WO2021180006A1 - 乙烯基取代吡啶类化合物 - Google Patents

乙烯基取代吡啶类化合物 Download PDF

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Publication number
WO2021180006A1
WO2021180006A1 PCT/CN2021/079337 CN2021079337W WO2021180006A1 WO 2021180006 A1 WO2021180006 A1 WO 2021180006A1 CN 2021079337 W CN2021079337 W CN 2021079337W WO 2021180006 A1 WO2021180006 A1 WO 2021180006A1
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compound
crude product
ethyl acetate
water
under reduced
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English (en)
French (fr)
Inventor
陆剑宇
贺辉君
胡国平
胡利红
丁照中
黎健
陈曙辉
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Medshine Discovery Inc
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Medshine Discovery Inc
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings

Definitions

  • the present invention relates to a class of vinyl-substituted pyridine compounds and pharmaceutically acceptable salts thereof, and the application of such compounds and pharmaceutically acceptable salts in the preparation of drugs for treating related diseases.
  • Tyrosine kinases can be classified as growth factor receptor (e.g., Axl, Mer, EGFR, PDGFR, FGFR and erbB2) or non-receptor (e.g. c-src and bcr-abl) kinases.
  • Receptor tyrosine kinases are composed of about 20 different subfamilies. Non-receptor tyrosine kinases constitute many subfamilies. These tyrosine kinases have a variety of biological activities.
  • Receptor tyrosine kinase is a large enzyme that spans the cell membrane.
  • VEGF-A vascular endothelial growth factor A
  • angiogenesis is a prerequisite for the growth of all solid tumors.
  • Angiogenesis is an important part of certain normal physiological processes (such as embryogenesis and wound healing), but abnormal angiogenesis leads to some pathological diseases, especially tumor growth.
  • VEGF can directly inhibit tumor immune response, and anti-angiogenesis therapy can enhance tumor immunity through blood vessel normalization.
  • VEGF-A vascular endothelial growth factor A
  • angiogenesis vascular endothelial growth factor A
  • VEGF induces endothelial cell proliferation and migration through signal transduction through receptors, namely VEGFR-1 (Flt-1), VEGFR-2 (KDR) and VEGFR-3 (Flt-4). These signal transduction responses are heavily dependent on receptor dimerization and activation of intrinsic receptor tyrosine kinase (RTK) activity.
  • RTK receptor tyrosine kinase
  • the binding of VEGF as a disulfide bond-linked homodimer stimulates receptor dimerization and activation of the RTK domain.
  • Kinase activity autophosphorylates cytoplasmic receptor tyrosine residues, which then serve as binding sites for molecules involved in the proliferation of the signal cascade.
  • VEGFR-2 signaling is the most widely studied, and its mitogenic response is thought to involve ERK-1 and ERK-2 mitogen-activated protein kinases.
  • Axl is a member of the TAM receptor family, which also includes Mer and Tyro3. These three are activated by a common ligand, growth arrest-specific protein 6 (Gas6), and they usually play a role in embryonic development in cell survival, migration and differentiation. Axl overexpression and signal transduction are associated with a variety of malignant tumors in humans, such as colon cancer, breast cancer, glioma, thyroid cancer, gastric cancer, melanoma, lung cancer, and renal cell carcinoma.
  • Axl can more completely prevent the growth of cancer.
  • therapeutic antibodies that target Axl can block the Axl function of the tumor stroma.
  • VEGFRs VEGF receptors
  • VEGFRs/Axl is a potential treatment strategy for targeting cancer cells, which can avoid the overcoming of the independent inhibition of VEGFRs and Axl by tumor cells, thus becoming an advanced cancer treatment plan.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from 5-membered heteroaryl groups, which contain 2 N heteroatoms;
  • ring A is selected from 6-membered heteroaryl groups, which contain up to 2 N atoms;
  • T 1 and T 2 are independently selected from C(R 5 ) and N;
  • R 1 and R 3 are each independently selected from H, F and CH 3 ;
  • R 2 chooses H, F and Cl
  • R 4 is each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, and -LR 6 , the C 1-6 6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl and -LR 6 are optionally substituted with 1, 2 or 3 R;
  • R 5 is selected from H and Cl
  • R 6 is selected from H, OH, 5- to 6-membered heterocycloalkyl and C 1-3 alkyl;
  • L is selected from -CH 2 -, -CH 2 -CH 2 -and
  • n is selected from 0, 1, 2 and 3;
  • the 5-membered heteroaryl, 6-membered heteroaryl, C 1-6 heteroalkyl and 3-6 heterocycloalkyl each independently comprise 1, 2 or 3 independently selected from O, S, N and NH heteroatom or heteroatom group.
  • Ring A is selected from 5-membered heteroaryl groups, which contain 2 N heteroatoms;
  • ring A is selected from 6-membered heteroaryl groups, which contain up to 2 N atoms;
  • T 1 and T 2 are independently selected from C(R 5 ) and N;
  • R 1 and R 3 are each independently selected from H, F and CH 3 ;
  • R 2 is selected from H, F and Cl;
  • R 4 is each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, The C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;
  • R 5 is selected from H and Cl
  • n is selected from 0, 1, 2 and 3;
  • the 5-membered heteroaryl, 6-membered heteroaryl, C 1-6 heteroalkyl and 3-6 heterocycloalkyl each independently comprise 1, 2 or 3 independently selected from O, S, N and NH heteroatom or heteroatom group.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof wherein R 4 is independently selected from H, C 1-4 alkyl, C 1-4 heteroalkyl, 5-6 membered hetero Cycloalkyl and -LR 6 , said C 1-4 alkyl, C 1-4 heteroalkyl, 5-6 membered heterocycloalkyl and -LR 6 are optionally substituted by 1, 2 or 3 R, Other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof wherein R 4 is independently selected from H, C 1-4 alkyl and C 1-4 heteroalkyl, the C 1-4
  • the 4- alkyl group and C 1-4 heteroalkyl group are optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.
  • R 41 is selected from H, C 1-4 alkyl, C 1-4 heteroalkyl, 6-membered heterocycloalkyl and -LR 6 , the H, C 1-4 alkyl, C 1-4 heteroalkyl , 6-membered heterocycloalkyl and -LR 6 are optionally substituted with 1, 2 or 3 R;
  • R 42 is selected from H and -LR 6 , said -LR 6 is optionally substituted by 1, 2 or 3 R;
  • R 6 is selected from H, OH, 6-membered heterocycloalkyl and C 1-3 alkyl;
  • R 2 , L and R are as defined in the present invention.
  • R 1 , R 2 , R 3 and R 4 are as defined in the present invention.
  • the present invention also provides a compound or a pharmaceutically acceptable salt thereof, which is selected from
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt as an active ingredient and a pharmaceutically acceptable carrier.
  • the present invention also provides the application of the compound or pharmaceutically acceptable salt or the above composition in the preparation of Axl and VEGFR-2 inhibitors.
  • the above-mentioned Axl and VEGFR-2 inhibitors are drugs for the treatment of cancer.
  • the compounds of the present invention can be used to treat tumor diseases that respond to the inhibition of protein tyrosine kinase activity, such as cancers that respond to inhibition of the protein tyrosine kinase activity of growth factor receptors.
  • the present invention also provides new compounds and methods for the treatment of diseases that are responsive to the inhibition of receptor-type tyrosine kinase signaling, for example, cancers that are responsive to VEGF receptor signaling inhibition and Axl kinase inhibition. .
  • the compound of the present invention has excellent in vitro activity and has good inhibitory activity on VEGFR2/KDR kinase and AXL kinase.
  • the representative compound of the present invention has greatly improved permeability, more stable performance in metabolic stability, and excellent performance in CYP inhibitory properties.
  • the compound of the present invention has good PK properties in vivo, and has good exposure and bioavailability.
  • the compound of the present invention has better drug-making properties and better curative effect in clinical practice.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
  • the acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or organic solvent or a mixture of both.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • any variable such as R
  • its definition in each case is independent.
  • the group can be optionally substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond, and -C 0 alkyl-A means that the structure is actually -A.
  • substituents When the listed substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the bond of a substituent can be cross-connected to two or more atoms on a ring, the substituent can be bonded with any atom on the ring, for example, a structural unit It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right
  • Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the connection method of the chemical bond is not positioned, and there is a H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will correspondingly decrease with the number of chemical bonds connected to become the corresponding valence number ⁇ The group.
  • the chemical bond between the site and other groups can be a straight solid bond Straight dashed key Or wavy line Express.
  • the straight solid bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in indicates that the phenyl group is connected to other groups through the 1 and 2 carbon atoms;
  • the number of atoms in a ring is usually defined as the number of members of the ring.
  • a "5- to 7-membered ring” refers to a “ring” in which 5 to 7 atoms are arranged around.
  • C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • C 1-4 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 4 carbon atoms.
  • the C 1-4 alkyl group includes C 1-2 , C 1-3 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent ( Such as methine).
  • Examples of C 1-4 alkyl groups include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl) and so on.
  • heteroalkyl by itself or in combination with another term means a stable linear or branched alkyl group or a combination thereof composed of a certain number of carbon atoms and at least one heteroatom or heteroatom group.
  • the heteroatoms are selected from B, O, N, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized.
  • the heteroalkyl group is a C 1-6 heteroalkyl group; in other embodiments, the heteroalkyl group is a C 1-4 heteroalkyl group.
  • the heteroatom or heteroatom group can be located in any internal position of the heteroalkyl group, including the connection position of the alkyl group to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkane The oxy) is a customary expression and refers to those alkyl groups that are connected to the rest of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively.
  • Up to two heteroatoms can be continuous
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system.
  • the C 3-6 cycloalkyl includes C 3 to 5 , C 4 to 5 and C 5 to 6 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • the term "3- to 6-membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms.
  • a heteroatom may occupy the connection position between the heterocycloalkyl group and the rest of the molecule.
  • the 3- to 6-membered heterocycloalkyl group includes 4- to 6-membered, 5- to 6-membered, 4-, 5-, and 6-membered heterocycloalkyl.
  • 3- to 6-membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazolid
  • the term "5- to 6-membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 5 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms.
  • a heteroatom may occupy the connection position between the heterocycloalkyl group and the rest of the molecule.
  • the 5- to 6-membered heterocycloalkyl group includes 5- and 6-membered heterocycloalkyl groups.
  • Examples of 5- to 6-membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) , Tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -Piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithiaalkyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiaziny
  • 6-membered heterocycloalkyl group a heteroatom may occupy the position of attachment of the heterocycloalkyl group to the rest of the molecule.
  • 6-membered heterocycloalkyl include, but are not limited to, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperidinyl). Piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazine Base and so on.
  • 5-6 membered heteroaryl ring and “5-6 membered heteroaryl group” can be used interchangeably in the present invention.
  • the 5- to 6-membered heteroaryl group can be connected to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5- to 6-membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.
  • Examples of the 5- to 6-membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4
  • 6-membered heteroaromatic ring and “6-membered heteroaryl” can be used interchangeably in the present invention.
  • the 6-membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • examples of the 6-membered heteroaryl include, but are not limited to, pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidine) Base etc.).
  • 5-membered heteroaromatic ring and “5-membered heteroaryl” can be used interchangeably in the present invention.
  • the 5-membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • Examples of the 5-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.) Etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazole) Base, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2, 4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • FA stands for formic acid
  • TFA trifluoroacetic acid
  • ACN stands for acetonitrile
  • DIEA diisopropylethylamine
  • P(o-tolyl) 3 stands for tris(o-methylphenyl)phosphine
  • TBAI stands for tetrabutylammonium iodide
  • T3P stands for 1-propyl phosphoric anhydride
  • TBSCl stands for tert-butyldimethylchlorosilane
  • HATU stands for 2-(7-azabenzotriazole)-N,N, N',N'-tetramethylurea hexafluorophosphate
  • HOBt stands for 1-hydroxybenzotriazole
  • PyBOP stands for hexafluorophosphate benzotriazol-1-yl-oxytripyrrolidinyl phosphorus
  • DMSO stands for two Methyl sulfoxide
  • ATP stands for two Me
  • the present invention will be described in detail through the following examples, but it is not meant to impose any disadvantageous restriction on the present invention.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.
  • Step A Compound 1-1 (12g, 91.23mmol), 1-2 (14.05g, 91.23mmol), tetrakis (triphenylphosphorus) palladium (5.27g, 4.56mmol), sodium carbonate (19.34g, 182.46mmol) ) was dissolved in 1,4-dioxane (100 mL) and water (20 mL), and the resulting mixture was replaced with nitrogen three times and stirred at 110°C for 12 hours. The reaction solution was quenched by adding water (50 mL) and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step B Combine compound 1-3 (1g, 8.12mmol), 1-4 (2.8g, 8.12mmol), palladium acetate (0.18g, 0.812mmol), cesium carbonate (5.29g, 16.24mmol), tetrabutyl bromide
  • the amine (2.62 g, 8.12 mmol) was dissolved in N,N-dimethylacetamide (30 mL), and the resulting mixture was replaced with nitrogen three times and stirred at 130°C for 12 hours.
  • the reaction solution was quenched by adding water (50 mL) and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step C Dissolve compound 1-5 (0.2g, 0.516mmol), 1-6 (0.078g, 0.619mmol), potassium carbonate (0.142g, 1.03mmol) in N-methylpyrrolidone (5mL). Stir in microwave at 150°C for 2 hours. The reaction solution was quenched by adding water (50 mL) and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • Step D Compound 1-8 (0.3g, 1.34mmol) was dissolved in thionyl chloride (5mL), the resulting mixture was stirred at 25°C for 12 hours. Concentrated under reduced pressure to obtain the crude product, and then combined with 1-7 (25mg, 50.55 ⁇ mol) was dissolved in dichloromethane (5 mL), DIEA (26.13 mg, 202.20 ⁇ mol) was added to the solution, and the resulting mixture was stirred at 25° C. for 1 hour. The reaction solution was quenched by adding water (50 mL) and extracted with dichloromethane (50 mL ⁇ 2).
  • Step E Dissolve compound 1-9 (45 mg, 64.31 ⁇ mol) in dichloromethane (1 mL), then add trifluoroacetic acid (770 mg, 6.75 mmol, 0.5 mL) to the reaction solution, and stir the resulting mixture at 25°C 0.5 hours.
  • the reaction solution was quenched by adding sodium bicarbonate aqueous solution (30 mL) and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and then depressurized Concentrate to obtain crude product.
  • the crude product was purified by (column information: Phenomenex Synergi C18 150*25*10 ⁇ m; mobile phase: [water (0.225% FA)-ACN]; ACN%: 17%-41%, 8 minutes) to obtain compound 1.
  • Step A Dissolve compound 2-1 (2g, 13.42mmol), 2-2 (2.11g, 13.42mmol), potassium carbonate (3.71g, 26.85mmol) in N,N-dimethylformamide (20mL) The resulting mixture was stirred at 80°C for 3 hours. The reaction solution was quenched by adding water (50 mL) and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-3. MS(ESI)m/z:269.7[M+H + ].
  • Step B Compound 2-3 (1.9g, 7.05mmol), 1-2 (1.19g, 7.75mmol), tetrakis(triphenylphosphorus) palladium (814.33mg, 704.71 ⁇ mol), sodium carbonate (1.49g, 14.09 mmol) was dissolved in 1,4-dioxane (20 mL) and water (4 mL), and the resulting mixture was replaced with nitrogen three times and stirred at 80°C for 3 hours. Water (100 mL) was added to the reaction solution to quench the reaction and extracted with ethyl acetate (100 mL ⁇ 2).
  • Step C Compound 2-4 (0.5g, 1.91mmol), 1-4 (0.66g, 1.91mmol), palladium acetate (42.97mg, 0.191mmol), triethylamine (387.39mg, 3.83mmol), tetrabutyl Amine bromide (617.07 mg, 1.91 mmol), P(o-tolyl) 3 (582.61 mg, 1.91 mmol) were dissolved in toluene (10 mL), the resulting mixture was replaced with nitrogen three times and stirred at 90°C for 12 hours. The reaction solution was quenched by adding water (50 mL) and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step D Dissolve compound 2-5 (90 mg, 171.26 mmol) in ethanol (10 mL), then add iron powder (191.28 mg, 3.43 mmol), ammonium chloride (18.32 mg, 0.342 mmol), and the resulting mixture at 100°C Stir for 12 hours.
  • the reaction solution was filtered and concentrated under reduced pressure to obtain a crude product, which was extracted with ethyl acetate (50 mL ⁇ 2).
  • the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-6.
  • Step E Compound 1-8 (0.3 g, 1.34 mmol) was dissolved in thionyl chloride (5 mL), and the resulting mixture was stirred at 25°C for 12 hours. Concentrate under reduced pressure to obtain crude acid chloride. 2-6 (80mg, 161.44 ⁇ mol) and crude acid chloride (78mg, 322.88 ⁇ mol) were dissolved in tetrahydrofuran (5mL). DIEA (83.46mg, 645.75 ⁇ mol) was added to the solution. Stir at °C for 1 hour. The reaction solution was quenched by adding water (50 mL) and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step F Compound 2-7 (72 mg, 102.75 ⁇ mol) was dissolved in dichloromethane (1 mL), and then trifluoroacetic acid (1.23 g, 10.79 mmol, 0.8 mL) was added to the reaction solution, and the resulting mixture was kept at 25°C Stir for 0.5 hour. To the reaction solution was added an aqueous sodium hydrogen carbonate solution (30 mL) to quench the reaction and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • Step A Dissolve compound 3-1 (3.4g, 23.13mmol), 3-2 (3.18g, 25.45mmol), cesium carbonate (11.31g, 34.70mmol), TBAI (1.71g, 4.63mmol) in N, N -In dimethylacetamide (15 mL), the resulting mixture was stirred at 90°C for 12 hours. Water (50mL) was added to the reaction solution to quench the reaction and extracted with ethyl acetate (50mL ⁇ 2). The combined organic phases were washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude compound 3-3. MS(ESI)m/z:191.1[M+H + ].
  • Step B Dissolve compound 3-3 (4.4g, 23.03mmol), TBSCl (4.17g, 27.64mmol), imidazole (3.14g, 46.07mmol) in N,N-dimethylacetamide (15mL) to obtain The mixture was stirred at 25°C for 12 hours. Water (50mL) was added to the reaction solution to quench the reaction and extracted with ethyl acetate (50mL ⁇ 2). The combined organic phases were washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product.
  • Step D The compound 3-5 (5g, 18.61mmol), 1-2 (3.44g, 22.34mmol), tetrakis (triphenylphosphorus) palladium (2.15g, 1.86mmol), sodium carbonate (3.95g, 37.23mmol) ) was dissolved in dioxane (50 mL) and water (10 mL), and the resulting mixture was replaced with nitrogen three times and stirred at 80°C for 3 hours. Water (100 mL) was added to the reaction solution to quench the reaction and extracted with ethyl acetate (100 mL ⁇ 2).
  • Step E Compound 3-6 (255.71mg, 982.69mmol), 3-4 (300mg, 982.69mmol), palladium acetate (22.06mg, 98.27 ⁇ mol,), triethylamine (497.19mg, 4.91mmol), lithium bromide ( 256.02 mg, 2.95 mmol), P(o-tolyl) 3 (299.10 mg, 982.69 mmol) was dissolved in toluene (10 mL), the resulting mixture was replaced with nitrogen three times and stirred at 110°C for 12 hours. Water (100mL) was added to the reaction solution to quench the reaction and extracted with ethyl acetate (100mL ⁇ 2).
  • Step F Dissolve compound 3-7 (200mg, 412.72 ⁇ mol) in ethanol (10mL) and water (2mL), then add iron powder (230.48mg, 4.13mmol) and ammonium chloride (110.38mg, 2.06mmol) to obtain The mixture was stirred at 90°C for 6 hours. The reaction solution was filtered and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-8. MS(ESI)m/z:455.0[M+H + ].
  • Step G Dissolve compound 3-8 (90mg, 197.97 ⁇ mol) in dichloromethane (5mL), and add 1-8 (88.3mg, 395.94 ⁇ mol), DIEA (127.93mg, 989.86 ⁇ mol) and T3P (377.94 mg, 593.91 ⁇ mol). The resulting mixture was stirred at 25°C for 12 hours. Water (50 mL) was added to the reaction solution and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 3-9. MS(ESI)m/z:660.2[M+H + ].
  • Step H Compound 3-9 (65mg, 98.52 ⁇ mol) was dissolved in dichloromethane (2mL), then trifluoroacetic acid (1.54g, 13.51mmol) was added to the reaction solution, and the resulting mixture was stirred at 25°C for 0.5 hours .
  • the reaction solution was concentrated under reduced pressure to obtain a crude product.
  • the crude product was purified by (Phenomenex Synergi C18 150*25*10 ⁇ m; mobile phase: [water (0.225% FA)-ACN]; ACN%: 17%-50%, 10 minutes) to obtain the formate salt of compound 3.
  • Step A Dissolve compound 3-1 (1g, 6.80mmol), 4-1 (1.46g, 10.21mmol), cesium carbonate (3.33g, 10.21mmol) in N,N-dimethylformamide (8mL) The resulting mixture was stirred at 60°C for 1 hour. Water (20mL) was added to the reaction solution to quench the reaction and extracted with ethyl acetate (30mL ⁇ 3). The combined organic phases were washed with saturated sodium chloride solution (50mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain Compound 4-2, the crude product was used directly in the next step.
  • Step B Compound 4-2 (1.43 g, 6.83 mmol) and compound 4-3 (1.54 g, 20.48 mmol) were dissolved in DMSO (5 mL), and the resulting mixture was stirred at 60° C. for 5 hours.
  • Step E Compound 3-6 (0.4g, 1.54mmol), 4-5 (1.07g, 3.07mmol), palladium acetate (69.02mg, 307.43 ⁇ mol), triethylamine (933.27mg, 9.22mmol), lithium bromide ( 534.01mg, 6.15mmol), P(o-tolyl) 3 (467.87mg, 1.54mmol) was dissolved in N,N-dimethylacetamide (10mL), the resulting mixture was replaced with nitrogen three times and stirred at 125°C for 12 Hour. Water (40mL) and ethyl acetate (40mL) were added to the reaction solution, and the layers were separated.
  • Step F Dissolve compound 4-6 (150 mg, 284.34 ⁇ mol) in ethanol (3 mL), then add iron powder (158.79 mg, 2.84 mmol), saturated ammonium chloride solution (0.3 mL), and stir the resulting mixture at 80°C 2 hours. After filtration, the filtrate was collected and concentrated to remove the organic solvent, then diluted with ethyl acetate (20 mL) and water (20 mL), separated, and the aqueous phase was extracted with ethyl acetate (30 mL ⁇ 3).
  • Step G Compound 1-8 (72.81mg, 326.20 ⁇ mol) was dissolved in dichloromethane (5mL), and oxalyl chloride (159.25mg, 1.25mmol) and N,N-dimethylformamide ( 1.83mg, 25.09 ⁇ mol), reacted at 25°C for half an hour. The solution was concentrated to obtain the corresponding acid chloride and dissolved in dichloromethane (5mL). 4-7 (124.85mg, 250.92 ⁇ mol) and pyridine (99.24mg, 1.25mmol) were added to the solution at 0°C. The resulting mixture was kept at 25°C. Stir for half an hour.
  • Step H Compound 4-8 (150 mg, 213.45 ⁇ mol) was dissolved in dichloromethane (5 mL), then trifluoroacetic acid (1 mL) was added to the reaction solution, and the resulting mixture was stirred at 20° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (column: Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: [water (0.05% ammonia v/v)-ACN]; B%: 38%-68%, 10 minutes) Compound 4 was obtained.
  • Step A Dissolve compound 5-1 (1.6g, 8.25mmol) in acetonitrile (20mL), add potassium carbonate (2.28g, 16.50mmol), potassium iodide (136.93mg, 824.86 ⁇ mol) and 5-2 (1.94g, 8.66 mmol), and the resulting mixture was stirred at 80°C for 12 hours. Water (100 mL) was added to the reaction solution, a white solid precipitated out, filtered and collected the filter cake, and concentrated under reduced pressure to obtain compound 5-3. MS(ESI)m/z:338.2[M+H + ].
  • Step B Combine compound 3-6 (0.4g, 1.54mmol), compound 5-3 (1.04g, 3.08mmol), palladium acetate (69.15mg, 308.00 ⁇ mol), triethylamine (935.00mg, 9.24mmol), lithium bromide (401.25mg, 4.62mmol), P(o-tolyl) 3 (468.73mg, 1.54mmol) was dissolved in N,N-dimethylacetamide (10mL), the resulting mixture was replaced with nitrogen three times and stirred at 125°C 36 hours. Water (40mL) and ethyl acetate (40mL) were added to the reaction solution, and the layers were separated.
  • Step C Dissolve compound 5-4 (370 mg, 788.13 ⁇ mol) in ethanol (6 mL), then add iron powder (440.17 mg, 7.88 mmol), saturated ammonium chloride solution (0.5 mL), and stir the resulting mixture at 80°C 2 hours. After filtration, the filtrate was collected and concentrated to remove the organic solvent, then diluted with ethyl acetate (20 mL) and water (20 mL), separated, and the aqueous phase was extracted with ethyl acetate (30 mL ⁇ 3).
