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WO2018153293A1 - Dioxanoquinazoline, composé de type dioxanoquinazoline, procédé de préparation et utilisation associés - Google Patents

Dioxanoquinazoline, composé de type dioxanoquinazoline, procédé de préparation et utilisation associés Download PDF

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Publication number
WO2018153293A1
WO2018153293A1 PCT/CN2018/076233 CN2018076233W WO2018153293A1 WO 2018153293 A1 WO2018153293 A1 WO 2018153293A1 CN 2018076233 W CN2018076233 W CN 2018076233W WO 2018153293 A1 WO2018153293 A1 WO 2018153293A1
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WIPO (PCT)
Prior art keywords
group
acid
compound
fluorenyl
fluorophenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2018/076233
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English (en)
Chinese (zh)
Inventor
张强
张宏波
杨磊夫
杨海龙
周利凯
郑南桥
于善楠
刘彦生
王钟祥
冯守业
徐占强
胡晨明
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Scitech MQ Pharmaceuticals Ltd
Original Assignee
Beijing Scitech MQ Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Priority claimed from CN201710161873.4A external-priority patent/CN108503650B/zh
Application filed by Beijing Scitech MQ Pharmaceuticals Ltd filed Critical Beijing Scitech MQ Pharmaceuticals Ltd
Priority to CN201810983341.3A priority Critical patent/CN110156803A/zh
Publication of WO2018153293A1 publication Critical patent/WO2018153293A1/fr
Priority to DK19751025.8T priority patent/DK3750893T3/da
Priority to AU2019218187A priority patent/AU2019218187B2/en
Priority to PL19751025.8T priority patent/PL3750893T3/pl
Priority to SG11202007554TA priority patent/SG11202007554TA/en
Priority to PCT/CN2019/073260 priority patent/WO2019154133A1/fr
Priority to KR1020207025607A priority patent/KR102433023B1/ko
Priority to ES19751025T priority patent/ES2945573T3/es
Priority to CA3090876A priority patent/CA3090876C/fr
Priority to JP2020542958A priority patent/JP7022454B2/ja
Priority to US16/968,797 priority patent/US11407760B2/en
Priority to CN201980012397.7A priority patent/CN111788207B/zh
Priority to EP19751025.8A priority patent/EP3750893B1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention relates to dioxindinoquinazoline and dioxin and quinoline compounds, which are pharmaceutically acceptable a salt, an isomer, a hydrate, a solvate, or a prodrug, and a process for its preparation and use.
  • RTKs Receptor tyrosine kinases
  • the active intracellular domain consists of three parts.
  • Binding of the ligand to the receptor stimulates receptor-associated tyrosine kinase activity, which leads to the acidification of tyrosine residues on the receptor and other intracellular molecules, leading to cascades that lead to various cellular responses. signal. Overexpression of tyrosine receptors activates downstream signal transduction pathways, which ultimately lead to abnormal cell transformation and proliferation, and promote tumorigenesis and development.
  • Vascular endothelial growth factor receptor is a family of receptor tyrosine kinases that combines with its ligand vascular endothelial growth factor (VEGF) to produce a range of biochemical and vascular endothelial growth factor receptors (VEGFs). The physiological process eventually promotes the formation of new blood vessels.
  • VEGF vascular endothelial growth factor receptor
  • VEGF vascular endothelial growth factor
  • VEGFR-1 vascular endometrial receptor 1
  • VEGFR-2 vascular endometrial receptor 1
  • VEGF vascular endometrial permeability
  • VEGF is an important stimulator of normal and pathological angiogenesis and vascular permeability (Jakeman et al., 1993, Endocrinology 133: 848-859; Kolch et al., 1995, Breast Cancer Research and Treatment 36: 139-155; Connolly et al, 1989, J. Biol. Chem. 264: 20017-20024).
  • Vascular endothelial growth factor induces a angiogenic phenotype by inducing endothelial cell proliferation, protease expression and migration, and subsequent formation of capillary cell tissue. Therefore, antagonism of VEGF by chelation of VEGF by antibodies can lead to inhibition of tumor growth (Kim et al., 1993, Nature 362: 841-844).
  • VEGFR-2 Since VEGFR-2 is mainly distributed in vascular endothelial cells, it can bind to VEGF-A, VEGF-C, VEGF-D, and VEGF-E.
  • the proliferation of VEGF, the increase of vascular permeability and the formation of new blood vessels by VEGF are mainly achieved by binding and activating VEGFR-2. If the activity of VEGFR-2 is blocked, tumor growth and metastasis can be inhibited by direct and indirect pathways, thereby achieving an ideal anti-tumor effect. Therefore, finding a small molecule inhibitor with high activity and high selectivity for VEGFR-2 has become a very promising tumor treatment strategy.
  • Hepatocyte growth factor receptor (c-Met) is a kind of tyrosine kinase receptor, and its abnormal activation plays an important role in the occurrence and development of various malignant tumors including lung cancer.
  • Hepatocyte growth factor (HGF) is a specific ligand for c-Met, and c-Met binds to HGF and exerts a biological effect through the HGF/c-Met signaling pathway.
  • HGF/c-Met signaling pathway can induce a series of biological effects such as cell proliferation, dispersion, migration, organ morphology, and angiogenesis.
  • Abnormal activation of c-Met can be expressed as receptor overexpression, gene mutation, amplification, ectopic, rearrangement, and the like.
  • c-Met plays an important role in cell proliferation, metabolism, tumor production, metastasis, and angiogenesis, and has become an important target for anti-tumor therapy.
  • Targeted therapy targeting c-Met has become important in the treatment of a variety of malignancies, including lung cancer.
  • the interaction of multiple signaling pathways may affect the effects of anti-tumor drugs.
  • the interaction of HFG/c-Met signaling pathway with other pathways affects the therapeutic effect of anti-tumor drugs.
  • Drug resistance Therefore, the combination of multi-kinase targets has become a new anti-tumor treatment, and the successful marketing of Crizotinib and Cabozantinib demonstrates the potential and application of multi-kinase target inhibitors.
  • Cabozantinib is a small molecule inhibitor of protein kinase that inhibits various kinases such as c-Met, VEGFR-2, Ret, Kit, and AXL.
  • Cabozantinib inhibits phosphorylation of c-Met and VEGFR-2 in tumor models and shows potent anti-tumor metastasis and anti-angiogenic activity in preclinical pharmacodynamic models.
  • No increase in tumor burden was observed in the lung tumor metastasis model treated with Cabozantinib compared to inhibitors acting alone on the VEGFR target, suggesting that Cabozantinib is a tumor angiogenesis and metastasis in patients with dysregulated c-Met and VEGFR2 signaling pathways. Effective inhibitor.
  • the FDA approved the listing of Cabozantinib for the treatment of progressive, metastatic medullary thyroid carcinoma (MTC) patients.
