次向反应瓶中加入M6(274mg)，碘甲烷(170mg)，碳酸钾(276mg)，N,N-二甲基甲酰胺(5mL)，室温下反应4h。反应完毕，减压旋蒸除去溶剂，粗品柱层析纯化(二氯甲烷/甲醇＝50/1(V/V))，得标题产物245mg。Add M6 (274 mg), methyl iodide (170 mg), potassium carbonate (276 mg), and N, N-dimethylformamide (5 mL) to the reaction bottle in sequence, and react at room temperature for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/methanol=50/1 (V/V)) to obtain 245 mg of the title product.
b)化合物45-2的制备b) Preparation of compound 45-2
依次向反应瓶中加入M12(72mg)，45-1(50mg)，正丁醇(5mL)，三氟乙酸(0.1mL)，400W微波120℃反应2h。反应完毕，减压旋蒸除去溶剂，粗品柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物47mg。Add M12 (72 mg), 45-1 (50 mg), n-butanol (5 mL), and trifluoroacetic acid (0.1 mL) to the reaction bottle in sequence, and microwave at 400W for 2 hours at 120°C. After the reaction was completed, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 47 mg of the title product.
c)化合物例45的制备c) Preparation of compound example 45
依次向反应瓶中加入45-2(47mg)，三氟乙酸(5mL)，室温反应过夜。反应完毕，减压旋蒸除去溶剂，粗品用二氯甲烷溶解，1M氢氧化钠溶液洗涤，分层，有机层干燥后浓缩，粗品柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物16mg。Add 45-2 (47 mg) and trifluoroacetic acid (5 mL) to the reaction bottle in sequence, and react at room temperature overnight. After the reaction is completed, the solvent is removed by rotary evaporation under reduced pressure. The crude product is dissolved in dichloromethane, washed with 1M sodium hydroxide solution, separated into layers, the organic layer is dried and concentrated, and the crude product is purified by column chromatography (dichloromethane/methanol=10/1(V /V)), 16 mg of the title product was obtained.
1H NMR(400MHz,DMSO-d6):δ13.55(s,1H),8.48(s,1H),8.41–8.32(m,3H),7.78–7.70(m,2H),7.52–7.39(m,2H),7.41–7.33(m,2H),7.34–7.24(m,2H),7.01(d,J＝6.2Hz,1H),6.86–6.76(m,2H),6.20(s,2H),3.88(s,3H),2.98(t,J＝5.0Hz,4H),2.44(t,J＝5.0Hz,4H),2.21(s,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ13.55(s,1H),8.48(s,1H),8.41–8.32(m,3H),7.78–7.70(m,2H),7.52–7.39( m,2H),7.41–7.33(m,2H),7.34–7.24(m,2H),7.01(d,J＝6.2Hz,1H),6.86–6.76(m,2H),6.20(s,2H) ,3.88(s,3H),2.98(t,J＝5.0Hz,4H),2.44(t,J＝5.0Hz,4H),2.21(s,3H).
MS(ESI+):635.2(M+H).MS(ESI+):635.2(M+H).
实施例46：
Example 46:
a)化合物46-1的制备a) Preparation of compound 46-1
依次向反应瓶中加入M6(100mg)，N,N-二甲基甲酰胺(5mL)，碳酸钾(103mg)，溴化苄(74mg)，室温下反应4h。反应完毕，减压旋蒸除去溶剂，粗品柱层析纯化(二氯甲烷/甲醇＝50/1(V/V))，得标题产物84mg。Add M6 (100 mg), N,N-dimethylformamide (5 mL), potassium carbonate (103 mg), and benzyl bromide (74 mg) to the reaction bottle in sequence, and react at room temperature for 4 hours. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/methanol=50/1 (V/V)) to obtain 84 mg of the title product.
b)化合物46-2的制备b) Preparation of compound 46-2
依次向反应瓶中加入M12(100mg)，正丁醇(5mL)，46-1(84mg)，三氟乙酸(0.1mL)，400W微波120℃反应2h。反应完毕，减压旋蒸除去溶剂，粗品柱层析纯化(二氯甲烷/甲醇＝20/1(V/V))，得标题产物76mg。Add M12 (100 mg), n-butanol (5 mL), 46-1 (84 mg), and trifluoroacetic acid (0.1 mL) to the reaction bottle in sequence, and microwave at 400W for 2 hours at 120°C. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/methanol=20/1 (V/V)) to obtain 76 mg of the title product.
c)化合物例46的制备c) Preparation of compound example 46
向反应瓶中依次加入46-2(76mg)，三氟乙酸(5mL)，室温反应过夜。反应完毕，减压旋蒸除去溶剂，粗品用二氯甲烷溶解，1M氢氧化钠溶液洗涤两次。分液，有机层干燥后浓缩，粗品柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物24mg。Add 46-2 (76 mg) and trifluoroacetic acid (5 mL) to the reaction bottle in sequence, and react at room temperature overnight. After the reaction is completed, the solvent is removed by rotary evaporation under reduced pressure. The crude product is dissolved in dichloromethane and washed twice with 1M sodium hydroxide solution. The liquids were separated, the organic layer was dried and concentrated, and the crude product was purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 24 mg of the title product.
1H NMR(400MHz,DMSO-d6):δ13.50(s,1H),8.61(s,1H),8.48(s,1H),8.32(dd,J＝13.4,2.2Hz,1H),8.28–8.18(m,2H),7.86–7.72(m,2H),7.51–7.26(m,10H),6.92(d,J＝6.4Hz,1H),6.85–6.76(m,2H),6.19(s,2H),5.60(s,2H),3.03–2.93(m,4H),2.44(t,J＝5.0Hz,4H),2.21(s,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ13.50 (s, 1H), 8.61 (s, 1H), 8.48 (s, 1H), 8.32 (dd, J = 13.4, 2.2Hz, 1H), 8.28 –8.18(m,2H),7.86–7.72(m,2H),7.51–7.26(m,10H),6.92(d,J＝6.4Hz,1H),6.85–6.76(m,2H),6.19(s ,2H),5.60(s,2H),3.03–2.93(m,4H),2.44(t,J＝5.0Hz,4H),2.21(s,3H).
MS(ESI+):711.3(M+H).MS(ESI+):711.3(M+H).
实施例47:
Example 47:
a)化合物47-1的制备a) Preparation of compound 47-1
将1-苄基-4-甲基-1,4-氮杂膦4-氧化物(1.35g)、甲酸铵(0.76g)和10％Pd/C(0.14g)放入8mL密封管中。在氮气保护下分别将甲醇(15mL)加入封管中，接着于50℃搅拌过夜。过滤所得混合物，滤饼用甲醇(3x2mL)洗涤。滤液减压浓缩，得标题产物650mg。Place 1-benzyl-4-methyl-1,4-azaphosphine 4-oxide (1.35g), ammonium formate (0.76g) and 10% Pd/C (0.14g) into an 8 mL sealed tube. Methanol (15 mL) was added to the sealed tubes under nitrogen protection, and then stirred at 50° C. overnight. The resulting mixture was filtered and the filter cake was washed with methanol (3x2 mL). The filtrate was concentrated under reduced pressure to obtain 650 mg of the title product.
b)化合物47-2的制备b) Preparation of compound 47-2
将47-1(250mg)，4-氟硝基苯(317.96mg)，碳酸钾(285.48mg)及二甲基亚砜(5mL)置于25mL单口瓶中，并于室温下搅拌过夜。将反应液直接脱溶，制砂，柱层析(二氯甲烷/甲醇＝100/0-100/10(V/V))得标题产物400mg。47-1 (250 mg), 4-fluoronitrobenzene (317.96 mg), potassium carbonate (285.48 mg) and dimethyl sulfoxide (5 mL) were placed in a 25 mL single-neck bottle, and stirred at room temperature overnight. The reaction solution was directly desolvated, sand was made, and column chromatography (dichloromethane/methanol=100/0-100/10 (V/V)) was performed to obtain 400 mg of the title product.
c)化合物47-3的制备c) Preparation of compound 47-3
参照实施例26的制备方法，将步骤b)中的26-1替换成47-2，得到标题产物289mg。Referring to the preparation method of Example 26, 26-1 in step b) was replaced with 47-2 to obtain 289 mg of the title product.
d)化合物47-4的制备d) Preparation of compound 47-4
参照实施例26的制备方法，将步骤c)中的26-2替换成47-3，得到标题产物408mg。Referring to the preparation method of Example 26, 26-2 in step c) was replaced with 47-3 to obtain 408 mg of the title product.
e)化合物47-5的制备e) Preparation of compound 47-5
参照实施例26的制备方法，将步骤d)中的26-3替换成47-4，得到标题产物178mg。Referring to the preparation method of Example 26, 26-3 in step d) was replaced with 47-4 to obtain 178 mg of the title product.
f)化合物47-6的制备f) Preparation of compound 47-6
参照实施例26的制备方法，将步骤e)中的26-4替换成47-5，得到标题产物90mg。Referring to the preparation method of Example 26, 26-4 in step e) was replaced with 47-5 to obtain 90 mg of the title product.
g)化合物例47的制备g) Preparation of compound example 47
参照实施例26的制备方法，将步骤f)中的26-5替换成47-6。所得粗品通过反相高效液相色谱法纯化(柱：XBridge Prep OBD C18，30×150mm，填料粒径5μm；流动相A:水溶液(10mmol/L HCOOH)，流动相B:乙腈；流速：60mL/min；梯度：10％B～62％B，8min；检测波长：220nm；目标化合物保留时间:7.75min)得到标题产物17.5mg。 Referring to the preparation method of 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 μm; 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.