  • Step D Dissolve compound 1-8 (211.27mg, 946.57 ⁇ mol) in dichloromethane (10mL), add oxalyl chloride (462.11mg, 3.64mmol, 318.69 ⁇ L) and N,N-dimethyl at 0°C Formamide (5.32mg, 72.81 ⁇ mol), reacted at 25°C for half an hour.
  • the solution was concentrated to obtain the corresponding acid chloride and dissolved in dichloromethane (5mL), 5-5 (320mg, 728.13 ⁇ mol) and pyridine (287.98mg, 3.64mmol) were added to the solution at 0°C. The resulting mixture was stirred at 25°C half an hour.
  • Step E Compound 5-6 (450 mg, 698.04 ⁇ mol) was dissolved in dichloromethane (20 mL), then trifluoroacetic acid (2 mL) was added to the reaction solution, and the resulting mixture was stirred at 20° C. for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high performance liquid chromatography (column: Phenomenex Synergi C18 150*25*10 ⁇ m; mobile phase: [water (0.225% FA)-ACN]; B%: 8%-38%, 10 minutes) to obtain the compound 5 formate.
  • Step A Dissolve compound 3-1 (7g, 47.63mmol) in tetrahydrofuran (100mL), add sodium hydride (2.48g, 61.92mmol, 60% content) in portions at 0°C and stir at 0°C for 30 minutes, 6-1 (9.93 g, 59.53 mmol) was added, and the resulting mixture was stirred at 25°C for 12 hours.
  • Step B Combine compound 6-2 (1.28 g, 4.61 mmol), compound 3-6 (1 g, 3.84 mmol), palladium acetate (86.28 mg, 384.29 ⁇ mol), triethylamine (1.94 g, 19.21 mmol), lithium bromide ( 1.00g, 11.53mmol), P(o-tolyl) 3 (1.17g, 3.84mmol) was dissolved in N,N-dimethylacetamide (10mL), the resulting mixture was replaced with nitrogen three times and stirred at 125°C 36 Hour. Water (50mL) and ethyl acetate (50mL) were added to the reaction solution, and the layers were separated.
  • the aqueous phase was extracted with ethyl acetate (50mL ⁇ 3).
  • the combined organic phases were washed with saturated sodium chloride solution (50mL) and anhydrous sodium sulfate Dry, filter and concentrate under reduced pressure to obtain the crude product.
  • Step C Compound 6-3 (580mg, 1.27mmol) was dissolved in ethanol (7mL), then iron powder (709.47mg, 12.70mmol) and saturated ammonium chloride solution (0.7mL) were added, and the resulting mixture was stirred at 80°C 10 hours. After filtration, the filtrate was collected and concentrated to remove the organic solvent, then diluted with ethyl acetate (30 mL) and water (30 mL), separated, and the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 3).
  • Step D Dissolve compound 1-8 (285.70mg, 1.28mmol) in dichloromethane (5mL), add oxalyl chloride (624.87mg, 4.92mmol) and N,N-dimethylformamide ( 7.20mg, 98.46 ⁇ mol), react at 25°C for half an hour.
  • the solution was concentrated to obtain the corresponding acid chloride and dissolved in dichloromethane (5mL), 6-4 (420mg, 984.63 ⁇ mol) and pyridine (389.42mg, 4.92mmol) were added to the solution at 0°C.
  • the resulting mixture was stirred at 25°C half an hour.
  • Step E Compound 6-5 (700 mg, 1.11 mmol) was dissolved in dichloromethane (14 mL), then trifluoroacetic acid (7 mL) was added to the reaction solution, and the resulting mixture was stirred at 25° C. for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product.
  • the crude product passed preparative high performance liquid chromatography (column: Waters Xbridge BEH C18 150*25mm*5 ⁇ m; mobile phase: [water (0.05% ammonia v/v)-ACN]; B%: 36%-66%, 10 minutes ) Purification to obtain compound 6.
  • Step B The compound 7-2 (4.5g, 17.95mmol), 1-2 (3.32g, 21.55mmo), tetrakis (triphenylphosphorus) palladium (2.07g, 1.80mmol), sodium carbonate (3.81g, 35.91 mmol) was dissolved in 1,4-dioxane (50 mL) and water (10 mL), and the resulting mixture was replaced with nitrogen three times and stirred at 80°C for 3 hours. The reaction solution was quenched by adding water (50mL) and extracted with ethyl acetate (50mL ⁇ 2).
  • Step C The compound 7-3 (1g, 4.13mmol), 3-4 (1.26g, 4.13mmol), palladium acetate (92.68mg, 412.83 ⁇ mol), triethylamine (2.09g, 20.64mmol), lithium bromide (1.08 g, 12.38 mmol) was dissolved in toluene (15 mL), the resulting mixture was replaced with nitrogen three times and stirred at 120°C for 12 hours. Water (100 mL) was added to the reaction solution and extracted with ethyl acetate (100 mL ⁇ 2).
  • Step D Dissolve compound 7-4 (1.5g, 3.21mmol) in ethanol (10mL) and water (2mL), then add iron powder (1.80g, 32.15mmol), ammonium chloride (859.78mg, 16.07mmol) . The resulting mixture was stirred at 90°C for 2 hours. The reaction solution was filtered and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7-5. MS(ESI) m/z: 437.3 [M+H + ].
  • Step E Dissolve compound 1-8 (500mg, 1.15mmol) in dichloromethane (10mL) and add 7-5 (330.09mg, 2.29mmol), T3P (2.91g, 4.58mmol, 2.72mL, 50% purity, ) And DIEA (888.00mg, 6.87mmol, 1.20mL,), react at 25°C for 12 hours. Water (50 mL) was added to the reaction solution and extracted with dichloromethane (25 mL ⁇ 2). The combined organic phase was washed with saturated sodium chloride solution (25 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7-6. MS(ESI) m/z: 563.1 [M+H + ].
  • Step F Compound 7-6 (550mg, 977.38 ⁇ mol) was dissolved in tetrahydrofuran (2mL) and water (0.5mL), and then lithium hydroxide monohydrate (82.02mg, 1.95mmol) was added to the reaction solution. The resulting mixture was Stir at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, water (10 mL) was added, the pH was adjusted to 6 with 1 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7-7. MS(ESI) m/z: 549.1 [M+H + ].
  • Step G Dissolve compound 7-7 (536.29 mg, 977.38 ⁇ mol,) in tetrahydrofuran (5 mL) and then add 7-8 (108.60 mg, 977.38 ⁇ mol), T 3 P (1.24 g, 1.95 mmol, 50% ethyl acetate) Solution) and DIEA (505.26mg, 3.91mmol), and react at 25°C for 12 hours. Water (50 mL) was added to the reaction solution and extracted with ethyl acetate (25 mL ⁇ 2). The combined organic phase was washed with saturated sodium chloride solution (25 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7-9. MS(ESI) m/z: 642.1 [M+H + ].
  • Step H Compound 7-9 (480mg, 747.89 ⁇ mol) was dissolved in dichloromethane (2mL), then trifluoroacetic acid (4.26g, 37.39mmol) was added to the reaction solution, and the resulting mixture was stirred at 25°C for half an hour .
  • the reaction solution was concentrated under reduced pressure to obtain a crude product.
  • the crude product was separated by preparative high performance liquid chromatography (column chromatography: Phenomenex Luna C18 75*30*3 ⁇ m; mobile phase: [water (0.225% FA)-ACN]; ACN%: 13%-35%, 10 minutes) and purified.
  • Step A Dissolve compound 3-1 (3g, 20.41mmol) in N,N-dimethylformamide (50mL), add 8-1 (3.12g, 22.45mmol), cesium carbonate (9.98 g, 30.62 mmol) and TBAI (1.51 g, 4.08 mmol), and the resulting mixture was stirred at 90°C for 4 hours.
  • the reaction solution was quenched by adding water (50 mL) and extracted with dichloromethane (25 mL ⁇ 2). The combined organic phase was washed twice with saturated sodium chloride solution (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • Step B Compound 8-2 (1g, 4.88mmol), 3-6 (1.27g, 4.88mmol), palladium acetate (109.49mg, 487.68 ⁇ mol), P(o-tolyl) 3 (1.48g, 4.88mmol) , Triethylamine ((2.47g, 24.38mmol, 3.39mL) and lithium bromide (1.27g, 14.63mmol) were dissolved in toluene (10mL), the resulting mixture was replaced with nitrogen three times and stirred at 110°C for 12 hours. In the reaction solution It was quenched by adding water (100 mL) and extracted with ethyl acetate (100 mL ⁇ 2).
  • Step C Compound 8-3 (230 mg, 598.40 ⁇ mol) was dissolved in water (2 mL) and ethanol (10 mL), and iron powder (334.20 mg, 5.98 mmol) and ammonium chloride (160.04 mg, 2.99) were added to the reaction system. mmol), the resulting mixture was stirred at 90°C for 3 hours. After the reaction solution was filtered through Celite, the filtrate was extracted with ethyl acetate (50mL ⁇ 2). The combined organic phases were washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 8-4 . MS(ESI) m/z: 355.1 [M+H + ].
  • Step D Compound 8-4 (100mg, 282.19 ⁇ mol) was dissolved in tetrahydrofuran (5mL), and 1-8 (125.97mg, 564.37 ⁇ mol), T3P (538.71mg, 846.56 ⁇ mol, 503.47 ⁇ L, 50 % Purity) and DIEA (182.35 mg, 1.41 mmol, 245.75 ⁇ L), and the resulting mixture was stirred at 25° C. for 12 hours. The reaction solution was quenched by adding water (50 mL) and extracted with dichloromethane (25 mL ⁇ 2).
  • the combined organic phase was washed twice with saturated sodium chloride solution (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • the crude product was purified by high performance liquid chromatography (column information: Phenomenex Gemini-NX C18 75*30mm*3 ⁇ m; mobile phase: water(0.1%TFA)-ACN]; B%: 30%-40%, 7 minutes) to obtain compound 8 .
  • Step A Dissolve compound 9-1 (4.75g, 30.21mmol), 2-2 (4.5g, 30.21mmol), potassium carbonate (8.35g, 60.41mmol) in N,N-dimethylformamide (100mL) The resulting mixture was stirred at 80°C for 12 hours. Water (300 mL) was added to the reaction solution to quench the reaction and extracted with ethyl acetate (100 mL ⁇ 3). The combined organic phase was washed with saturated sodium chloride solution (200 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 9-2. MS(ESI)m/z:270.1[M+H + ].
  • Step B The compound 9-2 (7g, 25.96mmol), 1-2 (4.80g, 31.16mmol), tetrakis (triphenylphosphorus) palladium (3.00g, 2.60mmol,), sodium carbonate (5.50g, 51.93 mmol) was dissolved in 1,4-dioxane (120 mL) and water (24 mL), and the resulting mixture was replaced with nitrogen three times and stirred at 84°C for 12 hours. The reaction solution was quenched by adding water (50 mL) and extracted with ethyl acetate (100 mL ⁇ 3).
  • Step C Compound 9-3 (200mg, 765.67 ⁇ mol,), 9-4 (539.47mg, 1.53mmol), palladium acetate (17.19mg, 76.57 ⁇ mol,), triethylamine (387.39mg, 3.83mmol, 532.86 ⁇ L) ), lithium bromide (199.48mg, 2.30mmol), P(o-tolyl) 3 (233.04mg, 765.67 ⁇ mol) was dissolved in N,N-dimethylacetamide (10mL), the resulting mixture was replaced with nitrogen three times and heated at 70 Stir at °C for 12 hours.
  • Step D Dissolve compound 9-5 (200mg, 411.88 ⁇ mol) in ethanol (5mL) and water (1mL), then add iron powder (230.01mg, 4.12mmol), ammonium chloride (110.16mg, 2.06mmol), The resulting mixture was stirred at 90°C for 1 hour. The reaction solution was filtered and extracted with ethyl acetate (20 mL ⁇ 2). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 9-6. MS(ESI) m/z: 456.1 [M+H + ].
  • Step E Compound 1-8 (82.79mg, 370.94 ⁇ mol) was dissolved in dichloromethane (3mL) and oxalyl chloride (181.08mg, 1.43mmol), N,N-dimethylformamide ((2.09mg , 28.53 ⁇ mol), the resulting mixture was stirred for half an hour at 25°C.
  • the crude acid chloride was obtained by concentration under reduced pressure, and then the acid chloride was dissolved in dichloromethane (3mL), and pyridine (112.85mg, 1.43mmol) was added to the solution at zero degrees.
  • Step F Compound 9-7 (170 mg, 257.27 ⁇ mol) was dissolved in dichloromethane (2 mL), then trifluoroacetic acid (2 mL) was added to the reaction solution, and the resulting mixture was stirred at 25° C. for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (column information: Phenomenex luna C18 150*40*15 ⁇ m; mobile phase: [water (0.1%TFA)-ACN]; ACN%: 30%-60%, 10 minutes) to obtain compound 9 The trifluoroacetate.
  • Step A Dissolve compound 10-1 (2g, 12.20mmol) in N,N-dimethylformamide (20mL), add 10-2 (3.88g, 24.39mmol), potassium carbonate (7.95g, 24.39 mmol), and the resulting mixture was stirred at 70°C for 12 hours.
  • Water (20 mL) was added to the reaction solution, and it was extracted with ethyl acetate (20 mL ⁇ 2).
  • the combined organic phase was washed twice with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product.
  • Step B Compound 10-3 (700 mg, 2.31 mmol), 1-2 (426.87 mg, 2.77 mmol), tetrakis (triphenylphosphorus) palladium (266.90 mg, 230.97 ⁇ mol), sodium carbonate (489.60 mg, 4.62 mmol) ) was dissolved in 1,4-dioxane (10 mL) and water (2 mL), and the resulting mixture was replaced with nitrogen three times and stirred at 85°C for 12 hours. The reaction solution was diluted with water (10 mL) and ethyl acetate (10 mL), and extracted with ethyl acetate (20 mL ⁇ 3).
  • Step C Compound 10-4 (0.65g, 2.21mmol), 3-4 (1.35g, 4.41mmol), palladium acetate (49.52mg, 220.59 ⁇ mol), triethylamine (1.12g, 11.03mmol), tetrabutyl Amine bromide (617.07mg, 1.91mmol), P(o-tolyl) 3 (671.40mg, 2.21mmol), lithium bromide (574.71mg, 6.62mmol) dissolved in N,N-dimethylacetamide (10mL) The resulting mixture was replaced with nitrogen three times and stirred at 125°C for 12 hours.
  • reaction solution was diluted with water (10 mL) and ethyl acetate (10 mL), and extracted with ethyl acetate (20 mL ⁇ 3).
  • the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • Step D Dissolve compound 10-5 (270mg, 520.19 ⁇ mol) in ethanol (10mL) and water (2mL), then add iron powder (290.50mg, 5.20mmol), ammonium chloride (139.13mg, 2.60mmol), The resulting mixture was stirred at 90°C for 1 hour. After the reaction solution was filtered, the filtrate was extracted with ethyl acetate (20 mL ⁇ 2). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 10-6. MS(ESI) m/z: 489.2 [M+H + ].
  • Step E Compound 1-8 (94.93mg, 425.31 ⁇ mol) was dissolved in dichloromethane (5mL), and N,N-dimethylformamide (2.39mg, 32.72 ⁇ mol) was added to the reaction.
  • Oxalyl chloride (207.63 mg, 1.64 mmol) was added to the reaction system, and the resulting mixture was stirred at 25°C for 0.5 hours. Concentrate under reduced pressure to obtain crude acid chloride.
  • the crude acid chloride was dissolved in dichloromethane (5 mL), and the temperature was reduced to 0°C. At this temperature, pyridine (129.39 mg, 1.64 mmol) was added to the reaction system, and then 10 was added dropwise to the reaction.
  • Step F Compound 10-7 (100 mg, 144.04 ⁇ mol) was dissolved in dichloromethane (5 mL), then trifluoroacetic acid (1 mL) was added to the reaction solution, and the resulting mixture was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by high performance liquid chromatography (column information: Phenomenex Gemini-NX C18 75*30mm*3 ⁇ m; mobile phase: [water (0.1%TFA)-ACN]; B%: 42%-52%, 7 minutes) and purified. Compound 10 trifluoroacetate salt.
  • Step A Dissolve compound 11-1 (2g, 13.61mmol) in N,N-dimethylformamide (10mL), add 2-bromoethanol (1.87g, 14.97mmol, 1.06mL), carbonic acid to the reaction system Cesium (6.65g, 20.41mmol,), TBAI (1.01g, 2.72mmol), the resulting mixture was stirred at 80°C for 12 hours.
  • the reaction solution was quenched by adding water (50 mL) and extracted with dichloromethane (20 mL ⁇ 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude compound 11-2.
  • Step B Dissolve compound 11-2 (3g, 15.70mmol) in N,N-dimethylformamide (20mL), add TBSCl (2.84g, 18.85mmol), imidazole (2.14g, 31.41) to the reaction system mmol), the resulting mixture was stirred at 25°C for 12 hours.
  • the reaction solution was quenched by adding water (20 mL) and ethyl acetate (50 mL) and extracted with ethyl acetate (50 mL ⁇ 3).
  • the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • Step C The compound 3-6 (1g, 3.84mmol), 11-3 (2.35g, 7.69mmol), palladium acetate (86.28mg, 384.29 ⁇ mol), triethylamine (1.94g, 19.21mmol), lithium bromide (1.00 g, 11.53mmol), P(o-tolyl) 3 (1.17g, 3.84mmol) was dissolved in N,N-dimethylacetamide (10mL), the resulting mixture was replaced with nitrogen three times and stirred at 125°C for 12 hours . The reaction solution was diluted with water (10 mL) and ethyl acetate (10 mL), and extracted with ethyl acetate (20 mL ⁇ 3).
  • Step D Dissolve compound 11-4 (500mg, 1.03mmol) in ethanol (10mL) and water (2mL), then add iron powder (576.20mg, 10.32mmol), ammonium chloride (1551.91mg, 10.32mmol), The resulting mixture was stirred at 90°C for 1 hour. After the reaction solution was filtered, the filtrate was extracted with ethyl acetate (20 mL ⁇ 2). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 11-5. MS(ESI)m/z:455.2[M+H + ].
  • Step E Dissolve compound 1-8 (287.22mg, 1.29mmol) in dichloromethane (10mL), add N,N-dimethylformamide (7.24mg, 98.99 ⁇ mol) to the reaction, and keep at 25°C Oxalyl chloride (628.19 mg, 4.95 mmol) was added to the reaction system, and the resulting mixture was stirred at 25°C for 0.5 hours. Concentrate under reduced pressure to obtain crude acid chloride. The crude acid chloride was dissolved in dichloromethane (10 mL), and the temperature was reduced to 0°C. At this temperature, pyridine (391.49 mg, 4.95 mmol) was added to the reaction system, and then 11 was added dropwise to the reaction.
  • Step F Compound 11-6 (.45g, 682.03 ⁇ mol) was dissolved in dichloromethane (10mL), then trifluoroacetic acid (77.77mg, 682.03 ⁇ mol) was added to the reaction solution, and the resulting mixture was stirred at 25°C for 5 Hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by (PPhenomenex Gemini-NX C18 75*30mm*3 ⁇ m; mobile phase: [water (0.1%TFA)-ACN]; B%: 30%-40%, 7 minutes) to obtain the trifluoroacetate salt of compound 11 .
  • Step A Dissolve compound 12-1 (5g, 34.02mmol), 2-bromoethanol (4.68g, 37.42mmol), cesium carbonate (16.63g, 51.03mmol), TBAI (2.51g, 6.80mmol) in N, N -In dimethylacetamide (50 mL) and water (20 mL), the resulting mixture was stirred at 90°C for 12 hours.
  • the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL ⁇ 2). The combined organic layer was washed with saturated sodium chloride solution (100 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure , Get 12-2.
  • Step B Dissolve compound 12-2 (6.5g, 34.03mmol), TBSCl (6.15g, 40.83mmol), imidazole (4.63g, 68.05mmol) in N,N-dimethylformamide (50mL), The resulting mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (100 mL ⁇ 2). The combined organic layer was washed with saturated sodium chloride solution (50 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure , Get the crude product.
  • Step C The compound 12-3 (1g, 3.84mmol), 3-6 (2.34g, 7.68mmol), palladium acetate (86.28mg, 384.00 ⁇ mol), tetrakis (triphenylphosphorus) palladium (1.17g, 3.84mmol) ), anhydrous lithium bromide (1.00g, 11.52mmol, 289.38 ⁇ L), triethylamine (1.94g, 19.20mmol), dissolved in N,N-dimethylacetamide (10mL), the resulting mixture was replaced with nitrogen three times and in Stir at 125°C for 12 hours. The reaction mixture was diluted with 300 mL of water and extracted with ethyl acetate (100 mL ⁇ 2).
  • Step D Dissolve compound 12-4 (560mg, 1.16mmol) in ethanol (5mL) and water (1mL), then add iron powder (645.41mg, 11.56mmol), ammonium chloride (309.07mg, 5.78mmol), The resulting mixture was stirred at 90°C for 2 hours. The reaction solution was filtered and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 12-5. MS(ESI)m/z:455.2[M+H + ].
  • Step E Dissolve compound 1-8 (294.58mg, 1.32mmol) in dichloromethane (5mL), add oxalyl chloride (698.01mg, 5.50mmol) and N,N-dimethylformamide ( 8.04mg, 109.98 ⁇ mol), reacted at 25°C for half an hour.
  • the solution was concentrated to obtain the corresponding acid chloride and dissolved in dichloromethane (5 mL), and 12-5 (500 mg, 1.10 mmol) and pyridine (434.99 mg, 5.50 mmol) were added to the solution at 0°C.
  • the resulting mixture was stirred at 25°C for half an hour.
  • Step F Compound 12-6 (450mg, 682.03 ⁇ mol) was dissolved in dichloromethane (4mL), then trifluoroacetic acid (3.89g, 34.10mmol) was added to the reaction solution, and the resulting mixture was stirred at 25°C for 1 hour . The reaction solution was concentrated to obtain a crude product.
  • Step A Dissolve compound 1-8 (2.63g, 11.80mmol) in dichloromethane (15mL), add oxalyl chloride (2.50g, 19.67mmol) and N,N-dimethylformamide ( (28.75mg, 393.34 ⁇ mol), reacted for half an hour at 25°C.
  • the solution was concentrated to obtain the corresponding acid chloride and dissolved in tetrahydrofuran (15mL), and 2-2((2g, 15.73mmol) was added to the solution at 0°C. The result was obtained.
  • the mixture was stirred at 70°C for two hours.
  • Step B Dissolve compound 13-7 (2g, 6.02mmol) in N,N-dimethylformamide (15mL), slowly add sodium hydride (262.63mg, 6.57mmol, 60% content) at 0°C, the mixture After reacting at 25°C for half an hour, compound 1-1 (719.69 mg, 5.47 mmol) was added to the reaction, and the resulting mixture was stirred at 120°C for 12 hours.
  • the reaction mixture was diluted with water (300 mL) and then diluted with ethyl acetate (150 mL ⁇ 2) Extraction, the mixed organic layer was washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • Step C Dissolve compound 3-4 (500mg, 1.64mmol), cuprous iodide (31.19mg, 163.78 ⁇ mol), Xantphos (94.77mg, 163.78 ⁇ mol), and palladium chloride (29.04mg, 163.78 ⁇ mol) in triethyl
  • the resulting mixture in the amine (50 mL) was replaced with nitrogen three times, and 13-1 (3.22 g, 32.76 mmol) was added to the resulting mixture and stirred at 65°C for 12 hours.
  • the reaction mixture was filtered with Celite, diluted with water (200 mL), and extracted with ethyl acetate (100 mL ⁇ 2).
  • Step D Compound 13-2 (2g, 6.20mmol) and potassium carbonate (1.71g, 12.40mmol) were dissolved in methanol (20mL), and the resulting mixture was stirred at 60°C for 2 hours.
  • the reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (150 mL ⁇ 2).
  • the combined organic layer was washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Crude.
  • Step E Dissolve compound 13-4 (1.570g, 6.18mmol), cuprous chloride (15.81mg, 159.74 ⁇ mol), Xantphos (92.43mg, 159.74 ⁇ mol) in tetrahydrofuran (5mL), and replace the resulting mixture with nitrogen Three times, add potassium tert-butoxide in tetrahydrofuran (1M, 1.60mL), then add 13-3 (400mg, 1.60mmol) and methyl iodide (453.46mg, 3.19mmol), the mixture was replaced with nitrogen once, the resulting mixture was at 25°C Stir for 12 hours.
  • Step F Compound 13-5 (130 mg, 331.28 ⁇ mol), compound 13-6 (176.44 mg, 397.54 ⁇ mol), tetrakis (triphenylphosphorus) palladium (38.28 mg, 33.13 ⁇ mol), sodium carbonate (70.23 mg, 662.56 ⁇ mol) was dissolved in 1,4-dioxane (1 mL) and water (0.4 mL), the mixture was replaced with nitrogen three times, and the resulting mixture was stirred at 85°C for 4 hours. The reaction mixture was diluted with 50 mL of water and extracted with 100 mL of ethyl acetate (50 mL ⁇ 2).