  • MTC metastatic medullary thyroid carcinoma
  • the present invention provides a compound represented by the formula (I), a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof, which can be used for the treatment or prevention of a tyrosine kinase (for example) VEGFR-2 and
  • Replacement page (Article 26) / or c-Met) causes diseases, including certain variants of the tyrosine kinase receptor.
  • Q is N or CH
  • G is 0 or NH
  • Z is N or CH
  • a linking group of a cyclononan hydrocarbon selected from the group consisting of
  • X is H or a decyl group of dC 3 ;
  • Y is a thiol group of H or dC 3 ;
  • R 1 is H, CC 9 fluorenyl, C 3 -C 7 cyclodecyl, 4-7 membered heterocyclic, C 3 -C 7 cyclodecyl substituted dC 6 fluorenyl, 4-7 membered heterocyclic ring a substituted dC 6 fluorenyl group, a substituted dC 9 fluorenyl group, the substituent of the substituted C r C 9 alkyl group being a hydroxyl group, a decyloxy group of C r C 6 , a thiol group of dC 6 or -NR 6
  • R 7 is H, CC 9 fluorenyl, C 3 -C 7 cyclodecyl, 4-7 membered heterocyclic, C 3 -C 7 cyclodecyl substituted dC 6 fluorenyl, 4-7 membered heterocyclic ring a substituted dC 6 fluorenyl group, a substituted d
  • R 6 and R 7 are each independently H, CC 6 fluorenyl, hydroxy-substituted dC 6 alkyl, dC 3 methoxy-substituted 6 alkyl;
  • the above 4-7 membered heterocyclic group is a 4-7 membered heterocyclic group having 1 to 2 atoms selected from N, 0, and S, and the 4-7 membered heterocyclic group is not substituted or dC 3 fluorenyl,
  • the dC 3 acyl group is substituted or oxidized by one to two oxygen atoms.
  • 1 2 is 11, decyl or halogen of dC 3 ;
  • 1 3 is 11, decyl or halogen of dC 3 ;
  • R 5 is H, CC 9 fluorenyl, C 3 -C 7 cyclodecyl, C 3 -C 7 cyclodecyl substituted CC 6 alkyl, aryl, aryl substituted dC 6 fluorenyl, heteroaryl Or a heteroaryl substituted - fluorenyl group;
  • the aryl or heteroaryl group is an unsubstituted or substituted alkyl group, an alkoxy group of dC 3 , a replacement page of ⁇ -3 ⁇ 4 (Rule 26)
  • the above heteroaryl group is a monocyclic or bicyclic group having 5 to 10 ring atoms; the heteroaryl group contains 1 to 3 hetero atoms selected from N, 0, and S.
  • the R 1 is H, dC 6 alkyl, C 3 -C 6 cyclodecyl, 5-6 membered heterocyclic, C 3 -C 6 cycloalkyl substituted dC 3 alkyl, 5-6 a heterocyclic group-substituted C C3 alkyl group, a substituted dC 6 fluorenyl group, the substituent of the substituted dC 6 fluorenyl group being a hydroxyl group, a dC 3 decyloxy group, a dC 3 thiol group or -NR 6 R 7 ,
  • R 6 and R 7 are each independently H, CC 3 fluorenyl, hydroxy-substituted dC 3 fluorenyl, C r C 3 alkoxy-substituted 3 fluorenyl.
  • the above 5- to 6-membered heterocyclic group is a 5-6 membered heterocyclic group having 1 to 2 atoms selected from N, 0, and S, which is unsubstituted or substituted by dC 3 fluorenyl group, dC 3 acyl group or Two oxygen atoms are oxidized.
  • the R 1 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, tetrahydrofuran- 3-yl, tetrahydro-2H-pyran-4-yl, tetrahydropyrrole small ethyl, tetrahydropyrrole-1-propyl, morpholin-4-ethyl, morpholin-4-propyl, methyl Piperazine-4-ethyl, methylpiperazine-4-propyl, N-formylpiperazine-4-ethyl, N-formylpiperazine-4-propyl, N-acetylpiperazine-4 -ethyl, N-acetylpiperazine-4-propyl, (1,1-dioxothiomorpholinyl)-4-ethyl,
  • the halogen described by R 2 , R 3 and R 4 is 0 or 1 ⁇ .
  • R 5 is H, dC 6 fluorenyl, C 3 -C 6 cyclodecyl, C 3 -C 6 cyclodecyl substituted CC 3 fluorenyl, aryl, aryl substituted cc 3 fluorenyl, heteroaryl or -3 ⁇ 4 heteroaryl substituted alkyl with the aryl group, a substituted heteroaryl group is c r c 3 alkyl, dC embankment group 3, group 3 CC embankment, mono- or di ⁇ - 3 ⁇ 4 take
  • the heteroaryl group is a monocyclic or bicyclic group having 5 to 10 ring atoms; the heteroaryl group contains 1-2 hetero atoms selected from N, 0, and S.
  • R 5 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-fluorophenyl, 3-fluoro Phenyl, 2-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-di Fluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 2-fluoro- 5-(Trifluoromethyl)phenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 3-fluoro-5-(trifluoromethyl)phen
  • the present invention provides a pharmaceutically acceptable salt of a compound of the formula (I), wherein the salt is an acidic/anionic salt or a basic/cationic salt; the pharmaceutically acceptable acidic/anionic salt is usually taken in a form Basic nitrogen is protonated by inorganic or organic acids, and representative organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, citric acid, formic acid, acetic acid, propionic acid, glycolic acid, Lactic acid, succinic acid, maleic acid, tartaric acid, malic acid, citric acid, fumaric acid, gluconic acid benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, oxalic acid, palmitic acid, 2- Naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexylaminesul
  • the present invention provides a process for the preparation of the above compound or a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof, which comprises the following steps, a compound of the formula (II) and a formula (III)
  • the compound is prepared by a reaction to obtain a compound of the formula (I), Q is N, G, Z, L, RR 2 , R 3 , R 4 and R 5 are as defined above.
  • the present invention provides a preparation of the above compound or a pharmaceutically acceptable salt thereof, isomer, hydrate, replacement page (Article 26)
  • a method of solvating a solvate or a prodrug comprising the steps of: reacting a compound of the formula (II ') with a compound of the formula (III ') to obtain a compound of the formula (I), wherein Q, G, Z , L, RR 2 , 3 , R 4 and R 5 are as defined above,
  • the present invention provides an intermediate for preparing the above compound, such as a compound represented by the formula ( ⁇ ), wherein G, Z, L, R 2 , R 3 , R 4 and R 5 are as before
  • the present invention provides an intermediate for preparing the above compound, a compound represented by the formula ( ⁇ '), wherein
  • substituted includes complex substituents (e.g., phenyl, aryl, heteroalkyl, heteroaryl), suitably 1 to 5 substituents, preferably 1 to 3
  • substituents e.g., phenyl, aryl, heteroalkyl, heteroaryl
  • 1 to 5 substituents preferably 1 to 3
  • alkyl groups including saturated straight chain, branched chain hydrocarbon, carbon atoms, represents alkyl of 1-9 carbon atoms, empathy C r C 3 alkyl carbon atoms such as 1 a carbon atom of -3, for example, C C6 fluorenyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl.
