WO2019154133A1 - 二噁烷并喹啉类化合物及其制备方法与应用 - Google Patents

二噁烷并喹啉类化合物及其制备方法与应用 Download PDF

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Publication number
WO2019154133A1
WO2019154133A1 PCT/CN2019/073260 CN2019073260W WO2019154133A1 WO 2019154133 A1 WO2019154133 A1 WO 2019154133A1 CN 2019073260 W CN2019073260 W CN 2019073260W WO 2019154133 A1 WO2019154133 A1 WO 2019154133A1
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group
alkyl
substituted
compound
pharmaceutically acceptable
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PCT/CN2019/073260
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English (en)
French (fr)
Inventor
张强
于善楠
王中祥
冯守业
孙月明
刘彦生
张宏波
杨磊夫
杨海龙
周利凯
郑南桥
胡晨明
徐占强
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北京赛特明强医药科技有限公司
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Priority claimed from PCT/CN2018/076233 external-priority patent/WO2018153293A1/zh
Priority claimed from CN201810983341.3A external-priority patent/CN110156803A/zh
Priority to DK19751025.8T priority Critical patent/DK3750893T3/da
Priority to EP19751025.8A priority patent/EP3750893B1/en
Priority to KR1020207025607A priority patent/KR102433023B1/ko
Priority to PL19751025.8T priority patent/PL3750893T3/pl
Application filed by 北京赛特明强医药科技有限公司 filed Critical 北京赛特明强医药科技有限公司
Priority to JP2020542958A priority patent/JP7022454B2/ja
Priority to SG11202007554TA priority patent/SG11202007554TA/en
Priority to ES19751025T priority patent/ES2945573T3/es
Priority to US16/968,797 priority patent/US11407760B2/en
Priority to CN201980012397.7A priority patent/CN111788207B/zh
Priority to CA3090876A priority patent/CA3090876C/en
Priority to AU2019218187A priority patent/AU2019218187B2/en
Publication of WO2019154133A1 publication Critical patent/WO2019154133A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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 dioxoquinoline compounds, pharmaceutically acceptable salts, isomers, hydrates, solvates, or prodrugs thereof, and processes for their preparation and use.
  • Receptor tyrosine kinases span the cell membrane and affect the transmembrane transport of biochemical signals, which consist of an extracellular domain containing a ligand binding site, a single transmembrane domain, and a tyrosine-containing protein kinase activity.
  • the intracellular domain is composed of three parts.
  • Ligand-receptor binding stimulates receptor-associated tyrosine kinase activity, which leads to phosphorylation of tyrosine residues on receptors and other intracellular molecules, leading to cascades that lead to various cellular responses. signal.
  • Overexpression of tyrosine receptors activates downstream signal transduction pathways, ultimately leading to abnormal cell transformation and proliferation, and promoting tumorigenesis and development.
  • Vascular endothelial growth factor receptor is a family of receptor tyrosine kinases that produces a range of biochemical properties by binding to its ligand vascular endothelial growth factor (VEGF). The physiological process eventually promotes the formation of new blood vessels. Tumor angiogenesis and their permeability are primarily regulated by vascular endothelial growth factor (VEGF), which acts through at least two different receptors (VEGFR-1, VEGFR-2).
  • VEGF vascular endothelial growth factor
  • 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.
  • antagonism of VEGF by chelation of antibodies to VEGF can result in 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. VEGF stimulates endothelial cell proliferation, increases vascular permeability and the formation of new blood vessels mainly 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 the desired anti-tumor effect. Therefore, the search for small molecule inhibitors with high activity and high selectivity for VEGFR-2 has become a promising tumor treatment strategy.
  • Hepatocyte growth factor receptor 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 role through the HGF/c-MET signaling pathway.
  • the 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 been shown to be important in the treatment of a variety of malignancies, including lung cancer.
  • 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 exhibits 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, indicating that Cabozantinib is a tumor angiogenesis in patients with dysregulated c-MET and VEGFR-2 signaling pathways.
  • a potent inhibitor of metastasis On November 29, 2012, the FDA approved the publication 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-). Diseases caused by 2 and/or c-MET), including certain variants of the tyrosine kinase receptor.
  • a tyrosine kinase for example, VEGFR-
  • Diseases caused by 2 and/or c-MET including certain variants of the tyrosine kinase receptor.
  • R 1 is H, C 1 -C 9 alkyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclic, C 3 -C 7 cycloalkyl substituted C 1 -C 6 alkyl, a 4-7 membered heterocyclic substituted C 1 -C 6 alkyl group, a substituted C 1 -C 9 alkyl group, the substituted C 1 -C 9 alkyl group having a hydroxy group, a C 1 -C 6 group One or more of an alkoxy group, a C 1 -C 6 alkylthio group or -NR 6 R 7 ,
  • R 6 and R 7 are each independently H, C 1 -C 6 alkyl, hydroxy-substituted C 1 -C 6 alkyl, C 1 -C 3 alkoxy-substituted C 1 -C 6 alkyl;
  • the above 4-7 membered heterocyclic group is a 4-7 membered heterocyclic group having 1 to 2 atoms selected from N, O and S, and the 4-7 membered heterocyclic group is not substituted or C 1 -C 3 An alkyl group, a C 1 -C 3 acyl group substituted or oxidized by one to two oxygen atoms;
  • R 2 is H, C 1 -C 3 alkyl or halogen
  • R 3 is H, C 1 -C 3 alkyl or halogen
  • R 4 is H, C 1 -C 3 alkyl or halogen
  • R 5 is H, C 1 -C 9 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl substituted C 1 -C 6 alkyl, aryl, aryl substituted C 1 -C 6 alkyl, heteroaryl or heteroaryl substituted C 1 -C 6 alkyl;
  • the aryl or heteroaryl group is not substituted or C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, mono or di C 1 -C 3
  • R 1 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 5-6 membered heterocyclyl, C 3 -C 6 cycloalkyl substituted C a 1- C 3 alkyl group, a 5-6 membered heterocyclic group-substituted C 1 -C 3 alkyl group, a substituted C 1 -C 6 alkyl group, the substituted C 1 -C 6 alkyl group having a hydroxy group a C 1 -C 3 alkoxy group, a C 1 -C 3 alkylthio group or -NR 6 R 7 ,
  • R 6 and R 7 are each independently -H, C 1 -C 3 alkyl, hydroxy-substituted C 1 -C 3 alkyl, C 1 -C 3 alkoxy-substituted C 1 -C 3 alkyl,
  • the above 5- to 6-membered heterocyclic group is a 5-6 membered heterocyclic group having 1 to 2 atoms selected from N, O, and S, and the 5-6 membered heterocyclic group is not substituted or C 1 -
  • the C 3 alkyl group, the C 1 -C 3 acyl group is substituted or oxidized by one to two oxygen atoms.
  • R 1 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxy Hexyl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydropyrrole-1-ethyl, tetrahydropyrrole-1-propyl, piperidin-1-ethyl, piperidine- 1-propyl, piperazine-1-ethyl, piperazine-1-propyl, morpholin-4-ethyl, morpholin-4-propyl, methylpiperazine-4-ethyl, methylper Pyrazin-4-propyl, N-formylpiperazine-4-ethyl, N-formylpiperazine-4-propyl, N-acetylpiperazine-4-
  • R 1 is selected from the group consisting of butyl, isobutyl, pentyl, isopentyl, hexyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, Cyclobutylethyl, cyclobutylpropyl, 4,4-dimethylpiperidine-1-ethyl, 4,4-dimethylpiperidine-1-propyl, oxetane-3- base.
  • the halogen described in R 2 , R 3 , R 4 is Cl or F.
  • R 5 is -H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted C 1 -C 3 alkyl, aryl An aryl-substituted C 1 -C 3 alkyl, heteroaryl or heteroaryl substituted C 1 -C 3 alkyl group, the aryl, heteroaryl substituent being a C 1 -C 3 alkane a C 1 -C 3 alkoxy group, a C 1 -C 3 alkylthio group, a mono or di C 1 -C 3 alkyl substituted amino group, a halogen, a trifluoromethyl group, an aryloxy group and a methylsulfonyl group One or more of them;
  • the heteroaryl group is a monocyclic or bicyclic group containing 1-2 hetero atoms selected from N, O, S and having 5 to 10 ring atoms.
  • R 5 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-fluorophenyl , 3-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3 , 4-difluorophenyl, 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)
  • the present application also provides a compound represented by the formula (I), a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof,
  • R 1 is a substituent consisting of 1 to 3 selected from a C 1 -C 3 acyl group, a halogen, a trifluoromethyl group, a cyano group, a -CONH 2 , a -NR a R b or a 4-7 membered heteroalicyclic group.
  • the 4-7 membered heteroalicyclic group being a 4-7 membered heteroalicyclic group having 1-2 atoms selected from N, O, and S as a ring atom, and
  • the 4-7 membered heteroalicyclic group is substituted with 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, hydroxy, -NH 2 , C 1 -C 3 acyl group,
  • R a and R b are each independently -H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy substituted C 1 -C 6 alkyl, C 1 - C 3 alkylthio substituted C 1 -C 6 alkyl, mono or di C 1 -C 3 alkyl substituted amino substituted C 1 -C 6 alkyl or unsubstituted amino substituted C 1 -C 6 alkane base;
  • R 2 , R 3 , and R 4 are each independently H, C 1 -C 3 alkyl or halogen;
  • R 5 is -H, C 1 -C 9 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl substituted C 1 -C 6 alkyl, aryl, aryl substituted C a 1 -C 6 alkyl, heteroaryl or heteroaryl substituted C 1 -C 6 alkyl;
  • Said aryl, heteroaryl or aryl group is not substituted with 1-3 substituents selected from hydroxy, amino, cyano, C 1 -C 3 alkyl, C 1 -C 3 alkoxy is, C 1 -C 3 Substituted with one or more substituents of an alkylthio, mono or di C 1 -C 3 alkyl substituted amino group, a halogen, a trifluoromethyl group, and a methylsulfonyl group;
  • the above heteroaryl group is a monocyclic or bicyclic group having 1 to 3 hetero atoms selected from N, O, and S and having 5 to 10 ring atoms.