  • Step G Compound 13-9 (100mg, 148.41 ⁇ mol) was dissolved in dichloromethane (1mL), and trifluoroacetic acid (846.07mg, 7.42mmol) was added to the reaction system. The resulting mixture was stirred at 25°C for 0.5 hours. The reaction was quenched by adding aqueous sodium bicarbonate solution (30 mL) to the solution and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • the crude product was purified by high performance liquid chromatography (column information: water Xbridge BEH C18 250*50mm*10 ⁇ m; mobile phase: [water (0.05% ammonia)-ACN]; ACN%: 40%-60%, 20 minutes) to obtain the compound 13.
  • Step A Compound 2-4 (855.62mg, 3.28mmol), 3-4 (1g, 3.28mmol), palladium acetate (73.54mg, 327.56 ⁇ mol), triethylamine (1.66g, 16.38mmol), P(o -tolyl) 3 (996.98 mg, 3.28 mmol), lithium bromide (853.41 mg, 9.83 mmol) was dissolved in toluene (30 mL), the resulting mixture was replaced with nitrogen three times and stirred at 110°C for 12 hours. Water (100 mL) was added to the reaction solution to quench the reaction and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step B Dissolve compound 14-1 (300mg, 617.81 ⁇ mol) in ethanol (10mL) and water (2mL), then add iron powder (345.02mg, 6.18mmol), ammonium chloride (165.24mg, 3.09mmol), The resulting mixture was stirred at 90°C for 6 hours. The reaction solution was filtered and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 14-2. MS(ESI) m/z: 456.1 [M+H + ].
  • Step C Dissolve compound 14-2 (100 mg, 219.49 ⁇ mol) in dichloromethane (5 mL), and then add 1-8 (97.98 mg, 438.98 ⁇ mol), T 3 P (419.03 mg, 658.47 ⁇ mol), DIEA ( 141.84mg, 1.10mmol). The mixture was stirred at 25°C for 12 hours. The reaction solution was quenched by adding water (50 mL) and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product 14-3. MS(ESI) m/z: 661.1 [M+H + ].
  • Step D Dissolve compound 14-3 (30 mg, 45.40 ⁇ mol) in dichloromethane (2 mL), add trifluoroacetic acid (709.19 mg, 6.22 mmol) to the reaction system, and stir the resulting mixture at 25°C for 1 hour.
  • the reaction mixture Concentrate under reduced pressure to obtain crude product.
  • the crude product was separated by high performance liquid chromatography (column information: Xtimate C18 150*40mm*10 ⁇ m; mobile phase: [water (0.05% ammonia)-ACN]; ACN%: 32%-62%, 10 minutes) to obtain compound 14 .
  • Step A Dissolve compound 15-1 (3g, 23.16mmol), compound 15-2 (4.07g, 23.16mmol), potassium carbonate (6.40g, 46.32mmol) in N,N-dimethylformamide (20mL) The resulting mixture was stirred at 100°C for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL ⁇ 2).
  • Step B Combine compound 15-3 (3g, 10.52mmol), 1-2 (1.94g, 12.63mmol), tetrakis (triphenylphosphorus) palladium (1.22g, 1.05mmol), sodium carbonate (2.23g, 21.05mmol) ) was dissolved in 1,4-dioxane (30 mL) and water (6 mL), and the resulting mixture was replaced with nitrogen three times and stirred at 84°C for 4 hours. The reaction solution was quenched by adding water (100 mL) and extracted with ethyl acetate (100 mL ⁇ 2).
  • Step C Compound 15-4 (906.28mg, 3.28mmol), 3-4 (1g, 3.28mmol), palladium acetate (73.54mg, 327.56 ⁇ mol), triethylamine (1.66g, 16.38mmol), P(o -tolyl) 3 (997.00 mg, 3.28 mmol), lithium bromide (853.46 mg, 9.83 mmol) was dissolved in toluene (10 mL), the resulting mixture was replaced with nitrogen three times and stirred at 110°C for 12 hours. Water (100 mL) was added to the reaction solution to quench the reaction and extracted with ethyl acetate (100 mL ⁇ 2).
  • Step D Dissolve compound 15-5 (400mg, 798.33 ⁇ mol) in ethanol (10mL) and water (2mL), then add iron powder (445.86mg, 7.98mmol), ammonium chloride (213.51mg, 3.99mmol), The resulting mixture was stirred at 90°C for 6 hours. The reaction solution was filtered and extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product 15-6. MS(ESI) m/z: 471.2 [M+H + ].
  • Step E Compound 1-8 (56.86mg, 254.74 ⁇ mol) was dissolved in dichloromethane (5mL), and oxalyl chloride (134.73mg, 1.06mmol) and N,N-dimethylformamide ( 1.55mg, 21.23 ⁇ mol), reacted at 25°C for half an hour. The solution was concentrated to obtain the corresponding acid chloride and dissolved in dichloromethane (10 mL), and 15-6 (100 mg, 212.28 ⁇ mol) and pyridine (83.96 mg, 1.06 mmol) were added to the solution at 0°C. The resulting mixture was stirred at 25°C for half an hour.
  • Step F Dissolve compound 15-7 (120mg, 177.45 ⁇ mol) in dichloromethane (2mL), add trifluoroacetic acid (2.77g, 24.31mmol) to the reaction system, and stir the resulting mixture at 25°C for 1 hour.
  • the reaction mixture Concentrate under reduced pressure to obtain crude product.
  • the crude product was separated by high performance liquid chromatography (column information: Xtimate C18 150*40mm*10 ⁇ m; mobile phase: [water (0.05% ammonia)-ACN]; ACN%: 37%-67%, 10 minutes) to obtain compound 15 .
  • Step A Dissolve compound 6 (300mg, 598.23 ⁇ mol), 16-1 (239.80mg, 1.79mmol), cesium carbonate (584.74mg, 1.79mmol), potassium iodide (9.93mg, 59.82 ⁇ mol) in N,N-dimethyl In methylacetamide (2 mL), the resulting mixture was stirred at 100°C for 12 hours.
  • Step A Dissolve compound 6 (50mg, 99.70 ⁇ mol), 17-1 (33.28mg, 119.64 ⁇ mol), cesium carbonate (97.46mg, 299.10 ⁇ mol) in N,N-dimethylacetamide (2mL), The resulting mixture was stirred at 60°C for 2 hours.
  • Step B Dissolve compound 17-2 (70mg, 100.18 ⁇ mol) in ethyl acetate (3mL), add hydrochloric acid methanol solution (4mol/L, 3mL) to the reaction system, and stir the mixture for 30 minutes at 20°C.
  • the reaction mixture Concentrate under reduced pressure to obtain crude product.
  • the crude product is separated by high performance liquid chromatography (column information: Unisil 3-100 C18 Ultra 150*50mm*3 ⁇ m; mobile phase: [water (0.225%FA)-ACN]; B%: 15%-35%, 10 minutes) Purification provides compound 17-3.
  • Step C Compound 17-3 (97.71 mg, 163.22 ⁇ mol) was dissolved in tetrahydrofuran (10 mL), and 37 aqueous formaldehyde solution (49.01 mg, 1.63 mmol) and sodium triacetyl borohydride (172.97 mg, 816.10 ⁇ mol) were added to obtain a mixture Stir at 20°C for 12 hours.
  • the reaction was quenched with saturated sodium bicarbonate (5mL), diluted with water (5mL), separated, the aqueous phase was extracted with ethyl acetate (20mL ⁇ 3), the mixed organic layer was washed with saturated brine (20mL), anhydrous Dry over sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product.
  • Step A Dissolve compound 6 (50mg, 99.70 ⁇ mol), 18-1 (34.96mg, 119.65 ⁇ mol), cesium carbonate (97.46mg, 299.10 ⁇ mol) in N,N-dimethylacetamide (2mL), The resulting mixture was stirred at 60°C for 2 hours.
  • Step B Dissolve compound 18-2 (70 mg, 98.21 ⁇ mol) in ethyl acetate (3 mL), add hydrochloric acid methanol solution (4 mol/L, 3 mL) to the reaction system, and stir the mixture for 30 minutes at 20°C.
  • the reaction mixture Concentrate under reduced pressure to obtain crude product.
  • the crude product was separated by preparative high performance liquid chromatography (column information: Unisil 3-100 C18 Ultra 150*50mm*3 ⁇ m; mobile phase: [water (0.225%FA)-ACN]; ACN%: 15%-35%, 10 Min) Purification to obtain compound 18-3.
  • Step C Compound 18-3 (100mg, 163.22 ⁇ mol) was dissolved in tetrahydrofuran (10mL), 37 formaldehyde aqueous solution (49.01mg, 1.63mmol) and sodium triacetyl borohydride (172.97mg, 816.10 ⁇ mol) were added, and the resulting mixture was Stir at 20°C for 12 hours. The reaction was quenched with saturated sodium bicarbonate (5mL), diluted with water (5mL), separated, the aqueous phase was extracted with ethyl acetate (20mL ⁇ 3), the mixed organic layer was washed with saturated brine (20mL), anhydrous Dry over sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product.
  • tetrahydrofuran 10mL
  • 37 formaldehyde aqueous solution 49.01mg, 1.63mmol
  • sodium triacetyl borohydride 172.97mg, 816.10 ⁇ mol
  • Step A Dissolve compound 6 (50mg, 99.70 ⁇ mol), 19-1 (35.08mg, 119.64 ⁇ mol), cesium carbonate (97.46mg, 299.10 ⁇ mol) in N,N-dimethylacetamide (2mL), The resulting mixture was stirred at 60°C for 2 hours.
  • Step B Dissolve compound 19-2 (70mg, 98.07 ⁇ mol) in ethyl acetate (3mL), add hydrochloric acid methanol solution (4mol/L, 3mL) to the reaction system, and stir the mixture for 30 minutes at 20°C.
  • the reaction mixture Concentrate under reduced pressure to obtain crude product.
  • the crude product is separated by high performance liquid chromatography (column information: Unisil 3-100 C18 Ultra 150*50mm*3 ⁇ m; mobile phase: [water (0.225%FA)-ACN]; B%: 15%-35%, 10 minutes) Purification afforded compound 19-3.
  • Step C Compound 19-3 (100 mg, 162.96 ⁇ mol) was dissolved in tetrahydrofuran (10 mL), and 37% aqueous formaldehyde solution (48.94 mg, 1.63 mmol) and sodium triacetyl borohydride (172.69 mg, 814.79 ⁇ mol) were added to obtain a mixture Stir at 20°C for 12 hours.
  • Step A Dissolve compound 20-1 (5.08g, 19.10mmol), compound 20-2 (5.02g, 21.00mmol), cesium carbonate (12.44g, 38.19mmol) in N,N-dimethylacetamide (50mL In), the resulting mixture was stirred at 60°C for 12 hours.
  • the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL ⁇ 2).
  • the mixed organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • MS(ESI) m/z: 425.3 [M+H + ].
  • Step B Compound 20-3 (2.4g, 5.66mmol) was dissolved in ethanol (20mL), sodium borohydride (641.91mg, 16.97mmol) was added to the reaction system, the resulting mixture was stirred at 90°C for 12 hours, and hydrochloric acid was added (1mol/L, 10mL) The reaction was quenched, water (50mL) was added, and the mixture was extracted with ethyl acetate (50mL ⁇ 2). The mixed organic layer was washed with saturated brine (50mL), dried with anhydrous sodium sulfate, and filtered. Concentrate under reduced pressure to obtain compound 20-4. MS(ESI) m/z: 383.3 [M+H + ].
  • Step C Dissolve compound 20-4 (2.9g, 7.59mmol) in N,N-dimethylacetamide (15mL), add TBSCl (1.37g, 9.10mmol) and imidazole (1.03g, 15.17mmol) to obtain The mixture was stirred at 25°C for 12 hours. Dilute with water (50mL) and extract with ethyl acetate (50mL ⁇ 2). The mixed organic layer was washed with saturated brine (80mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • Step D Combine compound 3-6 (655.04mg, 2.52mmol), compound 20-5 (1.25g, 2.52mmol), palladium acetate (56.51mg, 251.73 ⁇ mol), triethylamine (1.27g, 12.59mmol), lithium bromide (655.87mg, 7.55mmol), P(o-tolyl) 3 (766.18mg, 2.52mmol) was dissolved in N,N-dimethylacetamide (10mL), the resulting mixture was replaced with nitrogen three times and stirred at 110°C 12 hours. Water (50 mL) was added to the reaction solution and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step E Dissolve compound 20-6 (1.5g, 2.39mmol) in ethanol (15mL), then add iron powder (1.33g, 23.85mmol), ammonium chloride solution (127.59mg, 2.39mmol, 2.5mL water), The resulting mixture was stirred at 80°C for 12 hours. Filter, collect the filtrate, add water (50 mL), and extract with ethyl acetate (50 mL ⁇ 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 20-7, and the crude product was directly used in the next step. MS(ESI)m/z:599.5[M+H + ].
  • Step F Dissolve compound 1-8 (339.14mg, 1.52mmol) in dichloromethane (10mL), add oxalyl chloride (741.79mg, 5.84mmol) and N,N-dimethylformamide ( 8 ⁇ L), react at 25°C for half an hour. The solution was concentrated to obtain the corresponding acid chloride and dissolved in dichloromethane (10 mL), 20-7 (700 mg, 1.17 mmol) and pyridine (462.27 mg, 5.84 mmol) were added to the solution at 0°C. The resulting mixture was stirred at 25°C half an hour.
  • Step G Dissolve compound 20-8 (0.9g, 1.12mmol) in dichloromethane (20mL), then add hydrochloric acid methanol solution (4mol/L, 5mL) and ethyl acetate (5mL) to the reaction solution to obtain The mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (column information: Phenomenex luna C18 150*40mm*15 ⁇ m; mobile phase: [water (0.225% FA)-ACN]; ACN%: 15%-45%, 10 minutes) and purified. Compound 20.
  • Step A Compound 3-6 (735.87mg, 2.83mmol), compound 20-3 (1.2g, 2.83mmol), palladium acetate (63.49mg, 283.00 ⁇ mol), triethylamine (1.43g, 14.15mmol), lithium bromide (736.80mg, 8.49mmol), P(o-tolyl) 3 (860.72mg, 2.83mmol) was dissolved in N,N-dimethylacetamide (10mL), the resulting mixture was replaced with nitrogen three times and stirred at 110°C 12 hours. Water (50 mL) was added to the reaction solution and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step B Dissolve compound 21-1 (1.36g, 2.44mmol) in ethanol (25mL), then add iron powder (1.21g, 21.60mmol), ammonium chloride solution (1.34g, 24.97mmol, 2.5mL water), The resulting mixture was stirred at 80°C for 12 hours. Filter, collect the filtrate, add water (50 mL), and extract with ethyl acetate (50 mL ⁇ 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 21-2, and the crude product was directly used in the next step. MS(ESI) m/z: 527.4 [M+H + ].
  • Step C Dissolve compound 1-8 (330.56 mg, 1.48 mmol) in dichloromethane (10 mL), add oxalyl chloride (723.01 mg, 5.70 mmol) and N,N-dimethylformamide ( 8 ⁇ L), react at 25°C for half an hour. The solution was concentrated to obtain the corresponding acid chloride and dissolved in dichloromethane (10 mL). 21-2 (600 mg, 1.14 mmol) and pyridine (450.56 mg, 5.70 mmol) were added to the solution at 0°C. The resulting mixture was stirred at 25°C half an hour.
  • Step D Compound 21-3 (1g, 1.37mmol) was dissolved in methanol (5mL) and water (5mL), and then lithium hydroxide (65.45mg, 2.73mmol) was added to the reaction solution. The resulting mixture was kept at 25°C. Stir for 18 hours. Use hydrochloric acid (1mol/L) to adjust the pH to about 3, add water (50mL), and extract with ethyl acetate (50mL ⁇ 2). The combined organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 21-4, and the crude product was directly used in the next step. MS(ESI) m/z: 590.2 [M+H + ].
  • Step E Dissolve compound 21-4 (100mg, 169.62 ⁇ mol) in N,N-dimethylacetamide (2mL), add ammonium chloride (18.15mg, 339.24 ⁇ mol), PyBOP (105.92mg, 203.55 ⁇ mol) , DIEA (87.69 mg, 678.49 ⁇ mol) and HOBt (27.50 mg, 203.55 ⁇ mol), and the resulting mixture was stirred at 25°C for 12 hours. Water (20 mL) was added, and extraction was performed with ethyl acetate (20 mL ⁇ 2).
  • Step A Dissolve compound 21-4 (380mg, 644.56 ⁇ mol) in acetonitrile (9mL), add methylamine hydrochloride (87.04mg, 1.29mmol), HATU (269.59mg, 709.02 ⁇ mol), DIEA (333.21mg, 2.58 mmol) and N,N-dimethylacetamide (0.9 mL), and the resulting mixture was stirred at 25°C for 12 hours. Water (50 mL) was added, and extraction was performed with dichloromethane (50 mL ⁇ 2).
  • Step A Dissolve compound 21-4 (100mg, 169.62 ⁇ mol) in N,N-dimethylacetamide (2mL), add hydroxylamine hydrochloride (23.57mg, 339.24 ⁇ mol), PyBOP (105.92mg, 203.55 ⁇ mol), DIEA (109.61 mg, 848.11 ⁇ mol) and HOBt (27.50 mg, 203.55 ⁇ mol), the resulting mixture was stirred at 25°C for 12 hours. Water (20 mL) was added, and extraction was performed with ethyl acetate (20 mL ⁇ 2).
  • Step A Dissolve compound 21-4 (100mg, 169.62 ⁇ mol) in N,N-dimethylacetamide (2mL), add hydroxyethylamine (20.72mg, 339.24 ⁇ mol), PyBOP (105.92mg, 203.55 ⁇ mol) ), DIEA (109.61 mg, 848.11 ⁇ mol) and HOBt (27.50 mg, 203.55 ⁇ mol), and the resulting mixture was stirred at 25°C for 12 hours. Water (50 mL) was added, and extraction was performed with ethyl acetate (50 mL ⁇ 2).
  • VEGFR-2/KDR Vascular endothelial cell growth factor receptor 2
  • KDR Kinase Enzyme System (KDR kinase enzyme system) was purchased from Promega. Nivo multi-label analyzer (PerkinElmer).
  • kinase buffer in the kit to dilute the enzyme, substrate, ATP and inhibitor.
  • the compound to be tested was diluted 5 times with a discharge gun to the 8th concentration, that is, diluted from 50 ⁇ M to 0.65 nM, the final concentration of DMSO was 5%, and the double-well experiment was set up.
  • the reaction system was placed at 25°C for 60 minutes.
  • IC 50 can be obtained by curve fitting with four parameters (log (inhibition) vs. response in GraphPad Prism --The variable slope mode is derived).
  • the compound of the present invention has good inhibitory activity on VEGFR2/KDR kinase.
  • AXL Kinase Enzyme System (AXL Kinase Enzyme System) was purchased from Promega. Nivo multi-label analyzer (PerkinElmer). experimental method:
  • kinase buffer in the kit to dilute the enzyme, substrate, ATP, and inhibitor.
  • the compound to be tested was diluted 5-fold to the 8th concentration with a discharge gun, that is, diluted from 5 ⁇ M to 0.065 nM, with a DMSO concentration of 5%, and a double-well experiment was set up.
  • the reaction system was placed at 25°C for 60 minutes.
  • IC 50 can be obtained by curve fitting with four parameters (log (inhibition) vs. response in GraphPad Prism -The variable slope mode is derived).
  • Table 1 provides the AXL enzymatic inhibitory activity of the compounds of the present invention.
  • Test compound Axl(nM) VEGFR2(nM) Compound 1 23.16 25.84 Compound 2 formate 36.62 44.12 Compound 3 formate 11.34 37.37 Compound 4 19.14 31.59 Compound 6 37.98 96.48 Compound 7 20.17 76.98 Compound 8 13.25 / Compound 9 trifluoroacetate 34.23 74.28 Compound 11 trifluoroacetate 33.07 42.69 Compound 12 11.48 74.94 Compound 13 97.25 224.2 Compound 14 25.38 46.9 Compound 15 17.09 / Compound 16 8.5 17.09 Compound 17 formate 12.44 20.54 Compound 18 formate / 37.17 Formate of compound 19 13.89 20.51 Compound 20 / 33.56 Compound 21 1.79 19.47 Compound 22 4.22 12.76 Compound 23 / 48.71 Compound 24 / 14.81
  • the compound of the present invention has good inhibitory activity on AXL and VEGFR2 kinase.
  • Buffer solution 100mM phosphate buffer, pH 7.4, DMSO%: 1%; n-octanol saturated buffer (pH 7.4) solution; buffer (pH 7.4) saturated n-octanol solution
  • Test compound (10mM DMSO solution, 2 ⁇ L/well) and QC sample (10mM DMSO solution; 2 ⁇ L/well) were added from the stock solution to a 96-well polypropylene tube;
  • n-octanol layer is diluted Y times (200 times), and the buffer layer is diluted X times (20 times)
  • O-IS Internal standard peak area in the n-octanol layer
  • the sample analysis is carried out with a three-pole quadrupole mass spectrometer.
  • the diluted sample is injected into a small cylindrical high performance liquid chromatography column with an equal volume of water-loaded solvent, and then flushed into the mass spectrometer with a rapid gradient to obtain an organic elution solvent.
  • the peak area is calibrated by the dilution factor, combined with the internal standard, and the result (Log D value) is calculated by the ratio of the calibrated peak area.
  • Log D 7.4 is the oil-water distribution coefficient of the compound at pH 7.4, which represents the physical and chemical properties of the compound. Log D 7.4 around 3 is considered to have the best druggability. Therefore, the compound of the present invention has better physical and chemical properties than Sitravatinib.
  • MDR1-MDCKII cell line authorized by the Piet Borst Laboratory of the Netherlands Cancer Institute was used as the experimental in vitro model. It is a Madin-Darby canine kidney cell transfected with the human multi-drug resistance gene (MDR1). Cells can stably express the efflux transporter P-gp, so it is suitable for screening P-gp substrates or inhibitors, and predicts that compounds have high efflux effects in the duodenum, blood-brain barrier, hepatocyte nucleus and kidney units, etc. The permeability of the barrier. The purpose of this study is to use MDR1-MDCK II cells to determine the two-way permeability of the compound of the present invention through the MDR1-MDCK II cell model.
  • MDR1-MDCK II cells The purpose of this study is to use MDR1-MDCK II cells to determine the two-way permeability of the compound of the present invention through the MDR1-MDCK II cell model.
  • Two-way transfer including two directions: A ⁇ B and B ⁇ A;
  • HBSS buffer containing 10mM Hepes, pH7.4;
  • the sample solution in the dosing hole and the receiving hole is immediately mixed with the cold acetonitrile solution containing the internal standard.
  • the LC/MS/MS method was used to analyze the concentration of the test compound in all samples (including the initial dosing solution, the supernatant of the dosing hole, and the receiving solution). And calculate the apparent permeability coefficient, efflux ratio and other parameters.
  • Table 3 lists the permeability coefficients of Sitravatinib and compound 3 in MDR1-MDCK II monolayer cells. The results show that compound 3 has moderate permeability, while Sitravatinib has low permeability.
  • the test compound (10mM) is gradient, and the working solution (100 ⁇ final concentration) is prepared.
  • the concentration of the working solution are: 5, 1.5, 0.5, 0.15, 0.05, 0.015 and 0.005mM.
  • prepare P450 co-workers Enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) each positive inhibitor and its specific substrate mixture (5in 1) working solution; put the human liver microsomes frozen in the refrigerator at -80°C on ice to thaw and wait for others
  • the liver microsomes are completely dissolved and diluted with PB to prepare a working solution of a certain concentration (0.253mg/ml); add 20 ⁇ L of the substrate mixture to the reaction plate (add 20 ⁇ l PB to the Blank well) and 158 ⁇ L of human liver microsomes
  • the working solution is added to the reaction plate, and the reaction plate is placed on ice for use; at this time, 2 ⁇ l of each concentration of the test compound
  • the compound of the present invention is significantly better than the clinical phase III AXL&VEGFR2 inhibitor Sitravatinib in liver microsome stability (MMS), plasma protein binding rate (PPB), drug interaction (DDI) and in vitro permeability, which means
  • MMS liver microsome stability
  • PPB plasma protein binding rate
  • DAI drug interaction
  • MMS liver microsome stability
  • PPB plasma protein binding rate
  • DDI drug interaction
  • in vitro permeability which means This series of compounds have better metabolic stability; the improved permeability means that this series of compounds will be more easily absorbed, and at the same time, the risk of drug resistance due to active efflux is smaller; the CYP inhibitory activity of this series of compounds is low, and the drugs interact with each other. It has good properties of action, the safety risk of clinical combination with other drugs is smaller, and the developability is stronger.
  • CD-1 male mice aged 7-9 weeks were selected for oral administration with a volume of 10 mL/kg and a dose of 10 mg/kg.