  • a decyl ether consisting of a linear, branched chain as previously described.
  • alkenyl and alkynyl groups include straight-chain, branched alkenyl or alkynyl groups.
  • Cyclodecyl a cyclic group formed by a carbon atom.
  • C 3 -C 7 represents a fluorenyl group having 3-7 carbon atoms.
  • aryl refers to an unsubstituted or substituted aryl group, such as phenyl, naphthyl, anthracenyl.
  • aroyl refers to -C(O)-aryl.
  • Oxidation by one or two oxygen atoms means that a sulfur atom is oxidized by an oxygen atom to form a double bond between sulfur and oxygen, or is oxidized by two oxygen atoms to form sulfur and a double bond between two oxygen atoms.
  • heterocyclyl represents an unsubstituted or substituted stable 3 to 8 membered monocyclic saturated ring system selected from carbon atoms and from N, 0, S.
  • the heterocyclic ring can be combined with any hetero atom or carbon atom to form a stable structure.
  • heterocyclic rings include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidine Pyridyl, piperazinyl, piperazinyl, piperidinyl, dioxetolyl, dioxocyclohexyltetrahydroimidazolyl, tetrahydrooxazolyl, thiomorpholine sulfoxide, thio Morpholine sulfone and oxadiazolyl.
  • heteroaryl represents a stable 5 or 6 membered monocyclic aromatic ring system which is unsubstituted or substituted, and may also represent unsubstituted or substituted 9 or a 10-ring atomic benzene fused heteroaromatic ring system or a bicyclic heteroaromatic ring system consisting of a carbon atom and one or three heteroatoms selected from N, 0, S, wherein the N, S heteroatoms can be Oxidation, N heteroatoms can also be quaternized.
  • the heteroaryl group can be bonded to any hetero atom or carbon atom to form a stable structure.
  • Heteroaryl includes, but is not limited to, thienyl, furyl, imidazolyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, pyranyl, pyridyl, piperazinyl, pyrimidinyl, pyrazine, Pyridazinyl, pyrazolyl, thiadiazolyl, triazolyl, fluorenyl, azaindolyl, carbazolyl, azacarbazolyl, benzimidazolyl, benzofuranyl, benzothiophene Benzoisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenyl, quinolinyl or isoquinoline base.
  • carbonyl refers to the C(0) group.
  • alkyl or aryl or any of their prefix roots appear in the name of a substituent (eg, aryl fluorenyl, dimethylamino), it will be considered to contain the above " ⁇ Those limitations given by "and” aryl groups.
  • the specified number of carbon atoms e.g., d-
  • d- will independently represent the number of carbon atoms in a thiol moiety or an alkyl moiety in a larger substituent (where thiol is the prefix root).
  • the invention also provides a process for the preparation of the corresponding compounds, which can be prepared using a variety of synthetic methods, including the methods described below, a compound of the invention or a pharmaceutically acceptable salt thereof, a heterogeneous replacement page (fine 26)
  • the body or hydrate can be synthesized using the following methods and synthetic methods known in the art of organic chemical synthesis, or by variations of those methods as understood by those skilled in the art, and the preferred methods include, but are not limited to, the following methods.
  • the compound of the formula (I) of the present invention is prepared by reacting a compound of the formula (II ') with the formula (III'), and Z, L, RR 2 , R 3 , R 4 and R 5 are as described above.
  • the present invention further provides a compound of the formula (I), which is a compound of the formula (II '), wherein Q, G, Z, RR 2 , R 3 and R 4 are as defined above,
  • the compound of formula (I) of the present invention is prepared by reacting a compound of formula (II) with a compound of formula ( ⁇ ) wherein Q is N, G, Z, L, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above,
  • the invention also provides an intermediate, a compound of formula (II), wherein G, Z, L, R 2 , R 3 , R 4 and R 5 are as defined above,
  • the present invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt, isomer or hydrate thereof,
  • the compounds of the invention may be prepared by Schemes 1 through 4 or by technical schemes known to those skilled in the art.
  • reaction conditions are:
  • Step 1) The dicarboxylic acid starting material is reacted with thionyl chloride to remove the solvent, an organic base is added, and the aprotic organic solvent is reacted with the starting material VII to obtain a compound of the formula VI; wherein the organic base is preferably triethylamine or diisopropyl A combination of one or more of a base amine, pyridine.
  • the aprotic organic solvent is selected from the group consisting of tetrahydrofuran, toluene, methylene chloride, dioxane, DMF, DMA or a combination of two or more thereof.
  • Step 2 In a preferred embodiment, when a compound of the formula (VI) is reacted with a compound of the formula (V), wherein the formula (VI) is reacted with an acylating reagent, and then reacted with the formula (V).
  • the acylating agent includes, but is not limited to, one or a combination of two or more of phosphorus oxychloride, thionyl chloride, oxalyl chloride, phosphorus trichloride or phosphorus pentachloride.
  • a compound of formula (VI) is reacted with a compound of formula (V) in the presence of a condensing agent to provide a compound of formula (IV).
  • the condensing agent includes, but not limited to, a carbodiimide type condensing agent, a gun salt type condensing agent, an organic condensing agent, and one or more kinds of other types of condensing agents, preferably ruthenium, osmium-bicyclic ring Hexyl carbodiimide (DCC), hydrazine, hydrazine-diisopropylcarbodiimide (DIC), hydroxybenzotriazole (HOBt), hydrazine, hydrazine-diisopropylethylamine (DIEA), 1- Hydroxy-7-azobenzotriazole (HOAt), 0-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), benzotriazine Zin-1-yloxytris(dimethylamino) Phosphorus hexafluorodibenzoate (DCC),
  • HBTU 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate
  • HCTU 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate
  • HATU 2-(7-oxidized benzotriazole)-N,NN' , N'-tetramethylurea hexafluorophosphate
  • T3P propylphosphonic anhydride
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • EDC 1-ethyl(3-dimethylaminopropyl)carbodiimide
  • PyBOP hexafluoro-petic acid benzotriazol-1-yl-oxytripyrrolidine scale
  • PyAOP (3H-1 a combination of one or more of 2,3 triazolo[4,5-b]pyridin-3-yloxy)
  • this step can be carried out in an organic base including, but not limited to, triethylamine, diisopropylethylamine (DIEA), pyridine, 4-dimethylaminopyridine (DMAP), 2, One or a combination of two or more of 6-lutidine, 1,8-diazabicycloundec-7-ene (DBU) or N-methylmorpholine.