  • R 1 is from 1 to 3 selected from C 1 -C 3 acyl, -F, trifluoromethyl, cyano, -CONH 2 , -NR a R b or 4-7 a C 1 -C 6 alkyl group substituted by a substituent in the heteroalicyclic group
  • the 4-7 membered heteroalicyclic group having 1-2 atoms selected from N, O, and S as a ring atom a 4-7 membered heteroalicyclic group
  • the 4-7 membered heteroalicyclic group is 1 to 3 alkyl groups selected from -F, C 1 -C 3 , hydroxyl group, -NH 2 , C 1 -C 3 Substituted by a substituent in the acyl group,
  • R a and R b are each independently -H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy substituted C 1 -C 3 alkyl, C 1 - C 3 alkylthio substituted C 1 -C 3 alkyl, mono or di C 1 -C 3 alkyl substituted amino substituted C 1 -C 3 alkyl or unsubstituted amino substituted C 1 -C 3 alkane base;
  • R 2 , R 3 , R 4 are each independently -H, -F or -Cl;
  • R 5 is -H, aryl, aryl substituted C 1 -C 3 alkyl, heteroaryl or heteroaryl substituted C 1 -C 3 alkyl, said aryl, heteroaryl is not Substituted or substituted by 1-3 selected from hydroxy, amino, cyano, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, mono or di C 1 Substituting one or more substituents of a -C 3 alkyl substituted amino group, a halogen, a trifluoromethyl group, and a methylsulfonyl group;
  • 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, O, and S.
  • R 1 is selected from the group consisting of cyanomethyl, cyanoethyl, cyanopropyl, -CH 2 CONH 2 , -CH 2 CF 3 , 4-methyl-4-hydroxypiperidine-1-propyl, 4-methyl-4-hydroxypiperidine-1-ethyl, 4-methyl-4-aminopiperidine-1-propyl, 4-methyl- 4-aminopiperidin-1-ethyl, N-methyl-N-cyclobutylaminopropyl, N-methyl-N-cyclopropylaminopropyl, N-methyl-N-cyclopentylaminopropyl , N-methyl-N-cyclohexylaminopropyl, N-methyl-N-cyclobutylaminoethyl, N-methyl-N-cyclopropylaminoethyl, N-methyl-N- Cyclopentylaminoethyl, N-methyl-N-cyclohexylaminoethyl, N-
  • the present invention provides a pharmaceutically acceptable salt of a compound of 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 such that Basic nitrogen is protonated by inorganic or organic acids.
  • Representative organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, glycolic acid, and 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-naphthalene Sulfonic acid, p-toluenesulfonic acid, cyclohexylaminesulfonic acid, salicylic acid, hexanoic acid, trifluoroacetic acid.
  • Pharmaceutically acceptable basic/cationic salts include, of course, not limited to aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.
  • 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 steps of a compound represented by the formula (II') Prepared with a compound of formula (III') to give a compound of formula (I) wherein Q, G, Z, L, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above,
  • 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 steps of a compound represented by the formula (II') Prepared with a compound of formula (III) to give a compound of formula (I) wherein Q, G, Z, L, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above,
  • the present invention provides an intermediate for the preparation of the above compound, a compound of the formula (II'), wherein Q, G, Z, R 1 , R 2 , R 3 , and R 4 are as defined above,
  • 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 including saturated straight chain, branched hydrocarbon groups
  • C 1 -C 9 represents a carbon atom of the alkyl group having 1 to 9 carbon atoms
  • C 1 -C 3 represents an alkyl group, for example.
  • a carbon atom having 1 to 3 carbon atoms, for example, a C 1 -C 6 alkyl group includes a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tertiary group.
  • alkoxy group is an alkyl-O- group formed by the linear or branched alkyl group described above and -O-.
  • alkenyl and alkynyl groups include straight-chain, branched alkenyl or alkynyl groups.
  • a cycloalkyl group means a cyclic group formed by a carbon atom.
  • a C 3 -C 7 cycloalkyl group may include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like.
  • aryl refers to an unsubstituted or substituted aryl group, such as phenyl, naphthyl, anthracenyl.
  • 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 as used herein, unless otherwise specified, represents an unsubstituted or substituted stable 3 to 8 membered monocyclic saturated ring system selected from carbon atoms and from N, O, S.
  • heterocyclic rings include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidine Pyridyl, piperazinyl, piperazinyl, piperidinyl, dioxetane, dioxetyltetrahydroimidazolyl, 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, O, 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 groups include, but are not limited to, thienyl, furyl, imidazolyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, pyranyl, pyridyl, piperazinyl, pyrimidinyl, pyrazine, Pyridazinyl, pyrazolyl, thiadiazolyl, triazolyl, fluorenyl, azaindole, oxazolyl, azacarbazolyl, benzimidazolyl, benzofuranyl, benzothiophene Benzoisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenyl, quinolinyl or isoquinoline base.
  • carbonyl refers to a -C(O)- group.
  • alkyl or aryl or any of their prefix radicals appear in the name of a substituent (eg, aralkyl, dialkylamine), it will be considered to contain the above “alkane” Those limitations given by “base” and “aryl”.
  • base e.g., aralkyl, dialkylamine
  • aryl e.g., aralkyl, dialkylamine
  • the specified number of carbon atoms eg, C 1 -C 6
  • the invention also provides methods of preparing the corresponding compounds, which can be prepared using a variety of synthetic methods, including the methods described below, the compounds of the invention or pharmaceutically acceptable salts, isomers or hydrates thereof
  • the synthesis is carried out using the methods described below 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 methods described below.
  • the compound of formula (I) of the present invention is prepared by reacting a compound of formula (II') with a formula (III') or formula (III) wherein Q, G, Z, L, R 1 , R 2 , R 3 R 4 and R 5 are as described above.
  • the invention further provides for the preparation of an intermediate of the compound of formula (I), ie a compound of formula (II'), wherein Q, G, Z, R 1 , R 2 , R 3 and R 4 are as defined above,
  • the compounds of the present invention can be prepared by the following methods or technical schemes known to those skilled in the art,
  • 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;
  • the conditions of the nitro reduction reaction include, but are not limited to, hydrogen and Raney nickel, hydrogen and palladium carbon, iron powder or zinc powder under acidic conditions or stannous chloride;
  • Step 3) 1-(8-Methoxy-6-amino-2,3-ddihydrobenzo[b][1,4]dioxane-5-)ethan-1-one with methyl formate Or ethyl formate in an organic solvent, catalyzed by a base to give 10-hydroxy-5-methoxy-2,3-dihydro-[1,4]dioxane[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 at a temperature ranging from room temperature to reflux.
  • Step 4) Preparation of 10-hydroxy-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]-quinoline and chlorinating reagent in organic solvent 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[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) Preparation of 5-hydroxy-10-chloro-2,3-dihydro-[1,4]dioxane[2,3-f]-quinoline with R 1 X in an organic solvent A compound represented by A, wherein R 1 is as defined above; the organic solvent includes, but is not limited to, one of tetrahydrofuran, dioxane, DMF, DMA, DMSO, acetonitrile or a combination of two or more; X in R 1 X is chlorine , bromine, iodine, mesylate, p-toluenesulfonate or triflate.
  • Step 5 The compound of the formula III-A is mixed with the formula V' in an organic solvent and heated 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, xylene, One or a combination of two or more of DMF, DMA, and DMSO.
  • 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) when a compound of the formula (III') is reacted with a compound of the formula (II'-A), wherein the formula (III') can be reacted with an acylating reagent, and then with the formula (II) '-A) carries out the reaction.
  • 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.
  • the compound of formula (III') is reacted with a compound of formula (II'-A) in the presence of a condensing agent to provide a compound of formula (I-C).
  • the condensing agent includes, but not limited to, a carbodiimide type condensing agent, a cerium salt type condensing agent, an organic phosphorus type condensing agent, and one or more kinds of other types of condensing agents, preferably N, N-bicyclic ring.
  • Hexylcarbodiimide DCC
  • N,N-diisopropylcarbodiimide DIC
  • hydroxybenzotriazole HOBt
  • N,N-diisopropylethylamine DIEA
  • 1- Hydroxy-7-azobenzotriazole HAAt
  • O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate TBTU
  • benzotriazole Zin-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate BOP
  • 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate HBTU
  • 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate HCTU
  • this step can be carried out in an organic base including, but not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine , 1,8-diazabicycloundec-7-ene or N-methylmorpholine, one or a combination of two or more.
  • organic base including, but not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine , 1,8-diazabicycloundec-7-ene or N-methylmorpholine, one or a combination of two or more.
  • step 4a and step 4b may be omitted, and after step 4), the operation of step 5) may be performed.
  • step 4a and step 4b and step 5 is not fixed.
  • step 5 may be performed first, and then step 4a and step 4b 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 mixtures of diastereomers and pure enantiomers, are considered to be part of this invention.
  • the compound of the present invention as an active ingredient, and a method of preparing the same, are all 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 of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of the invention.
  • 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, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerol phosphate, gluconic acid Salt, hemisulfate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, methane Sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, per-3-phenylpropionate, Phosphate, picrate, propionate
  • 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 alkyl sulfonates and aryl sulfonates.
  • 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), 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 of an inflammatory, antifungal, antibiotic or anti-vascular hyperproliferative compound; and any pharmaceutically acceptable carrier, adjuvant or excipient.
  • a kinase inhibitor small molecule, polypeptide, antibody, etc.
  • an immunosuppressant an anticancer drug
  • an antiviral agent an antibiotic
  • an additional agent of an inflammatory, antifungal, antibiotic or anti-vascular hyperproliferative compound an additional agent of 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, in the treatment of cancer using radiation therapy or cytostatic agents, cytotoxic agents, other anticancer agents, and the like to improve Cancer-like.
  • the invention is not limited to the order of administration; the compounds of the invention may be administered previously, simultaneously, or after other anticancer or cytotoxic agents.
  • 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 a conventional pharmaceutical ingredient technique.
  • 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 have the following forms, for example, suitable for oral administration, such as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injections such as clear solutions, suspensions, Emulsion; or for topical use such as creams, creams; or as a suppository for rectal administration.
  • the pharmaceutical ingredient may also be presented in unit dosage form for administration in a 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, and the like.
  • 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 disease state or the disordered condition in which it is located.
  • the therapeutic compound can be administered to the animal in the form of a capsule, a bolus, or a pill.
  • 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 consistent with veterinary practice standards.
  • 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 .
  • the cancer includes, but is 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.
  • 1,1-Cyclopropyldicarboxylic acid (1.04 g) was added to anhydrous tetrahydrofuran (20 mL), and triethylamine (0.84 g) was slowly added dropwise to the stirred suspension under ice-water bath and stirred for half an hour. Then, thionyl chloride (1.1 g) was added dropwise at 0 ° C, and stirring was continued for 1 hour, followed by the addition of triethylamine (0.8 g), tetrafluoroaniline (0.9 g) in tetrahydrofuran (10 mL). After the reaction was stirred for 2 hours, it was concentrated, dissolved in 1N sodium hydroxide and extracted with ethyl acetate. The aqueous phase was adjusted to pH 2.0 with 1N diluted hydrochloric acid solution, stirring was continued for half an hour, and filtered to give a white solid product (1.1 g). 62%, MS: 224 [M+H] + .