  • the plasma clearance (CL) was 7.21 and 6.18 mL/min/kg
  • the steady-state apparent volume of distribution (Vd ss ) was 2.24 And 0.72L/kg
  • the elimination half-life (T 1/2 ) is 3.87 and 1.58h, respectively
  • the area under the plasma concentration curve (AUC 0-last ) from 0 o’clock to the last quantifiable time point is 7284 and 9645 nM ⁇ h, respectively .
  • the compound of the present invention has good oral maximum plasma concentration C max , half-life, clearance rate (CL), AUC and oral bioavailability.

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Abstract

提供了一类乙烯基取代吡啶化合物（I）及其药学上可接受的盐，以及该类化合物及其药学上可接受的盐在制备治疗相关疾病药物中的应用。

Description

乙烯基取代吡啶类化合物
本申请主张如下优先权：
CN202010163709.9，申请日2020年03月10日。
技术领域
本发明涉及一类乙烯基取代吡啶的化合物及其药学上可接受的盐，以及该类化合物及其药学上可接受的盐在制备治疗相关疾病药物中的应用。
背景技术
酪氨酸激酶可以分类为生长因子受体(例如Axl，Mer，EGFR，PDGFR，FGFR和erbB2)或非受体(例如c-src和bcr-abl)激酶。受体型酪氨酸激酶组成约20种不同的亚家族。非受体型酪氨酸激酶构成许多亚家族。这些酪氨酸激酶具有多种生物活性。受体酪氨酸激酶是跨越细胞膜的大酶，具有生长因子的细胞外结合结构域，跨膜结构域和作为激酶的细胞内部分，其磷酸化蛋白质中的特定酪氨酸残基并因此影响细胞增殖。异常或不适当的蛋白激酶活性可导致与这种异常激酶活性相关的疾病状态的升高。
VEGF受体信号传导的破坏是癌症中非常有吸引力的治疗靶标，因为血管生成是所有实体肿瘤生长的先决条件。血管生成是某些正常生理过程(例如胚胎发生和伤口愈合)的重要组成部分，但异常血管生成导致一些病理性疾病，特别是肿瘤生长。近期研究发现，VEGF可直接抑制肿瘤免疫反应，抗血管生成治疗可通过血管正常化增强肿瘤免疫。(Fukumura等“Enhancing cancer immunotherapy using antiangiogenics:opportunities and challenges”，Nat Rev Clin Oncol。2018)。VEGF-A(血管内皮生长因子A)是促进肿瘤新血管形成(血管生成)的关键因子。VEGF通过受体，即VEGFR-1(Flt-1)，VEGFR-2(KDR)和VEGFR-3(Flt-4)通过信号传导诱导内皮细胞增殖和迁移。这些信号传导反应严重依赖于受体二聚化和内在受体酪氨酸激酶(RTK)活性的激活。VEGF作为二硫键连接的同型二聚体的结合刺激受体二聚化和RTK结构域的活化。激酶活性使细胞质受体酪氨酸残基自身磷酸化，然后其作为参与信号级联增殖的分子的结合位点。尽管三种受体可能都有多种途径被阐明，但VEGFR-2信号传导是最广泛研究的，其促有丝分裂反应被认为涉及ERK-1和ERK-2丝裂原活化蛋白激酶。
Axl是TAM受体家族的成员，成员还包括Mer及Tyro3。这三者由共同的配体——生长停滞特异性蛋白6(Gas6)活化，他们通常在细胞存活、迁移和分化中祈祷胚胎发育的作用。Axl过表达和信号转导与人类得多种恶性肿瘤有关联，例如结肠癌、乳腺癌、神经胶质瘤、甲状腺癌、胃癌、黑色素瘤、肺癌以及肾细胞癌等。
Axl的抑制时可以更彻底的阻止癌症的生长，两者发挥互补和重叠的作用，靶向这两种RTKs的治疗方案可能比单靶向试剂更有效。另外，靶向Axl的治疗抗体可以阻断肿瘤间质的Axl功能，将抑制Axl与抑制VEGF受体(VEGFRs)合用，其累加效应提示了阻断Axl功能是促进“抗血管生成治疗”的一种有效手段。癌细胞会采用多种机制来逃避严格的细胞调节过程，如细胞增殖、凋亡及衰老等。因此，很多肿瘤能逃脱单激酶抑制剂的作用。Sitravatinib通过同时抑制VEGFR-2和Axl信号传导增强肿瘤免疫。因此靶向VEGFRs/Axl是一种靶向癌症细胞的潜在治疗策略，可以避开肿瘤细胞对VEGFRs，Axl等单独抑制作用的克服，从而成为一种进步的癌症治疗方案。
Figure PCTCN2021079337-appb-000001
发明内容
本发明提供式(I)化合物或其药学上可接受的盐，
Figure PCTCN2021079337-appb-000002
其中，
环A选自5元杂芳基，所述5元杂芳基包含2个N杂原子；
或者，环A选自6元杂芳基，所述6元杂芳基至多包含2个N原子；
T 1和T 2分别独立地选自C(R 5)和N；
R 1和R 3分别独立地选自H、F和CH 3；
R 2选H、F和Cl；
R 4分别独立地选自H、C 1～6烷基、C 1～6杂烷基、C 3～6环烷基、3～6元杂环烷基和-L-R 6，所述C 1～6烷基、C 1～6杂烷基、C 3～6环烷基、3～6元杂环烷基和-L-R 6任选被1、2或3个R取代；
R 5选自H和Cl；
R 6选自H、OH、5～6元杂环烷基和C 1～3烷基；
L选自-CH 2-、-CH 2-CH 2-和
Figure PCTCN2021079337-appb-000003
n选自0、1、2和3；
R分别独立地选自F、Cl、Br、I、OH、CN、COOH、NH 2、-NHCH 3、-N(CH3) 2、CH 3、CH 2CH 3、CF 3、-OCH 3、-OCH 2CH 3、-O-CH(CH 3) 2、-C(＝O)OCH 3、-C(＝O)CH 3和-C(＝O)CH 2CH 3；
所述5元杂芳基、6元杂芳基、C 1～6杂烷基和3～6元杂环烷基分别独立地包含1、2或3个独立地选自O、S、N和NH的杂原子或杂原子团。
在本发明的一些方案中，上述式(I)化合物或其药学上可接受的盐，其中，
环A选自5元杂芳基，所述5元杂芳基包含2个N杂原子；
或者，环A选自6元杂芳基，所述6元杂芳基至多包含2个N原子；
T 1和T 2分别独立地选自C(R 5)和N；
R 1和R 3分别独立地选自H、F和CH 3；
R 2选H、F和Cl；R 4分别独立地选自H、C 1～6烷基、C 1～6杂烷基、C 3～6环烷基和3～6元杂环烷基，所述 C 1～6烷基、C 1～6杂烷基、C 3～6环烷基和3～6元杂环烷基任选被1、2或3个R取代；
R 5选自H和Cl；
n选自0、1、2和3；
R分别独立地选自F、Cl、Br、I、OH、CN、COOH、NH2、-NHCH3、-N(CH3)2、CH3、CH2CH3、CF3、-OCH3、-OCH2CH3、-O-CH(CH3)2、-C(＝O)OCH3、-C(＝O)CH3和-C(＝O)CH2CH3。
所述5元杂芳基、6元杂芳基、C 1～6杂烷基和3～6元杂环烷基分别独立地包含1、2或3个独立地选自O、S、N和NH的杂原子或杂原子团。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，环A选自吡啶基、吡唑基和咪唑基，其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，R 4分别独立地选自H、C 1～4烷基、C 1～4杂烷基、5～6元杂环烷基和-L-R 6，所述、C 1～4烷基、C 1～4杂烷基、5～6元杂环烷基和-L-R 6任选被1、2或3个R取代，其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，R 4分别独立地选自H、
Figure PCTCN2021079337-appb-000004
Figure PCTCN2021079337-appb-000005
所述
Figure PCTCN2021079337-appb-000006
Figure PCTCN2021079337-appb-000007
任选被1、2或3个R取代，其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，R 4分别独立地选自H、
Figure PCTCN2021079337-appb-000008
Figure PCTCN2021079337-appb-000009
其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，R 4分别独立地选自H、C 1～4烷基和C 1～4杂烷基，所述C 1～4烷基和C 1～4杂烷基任选被1、2或3个R取代，其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，R 4分别独立地选自H、
Figure PCTCN2021079337-appb-000010
所述
Figure PCTCN2021079337-appb-000011
任选被1、2或3个R取 代，其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，R 4分别独立地选自H、
Figure PCTCN2021079337-appb-000012
其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，结构单元
Figure PCTCN2021079337-appb-000013
选自
Figure PCTCN2021079337-appb-000014
其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，结构单元
Figure PCTCN2021079337-appb-000015
选自
Figure PCTCN2021079337-appb-000016
其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，结构单元
Figure PCTCN2021079337-appb-000017
选自
Figure PCTCN2021079337-appb-000018
Figure PCTCN2021079337-appb-000019
其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，结构单元
Figure PCTCN2021079337-appb-000020
选自
Figure PCTCN2021079337-appb-000021
Figure PCTCN2021079337-appb-000022
其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，化合物选自
Figure PCTCN2021079337-appb-000023
其中，
R 41选自H、C 1～4烷基、C 1～4杂烷基、6元杂环烷基和-L-R 6，所述H、C 1～4烷基、C 1～4杂烷基、6元杂环烷基和-L-R 6任选被1、2或3个R取代；
R 42选自H和-L-R 6，所述-L-R 6任选被1、2或3个R取代；
R 6选自H、OH、6元杂环烷基和C 1～3烷基；
R 2、L和R如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，化合物选自
Figure PCTCN2021079337-appb-000024
R 1、R 2、R 3和R 4如本发明所定义。
本发明还提供化合物或其药学上可接受的盐，其选自
Figure PCTCN2021079337-appb-000025
Figure PCTCN2021079337-appb-000026
本发明还有一些技术方案是由上述各变量任意组合而来。
本发明还提供一种药物组合物，包含治疗有效量的上述的化合物或药学上可接受的盐作为活性成份以及药学上可接受的载体。
本发明还提上所述的化合物或药学上可接受的盐或上述组合物在制备Axl和VEGFR-2抑制剂中的应用。
在本发明的一些方案中，上述Axl和VEGFR-2抑制剂是治疗癌症的药物。
技术效果
本发明化合物可用于治疗对蛋白酪氨酸激酶活性的抑制有响应的肿瘤疾病，例如对抑制生长因子受体的蛋白酪氨酸激酶活性有响应的癌症。本发明还提供了用于治疗对受体型酪氨酸激酶信号传导的抑制有响应的疾病的新化合物和方法，例如，对VEGF受体信号传导抑制有响应、对Axl激酶抑制有响应的癌症。本发明化合物体外活性表现优秀，对VEGFR2/KDR激酶及AXL激酶有良好的抑制活性。本发明代表化合物较现有技术在渗透性上有极大改善，在代谢稳定性上面表现更稳定，在CYP抑制性质上面也表现极佳。本发明化合物在体内PK性质良好，具有较好的暴露量及生物利用度。本发明化合物在临床上具备更佳的成药性及更好的疗效。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
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。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中 所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。
术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0～2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键，-C 0烷基-A表示该结构实际上是-A。
当一个取代基数量为0时，表示该取代基是不存在的，比如-A-(R) 0表示该结构实际上是-A。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。
当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当一个取代基的键可以交叉连接到一个环上的两一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2021079337-appb-000027
表示其取代基R可在环己基或者环己二烯上的任意一个位置发生取代。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2021079337-appb-000028
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2021079337-appb-000029
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2021079337-appb-000030
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过 化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2021079337-appb-000031
直形虚线键
Figure PCTCN2021079337-appb-000032
或波浪线
Figure PCTCN2021079337-appb-000033
表示。例如-OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2021079337-appb-000034
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2021079337-appb-000035
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；
Figure PCTCN2021079337-appb-000036
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
Figure PCTCN2021079337-appb-000037
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2021079337-appb-000038
仍包括
Figure PCTCN2021079337-appb-000039
这种连接方式的基团，只是在连接1个化学键时，该位点的的H会对应减少1个变成相应的一价哌啶基。
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子的“环”。
除非另有规定，术语“C 1～6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C 1～6烷基包括C 1～5、C 1～4、C 1～3、C 1～2、C 2～6、C 2～4、C 6和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1～6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，术语“C 1～4烷基”用于表示直链或支链的由1至4个碳原子组成的饱和碳氢基团。所述C 1～4烷基包括C 1～2、C 1～3和C 2～3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1～4烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)等。
术语“杂烷基”本身或者与另一术语联合，表示由一定数目碳原子和至少一个杂原子或杂原子团组成的，稳定的直链或支链的烷基原子团或其组合物。在一些实施方案中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。在另一些实施方案中，杂原子团选自-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-和-S(＝O)N(H)-。在一些实施方案中，所述杂烷基为C 1～6杂烷基；在另一些实施方案中，所述杂烷基为C 1～4杂烷基。杂原子或杂原子团可以位于杂烷基的任何内部位置，包括该烷基与分子其余部分的连接位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。杂烷基的实例包括但不限于-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH 2(CH 3) 2、-CH 2-CH 2-O-CH 3、-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)(CH 2CH 3)、-CH 2-CH 2-NH- CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-SCH 3、-SCH 2CH 3、-SCH 2CH 2CH 3、-SCH 2(CH 3) 2、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(＝O)-CH 3、-CH 2-CH 2-S(＝O) 2-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，“C 3～6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C 3～6环烷基包括C 3～5、C 4～5和C 5～6环烷基等；其可以是一价、二价或者多价。C 3～6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。
除非另有规定，术语“3～6元杂环烷基”本身或者与其他术语联合分别表示由3至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3～6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3～6元杂环烷基包括4～6元、5～6元、4元、5元和6元杂环烷基等。3～6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。
除非另有规定，术语“5～6元杂环烷基”本身或者与其他术语联合分别表示由5至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“5～6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述5～6元杂环烷基包括5元和6元杂环烷基。5～6元杂环烷基的实例包括但不限于吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。
除非另有规定，术语“6元杂环烷基”本身或者与其他术语联合分别表示由6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。6元杂环烷基的实例包括但不限于哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基等。
除非另有规定，本发明术语“5～6元杂芳环”和“5～6元杂芳基”可以互换使用，术语“5～6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(O)p，p是1或2)。5～6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5～6元 杂芳基包括5元和6元杂芳基。所述5～6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
除非另有规定，本发明术语“6元杂芳环”和“6元杂芳基”可以互换使用，术语“6元杂芳基”表示由6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(O)p，p是1或2)。6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述6元杂芳基的实例包括但不限于吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
除非另有规定，本发明术语“5元杂芳环”和“5元杂芳基”可以互换使用，术语“5元杂芳基”表示由5个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(O)p，p是1或2)。5元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。
本发明采用下述缩略词：FA代表甲酸；TFA代表三氟乙酸；ACN代表乙腈；DIEA代表二异丙基乙基胺；P(o-tolyl) 3代表三(邻甲基苯基)膦；TBAI代表四丁基碘化铵；T3P代表1-丙基磷酸酐；TBSCl代表叔丁基二甲基氯硅烷；HATU代表2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐；HOBt代表1-羟基苯并三唑；PyBOP代表六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷；DMSO代表二甲基亚砜；ATP代表腺苷三磷酸。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2021079337-appb-000040
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合 成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1：化合物1
Figure PCTCN2021079337-appb-000041
步骤A：将化合物1-1(12g，91.23mmol)，1-2(14.05g，91.23mmol)，四(三苯基磷)钯(5.27g，4.56mmol)，碳酸钠(19.34g，182.46mmol)溶于1，4-二氧六环(100mL)和水(20mL)中，所得混合物用氮气置换三次并在110℃下搅拌12小时。反应液中加入水(50mL)淬灭并用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过硅胶柱分离纯化(石油醚：乙酸乙酯＝20/1～5/1)纯化得到1-3。MS(ESI)m/z:124.0[M+H +]。
步骤B：将化合物1-3(1g，8.12mmol)，1-4(2.8g，8.12mmol)，醋酸钯(0.18g，0.812mmol)，碳酸 铯(5.29g，16.24mmol)，四丁基溴化胺(2.62g，8.12mmol)溶于N，N-二甲基乙酰胺(30mL)中，所得混合物用氮气置换三次并在130℃下搅拌12小时。反应液中加入水(50mL)淬灭并用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过高效液相色谱分离(
Figure PCTCN2021079337-appb-000042
40g
Figure PCTCN2021079337-appb-000043
快速硅胶柱，洗脱液为0～50％ACN/H 2O，流速60mL/min)纯化得到1-5。MS(ESI)m/z:387.9[M+H +]。
步骤C：将化合物1-5(0.2g，0.516mmol)，1-6(0.078g，0.619mmol)，碳酸钾(0.142g，1.03mmol)溶于N-甲基吡咯烷酮(5mL)中所得混合物在150℃下微波搅拌2小时。反应液中加入水(50mL)淬灭并用乙酸乙酯(50mL×2)萃取.合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过高效液相色谱分离(
Figure PCTCN2021079337-appb-000044
40g
Figure PCTCN2021079337-appb-000045
快速硅胶柱，洗脱液为0～50％ACN/H 2O，流速60mL/min)纯化得到1-7。MS(ESI)m/z:495.0[M+H +]。
步骤D：将化合物1-8(0.3g，1.34mmol)溶于氯化亚砜(5mL)中，所得混合物在25℃下搅拌12小时.减压浓缩得到粗品，然后和1-7(25mg，50.55μmol)溶于二氯甲烷(5mL)中，往溶液中加入DIEA(26.13mg，202.20μmol)，所得混合物在25℃下搅拌1小时。反应液中加入水(50mL)淬灭反应并用二氯甲烷(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品1-9.MS(ESI)m/z:700.2[M+H +].
步骤E：将化合物1-9(45mg，64.31μmol)溶于二氯甲烷(1mL)中，然后向反应液中加三氟乙酸(770mg，6.75mmol，0.5mL)，所得混合物在25℃下搅拌0.5小时。向反应液中加入碳酸氢钠水溶液(30mL)淬灭反应并用乙酸乙酯(50mL×2)萃取.合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过(柱信息:Phenomenex Synergi C18 150*25*10μm；流动相:[水(0.225％FA)-ACN]；ACN％:17％-41％，8分钟)纯化得到化合物1。 1H NMR(400MHz,DMSO-d 6)δ＝10.38(s,1H),10.00(s,1H),8.53(d,J＝2.0Hz,1H),8.48(d,J＝5.6Hz,1H),7.88(dd,J＝13.2,2.4Hz,1H),7.75(dd,J＝8.0,2.0Hz,1H),7.72-7.57(m,5H),7.50(dd,J＝8.8,1.2Hz,1H),7.39-7.33(m,1H),7.19(d,J＝2.4Hz,1H),7.18-7.13(m,2H),6.80(dd,J＝5.6,2.4Hz,1H),3.76(s,2H)3.41(br s,2H),3.24(s,3H),2.69-2.64(m,2H),1.47(br d,J＝10.0Hz,4H).MS(ESI)m/z:600.1[M+H +].
实施例2：化合物2
Figure PCTCN2021079337-appb-000046
Figure PCTCN2021079337-appb-000047
步骤A：将化合物2-1(2g，13.42mmol)，2-2(2.11g，13.42mmol)，碳酸钾(3.71g，26.85mmol)溶于N，N-二甲基甲酰胺(20mL)中，所得混合物在80℃下搅拌3小时。反应液中加入水(50mL)淬灭反应并用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到2-3。MS(ESI)m/z:269.7[M+H +].
步骤B：将化合物2-3(1.9g，7.05mmol)，1-2(1.19g，7.75mmol)，四(三苯基磷)钯(814.33mg，704.71μmol)，碳酸钠(1.49g，14.09mmol)溶于1，4-二氧六环(20mL)和水(4mL)中，所得混合物用氮气置换三次并在80℃下搅拌3小时。反应液中加入水(100mL)淬灭反应并用乙酸乙酯(100mL×2)萃取.合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过硅 胶柱分离(石油醚：乙酸乙酯＝20/1～5/1)纯化得到2-4。MS(ESI)m/z:261.8[M+H +].
步骤C：将化合物2-4(0.5g，1.91mmol)，1-4(0.66g，1.91mmol)，醋酸钯(42.97mg，0.191mmol)，三乙胺(387.39mg，3.83mmol)，四丁基溴化胺(617.07mg，1.91mmol)，P(o-tolyl) 3(582.61mg，1.91mmol)溶于甲苯(10mL)中，所得混合物用氮气置换三次并在90℃下搅拌12小时。反应液中加入水(50mL)淬灭反应并用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过硅胶柱分离纯化(石油醚：乙酸乙酯＝20/1～5/1)纯化得到2-5。MS(ESI)m/z:526.1[M+H +]。
步骤D：将化合物2-5(90mg，171.26mmol)溶于乙醇(10mL)中，然后加入铁粉(191.28mg，3.43mmol)，氯化铵(18.32mg，0.342mmol)，所得混合物在100℃下搅拌12小时。反应液过滤后减压浓缩得到粗品，用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到2-6。MS(ESI)m/z:496.1[M+H +]。
步骤E：将化合物1-8(0.3g，1.34mmol)溶于氯化亚砜(5mL)中，所得混合物在25℃下搅拌12小时。减压浓缩得到粗品酰氯，2-6(80mg，161.44μmol)和粗品酰氯(78mg，322.88μmol)溶于四氢呋喃(5mL)中，往溶液中加入DIEA(83.46mg，645.75μmol)，所得混合物在25℃下搅拌1小时。反应液中加入水(50mL)淬灭反应并用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品，粗品通过反相柱分离(
Figure PCTCN2021079337-appb-000048
40g
Figure PCTCN2021079337-appb-000049
快速硅胶柱，洗脱液为0～50％ACN/0.1％FA-H 2O，流速60mL/min)纯化得到2-7。MS(ESI)m/z:701.2[M+H +]。
步骤F：将化合物2-7(72mg，102.75μmol)溶于二氯甲烷(1mL)中，然后向反应液中加三氟乙酸(1.23g，10.79mmol，0.8mL)，所得混合物在25℃下搅拌0.5小时。向反应液中加入碳酸氢钠水溶液(30mL)淬灭反应并用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过高效液相色谱分离(柱信息:Phenomenex Synergi C18 150*25*10μm；流动相:[水(0.225％FA)-ACN]；ACN％:20％-40％，10分钟)纯化得到化合物2的甲酸盐。 1H NMR(400MHz,DMSO-d 6)δ＝10.34(s,1H),10.03(s,1H),8.72(s,1H),8.61(d,J＝2.0Hz,1H),8.19(s,1H),7.95(d,J＝15.6Hz,1H),7.85-7.78(m,2H),7.72-7.63(m,4H),7.46-7.44(m,2H),7.37-7.32(m,1H),7.16(t,J＝8.88Hz,2H),3.82(s,2H),3.43(t,J＝8.8Hz,2H),3.25(s,3H),2.71(t,J＝5.6Hz,2H),1.47(br d,J＝2.8Hz,4H)；MS(ESI)m/z:601.1[M+H +]
实施例3：化合物3
Figure PCTCN2021079337-appb-000050
Figure PCTCN2021079337-appb-000051
步骤A：将化合物3-1(3.4g,23.13mmol),3-2(3.18g,25.45mmol),碳酸铯(11.31g,34.70mmol),TBAI(1.71g,4.63mmol)溶于N,N-二甲基乙酰胺(15mL)中，所得混合物在90℃下搅拌12小时。反应液中加入水(50mL)淬灭反应并用乙酸乙酯(50mL×2)萃取.合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到粗品化合物3-3。MS(ESI)m/z:191.1[M+H +].
步骤B：将化合物3-3(4.4g,23.03mmol),TBSCl(4.17g,27.64mmol)，咪唑(3.14g,46.07mmol)溶于N,N-二甲基乙酰胺(15mL)中，所得混合物在25℃下搅拌12小时。反应液中加入水(50mL)淬灭反应并用乙酸乙酯(50mL×2)萃取.合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到粗品,粗品通过反相柱分离(waters Xbridge BEH C18 250*50mm*10μm；流动相:[水(0.05％氨水v/v)-ACN]；ACN％:65％-80％,20分钟)纯化得到3-4。MS(ESI)m/z:304.9[M+H +].
步骤C：将化合物1-1(10g,76.03mmol)，2-2(10g,76.03mmol)，碳酸钾(21.01g,152.05mmol)溶于N,N-二甲基乙酰胺(20mL)中，所得混合物在100℃下搅拌3小时。反应液中加入水(50mL)淬灭反应并用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过硅胶柱分离纯化(石油醚：乙酸乙酯＝20/1，5/1)纯化得到化合物3-5。MS(ESI)m/z:268.7[M+H +].
步骤D：将化合物3-5(5g,18.61mmol),1-2(3.44g,22.34mmol)，四(三苯基磷)钯(2.15g,1.86mmol)，碳酸钠(3.95g,37.23mmol)溶于二氧六环(50mL)和水(10mL)中，所得混合物用氮气置换三次并在80℃下搅拌3小时。反应液中加入水(100mL)淬灭反应并用乙酸乙酯(100mL×2)萃取.合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到粗品。粗品通过硅胶柱分离纯化(石油醚：乙酸乙酯＝20/1，5/1)纯化得到3-6。MS(ESI)m/z:260.8[M+H +].