  • organic base including, but not limited to, triethylamine, diisopropylethylamine (DIEA), pyridine, 4-dimethylaminopyridine (DMAP), 2, One or a combination of two or more of 6-lutidine, 1,8-diazabicycloundec-7-ene (DBU) or N-methylmorpholine.
  • Step 3 conditions for the nitro reduction reaction include, but are not limited to, hydrogen and Raney nickel, hydrogen or ammonium formate with palladium carbon, iron powder, zinc powder, stannous chloride;
  • Step 4) In a organic solvent, base-catalyzed reaction at room temperature to reflux temperature.
  • the base is selected from one or a combination of two or more of sodium carbonate, potassium carbonate and cesium carbonate;
  • the organic solvent is selected from the group consisting of tetrahydrofuran, dioxane, isopropanol, ethanol, DMF, DMA, acetonitrile or both The combination of the above.
  • reaction conditions are:
  • Step 1) when a compound of the formula (VI) is reacted with a compound of the formula (VIII), wherein the formula (VI) is reacted with an acylating reagent and then with the formula (VIII).
  • the acylating agent includes, but is not limited to, one or a combination of two or more of phosphorus oxychloride, thionyl chloride, oxalyl chloride, phosphorus trichloride or phosphorus pentachloride.
  • a compound of formula (VI) is reacted with a compound of formula (VIII) in the presence of a condensing agent to provide a compound of formula ( ⁇ - ⁇ ),
  • the condensing agent includes, but not limited to, a carbodiimide type condensing agent, a gun salt type condensing agent, a organic condensing agent, and one or more kinds of other types of condensing agents, preferably ruthenium, osmium-dicyclohexyl carbon Diimine
  • HBTU 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate
  • HCTU 6-chlorobenzotriazole-1,1,3,3-tetramethylurea hexafluorophosphate
  • HATU 2-(7-benzotriazole)-N,NN' , N'-tetramethylurea hexafluorophosphate
  • T3P propylphosphonic anhydride
  • T3P 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) , 1-ethyl(3-dimethylaminopropyl)carbodiimide (EDC), hexafluoro-petic acid benzotriazol-1-yl-oxytripyrrole scale (PyBOP), (3H-1 a combination of one or more of 2,3 triazolo[4,5-b]pyridin-3-oxy)tri-1-pyr
  • this step can be carried out in an organic base including, but not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine One or a combination of two or more of 1,8-diazabicycloundec-7-ene or N-methylmorpholine.
  • organic base including, but not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine One or a combination of two or more of 1,8-diazabicycloundec-7-ene or N-methylmorpholine.
  • Step 2) Base-catalyzed the reaction in an organic solvent at room temperature to reflux temperature.
  • the base is selected from one or a combination of two or more of sodium carbonate, potassium carbonate and cesium carbonate;
  • the organic solvent is selected from the group consisting of tetrahydrofuran, dioxane, isopropanol, ethanol, DMF, DMA, acetonitrile or both. combination.
  • the introduction of the substituents R 1 , R 2 , R 3 , R 4 and R 5 can also be introduced by other methods known to those skilled in the art, for example, the introduction of a substituent of -0-R 1 can be passed
  • the benzyloxy intermediate is debenzyloxy protected, the phenolic hydroxyl group is prepared, and the compound of the formula (I) or the intermediate product X is obtained by substitution reaction, and the intermediate product X is further substituted with an amine compound (or Grignard reagent).
  • reaction conditions of the above reaction are:
  • the organic solvent is selected from the group consisting of one or more of methanol, ethanol, and isopropanol, or a mixture of one or more of methanol, ethanol, and isopropanol mixed with ethyl acetate or tetrahydrofuran;
  • Step 2 Base-catalyzed reaction in an organic solvent at room temperature to reflux temperature.
  • the base is selected from one or a combination of two or more of sodium carbonate, potassium carbonate, and cesium carbonate;
  • the organic solvent is selected from the group consisting of tetrahydrofuran, dioxane, isopropanol, ethanol, DMF, DMA, acetonitrile, DMSO, or both. The combination above.
  • Protection of the protecting group can be used during the preparation of the compounds of the invention.
  • the substituent R 1 can be protected by a protecting group before or during the reaction, and the "protecting group" is used to temporarily block a chemical reaction at a potential reaction site (for example, an amine, a hydroxyl group, a thiol group, an aldehyde, etc.) Thereby achieving a selective reaction of the chemical reaction.
  • a potential reaction site for example, an amine, a hydroxyl group, a thiol group, an aldehyde, etc.
  • a highly selective reaction is achieved by introducing a protecting group; the protecting group is selectively removed in high yield by a rapidly available preferred reagent which does not unduly affect other functional groups of the invention;
  • the protecting group preferably forms a readily separable derivative (more preferably does not produce a new stereocenter); and the protecting group preferably has minimal other functionality to avoid complicating other sites of the reaction.
  • a variety of protecting groups and protocols, reagents, and conditions for using and removing such protecting groups are known in the art. See, for example, "Protective Groups in Organic Synthesis” Third Ed. Greene, TW. Wouts, PG., Eds "John Wiley & Sons, New York: 1999.
  • Step 1) The nitration reaction is carried out.
  • the nitration reaction conditions are nitric acid and acetic acid.
  • Step 2) performing a nitro reduction reaction, and the nitro reduction is carried out by a person skilled in the art; preferably, the conditions of the nitro reduction reaction include, but are not limited to, hydrogen and Raney nickel, hydrogen and palladium carbon, and iron powder under acidic conditions. Or zinc powder or stannous chloride;
  • Step 3) 1-(8-Methoxy-6-amino-2,3-ddihydrobenzo[b][l,4]dioxin-5-)ethan-1-one and methyl formate Or ethyl formate in an organic solvent, catalyzed by a base to give 10-hydroxy-5-methoxy-2,3-dihydro-[1,4]dioxin and [2,3-f]-quinoline
  • the organic solvent includes, but is not limited to, one or a combination of two or more of dioxane, tetrahydrofuran, tert-butanol, ethanol, methanol
  • the base includes, but is not limited to, sodium t-butoxide, tert-butyl Potassium alkoxide, sodium methoxide, sodium ethoxide; the reaction can also be carried out under heating, heating at room temperature to reflux.
  • Step 4) Preparation of 10-hydroxy-5-methoxy-2,3-dihydro-[1,4]dioxamic [2,3-f]-quinoline and chlorinating reagent in organic solvent 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxaindolo[2,3-f]-quinoline, wherein the chlorinating reagent is phosphorus oxychloride;
  • the organic solvent includes, but is not limited to, one or a combination of two or more of benzene, toluene, chlorobenzene, and xylene; the reaction can also be carried out in the presence of an organic base, which is triethylamine. Or diisopropylethylamine.