  • Step 1) 10-Chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline (251 mg, 1 mmol) with p-nitrophenol (139 mg, 1 mmol) was placed in a reaction flask, chlorobenzene was added, and the mixture was heated to reflux to complete the reaction. After cooling, suction filtration, the obtained solid was washed with aqueous potassium carbonate to give a pale-yellow solid (5-methoxy-10-(4-nitrophenoxy)-2,3-dihydro-[1,4] diox. Alkano[2,3-f]quinoline 250 mg, 71% yield. MS: 355 [M+H] + .
  • Step 2) The product obtained in the step 1) (250 mg, 0.7 mmol) is placed in a reaction flask, methanol, Raney nickel (250 mg) is added, and the reaction is completed under a hydrogen atmosphere until the reaction is completed, and the mixture is filtered and concentrated to give a white solid product. (4-((5-Methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl)oxy)aniline) 226 mg, produced The rate is 99%. MS: 325 [M+H] + .
  • Step 3) The product obtained in the step 2) (226 mg, 0.7 mmol) and 1-((4-fluorophenyl)carbamoyl)cyclopropane-1-carboxylic acid were placed in a reaction flask, and N, N-di was added.
  • the p-nitrophenol can be replaced by the same molar equivalent of 2-fluoro-4-nitrophenol.
  • Step 1) Dissolving 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline (251 mg, 1 mmol) in dichloromethane 1 mol of a solution of boron tribromide in dichloromethane (3 mL, 3 mmol) was added dropwise and stirred until the reaction was completed.
  • the light yellow solid product (5-hydroxy-10-chloro-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline) 236 mg was obtained.
  • Step 2) The product obtained in step 1) (236 mg, 1 mmol) was dissolved in N,N-dimethylformamide, and 4-(3-chloropropyl)morpholine (163 mg, 1 mmol) and potassium carbonate (414 mg, 3 mmol) ), heating and stirring until the reaction is completed. Add water and ethyl acetate for extraction, and concentrate the organic phase to give a white solid (10-chloro-5-(3-morpholinepropoxy)-2,3-dihydro-[1,4] dioxins. Alkano[2,3-f]-quinoline) 291 mg, yield 80%.
  • Step 3 in the same molar equivalent of 4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3 -f]quinoline-10-yloxy)aniline instead of 4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline Benzyl)oxy)aniline can be used.
  • Steps 1 to 2 are the same as Steps 1 to 2 of the preparation of Example 4.
  • Step 5 N-(3-Fluoro-4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quina Preparation of porphyrin-10-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylamide
  • Steps 1 to 2 are the same as Steps 1 to 2 of the preparation of Example 4.
  • Step 5 N-(2-Fluoro-4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quina Preparation of porphyrin-10-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylamide
  • Step 2 The product obtained in the step 1 (350 mg, 1 mmol) was added to a solution of hydrogen bromide in acetic acid (33%, 5 mL), heated to 90 ° C for 15 hours, cooled, and then added with ethyl acetate (15 mL).
  • Light green solid (10-(2-fluoro-4-nitrophenoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinolin-5-ol Hydrogen bromide) 3.8 g, yield 87%, MS: 359 [M+H] + ;
  • Step 3 To a solution of the product obtained in Step 2 (440 mg, 1 mmol) in DMF (5 mL), bromoethane (165 mg, 1.5 mmol) and potassium carbonate (280 mg, 2 mmol), and heated to 80 ° C for 10 hours. After cooling, adding water, ethyl acetate extraction, washing with saturated sodium chloride solution, drying, concentration and purification by column chromatography to give pale yellow solid product (10-(2-fluoro-4-nitrophenoxy)-5-ethoxy Base-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline 320 mg, yield 83%;
  • Step 4 The product obtained in Step 3 (320 mg) in methanol (30 mL) was added to Raney nickel, and the mixture was stirred at room temperature under hydrogen atmosphere for 3 hours, filtered, washed, and concentrated to give a purple solid product (3-fluoro-4). -((5-ethoxy-2,3-dihydro-[1,4]dioxol[2,3-f]quinolin-10-yl)oxy)phenylamine) 290 mg, yield 81% , MS: 357 [M+H] + ;
  • Step 5 Add 1-((4-fluorophenyl)aminoformyl)cyclopropyl-1-carbonyl chloride (24 mg, respectively) to a solution of the product (36 mg, 0.1 mmol) in NMeOH (1 mL). 0.1 mmol) of a solution of dichloromethane (0.5 mL) and triethylamine (0.1 mL), and the mixture was stirred at room temperature for 5 hr, then quenched with water and filtered to give a pale yellow solid.
  • Example 22 N-(3-Fluoro-4-((5-(3-(4-hydroxy-4-methylpiperidin-1-yl)propoxy)-2,3-dihydro-[1 ,4]dioxocyclo[2,3-f]quinolin-10-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropyl-1,1-dimethylformamide
  • Example 7 was prepared similar manner, except that, in step 3 to an equivalent amount of 3- (cyclobutyl (methyl) amino) propyl bromide instead of ethyl bromide is reacted to give a white solid;
  • Example 25 N-(3-Fluoro-4-((5-(3-(pyrrol-1-yl)propoxy)-2,3-dihydro-[1,4]dioxane [2] ,3-f]quinoline-10-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropyl-1,1-dimethylformamide
  • Example 28 N-(3-Fluoro-4-((5-(oxetan-3-oxy)-2,3-dihydro-[1,4]dioxane [2,3] -f]quinoline-10-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropyl-1,1-dimethylformamide
  • Example 7 was prepared similar manner, except that, in step 3 to an equivalent amount of p-toluenesulfonic acid oxetan-3-acetate instead of ethyl bromide is reacted to give a white solid;
  • Example 30 N-(3-Fluoro-4-((5-(3-(4-amino-4-methylpiperidin-1-yl)propoxy)-2,3-dihydro-[1 ,4]dioxocyclo[2,3-f]quinolin-10-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropyl-1,1-dimethylformamide
  • test method is as follows:
  • Negative control 2.5 ⁇ L/well 4X substrate/ATP mixture and 7.5 ⁇ L 1X Kinase Assay Buffe were added to the 384-well plate well.
  • Color reaction 5 ⁇ L of 4X detection solution was added to the wells of a 384-well plate for color development, and the mixture was centrifuged at room temperature for 60 minutes.
  • Table 1 lists the results of measurement of the tyrosine kinase c-MET inhibitory activity of some compounds of the present invention, wherein A represents an IC 50 of less than or equal to 50 nM, and B represents an IC 50 of more than 50 nM but less than or equal to 500 nM, and C represents an IC 50 . Greater than 500 nM but less than or equal to 5000 nM, D indicates an IC 50 greater than 5000 nM.
  • test method is as follows:
  • Negative control 2.5 ⁇ L/well 4X substrate/ATP mixture and 7.5 ⁇ L 1X Kinase Assay Buffe were added to the 384-well plate well.
  • Color reaction 5 ⁇ L of 4X detection solution was added to a well of a 384-well plate for color development, and the mixture was centrifuged at room temperature for 60 minutes.
  • inhibition rate (%) (positive well reading value - experimental well reading value) / (positive control well reading value - negative control well) Read value) x100%.
  • inhibition rate (%) (positive well reading value - experimental well reading value) / (positive control well reading value - negative control well) Read value) x100%.
  • the corresponding IC 50 value was obtained by processing with GraphPad Prism5 software (the highest inhibition rate of the enzyme was 50%).
  • Table 2 lists the results of assays for the tyrosine kinase VEGFR-2 inhibitory activity of some of the compounds of the present invention, wherein A represents an IC 50 of less than or equal to 50 nM, and B represents an IC 50 of greater than 50 nM but less than or equal to 500 nM, and C represents an IC 50 . Greater than 500 nM but less than or equal to 5000 nM, D indicates an IC 50 greater than 5000 nM.
  • MHCC97H cells were collected, transferred to a 15 mL centrifuge tube, and centrifuged at 1000 rpm for 5 minutes.
  • Table 3 lists the results of tests for the proliferation inhibitory activity of some of the compounds of the present invention on the MHCC97H cell line.
  • 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 or c-MET kinase.
  • 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, etc.
  • the compounds of the invention also include cancers that are resistant to one or more other therapeutic methods.
  • 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.