1H NMR(400MHz,DMSO-d6):δ12.03(s,1H),8.48(s,1H),8.38–8.25(m,2H),7.59–7.28(m,8H),6.95(d,J＝5.5Hz,1H),6.89–6.78(m,2H),6.68(s,1H),6.19(s,2H),3.70(ddt,J＝20.3,14.1,5.0Hz,2H),3.28–3.18(m,2H),1.99(s,3H),1.91–1.63(m,4H),1.47(d,J＝12.9Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.03(s,1H),8.48(s,1H),8.38–8.25(m,2H),7.59–7.28(m,8H),6.95(d, J＝5.5Hz,1H),6.89–6.78(m,2H),6.68(s,1H),6.19(s,2H),3.70(ddt,J＝20.3,14.1,5.0Hz,2H),3.28–3.18 (m,2H),1.99(s,3H),1.91–1.63(m,4H),1.47(d,J＝12.9Hz,3H).
MS(ESI+):668.3(M+H).MS(ESI+):668.3(M+H).
实施例48：
Example 48:
a)化合物48-1的制备a) Preparation of compound 48-1
将M12(100mg)，21-1(59.47mg)，三(二亚苄基丙酮)二钯(17.19mg)，1,1'-联萘-2,2'-双二苯膦(23.38mg mg)，叔丁醇钾(42.14mg mg)溶于甲苯(2mL)，并用氮气保护，80℃搅拌2h。将反应液冷至室温，直接脱溶，制砂，柱层析(二氯甲烷/甲醇＝100/0-100/10(V/V))得到标题产物104mg。M12 (100mg), 21-1 (59.47mg), tris(dibenzylideneacetone)dipalladium (17.19mg), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (23.38mg mg ), potassium tert-butoxide (42.14 mg mg) was dissolved in toluene (2 mL), protected with nitrogen, and stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature, directly desolvated, sand was made, and column chromatography (dichloromethane/methanol=100/0-100/10 (V/V)) was performed to obtain 104 mg of the title product.
b)化合物例48的制备b) Preparation of compound example 48
将48-1(30mg)、三氟乙酸(2mL)与正丁醇(2mL)置于10mL单口瓶中。反应液在氮气保护下于120摄氏度反应2小时。接着将反应液脱溶至干。所得粗品采用反相高效液相色谱法纯化(柱：Xselect CSH C18 OBD柱，30×150mm填料粒径5μm；流动相A:水溶液(10mmol/L HCOOH)，流动相B:乙腈；流速：60mL/min；梯度：10％B～62％B，8min；检测波长：220nm；目标化合物保留时间:7.75min)，得到了标题产物34.1mg。Place 48-1 (30 mg), trifluoroacetic acid (2 mL) and n-butanol (2 mL) in a 10 mL single-mouth bottle. The reaction solution was reacted at 120 degrees Celsius for 2 hours under nitrogen protection. The reaction solution was then desolvated to dryness. The crude product obtained was purified by reversed-phase high performance liquid chromatography (column: Xselect CSH C18 OBD column, 30×150mm packing particle size 5μm; 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.
1H NMR(400MHz,DMSO-d6):δ13.69(s,1H),8.51(s,1H),8.40–8.30(m,2H),8.26(s,1H),7.77–7.68(m,2H),7.50–7.41(m,2H),7.38(dd,J＝9.4,7.3Hz,2H),7.33–7.21(m,3H),6.85–6.77(m,2H),6.21(s,2H),5.04(p,J＝6.7Hz,1H),3.00(t,J＝4.8Hz,4H),2.50(d,J＝1.9Hz,4H),2.27(s,3H),1.53(d,J＝6.5Hz,6H). 1 H NMR (400MHz, DMSO-d 6 ): δ13.69(s,1H),8.51(s,1H),8.40–8.30(m,2H),8.26(s,1H),7.77–7.68(m, 2H),7.50–7.41(m,2H),7.38(dd,J＝9.4,7.3Hz,2H),7.33–7.21(m,3H),6.85–6.77(m,2H),6.21(s,2H) ,5.04(p,J＝6.7Hz,1H),3.00(t,J＝4.8Hz,4H),2.50(d,J＝1.9Hz,4H),2.27(s,3H),1.53(d,J＝ 6.5Hz,6H).
MS(ESI+):663.3(M+H).MS(ESI+):663.3(M+H).
实施例49：

Example 49:

a)化合物49-1的制备a) Preparation of compound 49-1
氮气保护下，将4-氟硝基苯(800mg)，2-甲基-2,5-二氮杂双环[2.2.1]庚烷二氢溴酸盐(954mg)，N,N-二异丙基乙胺(3.663g)及乙腈(10mL)置于25mL单口瓶中，并于100℃下反应过夜。反应液脱溶至干，柱层析纯化(甲醇/二氯甲烷＝1/10(V/V))，得标题产物600mg。Under nitrogen protection, 4-fluoronitrobenzene (800mg), 2-methyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide (954mg), N,N-diiso Propylethylamine (3.663g) and acetonitrile (10mL) were placed in a 25mL single-neck bottle, and reacted at 100°C overnight. The reaction solution was desolvated to dryness and purified by column chromatography (methanol/dichloromethane=1/10 (V/V)) to obtain 600 mg of the title product.
b)化合物49-2的制备b) Preparation of compound 49-2
参考实施例24的制备方法，将步骤b)中的24-1替换成59-1，得到标题产物400mg。Referring to the preparation method of Example 24, 24-1 in step b) was replaced with 59-1 to obtain 400 mg of the title product.
c)化合物49-3的制备c) Preparation of compound 49-3
参考实施例22的制备方法，将步骤a)中的(7S)-7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]环烯-2-胺替换成4-(5-甲基-2,5-二氮杂双环[2.2.1]庚-2-基)苯胺，得到标题产物130mg。Referring to the preparation method of Example 22, (7S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]cycloene- The 2-amine was replaced with 4-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)aniline to obtain 130 mg of the title product.
d)化合物49-4的制备d) Preparation of compound 49-4
参考实施例22的制备方法，将步骤b)中的22-1替换成49-3，得到标题产物80mg。Referring to the preparation method of Example 22, 22-1 in step b) was replaced with 49-3 to obtain 80 mg of the title product.
e)化合物49-5的制备e) Preparation of compound 49-5
参考实施例22的制备方法，将步骤c)中的22-2替换成49-4，得到标题产物70mg。Referring to the preparation method of Example 22, 22-2 in step c) was replaced with 49-4 to obtain 70 mg of the title product.
f)化合物例49的制备f) Preparation of compound example 49
将49-5(45mg)与三氟乙酸(4mL)置于10mL单口瓶中。反应液在氮气保护下于室温下反应2天。接着将反应液脱溶至干。所得粗品采用反相高效液相色谱法纯化(柱：XBridge Shield RP18 OBD柱，30×150mm填料粒径5μm；流动相A:水溶液(10mmol/L NH4HCO3)，流动相B:乙腈；流速：60mL/min；梯度：25％B～57％B，10min；检测波长：220nm；目标化合物保留时间:9.37min)，得到了标题产物3.6mg。Place 49-5 (45 mg) and trifluoroacetic acid (4 mL) in a 10 mL single-neck bottle. The reaction solution was reacted under nitrogen protection at room temperature for 2 days. The reaction solution was then desolvated to dryness. The crude product obtained was purified by reversed-phase high performance liquid chromatography (column: XBridge Shield RP18 OBD column, 30×150mm packing particle size 5 μm; mobile phase A: aqueous solution (10mmol/L NH 4 HCO 3 ), mobile phase B: acetonitrile; flow rate : 60mL/min; gradient: 25% B ~ 57% B, 10 min; detection wavelength: 220 nm; target compound retention time: 9.37 min), and 3.6 mg of the title product was obtained.
1H NMR(400MHz,DMSO-d6):δ12.02(s,1H),8.33(d,J＝5.5Hz,1H),8.31–8.24(m,2H),7.54–7.48(m,2H),7.47–7.35(m,4H),7.36–7.29(m,2H),6.95(d,J＝5.5Hz,1H),6.68(s,1H),6.51–6.41(m,2H),6.14(s,2H),4.26–4.15(m,1H),3.53(s,1H),3.31(s,1H),3.08(d,J＝9.3Hz,1H),2.79(d,J＝9.7Hz,1H),2.67(p,J＝1.9Hz,1H),2.39–2.26(m,3H),1.99(s,3H),1.90(d,J＝9.2Hz,1H),1.79(d,J＝9.5Hz,1H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.02 (s, 1H), 8.33 (d, J = 5.5Hz, 1H), 8.31–8.24 (m, 2H), 7.54–7.48 (m, 2H) ,7.47–7.35(m,4H),7.36–7.29(m,2H),6.95(d,J＝5.5Hz,1H),6.68(s,1H),6.51–6.41(m,2H),6.14(s ,2H),4.26–4.15(m,1H),3.53(s,1H),3.31(s,1H),3.08(d,J＝9.3Hz,1H),2.79(d,J＝9.7Hz,1H) ,2.67(p,J＝1.9Hz,1H),2.39–2.26(m,3H),1.99(s,3H),1.90(d,J＝9.2Hz,1H),1.79(d,J＝9.5Hz, 1H).
MS(ESI+):647.3(M+H).MS(ESI+):647.3(M+H).