  • Step 4b) wherein 5-hydroxy-10-chloro-2,3-dihydro-[1,4]dioxamic [2,3-f]-quinoline is prepared in an organic solvent.
  • Step 5 The compound represented by the formula ⁇ - ⁇ is heated in an organic solvent and mixed with the formula V' to 100 ° C to 140 ° C to obtain a compound represented by IV';
  • the organic solvent is selected from the group consisting of toluene, chlorobenzene, and Toluene, DMF,
  • Step 6) performing a nitro reduction reaction, and the nitro reduction can be carried out by a person skilled in the art;
  • the nitro reduction reaction conditions include, but are not limited to, hydrogen and Raney nickel, hydrogen and palladium carbon, iron powder under acidic conditions, zinc powder or stannous chloride;
  • Step 7) the compound of the formula ( ⁇ ) is shown by the formula ( ⁇ ' -A)
  • the formula ( ⁇ ) can be reacted with an acylating reagent and then reacted with the formula ( ⁇ '-A).
  • the acylating agent includes, but is not limited to, one or a combination of two or more of phosphorus oxychloride, thionyl chloride, oxalyl chloride, phosphorus trichloride or phosphorus pentachloride.
  • a compound of the formula (I') is reacted with a compound of the formula (II'-A) in the presence of a condensing agent to provide a compound of the formula (I-C).
  • the condensing agent includes, but not limited to, a carbodiimide type condensing agent, a gun salt type condensing agent, an organic phosphorus type condensing agent, and one or more kinds of other types of condensing agents, preferably ruthenium, osmium-bicyclic ring Hexyl carbodiimide (DCC), hydrazine, hydrazine-diisopropylcarbodiimide (DIC), hydroxybenzotriazole (HOBt), hydrazine, hydrazine-diisopropylethylamine (DIEA), 1- Hydroxy-7-azobenzotriazole (HOAt), 0-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), benzotriazine Zin-1-yloxytris(dimethylamino) Phosphorus hexafluorophosphat
  • this step can be carried out in an organic base including, but not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine One or a combination of two or more of 1,8-diazabicycloundec-7-ene or N-methylmorpholine.
  • organic base including, but not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine One or a combination of two or more of 1,8-diazabicycloundec-7-ene or N-methylmorpholine.
  • step 4a and step 4b may be omitted, and after step 4), the operation of step 5) may be performed.
  • the compounds, isomers, crystalline forms or prodrugs of formula I, and pharmaceutically acceptable salts thereof may exist in both solvated and unsolvated forms.
  • the solvated form can be in a water soluble form.
  • the invention includes all such solvated and unsolvated forms.
  • the compounds of the invention may have asymmetric carbon atoms which, depending on their physicochemical differences, may be separated by known techniques, such as by chromatography or fractional crystallization. Into a single diastereomer. Separation of the enantiomers can be carried out by first reacting the appropriate optically active compound, converting the enantiomeric mixture into a diastereomeric mixture, separating the diastereomers, and then separating the individual The enantiomers are converted (hydrolyzed) to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers, are considered part of this invention.
  • the compound of the present invention as an active ingredient, and a method of preparing the same are all the contents of the present invention.
  • the crystalline form of some of the compounds may exist as polycrystals, and such forms may also be included in the current invention.
  • some compounds can be combined with water (ie hydrates) or common organic solvents.
  • the compounds of the invention may be used in the free form for treatment or, where appropriate, in the form of a pharmaceutically acceptable salt or other derivative for treatment.
  • pharmaceutically acceptable salt refers to organic and inorganic salts of the compounds of the present invention which are suitable for use in humans and lower animals without undue toxicity, irritation, allergic response, etc., and have reasonable Benefit/risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art.
  • the salt can be formed by reacting a compound of the invention with a suitable free base or acid.
  • salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid,
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, hydrogen sulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, citrate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerol phosphate, gluconic acid Salt, hemisulfate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, A Anthracene sulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, per-3-phenylpropionate , pity salt
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Other pharmaceutically acceptable salts include suitable non-toxic ammonium, quaternary ammonium, and the use of such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates and arylsulfonates.
  • prodrug as used herein means that a compound can be converted into a compound of the formula (I) of the present invention in vivo. This transformation is affected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent compound in the blood or tissue.
  • the pharmaceutical composition of the present invention comprises a compound of the formula (I) described herein or a pharmaceutically acceptable salt thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressant, an anticancer drug, an antiviral agent, an antibiotic An additional agent for an inflammatory, antifungal, antibiotic or anti-vascular hyperproliferative compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • a kinase inhibitor small molecule, polypeptide, antibody, etc.
  • an immunosuppressant an anticancer drug
  • an antiviral agent an antibiotic
  • an additional agent for an inflammatory, antifungal, antibiotic or anti-vascular hyperproliferative compound an additional agent for an inflammatory, antifungal, antibiotic or anti-vascular hyperproliferative compound.
  • the compounds of the invention may be used alone or in combination with one or more other compounds of the invention or with one or more other agents.
  • the therapeutic agents can be formulated for simultaneous administration or sequentially at different times, or the therapeutic agents can be administered as a single composition.
  • “combination therapy” is meant the use of a compound of the invention in combination with another agent in the form of co-administration of each agent or sequential administration of each agent, in either case, for the purpose Achieve the best results of the drug.
  • Co-administration includes simultaneous delivery of the dosage form, as well as separate dosage forms for each compound.
  • administration of the compounds of the invention can be used in conjunction with other therapies known in the art, for example,
  • one or more compounds or salts of the formula (I) as an active ingredient thereof can be intimately mixed with a pharmaceutical carrier, which is carried out according to conventional pharmaceutical ingredient technology.
  • the carrier can be used in a wide variety of forms depending on the form of preparation which is designed for different modes of administration (for example, oral or parenteral administration).
  • Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and the British Pharmaceutical Society.
  • the pharmaceutical composition of the present invention may be in the form of, for example, a suitable oral administration such as a tablet, a capsule, a pill, a powder, a sustained release form, a solution or a suspension; for parenteral injection such as a clear liquid, a suspension, Emulsion; or for topical use such as creams, creams; or as a suppository for rectal administration.
  • a suitable oral administration such as a tablet, a capsule, a pill, a powder, a sustained release form, a solution or a suspension
  • parenteral injection such as a clear liquid, a suspension, Emulsion
  • topical use such as creams, creams; or as a suppository for rectal administration.
  • the medicinal ingredients can also be administered in unit dosage form for a single dose of precise dosage.