步骤E：将化合物3-6(255.71mg,982.69mmol),3-4(300mg,982.69mmol),醋酸钯(22.06mg,98.27μmol,)，三乙胺(497.19mg,4.91mmol)，溴化锂(256.02mg,2.95mmol)，P(o-tolyl) 3(299.10mg,982.69mmol)溶于甲苯(10mL)中，所得混合物用氮气置换三次并在110℃下搅拌12小时。反应液中加入水(100mL)淬灭反应并用乙酸乙酯(100mL×2)萃取.合并有机相用饱和氯化钠溶液(25mL×2)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到粗品。粗品通过反相柱分离柱信息:waters Xbridge BEH C18 250*50mm*10μm；流动相:[水(0.05％氨水v/v)-ACN]；ACN％:55％-85％,20分钟纯化得到3-7。MS(ESI)m/z:485.0[M+H +].
步骤F：将化合物3-7(200mg,412.72μmol)溶于乙醇10mL)和水(2mL)中，然后加入铁粉(230.48mg,4.13mmol)，氯化铵(110.38mg,2.06mmol)，所得混合物在90℃下搅拌6小时。反应液过滤后用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到3-8。MS(ESI)m/z:455.0[M+H +].
步骤G：将化合物3-8(90mg,197.97μmol)溶于二氯甲烷(5mL)中，并在25℃下，往溶液中加入1-8(88.3mg,395.94μmol),DIEA(127.93mg,989.86μmol)和T3P(377.94mg,593.91μmol).所得混合物在25℃下搅拌12小时。反应液中加入水(50mL)并用乙酸乙酯(50mL×2)萃取.合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到粗品3-9。MS(ESI)m/z:660.2[M+H +].
步骤H：将化合物3-9(65mg,98.52μmol)溶于二氯甲烷(2mL)中，然后向反应液中加三氟乙酸(1.54g,13.51mmol),所得混合物在25℃下搅拌0.5小时。反应液减压浓缩得到粗品。粗品通过(Phenomenex Synergi C18 150*25*10μm；流动相:[水(0.225％FA)-ACN]；ACN％:17％-50％,10分钟)纯化得到化合物3的甲酸盐。1H NMR(400MHz,DMSO-d6)δ＝10.39(s,1H),10.01(s,1H),8.40(d,J＝5.6Hz,1H),8.22(s,1H),7.97(s,1H),7.87(dd,J＝2.4,13.2Hz,1H),7.77(s,1H),7.70-7.60(m,2H),7.54(s,1H),7.50-7.46(m,1H),7.39-7.31(m,1H),7.21-7.11(m,2H),6.92(d,J＝16.0Hz,1H),6.86(d,J＝2.4Hz,1H),6.74(dd,J＝2.4,5.6Hz,1H),4.12(t,J＝5.6Hz,2H),3.72(t,J＝5.6Hz,2H),1.47(br d,J＝7.2Hz,4H)；MS(ESI)m/z:546.1[M+H +]。
实施例4：化合物4
Figure PCTCN2021079337-appb-000052
Figure PCTCN2021079337-appb-000053
步骤A：将化合物3-1(1g,6.80mmol)，4-1(1.46g,10.21mmol),碳酸铯(3.33g,10.21mmol)溶于N,N-二甲基甲酰胺(8mL)中，所得混合物在60℃下搅拌1小时。反应液中加入水(20mL)淬灭反应并用乙酸乙酯(30mL×3)萃取.合并有机相用饱和氯化钠溶液(50mL×3)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到化合物4-2，粗品直接用于下一步。
步骤B：将化合物4-2(1.43g,6.83mmol),化合物4-3(1.54g,20.48mmol)溶于DMSO(5mL)中，所得混合物在60℃下搅拌5小时。反应液中加入1mol/L盐酸(10mL)和乙酸乙酯(20mL)稀释，分液，水相用乙酸乙酯(30mL)洗涤，有机相丢弃，水相使用1mol/L氢氧化钠调节pH＝8并用乙酸乙酯(30mL×3)萃取)，合并有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到4-4。MS(ESI)m/z:247.8[M+H +].
步骤C：将化合物4-4(900mg,3.63mmol)溶于四氢呋喃(10mL)中，加入二碳酸二叔丁酯(949.97mg,4.35mmol,)，所得混合物在20℃下搅拌12小时。减压浓缩得到粗品。粗品通过硅胶柱分离纯化(乙酸乙酯/石油醚＝0％～50％)纯化得到化合物4-5。
步骤E：将化合物3-6(0.4g,1.54mmol),4-5(1.07g,3.07mmol)，醋酸钯(69.02mg,307.43μmol)，三乙胺(933.27mg,9.22mmol)，溴化锂(534.01mg,6.15mmol)，P(o-tolyl) 3(467.87mg,1.54mmol)溶于N,N-二甲基乙酰胺(10mL)中，所得混合物用氮气置换三次并在125℃下搅拌12小时。反应液中加入水(40mL)和乙酸乙酯(40mL)，分液，水相用乙酸乙酯(40mL×3)萃取.合并有机相用饱和氯化钠溶液(50mL×3)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到粗品。粗品通过硅胶柱分离纯化(乙酸乙酯/石油醚＝20％～80％)纯化得到4-6。MS(ESI)m/z:528.3[M+H +].
步骤F：将化合物4-6(150mg,284.34μmol)溶于乙醇(3mL)，然后加入铁粉(158.79mg,2.84mmol)，饱和氯化铵溶液(0.3mL)，所得混合物在80℃下搅拌2小时。过滤，收集滤液浓缩除去有机溶剂，然 后用乙酸乙酯(20mL)和水(20mL)稀释，分液，水相用乙酸乙酯(30mL×3)萃取。合并有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到4-7，粗品直接用于下一步。MS(ESI)m/z:498.3[M+H +].
步骤G：将化合物1-8(72.81mg,326.20μmol)溶于二氯甲烷(5mL)中，于0℃下加入草酰氯(159.25mg,1.25mmol)和N,N-二甲基甲酰胺(1.83mg,25.09μmol)，在25℃下反应半小时。溶液浓缩得到相应的酰氯并溶于二氯甲烷(5mL)，在0℃下往溶液中加入4-7(124.85mg,250.92μmol)和吡啶(99.24mg,1.25mmol).所得混合物在25℃下搅拌半小时。反应液中加入水(20mL)，分液，水相用二氯甲烷(20mL×3)萃取。合并有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到4-8，粗品直接用于下一步。MS(ESI)m/z:703.2[M+H +].
步骤H：将化合物4-8(150mg,213.45μmol)溶于二氯甲烷(5mL)中，然后向反应液中加三氟乙酸(1mL),所得混合物在20℃下搅拌1小时。反应液减压浓缩得到粗品。粗品通过制备级高效液相色谱(色谱柱:Waters Xbridge 150*25mm*5μm；流动相:[水(0.05％氨水v/v)-ACN]；B％:38％-68％,10分钟)纯化得到化合物4。 1H NMR(400MHz,DMSO-d6)δ＝10.39(s,1H),10.01(s,1H),8.40(d,J＝5.6Hz,1H),7.99(s,1H),7.88(dd,J＝2.4,13.2Hz,1H),7.77(s,1H),7.65(dd,J＝5.2,9.1Hz,2H),7.54-7.47(m,2H),7.35(t,J＝9.2Hz,1H),7.16(t,J＝8.8Hz,2H),6.92(d,J＝16.0Hz,1H),6.86(d,J＝2.4Hz,1H),6.74(dd,J＝2.4,5.6Hz,1H),4.14(t,J＝6.0Hz,2H),3.35(t,J＝5.6Hz,2H),3.22(s,3H),2.92(t,J＝6.0Hz,2H),2.65(t,J＝5.6Hz,2H),1.54-1.41(m,4H)；MS(ESI)m/z:603.2[M+H +]。
实施例5：化合物5
Figure PCTCN2021079337-appb-000054
步骤A：将化合物5-1(1.6g,8.25mmol)溶于乙腈(20mL)中，加入碳酸钾(2.28g,16.50mmol),碘化钾(136.93mg,824.86μmol)和5-2(1.94g,8.66mmol)，所得混合物在80℃下搅拌12小时。反应液中加入水(100mL)，白色固体析出，过滤并收集滤饼，减压浓缩得到化合物5-3。MS(ESI)m/z:338.2[M+H +].
步骤B：将化合物3-6(0.4g,1.54mmol),化合物5-3(1.04g,3.08mmol)，醋酸钯(69.15mg,308.00μmol)，三乙胺(935.00mg,9.24mmol)，溴化锂(401.25mg,4.62mmol)，P(o-tolyl) 3(468.73mg,1.54mmol)溶于N,N-二甲基乙酰胺(10mL)中，所得混合物用氮气置换三次并在125℃下搅拌36小时。反应液中加入水(40mL)和乙酸乙酯(40mL)，分液，水相用乙酸乙酯(40mL×3)萃取.合并有机相用饱和氯化钠溶液(50mL×3)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到粗品。粗品通过硅胶柱分离纯化(乙酸乙酯/石油醚＝20％～80％)纯化得到5-4。MS(ESI)m/z:470.0[M+H +].
步骤C：将化合物5-4(370mg,788.13μmol)溶于乙醇(6mL)，然后加入铁粉(440.17mg,7.88mmol)，饱和氯化铵溶液(0.5mL)，所得混合物在80℃下搅拌2小时。过滤，收集滤液浓缩除去有机溶剂，然后用乙酸乙酯(20mL)和水(20mL)稀释，分液，水相用乙酸乙酯(30mL×3)萃取。合并有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到5-5，粗品直接用于下一步。MS(ESI)m/z:440.3[M+H +].
步骤D：将化合物1-8(211.27mg,946.57μmol)溶于二氯甲烷(10mL)中，于0℃下加入草酰氯(462.11mg,3.64mmol,318.69μL)和N,N-二甲基甲酰胺(5.32mg,72.81μmol)，在25℃下反应半小时。溶液浓缩得到相应的酰氯并溶于二氯甲烷(5mL)，在0℃下往溶液中加入5-5(320mg,728.13μmol)和吡啶(287.98mg,3.64mmol).所得混合物在25℃下搅拌半小时。反应液中加入水(20mL)，分液，水相用二氯甲烷(20mL×3)萃取。合并有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到5-6，粗品直接用于下一步。MS(ESI)m/z:645.2[M+H +].
步骤E：将化合物5-6(450mg,698.04μmol)溶于二氯甲烷(20mL)中，然后向反应液中加三氟乙酸(2mL)，所得混合物在20℃下搅拌3小时。反应液减压浓缩得到粗品。粗品通过制备级高效液相色谱(色谱柱:Phenomenex Synergi C18 150*25*10μm；流动相:[水(0.225％FA)-ACN]；B％:8％-38％,10分钟)纯化得到化合物5的甲酸盐。 1H NMR(400MHz,DMSO-d 6)δ＝10.40(br d,J＝2.4Hz,1H),10.01(br s,1H),8.40(d,J＝5.6Hz,1H),8.30(br s,1H),8.02(s,1H),7.91-7.81(m,2H),7.65(dd,J＝5.0,9.2Hz,2H),7.58-7.44(m,2H),7.35(t,J＝9.2Hz,1H),7.16(t,J＝8.8Hz,2H),6.95(d,J＝16.0Hz,1H),6.87(d,J＝2.4Hz,1H),6.75(dd,J＝2.4,5.6Hz,1H),4.22(br t,J＝6.0Hz,2H),3.16-3.03(m,2H),1.55-1.38(m,4H)；MS(ESI)m/z:545.3[M+H +]。
实施例6：化合物6
Figure PCTCN2021079337-appb-000055
Figure PCTCN2021079337-appb-000056
步骤A：将化合物3-1(7g,47.63mmol)溶于四氢呋喃(100mL)中，在0℃下分批加入氢化钠(2.48g,61.92mmol,60％含量)并在0℃搅拌30分钟，加入6-1(9.93g,59.53mmol)，所得混合物在25℃下搅拌12小时。在0℃下小心加入饱和氯化铵(50mL)淬灭反应，分液，水相使用乙酸乙酯(50mL×3)萃取，合并有机相，使用饱和氯化钠(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到化合物6-2。
步骤B：将化合物6-2(1.28g,4.61mmol),化合物3-6(1g,3.84mmol)，醋酸钯(86.28mg,384.29μmol)，三乙胺(1.94g,19.21mmol)，溴化锂(1.00g,11.53mmol)，P(o-tolyl) 3(1.17g,3.84mmol)溶于N,N-二甲基乙酰胺(10mL)中，所得混合物用氮气置换三次并在125℃下搅拌36小时。反应液中加入水(50mL)和乙酸乙酯(50mL)，分液，水相用乙酸乙酯(50mL×3)萃取.合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到粗品。粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝10/1～2/1)纯化得到6-3。MS(ESI)m/z:457.2[M+H +].
步骤C：将化合物6-3(580mg,1.27mmol)溶于乙醇(7mL)，然后加入铁粉(709.47mg,12.70mmol)，饱和氯化铵溶液(0.7mL)，所得混合物在80℃下搅拌10小时。过滤，收集滤液浓缩除去有机溶剂，然后用乙酸乙酯(30mL)和水(30mL)稀释，分液，水相用乙酸乙酯(50mL×3)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到6-4，粗品直接用于下一步。MS(ESI)m/z:427.1[M+H +].
步骤D：将化合物1-8(285.70mg,1.28mmol)溶于二氯甲烷(5mL)中，于0℃下加入草酰氯(624.87mg,4.92mmol)和N,N-二甲基甲酰胺(7.20mg,98.46μmol)，在25℃下反应半小时。溶液浓缩得到相应的酰氯并溶于二氯甲烷(5mL)，在0℃下往溶液中加入6-4(420mg,984.63μmol)和吡啶(389.42mg,4.92mmol).所得混合物在25℃下搅拌半小时。反应液中加入水(30mL)和二氯甲烷(30mL)，分液，水相用二氯甲烷(50mL×3)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到6-5，粗品直接用于下一步。MS(ESI)m/z:632.3[M+H +].
步骤E：将化合物6-5(700mg,1.11mmol)溶于二氯甲烷(14mL)中，然后向反应液中加三氟乙酸(7mL)，所得混合物在25℃下搅拌2小时。反应液减压浓缩得到粗品。粗品通过制备级高效液相色谱(色谱柱:Waters Xbridge BEH C18 150*25mm*5μm；流动相：[水(0.05％氨水v/v)-ACN]；B％:36％-66％,10分 钟)纯化得到化合物6。 1H NMR(400MHz,DMSO-d 6)δ＝12.94(br s,1H),10.38(s,1H),10.00(s,1H),8.40(d,J＝5.6Hz,1H),8.09-7.76(m,3H),7.65(dd,J＝5.2,9.2Hz,2H),7.56(d,J＝16.0Hz,1H),7.49(dd,J＝1.2,8.8Hz,1H),7.35(t,J＝9.2Hz,1H),7.16(t,J＝8.8Hz,2H),6.94(d,J＝16.0Hz,1H),6.84(d,J＝2.4Hz,1H),6.75(dd,J＝2.4,5.6Hz,1H),1.53-1.43(m,4H)；MS(ESI)m/z:502.3[M+H +]。
实施例7：化合物7
Figure PCTCN2021079337-appb-000057
步骤A：将化合物1-1(3.5g,26.61mmol)，7-1(3.70g,26.61mmol)，碳酸钾(7.36g,53.22mmol)溶于N,N-二甲基甲酰胺(10mL)中，所得混合物在100℃下搅拌12小时。反应液中加入水(100mL)淬灭反应并用乙酸乙酯(100mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过硅胶柱分离(石油醚：乙酸乙酯＝20/1～5/1)纯化得到7-2。MS(ESI)m/z:250.8[M+H +].
步骤B：将化合物7-2(4.5g,17.95mmol)，1-2(3.32g,21.55mmo)，四(三苯基磷)钯(2.07g,1.80mmol)，碳酸钠(3.81g,35.91mmol)溶于1，4-二氧六环(50mL)和水(10mL)中，所得混合物用氮气置换三次并在80℃下搅拌3小时。反应液中加入水(50mL)淬灭反应并用乙酸乙酯(50mL×2)萃取.合并有机相用饱和氯化钠溶液(25mL×2)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过硅胶柱 分离(石油醚：乙酸乙酯＝1/0～1/2)纯化得到7-3。MS(ESI)m/z:243.0[M+H +].
步骤C：将化合物7-3(1g,4.13mmol)，3-4(1.26g,4.13mmol)，醋酸钯(92.68mg,412.83μmol)，三乙胺(2.09g,20.64mmol)，溴化锂(1.08g,12.38mmol)溶于甲苯(15mL)中，所得混合物用氮气置换三次并在120℃下搅拌12小时。反应液中加入水(100mL)用乙酸乙酯(100mL×2)萃取。合并有机相用饱和氯化钠溶液(25mL×2)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过硅胶柱分离纯化(石油醚：乙酸乙酯＝1/0～1/2)纯化得到7-4。MS(ESI)m/z:467.0[M+H +]。
步骤D：将化合物7-4(1.5g,3.21mmol)溶于乙醇(10mL)和水(2mL)中，然后加入铁粉(1.80g,32.15mmol)，氯化铵(859.78mg,16.07mmol)。所得混合物在90℃下搅拌2小时。反应液过滤后用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到7-5。MS(ESI)m/z:437.3[M+H +]。
步骤E：将化合物1-8(500mg,1.15mmol)溶于二氯甲烷(10mL)然后加入7-5(330.09mg,2.29mmol)，T3P(2.91g,4.58mmol,2.72mL,50％纯度,)和DIEA(888.00mg,6.87mmol,1.20mL,)，在25℃下反应12小时。反应液中加入水(50mL)并用二氯甲烷(25mL×2)萃取。合并有机相用饱和氯化钠溶液(25mL×2)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到7-6。MS(ESI)m/z:563.1[M+H +]。
步骤F：将化合物7-6(550mg,977.38μmol)溶于四氢呋喃(2mL)和水(0.5mL)中，然后向反应液中加一水合氢氧化锂(82.02mg,1.95mmol)，所得混合物在25℃下搅拌1小时。反应液减压浓缩后加入水(10mL)，用1mol/L盐酸调节pH至6，并用乙酸乙酯(20mL×3)萃取。合并有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到7-7。MS(ESI)m/z:549.1[M+H +]。
步骤G：将化合物7-7(536.29mg,977.38μmol,)溶于四氢呋喃(5mL)然后加入7-8(108.60mg,977.38μmol)，T 3P(1.24g,1.95mmol,50％乙酸乙酯溶液)和DIEA(505.26mg,3.91mmol)，反应在25℃下反应12小时。反应液中加入水(50mL)并用乙酸乙酯(25mL×2)萃取。合并有机相用饱和氯化钠溶液(25mL×2)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到7-9。MS(ESI)m/z:642.1[M+H +]。
步骤H：将化合物7-9(480mg,747.89μmol)溶于二氯甲烷(2mL)中，然后向反应液中加三氟乙酸(4.26g,37.39mmol)，所得混合物在25℃下搅拌半小时。反应液通过减压浓缩得到粗品。粗品通过制备级高效液相色谱分离(柱色谱:Phenomenex Luna C18 75*30*3μm；流动相:[水(0.225％FA)-ACN]；ACN％:13％-35％，10分钟)纯化得到化合物7。 1H NMR(400MHz,DMSO-d 6)δ＝10.17(s,1H),10.04(s,1H),8.38(d,J＝5.6Hz,1H),7.97(s,1H),7.77(s,1H),7.73(d,J＝8.8Hz,2H),7.69-7.61(m,2H),7.50(d,J＝16.0Hz,1H),7.22-7.07(m,4H),6.90(d,J＝16.0Hz,1H),6.84(d,J＝2.4Hz,1H),6.71(dd,J＝2.4,5.6Hz,1H),5.12-4.78(m,1H),4.12(t,J＝5.6Hz,2H),3.73(q,J＝5.2Hz,2H),1.47(s,4H)；MS(ESI)m/z:528.1[M+H +]。
实施例8：化合物8
Figure PCTCN2021079337-appb-000058
步骤A：将化合物3-1(3g,20.41mmol)溶于N,N-二甲基甲酰胺(50mL)中，向反应体系中加8-1(3.12g,22.45mmol)，碳酸铯(9.98g,30.62mmol)和TBAI(1.51g,4.08mmol)，所得混合物在90℃下搅拌4小时。反应液中加入水(50mL)淬灭并用二氯甲烷(25mL×2)萃取。合并有机相用饱和氯化钠溶液(25mL)洗涤两次，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过制备级高效液相色谱分离(色谱柱:Waters Xbridge BEH C18 250*50mm*10μm；流动相:[水(0.05％氨水v/v)-ACN]；B％:15％-40％,20分钟)纯化得到8-2。MS(ESI)m/z:206.8[M+H +]。
步骤B：将化合物8-2(1g,4.88mmol)，3-6(1.27g,4.88mmol)，醋酸钯(109.49mg,487.68μmol)，P(o-tolyl) 3(1.48g,4.88mmol)，三乙胺((2.47g,24.38mmol,3.39mL)和溴化锂(1.27g,14.63mmol)溶于甲苯(10mL)中，所得混合物用氮气置换三次并在110℃下搅拌12小时。反应液中加入水(100mL)淬灭并用乙酸乙酯(100mL×2)萃取。合并有机相用饱和氯化钠溶液(25mL)洗涤两次，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过硅胶柱层析分离(石油醚：乙酸乙酯＝20：1–0：1)得到8-3。MS(ESI)m/z:384.9[M+H +]。
步骤C：将化合物8-3(230mg,598.40μmol)溶于水(2mL)和乙醇(10mL)中，向反应体系中加铁粉(334.20mg,5.98mmol)和氯化铵(160.04mg,2.99mmol)，所得混合物在90℃下搅拌3小时。反应液经过硅藻土过滤后，滤液用乙酸乙酯(50mL×2)萃取.合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到8-4。MS(ESI)m/z:355.1[M+H +]。
步骤D：将化合物8-4(100mg,282.19μmol)溶于四氢呋喃(5mL)中，向反应体系中加1-8(125.97mg,564.37μmol)，T3P(538.71mg,846.56μmol,503.47μL,50％purity)和DIEA(182.35mg,1.41mmol,245.75μL)，所得混合物在25℃下搅拌12小时。反应液中加入水(50mL)淬灭反应并用二氯甲烷(25mL×2)萃取。合并有机相用饱和氯化钠溶液(25mL)洗涤两次，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过高效液相色谱(柱信息:Phenomenex Gemini-NX C18 75*30mm*3μm；流动相:water(0.1％TFA)-ACN]；B％:30％-40％,7分钟)纯化得到化合物8。 1H NMR(400MHz,DMSO-d 6)δ＝10.45(s,1H),9.97(s,1H),8.54(d,J＝6.4Hz,1H),8.06(s,1H),7.92(br dd,J＝1.6,13.2Hz,1H),7.84(s,1H),7.70(br d,J＝16.4Hz,1H),7.63(br dd,J＝5.2,8.8Hz,2H),7.52(br s,1H),7.42(s,1H),7.34(br s,1H),7.16(br t,J＝8.8Hz,2H),7.11-7.05(m,1H),6.98(d,J＝16.4Hz,1H),4.28(br t,J＝5.2Hz,2H),3.69(br d,J＝5.2Hz,2H),3.25-3.21(m,3H),1.48(br d,J＝13.2Hz,4H)；MS(ESI)m/z:560.1[M+H +].
实施例9：化合物9
Figure PCTCN2021079337-appb-000059
步骤A：将化合物9-1(4.75g,30.21mmol)，2-2(4.5g,30.21mmol)，碳酸钾(8.35g,60.41mmol)溶于N，N-二甲基甲酰胺(100mL)中，所得混合物在80℃下搅拌12小时。反应液中加入水(300mL)淬灭反应并用乙酸乙酯(100mL×3)萃取。合并有机相用饱和氯化钠溶液(200mL×2)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到9-2。MS(ESI)m/z:270.1[M+H +].
步骤B：将化合物9-2(7g,25.96mmol)，1-2(4.80g,31.16mmol)，四(三苯基磷)钯(3.00g,2.60mmol,)，碳酸钠(5.50g,51.93mmol)溶于1，4-二氧六环(120mL)和水(24mL)中，所得混合物用氮气置换三次并在84℃下搅拌12小时。反应液中加入水(50mL)淬灭反应并用乙酸乙酯(100mL×3)萃取。合 并有机相用饱和氯化钠溶液(100mL×2)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过硅胶柱分离(石油醚：乙酸乙酯＝1/0～3/5)纯化得到9-3。MS(ESI)m/z:262.1[M+H +].