实施例50：

Example 50:

a)化合物50-1的制备a) Preparation of compound 50-1
将5-硝基-1H-苯并[d]咪唑(0.99g)，三苯基膦(2.26g)，(S)-(1,4-二恶烷-2-基)甲醇(600mg)及四氢呋喃(20mL)置于100mL三口瓶中。氮气保护，将反应液内温降至0摄氏度并搅拌。接着向反应液中滴加偶氮二甲酸二乙酯(1.75g)。滴毕后，将反应液置于室温，反应过夜。反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇20/1(V/V))，得标题产物840mg。5-Nitro-1H-benzo[d]imidazole (0.99g), triphenylphosphine (2.26g), (S)-(1,4-dioxan-2-yl)methanol (600mg) and Tetrahydrofuran (20mL) was placed in a 100mL three-necked flask. Under nitrogen protection, lower the internal temperature of the reaction solution to 0 degrees Celsius and stir. Then, diethyl azodicarboxylate (1.75 g) was added dropwise to the reaction liquid. After the dripping is completed, the reaction solution is placed at room temperature and allowed to react overnight. The reaction solution was desolvated to dryness and purified by column chromatography (dichloromethane/methanol 20/1 (V/V)) to obtain 840 mg of the title product.
b)化合物50-2的制备b) Preparation of compound 50-2
参考实施例24的制备方法，将步骤b)的24-1替换成50-1即可，得标题产物670mg。Referring to the preparation method of Example 24, just replace 24-1 in step b) with 50-1 to obtain 670 mg of the title product.
c)化合物50-3的制备c) Preparation of compound 50-3
参考实施例22的制备方法，将步骤a)中的(7S)-7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]环烯-2-胺替换成(S)-1-((1,4-二恶烷-2-基)甲基)-1H-苯并[d]咪唑-5-胺即可，得标题产物450mg。Referring to the preparation method of Example 22, (7S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]cycloene- The 2-amine can be replaced with (S)-1-((1,4-dioxan-2-yl)methyl)-1H-benzo[d]imidazole-5-amine to obtain 450 mg of the title product.
d)化合物50-4的制备d) Preparation of compound 50-4
参考实施例22的制备方法，将步骤b)中的22-1替换成50-3即可，得标题产物360mg。Referring to the preparation method of Example 22, just replace 22-1 in step b) with 50-3 to obtain 360 mg of the title product.
e)化合物50-5的制备e) Preparation of compound 50-5
参考实施例22的制备方法，将步骤c)中的22-2替换成50-4即可，得标题产物300mg。Referring to the preparation method of Example 22, just replace 22-2 in step c) with 50-4 to obtain 300 mg of the title product.
f)化合物例50的制备f) Preparation of compound example 50
将50-5(300mg)、正丁醇(3mL)与三氟乙酸(3mL)置于10mL单口瓶中。反应液在氮气保护下于120摄氏度反应1小时。接着将反应液脱溶至干。所得粗品(250mg粗品)采用反相高效液相色谱法纯化(柱：Xselect CSH C18 OBD柱，30×150mm填料粒径5μm；流动相A:0.05％三氟乙酸水溶液，流动相B:乙腈；流速：60mL/min；梯度：10％B～40％B，10min；检测波长：220nm；目标化合物保留时间:9.18min)，得到混合物100mg(实施例50和实施例53)。实施例50通过反相手性高效液相色谱法纯化(柱：CHIRALPAK IA C18柱，2×25mm填料粒径5μm；流动相A:甲基叔丁基醚(0.1％二乙胺)，流动相B:乙醇；流速：20mL/min；梯度：50％B～50％B，22min；检测波长：256/220nm；目标化合物保留时间:9.08min)，得标题化合物29.3mg。Place 50-5 (300 mg), n-butanol (3 mL) and trifluoroacetic acid (3 mL) in a 10 mL single-mouth bottle. The reaction solution was reacted at 120 degrees Celsius for 1 hour under nitrogen protection. The reaction solution was then desolvated to dryness. 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 μm; 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 μm; 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.
1H NMR(400MHz,DMSO-d6):δ12.04(s,1H),8.67(s,1H),8.37–8.27(m,2H),7.96(s,2H),7.50(ddd,J＝11.2,5.6,2.2Hz,3H),7.43(ddd,J＝12.0,8.7,3.0Hz,4H),7.28(dd,J＝8.8,2.1Hz,1H),6.95(d,J＝5.5Hz,1H),6.69–6.65(m,1H),6.22(s,2H),4.26–4.10(m,2H),3.89–3.75(m,2H),3.75–3.68(m,1H),3.64–3.57(m,1H),3.50(td,J＝11.1,2.3Hz,1H),3.42(td,J＝11.0,2.4Hz,1H),3.21(dd,J＝11.3,9.7Hz,1H),2.03–1.94(m,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.04 (s, 1H), 8.67 (s, 1H), 8.37–8.27 (m, 2H), 7.96 (s, 2H), 7.50 (ddd, J＝ 11.2,5.6,2.2Hz,3H),7.43(ddd,J＝12.0,8.7,3.0Hz,4H),7.28(dd,J＝8.8,2.1Hz,1H),6.95(d,J＝5.5Hz,1H ),6.69–6.65(m,1H),6.22(s,2H),4.26–4.10(m,2H),3.89–3.75(m,2H),3.75–3.68(m,1H),3.64–3.57(m ,1H),3.50(td,J＝11.1,2.3Hz,1H),3.42(td,J＝11.0,2.4Hz,1H),3.21(dd,J＝11.3,9.7Hz,1H),2.03–1.94( m,3H).
MS(ESI+):677.2(M+H).MS(ESI+):677.2(M+H).
实施例51:
Example 51:
a)化合物51-1的制备a) Preparation of compound 51-1
氮气保护下，将(2S)-1,4-二恶烷-2-基甲醇(1g)、对甲苯磺酰氯(1.94g)和1，2-二氯乙烷(20mL)置于100mL三口瓶中，并于室温下搅拌。接着向反应液中加入三乙胺(1.71g)，接着于50摄氏度下反应4小时。反应液脱溶至干，柱层析纯化(石油醚/乙酸乙酯＝1/1(V/V))，得标题产物1.6g。Under nitrogen protection, place (2S)-1,4-dioxan-2-ylmethanol (1g), p-toluenesulfonyl chloride (1.94g) and 1,2-dichloroethane (20mL) in a 100mL three-necked flask medium and stir at room temperature. Then, triethylamine (1.71g) was added to the reaction solution, and the reaction was carried out at 50 degrees Celsius for 4 hours. The reaction solution was desolvated to dryness and purified by column chromatography (petroleum ether/ethyl acetate = 1/1 (V/V)) to obtain 1.6 g of the title product.
b)化合物51-2的制备b) Preparation of compound 51-2
氮气保护下，将钠氢(0.21g)加入到-10摄氏度的5-硝基吲哚(0.95g)的N,N-二甲基甲酰胺(30mL)的溶液中。向反应液中加入51-1(1.59g)，接着将反应加热至60摄氏度下反应2小时。待原料消失，将水(100mL)缓慢加入到0摄氏度的反应液。用乙酸乙酯(100mL)萃取，共三次。有机相脱溶至干，所得粗品通过柱层析纯化(石油醚/乙酸乙酯＝1/2(V/V))，得标题产物1.1g。Under nitrogen protection, sodium hydrogen (0.21g) was added to a solution of 5-nitroindole (0.95g) in N,N-dimethylformamide (30mL) at -10 degrees Celsius. 51-1 (1.59g) was added to the reaction solution, and then the reaction was heated to 60 degrees Celsius for 2 hours. When the raw materials disappear, water (100 mL) is slowly added to the reaction solution at 0 degrees Celsius. Extract with ethyl acetate (100 mL) three times. The organic phase was desolvated to dryness, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate = 1/2 (V/V)) to obtain 1.1 g of the title product.
c)化合物51-3的制备c) Preparation of compound 51-3
将10％钯碳(0.15g)加入到51-2(1.1g)的甲醇(30mL)中。反应液加氢至4Mpa，然后于50摄氏度下反应2小时。待原料反应完全，反应液于室温下过滤，滤饼用甲醇(30mL)洗涤。有机相脱溶至干，得标题产物800mg。10% palladium on carbon (0.15 g) was added to 51-2 (1.1 g) in methanol (30 mL). The reaction solution was hydrogenated to 4Mpa, and then reacted at 50 degrees Celsius for 2 hours. After the reaction of the raw materials is complete, the reaction solution is filtered at room temperature, and the filter cake is washed with methanol (30 mL). The organic phase was desolvated to dryness to obtain 800 mg of the title product.
d)化合物51-4的制备d) Preparation of compound 51-4
将M12-2(2g)、正丁醇(10mL)与三氟乙酸(20mL)置于100mL单口瓶中。反应液在氮气保护下于120摄氏度反应1小时。接着将反应液脱溶，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物1.1g。Place M12-2 (2g), n-butanol (10mL) and trifluoroacetic acid (20mL) in a 100mL single-mouth bottle. The reaction solution was reacted at 120 degrees Celsius for 1 hour under nitrogen protection. The reaction solution was then desolvated and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 1.1 g of the title product.
e)化合物51-5的制备e) Preparation of compound 51-5
参考实施例22的制备方法，将步骤a)中的(7S)-7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]环烯-2-胺替换成3-溴-1-(2-氟-4-硝基苯基)-1H-1,2,4-***-5-胺即可，得标题产物110mg。Referring to the preparation method of Example 22, (7S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]cycloene- The 2-amine can be replaced by 3-bromo-1-(2-fluoro-4-nitrophenyl)-1H-1,2,4-triazole-5-amine to obtain 110 mg of the title product.
f)化合物51-6的制备f) Preparation of compound 51-6
参考实施例22的制备方法，将步骤b)中的22-1替换成51-5即可，得标题产物60mg。Referring to the preparation method of Example 22, just replace 22-1 in step b) with 51-5 to obtain 60 mg of the title product.
g)化合物例51的制备g) Preparation of compound example 51
参考实施例22的制备方法，将步骤c)中的22-2替换成51-6即可。接着将反应液脱溶至干。所得粗品采用反 相高效液相色谱法纯化(柱：XBridge Prep Phenyl OBD柱，19×150mm填料粒径5μm；流动相A:10mmol/L碳酸氢铵水溶液，流动相B:乙腈；流速：60mL/min；梯度：20％B～75％B，10min；检测波长：220nm；目标化合物保留时间:8.92min)，得到了标题产物10mg。Referring to the preparation method of Example 22, just replace 22-2 in step c) with 51-6. The reaction solution was then desolvated to dryness. The crude product obtained was reacted with Phase high performance liquid chromatography purification (column: XBridge Prep Phenyl OBD column, 19×150mm packing particle size 5μm; mobile phase A: 10mmol/L ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile; flow rate: 60mL/min; gradient: 20% B ~ 75% B, 10 min; detection wavelength: 220 nm; target compound retention time: 8.92 min), and 10 mg of the title product was obtained.