  • the pharmaceutical ingredient will include a conventional pharmaceutical carrier or excipient and a compound as an active ingredient prepared according to the present invention, and may also include other medical or pharmaceutical preparations, carriers, adjuvants
  • Therapeutic compounds can also be administered to mammals other than humans.
  • the dosage of the drug to be administered to a mammal will depend on the species of the animal and its condition or the condition in which it is placed.
  • the therapeutic compound can be administered to the animal in the form of a capsule, a bolus, or a tablet.
  • the therapeutic compound can also be introduced into the animal by injection or infusion. We prepare these forms of the drug in a traditional manner that meets the standards of veterinary practice.
  • the pharmaceutical synthetic drug can be mixed with the animal feed and fed to the animal, so that the concentrated feed additive or premix can be prepared by mixing ordinary animal feed.
  • the invention also encompasses the use of a compound of the invention, or a pharmaceutically acceptable derivative thereof, for the manufacture of a cancer (including non-solid tumors, solid tumors, primary or metastatic cancer, as indicated elsewhere herein and including cancer)
  • a cancer including non-solid tumors, solid tumors, primary or metastatic cancer, as indicated elsewhere herein and including cancer
  • An agent that is resistant or refractory to one or more other treatments, as well as other diseases including, but not limited to, fundus diseases, psoriasis, atheroma, pulmonary fibrosis, liver fibrosis, myelofibrosis, and the like .
  • Such cancers include, but are not limited to, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, intrauterine Membrane cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, esophageal cancer, brain Any of tumor, B cell and T cell lymphoma, lymphoma, multiple myeloma, cholangiocarcinoma, and cholangiocarcinoma.
  • the invention is better illustrated by the examples provided below, all temperatures being in degrees Celsius unless otherwise stated.
  • FIG. 26 Replacement page (Article 26) 1 is a schematic diagram showing experimental results of inhibition of c-MET signaling pathway in Example 21 of the present invention; and FIG. 2 is a schematic diagram showing experimental results of inhibition of c-MET signaling pathway in Example 24 of the present invention.
  • the intermediate involved in the compound of the present invention can be produced by the following method, but is not limited to the following method.
  • a part of the intermediates of the present invention can be synthesized by referring to the method of the patent CN104530063, and a simple replacement of some functional groups, and those skilled in the art can obtain corresponding intermediates according to the knowledge of the chemical synthesis field.
  • the following invention provides the preparation route of the intermediate, and the intermediate involved in the compound of the present invention can be produced by the following scheme, but is not limited to the following scheme.
  • Method B 240 mg of 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid was dissolved in chlorosulfoxide (5 mL) and heated under reflux for 1 hour, cooled and concentrated to give a yellow oil.
  • dichloromethane 2 mL
  • 3-fluoro-4-nitroaniline 160 mg
  • dichloromethane 1 mL
  • Example 3 consisting of 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxamic [2,3;] quinazoline and Reaction of N-(3-fluoro-4-hydroxyphenyl)-N-(4-chlorophenyl)cyclopropane-1, 1-dimethylformamide gave a white solid (yield: 79%).
  • Example 3 consisting of 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3;]quinazoline and Reaction of N-(3-fluoro-4-hydroxyphenyl)-N-(3-chlorophenyl)cyclopropane-1,1-dimethylamide gave a white solid in a yield of 75%.
  • Example 3 consisting of 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3;]quinazoline and Reaction of fluorophenyl)-N-(3-fluoro-4-hydroxyphenyl)cyclopropane-1, 1-dimethylformamide gave a white solid in a yield of 68%.
  • Example 20 N-(4-fluorophenyl)-N- (4-((5-(3-(tetrahydropyrrol-1-yl)propoxy)-2,3-dihydro-[1,4] dioxo[2,3-f
  • Example 22 N-(3-fluoro-4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4] Preparation of oxane-[2,3-f]quinazolin-10-yl)amino)phenyl)-N-(4-fluorophenyl)cyclopropyl-1,1-dimethylamide
  • Example 25 N-(2-chloro-4-((5-(3-morpholinepropoxy)) 2,3-Dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane- Preparation of 1,1-dimethyl amide
  • Example 34 N-(3-Fluoro-4-((5-(3-(methylthio)propoxy)-2,3-dihydro-[l,4j dioxane[2,3- Preparation of f]quinazolin-10-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylamide
  • Example 36 N-(4-((5-(3-(l,1-dithiomorpholino)propoxy)-2,3-dihydro-[1,41 dioxane[2, Preparation of 3-f
  • Example 38 N-(3-fluoro-4-((5-(2-(tetrahydropyrrol-1-yl)ethoxy)) -2,3-dihydro-[1,4]dioxane [2,3-f
  • Example 24 The compound obtained in Example 24 (660 mg, 1 mmol) was dissolved in 15 mL of acetone, and stirred at room temperature for 15 min, then 2 mL of aqueous solution of L-malic acid (134 mg, 1 mmol) was added, stirring was continued for 12 hours, and the reaction mixture was filtered to give a white solid (400 mg). The solid was dissolved in 15 mL of ethanol and heated under reflux. After completely dissolved, the mixture was cooled and allowed to stand to afford white crystal compound 260 mg, HPLC >99%.
  • Step 2) N-(4-Fluorophenyl)-N-(4-((5-hydroxy-2,3-dihydro-[1,4]dioxin[2,3-quinazoline-10 - base)
  • Example 53 N-(4-Fluorophenyl)-N-(4-((5-(3-((2-hydroxyethyl))amino)propoxy)-2,3-dihydro-[1 , 4] Preparation of dioxo[2,3-f
  • Step 4) 7V-(4-Fluorophenyl)-N-(4-((5-(3-((2-methoxyethyl)amino)propoxy)-2,3-dihydro-[ 1,4] Preparation of dioxo[2,3:/]quinazolin-10-yl)oxy)phenyl)cyclopropyl-1,1-dimethylformamide
  • Step 4 N-(4-Fluorophenyl)-N-(4-((5-(3-((2-hydroxyethyl)methyl)amino)propoxy)-2,3-dihydro- Preparation of [1,4]-]quinazolin-10-yl)oxy)phenyl)cyclopropyl-1,1-dimethylformamide
  • Example 58 N-(3-Fluoro-4-((5-(3-hydroxypropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f
  • step 3 was carried out from N-(3-fluoro-4-((5-hydroxy-2,3-dihydro-[1,4]dioxin and [2,3;]
  • Example 59 N-(3-Fluoro-4-((5-(2-hydroxy-2-methylpropoxy)-2,3-dihydro-[1,4]dioxane[2,3 -f] quinazolin-10-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropyl-1,1-dimethylamide Preparation Step 1) 2) Operation as in Example 57 .