步骤C：将化合物9-3(200mg,765.67μmol,)，9-4(539.47mg,1.53mmol)，醋酸钯(17.19mg,76.57μmol,)，三乙胺(387.39mg,3.83mmol,532.86μL)，溴化锂(199.48mg,2.30mmol)，P(o-tolyl) 3(233.04mg,765.67μmol)溶于N,N-二甲基乙酰胺(10mL)中，所得混合物用氮气置换三次并在70℃下搅拌12小时。反应液中加入水(30mL)淬灭乙酸乙酯(30mL)稀释，硅藻土过滤，滤液用乙酸乙酯(30mL×3)萃取。合并有机相用饱和氯化钠溶液(30mL×2)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过硅胶柱分离纯化(石油醚：乙酸乙酯＝1/0～1/2)纯化得到9-5。MS(ESI)m/z:486.1[M+H +]。
步骤D：将化合物9-5(200mg,411.88μmol)溶于乙醇(5mL)和水(1mL)中，然后加入铁粉(230.01mg,4.12mmol)，氯化铵(110.16mg,2.06mmol)，所得混合物在90℃下搅拌1小时。反应液过滤后用乙酸乙酯(20mL×2)萃取。合并有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到9-6。MS(ESI)m/z:456.1[M+H +]。
步骤E：将化合物1-8(82.79mg,370.94μmol)溶于二氯甲烷(3mL)零度下滴加草酰氯(181.08mg,1.43mmol)、N,N-二甲基甲酰胺((2.09mg,28.53μmol)，所得混合物在25℃下搅拌半小时。减压浓缩得到粗品酰氯，然后将酰氯溶于二氯甲烷(3mL)中，零度下往溶液中加入吡啶(112.85mg,1.43mmol)，然后将9-6(130mg,285.34μmol)溶于二氯甲烷(3mL)中滴加到混合溶液中，所得混合物在0℃下搅拌十分钟，然后25℃下搅拌半小时。反应液中加入水(10mL)淬灭反应并用二氯甲烷(10mL×2)萃取。合并有机相用饱和氯化钠溶液(20mL×2)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到9-7。MS(ESI)m/z:661.2[M+H +]。
步骤F：将化合物9-7(170mg,257.27μmol)溶于二氯甲烷(2mL)中，然后向反应液中加三氟乙酸(2mL)，所得混合物在25℃下搅拌12小时。反应液通过减压浓缩得到粗品。粗品通过高效液相色谱分离(柱信息:Phenomenex luna C18 150*40*15μm；流动相:[水(0.1％TFA)-ACN]；ACN％:30％-60％，10分钟)纯化得到化合物9的三氟乙酸盐。 1H NMR(400MHz,DMSO-d 6)δ＝10.33(s,1H),10.01(s,1H),8.63(d,J＝5.6Hz,1H),8.07(s,1H),7.87-7.77(m,2H),7.68-7.57(m,3H),7.49-7.43(m,1H),7.38-7.31(m,1H),7.15(t,J＝8.8Hz,2H),6.94(d,J＝6.0Hz,1H),6.72(d,J＝15.6Hz,1H),4.13-4.09(m,2H),3.71(t,J＝5.6Hz,2H),1.47(br d,J＝4.0Hz,4H)；MS(ESI)m/z:547.1[M+H +]。
实施例10：化合物10
Figure PCTCN2021079337-appb-000060
Figure PCTCN2021079337-appb-000061
步骤A：将化合物10-1(2g,12.20mmol)溶于N，N-二甲基甲酰胺(20mL)，向反应中加10-2(3.88g,24.39mmol)，碳酸钾(7.95g,24.39mmol)，所得混合物在70℃下搅拌12小时。反应液中加入水(20mL)，并用乙酸乙酯(20mL×2)萃取。合并有机相用饱和氯化钠溶液(20mL)洗涤两次，无水硫酸钠干燥，过滤后减压浓缩得到粗品，粗品通过硅胶柱层析分离(石油醚：乙酸乙酯＝1:0–5/1/,v/v)得到10-3。MS(ESI)m/z:303.0[M+H +].
步骤B：将化合物10-3(700mg,2.31mmol)，1-2(426.87mg,2.77mmol)，四(三苯基磷)钯(266.90mg,230.97μmol)，碳酸钠(489.60mg,4.62mmol)溶于1，4-二氧六环(10mL)和水(2mL)中，所得混合物用氮气置换三次并在85℃下搅拌12小时。反应液用水(10mL)和乙酸乙酯(10mL)稀释，用乙酸乙酯(20mL×3)萃取。合并有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过柱分离(
Figure PCTCN2021079337-appb-000062
10g
Figure PCTCN2021079337-appb-000063
快速硅胶柱，洗脱液为乙酸乙酯/石油醚＝0～10％)纯化得到10-4。MS(ESI)m/z:295.0[M+H +].
步骤C：将化合物10-4(0.65g,2.21mmol)，3-4(1.35g,4.41mmol)，醋酸钯(49.52mg,220.59μmol)，三乙胺(1.12g,11.03mmol)，四丁基溴化胺(617.07mg,1.91mmol)，P(o-tolyl) 3(671.40mg,2.21mmol)，溴化锂(574.71mg,6.62mmol)溶于N，N-二甲基乙酰胺(10mL)中，所得混合物用氮气置换三次并在125℃下搅拌12小时。反应液用水(10mL)和乙酸乙酯(10mL)稀释，用乙酸乙酯(20mL×3)萃取。合并有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过硅胶柱分离纯化(石油醚：乙酸乙酯＝1/0～1/1)纯化得到10-5。MS(ESI)m/z:519.0[M+H +]。
步骤D：将化合物10-5(270mg,520.19μmol)溶于乙醇(10mL)和水(2mL)中，然后加入铁粉(290.50mg,5.20mmol)，氯化铵(139.13mg,2.60mmol)，所得混合物在90℃下搅拌1小时。反应液过滤后滤液用乙酸乙酯(20mL×2)萃取。合并有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到10-6。MS(ESI)m/z:489.2[M+H +]。
步骤E：将化合物1-8(94.93mg,425.31μmol)溶于二氯甲烷(5mL)中，向反应中加N,N-二甲基甲酰胺(2.39mg,32.72μmol)，在25℃下向反应体系中加草酰氯(207.63mg,1.64mmol)，所得混合物在25℃下搅拌0.5小时。减压浓缩得到粗品酰氯，粗品酰氯溶于二氯甲烷(5mL)中，降温至0℃，并在该温度下向反应体系中加吡啶(129.39mg,1.64mmol)，然后向反应中滴加10-6(160mg,327.16μmol)的二氯甲烷(1mL)溶液，滴完后的反应体系在0℃下搅拌10分钟，然后升温至25℃下搅拌30分钟。反应液用水(10mL)和二氯甲烷(20mL)稀释，用二氯甲烷(20mL×3)萃取.合并有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品，粗品通过反相柱分离(
Figure PCTCN2021079337-appb-000064
10g
Figure PCTCN2021079337-appb-000065
快速硅胶柱，洗脱液为乙酸乙酯/石油醚＝0～50％)纯化得到10-7。MS(ESI)m/z:694.4[M+H +]。
步骤F：将化合物10-7(100mg,144.04μmol)溶于二氯甲烷(5mL)中，然后向反应液中加三氟乙酸(1mL)，所得混合物在25℃下搅拌1小时。反应液减压浓缩得到粗品。粗品通过高效液相色谱分离(柱信息:Phenomenex Gemini-NX C18 75*30mm*3μm；流动相:[水(0.1％TFA)-ACN]；B％:42％-52％,7分钟)纯化得到化合物10的三氟乙酸盐。 1H NMR(400MHz,DMSO-d 6)δ＝10.40(d,J＝2.4Hz,1H),10.00(s,1H),8.47-8.31(m,1H),8.18(d,J＝22.8Hz,1H),7.92-7.88(m,1H),7.76(d,J＝15.6Hz,1H),7.64(t,J＝6.8Hz,3H),7.51(br d,J＝8.8Hz,1H),7.43-7.31(m,2H),7.16(t,J＝8.8Hz,2H),6.77-6.67(m,1H),6.63-6.54(m,1H),4.14(td,J＝5.6,16.8Hz,2H),3.78-3.67(m,2H),1.47(br d,J＝4.8Hz,4H)；MS(ESI)m/z:601.1[M+H +].
实施例11：化合物11
Figure PCTCN2021079337-appb-000066
步骤A：将化合物11-1(2g,13.61mmol)溶于N,N-二甲基甲酰胺(10mL)，向反应体系中加2-溴乙醇(1.87g,14.97mmol,1.06mL)，碳酸铯(6.65g,20.41mmol,)，TBAI(1.01g,2.72mmol)，所得混合物在 80℃下搅拌12小时。反应液中加入水(50mL)淬灭反应并用二氯甲烷(20mL×3)萃取。合并有机相用无水硫酸钠干燥，过滤后减压浓缩得到粗品化合物11-2。
步骤B：将化合物11-2(3g,15.70mmol)溶于N,N-二甲基甲酰胺(20mL)中,向反应体系中加入TBSCl(2.84g,18.85mmol)，咪唑(2.14g,31.41mmol)，所得混合物在25℃下搅拌12小时。反应液中加入水(20mL)和乙酸乙酯(50mL)淬灭反应并用乙酸乙酯(50mL×3)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品，粗品通过反相柱分离(
Figure PCTCN2021079337-appb-000067
10g
Figure PCTCN2021079337-appb-000068
快速硅胶柱，洗脱液为0～10％石油醚/乙酸乙酯)纯化得到11-3。MS(ESI)m/z:305.1[M+H +].
步骤C：将化合物3-6(1g,3.84mmol),11-3(2.35g,7.69mmol),醋酸钯(86.28mg,384.29μmol)，三乙胺(1.94g,19.21mmol)，溴化锂(1.00g,11.53mmol)，P(o-tolyl) 3(1.17g,3.84mmol)溶于N,N-二甲基乙酰胺(10mL)中，所得混合物用氮气置换三次并在125℃下搅拌12小时。反应液用水(10mL)和乙酸乙酯(10mL)稀释，用乙酸乙酯(20mL×3)萃取。合并有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过反相柱分离(
Figure PCTCN2021079337-appb-000069
10g
Figure PCTCN2021079337-appb-000070
快速硅胶柱，洗脱液为乙酸乙酯/石油醚＝0～100％)纯化得到11-4。MS(ESI)m/z:485.2[M+H +].
步骤D：将化合物11-4(500mg,1.03mmol)溶于乙醇(10mL)和水(2mL)中，然后加入铁粉(576.20mg,10.32mmol)，氯化铵(1551.91mg,10.32mmol)，所得混合物在90℃下搅拌1小时。反应液过滤后滤液用乙酸乙酯(20mL×2)萃取。合并有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到11-5。MS(ESI)m/z:455.2[M+H +].
步骤E：将化合物1-8(287.22mg,1.29mmol)溶于二氯甲烷(10mL)中，向反应中加N,N-二甲基甲酰胺(7.24mg,98.99μmol)，在25℃下向反应体系中加草酰氯(628.19mg,4.95mmol)，所得混合物在25℃下搅拌0.5小时。减压浓缩得到粗品酰氯，粗品酰氯溶于二氯甲烷(10mL)中，降温至0℃，并在该温度下向反应体系中加吡啶(391.49mg,4.95mmol)，然后向反应中滴加11-5(450mg,989.86μmol)的二氯甲烷(1mL)溶液，滴完后的反应体系在0℃下搅拌10分钟，然后升温至25℃下搅拌30分钟。反应液用水(10mL)和二氯甲烷(20mL)稀释，用二氯甲烷(20mL×3)萃取。合并有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品，粗品通过层析板(石油醚/乙酸乙酯＝1/2)分离纯化得到11-6。MS(ESI)m/z:660.2[M+H +]。
步骤F：将化合物11-6(.45g,682.03μmol)溶于二氯甲烷(10mL)中，然后向反应液中加三氟乙酸(77.77mg,682.03μmol),所得混合物在25℃下搅拌5小时。反应液减压浓缩得到粗品。粗品通过(PPhenomenex Gemini-NX C18 75*30mm*3μm；流动相:[水(0.1％TFA)-ACN]；B％:30％-40％,7分钟)纯化得到化合物11的三氟乙酸盐。 1H NMR(400MHz,DMSO-d 6)δ＝10.44(s,1H),9.98(s,1H),8.58(d,J＝6.4Hz,1H),7.92(dd,J＝2.4,13.2Hz,1H),7.79-7.59(m,4H),7.58-7.38(m,3H),7.26-7.05(m,4H),6.62(d,J＝2.4Hz,1H),4.17(br t,J＝5.6Hz,2H),3.75(t,J＝5.6Hz,2H),1.53-1.41(m,4H)；MS(ESI)m/z:546.2[M+H +]
实施例12：化合物12
Figure PCTCN2021079337-appb-000071
步骤A：将化合物12-1(5g，34.02mmol)，2-溴乙醇(4.68g，37.42mmol)，碳酸铯(16.63g，51.03mmol)，TBAI(2.51g，6.80mmol)溶于N，N-二甲基乙酰胺(50mL)和水(20mL)中，所得混合物在90℃下搅拌12小时。反应混合物用水(200mL)稀释，用乙酸乙酯(100mL×2)萃取，混合后的有机层用饱和氯化钠溶液(100mL×2)洗涤，在无水硫酸钠上干燥，过滤，减压浓缩，得到12-2。MS(ESI)m/z:192.03[M+H +]。
步骤B：将化合物12-2(6.5g，34.03mmol)，TBSCl(6.15g,40.83mmol)，咪唑(4.63g,68.05mmol)，溶于N，N-二甲基甲酰胺(50mL)中，所得混合物在25℃下搅拌12小时。反应混合物用水(200mL)稀释，用乙酸乙酯(100mL×2)萃取，混合后的有机层用饱和氯化钠溶液(50mL×2)洗涤，在无水硫酸钠上干燥，过滤，减压浓缩，得到粗品。粗品通过硅胶柱分离(
Figure PCTCN2021079337-appb-000072
80g
Figure PCTCN2021079337-appb-000073
快速硅胶柱，洗脱液为乙酸乙酯/石油醚＝0～100％，流速60mL/min)纯化得到12-3。MS(ESI)m/z:307.0[M+H +]。
步骤C：将化合物12-3(1g，3.84mmol)，3-6(2.34g,7.68mmol)，醋酸钯(86.28mg,384.00μmol)，四(三苯基磷)钯(1.17g,3.84mmol)，无水溴化锂(1.00g,11.52mmol,289.38μL)，三乙胺(1.94g,19.20mmol)，溶于N,N-二甲基乙酰胺(10mL)中所得混合物用氮气置换三次并在125℃下搅拌12小时。反应混合物用水300mL稀释，用乙酸乙酯(100mL×2)萃取，混合后的有机层用饱和氯化钠溶液(100mL×2)洗涤，在无水硫酸钠上干燥，过滤，减压浓缩，得到粗品。残渣用硅胶柱层析法(石油醚/乙酸乙酯＝10/1～0/1)纯化得到12-4。MS(ESI)m/z:485.3[M+H +]。
步骤D：将化合物12-4(560mg,1.16mmol)溶于乙醇(5mL)和水(1mL)中，然后加入铁粉(645.41mg,11.56mmol)，氯化铵(309.07mg,5.78mmol)，所得混合物在90℃下搅拌2小时。反应液过滤后用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到12-5。MS(ESI)m/z:455.2[M+H +].
步骤E:将化合物1-8(294.58mg,1.32mmol)溶于二氯甲烷(5mL)中，于0℃下加入草酰氯(698.01mg,5.50mmol)和N,N-二甲基甲酰胺(8.04mg,109.98μmol)，在25℃下反应半小时。溶液浓缩得到相应的酰氯并溶于二氯甲烷(5mL)，在0℃下往溶液中加入12-5(500mg,1.10mmol)和吡啶434.99mg,5.50mmol)。所得混合物在25℃下搅拌半小时。反应液中加入水(20mL)，分液，水相用二氯甲烷(30mL×2)萃取。合并有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到12-6，粗品直接用于下一步。MS(ESI)m/z:660.3[M+H +].
步骤F：将化合物12-6(450mg,682.03μmol)溶于二氯甲烷(4mL)中，然后向反应液中加三氟乙酸(3.89g,34.10mmol)，所得混合物在25℃下搅拌1小时。反应液浓缩得到粗品。使用高效液相色谱法分离(柱信息:Phenomenex Luna C18 150*25mm*10μm；流动相:[水(0.225％FA)-ACN]；B％:18％-48％,9分钟)纯化得到粗品，继续用超临界流体色谱法分离(柱信息:DAICEL CHIRALCEL OD(250mm*30mm,10μm)；流动相:[0.1％氨水的乙醇]；B％:60％-60％,3.9min；100min)纯化得到化合物12。 1H NMR(400MHz,DMSO-d 6)δ＝10.37(s,1H),10.00(s,1H),8.39(d,J＝5.6Hz,1H),8.14(s,1H),7.87(dd,J＝2.4,13.2Hz,1H),7.69-7.61(m,3H),7.52-7.46(m,2H),7.42(s,1H),7.37-7.30(m,1H),7.16(t,J＝8.8Hz,2H),7.07(d,J＝16Hz,1H),7.01(d,J＝2.4Hz,1H),6.67(dd,J＝2.4,5.6Hz,1H),4.99(br t,J＝5.2Hz,1H),4.00(t,J＝5.6Hz,2H),3.66(q,J＝5.2Hz,2H),1.47(br d,J＝4.4Hz,4H)；MS(ESI)m/z:546.0[M+H +].
实施例13：化合物13
Figure PCTCN2021079337-appb-000074
步骤A：将化合物1-8(2.63g,11.80mmol)溶于二氯甲烷(15mL)中，于0℃下加入草酰氯(2.50g,19.67mmol)和N,N-二甲基甲酰胺((28.75mg,393.34μmol)，在25℃下反应半小时。溶液浓缩得到相应的酰氯并溶于四氢呋喃(15mL)，在0℃下往溶液中加入2-2((2g,15.73mmol)。所得混合物在70℃下搅拌两小时。反应液中加入水(300mL)，分液，水相用二氯甲烷(100mL×2)萃取。合并有机相用饱和氯化钠溶液(200mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到13-7，粗品直接用于下一步。MS(ESI)m/z:333.1[M+H +]。
步骤B：将化合物13-7(2g,6.02mmol)溶入N,N-二甲基甲酰胺(15mL)中，在0℃缓慢加入氢化钠(262.63mg,6.57mmol,60％含量)，混合物在25℃下反应半小时，再在反应中加入化合物1-1(719.69mg,5.47mmol)，所得混合物在120℃下搅拌12小时.反应混合物用水(300mL)稀释，用乙酸乙酯(150mL×2)萃取，混合后的有机层用饱和氯化钠溶液(200mL)洗涤，在无水硫酸钠上干燥，过滤，减压浓缩，得到粗品。粗品通过硅胶柱分离(
Figure PCTCN2021079337-appb-000075
40g
Figure PCTCN2021079337-appb-000076
快速硅胶柱，洗脱液为乙酸乙酯/石油醚＝0～100％)纯化得到13-6。MS(ESI)m/z:444.2[M+H +]。
步骤C:将化合物3-4(500mg,1.64mmol)，碘化亚铜(31.19mg,163.78μmol)，Xantphos(94.77mg,163.78μmol)，氯化钯(29.04mg,163.78μmol)溶于三乙胺(50mL)中所得混合物用氮气置换三次，加入13-1(3.22g,32.76mmol)所得混合物在65℃下搅拌12小时。反应混合物用硅藻土过滤，再用水(200mL)稀释，用乙酸乙酯(100mL×2)萃取，混合后的有机层用饱和氯化钠溶液(200mL)洗涤，在无水硫酸钠上干燥，过滤，减压浓缩，得到13-2。MS(ESI)m/z:323.2[M+H +]。
步骤D：将化合物13-2(2g,6.20mmol)，碳酸钾(1.71g,12.40mmol)溶于甲醇(20mL)中，所得混合物在60℃下搅拌2小时。反应混合物用水(300mL)稀释，用乙酸乙酯(150mL×2)萃取，混合后的有机层用饱和氯化钠溶液(200mL)洗涤，在无水硫酸钠上干燥，过滤，减压浓缩，得到粗品。粗品通过硅胶柱分离(
Figure PCTCN2021079337-appb-000077
24g
Figure PCTCN2021079337-appb-000078
快速硅胶柱，洗脱液为乙酸乙酯/石油醚＝0～100％)纯化得到13-3.MS(ESI)m/z:251.2[M+H +]。
步骤E：将化合物13-4(1.570g,6.18mmol)，氯化亚铜(15.81mg,159.74μmol)，Xantphos(92.43mg,159.74μmol)，溶于四氢呋喃(5mL)中，所得混合物用氮气置换三次，加入叔丁醇钾的四氢呋喃溶液(1M,1.60mL)，再加入13-3(400mg,1.60mmol)以及碘甲烷(453.46mg,3.19mmol)，混合物用氮气置换一次，所得混合物在25℃下搅拌12小时。反应完成后，把饱和氯化铵水溶液加入反应体系搅拌一小时淬灭。混合物用水(50ml)稀释，用乙酸乙酯(100ml)萃取，混合后的有机层用饱和氯化钠溶液(50mL×2)洗涤，在无水硫酸钠上干燥，过滤，减压浓缩，得到粗品。粗品用薄层色谱法纯化得到13-5。MS(ESI)m/z:393.3[M+H +]。
步骤F：将化合物13-5(130mg,331.28μmol)，化合物13-6(176.44mg,397.54μmol)，四(三苯基磷)钯(38.28mg,33.13μmol)，碳酸钠(70.23mg,662.56μmol)溶于1，4-二氧六环(1mL)和水(0.4mL)中，混合物用氮气置换三次，所得混合物在85℃下搅拌4小时。将反应混合物用水50mL稀释，用乙酸乙酯100mL(50mL×2)萃取，混合后的有机层用饱和氯化钠溶液(25mL×2)洗涤，在无水硫酸钠上干燥，过滤，减压浓缩，得到粗品。粗品用薄层色谱法纯化得到13-9。MS(ESI)m/z:674.3[M+H +]。
步骤G:将化合物13-9(100mg,148.41μmol)溶于二氯甲烷(1mL)中，反应体系中加入三氟乙酸 (846.07mg,7.42mmol)所得混合物在25℃下搅拌0.5小时，向反应液中加入碳酸氢钠水溶液(30mL)淬灭反应并用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过高效液相色谱法(柱信息:water Xbridge BEH C18 250*50mm*10μm；流动相:[水(0.05％氨水)-ACN]；ACN％:40％-60％，20分钟)纯化得到化合物13。 1H NMR(400MHz,DMSO-d 6)δ＝10.38(s,1H),10.01(s,1H),8.45(d,J＝5.6Hz,1H),7.96(s,1H),7.87(dd,J＝2.4,13.2Hz,1H),7.78(s,1H),7.67-7.61(m,2H),7.51-7.46(m,1H),7.34(t,J＝8.8Hz,1H),7.16(t,J＝8.8Hz,2H),6.81(dd,J＝1.6,5.3Hz,2H),6.74(dd,J＝2.4,5.7Hz,1H),4.92(br s,1H),4.11(t,J＝5.6Hz,2H),3.73(t,J＝5.6Hz,2H),2.45(d,J＝1.2Hz,3H),1.52-1.42(m,4H)。MS(ESI)m/z:560.1[M+H +].
实施例14：化合物14
Figure PCTCN2021079337-appb-000079
步骤A：将化合物2-4(855.62mg,3.28mmol)，3-4(1g,3.28mmol)，醋酸钯(73.54mg,327.56μmol)，三乙胺(1.66g,16.38mmol)，P(o-tolyl) 3(996.98mg,3.28mmol)，溴化锂(853.41mg,9.83mmol)溶于甲苯(30mL)中，所得混合物用氮气置换三次并在110℃下搅拌12小时。反应液中加入水(100mL)淬灭反应并用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝10/1～0/1)纯化得到14-1。MS(ESI)m/z:486.3[M+H +]。
步骤B：将化合物14-1(300mg,617.81μmol)溶于乙醇(10mL)和水(2mL)中，然后加入铁粉(345.02mg,6.18mmol)，氯化铵(165.24mg,3.09mmol)，所得混合物在90℃下搅拌6小时。反应液过滤后用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到14-2。MS(ESI)m/z:456.1[M+H +]。
步骤C:将化合物14-2(100mg,219.49μmol)溶于二氯甲烷(5mL)中，然后加入1-8(97.98mg,438.98μmol)，T 3P(419.03mg,658.47μmol)，DIEA(141.84mg,1.10mmol)。混合物在25℃下搅拌12小时。反应液中加入水(50mL)淬灭反应并用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品14-3。MS(ESI)m/z:661.1[M+H +]。
步骤D:将化合物14-3(30mg,45.40μmol)溶于二氯甲烷(2mL)中，反应体系中加入三氟乙酸(709.19mg,6.22mmol)所得混合物在25℃下搅拌1小时，反应混合物在减压下浓缩得到粗品。粗品通过高效液相色谱法分离(柱信息:Xtimate C18 150*40mm*10μm；流动相:[水(0.05％氨水)-ACN]；ACN％:32％-62％,10分钟)纯化得到化合物14。 1H NMR(400MHz,DMSO-d 6)δ＝10.32(s,1H),10.02(s,1H),8.62(s,1H),8.09(s,1H),7.87-7.77(m,3H),7.67-7.62(m,2H),7.44(dd,J＝1.2,8.8Hz,1H),7.33(t,J＝8.8Hz,1H),7.16(t,J＝8.8Hz,2H),7.10(s,1H),6.97(d,J＝16.0Hz,1H),4.94(t,J＝5.2Hz,1H),4.16(t,J＝5.6Hz,2H),3.74(q,J＝5.2Hz,2H),1.47(br d,J＝2.8Hz,4H)；MS(ESI)m/z:547.1[M+H +].