1H NMR(400MHz,DMSO-d6):δ12.03(s,1H),8.44(s,1H),8.38–8.25(m,2H),7.77(d,J＝2.0Hz,1H),7.50(ddd,J＝9.5,5.8,3.6Hz,3H),7.42(td,J＝8.7,2.5Hz,3H),7.29(d,J＝8.9Hz,1H),7.18(dd,J＝10.2,2.6Hz,2H),6.95(d,J＝5.5Hz,1H),6.70–6.64(m,1H),6.24(d,J＝3.1Hz,1H),6.17(s,2H),4.16–4.02(m,2H),3.80(qd,J＝6.7,3.6Hz,1H),3.75–3.64(m,2H),3.60(d,J＝10.7Hz,1H),3.50(td,J＝11.2,2.3Hz,1H),3.42(dd,J＝11.0,2.4Hz,1H),3.20(dd,J＝11.4,9.8Hz,1H),2.08–1.89(m,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.03 (s, 1H), 8.44 (s, 1H), 8.38–8.25 (m, 2H), 7.77 (d, J = 2.0Hz, 1H), 7.50 (ddd,J＝9.5,5.8,3.6Hz,3H),7.42(td,J＝8.7,2.5Hz,3H),7.29(d,J＝8.9Hz,1H),7.18(dd,J＝10.2,2.6 Hz,2H),6.95(d,J＝5.5Hz,1H),6.70–6.64(m,1H),6.24(d,J＝3.1Hz,1H),6.17(s,2H),4.16–4.02(m ,2H),3.80(qd,J＝6.7,3.6Hz,1H),3.75–3.64(m,2H),3.60(d,J＝10.7Hz,1H),3.50(td,J＝11.2,2.3Hz, 1H), 3.42 (dd, J＝11.0, 2.4Hz, 1H), 3.20 (dd, J＝11.4, 9.8Hz, 1H), 2.08–1.89 (m, 3H).
MS(ESI+):676.3(M+H).MS(ESI+):676.3(M+H).
实施例52：
Example 52:
a)化合物52-1的制备a) Preparation of compound 52-1
将3-(4-氟苯基)-1-异丙基-2,4-二氧嘧啶-5-羧酸(60.40mg)、N,N-二异丙基乙基胺(44.52mg)和N,N-二甲基甲酰胺(1mL)置于10mL单口瓶。室温反应10分钟后，向反应液中加入24-4(100mg)。接着将反应液置于50摄氏度下反应2小时。反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物100mg。3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxopyrimidine-5-carboxylic acid (60.40 mg), N,N-diisopropylethylamine (44.52 mg) and N,N-dimethylformamide (1 mL) was placed in a 10 mL single-neck bottle. After reacting at room temperature for 10 minutes, 24-4 (100 mg) was added to the reaction solution. Then the reaction solution was placed at 50 degrees Celsius for 2 hours. The reaction solution was desolvated to dryness and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 100 mg of the title product.
b)化合物例52的制备b) Preparation of compound example 52
将52-1(100mg)、正丁醇(3mL)与三氟乙酸(3mL)置于10mL单口瓶中。反应液在氮气保护下于120摄氏度反应5小时。接着将反应液脱溶至干。所得粗品采用反相高效液相色谱法纯化(柱：Kinetex EVO C18柱，21.2×150mm填料粒径5μm；流动相A:10mmol/L碳酸氢铵溶液，流动相B:乙腈；流速：60mL/min；梯度：20％B～50％B，10min；检测波长：220nm；目标化合物保留时间:10.15min)，得到标题产物7.1mg。Place 52-1 (100 mg), n-butanol (3 mL) and trifluoroacetic acid (3 mL) in a 10 mL single-neck bottle. The reaction solution was reacted at 120 degrees Celsius for 5 hours under nitrogen protection. The reaction solution was then desolvated to dryness. 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 μm; 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.
1H NMR(400MHz,DMSO-d6):δ11.08(s,1H),8.69(s,1H),8.58(s,1H),8.05–7.84(m,1H),7.51–7.39(m,4H),7.36(t,J＝8.8Hz,2H),7.16(d,J＝2.6Hz,1H),7.05(dd,J＝8.7,2.5Hz,1H),6.79(d,J＝8.7Hz,1H),6.26(s,2H),4.78(p,J＝6.8Hz,1H),3.87–3.74(m,4H),3.69(s,4H),3.65–3.54(m,2H),3.52–3.43(m,1H),3.42–3.35(m,1H),1.43(d,J＝6.8Hz,6H). 1 H NMR (400MHz, DMSO-d 6 ): δ11.08(s,1H),8.69(s,1H),8.58(s,1H),8.05–7.84(m,1H),7.51–7.39(m, 4H),7.36(t,J＝8.8Hz,2H),7.16(d,J＝2.6Hz,1H),7.05(dd,J＝8.7,2.5Hz,1H),6.79(d,J＝8.7Hz, 1H),6.26(s,2H),4.78(p,J＝6.8Hz,1H),3.87–3.74(m,4H),3.69(s,4H),3.65–3.54(m,2H),3.52–3.43 (m,1H),3.42–3.35(m,1H),1.43(d,J＝6.8Hz,6H).
MS(ESI+):705.2(M+H).MS(ESI+):705.2(M+H).
实施例53：

Example 53:

a)化合物53-1的制备a) Preparation of compound 53-1
将5-硝基-1H-苯并[d]咪唑(0.99g)，三苯基膦(2.26g)，(S)-(1,4-二恶烷-2-基)甲醇(600mg)及四氢呋喃(20mL)置于100mL三口瓶中。氮气保护，将反应液内温降至0摄氏度并搅拌。接着向反应液中滴加偶氮二甲酸二乙酯(1.75g)。滴毕后，将反应液置于室温，反应过夜。反应液脱溶至干，柱层析纯化(二氯甲烷/甲醇20/1(V/V))，得标题产物840mg。5-Nitro-1H-benzo[d]imidazole (0.99g), triphenylphosphine (2.26g), (S)-(1,4-dioxan-2-yl)methanol (600mg) and Tetrahydrofuran (20mL) was placed in a 100mL three-necked flask. Under nitrogen protection, lower the internal temperature of the reaction solution to 0 degrees Celsius and stir. Then, diethyl azodicarboxylate (1.75 g) was added dropwise to the reaction liquid. After the dripping is completed, the reaction solution is placed at room temperature and allowed to react overnight. The reaction solution was desolvated to dryness and purified by column chromatography (dichloromethane/methanol 20/1 (V/V)) to obtain 840 mg of the title product.
b)化合物53-2的制备b) Preparation of compound 53-2
参考实施例24的制备方法，将步骤b)的24-1替换成53-1即可，得标题产物670mg。Referring to the preparation method of Example 24, just replace 24-1 in step b) with 53-1 to obtain 670 mg of the title product.
c)化合物53-3的制备c) Preparation of compound 53-3
参考实施例22的制备方法，将步骤a)中的(7S)-7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]环烯-2-胺替换成(S)-1-((1,4-二恶烷-2-基)甲基)-1H-苯并[d]咪唑-6-胺即可，得标题产物450mg。Referring to the preparation method of Example 22, (7S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]cycloene- The 2-amine can be replaced with (S)-1-((1,4-dioxan-2-yl)methyl)-1H-benzo[d]imidazole-6-amine to obtain 450 mg of the title product.
d)化合物53-4的制备d) Preparation of compound 53-4
参考实施例22的制备方法，将步骤b)中的22-1替换成53-3即可，得标题产物360mg。Referring to the preparation method of Example 22, just replace 22-1 in step b) with 53-3 to obtain 360 mg of the title product.
e)化合物53-5的制备e) Preparation of compound 53-5
参考实施例22的制备方法，将步骤c)中的22-2替换成53-4即可，得标题产物300mg。Referring to the preparation method of Example 22, just replace 22-2 in step c) with 53-4 to obtain 300 mg of the title product.
f)化合物例53的制备f) Preparation of compound example 53
将53-5(300mg)、正丁醇(3mL)与三氟乙酸(3mL)置于10mL单口瓶中。反应液在氮气保护下于120摄氏度反应1小时。接着将反应液脱溶至干。所得粗品(250mg粗品)采用反相高效液相色谱法纯化(柱：Xselect CSH C18 OBD柱，30×150mm填料粒径5μm；流动相A:0.05％三氟乙酸水溶液，流动相B:乙腈；流速：60mL/min；梯度：10％B～40％B，10min；检测波长：220nm；目标化合物保留时间:9.18min)，得到混合物100mg(实施例50和实施例53)。实施例53通过反相手性高效液相色谱法纯化(柱：CHIRALPAK IA C18柱，2×25mm填料粒径5μm；流动相A:甲基叔丁基醚(0.1％二乙胺)，流动相B:乙醇；流速：20mL/min；梯度：50％B～50％B，22min；检测波长：256/220nm；目标化合物保留时间:19.32min)，得标题化合物36mg。Place 53-5 (300 mg), n-butanol (3 mL) and trifluoroacetic acid (3 mL) in a 10 mL single-mouth bottle. The reaction solution was reacted at 120 degrees Celsius for 1 hour under nitrogen protection. The reaction solution was then desolvated to dryness. 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 μm; 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 μm; 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.