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Abstract

本发明公开了具有式（I）的二噁烷并喹啉类化合物或其可药用盐。本发明还提供了一种式（I）所述化合物及其可药用盐的制备和作为药物的应用，所述药物作为酪氨酸激酶（例如VEGFR-2和c-MET）抑制剂用于治疗与酪氨酸激酶相关的疾病。

Description

二噁烷并喹啉类化合物及其制备方法与应用 技术领域
本发明涉及二噁烷并喹啉类化合物，其药学上可接受的盐，异构体，水合物，溶剂化物，或前药，及其制备方法和用途。
背景技术
受体酪氨酸激酶(RTKs)横跨细胞膜，影响生物化学信号的跨细胞膜传输，其由含有配体结合位点的细胞外结构域、单次跨膜区、含有酪氨酸蛋白激酶活性的细胞内结构域三部分组成。配体与受体的结合会刺激受体相关的酪氨酸激酶活性，该活性导致受体和其他细胞内分子上的酪氨酸残基的磷酸化，进而引发导致各种细胞反应的级联信号。酪氨酸受体的过度表达激活了下游信号转导通路，最终导致细胞的异常转化和增殖，促进肿瘤的发生、发展。
血管内皮生长因子受体(vascular endothelial growth factor receptor，VEGFR)是受体酪氨酸激酶家族中的一种，通过与其配体血管内皮生长因子(vascular endothelial growth factor,VEGF)结合产生一系列生化和生理过程，最终促使新生血管形成。肿瘤血管的生成和它们的通透性主要通过血管内皮细胞生长因子(VEGF)调节，其通过至少两种不同的受体(VEGFR-1、VEGFR-2)发挥作用。根据Jakeman、Kolch、Connolly等的研究显示：VEGF是正常和病理性血管生成和血管渗透性的重要刺激物(Jakeman等，1993，Endocrinology 133：848-859；Kolch等，1995，Breast Cancer Research and Treatment，36：139-155；Connolly等，1989，J.Biol.Chem.264：20017-20024)。血管内皮细胞生长因子通过诱导内皮细胞增殖、蛋白酶表达和迁移及随后形成毛细管的细胞组织来诱发血管芽生表型。因此，通过抗体对VEGF的螯合作用产生的对VEGF的拮抗作用可导致肿瘤生长的抑制(Kim等，1993，Nature 362：841-844)。
由于VEGFR-2主要分布在血管内皮细胞内，可以与VEGF-A、VEGF-C、VEGF-D、VEGF-E结合。而VEGF刺激内皮细胞的增殖、增加血管的通透性和新血管的生成作用主要是通过结合和激活VEGFR-2来实现的。如果阻断VEGFR-2的活性，可以通过直接和间接途径抑制肿瘤的生长和转移，进而达到理想的抗肿瘤效果。因此，寻找对VEGFR-2具 有高活性、高选择性的小分子抑制剂成为非常有前景的肿瘤治疗策略。
肝细胞生长因子受体(hepatocyte growth factor receptor，c-MET)是酪氨酸激酶受体的一种，其异常活化在多种恶性肿瘤包括肺癌的发生和发展中起着重要的作用。肝细胞生长因子(HGF)为c-MET的特异性配体，c-MET与HGF结合后通过HGF/c-MET信号通路发挥生物学作用。HGF/c-MET信号通路能诱导细胞增殖、分散、迁移、器官形态形成、血管发生等一系列生物效应。c-MET的异常活化可表现为受体过表达、基因突变、扩增、异位、重排等。这些变化可导致下游信号通路失调，如丝氨酸/苏氨酸蛋白激酶(AKT)、胞外信号激酶(ERK)、磷脂酰肌醇-3-羟基激酶、视网膜母细胞瘤抑制蛋白(Rb)通路等，介导肿瘤发生、侵袭和转移、血管新生、上皮间质转化等过程。c-MET在细胞的增殖、代谢以及肿瘤的产生、转移、血管生成中扮演着重要角色，已成为抗肿瘤治疗的重要靶点。以c-MET为靶点的靶向治疗已在包括肺癌在内的多种恶性肿瘤的治疗中显现出其重要意义。
在使用抗肿瘤药物的治疗过程中，多个信号通路的相互作用会影响抗肿瘤药物的作用效果，如HFG/c-MET信号通路与其他通路的相互作用影响了抗肿瘤药物的治疗效果，产生药物耐药性。因此，多激酶靶点联合用药成为新的抗肿瘤治疗手段，而Crizotinib和Cabozantinib的成功上市说明了多激酶靶点抑制剂的开发具有良好的潜力和应用价值。
Cabozantinib是一种蛋白激酶的小分子抑制剂，对c-MET、VEGFR-2、Ret、Kit、AXL等多种激酶有抑制作用。Cabozantinib在肿瘤模型中能抑制c-MET和VEGFR-2的磷酸化，在临床前药效模型中显示出有效的抗肿瘤转移和抗血管生成活性。同单独作用于VEGFR靶标的抑制剂相比，在用Cabozantinib治疗的肺部肿瘤转移模型中并未发现肿瘤负荷增加，说明Cabozantinib是c-MET和VEGFR-2信号通路失调肿瘤患者中肿瘤血管生成和转移的有效抑制剂。FDA于2012年11月29日批准Cabozantinib上市用于进展性，转移甲状腺髓样癌(MTC)患者的治疗。
类似于Cabozantinib这样作用于多靶标的抑制剂有许多优点，对于此种类型抑制剂的研究也十分火热。目前上市的药物很少，获得的渠道有限，并且已上市的药物在使用中会出现耐药性和副作用等问题。因此，相比已经上市的单靶点抑制剂而言，多靶标的小分子抑制剂会有更好的治疗效果和应用前景。
发明内容
本发明所提供式(I)表示的化合物，其药学上可接受的盐，异构体，水合物，溶剂化物，或前药，其可用作治疗或预防由酪氨酸激酶(例如VEGFR-2和/或c-MET)引起的疾病，包括酪氨酸激酶受体的某些变种。
Figure PCTCN2019073260-appb-000001
式(I)中，
Q为CH；
G为O；
Z为CH；
L选自以下基团
Figure PCTCN2019073260-appb-000002
其中X为H或C 1-C 3的烷基；Y为H或C 1-C 3的烷基；n＝0-3，且当n＝0时，L表示
Figure PCTCN2019073260-appb-000003
R 1为H，C 1-C 9烷基，C 3-C 7的环烷基，4-7元杂环基，C 3-C 7的环烷基取代的C 1-C 6烷基，4-7元杂环基取代的C 1-C 6烷基，取代的C 1-C 9烷基，所述取代的C 1-C 9烷基的取代基为羟基、C 1-C 6的烷氧基、C 1-C 6的烷硫基或-NR 6R 7中的一种或一种以上，
R 6和R 7分别独立地为H、C 1-C 6烷基、羟基取代的C 1-C 6烷基、C 1-C 3烷氧基取代的C 1-C 6烷基；
上述4-7元杂环基为含有1-2个选自N、O、S中的原子的4-7元杂环基，4-7元杂环基不被取代或被C 1-C 3烷基、C 1-C 3酰基取代或被一至二个氧原子氧化；
R 2为H、C 1-C 3的烷基或卤素；
R 3为H、C 1-C 3的烷基或卤素；
R 4为H、C 1-C 3的烷基或卤素；
R 5为H，C 1-C 9烷基，C 3-C 7的环烷基，C 3-C 7环烷基取代的C 1-C 6烷基，芳基，芳基取代的C 1-C 6烷基，杂芳基或杂芳基取代的C 1-C 6烷基；
所述芳基、杂芳基不被取代或被C 1-C 3的烷基、C 1-C 3的烷氧基、C 1-C 3的烷硫基、单或双C 1-C 3烷基取代的氨基、卤素、三氟甲基、芳氧基和甲砜基中的一种或一种以上取代；所述杂芳基为含有1-3个选自N、O、S中的杂原子且含有5至10个环原子的单环或双环基团。
根据一个优选的实施方案，R 1为H，C 1-C 6烷基，C 3-C 6的环烷基，5-6元杂环基，C 3-C 6 的环烷基取代的C 1-C 3烷基，5-6元杂环基取代的C 1-C 3烷基，取代的C 1-C 6烷基，所述取代的C 1-C 6烷基的取代基为羟基、C 1-C 3的烷氧基、C 1-C 3的烷硫基或-NR 6R 7，
R 6和R 7分别独立地为-H、C 1-C 3烷基、羟基取代的C 1-C 3烷基、C 1-C 3烷氧基取代的C 1-C 3烷基，
上述5-6元杂环基为含有1-2个选自N、O、S中的原子的5-6元杂环基，所述5-6元杂环基不被取代或被C 1-C 3烷基、C 1-C 3酰基取代或被一至二个氧原子氧化。
根据一个优选的实施方案，R 1选自甲基、乙基、丙基、异丙基、甲氧基乙基、甲氧基丙基、甲氧基丁基、甲氧基戊基、甲氧基己基、四氢呋喃-3-基、四氢-2H-吡喃-4-基、四氢吡咯-1-乙基、四氢吡咯-1-丙基、哌啶-1-乙基、哌啶-1-丙基、哌嗪-1-乙基、哌嗪-1-丙基、吗啉-4-乙基、吗啉-4-丙基、甲基哌嗪-4-乙基、甲基哌嗪-4-丙基、N-甲酰基哌嗪-4-乙基、N-甲酰基哌嗪-4-丙基、N-乙酰基哌嗪-4-乙基、N-乙酰基哌嗪-4-丙基、(1,1-二氧硫代吗啉基)-4-乙基、(1,1-二氧硫代吗啉基)-4-丙基、甲硫基乙基、甲硫基丙基、二甲氨基乙基、二甲氨基丙基、二甲氨基丁基、二甲氨基戊基、二甲氨基己基、二乙氨基乙基、二乙氨基丙基、羟基乙基、羟基丙基、羟乙基氨基乙基、羟丙基氨基乙基、羟乙基氨基丙基、甲氧基乙基氨基乙基、甲氧基丙基氨基乙基、甲氧基乙基氨基丙基、氨基乙基、氨基丙基、氨基丁基、N-甲基-N-羟乙基氨基乙基、N-甲基-N-羟丙基氨基乙基、N-甲基-N-羟乙基氨基丙基、N-甲基-N-甲氧基乙基氨基乙基、N-甲基-N-甲氧基丙基氨基乙基、N-甲基-N-甲氧基乙基氨基丙基、2-甲基-2-羟基丙基、3-甲基-3-羟基丁基、(3S)-3-氨基丁基、(3R)-3-氨基丁基、(3S)-3-羟基丁基或(3R)-3-羟基丁基中的一种或一种以上。
根据一个优选的实施方案，R 1选自：丁基、异丁基、戊基、异戊基、己基、环丙基甲基、环丙基乙基、环丙基丙基、环丁基甲基、环丁基乙基、环丁基丙基、4,4-二甲基哌啶-1-乙基、4,4-二甲基哌啶-1-丙基、氧杂环丁烷-3-基。
根据一个优选的实施方案，R 2、R 3、R 4中所述的卤素为Cl或F。
根据一个优选的实施方案，R 5为-H，C 1-C 6烷基，C 3-C 6环烷基，C 3-C 6环烷基取代的C 1-C 3烷基，芳基，芳基取代的C 1-C 3烷基，杂芳基或杂芳基取代的C 1-C 3烷基，所述的芳基、杂芳基的取代基为C 1-C 3的烷基、C 1-C 3的烷氧基、C 1-C 3的烷硫基、单或双C 1-C 3烷基取代的氨基、卤素、三氟甲基、芳氧基和甲砜基中的一种或一种以上；
所述杂芳基为含有1-2个选自N、O、S中的杂原子且含有5至10个环原子的单环或双环基团。
更优选地，R 5选自H、甲基、乙基、丙基、异丙基、异戊基、环丙基、环丁基、环戊基、环己基、苯基、4-氟苯基、3-氟苯基、2-氟苯基、4-氯苯基、3-氯苯基、2-氯苯基、2,4- 二氟苯基、2,5-二氟苯基、3,4-二氟苯基、2,4-二氯苯基、2,5-二氯苯基、3,4-二氯苯基、2-氟-4-(三氟甲基)苯基、2-氟-5-(三氟甲基)苯基、3-氟-4-(三氟甲基)苯基、3-氟-5-(三氟甲基)苯基、3-三氟甲基-4氟苯基、2-氟-4-氯苯基、2-氟-5-氯苯基、3-氟-4-氯苯基、3-氟-5-氯苯基、3-氯-4-氟苯基、2-氯-4-(三氟甲基)苯基、2-氯-5-(三氟甲基)苯基、3-氯-4-(三氟甲基)苯基、3-氯-5-(三氟甲基)苯基、3-三氟甲基-4-氯苯基、2-氯-4-氟苯基、2-氯-5-氟苯基、3-氯-4-氟苯基、苄基、苯乙基、4-氟苄基、萘-1-基、3-甲基-异噁唑-5-基、4-苯氧基苯基、3-(甲砜基)苯基、4-(甲砜基)苯基、吡啶-2-基、吡啶-3-基、吡啶-4-基、3-甲氧基苄基或4-甲氧基苄基。
本申请还提供一种式(I)表示的化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药，
Figure PCTCN2019073260-appb-000004
式(I)中，
Q为CH；
G为O；
Z为CH；
L选自以下基团
Figure PCTCN2019073260-appb-000005