实施例15：化合物15
Figure PCTCN2021079337-appb-000080
步骤A：将化合物15-1(3g,23.16mmol)，化合物15-2(4.07g,23.16mmol)，碳酸钾(6.40g,46.32mmol)溶于N,N-二甲基甲酰胺(20mL)中，所得混合物在100℃下搅拌12小时。反应混合物用水(100mL)稀释，用乙酸乙酯(100mL×2)萃取，混合后的有机层用饱和氯化钠溶液(50mL)洗涤，在无水硫酸钠上干燥，过滤，减压浓缩，得到粗品，粗品通过硅胶柱分离(
Figure PCTCN2021079337-appb-000081
120g
Figure PCTCN2021079337-appb-000082
快速硅胶柱，洗脱液为乙酸乙酯/石油醚＝0～100％)纯化得到15-3.MS(ESI)m/z:284.7[M+H +]。
步骤B：将化合物15-3(3g,10.52mmol)，1-2(1.94g,12.63mmol)，四(三苯基磷)钯(1.22g,1.05mmol)，碳酸钠(2.23g,21.05mmol)溶于1，4-二氧六环(30mL)和水(6mL)中，所得混合物用氮气置换三次并在84℃下搅拌4小时。反应液中加入水(100mL)淬灭并用乙酸乙酯(100mL×2)萃取。合并有机相用 饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过柱层析法(SiO2，石油醚:乙酸乙酯＝20/1～5/1)纯化得到15-4。MS(ESI)m/z:277.0[M+H +]。
步骤C：将化合物15-4(906.28mg,3.28mmol)，3-4(1g,3.28mmol)，醋酸钯(73.54mg,327.56μmol)，三乙胺(1.66g,16.38mmol)，P(o-tolyl) 3(997.00mg,3.28mmol)，溴化锂(853.46mg,9.83mmol)溶于甲苯(10mL)中，所得混合物用氮气置换三次并在110℃下搅拌12小时。反应液中加入水(100mL)淬灭反应并用乙酸乙酯(100mL×2)萃取。合并有机相用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品。粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝10/1～0/1)纯化得到15-5。MS(ESI)m/z:501.2[M+H +]。
步骤D:将化合物15-5(400mg,798.33μmol)溶于乙醇(10mL)和水(2mL)中，然后加入铁粉(445.86mg,7.98mmol)，氯化铵(213.51mg,3.99mmol)，所得混合物在90℃下搅拌6小时。反应液过滤后用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品15-6。MS(ESI)m/z:471.2[M+H +]。
步骤E:将化合物1-8(56.86mg,254.74μmol)溶于二氯甲烷(5mL)中，于0℃下加入草酰氯(134.73mg,1.06mmol)和N,N-二甲基甲酰胺(1.55mg,21.23μmol)，在25℃下反应半小时。溶液浓缩得到相应的酰氯并溶于二氯甲烷(10mL)，在0℃下往溶液中加入15-6(100mg,212.28μmol)和吡啶(83.96mg,1.06mmol)。所得混合物在25℃下搅拌半小时。反应液中加入水(20mL)，分液，水相用二氯甲烷(20mL×3)萃取。合并有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到15-7，粗品直接用于下一步。MS(ESI)m/z:676.3[M+H +].
步骤F:将化合物15-7(120mg,177.45μmol)溶于二氯甲烷(2mL)中，反应体系中加入三氟乙酸(2.77g,24.31mmol)所得混合物在25℃下搅拌1小时，反应混合物在减压下浓缩得到粗品。粗品通过高效液相色谱法分离(柱信息:Xtimate C18 150*40mm*10μm；流动相:[水(0.05％氨水)-ACN]；ACN％:37％-67％，10分钟)纯化得到化合物15。 1H NMR(400MHz,DMSO-d 6)δ＝10.34(s,1H),10.01(s,1H),8.40(d,J＝5.6Hz,1H),8.06(d,J＝2.4Hz,1H),7.97(s,1H),7.77(s,1H),7.68-7.62(m,3H),7.52(d,J＝16Hz,1H),7.35(d,J＝8.8Hz,1H),7.16(t,J＝8.8Hz,2H),6.92(d,J＝16Hz,1H),6.81(d,J＝2.4Hz,1H),6.69(dd,J＝2.4,5.6Hz,1H),4.91(br s,1H),4.12(t,J＝5.6Hz,2H),3.73(br d,J＝4.4Hz,2H),1.47(br d,J＝5.6Hz,4H)；MS(ESI)m/z:562.4[M+H +].
实施例16：化合物16
Figure PCTCN2021079337-appb-000083
步骤A：将化合物6(300mg,598.23μmol)，16-1(239.80mg,1.79mmol)，碳酸铯(584.74mg,1.79mmol)，碘化钾(9.93mg,59.82μmol)溶于N,N-二甲基乙酰胺(2mL)中，所得混合物在100℃下搅拌12小时。反应混合物用水(10mL)和乙酸乙酯(20mL)稀释，分液，水相用乙酸乙酯(20mL×2)萃取，混合后的有机层用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到粗品，使用制备级薄层色谱分离(二氯甲烷/甲醇＝5/1)得到化合物16。 1H NMR(400MHz,DMSO-d 6)δ＝10.40(s,1H),10.01(s,1H),8.39(d,J＝5.6Hz,1H),8.07(s,1H),7.87(dd,J＝2.2,13.2Hz,1H),7.78(s,1H),7.67-7.60(m,2H),7.54-7.45(m,2H),7.39-7.31(m,1H),7.20-7.12(m,2H),6.92(d,J＝16.0Hz,1H),6.83(d,J＝2.4Hz,1H),6.74(dd,J＝2.4,5.6Hz,1H),4.16-4.05(m,1H),2.88(br d,J＝11.2Hz,2H),2.24(s,3H),2.17-2.04(m,2H),2.03-1.89(m,4H),1.51-1.41(m,4H)；MS(ESI)m/z:599.4[M+H +]。
实施例17：化合物17
Figure PCTCN2021079337-appb-000084
步骤A：将化合物6(50mg,99.70μmol)，17-1(33.28mg,119.64μmol)，碳酸铯(97.46mg,299.10μmol)，溶于N,N-二甲基乙酰胺(2mL)中，所得混合物在60℃下搅拌2小时。反应混合物用水(10mL)和乙酸乙酯(20mL)稀释，分液，水相用乙酸乙酯(20mL×2)萃取，混合后的有机层用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到粗品，使用制备级薄层色谱分离(二氯甲烷/甲醇＝5/1)得到化合物17-2。MS(ESI)m/z:699.2[M+H +]。
步骤B：将化合物17-2(70mg,100.18μmol)溶于乙酸乙酯(3mL)中，反应体系中加入盐酸甲醇溶液(4mol/L,3mL)所得混合物在20℃下搅拌30分钟，反应混合物在减压下浓缩得到粗品。粗品通过高效液相色谱法分离(柱信息:Unisil 3-100 C18 Ultra 150*50mm*3μm；流动相:[水(0.225％FA)-ACN]；B％:15％-35％,10分钟)纯化得到化合物17-3。MS(ESI)m/z:599.3[M+H +]。
步骤C：将化合物17-3(97.71mg,163.22μmol)溶于四氢呋喃(10mL)，加入37甲醛水溶液(49.01mg,1.63mmol)和三乙酰基硼氢化钠(172.97mg,816.10μmol)，所得混合物在20℃下搅拌12小时。使用饱和碳酸氢钠(5mL)淬灭反应，加水(5mL)稀释，分液，水相用乙酸乙酯(20mL×3)萃取，混合后的有机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到粗品，粗品通过制备级高效液 相色谱法分离(柱信息:Unisil 3-100 C18 Ultra 150*50mm*3μm；流动相:[水(0.225％FA)-ACN]；B％:15％-35％,10分钟)纯化得到化合物17的甲酸盐。 1H NMR(400MHz,DMSO-d 6)δ＝10.41(s,1H),10.02(s,1H),8.40(d,J＝5.6Hz,1H),8.27(s,1H),7.98(s,1H),7.88(dd,J＝2.4,13.2Hz,1H),7.78(s,1H),7.65(dd,J＝5.2,9.2Hz,2H),7.55-7.45(m,2H),7.35(t,J＝9.2Hz,1H),7.16(t,J＝8.8Hz,2H),6.92(d,J＝16.0Hz,1H),6.86(d,J＝2.4Hz,1H),6.74(dd,J＝2.4,5.6Hz,1H),3.99(br d,J＝7.2Hz,2H),2.92(br d,J＝11.2Hz,2H),2.30(s,3H),2.12(br t,J＝11.2Hz,2H),1.83(br dd,J＝3.6,6.8Hz,1H),1.57-1.41(m,6H),1.28(q,J＝10.8Hz,2H)；MS(ESI)m/z:613.3[M+H +]。
实施例18：化合物18
Figure PCTCN2021079337-appb-000085
步骤A：将化合物6(50mg,99.70μmol)，18-1(34.96mg,119.65μmol)，碳酸铯(97.46mg,299.10μmol)，溶于N,N-二甲基乙酰胺(2mL)中，所得混合物在60℃下搅拌2小时。反应混合物用水(10mL)和乙酸乙酯(20mL)稀释，分液，水相用乙酸乙酯(20mL×2)萃取，混合后的有机层用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到粗品，使用制备级薄层色谱分离(二氯甲烷/甲醇＝5/1)得到化合物18-2。MS(ESI)m/z:713.2[M+H +]。
步骤B：将化合物18-2(70mg,98.21μmol)溶于乙酸乙酯(3mL)中，反应体系中加入盐酸甲醇溶液(4mol/L,3mL)所得混合物在20℃下搅拌30分钟，反应混合物在减压下浓缩得到粗品。粗品通过制备级高效液相色谱法分离(柱信息:Unisil 3-100 C18 Ultra 150*50mm*3μm；流动相:[水(0.225％FA)-ACN]；ACN％:15％-35％,10分钟)纯化得到化合物18-3。MS(ESI)m/z:613.3[M+H +]。
步骤C：将化合物18-3(100mg,163.22μmol)溶于四氢呋喃(10mL)，加入37甲醛水溶液(49.01mg,1.63mmol)和三乙酰基硼氢化钠(172.97mg,816.10μmol)，所得混合物在20℃下搅拌12小时。使用饱和碳酸氢钠(5mL)淬灭反应，加水(5mL)稀释，分液，水相用乙酸乙酯(20mL×3)萃取，混合后的有机层 用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到粗品，粗品通过制备级高效液相色谱法分离(柱信息:Unisil 3-100 C18 Ultra 150*50mm*3μm；流动相:[水(0.225％FA)-ACN]；ACN％:15％-35％,10分钟)纯化得到化合物18的甲酸盐。 1H NMR(400MHz,DMSO-d 6)δ＝10.42(br s,1H),10.03(s,1H),8.40(d,J＝5.6Hz,1H),8.31(s,1H),8.01(s,1H),7.88(dd,J＝2.3,13.2Hz,1H),7.77(s,1H),7.68-7.62(m,2H),7.54-7.47(m,2H),7.35(t,J＝9.0Hz,1H),7.16(t,J＝9.0Hz,2H),6.92(d,J＝15.9Hz,1H),6.86(d,J＝2.4Hz,1H),6.74(dd,J＝2.4,5.6Hz,1H),4.12(br t,J＝7.1Hz,2H),2.93(br d,J＝11.7Hz,2H),2.31(s,3H),2.16(br t,J＝10.9Hz,2H),1.79-1.60(m,4H),1.54-1.39(m,4H),1.33-1.08(m,3H)；MS(ESI)m/z:627.3[M+H +]。
实施例19：化合物19
Figure PCTCN2021079337-appb-000086
步骤A：将化合物6(50mg,99.70μmol)，19-1(35.08mg,119.64μmol)，碳酸铯(97.46mg,299.10μmol)，溶于N,N-二甲基乙酰胺(2mL)中，所得混合物在60℃下搅拌2小时。反应混合物用水(10mL)和乙酸乙酯(20mL)稀释，分液，水相用乙酸乙酯(20mL×2)萃取，混合后的有机层用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到粗品，使用制备级薄层色谱分离(二氯甲烷/甲醇＝5/1)得到化合物19-2。MS(ESI)m/z:714.2[M+H +]。
步骤B：将化合物19-2(70mg,98.07μmol)溶于乙酸乙酯(3mL)中，反应体系中加入盐酸甲醇溶液(4mol/L,3mL)所得混合物在20℃下搅拌30分钟，反应混合物在减压下浓缩得到粗品。粗品通过高效液相色谱法分离(柱信息:Unisil 3-100 C18 Ultra 150*50mm*3μm；流动相:[水(0.225％FA)-ACN]；B％:15％-35％,10分钟)纯化得到化合物19-3。MS(ESI)m/z:614.3[M+H +]。
步骤C：将化合物19-3(100mg,162.96μmol)溶于四氢呋喃(10mL)，加入37％甲醛水溶液(48.94mg,1.63mmol)和三乙酰基硼氢化钠(172.69mg,814.79μmol)，所得混合物在20℃下搅拌12小时。使用饱和碳酸氢钠(5mL)淬灭反应，加水(5mL)稀释，分液，水相用乙酸乙酯(20mL×3)萃取，混合后的有 机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到粗品，粗品通过高效液相色谱法分离(柱信息:Unisil 3-100 C18 Ultra 150*50mm*3μm；流动相:[水(0.225％FA)-ACN]；B％:15％-35％,10分钟)纯化得到化合物19的甲酸盐。 1H NMR(400MHz,DMSO-d 6)δ＝10.40(s,1H),10.02(s,1H),8.40(d,J＝5.6Hz,1H),8.23(s,1H),7.99(s,1H),7.88(dd,J＝2.0,13.2Hz,1H),7.77(s,1H),7.65(dd,J＝5.2,8.8Hz,2H),7.56-7.45(m,2H),7.35(t,J＝9.2Hz,1H),7.16(t,J＝8.8Hz,2H),6.91(d,J＝16.0Hz,1H),6.87(d,J＝2.0Hz,1H),6.74(dd,J＝2.4,5.6Hz,1H),4.19(br t,J＝6.4Hz,2H),2.70(br t,J＝6.4Hz,2H),2.50-2.31(m,8H),2.20(s,3H),1.57-1.39(m,4H)；MS(ESI)m/z:628.3[M+H +]。
实施例20：化合物20
Figure PCTCN2021079337-appb-000087
步骤A：将化合物20-1(5.08g,19.10mmol)，化合物20-2(5.02g,21.00mmol)，碳酸铯(12.44g,38.19mmol)溶于N,N-二甲基乙酰胺(50mL)中，所得混合物在60℃下搅拌12小时。反应混合物用水(100mL)稀释，用乙酸乙酯(100mL×2)萃取，混合后的有机层用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到粗品，使用硅胶柱分离(石油醚/乙酸乙酯＝1:0～5:1)纯化得到化合物20-3。MS(ESI)m/z:425.3[M+H +]。
步骤B：将化合物20-3(2.4g,5.66mmol)溶于乙醇(20mL)中，反应体系中加入硼氢化钠(641.91mg,16.97mmol)，所得混合物在90℃下搅拌12小时，加入盐酸(1mol/L,10mL)淬灭反应，加入水(50mL)， 用乙酸乙酯(50mL×2)萃取，混合后的有机层用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到化合物20-4。MS(ESI)m/z:383.3[M+H +]。
步骤C：将化合物20-4(2.9g,7.59mmol)溶于N,N-二甲基乙酰胺(15mL)，加入TBSCl(1.37g,9.10mmol)和咪唑(1.03g,15.17mmol)，所得混合物在25℃下搅拌12小时。加水(50mL)稀释，用乙酸乙酯(50mL×2)萃取，混合后的有机层用饱和食盐水(80mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到粗品，粗品通过制备级高效液相色谱法分离(柱信息:Phenomenex luna C18(250*70mm,15μm)；流动相:[水(0.1％TFA)-ACN]；B％:70ACN％-100ACN％,30分钟)纯化得到化合物20-5。MS(ESI)m/z:497.4[M+H +]。
步骤D：将化合物3-6(655.04mg,2.52mmol),化合物20-5(1.25g,2.52mmol)，醋酸钯(56.51mg,251.73μmol)，三乙胺(1.27g,12.59mmol)，溴化锂(655.87mg,7.55mmol)，P(o-tolyl) 3(766.18mg,2.52mmol)溶于N,N-二甲基乙酰胺(10mL)中，所得混合物用氮气置换三次并在110℃下搅拌12小时。反应液中加入水(50mL)，用乙酸乙酯(50mL×2)萃取.合并有机相用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到粗品。粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝5:1)纯化得到20-6。MS(ESI)m/z:629.5[M+H +].
步骤E：将化合物20-6(1.5g,2.39mmol)溶于乙醇(15mL)，然后加入铁粉(1.33g,23.85mmol)，氯化铵溶液(127.59mg,2.39mmol,2.5mL水中)，所得混合物在80℃下搅拌12小时。过滤，收集滤液加入水(50mL)，用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到20-7，粗品直接用于下一步。MS(ESI)m/z:599.5[M+H +].
步骤F：将化合物1-8(339.14mg,1.52mmol)溶于二氯甲烷(10mL)中，于0℃下加入草酰氯(741.79mg,5.84mmol)和N,N-二甲基甲酰胺(8μL)，在25℃下反应半小时。溶液浓缩得到相应的酰氯并溶于二氯甲烷(10mL)，在0℃下往溶液中加入20-7(700mg,1.17mmol)和吡啶(462.27mg,5.84mmol).所得混合物在25℃下搅拌半小时。反应液中加入水(30mL)，分液，水相用二氯甲烷(20mL×3)萃取。合并有机相用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到20-8，粗品直接用于下一步。MS(ESI)m/z:804.2[M+H +].
步骤G：将化合物20-8(0.9g,1.12mmol)溶于二氯甲烷(20mL)中，然后向反应液中加盐酸甲醇溶液(4mol/L,5mL)和乙酸乙酯(5mL)，所得混合物在25℃下搅拌1小时。反应液减压浓缩得到粗品。粗品通过制备级高效液相色谱分离(柱信息:Phenomenex luna C18 150*40mm*15μm；流动相:[水(0.225％FA)-ACN]；ACN％:15％-45％,10分钟)纯化得到化合物20。 1H NMR(400MHz,DMSO-d 6)δ＝10.36(s,1H),9.99(s,1H),8.39(d,J＝5.6Hz,1H),8.00(s,1H),7.86(dd,J＝2.4,13.2Hz,1H),7.66-7.59(m,3H),7.48(dd,J＝1.2,8.8Hz,1H),7.38-7.31(m,1H),7.15(t,J＝8.8Hz,2H),6.91-6.84(m,2H),6.71(dd,J＝2.4,5.6Hz,1H),5.08(t,J＝5.2Hz,1H),4.91(t,J＝5.2Hz,1H),4.49(d,J＝5.2Hz,2H),4.07(t,J＝5.6Hz,2H),3.72(q,J＝5.6Hz,2H),1.50-1.43(m,4H)；MS(ESI)m/z:576.3[M+H +].
实施例21：化合物21
Figure PCTCN2021079337-appb-000088
Figure PCTCN2021079337-appb-000089
步骤A：将化合物3-6(735.87mg,2.83mmol),化合物20-3(1.2g,2.83mmol)，醋酸钯(63.49mg,283.00μmol)，三乙胺(1.43g,14.15mmol)，溴化锂(736.80mg,8.49mmol)，P(o-tolyl) 3(860.72mg,2.83mmol)溶于N,N-二甲基乙酰胺(10mL)中，所得混合物用氮气置换三次并在110℃下搅拌12小时。反应液中加入水(50mL)，用乙酸乙酯(50mL×2)萃取.合并有机相用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到粗品。粗品通过硅胶柱分离纯化(石油醚/乙酸乙酯＝1:1～0:1)纯化得到21-1。MS(ESI)m/z:557.4[M+H +]。
步骤B：将化合物21-1(1.36g,2.44mmol)溶于乙醇(25mL)，然后加入铁粉(1.21g,21.60mmol)，氯化铵溶液(1.34g,24.97mmol,2.5mL水中)，所得混合物在80℃下搅拌12小时。过滤，收集滤液加入水(50mL)，用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到21-2，粗品直接用于下一步。MS(ESI)m/z:527.4[M+H +]。
步骤C：将化合物1-8(330.56mg,1.48mmol)溶于二氯甲烷(10mL)中，于0℃下加入草酰氯(723.01mg,5.70mmol)和N,N-二甲基甲酰胺(8μL)，在25℃下反应半小时。溶液浓缩得到相应的酰氯并溶于二氯甲烷(10mL)，在0℃下往溶液中加入21-2(600mg,1.14mmol)和吡啶(450.56mg,5.70mmol).所得混合物在25℃下搅拌半小时。反应液中加入水(30mL)，分液，水相用二氯甲烷(20mL×3)萃取。合并有机相用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥,过滤后减压浓缩得到21-3，粗品直接用于下一步。MS(ESI)m/z:732.3[M+H +]。
步骤D：将化合物21-3(1g,1.37mmol)溶于甲醇(5mL)和水(5mL)中，然后向反应液中加入氢氧化锂(65.45mg,2.73mmol)，所得混合物在25℃下搅拌18小时。使用盐酸(1mol/L)调节pH值至3左右，加入水(50mL)，用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(100mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到21-4，粗品直接用于下一步。MS(ESI)m/z:590.2[M+H +]。
步骤E：将化合物21-4(100mg,169.62μmol)溶于N,N-二甲基乙酰胺(2mL)中，加入氯化铵(18.15mg,339.24μmol)，PyBOP(105.92mg,203.55μmol)，DIEA(87.69mg,678.49μmol)和HOBt(27.50mg,203.55μmol)，所得混合物于25℃搅拌12小时。加入水(20mL)，用乙酸乙酯(20mL×2)萃取。合并有 机相用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品，使用高效液相色谱法分离(柱信息:Phenomenex Luna C18 150*25mm*10μm；流动相:[water(0.225％FA)-ACN]；ACN％:22％-52％,11分钟)纯化得到化合物21。 1H NMR(400MHz,DMSO-d 6)δ＝10.39(s,1H),10.02(s,1H),8.42(d,J＝5.6Hz,1H),8.23(s,1H),8.12(d,J＝16.4Hz,1H),7.87(dd,J＝2.4,13.2Hz,1H),7.68-7.60(m,2H),7.49(dd,J＝1.2,8.8Hz,1H),7.43(s,1H),7.35(t,J＝9.2Hz,1H),7.26(s,1H),7.19-7.11(m,2H),7.00(d,J＝16.4Hz,1H),6.80(d,J＝2.4Hz,1H),6.76(dd,J＝2.4,5.6Hz,1H),4.16(t,J＝5.2Hz,2H),3.78(t,J＝5.2Hz,2H),1.49–1.41(m,4H)；MS(ESI)m/z:589.4[M+H +].
实施例22：化合物22
Figure PCTCN2021079337-appb-000090
步骤A：将化合物21-4(380mg,644.56μmol)溶于乙腈(9mL)中，加入甲胺盐酸盐(87.04mg,1.29mmol)，HATU(269.59mg,709.02μmol)，DIEA(333.21mg,2.58mmol)和N,N-二甲基乙酰胺(0.9mL)，所得混合物于25℃搅拌12小时。加入水(50mL)，用二氯甲烷(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品，使用高效液相色谱法分离(柱信息:Waters Xbridge 150*25mm*5μm；流动相:[water(10mM NH4HCO3)-ACN]；ACN％:27％-57％,9分钟)纯化得到化合物22。1H NMR(400MHz,DMSO-d6)δ＝10.36(s,1H),9.99(s,1H),8.42(d,J＝5.6Hz,1H),8.23(s,1H),8.11(d,J＝16.4Hz,1H),8.05(d,J＝4.8Hz,1H),7.86(dd,J＝2.4,13.2Hz,1H),7.67-7.60(m,2H),7.49(dd,J＝1.2,8.8Hz,1H),7.38-7.32(m,1H),7.19-7.11(m,2H),7.00(d,J＝16.4Hz,1H),6.81(d,J＝2.4Hz,1H),6.75(dd,J＝2.4,5.6Hz,1H),4.99(t,J＝5.2Hz,1H),4.16(t,J＝5.6Hz,2H),3.78(q,J＝4.8Hz,2H),2.74(d,J＝4.8Hz,3H),1.49-1.43(m,4H)；MS(ESI)m/z:603.2[M+H+].