1H NMR(400MHz,DMSO-d6)δ12.02(s,1H),8.81(s,1H),8.33(d,J＝5.5Hz,1H),8.33–8.28(m,1H),7.92(s,1H),7.83(d,J＝2.0Hz,1H),7.54–7.38(m,7H),7.28(dd,J＝8.8,2.0Hz,1H),6.95(d,J＝5.5Hz,1H),6.67(d,J＝1.1Hz,1H),6.25(s,2H),4.17–4.06(m,2H),3.88(dddd,J＝9.6,7.1,4.6,2.6Hz,1H),3.71(ddd,J＝12.2,6.4,2.5Hz,2H),3.63–3.57(m,1H),3.49(td,J＝11.2,2.4Hz,1H),3.39(td,J＝11.0,2.5Hz,1H),3.25(dd,J＝11.6,9.7Hz,1H),2.02–1.94(m,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.02 (s, 1H), 8.81 (s, 1H), 8.33 (d, J = 5.5Hz, 1H), 8.33–8.28 (m, 1H), 7.92 ( s,1H),7.83(d,J＝2.0Hz,1H),7.54–7.38(m,7H),7.28(dd,J＝8.8,2.0Hz,1H),6.95(d,J＝5.5Hz,1H ),6.67(d,J＝1.1Hz,1H),6.25(s,2H),4.17–4.06(m,2H),3.88(dddd,J＝9.6,7.1,4.6,2.6Hz,1H),3.71( ddd,J＝12.2,6.4,2.5Hz,2H),3.63–3.57(m,1H),3.49(td,J＝11.2,2.4Hz,1H),3.39(td,J＝11.0,2.5Hz,1H) ,3.25(dd,J＝11.6,9.7Hz,1H),2.02–1.94(m,3H).
MS(ESI+):677.2(M+H).MS(ESI+):677.2(M+H).
实施例54：
Example 54:
a)化合物54-1的制备a) Preparation of compound 54-1
参考实施例50的操作，将步骤a)中的5-硝基-1H-苯并[d]咪唑替换成6-硝基-2H-吲唑即可，得标题产物800mg。Referring to the operation of 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.
b)化合物54-2的制备b) Preparation of compound 54-2
参考实施例24的制备方法，将步骤b)的24-1替换成50-1即可，得标题产物720mg。Referring to the preparation method of Example 24, just replace 24-1 in step b) with 50-1 to obtain 720 mg of the title product.
c)化合物54-3的制备c) Preparation of compound 54-3
参考实施例22的制备方法，将步骤a)中的(7S)-7-(吡咯烷-1-基)-6,7,8,9-四氢-5H-苯并[7]环烯-2-胺替换成(S)-2-((1,4-二恶烷-2-基)甲基)-2H-吲唑-6-胺即可，得标题产物280mg。Referring to the preparation method of Example 22, (7S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]cycloene- The 2-amine can be replaced with (S)-2-((1,4-dioxan-2-yl)methyl)-2H-indazole-6-amine to obtain 280 mg of the title product.
d)化合物54-4的制备d) Preparation of compound 54-4
将54-3(280mg)和甲醇(10mL)置于50mL高压釜中。将反应釜加氢至4Mpa，反应液于50摄氏度下反应5小时。待反应液冷却至室温，反应液过滤，滤液脱溶至干，得标题产物190mg。54-3 (280 mg) and methanol (10 mL) were placed in a 50 mL autoclave. The reaction kettle was hydrogenated to 4Mpa, and the reaction solution was reacted at 50 degrees Celsius for 5 hours. After the reaction solution was cooled to room temperature, the reaction solution was filtered, and the filtrate was desolvated to dryness to obtain 190 mg of the title product.
e)化合物54-5的制备e) Preparation of compound 54-5
将54-4(170mg)、8-氯-2-(4-氟苯基)-3-甲基-2,7-萘啶-1-酮(102.5mg)、三氟乙酸(0.5mL)和正丁醇(5mL)置于25mL单口瓶中。反应液于80摄氏度下反应2小时。待原料完全转化，反应液脱溶，柱层析纯化(二氯甲烷/甲醇＝10/1(V/V))，得标题产物100mg。54-4 (170 mg), 8-chloro-2-(4-fluorophenyl)-3-methyl-2,7-naphthyridin-1-one (102.5 mg), trifluoroacetic acid (0.5 mL) and n- Butanol (5 mL) was placed in a 25 mL single-neck bottle. The reaction solution was reacted at 80 degrees Celsius for 2 hours. After the raw materials are completely converted, the reaction solution is desolvated and purified by column chromatography (dichloromethane/methanol=10/1 (V/V)) to obtain 100 mg of the title product.
f)化合物54的制备f) Preparation of compound 54
将54-5(100mg)、正丁醇(3mL)与三氟乙酸(3mL)置于10mL单口瓶中。反应液在氮气保护下于120摄氏度反应1小时。接着将反应液脱溶至干。所得粗品采用反相高效液相色谱法纯化(柱：Kinetex EVO prep C18柱，30×150mm填料粒径5μm；流动相A:水(10mmol/L碳酸氢铵)，流动相B:乙腈；流速：60mL/min；梯度：20％B～60％B，10min；检测波长：220nm；目标化合物保留时间:9.68min)，得标题产物16.4mg。Place 54-5 (100 mg), n-butanol (3 mL) and trifluoroacetic acid (3 mL) in a 10 mL single-mouth bottle. The reaction solution was reacted at 120 degrees Celsius for 1 hour under nitrogen protection. The reaction solution was then desolvated to dryness. 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 μm; 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.
1H NMR(400MHz,DMSO-d6):δ12.03(s,1H),9.06(s,1H),8.38–8.26(m,2H),7.84(d,J＝1.9Hz,2H),7.50(ddd,J＝8.2,5.5,2.9Hz,4H),7.47–7.36(m,3H),7.17(dd,J＝8.8,1.7Hz,1H),6.95(d,J＝5.6Hz,1H),6.68(d,J＝1.0Hz,1H),6.30(s,2H),4.30–4.13(m,2H),3.92(qd,J＝7.3,6.1,2.4Hz,1H),3.72–3.62(m,2H),3.58(d,J＝11.0Hz,1H),3.49(td,J＝11.3,10.9,2.3Hz,1H),3.38(dd,J＝10.7,2.5Hz,1H),3.34(s,1H),2.00(d,J＝0.9Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ): δ12.03 (s, 1H), 9.06 (s, 1H), 8.38–8.26 (m, 2H), 7.84 (d, J = 1.9Hz, 2H), 7.50 (ddd,J＝8.2,5.5,2.9Hz,4H),7.47–7.36(m,3H),7.17(dd,J＝8.8,1.7Hz,1H),6.95(d,J＝5.6Hz,1H), 6.68(d,J＝1.0Hz,1H),6.30(s,2H),4.30–4.13(m,2H),3.92(qd,J＝7.3,6.1,2.4Hz,1H),3.72–3.62(m, 2H),3.58(d,J＝11.0Hz,1H),3.49(td,J＝11.3,10.9,2.3Hz,1H),3.38(dd,J＝10.7,2.5Hz,1H),3.34(s,1H ),2.00(d,J＝0.9Hz,3H).
MS(ESI+):677.3(M+H).MS(ESI+):677.3(M+H).
生物活性测试Bioactivity testing
活性测试中所使用的阳性药BGB-324购买自湖北科乐精细化工有限公司。The positive drug BGB-324 used in the activity test was purchased from Hubei Kele Fine Chemical Co., Ltd.