其中X为H或C 1-C 3的烷基；Y为H或C 1-C 3的烷基；n＝0-3，且当n＝0时，L表示
Figure PCTCN2019073260-appb-000006
R 1为由1至3个选自C 1-C 3酰基、卤素、三氟甲基、氰基、-CONH 2、-NR aR b或4-7元杂脂环基中的取代基所取代的C 1-C 6烷基，所述4-7元杂脂环基为含有1-2个选自N、O、S中的原子作为环原子的4-7元杂脂环基，且所述4-7元杂脂环基被1至3个选自卤素、C 1-C 3的烷基、羟基、-NH 2、C 1-C 3酰基中的取代基所取代，
R a和R b各自独立地为-H、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基取代的C 1-C 6烷基、C 1-C 3烷硫基取代的C 1-C 6烷基、单或双C 1-C 3烷基取代的氨基取代的C 1-C 6烷基或者非取代的氨基取代的C 1-C 6烷基；
R 2、R 3、R 4各自独立地为H、C 1-C 3的烷基或卤素；
R 5为-H，C 1-C 9烷基，C 3-C 7的环烷基，C 3-C 7环烷基取代的C 1-C 6烷基，芳基，芳基取代的C 1-C 6烷基，杂芳基或杂芳基取代的C 1-C 6烷基；
所述芳基、杂芳基不被取代或被1-3个选自羟基、氨基、氰基、C 1-C 3的烷基、C 1-C 3的烷氧基、C 1-C 3的烷硫基、单或双C 1-C 3烷基取代的氨基、卤素、三氟甲基和甲砜基中的一种或多种取代基取代；
上述杂芳基为含有1-3个选自N、O、S中的杂原子且含有5至10个环原子的单环或双环基团。
根据一个优选的实施方案，其中，R 1为由1至3个选自C 1-C 3酰基、-F、三氟甲基、氰基、-CONH 2、-NR aR b或4-7元杂脂环基中的取代基所取代的C 1-C 6烷基，所述4-7元杂脂环基为含有1-2个选自N、O、S中的原子作为环原子的4-7元杂脂环基，且所述4-7元杂脂环基被1至3个选自-F、C 1-C 3的烷基、羟基、-NH 2、C 1-C 3酰基中的取代基所取代，
R a和R b各自独立地为-H、C 1-C 3烷基、C 3-C 6环烷基、C 1-C 3烷氧基取代的C 1-C 3烷基、C 1-C 3烷硫基取代的C 1-C 3烷基、单或双C 1-C 3烷基取代的氨基取代的C 1-C 3烷基或者非取代的氨基取代的C 1-C 3烷基；
R 2、R 3、R 4各自独立地为-H、-F或-Cl；
R 5为-H，芳基，芳基取代的C 1-C 3烷基，杂芳基或杂芳基取代的C 1-C 3烷基，所述的芳基、杂芳基为不被取代或被1-3个选自羟基、氨基、氰基、C 1-C 3的烷基、C 1-C 3的烷氧基、C 1-C 3的烷硫基、单或双C 1-C 3烷基取代的氨基、卤素、三氟甲基和甲砜基中的一种或多种取代基取代；
所述杂芳基为含有5至10个环原子的单环或双环基团；杂芳基含有1-2个选自N、O、S中的杂原子。
更优选地，R 1选自氰基甲基、氰基乙基、氰基丙基、-CH 2CONH 2、-CH 2CF 3、
Figure PCTCN2019073260-appb-000007
4-甲基-4羟基哌啶-1-丙基、4-甲基-4羟基哌啶-1-乙基、4-甲基-4氨基哌啶-1-丙基、4-甲基-4氨基哌啶-1-乙基、N-甲基-N-环丁基氨基丙基、N-甲基-N-环丙基氨基丙基、N-甲基-N-环戊基氨基丙基、N-甲基-N-环己基氨基丙基、N-甲基-N-环丁基氨基乙基、N-甲基-N-环丙基氨基乙基、N-甲基-N-环戊基氨基乙基、N-甲基-N-环己基氨基乙基。
本发明提供了的式(I)化合物可药用的盐，其中所述的盐是酸性/阴离子盐或碱性/阳离子盐；药学上可接受的酸性/阴离子盐通常采取的形式是让其中的碱性氮被无机或有机酸质子化，代表性的有机或无机酸包括盐酸、氢溴酸、氢碘酸、高氯酸、硫酸、硝酸、磷酸、甲酸、乙酸、丙酸、羟基乙酸、乳酸、琥珀酸、马来酸、酒石酸、苹果酸、柠檬酸、富马酸、葡萄糖酸安息香酸、扁桃酸、甲磺酸、羟乙基磺酸、苯磺酸、草酸、棕榈酸、2-萘磺酸、对甲苯磺酸、环己胺基磺酸、水杨酸、己糖酸、三氟乙酸。药学上可接受的碱性/阳离 子盐类包括(当然不仅限于此)铝、钙、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、锂、镁、钾、钠和锌。
本发明提供一种制备上述化合物或者其药学上可接受的盐，异构体、水合物、溶剂化物、或前药的方法，其特征在于，包括以下步骤，由式(II＇)所示化合物与式(III＇)所示化合物反应制备得到式(I)化合物，其中Q、G、Z、L、R 1、R 2、R 3、R 4和R 5如前文所定义，
Figure PCTCN2019073260-appb-000008
本发明提供一种制备上述化合物或者其药学上可接受的盐，异构体、水合物、溶剂化物、或前药的方法，其特征在于，包括以下步骤，由式(II＇)所示化合物与式(III)所示化合物反应制备得到式(I)化合物，其中Q、G、Z、L、R 1、R 2、R 3、R 4和R 5如前文所定义，
Figure PCTCN2019073260-appb-000009
本发明提供制备上述化合物的中间体，一种式(II＇)所示的化合物，其中，Q、G、Z、R 1、R 2、R 3、和R 4如前文所定义，
Figure PCTCN2019073260-appb-000010
具体实施方式
除非另有说明，在本申请(包括说明书和权利要求书)中使用的以下术语具有下面给出的定义。在本申请中，除非另外说明，使用“或”或“和”意味着“和/或”。此外，术语“包括”以及其它形式的使用，例如“包含”、“含有”和“具有”，不是限制性的。本文使用的章节标题仅仅是为了组织的目的，而不应解释为对所述的主题的限制。
在这里所指的术语“取代”，包括复杂取代基(比如，苯基，芳基，杂烷基，杂芳基)，比较合适的是1至5个取代基，较好的是1到3个，最好是1到2个，可从取代基列表上 自由选择。
除非有特殊说明，烷基，包括饱和直链、支链烃基，C 1-C 9表示烷基的碳原子数为1-9的碳原子，同理的C 1-C 3比如表示烷基的碳原子数为1-3的碳原子，比如，C 1-C 6烷基包括甲基，乙基，丙基，异丙基，n-丁基，异丁基，仲-丁基，叔-丁基，n-戊基，3-(2-甲基)丁基，2-戊基，2-甲基丁基，新戊基，n-己基，2-己基和2-甲基戊基等。烷氧基由先前描述的直链或支链烷基与-O-形成的烷基-O-基团。类似的，烯基和炔基包括直链，支链烯基或炔基。
环烷基，指碳原子形成的环状基团，例如，C 3-C 7的环烷基可以包括环丙基、环丁基、环戊基、环己基、环庚基，类似的，同样包括环状烯基。
在这里使用的术语“芳基”，除非有特别说明，指的是未被取代的或已被取代的芳香基，例如苯基，萘基，蒽基。
“被一至两个氧原子氧化”是指硫原子被一个氧原子氧化形成硫和氧之间以双键连接，或被两个氧原子氧化形成硫和两个氧之间以双键连接。
在这里使用的术语“杂环基”，除非有特殊说明，代表未被取代的或已被取代的稳定的3至8元单环饱和环体系，它们由碳原子以及从N，O，S中选的1至3个杂原子组成，其中N，S杂原子可以被随意氧化，N杂原子还可以被随意季铵化。这类杂环的例子包括(但并不局限于)氮杂环丁烷基，吡咯烷基，四氢呋喃基，四氢噻唑基，四氢吡喃基，吗啉基，硫代吗啉基，哌啶基，哌嗪基，氧化哌嗪基，氧化哌啶基，二氧环戊烷基，二氧环己烷基四氢咪唑基，四氢噁唑基，硫代吗啉亚砜，硫代吗啉砜以及噁二唑基。
在这里使用的术语“杂芳基”，除非有特别说明，代表未被取代或已被取代的稳定的5或6元单环芳香环体系，也可以代表未被取代或已被取代的9或10个环原子的苯稠杂芳环体系或二环杂芳环体系，它们由碳原子和由1至3个从N，O，S中选择的杂原子组成，其中N、S杂原子可以被氧化，N杂原子还可以被季铵化。杂芳基可以和任何杂原子或碳原子连接组成一个稳定的结构。杂芳基包括但并不局限于噻吩基，呋喃基，咪唑基，吡咯基，噻唑基，噁唑基，异噁唑基，吡喃基，吡啶基，哌嗪基，嘧啶基，吡嗪，哒嗪基，吡唑基，噻二唑基，三唑基，吲哚基，氮杂吲哚基，吲唑基，氮杂吲唑基，苯并咪唑基，苯并呋喃基，苯并噻吩基，苯并异噁唑基，苯并噁唑基，苯并吡唑基，苯并噻唑基，苯并噻二唑基，苯并三唑基，腺嘌呤基，喹啉基或异喹啉基。
术语“羰基”指的是-C(O)-基。
无论何时术语“烷基”或“芳基”或任何它们的前缀词根出现在一个取代物的名称中(例如，芳烷基，二烷基氨)，它将被认为包含了以上为“烷基”和“芳基”而给出的那些限制。碳原子的指定数量(比如，C 1-C 6)将独立的表示在一个烷基部分或在一个更大的取代基中的烷基部分(其中烷基作为其前缀词根)中的碳原子的数量。
本发明还提供了制备相应化合物的方法，可以使用多种合成方法制备本文所述的化合物，包括下述的方法，本发明的化合物或者其药学上可接受的盐，异构体或水合物可以使用下述方法与有机化学合成领域已知的合成方法，或通过本领域技术人员理解对这些方法的变化方法合成，优选方法包括但不限于下述方法。
在一个方案中，本发明式(I)化合物由式(II＇)化合物与式(III＇)或式(III)反应制备，其中Q、G、Z、L、R 1、R 2、R 3、R 4和R 5如前文所述。
Figure PCTCN2019073260-appb-000011
本发明进一步提供了制备式(I)化合物中间体，即式(II＇)所示的化合物，其中，Q、G、Z、R 1、R 2、R 3和R 4如前文所定义，
Figure PCTCN2019073260-appb-000012
本发明化合物可以通过如下方法或本领域技术人员已知的技术方案制备，
Figure PCTCN2019073260-appb-000013
Figure PCTCN2019073260-appb-000014
步骤1)进行硝化反应，优选的，硝化反应条件为硝酸和醋酸。
步骤2)进行硝基还原反应，硝基还原采用本领域技术人员常规操作进行；
优选的，硝基还原反应的条件包含但不限于氢气与雷尼镍、氢气与钯碳、酸性条件下铁粉或锌粉或氯化亚锡；
步骤3)中1-(8-甲氧基-6-氨基-2,3-d二氢苯并[b][1,4]二噁烷-5-)乙-1-酮与甲酸甲酯或甲酸乙酯在有机溶剂中，碱的催化下得到10-羟基-5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]-喹啉，其中所述的有机溶剂包含但不限于二氧六环、四氢呋喃、叔丁醇、乙醇、甲醇的其中一个或者两个以上的组合；所述的碱包含但不限于叔丁醇钠、叔丁醇钾、甲醇钠、乙醇钠；该反应也可在加热条件下进行，加热的温度为室温至回流。
步骤4)中10-羟基-5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]-喹啉与氯化试剂在有机溶剂中反应制备10-氯-5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]-喹啉，其中所述的氯化试剂为三氯氧磷；所述的有机溶剂包含但不限于苯、甲苯、氯苯、二甲苯的其中一个或者两个以上的组合；该反应也可在有机碱存在的条件下进行，所述的有机碱为三乙胺或者二异丙基乙基胺。
步骤4a)中10-氯-5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]-喹啉在有机溶剂中，路易斯酸的作用下得到5-羟基-10-氯-2,3-二氢-[1,4]二噁烷并[2,3-f]-喹啉，其中所述的路易斯酸为三溴化硼或三氯化硼；有机溶剂为二氯甲烷。
步骤4b)中5-羟基-10-氯-2,3-二氢-[1,4]二噁烷并[2,3-f]-喹啉与R 1X在有机溶剂中制备式III-A所示化合物，其中R 1如前文所定义；有机溶剂包含但不限于四氢呋喃、二氧六环、DMF、DMA、DMSO、乙腈之一或者两者以上的组合；R 1X中的X为氯、溴、碘、甲磺酸酯、对甲苯磺酸酯或三氟甲磺酸酯。
步骤5)将式III-A所示化合物在有机溶剂中，与式V＇混合加热至100℃至140℃得到IV＇所示化合物；所述的有机溶剂选自甲苯、氯苯、二甲苯、DMF、DMA、DMSO的其中一个或者两个以上的组合。