  • EtOAc EtOAc (EtOAc)EtOAc. - ⁇ 6 ) ⁇ 10.30 (s, 1H), 10.02 (s, 1H), 8.43 (s, 1H), 7.79 (dd, J 12.9, 2.4 Hz, 1H), 7.68 ⁇ 7.58 (m, 2H), 7.49 - 7.40 (m, 1H), 7.36 - 7.25
  • Example 60 N-(4-((5-(3-Aminopropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline-10- Preparation of 3-fluorophenyl)-N-(4-fluorophenyl)cyclopropyl-1,1-dimethylamide Step 1) 2) Operation as in Example 57.
  • Step 4) N-(4-((5-(3-Aminopropoxy)-2,3-dihydro-[1,4]dioxin[2,3-]quinazolin-10-yl) Preparation of oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropyl-1,1-dimethylamide
  • tert-Butyl (R)-(4-hydroxybutyl-2-yl)carbamate 400 mg, 2.11 mmol
  • pyridine 3 mL
  • a solution of benzenesulfonyl chloride (606 mg, 3.2 mmol) in dichloromethane (2 mL).
  • the reaction mixture was diluted with chloroformic acid, and washed with EtOAc EtOAc EtOAc (EtOAc m. +H) + .
  • step 1) from 5-benzyloxy-10-chloro-2,3-dihydro-[1,4]dioxime[2,3;]quinazoline and N-(2 -Fluoro-4-hydroxyphenyl)-N-(4-fluorophenyl)cyclopropane-1, 1-dimethylformamide is obtained as a brown solid.
  • Step 2) Preparation of l-(8-methoxy-6-amino-2,3-dihydrobenzo[b][l,4]dioxin-5-yl)ethyl-1-one
  • Steps 1 to 4 are the same as Steps 1 to 4 of the preparation of Example 66.
  • Step 7) N-(3-Fluoro-4-((5-methoxy-2,3-dihydro-[1,4]dioxin[2,3-f]quinolin-10-yl) yloxy) phenyl) - N - (4- fluorophenyl) cycloalkyl
  • Steps 1 through 4 are the same as steps 1 through 4 of the preparation of Example 66.
  • Step 7) N-(2-Fluoro-4-((5-methoxy-2,3-dihydro-[1,4]dioxin[2,3-f]quinolin-10-yl) yloxy) phenyl) - N - (4- fluorophenyl) cyclopropane - preparation dicarboxamide - 1, 1
  • Steps 1 to 4 are the same as Steps 1 to 4 of the preparation of Example 66.
  • Steps 1 to 4b are the same as Steps 1 to 4b of the preparation of Example 69.
  • Compound dilution a total of 12 concentrations after a 4-fold gradient dilution from the highest concentration of 10000 nM (the maximum final concentration of the drug used in this experiment is 10000 nM, the minimum final concentration is 0.002384 nM).
  • Stop the enzymatic reaction Add 5 ⁇ 4 ⁇ Stop solution to the well of a 384-well plate, mix by centrifugation, and react at room temperature for 5 min.
  • Inhibition rate (%) [1- (experimental well reading - negative control well reading) / (positive control well reading) - Negative control well reading)) ⁇ 100%.
  • Using GraphPad Prism5 software deal with the corresponding IC 50 values (concentration of compound inhibition rate of enzyme up 50%).
  • Table (1) lists the results of measurement of tyrosine kinase inhibitory activity by some of the compounds of the present invention, wherein A represents IC 5 o is less than or equal to 50 nM, and B represents IC 5 . Greater than 50 nM but less than or equal to 500 nM, C means IC 5Q is greater than 500 nM but less than or equal to 5000 nM, and D represents IC 5 . More than 5000 nM.
  • Positive control Add 2.5 ⁇ ! well to the 384-well plate 4 ⁇ substrate / ATP Mix, 2.5 ⁇ ! 7 well IX Kinase Assay Buffer with 4% DMSO, 5 ⁇ ! well 2 ⁇ c-Met solution. The final concentration of DMSO in the reaction system is 4%.
  • Stop the enzymatic reaction Add 5 ⁇ 4 ⁇ Stop solution to the well of a 384-well plate, mix by centrifugation, and react at room temperature for 5 min.
  • Inhibition rate (%) [1 - (experimental well reading - negative control well reading) / (positive control well reading) - Negative control well reading)) ⁇ 100%.
  • the corresponding IC 5 was obtained by processing with GraphPad Prism5 software. Value (concentration of compound at the highest inhibition rate of enzyme 50%).
  • Table (b) lists the results of the determination of tyrosine kinase inhibitory activity by some of the compounds in this patent, wherein A represents IC 5 .
  • B means IC 50 is greater than 50 nM but less than or equal to 500 nM, and C represents IC 5 . More than 500 nM but less than or equal to 5000 nM, D represents IC 5 . More than 5000 nM.
  • test for cell survival of small molecule compounds is as follows:
  • Table (3) lists the results of assays for the activity of representative compounds of the present invention against various cancer cells, wherein MHCC97H, HuH7, and HepG2 are liver cancer cell lines, A549 is a lung cancer cell line, and 8505C is a thyroid cancer cell line. NT indicates that the corresponding cell activity was not tested. Table (3) Results of measurement of cell activity of representative compounds of the present invention
  • Electrophoresis First electrophoresis at 100V for 30 min, then increase the voltage by only 120 V until the electrophoresis is completed.
  • Transfer film Transfer film by wet transfer method, constant pressure 100V, transfer film for 90min.
  • the highly metastatic MHCC97H hepatoma cell line was selected as the experimental object, and the results showed that the cell itself highly expressed pERK and c-Met.
  • pERK and c-Met replacement page fine 26
  • the expression was significantly reduced and presented a dose-dependent response.
  • the small molecule compounds of Examples 21 and 24 of this patent exhibited the same effects as cabozantinib, as shown in Figures 1 and 2.
  • the experimental results of Examples 21 and 24 are only representative of a plurality of experiments.
  • the biological data provided by the present invention indicate that the compounds of the present invention are useful for treating or preventing diseases caused by abnormalities of VEGFR-2 and c-Met kinase.
  • Some of the compounds of the present invention have potent in vitro inhibitory activities against cancer cells, including liver cancer cells MHCC97, HuH7, HepG2, lung cancer cells A549, and thyroid cancer cells 8505C.
  • the compounds of the invention are useful in the treatment of cancer, including primary and metastatic cancers, including solid tumors.
  • Such cancers include, but are not limited to, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, intrauterine Membrane cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, esophageal cancer, brain Tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary sarcoma, cholangiocarcinoma.
  • the compounds of the invention also include cancers that are resistant to one or more other therapeutic remedies.
  • the compounds of the invention are also useful in diseases other than cancer associated with VEGFR-2 kinase and/or c-Met kinase, including but not limited to fundus diseases, psoriasis, rheumatoid arthritis, atheroma, lung Fibrosis, liver fibrosis.