1.TAM家族激酶(AXL、Mer、Tyro3)抑制剂筛选实验1. TAM family kinase (AXL, Mer, Tyro3) inhibitor screening experiment
1)AXL、Mer、Tyro3激酶(Carna，08-107，08-108，08-109)配制及加样：使用1×酶缓冲液(5×酶缓冲液(Cisbio，62EZBFDD)，5mM MgCl2，1mM DTT，15.62nM SEB，H2O)将AXL稀释到工作液浓度0.027ng/μL (1.67×，终浓度0.016ng/uL)；Mer稀释到1.25ng/μL(1.67×，终浓度0.75ng/uL)；Tyro3稀释到0.017ng/μL(1.67×，终浓度0.01ng/uL)，使用BioTek(MultiFlo FX)自动分液仪，加入白色384孔板(Greiner)中，每孔加入6μL，空白对照组加入等体积的1×酶缓冲液；1) Preparation and sample addition of AXL, Mer, Tyr3 kinase (Carna, 08-107, 08-108, 08-109): use 1× enzyme buffer (5× enzyme buffer (Cisbio, 62EZBFDD), 5mM MgCl 2 , 1mM DTT, 15.62nM SEB, H 2 O) Dilute AXL to a working solution concentration of 0.027ng/μL (1.67×, final concentration 0.016ng/uL); Mer was diluted to 1.25ng/μL (1.67×, final concentration 0.75ng/uL); Tyro3 was diluted to 0.017ng/μL (1.67×, final concentration 0.01ng/uL), Use BioTek (MultiFlo FX) automatic liquid dispenser, add it to a white 384-well plate (Greiner), add 6 μL to each well, and add an equal volume of 1× enzyme buffer to the blank control group;
2)化合物配制及加样：使用DMSO将实施例中制备的化合物从10mM稀释到100μM，使用化合物滴定仪(Tecan，D300e)进行滴定，滴定仪自动喷入每孔所需浓度，起始浓度为1μM，1/2log梯度稀释，共8个浓度，2500rpm离心30s，室温孵育15min；2) Compound preparation and sample addition: Use DMSO to dilute the compound prepared in the example from 10mM to 100μM, use a compound titrator (Tecan, D300e) for titration, and the titrator automatically sprays the required concentration into each well. The starting concentration is 1μM, 1/2log gradient dilution, a total of 8 concentrations, centrifuged at 2500rpm for 30s, and incubated at room temperature for 15min;
3)ATP、底物配制及加样：使用1×酶缓冲液依次配制AXL、Mer和Tyro3激酶反应的ATP(Sigma，A7699)工作液：从10mM依次稀释到75μM(5×，终浓度15μM)、50μM(5×，终浓度10μM)、2μM(5×，终浓度0.4μM)，使用1×酶缓冲液将底物TK Substrate-biotin(Cisbio，61TK0BLC)从500μM稀释到5μM(5×，终浓度为1μM)；分别将ATP同底物等体积混合，使用BioTek自动分液仪4μL加入每孔；2500rpm离心30s，25℃分别反应45min(AXL激酶反应时间)，45min(Mer激酶反应时间)，30min(Tyro3激酶反应时间)；3) 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 75μM (5×, final concentration 15μM) , 50 μM (5×, final concentration 10 μM), 2 μM (5×, final concentration 0.4 μM), use 1× enzyme buffer to dilute the substrate TK Substrate-biotin (Cisbio, 61TK0BLC) from 500 μM to 5 μM (5×, final concentration The concentration is 1 μM); mix ATP and substrate in equal volumes, and add 4 μL 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);
4)检测试剂配制及加样：使用检测缓冲液(Cisbio，62SDBRDF)将Streptavidin-XL665(Cisbio，610SAXLG)从16.67μM稀释到250nM(4×，终浓度为62.5nM)；使用检测缓冲液将TK Antibody-Cryptate(Cisbio)从100×稀释到1×；将Streptavidin-XL665同TK Antibody-Cryptate等体积混合，使用BioTek自动分液仪10μL加入每孔，2500rpm离心30s，25℃反应1小时。反应结束后，使用多功能读板仪(PerkinElmer,Envision)的HTRF模块进行检测；4) Detection reagent preparation and sample addition: Use detection buffer (Cisbio, 62SDBRDF) to dilute Streptavidin-XL665 (Cisbio, 610SAXLG) from 16.67μM 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 μL 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;
5)数据计算5)Data calculation
Ratio＝(Signal 665nm/Signal 615nm)*10,000Ratio＝(Signal 665nm/Signal 615nm)*10,000
抑制率(％)＝(Ratio阴性对照组—Ratio化合物组)/(Ratio阴性对照组—Ratio空白对照组)×100％Inhibition rate (%) = (Ratio negative control group - Ratio compound group)/(Ratio negative control group - Ratio blank control group) × 100%
使用GraphPad Prism 5软件拟合量效曲线：log(化合物浓度)vs.抑制率-Variable slope，得到化合物对酶抑制的IC50值。Use GraphPad Prism 5 software to fit the dose-effect curve: log (compound concentration) vs. inhibition rate-Variable slope, and obtain the IC 50 value of the compound for enzyme inhibition.
6)实验结果6)Experimental results
实验结果如表1所示，阳性药BGB-324AXL抑制活性IC50：2.2nM，Mer抑制活性IC50：6.6nM，Tyro3抑制活性IC50：93.4nM。从表1的实验结果可以看出，本申请制备得到的实施例化合物均对AXL激酶活性具有良好的抑制效果，其抑制活性IC50值均低于700nM，或低于100nM或10nM，甚至低于1nM。The experimental results are shown in Table 1. The inhibitory activity IC 50 of the positive drug BGB-324AXL: 2.2nM, the inhibitory activity IC 50 of Mer: 6.6nM, and the inhibitory activity IC 50 of Tyro3: 93.4nM. It can be seen from the experimental results in Table 1 that the example compounds prepared in this application all have good inhibitory effects on AXL kinase activity, and their inhibitory activity IC50 values are all lower than 700nM, or lower than 100nM or 10nM, or even lower than 1nM.
表1.化合物对AXL、Mer和Tyro3活性抑制IC50数据

Table 1. IC 50 data of compounds inhibiting AXL, Mer and Tyro3 activities

注：“-”表示未测试。Note: "-" means not tested.
2.化合物对Ba/F3、Ba/F3-TEL-AXL细胞增殖抑制实验2. Experiment on the inhibition of proliferation of Ba/F3 and Ba/F3-TEL-AXL cells by compounds
Ba/F3(鼠源B淋巴细胞，培养基：RPMI1640+10％FBS+IL-3(10ng/ml))，购自北京协和细胞资源中心。Ba/F3-TEL-AXL(稳定表达TEL-AXL的鼠源B淋巴细胞，培养基：RPMI1640+10％FBS)，来源于南京正大天晴制药有限公司自建，细胞置于37℃,5％CO2的培养箱中培养。取对数生长期的上述细胞以3000个/孔/150μL的细胞密度铺在96孔板中，并同时设置空白对照组。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 μL, and a blank control group was set at the same time.
将待测化合物溶解在二甲基亚砜(DMSO)中以制备10mM的储液，并置于-80℃冰箱中长期保存。细胞铺板24h后，用DMSO稀释10mM的化合物储液得到5mM的溶液，使用化合物滴定仪(Tecan，D300e)进行滴定， 滴定仪自动喷入每孔所需浓度，起始浓度为10μM，3倍梯度，共10个浓度(DMSO终浓度为0.3％,v/v)，每个浓度设置两个复孔。加药处理72h后，每孔加入50μL的(购自Promega)，按照说明书的操作流程在Envision(PerkinElmer)上测定荧光信号，使用GraphPad Prism 5软件log(inhibitor)vs.response-Variable slope拟合量效曲线，得到化合物对细胞增殖抑制的IC50值。抑制率计算公式：
Dissolve the compound to be tested in dimethyl sulfoxide (DMSO) to prepare a 10mM stock solution and place it in a -80°C refrigerator for long-term storage. After 24 hours of cell plating, the 10mM compound stock solution was diluted with DMSO to obtain a 5mM solution, and titrated using a compound titrator (Tecan, D300e). The titrator automatically sprays the required concentration into each well. The starting concentration is 10 μM, 3-fold gradient, a total of 10 concentrations (final concentration of DMSO is 0.3%, v/v), and two duplicate holes are set for each concentration. After 72 hours of drug treatment, 50 μL of (purchased from Promega), measure the fluorescence signal on Envision (PerkinElmer) according to the operating procedures of the instructions, use GraphPad Prism 5 software log (inhibitor) vs. response-Variable slope to fit the dose-effect curve, and obtain the IC of the compound's inhibition of cell proliferation. 50 value. Inhibition rate calculation formula:
其中：in:
受试物信号值：细胞+培养基+化合物组荧光信号均值；Test substance signal value: mean fluorescence signal value of cells + culture medium + compound group;
空白组信号值：培养基组(含0.3％DMSO)荧光信号均值；Signal value of blank group: mean fluorescence signal value of culture medium group (containing 0.3% DMSO);
阴性对照组信号值：细胞+培养基组(含0.3％DMSO)荧光信号均值。Signal value of negative control group: mean fluorescence signal value of cells + culture medium group (containing 0.3% DMSO).
2.实验结果2.Experimental results
实验结果如表2所示，从表2的实验结果可以看出，本申请示例性化合物均对稳定表达TEL-AXL的B淋巴细胞增值具有良好的抑制效果，其抑制活性IC50值均低于60nM，或低于30nM，甚至低于10nM。The experimental results are shown in Table 2. From the experimental results in Table 2, it can be seen that the exemplary compounds of the present application all have good inhibitory effects on the proliferation of B lymphocytes stably expressing TEL-AXL, and their inhibitory activity IC 50 values are all lower than 60nM, or less than 30nM, or even less than 10nM.