步骤6)进行硝基还原反应，硝基还原采用本领域技术人员可以常规进行操作；
优选的，硝基还原反应条件包含但不限于氢气与雷尼镍、氢气与钯碳、酸性条件下铁粉，锌粉或氯化亚锡；
步骤7)在一个优选的方案中，式(III＇)所示化合物与式(II＇-A)所示化合物反应时，其中式(III＇)可与酰化试剂反应，再与式(II＇-A)进行反应。
优选地，所述的酰化试剂包括但不限于三氯氧磷、二氯亚砜、草酰氯、三氯化磷或五氯化磷中一种或两种以上的组合。
在另一个实施方案中，式(III＇)所示化合物，在缩合剂存在下，与式(II＇-A)所示化合物反应，得到式(I-C)所示化合物，
优选地，所述缩合剂包括但不限于碳二亚胺型缩合剂，鎓盐类缩合剂，有机磷类缩合剂及其他类别缩合剂的一种或两种以上，优选N,N-二环己基碳二亚胺(DCC)，N,N-二异丙基碳二亚胺(DIC)，羟基苯并三唑(HOBt)，N,N-二异丙基乙胺(DIEA)，1-羟基-7-偶氮苯并三氮唑(HOAt)，O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU)，苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)，2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU)、6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(HCTU)，2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)，丙基磷酸酐(T3P)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)，1-乙基(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC)，六氟磷酸苯并三唑-1-基-氧基三吡咯烷鏻(PyBOP)，(3H-1,2,3三唑并[4,5-b]吡啶-3氧基)三-1-吡咯烷基鏻六氟磷酸盐(PyAOP)中一种或两种以上的组合；
优选地，此步骤可在有机碱中进行，所述的有机碱包含但不限于三乙胺、二异丙基乙基胺，吡啶，4-二甲氨基吡啶，2,6-二甲基吡啶，1,8-二氮杂二环十一碳-7-烯或N-甲基吗啉一种或两种以上的组合。
当R 1为-CH 3时，可省略步骤4a和步骤4b，完成步骤4)后进行步骤5)的操作。
同时，例如步骤4a和步骤4b与步骤5的顺序并不固定，例如也可以先进行步骤5，再进行步骤4a和步骤4b。
很清楚，式I的化合物、异构体、晶型或前药及其可药用盐可以存在溶剂化形式和非溶剂化形式。例如溶剂化形式可以是水溶形式。本发明包括所有这些溶剂化的和未溶剂化的形式。
本发明的化合物可能有不对称的碳原子，根据它们的理化差异，通过已知技术上已成熟的方法，比如，通过色谱或分步结晶法，这种非对映异构的混合物可以被分离成单一的非对映异构体。对映异构体的分离可通过先用适当有旋光活性的化合物进行反应，把对映异构的混合物转化成非对映异构的混合物，分离非对映异构体，再把单一非对映异构体转化(水解)成相应的纯的对映异构体。所有这样的异构体，包括非对映异构体混合物和纯对映体被认为是该发明的一部分。
作为活性成分的本发明的化合物，以及制备该化合物的方法，都是本发明的内容。而且，一些化合物的晶型形式可以作为多晶体存在，这种形式也可以被包括在目前的发明里。另外，一些化合物可以和水(即水合物)或普通的有机溶剂一起形成溶剂化物，这种溶剂化物也被包括在此项发明的范畴内。
本发明的化合物可以以游离的形式用于治疗，或者在适当情况下以药学上可接受的盐或其它衍生物的形式用于治疗。如本文所用，术语“药学上可接受的盐”是指本发明的化合物的有机盐及无机盐，此盐适用于人类和低等动物，无过度毒性、刺激性、过敏反应等， 具有合理的利益/风险比。胺，羧酸，膦酸盐，和其它类型的化合物的药学上可接受的盐在所属领域中是众所周知的。该盐可以由本发明的化合物与合适的游离碱或酸反应而成。包括但不限于，与无机酸如盐酸、氢溴酸、磷酸、硫酸、高氯酸或与有机酸如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸、丙二酸形成的盐，或通过使用本领域熟知的方法，例如离子交换法，来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、己酸盐、氢碘酸盐、2‐羟基乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、甲烷磺酸盐、2‐萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、过3‐苯基丙酸盐、磷酸盐、苦味酸盐、丙酸盐、硬脂酸盐、硫酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐等。代表性的碱或碱土金属盐包括钠、锂、钾、钙、镁等。其他药学上可接受的盐包括适当的无毒的铵、季铵，和使用诸如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根，低级烷基磺酸盐和芳基磺酸盐形成的胺基阳离子。
另外，本文所用术语“前药”是指一个化合物在体内可以转化为本发明式(I)所示的化合物。此转化受前体药物在血液中水解或在血液或组织中经酶转化为母体化合物的影响。
本发明的药物组合物包含本文所述结构式(I)化合物或其药学上可接受的盐、激酶抑制剂(小分子，多肽，抗体等)、免疫抑制剂、抗癌药、抗病毒剂、抗炎剂、抗真菌剂、抗生素或抗血管过度增生化合物的另外的活性剂；以及任何药学上可接受的载体、佐剂或赋形剂。
本发明的化合物可以作为单独使用，也可以与一种或多种其它本发明的化合物或与一种或多种其它药剂联合使用。当联合给药时，治疗剂可以配制成同时给药或顺序地在不同的时间给药，或者所述治疗剂可以作为单一组合物给药。所谓“组合疗法”，指的是使用本发明的化合物与另一种药剂一起使用，给药方式为每种药剂同时共同给药或每种药剂顺序给药，无论哪种情况，目的都是要达到药物的最佳效果。共同给药包括同时递送剂型，以及每种化合物分别的单独剂型。因此，本发明的化合物的给药可以与已知的本领域的其他疗法同时使用，例如，在癌症治疗中使用放射治疗或细胞生长抑制剂、细胞毒性剂、其它抗癌剂等附加疗法来改善癌症状。本发明并不限于给药的顺序；本发明的化合物可以先前施用，同时施用，或在其他抗癌剂或细胞毒性剂之后施用。
为了制备这一发明的药学成分，作为其活性成分的分子式(I)的一种或多种化合物或盐类可紧密的与药学载体混合在一起，这是根据传统的制药配料技术而进行的，其中的载体可根据按不同的给药方式(例如，口服或肠外给药)设计好的制备形式而采用多种多样的形式。适当的药学上可接受的载体在技术上是众所周知的。对一些这类药学可接受的载体的描述可以在《药学赋形剂手册》里找到，该书由美国药学会和英国药学社联合出版。
本发明药物组合物可以有以下形式，比如说，适合口服给药，例如药片，胶囊，药丸，药粉，持续释放的形式，溶液或悬浮液；用于胃肠外注射如透明液，悬浮液，乳状液；或者用于局部用药如膏，霜；亦或作为栓剂用于直肠给药。药学成分也可以单位剂量的形式适合用于精确剂量的一次性给药。该药学成分将包括一种传统的药学载体或赋形剂以及根据目前的发明制成的作为活性成分的化合物，另外，也可以包括其他的医学或药学制剂，载体，辅助剂，等等。
治疗性化合物也可给于哺乳动物而非人类。给一个哺乳动物所用的药物剂量将取决于该动物的种类以及它的疾病状况或其所处的失调状态。治疗性化合物可以以胶囊，大丸药，药片药水的形式喂给动物。也可以通过注射或灌输的方式让治疗性化合物进入动物体内。我们根据符合兽医实践标准的传统的方式制备好这些药物形式。作为一种可选择的方式，药学合成药可以同动物饲料混合在一起喂给动物，因此，浓缩的饲料添加剂或预拌和料可以备以混合普通的动物饲料。
本发明的又一目的是在于提供一种用于治疗有需要的受试者中癌症的方法，其包括给受试者施用含本发明的化合物的组合物的治疗有效量的一种方法。
本发明还包括本发明的化合物或其药学上可接受的衍生物的使用，制造用于治疗癌症(包括非实体瘤、实体瘤、原发性或转移性癌症，如本文别处所指出和包括癌症具有抗性或难治的一种或多种其它治疗)以及其它疾病(包括但不限于眼底疾病、银屑病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化等)的药剂。所述癌症包括但不限于：非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌中的任一种。
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合具体实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。下面提供的实施例可以更好的说明本发明，除非特别说明，所有的温度为℃。
中间体：10-氯-5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉的制备
Figure PCTCN2019073260-appb-000015
步骤1)1-(8-甲氧基-6-硝基-2,3-二氢苯并[b][1,4]二噁烷-5-基)乙基-1-酮的制备
将1-(8-甲氧基-2,3-二氢苯并[b][1,4]二噁烷-5-基)乙基-1-酮(20.8g,100mmol)，硝酸(22mL)和醋酸(44mL)置于圆底烧瓶搅拌至反应完毕，倒入碎冰中，抽滤，得黄色固体产品16.5克，产率66％。 1HNMR(400MHz,Chloroform-d)δ7.37(s,1H),4.43(dd,J＝5.4,2.7Hz,2H),4.35(dd,J＝5.3,2.7Hz,2H),3.98(s,3H),2.57(s,3H)；MS:254[M+H] +。
步骤2)1-(8-甲氧基-6-氨基-2,3-二氢苯并[b][1,4]二噁烷-5-基)乙基-1-酮的制备
将1-(8-甲氧基-6-硝基-2,3-二氢苯并[b][1,4]二噁烷-5-基)乙基-1-酮(16.5g,65mmol)置于反应瓶中，加入钯碳(2g)在氢气环境下搅拌至反应完毕，抽滤浓缩得类白色固体产品13.7克，产率95％。 1HNMR(400MHz,DMSO-d6)δ6.90(s,2H),5.96(s,1H),4.32–4.25(m,2H),4.18–4.09(m,2H),3.72(s,3H),2.41(s,3H)；MS:224[M+H] +。
步骤3)10-羟基-5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉的制备
将1-(6-氨基-8-甲氧基-2,3-二氢苯并[b][1,4]二噁烷-5-基)乙基-1-酮(13.7g,62mmol)与甲酸乙酯(27.5g,372mmol)溶于二氧六环中，加入叔丁醇钠(17.8g,186mmol)搅拌至原料消失，加入甲醇10毫升继续搅拌至反应完毕，盐酸中和反应液至中性后抽滤、浓缩、得类白色固体产品14.4克，产率99％。 1HNMR(400MHz,DMSO-d6)δ11.26(s,1H),7.59(d,J＝7.3Hz,1H),6.55(s,1H),5.77(d,J＝7.2Hz,1H),4.34–4.13(m,4H),3.82(s,3H)；MS:234[M+H] +。
步骤4)10-氯-5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉的制备