实施例23：化合物23
Figure PCTCN2021079337-appb-000091
Figure PCTCN2021079337-appb-000092
步骤A：将化合物21-4(100mg,169.62μmol)溶于N,N-二甲基乙酰胺(2mL)中，加入盐酸羟胺(23.57mg,339.24μmol)，PyBOP(105.92mg,203.55μmol)，DIEA(109.61mg,848.11μmol)和HOBt(27.50mg,203.55μmol)，所得混合物于25℃搅拌12小时。加入水(20mL)，用乙酸乙酯(20mL×2)萃取。合并有机相用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品，使用高效液相色谱法分离(柱信息:Unisil 3-100 C18 Ultra 150*50mm*3μm；流动相:[water(0.225％FA)-ACN]；ACN％:25％-45％,10分钟)纯化得到化合物23。 1H NMR(400MHz,DMSO-d 6)δ＝10.88(s,1H),10.37(s,1H),10.00(s,1H),8.94(d,J＝1.2Hz,1H),8.43(d,J＝5.6Hz,1H),8.23(s,1H),7.99(d,J＝16.4Hz,1H),7.87(dd,J＝2.4,13.2Hz,1H),7.70-7.60(m,2H),7.49(dd,J＝1.6,8.8Hz,1H),7.40-7.32(m,1H),7.16(t,J＝9.2Hz,2H),7.02(d,J＝16.4Hz,1H),6.83-6.73(m,2H),4.98(t,J＝5.6Hz,1H),4.16(t,J＝5.2Hz,2H),3.78(q,J＝5.2Hz,2H),1.51–1.44(m,4H)；MS(ESI)m/z:605.4[M+H +].
实施例24：化合物24
Figure PCTCN2021079337-appb-000093
步骤A：将化合物21-4(100mg,169.62μmol)溶于N,N-二甲基乙酰胺(2mL)中，加入羟乙基胺(20.72mg,339.24μmol)，PyBOP(105.92mg,203.55μmol)，DIEA(109.61mg,848.11μmol)和HOBt(27.50mg,203.55μmol)，所得混合物于25℃搅拌12小时。加入水(50mL)，用乙酸乙酯(50mL×2)萃取。合并有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤后减压浓缩得到粗品，使用高效液相色谱法分离(柱信息:Phenomenex Gemini-NX C18 75*30mm*3μm；流动相:[水(0.225％FA)-ACN]；ACN％:15％-45％,7分钟)纯化得到化合物24。 1H NMR(400MHz,DMSO-d 6)δ＝10.42(s,1H),9.99(s,1H),8.50(d,J＝6.0Hz,1H),8.27(s,1H),8.17(d,J＝16.4Hz,1H),7.98(t,J＝5.8Hz,1H),7.90(dd,J＝2.4,13.2Hz,1H),7.67-7.60(m,2H),7.52(dd,J＝1.2,8.8Hz,1H),7.40(t,J＝8.8Hz,1H),7.19-7.11(m,3H),7.09(s,1H),6.96(s,1H),4.20(t,J＝5.2Hz,2H),3.79(t,J＝5.2Hz,2H),3.53-3.48(m,4H),1.52-1.42(m,4H)；MS(ESI)m/z:633.1[M+H +].
实验例1：血管内皮细胞生长因子受体2(VEGFR-2/KDR)激酶活性抑制实验(体外评价)
实验材料：
KDR Kinase Enzyme System(KDR激酶酶系统)购自Promega。Nivo多标记分析仪(PerkinElmer)。
实验方法：
使用试剂盒里的激酶缓冲液稀释酶，底物，ATP和抑制剂。将待测化合物用排枪进行5倍稀释至第8个浓度，即从50μM稀释至0.65nM，DMSO终浓度为5％，设置双复孔实验。向微孔板中加入1μL抑制剂各浓度梯度，2μL KDR酶(1.5ng)，2μL底物和ATP的混合物(138.8μM ATP，0.2μg/μl Poly E 4Y 1)，此时化合物终浓度梯度为10μM稀释至0.13nM。反应体系置于25℃反应60分钟。反应结束后，每孔加入5μl ADP-Glo试剂，25℃继续反应40分钟，结束反应后每孔加入10μL的激酶检测试剂，25度反应30分钟后采用PerkinElmer Envision多标记分析仪读数化学发光，积分时间0.5秒。
数据分析：
利用方程式(样品-Min)/(Max-Min)*100％将原始数据换算成抑制率，IC 50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中log(抑制)vs.响应--可变斜率模式得出)。
实验结果见表1。
实验结论：本发明化合物对VEGFR2/KDR激酶具有良好的抑制活性。
实验例2：Axl激酶活性抑制实验(体外评价)
实验材料：
AXL Kinase Enzyme System(AXL激酶酶系统)购自Promega。Nivo多标记分析仪(PerkinElmer)。实验方法：
使用试剂盒里的激酶缓冲液稀释酶、底物、ATP和抑制剂。
将待测化合物用排枪进行5倍稀释至第8个浓度，即从5μM稀释至0.065nM，DMSO浓度为5％，设置双复孔实验。向微孔板中加入1μL抑制剂各浓度梯度，2μl AXL酶(6ng)，2μL底物和ATP的混合物(89.37μM ATP，0.2μg/μL Axltide)，此时化合物终浓度梯度为1μM稀释至0.013nM。反应体系置于25℃反应60分钟。反应结束后，每孔加入5μL ADP-Glo试剂，25℃继续反应40分钟，结束反应后每孔加入10μL的kinase detection试剂，25℃反应30分钟后采用PerkinElmer Envision多标记分析仪读数化学发光，积分时间0.5秒。
数据分析：
利用方程式(样品-Min)/(Max-Min)*100％将原始数据换算成抑制率，IC 50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中log(抑制)vs.响应–可变斜率模式得出)。表1提供了本发明的化合物对AXL酶学抑制活性。
实验结果见表1。
表1激酶活性抑制实验结果
受试化合物 Axl(nM) VEGFR2(nM)
化合物1 23.16 25.84
化合物2的甲酸盐 36.62 44.12
化合物3的甲酸盐 11.34 37.37
化合物4 19.14 31.59
化合物6 37.98 96.48
化合物7 20.17 76.98
化合物8 13.25 /
化合物9的三氟乙酸盐 34.23 74.28
化合物11的三氟乙酸盐 33.07 42.69
化合物12 11.48 74.94
化合物13 97.25 224.2
化合物14 25.38 46.9
化合物15 17.09 /
化合物16 8.5 17.09
化合物17的甲酸盐 12.44 20.54
化合物18的甲酸盐 / 37.17
化合物19的甲酸盐 13.89 20.51
化合物20 / 33.56
化合物21 1.79 19.47
化合物22 4.22 12.76
化合物23 / 48.71
化合物24 / 14.81
“/”表示尚未获得测试结果。
实验结论：本发明化合物体对AXL和VEGFR2激酶具有良好的抑制活性。
实验例3：正辛醇/水分配系数pH7.4(Log D 7.4)
实验材料：
DMSO储备液配制测试化合物和对照物(纳多洛尔、美西汀、普萘洛尔、奎尼丁、阿米替林、氯丙嗪)的10Mm DMSO储备液
缓冲溶液100mM磷酸缓冲液,pH 7.4,DMSO％:1％；正辛醇饱和缓冲液(pH 7.4)溶液；缓冲液(pH7.4)饱和正辛醇溶液
实验操作：
1.测试化合物(10mM DMSO溶液，2μL/孔)和QC样品(10mM DMSO溶液；2μL/孔)分别从储备液添加到96孔聚丙烯管；
2.每孔添加正辛醇饱和缓冲液溶液(150μL/孔)和缓冲液(pH7.4)饱和正辛醇(150μL/孔)溶液；
3.强力搅拌一分钟，然后摇一摇，每分钟600转，温度为28℃；
4.每分钟2500转离心10分钟
5.正辛醇层稀释Y倍(200倍)，缓冲液层稀释X倍(20倍)
6.用LCMS/MS法测定滤液的试验混合浓度。
化合物的Log D值计算公式如下:
Figure PCTCN2021079337-appb-000094
O-S：正辛醇层中样品峰面积
O-IS：正辛醇层中内标峰面积
B-S：缓冲液层中样品峰面积
B-IS：缓冲液层中内标峰面积
Y：正辛醇层中样品的稀释倍数
X：缓冲液层中样品的稀释倍数
注：样品分析采用三极四极质谱仪进行。将稀释后的样品用等容水负载溶剂注射到一个小的柱形高效液相色谱柱上，然后以快速梯度冲入质谱仪，得到有机洗脱溶剂。采用稀释因子校正峰面积，结合内部标准，用校正峰面积之比计算结果(Log D值)。
实验结果：见表2。
表2 Log D 7.4测试结果
受试化合物 Sitravatinib 化合物3的甲酸盐
Log D 7.4 >4.0 3.65
实验结论：Log D 7.4为化合物在pH7.4下的油水分布系数，代表着化合物的理化性质，Log D 7.4在3左右被认为具备最好的成药性。因此，本发明化合物相比Sitravatinib具备更好的理化性质。
实验例4：体外药代动力学研究
(1)MDR1-MDCK细胞双向渗透性评估实验
本研究采用经荷兰癌症研究所Piet Borst实验室授权的MDR1-MDCKII细胞系作为实验的体外模型，它是一种转染了人的多耐药基因(MDR1)的Madin-Darby犬肾细胞，该细胞能稳定表达外排转运体P-gp，因此适用于筛选P-gp底物或者抑制剂，并预测化合物在如十二指肠、血脑屏障、肝细胞核和肾单元等具有高外排作用屏障的渗透性。本研究的目的是利用MDR1-MDCK II细胞测定本发明化合物穿过MDR1-MDCK II细胞模型的双向渗透性。
实验操作：实验标准条件如下：
- 测试浓度:2μM(DMSO≤1％)；
- 重复：n＝2；
- 方向：双向转运，包括A→B和B→A两个方向；
- 孵育时间：单个时间点，2.5小时；
- 转运缓冲液：含10mM Hepes的HBSS缓冲液,pH7.4；
- 孵育条件：37℃,5％CO 2。
孵育结束后，取给药孔和接收孔内的样品溶液立即与含有内标的冷乙腈溶液混合。采用LC/MS/MS方法分析待测化合物在所有样品(包括起始给药液，给药孔上清液，接收液)中的浓度。并计算表观渗透系数，外排比等参数。
实验结果：表3列出了Sitravatinib和化合物3在MDR1-MDCK II单层细胞中的渗透系数。结果表明化合物3具有中等的渗透性，而Sitravatinib为低等的渗透性。
表3渗透性实验结果
Figure PCTCN2021079337-appb-000095
(2)细胞色素P450同工酶抑制性研究
实验目的：测定受试化合物对对人肝微粒体细胞色素P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)活性的抑制作用。
实验操作：首先将受试化合物(10mM)进行梯度，制备工作液(100×最终浓度)，工作液浓度分别为：5、1.5、0.5、0.15、0.05、0.015和0.005mM，同时准备P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)各阳性抑制剂及其特异性底物混合物(5in 1)的工作液；将冷冻于–80℃冰箱的人肝微粒体置于冰上解冻，待人肝微粒体全部溶解，用PB进行稀释，制备一定浓度工作液(0.253mg/ml)；并将20μL底物混合液加至反应板中(Blank孔中加入20μl PB)同时将158μL人肝微粒体工作液加入反应板中，将反应板置于冰上，待用；此时将2μl各个浓度的受试化合物(N＝1)及特异性抑制剂(N＝2)加入对应孔中，无抑制剂(受试化合物或阳性抑制剂)组加入对应的有机溶剂，作为对照组样品(受试化合物对照样品为1:1DMSO:甲醇,阳性对照样品为1:9DMSO:甲醇,)；在37℃水浴预孵育10分钟后，将20μl辅酶因子(NADPH)溶液加入反应板中，置于37℃水浴孵育10分钟；加入400μL冷的乙腈溶液(内标为200ng/mL Tolbutamide和Labetalol)终止反应；将反应板置于摇床，振荡10分钟；4,000rpm离心20分钟；取200μL上清加至100μL水中，进行样品稀释；最后封板，振荡，摇匀，进行LC/MS/MS检测。
实验结果：本发明化合物和Sitravatinib均对CYP1A2无明显抑制作用，对CYP2C9和CYP2C19有中等抑制作用。本发明化合物分别对CYP2D6和CYP3A4(底物为咪达唑仑)有弱抑制和无抑制作用，而Sitravatinib对CYP2D6和CYP3A4(底物为咪达唑仑)均有强抑制作用。
表4细胞色素P450同工酶抑制性实验结果
Figure PCTCN2021079337-appb-000096
(3)血浆蛋白结合率研究
实验目的：测定受试化合物在人、CD-1小鼠和SD大鼠血浆中的蛋白结合率
实验操作：取人、CD-1小鼠和SD大鼠的空白血浆796μL，加入4μL受试化合物工作溶液(400μM)或华法林工作溶液(400μM)，使血浆样品中受试化合物与华法林终浓度均为2μM。将样品充分混合。有机相DMSO的终浓度为0.5％；移取50μL受试化合物和华法林血浆样品到样品接收板中(三个平行)，立即加入相应体积的对应空白血浆或缓冲液，使得每个样品孔的终体积为100μL，血浆：透析缓冲液的体积比为1:1，然后向这些样品中加入400μL终止液，此样品将作为T0样品用于回收率及稳定性测定。将T0样品存储于2-8℃，等待与其它透析完的样品一起进行后续处理；将150μL受试化合物和华法林血浆样品加入到每个透析孔的给药端，在透析孔对应的接收端中加入150μL空白透析缓冲液。然后将透析板封上透气膜后置于湿润的、5％CO 2的培养箱中，在37℃下、约100rpm振荡孵育4-hr。透析结束后，移取50μL透析后的缓冲液样品和透析后的血浆样品到新的样品接收板。在样品中加入相应体积的对应空白血浆或缓冲液，使得每个样品孔的终体积为100μL，血浆：透析缓冲液的体积比为1:1。所有样品经过蛋白沉淀后进行LC/MS/MS分析，并通过公式：％Unbound＝100*FC/TC；％Bound＝100-％Unbound；％Recovery＝100*(FC+TC)/T0计算蛋白结合率以及回收率。
实验结论：化合物3的甲酸盐和Sitravatinib均呈现较高血浆蛋白结合率。化合物3在人、CD-1小鼠和SD大鼠血浆中的蛋白结合率分别为99.7％、99.7％和99.8％，Sitravatinib在人、CD-1小鼠和SD大鼠血浆中的蛋白结合率分别为99.95％、99.97％和NA(数值无法计算，因游离端未检测到游离化合物)。
(4)微粒体代谢稳定性研究
实验目的：测定受试化合物在人、CD-1小鼠和SD大鼠的肝微粒体中的稳定性。
实验操作：首先准备8块96孔板，分别命名为T0、T5、T10、T20、T30、T60、NCF60和BLANK；除BLANK(加10μL/孔缓冲液)外，每块板加10μL/孔药物溶液；将准备好的微粒体加入到7块板(80μL/孔)，除T0板外；在NCF60板中加入10μL/孔缓冲液，放入37度水浴锅孵育，开始计时：
Figure PCTCN2021079337-appb-000097
然后将配好的NADPH cofactor分装到作为加样槽的96孔浅孔板中，用96通道移液器每块板分10μL/孔放入37℃水浴锅孵育，开始反应：
Figure PCTCN2021079337-appb-000098
每个时间点加300(μL/孔)终止液(冷乙腈，含100ng/mL甲糖宁和100ng/mL拉贝洛尔作内标)终止反应，混匀；离心机4000rpm离心20分钟，沉淀蛋白；离心后，用96通道移液器移取100μL/孔上清液至加有300μL/孔HPLC水的新板中，混匀，送交分析人员用LC/MS/MS检测。
实验结果：化合物3的甲酸盐在人、CD-1小鼠和SD大鼠肝微粒体中孵育60分钟的剩余百分比分别是：65.7％、63.3％和64.8％，Sitravatinib在人、CD-1小鼠和SD大鼠肝微粒体中孵育60分钟的剩余百分比分别是：77.3％、10.2％和34.4％。化合物3在三个种属中均以中等代谢速度，Sitravatinib在人和SD大鼠肝微粒体中以中等速度代谢，在CD-1小鼠肝微粒体中代谢较快。
体外DMPK性质评价结果汇总见表5：
表5体外DMPK性质评价结果汇总
Figure PCTCN2021079337-appb-000099
实验结论：本发明化合物在肝微粒体稳定性(MMS)、血浆蛋白结合率(PPB)、药物相互作用(DDI)及体外渗透性上明显优于临床III期的AXL&VEGFR2抑制剂Sitravatinib，这意味着本系列化合物具备更好的代谢稳定性；渗透性的改善意味着本系列化合物将更易吸收，同时，由于主动外排而导致耐药的风险更小；本系列化合物CYP抑制活性较低，药物相互作用性质佳，临床上与其他药物联用的安全性风险更小，可开发性更强。
实验例5：体内药代动力学研究
实验目的：CD-1小鼠口服及静脉注射化合物3或Sitravatinib后药代动力学研究
实验操作：称取适量化合物3的甲酸盐或Sitravatinib，分别溶解在溶媒5％DMSO/95％(20％HP-β-CD)中，搅拌并超声，制备得到0.4mg/mL的澄清溶液，微孔滤膜过滤后备用。选取7-9周龄的CD-1雄性小鼠，静脉注射给药，给药体积为5mL/kg，剂量为2mg/kg。
适量称取化合物3或Sitravatinib，分别溶解在溶媒5％DMSO/95％(20％HP-β-CD)中，搅拌并超声，制备得到1mg/mL的澄清溶液。选取7-9周龄的CD-1雄性小鼠，口服给药，给药体积为10mL/kg，剂量为10mg/kg。
收集一定时间的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数。
实验结果：
雄性CD-1小鼠单次静脉注射给药2mg/kg Sitravatinib和化合物3后，其血浆清除率(CL)为7.21和6.18mL/min/kg，稳态表观分布容积(Vd ss)为2.24和0.72L/kg，消除半衰期(T 1/2)分别为3.87和1.58h，0点到最后一个可定量时间点血浆浓度曲线下面积(AUC 0-last)的值分别为7284和9645nM·h。
雄性CD-1小鼠单次灌胃给予10mg/kg Sitravatinib和化合物3后，其生物利用度分别为65.8％和 109％,AUC 0-last分别为24003和53755nM·h，达峰浓度(C max)为2530和10600nM，达峰时间出现在给药后2.00和1.00h。体内PK性质评价结果汇总见表6。
表6体内PK性质评价结果汇总
Figure PCTCN2021079337-appb-000100
实验结论：
本发明化合物具有较好的口服最高血药浓度C max、半衰期、清除率(CL)、AUC和口服生物利用度。

Claims (14)

  1. 式(I)化合物或其药学上可接受的盐，
    Figure PCTCN2021079337-appb-100001
    其中，
    环A选自5元杂芳基，所述5元杂芳基包含2个N杂原子；
    或者，环A选自6元杂芳基，所述6元杂芳基至多包含2个N原子；
    T 1和T 2分别独立地选自C(R 5)和N；
    R 1和R 3分别独立地选自H、F和CH 3；
    R 2选H、F和Cl；
    R 4分别独立地选自H、C 1～6烷基、C 1～6杂烷基、C 3～6环烷基、3～6元杂环烷基和-L-R 6，所述C 1～6烷基、C 1～6杂烷基、C 3～6环烷基、3～6元杂环烷基和-L-R 6任选被1、2或3个R取代；
    R 5选自H和Cl；
    R 6选自H、OH、5～6元杂环烷基和C 1～3烷基；
    L选自-CH 2-、-CH 2-CH 2-和
    Figure PCTCN2021079337-appb-100002
    n选自0、1、2和3；
    R分别独立地选自F、Cl、Br、I、OH、CN、COOH、NH 2、-NHCH 3、-N(CH3) 2、CH 3、CH 2CH 3、CF 3、-OCH 3、-OCH 2CH 3、-O-CH(CH 3) 2、-C(＝O)OCH 3、-C(＝O)CH 3和-C(＝O)CH 2CH 3；
    所述5元杂芳基、6元杂芳基、C 1～6杂烷基和3～6元杂环烷基分别独立地包含1、2或3个独立地选自O、S、N和NH的杂原子或杂原子团。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，环A选自吡啶基、吡唑基和咪唑基。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 4分别独立地选自H、C 1～4烷基、C 1～4杂烷基、5～6元杂环烷基和-L-R 6，所述C 1～4烷基、C 1～4杂烷基、5～6元杂环烷基和-L-R 6任选被1、2或3个R取代。
  4. 根据权利要求3所述的化合物或其药学上可接受的盐，其中，R 4分别独立地选自H、
    Figure PCTCN2021079337-appb-100003
    Figure PCTCN2021079337-appb-100004
    Figure PCTCN2021079337-appb-100005
    所述
    Figure PCTCN2021079337-appb-100006
    Figure PCTCN2021079337-appb-100007
    任选被1、2或3个R取代。
  5. 根据权利要求4所述的化合物或其药学上可接受的盐，其中，R 4分别独立地选自H、
    Figure PCTCN2021079337-appb-100008
    Figure PCTCN2021079337-appb-100009
  6. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2021079337-appb-100010
    选自
    Figure PCTCN2021079337-appb-100011
    Figure PCTCN2021079337-appb-100012
  7. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2021079337-appb-100013
    选自
    Figure PCTCN2021079337-appb-100014
  8. 根据权利要求7所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2021079337-appb-100015
    选自
    Figure PCTCN2021079337-appb-100016
    Figure PCTCN2021079337-appb-100017
  9. 根据权利要求1～5任意一项所述的化合物或其药学上可接受的盐，其中，化合物选自
    Figure PCTCN2021079337-appb-100018
    其中，
    R 41选自H、C 1～4烷基、C 1～4杂烷基、6元杂环烷基和-L-R 6，所述H、C 1～4烷基、C 1～4杂烷基、6元杂环烷基和-L-R 6任选被1、2或3个R取代；
    R 42选自H和-L-R 6，所述-L-R 6任选被1、2或3个R取代；
    R 6选自H、OH、6元杂环烷基和C 1～3烷基；
    R 2、L和R如权利要求1所定义。
  10. 根据权利要求1～5任意一项所述的化合物或其药学上可接受的盐，其中，化合物选自
    Figure PCTCN2021079337-appb-100019
    R 1、R 2、R 3和R 4如权利要求1～5所定义。
  11. 化合物或其药学上可接受的盐，其选自
    Figure PCTCN2021079337-appb-100020
    Figure PCTCN2021079337-appb-100021
  12. 一种药物组合物，包含治疗有效量的根据权利要1～11任意一项所述的化合物或药学上可接受的盐 作为活性成份以及药学上可接受的载体。
  13. 根据权利要求1～11任意一项所述的化合物或药学上可接受的盐或权利要求12所述的组合物在制备Axl和/或VEGFR-2抑制剂中的应用。
  14. 根据权利要求13所述的应用，其中，所述Axl和/或VEGFR-2抑制剂是治疗癌症的药物。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102256493A (zh) * 2008-10-29 2011-11-23 迪赛孚尔制药有限公司 表现出抗癌活性和抗增殖活性的环丙烷酰胺及其类似物
CN102964308A (zh) * 2012-11-30 2013-03-13 中国药科大学 新型嘧啶类化合物、其制备方法、包含此类化合物的药物组合物及其用途
CN107793363A (zh) * 2016-09-06 2018-03-13 上海医药工业研究院 一种取代芳胺基芳杂环类化合物及其作为抗肿瘤药物的应用
CN108530464A (zh) * 2017-03-02 2018-09-14 深圳海王医药科技研究院有限公司 一种多靶点激酶抑制剂
WO2019148036A1 (en) * 2018-01-26 2019-08-01 Exelixis, Inc. Compounds for the treatment of kinase-dependent disorders
CN110862397A (zh) * 2018-08-27 2020-03-06 北京赛特明强医药科技有限公司 二噁烷并喹唑啉与二噁烷并喹啉类化合物及其制备方法与应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102256493A (zh) * 2008-10-29 2011-11-23 迪赛孚尔制药有限公司 表现出抗癌活性和抗增殖活性的环丙烷酰胺及其类似物
CN102964308A (zh) * 2012-11-30 2013-03-13 中国药科大学 新型嘧啶类化合物、其制备方法、包含此类化合物的药物组合物及其用途
CN107793363A (zh) * 2016-09-06 2018-03-13 上海医药工业研究院 一种取代芳胺基芳杂环类化合物及其作为抗肿瘤药物的应用
CN108530464A (zh) * 2017-03-02 2018-09-14 深圳海王医药科技研究院有限公司 一种多靶点激酶抑制剂
WO2019148036A1 (en) * 2018-01-26 2019-08-01 Exelixis, Inc. Compounds for the treatment of kinase-dependent disorders
CN110862397A (zh) * 2018-08-27 2020-03-06 北京赛特明强医药科技有限公司 二噁烷并喹唑啉与二噁烷并喹啉类化合物及其制备方法与应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHIA STEPHEN K., ELLARD SUSAN L., MATES MIHAELA, WELCH STEPHEN, MIHALCIOIU CATALIN, MILLER WILSON H., GELMON KAREN, LOHRISCH CAROL: "A phase-I study of lapatinib in combination with foretinib, a c-MET, AXL and vascular endothelial growth factor receptor inhibitor, in human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer", BREAST CANCER RESEARCH, CURRENT MEDICINE GROUP LTD., GB, vol. 19, no. 1, 54, 1 December 2017 (2017-12-01), GB, pages 1 - 8, XP055846788, ISSN: 1465-5411, DOI: 10.1186/s13058-017-0836-3 *

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