表2.化合物对Ba/F3、Ba/F3-TEL-AXL细胞增殖抑制IC50数据
Table 2. IC 50 data of compounds inhibiting Ba/F3 and Ba/F3-TEL-AXL cell proliferation
前述对本发明的具体示例性实施方案的描述是为了说明和例证的目的。这些描述并非想将本发明限定为所公开的精确形式，并且很显然，根据上述教导，可以进行很多改变和变化。对示例性实施例进行选择和描述的目的在于解释本发明的特定原理及其实际应用，从而使得本领域的技术人员能够实现并利用本发明的各种不同的示例性实施方案以及各种不同的选择和改变。本发明的范围意在由权利要求书及其等同形式所限定。 The foregoing descriptions of specific exemplary embodiments of the present invention have been presented for purposes of illustration and illustration. These descriptions are not intended to limit the invention to the precise form disclosed, and obviously many modifications and variations are possible in light of the above teachings. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical applications, thereby enabling others skilled in the art to make and utilize various exemplary embodiments of the invention and various different applications. Choice and change. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims (11)

  1. 如式I所示的化合物或其药学上可接受的盐：
    A compound represented by formula I or a pharmaceutically acceptable salt thereof:
    其中，in,
    Y选自NR3或O；Y is selected from NR 3 or O;
    X选自氢、卤素、氨基、氰基、硝基、羟基、C1-C3烷基、卤代C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷氧基、羟基(C1-C3)烷基或C1-C3烷酰基；The -C3) alkyl or C1-C3 alkanoyl;
    R1、R5和R6各自独立地选自氢、C1-C6烷基、6-10元芳基、6-10元芳基(C1-C6)烷基、-C(O)R9、-C(O)N(R7)R8或-C(＝NH)N(R7)R8；R 1 , R 5 and R 6 are each independently selected from hydrogen, C1-C6 alkyl, 6-10 membered aryl, 6-10 membered aryl (C1-C6)alkyl, -C(O)R 9 , -C(O)N(R 7 )R 8 or -C(=NH)N(R 7 )R 8 ;
    R2选自-C(O)NH-R2a、6-15元芳基、3-18元杂环基或苯并(C3-C8)环烷基，其中所述的6-15元芳基、3-18元杂环基或苯并(C3-C8)环烷基任选地被酰胺基、氰基、硝基、卤素、卤代C1-C6烷基、C1-C6烷基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基、3-10元杂环基或6-10元芳基取代，所述酰胺基任选地被C1-C3烷基、C3-C6环烷基或3-6元杂环基取代，其中所述的3-10元杂环基任选地被C1-C3烷基、卤素或3-8元杂环基取代，其中所述的C1-C6烷基和C1-C6烷氧基任选地被3-8元杂环基或C1-C3烷氧基取代；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-C3 alkyl, halogen or 3-8 membered heterocyclyl , wherein the C1-C6 alkyl and C1-C6 alkoxy groups are optionally substituted by 3-8 membered heterocyclic groups or C1-C3 alkoxy groups;
    R2a选自6-15元芳基、3-18元杂环基或苯并(C3-C8)环烷基，其中所述的6-15元芳基、3-18元杂环基或苯并(C3-C8)环烷基任选地被氰基、硝基、卤素、卤代C1-C6烷基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、3-10元杂环基或6-10元芳基取代，其中所述的C1-C6烷基和C1-C6烷氧基任选地被3-8元杂环基或C1-C3烷氧基取代，所述3-10元杂环基任选地被C1-C3烷基或卤素取代；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;
    R3选自氢、C1-C6烷基或3-10元杂环基；R4选自-C(O)-R10或3-18元杂环基，其中所述3-18元杂环基任选地被酰胺基、C1-C6烷基、卤代C1-C6烷基、卤素、硝基、氰基、氨基、羟基、C1-C6烷氧基、卤代C1-C6烷氧基、6-10元芳基、5-7元杂环基或C3-C6环烷基取代，所述6-10元芳基或5-7元杂环基任选地被卤素、C1-C3烷基或C1-C3烷氧基取代，所述C1-C6烷基任选地被苯基、C3-C6环烷基或3-10元杂环基取代，所述酰胺基任选地被C1-C3烷基、6-8元芳基、C3-C6环烷基或3-8元杂环基取代，所述6-8元芳基、C3-C6环烷基或3-8元杂环基任选地被卤素、C1-C3烷基或C1-C3烷氧基取代；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 The radical is optionally amide, C1-C6 alkyl, haloC1-C6 alkyl, halogen, nitro, cyano, amino, hydroxyl, C1-C6 alkoxy, haloC1-C6 alkoxy, 6-10-membered aryl, 5-7-membered heterocyclyl or C3-C6 cycloalkyl substituted, the 6-10-membered aryl or 5-7-membered heterocyclyl is optionally substituted by halogen, C1-C3 alkyl Or C1-C3 alkoxy substituted, the C1-C6 alkyl is optionally substituted by phenyl, C3-C6 cycloalkyl or 3-10 membered heterocyclyl, the amide group is optionally substituted by C1-C3 Alkyl, 6-8 membered aryl, C3-C6 cycloalkyl or 3-8 membered heterocyclyl substituted, the 6-8 membered aryl, C3-C6 cycloalkyl or 3-8 membered heterocyclyl may be Optionally substituted by halogen, C1-C3 alkyl or C1-C3 alkoxy;
    R10选自6-10元芳基、3-10元杂环基或C3-C8环烷基，其中所述的6-10元芳基、3-10元杂环基或C3-C8环烷基任选地被6-8元芳基、5-7元杂环基、C1-C6烷基、C1-C6烷氧基、酰胺基、卤素、硝基或氰基取代，其中所述的C1-C6烷基任选地被卤素或3-8元杂环基取代，所述的6-8元芳基或5-7元杂环基任选地被卤素、C1-C3烷基、C1-C3烷氧基、卤代C1-C3烷基或卤代C1-C3烷氧基取代，所述的酰胺基任选地被C1-C3烷基、3-6元杂环基或苯基取代，所述的3-6元杂环基或苯基任选地被卤素、C1-C6烷基、硝基或氰基取代；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 alkoxy, halogenated C1-C3 alkyl or halogenated C1-C3 alkoxy is substituted, and the amide group is optionally substituted by C1-C3 alkyl, 3-6 membered heterocyclyl or phenyl, The 3-6 membered heterocyclic group or phenyl group is optionally substituted by halogen, C1-C6 alkyl group, nitro group or cyano group;
    R7和R8独立地选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6)烷基、卤代(C2-C6)烯基、卤代(C2-C6)炔基、羟基(C1-C6)烷基、6-10元芳基、6-10元芳(C1-C6)烷基、6-10元芳(C2-C6)烯基、6-10元芳(C2-C6)炔基、C3-C8环烷基、C3-C8环烷基(C1-C6)烷基、C3-C8环烷基(C2-C6)烯基、C3-C8环烷基(C2-C6)炔基、3-10元杂环基、3-10元杂环基(C1-C6)烷基、3-10元杂环基(C2-C6)烯基或3-10元杂环基(C2-C6)炔基，或者R7和R8同与它们均连接的共同的氮一起形成N-杂环基； 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 heterocyclyl (C1-C6) alkyl, 3-10 membered heterocyclyl (C2-C6) alkenyl Or 3-10 membered heterocyclyl (C2-C6) alkynyl, or R 7 and R 8 together with the common nitrogen connected to them form N-heterocyclyl;
    R9选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代(C1-C6)烷基、卤代(C2-C6)烯基、卤代(C2-C6)炔基、羟基(C1-C6)烷基、6-10元芳基、6-10元芳(C1-C6)烷基、6-10元芳(C2-C6)烯基、6-10元芳(C2-C6)炔基、C3-C8环烷基、C3-C8环烷基(C1-C6)烷基、C3-C8环烷基(C2-C6)烯基、C3-C8环烷基(C2-C6)炔基、3-10元杂环基、3-10元杂环基(C1-C6)烷基、3-10元杂环基(C2-C6)烯基或3-10元杂环基(C2-C6)炔基。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 (C1-C6)alkyl, 3-10-membered heterocyclyl (C2-C6)alkenyl or 3-10-membered Heterocyclyl (C2-C6)alkynyl.
  2. 如权利要求1所述的式I化合物，其具有如式II所示的结构，
    The compound of formula I as claimed in claim 1, which has a structure shown as formula II,
    其中，R1、R2、R3、R4、R5、R6和X定义如式I所述；优选地，前述式I化合物具有如式III所示的结构，
    Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and
    其中，W选自CH或N；Wherein, W is selected from CH or N;
    RY1选自酰胺基、3-10元杂环基、3-10元杂环基(C1-C6)烷基或C1-C6烷氧基，其中所述的酰胺基任选地被C1-C3烷基取代，其中所述3-10元杂环基或3-10元杂环基(C1-C6)烷基任选地被C1-C6烷基或3-8元杂环基取代，所述的C1-C6烷氧基任选地被3-8元杂环基取代；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;
    RY2选自氢、卤素、3-10元杂环基、3-10元杂环基(C1-C6)烷基、C1-C6烷氧基、氘代C1-C6烷氧基或卤代C1-C6烷氧基，其中所述3-10元杂环基或3-10元杂环基(C1-C6)烷基任选地被C1-C6烷基或3-8元杂环基取代，所述的C1-C6烷氧基任选地被3-8元杂环基取代；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;
    和RY3选自氢、卤素、C1-C6烷氧基或卤代C1-C6烷氧基；and R Y3 are selected from hydrogen, halogen, C1-C6 alkoxy or halogenated C1-C6 alkoxy;
    优选地，前述式I所示的化合物具有如式IV所示的结构，
    Preferably, the compound represented by the aforementioned formula I has a structure represented by formula IV,
    其中，Rq选自C1-C6烷基或3-6元杂环基；Rm选自氢、卤素或C1-C6烷氧基；Wherein, R q is selected from C1-C6 alkyl or 3-6 membered heterocyclyl; R m is selected from hydrogen, halogen or C1-C6 alkoxy;
    优选地，前述式I所示的化合物具有如式V所示的结构，
    Preferably, the compound represented by the aforementioned formula I has a structure represented by formula V,
    优选地，前述式I所示的化合物具有如式VI所示的结构，
    Preferably, the compound represented by the aforementioned formula I has a structure represented by formula VI,
    其中，Rv1选自氢、卤素、C1-C6烷基或C1-C6烷氧基，Rv2选自氢、卤素、C1-C6烷基或C1-C6烷氧基，Rv3选自氢、C1-C6烷基、6-10元芳基或5-7元杂环基，所述6-10元芳基或5-7元杂环基任选地被卤素、C1-C3烷基或C1-C3烷氧基取代。Wherein, R v1 is selected from hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy group, R v2 is selected from hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy group, R v3 is selected from hydrogen, C1-C6 alkyl, 6-10-membered aryl or 5-7-membered heterocyclyl, the 6-10-membered aryl or 5-7-membered heterocyclyl is optionally replaced by halogen, C1-C3 alkyl or C1 -C3 alkoxy substitution.
  3. 如权利要求1或2所述的式I化合物，Y为NR3，R3选自氢、C1-C6烷基或3-10元杂环基；优选地，R3为氢或C1-C6烷基；优选地，Y为NH。The compound of formula I as claimed in claim 1 or 2, Y is NR 3 , R 3 is selected from hydrogen, C1-C6 alkyl or 3-10 membered heterocyclyl; preferably, R 3 is hydrogen or C1-C6 alkyl group; preferably, Y is NH.
  4. 如权利要求1-3任一项所述的式I化合物，X选自氢或卤素；优选地，X选自氢或氟。The compound of formula I according to any one of claims 1 to 3, X is selected from hydrogen or halogen; preferably, X is selected from hydrogen or fluorine.
  5. 如权利要求1-4任一项所述的式I化合物，R1、R5和R6均为氢。The compound of formula I according to any one of claims 1 to 4, wherein R 1 , R 5 and R 6 are all hydrogen.