将10-羟基-5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉(14.4g,61mmol)置于反应瓶中，加入甲苯溶解，之后加入三乙胺(42mL,305mmol)、三氯氧磷(17mL,183mmol)加热搅拌至反应完毕，蒸去溶剂后所得固体用碳酸氢钠水溶液洗涤后抽滤，得类白色固体14.1克，产率92％。 1HNMR(400MHz,DMSO-d 6)δ8.51(d,J＝4.9Hz,1H),7.38(d,J＝4.8Hz,1H),7.12(s,1H),4.49–4.29(m,4H),3.93(s,3H)；MS:252[M+H] +。
中间体1-((4-氟苯基)氨基甲酰基)环丙烷-1-羧酸的制备
Figure PCTCN2019073260-appb-000016
将1,1-环丙基二羧酸(1.04克)加入无水四氢呋喃(20mL)中，在冰水浴条件下向搅拌的悬浊液中缓慢滴加三乙胺(0.84g)并搅拌半小时,随后在0℃条件下逐滴加入二氯亚砜(1.1g)， 加完继续搅拌1小时，随后分别加入三乙胺(0.8g)，四氟苯胺(0.9g)的四氢呋喃(10mL)溶液，反应搅拌2小时完毕；浓缩，溶于1N的氢氧化钠，乙酸乙酯萃取，取水相用1N的稀盐酸溶液调节pH至2.0，继续搅拌半小时，过滤得白色固体产物1.1g，收率62％，MS：224[M+H] +。
中间体1-((4-氟苯基)氨基甲酰基)环丙烷-1-甲酰氯的制备
Figure PCTCN2019073260-appb-000017
1-((4-氟苯基)氨基甲酰基)环丙烷-1-羧酸(111mg，0.5mmol)的二氯亚砜(2mL)加热回流搅拌反应，反应溶液澄清后继续回流1小时，冷却，浓缩得到浅黄色固体产物120mg，收率100％；
实施例1.N-(4-氟苯基)-N-(4-((5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]-喹啉-10-基)氧基)苯基)环丙烷-1,1-二甲酰胺的制备
Figure PCTCN2019073260-appb-000018
步骤1)：将10-氯-5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉(251mg,1mmol)与对硝基苯酚(139mg,1mmol)置于反应瓶中，加入氯苯，加热至回流搅拌至反应完毕。冷却后抽滤，所得固体用碳酸钾水溶液洗涤后得浅黄色固体(5-甲氧基-10-(4-硝基苯氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉)250毫克，产率71％。MS:355[M+H] +。
步骤2)：将步骤1)所得产品(250mg,0.7mmol)置于反应瓶中，加入甲醇，雷尼镍(250mg)，在氢气环境下搅拌至反应完毕，抽滤、浓缩得类白色固体产品(4-((5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯胺)226毫克，产率99％。MS:325[M+H] +。
步骤3)：将步骤2)所得产品(226mg,0.7mmol)和1-((4-氟苯基)氨基甲酰基)环丙烷-1-羧酸置于反应瓶中，加入N,N-二甲基甲酰胺溶解，随后加入2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)(380mg,1mmol)和二乙基异丙基胺(0.25mL,1.5mmol)，搅拌至反应完毕，加入碳酸钠水溶液洗涤、抽滤、柱层析得白色固体296毫克，产率80％。 1HNMR(300MHz,DMSO-d 6)δ10.19–10.02(m,2H),8.43(d,J＝5.2Hz,1H),7.78–7.67(m,2H),7.67–7.56(m,2H),7.22–7.01(m,5H),6.42(d,J＝5.3Hz,1H),4.38–4.25(m,4H),3.92(s,3H),1.50–1.40(m,4H).MS:530[M+H] +。
实施例2.N-(3-氟-4-((5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]-喹啉-10-基)氧基)苯基)-N-(4- 氟苯基)环丙烷-1,1-二甲酰胺的制备
Figure PCTCN2019073260-appb-000019
步骤1)10-(2-氟-4-硝基苯氧基)-5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]-喹啉的制备
参考实施例1步骤1)操作，以相同摩尔当量的2-氟-4硝基苯酚替代对硝基苯酚即可。 1HNMR(400MHz,DMSO-d 6)δ8.67(d,J＝5.0Hz,1H),8.44–8.27(m,1H),8.13–7.93(m,1H),7.19(s,1H),7.07(d,J＝4.9Hz,1H),6.98(t,J＝8.7Hz,1H),4.31–4.18(m,2H),4.16–4.06(m,2H),3.95(s,3H)；MS:373[M+H] +。
步骤2)3-氟-4-((5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯胺的制备
参考实施例1步骤2)操作，以相同摩尔当量的10-(2-氟-4-硝基苯氧基)-5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉替代5-甲氧基-10-(4-硝基苯氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]-喹啉即可。 1HNMR(400Hz,DMSO-d6)δ8.38(d,J＝5.2Hz,1H),7.05(s,1H),6.99(t,J＝9.0Hz,1H),6.61–6.49(m,1H),6.49–6.38(m,1H),6.33(d,J＝5.3Hz,1H),5.53–5.37(m,2H),4.36–4.38(m,4H),3.92(s,3H)；MS:343[M+H] +。
步骤3)N-(3-氟-4-((5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的制备
参考实施例1步骤3)操作，以相同摩尔当量的3-氟-4-((5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯胺替代4-((5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯胺即可。 1HNMR(400MHz,DMSO-d 6)δ10.30(s,1H),9.97(s,1H),8.35(d,J＝5.2Hz,1H),7.94–7.69(m,1H),7.64–7.52(m,2H),7.48–7.32(m,1H),7.19(t,J＝9.0Hz,1H),7.09(t,J＝8.8Hz,2H),7.01(s,1H),6.32(d,J＝5.2Hz,1H),4.28(s,4H),3.85(s,3H),1.55–1.28(m,4H).MS:548[M+H] +。
实施例3.N-(2-氟-4-((5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的制备
步骤1)10-(3-氟-4-硝基苯氧基)-5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉的制备
参考实施例1步骤1)操作，以相同摩尔当量的3-氟-4硝基苯酚替代对硝基苯酚即可。MS:373[M+H] +。
步骤2)2-氟-4-((5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯胺的制备
参考实施例1步骤2)操作，以相同摩尔当量的10-(3-氟-4-硝基苯氧基)-5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉替代5-甲氧基-10-(4-硝基苯氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉即可。 1HNMR(400MHz,DMSO-d6)δ8.38(d,J＝5.2Hz,1H),7.04(s,1H),6.98–6.91(m,1H),6.89–6.79(m,1H),6.78–6.67(m,1H),6.37(d,J＝5.2Hz,1H),5.14(s,2H),4.43– 4.30(m,4H),3.91(s,3H)；MS:343[M+H] +。
步骤3)N-(2-氟-4-((5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的制备
Figure PCTCN2019073260-appb-000020
参考实施例1步骤3)操作，以相同摩尔当量的2-氟-4-((5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯胺替代4-((5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯胺即可。 1HNMR(400MHz,DMSO-d 6)δ10.49(s,1H),9.97(s,1H),8.50(d,J＝5.1Hz,1H),7.92–7.82(m,1H),7.65–7.57(m,2H),7.25–7.06(m,4H),6.89–6.84(m,1H),6.63(d,J＝5.1Hz,1H),4.33–4.22(m,4H),3.92(s,3H),1.63–1.52(m,4H)；MS:548[M+H] +。
实施例4.N-(4-氟苯基)-N-(4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)环丙烷-1,1-二甲酰胺的制备
Figure PCTCN2019073260-appb-000021
步骤1)将10-氯-5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉(251mg,1mmol)溶于二氯甲烷中，滴入1摩尔每升的三溴化硼的二氯甲烷溶液(3mL,3mmol)，搅拌至反应完毕。浓缩得浅黄色固体产品(5-羟基-10-氯-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉)236mg，产率99％。MS:238[M+H] +。
步骤2)将步骤1)所得产品(236mg,1mmol)溶于N,N-二甲基甲酰胺，加入4-(3-氯丙基)吗啉(163mg,1mmol)和碳酸钾(414mg,3mmol)，加热搅拌至反应完毕。加入水和乙酸乙酯萃取，有机相浓缩后柱层析得类白色固体(10-氯-5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]-喹啉)291mg，产率80％。 1H NMR(400MHz,DMSO-d 6)δ8.50(d,J＝4.8Hz,1H),7.37(d,J＝4.8Hz,1H),7.10(s,1H),4.47–4.30(m,4H),4.17(t,J＝6.4Hz,2H),3.59(t,J＝4.6Hz,4H),2.45(t,J＝7.1Hz,2H),2.39(d,J＝4.5Hz,4H),1.97-1.95(m,2H).MS:365[M+H] +。
步骤3)5-(3-吗啉丙氧基)-10-(4-硝基苯氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉的制备
参考实施例1步骤1)操作，以相同摩尔当量的10-氯-5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉替代10-氯-5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉。MS:468[M+H] +。