  • the compounds of the present invention may be administered as a monotherapy or a combination therapy, in combination with a plurality of compounds of the present invention or in combination with other drugs other than the present invention.
  • the compounds of the invention are also useful as standards and reagents for characterizing various kinases, particularly but not limited to protein tyrosine kinases, and are useful for studying the role of such kinases in biological and pathological phenomena: Intracellular signal transduction pathways mediated by such kinases are studied for comparative evaluation of new kinase inhibitors; and in cell lines and animal models for studying different cancers.

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Abstract

La présente invention concerne la dioxanoquinazoline de formule (I) et un composé de type dioxanoquinazoline ou un sel pharmaceutiquement acceptable de celui-ci. La présente invention concerne en outre un procédé de préparation du composé de formule (I) et un sel pharmaceutiquement acceptable de celui-ci et son utilisation en tant que médicament. Le médicament est utilisé pour traiter des maladies associées à la tyrosine kinase en tant qu'inhibiteur de tyrosine kinase (par exemple VEGFR -2 et c-Met).
PCT/CN2018/076233 2017-02-27 2018-02-11 Dioxanoquinazoline, composé de type dioxanoquinazoline, procédé de préparation et utilisation associés Ceased WO2018153293A1 (fr)

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CN201810983341.3A CN110156803A (zh) 2017-02-27 2018-08-27 二噁烷并喹啉类化合物及其制备方法与应用
EP19751025.8A EP3750893B1 (fr) 2018-02-11 2019-01-25 Composé de dioxazoline, son procédé de préparation et ses applications
CN201980012397.7A CN111788207B (zh) 2017-02-27 2019-01-25 二噁烷并喹啉类化合物及其制备方法与应用
PCT/CN2019/073260 WO2019154133A1 (fr) 2018-02-11 2019-01-25 Composé de dioxazoline, son procédé de préparation et ses applications
CA3090876A CA3090876C (fr) 2018-02-11 2019-01-25 Compose de dioxazoline, son procede de preparation et ses applications
PL19751025.8T PL3750893T3 (pl) 2018-02-11 2019-01-25 Związek dioksazoliny, sposób jego wytwarzania oraz jego zastosowania
SG11202007554TA SG11202007554TA (en) 2017-02-27 2019-01-25 Dioxazoline compound, preparation method therefor, and uses thereof
DK19751025.8T DK3750893T3 (da) 2017-02-27 2019-01-25 Dioxazolinforbindelse, fremgangsmåde til fremstilling deraf og anvendelser deraf
KR1020207025607A KR102433023B1 (ko) 2018-02-11 2019-01-25 디옥시노퀴놀린 화합물, 이의 제조방법 및 용도
ES19751025T ES2945573T3 (es) 2017-02-27 2019-01-25 Compuesto de dioxazolina, método de preparación y usos del mismo
AU2019218187A AU2019218187B2 (en) 2017-02-27 2019-01-25 Dioxinoquinoline compounds, preparation method and uses thereof
JP2020542958A JP7022454B2 (ja) 2018-02-11 2019-01-25 ジオキシノキノリン系化合物、その調製方法および使用
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CN111217821A (zh) * 2020-03-13 2020-06-02 北京工业大学 系列二噁烷并喹唑啉衍生物的制备方法
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
CN111788207A (zh) * 2017-02-27 2020-10-16 北京赛特明强医药科技有限公司 二噁烷并喹啉类化合物及其制备方法与应用
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
US11731946B2 (en) 2017-10-19 2023-08-22 The General Hospital Corporation Broad spectrum antivirulence, anti-persistence compounds
EP4103188A4 (fr) * 2020-02-10 2024-04-10 StemSynergy Therapeutics, Inc. Inhibiteurs de myc et leurs utilisations
CN111936487B (zh) * 2018-01-26 2024-07-09 埃克塞里艾克西斯公司 用于治疗激酶依赖性病症的化合物

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CN111788207B (zh) * 2017-02-27 2021-03-23 北京赛特明强医药科技有限公司 二噁烷并喹啉类化合物及其制备方法与应用
AU2019218187B2 (en) * 2017-02-27 2021-10-14 Beijing Scitech-Mq Pharmaceuticals Limited Dioxinoquinoline compounds, preparation method and uses thereof
CN111788207A (zh) * 2017-02-27 2020-10-16 北京赛特明强医药科技有限公司 二噁烷并喹啉类化合物及其制备方法与应用
US11731946B2 (en) 2017-10-19 2023-08-22 The General Hospital Corporation Broad spectrum antivirulence, anti-persistence compounds
CN111936487B (zh) * 2018-01-26 2024-07-09 埃克塞里艾克西斯公司 用于治疗激酶依赖性病症的化合物
US11407760B2 (en) 2018-02-11 2022-08-09 Beijing Scitech-Mq Pharmaceuticals Limited Dioxinoquinoline compounds, preparation method and uses thereof
WO2019154133A1 (fr) * 2018-02-11 2019-08-15 北京赛特明强医药科技有限公司 Composé de dioxazoline, son procédé de préparation et ses applications
WO2020103769A1 (fr) * 2018-11-19 2020-05-28 北京赛特明强医药科技有限公司 Composés de dioxane-quinazoline ou dioxane-quinoléine liés à un cycle aromatique, compositions et utilisation associées
TWI732344B (zh) * 2018-11-19 2021-07-01 大陸商北京賽特明強醫藥科技有限公司 芳環連二噁烷並喹唑啉或喹啉類化合物、組合物及其應用
US12202835B2 (en) 2018-11-19 2025-01-21 Beijing Scitech-Mq Pharmaceuticals Limited Substituted aromatic ring-linked dioxinoquinazolines and dioxinoquinolines as kinase inhibitors
JP2022509076A (ja) * 2018-11-19 2022-01-20 北京賽特明強医薬科技有限公司 芳香環結合ジオキシノ－キナゾリンまたはジオキシノ－キノリン系化合物、組成物およびその使用
AU2019383103B2 (en) * 2018-11-19 2023-02-02 Beijing Scitech-Mq Pharmaceuticals Limited Aromatic ring-linked dioxane-quinazoline or -quinoline compounds, compositions and use thereof
JP7251841B2 (ja) 2018-11-19 2023-04-04 北京賽特明強医薬科技有限公司 芳香環結合ジオキシノ－キナゾリンまたはジオキシノ－キノリン系化合物、組成物およびその使用
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
EP4103188A4 (fr) * 2020-02-10 2024-04-10 StemSynergy Therapeutics, Inc. Inhibiteurs de myc et leurs utilisations
CN111217821A (zh) * 2020-03-13 2020-06-02 北京工业大学 系列二噁烷并喹唑啉衍生物的制备方法
CN111217821B (zh) * 2020-03-13 2021-04-23 北京工业大学 系列二噁烷并喹唑啉衍生物的制备方法

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