  6. 如权利要求1-5任一项所述的式I化合物，R2选自-C(O)NH-R2a、6-15元芳基、3-18元杂环基或苯并(C3-C8)环烷基，其中所述的6-15元芳基、3-18元杂环基或苯并(C3-C8)环烷基任选地被酰胺基、卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基或3-10元杂环基取代，其中所述的酰胺基任选地被C1-C3烷基取代，其中所述的3-10元杂环基任选地被C1-C3烷基或3-8元杂环基取代，其中所述的C1-C6烷基和C1-C6烷氧基任选地被3-8元杂环基或C1-C3烷氧基取代；The compound of formula I according to any one of claims 1 to 5, R 2 is selected from -C(O)NH-R 2a , 6-15-membered aryl, 3-18-membered heterocyclyl or benzo (C3- C8) cycloalkyl, wherein the 6-15-membered aryl, 3-18-membered heterocyclyl or benzo(C3-C8) cycloalkyl is optionally replaced 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 The heterocyclyl group is optionally substituted by a C1-C3 alkyl group or a 3-8 membered heterocyclyl group, wherein the C1-C6 alkyl group and C1-C6 alkoxy group are optionally substituted by a 3-8 membered heterocyclyl group or C1-C3 alkoxy substitution;
    R2a为6-10元芳基，所述6-10元芳基任选地被3-10元杂环基取代，其中所述3-10元杂环基任选地被C1-C3烷基取代；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;
    优选地，R2选自 且R2任选地被酰胺基、卤素、C1-C6烷基、C1-C6烷氧基、氘代C1-C6烷氧基、卤代C1-C6烷氧基或3-10元杂环基取代，其中所述3-10元杂环基任选地被C1-C3烷基或3-8元杂环基取代，其中所述的酰胺基任选地被C1-C3烷基取代，其中所述的C1-C6烷基和C1-C6烷氧基任选地被3-8元杂环基或C1-C3烷氧基取代；Preferably, R 2 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;
    更为优选地，R2选自 且R2任选地被-F、-Cl、甲基、甲氧基、 取代；More preferably, R 2 is selected from and R 2 is optionally -F, -Cl, methyl, methoxy, replace;
    更为优选地，R2选自 More preferably, R 2 is selected from
    更为优选地，R2选自 More preferably, R 2 is selected from
    最为优选地，R2选自 Most preferably, R 2 is selected from
  7. 如权利要求1所述的式I化合物，R4选自-C(O)-R10或3-18元杂环基，其中所述的3-18元杂环基任选地被酰胺基、C1-C6烷基、C1-C6烷氧基、卤素、6-10元芳基、5-7元杂环基或C3-C6环烷基取代，所述6-10元芳基或5-7元杂环基任选地被卤素、C1-C3烷基或C1-C3烷氧基取代，所述C1-C6烷基任选地被苯基、C3-C6环烷基或3-8元杂环基取代，所述酰胺基任选地被C1-C3烷基、苯基或卤素取代的苯基取代；The compound of formula I as claimed in claim 1, 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, C1-C6 alkoxy, halogen, 6-10 membered aryl, 5-7 membered heterocyclyl or C3-C6 cycloalkyl substituted, the 6-10 membered aryl or 5-7 The one-membered heterocyclyl group is optionally substituted by halogen, C1-C3 alkyl or C1-C3 alkoxy group, and the C1-C6 alkyl group is optionally substituted by phenyl, C3-C6 cycloalkyl or 3-8 membered heterocyclyl group. Ring group substitution, the amide group is optionally substituted by C1-C3 alkyl, phenyl or halogen-substituted phenyl;
    R10选自3-10元杂环基或C3-C8环烷基，其中所述3-10元杂环基或C3-C8环烷基任选地被6-8元芳基、5-7元杂环基、C1-C6烷基、C1-C6烷氧基或酰胺基取代，其中所述的6-8元芳基或5-7元杂环基任选地被卤素或C1-C3烷基取代，所述的C1-C6烷基任选地被3-8元杂环基取代，所述酰胺基任选地被苯基或卤素取代的苯基取代；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, and the amide group is optionally substituted by a phenyl group or a halogen-substituted phenyl group;
    优选地，R4选自-C(O)-R10或3-18元杂环基，其中所述3-18元杂环基任选地被乙氧基、甲基、异丙基、Br、F、Cl、苯基、吡啶基、环丙基或环戊基取代，所述甲基任选地被苯基、环丙基或取代，所述苯基或吡啶基任选地被F、甲基或甲氧基取代；Preferably, R 4 is selected from -C(O)-R 10 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;
    其中R10选自3-10元杂环基或C3-C8环烷基，其中所述3-10元杂环基或C3-C8环烷基任选地被苯基、吡啶基、甲基、异丙基、乙氧基或取代，其中所述的甲基任选地被取代，所述的苯基或吡啶基任选地被卤素、甲基取代；Wherein 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 is optionally substituted by halogen or methyl;
    更为优选地，R4选自 其中所述 任选地被F、Cl、Br、甲基、4-氟苯基、4-甲氧基苯基、取代；More preferably, R 4 is selected from stated therein optionally F, Cl, Br, methyl, 4-fluorophenyl, 4-methoxyphenyl, replace;
    其中所述任选地被甲基、异丙基、苯基、乙氧基、4-氟苯基、取代；stated therein optionally methyl, isopropyl, phenyl, ethoxy, 4-fluorophenyl, replace;
    更为优选地，R4选自 More preferably, R 4 is selected from
  8. 以下化合物或其药学上可接受的盐：


    The following compounds or pharmaceutically acceptable salts thereof:


  9. 一种药物组合物，其包含治疗有效量的式I、II、III、IV、V或式VI化合物或其药学上可接受的盐和药学上可接受的载体。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.
  10. 式I、II、III、IV、V或式VI化合物或其药学上可接受的盐或权利要求9所述的药物组合物在制备用于治疗和/或预防AXL受体酪氨酸激酶诱发的病症的药物中的应用；优选地，所述AXL受体酪氨酸激酶诱发的病症是由AXL激酶功能亢进引起、与AXL激酶功能亢进相关和/或伴随AXL激酶功能亢进的病症；更为优选地，所述AXL受体酪氨酸激酶诱发的病症为癌症，所述癌症为实体瘤或血液癌症；最为优选地，所述AXL受体酪氨酸激酶诱发的病症为实体瘤癌症。A compound of formula I, II, III, IV, V or formula VI or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 9 for use in the treatment and/or prevention of AXL receptor tyrosine kinase-induced Application in medicine for diseases; Preferably, the AXL receptor tyrosine kinase-induced disease is caused by, associated with, and/or accompanied by AXL kinase hyperfunction; more preferably, Preferably, the disorder induced by the AXL receptor tyrosine kinase is cancer, and the cancer is a solid tumor or a blood cancer; most preferably, the disorder induced by the AXL receptor tyrosine kinase is a solid tumor cancer.
  11. 一种治疗AXL受体酪氨酸激酶诱发的病症的方法，其包括向有需要的患者施用治疗有效量的式I、II、III、IV、V或式VI化合物或其药学上可接受的盐或权利要求9所述的药物组合物的步骤。 A method of treating an AXL receptor tyrosine kinase-induced disorder, comprising 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 pharmaceutically acceptable salt thereof Or the step of the pharmaceutical composition of claim 9.
PCT/CN2023/116897 2022-09-05 2023-09-05 Substituted triazole compound having axl inhibitory activity WO2024051667A1 (en)

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WO2007030680A2 (en) * 2005-09-07 2007-03-15 Rigel Pharmaceuticals, Inc. Triazole derivatives useful as axl inhibitors
WO2008083353A1 (en) * 2006-12-29 2008-07-10 Rigel Pharmaceuticals, Inc. Bicyclic aryl and bicyclic heteroaryl substituted triazoles useful as axl inhibitors
WO2008083354A1 (en) * 2006-12-29 2008-07-10 Rigel Pharmaceuticals, Inc. N3-heteroaryl substituted triazoles and n5-heteroaryl substituted triazoles useful as axl inhibitors
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WO2008083356A1 (en) * 2006-12-29 2008-07-10 Rigel Pharmaceuticals, Inc. Substituted triazoles useful as axl inhibitors
WO2008083357A1 (en) * 2006-12-29 2008-07-10 Rigel Pharmaceuticals, Inc. Bridged bicyclic aryl and bridged bicyclic heteroaryl substituted triazoles useful as axl inhibitors
WO2009054864A1 (en) * 2007-10-26 2009-04-30 Rigel Pharmaceuticals, Inc. Polycyclic aryl substituted triazoles and polycyclic heteroaryl substituted triazoles useful as axl inhibitors
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004046120A2 (en) * 2002-11-15 2004-06-03 Vertex Pharmaceuticals Incorporated Diaminotriazoles useful as inhibitors of protein kinases
WO2007030680A2 (en) * 2005-09-07 2007-03-15 Rigel Pharmaceuticals, Inc. Triazole derivatives useful as axl inhibitors
WO2008083353A1 (en) * 2006-12-29 2008-07-10 Rigel Pharmaceuticals, Inc. Bicyclic aryl and bicyclic heteroaryl substituted triazoles useful as axl inhibitors
WO2008083354A1 (en) * 2006-12-29 2008-07-10 Rigel Pharmaceuticals, Inc. N3-heteroaryl substituted triazoles and n5-heteroaryl substituted triazoles useful as axl inhibitors
WO2008083367A2 (en) * 2006-12-29 2008-07-10 Rigel Pharmaceuticals, Inc. Polycyclic heteroaryl substituted triazoles useful as axl inhibitors
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WO2008083357A1 (en) * 2006-12-29 2008-07-10 Rigel Pharmaceuticals, Inc. Bridged bicyclic aryl and bridged bicyclic heteroaryl substituted triazoles useful as axl inhibitors
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