步骤4)4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]-喹啉-10-基)氧基)苯胺的制备
参考实施例1步骤2)操作，以相同摩尔当量的5-(3-吗啉丙氧基)-10-(4-硝基苯氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉替代5-甲氧基-10-(4-硝基苯氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉即可。 1H NMR(400MHz,DMSO-d6)δ8.33(d,J＝5.3Hz,1H),7.00(s,1H),6.84(d,J＝8.1Hz,2H),6.65(d,J＝8.2Hz,2H),6.29(d,J＝5.3Hz,1H),5.10(s,2H),4.35(s,4H),4.20–4.11(m,2H),3.62–3.56(m,4H),2.48–2.36(m,6H),2.00–1.91(m,2H).MS:438[M+H] +。
步骤5)N-(4-氟苯基)-N-(4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)环丙烷-1,1-二甲酰胺的制备
参考实施例1步骤3)操作，以相同摩尔当量的4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯胺替代4-((5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯胺即可。 1HNMR(400MHz,DMSO-d 6)δ10.14(s,1H),10.07(s,1H),8.41(d,J＝5.3Hz,1H),7.70(d,J＝8.6Hz,2H),7.63(dd,J＝9.1,5.1Hz,2H),7.18–7.12(m,2H),7.11–7.03(m,3H),6.41(d,J＝5.2Hz,1H),4.37–4.26(m,4H),4.26–4.10(m,2H),3.68–3.54(m,4H),2.44–2.39(m,4H),2.02–1.92(m,2H),1.52–1.41(m,6H)； 13C NMR(101MHz,DMSO-d6)δ168.6,168.5,161.3,151.7,151.1,149.6,146.7,138.2,136.0,135.6,132.28,122.9,122.8,122.6,120.7,115.6,115.3,108.7,105.7,102.2,67.1,66.7,64.4,63.9,55.3,53.8,31.9,26.2,15.8；MS:643[M+H] +。
实施例5.N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的制备
步骤1至步骤2与实施例4的制备的步骤1至步骤2相同。
步骤3)10-(2-氟-4-硝基苯氧基)-5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉的制备
Figure PCTCN2019073260-appb-000022
参考实施例4步骤3)操作，以相同摩尔当量的2-氟-4硝基苯酚替代对硝基苯酚即可。MS:486[M+H] +。
步骤4)3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯胺的制备
Figure PCTCN2019073260-appb-000023
参考实施例1步骤2)操作，以相同摩尔当量的10-(2-氟-4-硝基苯氧基)-5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉替代5-甲氧基-10-(4-硝基苯氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉即可。 1H NMR(400MHz,DMSO-d 6)δ8.37(d,J＝5.3Hz,1H),7.08–6.88(m,2H),6.60–6.49(m,1H),6.48–6.40(m,1H),6.32(d,J＝5.2Hz,1H),5.44(s,2H),4.37–4.39(m,4H),4.16(t,J＝6.4Hz,2H),3.59(t,J＝4.6Hz,4H),2.46(d,J＝7.0Hz,2H),2.39(s,4H),1.95–1.97(m,2H)；MS:456[M+H] +。
步骤5)N-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的制备
Figure PCTCN2019073260-appb-000024
参考实施例1步骤3)操作，以相同摩尔当量的3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]-喹啉-10-基)氧基)苯胺替代4-((5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯胺即可。 1HNMR(400MHz,DMSO-d6)δ10.32(s,1H),10.00(s,1H),8.41(d,J＝5.2Hz,1H),7.98–7.79(m,1H),7.67–7.59(m,2H),7.53–7.39(m,1H),7.24(t,J＝9.0Hz,1H),7.18–7.11(m,2H),7.06(s,1H),6.43–6.34(m,1H),4.37-4.34(m,4H),4.17(t,J＝6.4Hz,2H),3.59(t,J＝4.6Hz,4H),2.46(t,J＝7.1Hz,2H),2.39(d,J＝4.6Hz,4H),2.08–1.79(m,2H),1.47(d,J＝2.3Hz,4H)；13C NMR(101MHz,DMSO-d6)δ168.7,168.4,160.9,151.8,149.6,146.6,138.2,133.8,129.8,127.7,123.4,122.9,115.6,115.4,107.9,102.2,67.1,66.7,64.4,63.97,55.2,53.8,32.3,26.2,15.7；MS:661[M+H] +。
实施例6.N-(2-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的制备
步骤1至步骤2与实施例4的制备的步骤1至步骤2相同。
步骤3)10-(3-氟-4-硝基苯氧基)-5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉的制备
Figure PCTCN2019073260-appb-000025
参考实施例4步骤3)操作，以相同摩尔当量的3-氟-4硝基苯酚替代对硝基苯酚即可。 1H NMR(400MHz,DMSO-d 6)δ8.69(s,1H),8.29–8.09(m,1H),7.51–7.35(m,1H),7.22–7.08(m,2H),6.97–6.72(m,1H),4.33–4.16(m,4H),4.12–3.98(m,2H),3.65–3.54(m,4H),2.47–2.26(m,6H),2.05–1.82(m,2H).MS:486[M+H] +。
步骤4)2-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯胺的制备
Figure PCTCN2019073260-appb-000026
参考实施例1步骤2)操作，以相同摩尔当量的10-(3-氟-4-硝基苯氧基)-5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]-喹啉替代5-甲氧基-10-(4-硝基苯氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉即可。 1H NMR(400MHz,DMSO-d6)δ8.37(d,J＝5.2Hz,1H),7.02(s,1H),6.98–6.92(m,1H),6.89–6.80(m,1H),6.78–6.70(m,1H),6.36(d,J＝5.2Hz,1H),5.13(s,2H),4.35(s,4H),4.15(t,J＝6.5Hz,2H),3.59(t,J＝4.6Hz,4H),2.47(t,J＝7.2Hz,2H),2.39(d,J＝4.9Hz,4H),1.95–1.97(m,2H).MS:456[M+H] +。
步骤5)N-(2-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的制备
Figure PCTCN2019073260-appb-000027
参考实施例1步骤3)操作，以相同摩尔当量的2-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯胺替代4-((5-甲氧基-2,3-二氢-[1,4]二噁烷并[2,3-f]喹啉-10-基)氧基)苯胺即可。 1H NMR(400MHz,DMSO-d 6)δ10.48(s,1H),9.97(s,1H),8.50(d,J＝5.1Hz,1H),7.86(s,1H),7.71–7.48(m,2H),7.16(dd,J＝9.9,7.9Hz,2H),7.10(d,J＝10.5Hz,2H),6.95–6.80(m,1H),6.63(d,J＝5.1Hz,1H),4.34–4.28(m,2H),4.27-4.24(m,2H),4.17(t,J＝6.4Hz,2H),3.59(t,J＝4.6Hz,4H),2.46(t,J＝7.2Hz,2H),2.38(d,J＝4.8Hz,4H),1.95(q,J＝6.8Hz,2H),1.56-1.58(m,4H).MS:661[M+H] +。
实施例7.N-(4-((5-乙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000028
步骤1.10-氯-5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉(2.5g,10mmol)，2-氟-4-硝基苯酚(1.6g,10mmol)和碳酸钾(2.1g,15mmol)的DMF溶液(20mL)加热至80℃反应3小时，冷却，加水打浆，过滤干燥得类白色固体产物(10-(2-氟-4-硝基苯氧基)-5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉)3.5g,收率94％；
步骤2.将步骤1所得的产品(350mg，1mmol)加入到溴化氢的乙酸溶液(33％,5mL)，加热至90℃反应15小时，冷却，加入乙酸乙酯(15mL)打浆，过滤干燥得浅绿色固体(10-(2-氟-4-硝基苯氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-5-醇的溴化氢盐)3.8g，收率87％，MS:359[M+H] +；
步骤3.将步骤2所得的产品(440mg,1mmol)的DMF(5mL)溶液中分别加入溴乙烷(165mg,1.5mmol)和碳酸钾(280mg,2mmol)，加热至80℃，反应10小时，冷却，加水，乙酸乙酯萃取，饱和氯化钠溶液洗涤，干燥，浓缩，柱层析纯化得浅黄色固体产物(10-(2-氟-4-硝基苯氧基)-5-乙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉)320mg,收率83％；
步骤4.将步骤3所得的产品(320mg)的甲醇(30mL)溶液加入雷尼镍，在氢气氛围条件下室温搅拌反应3小时，过滤，洗涤，滤液浓缩得紫色固体产物(3-氟-4-((5-乙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯胺)290mg,收率81％,MS:357[M+H] +；
步骤5.向步骤4所得的产品(36mg，0.1mmol)的NMP溶液(1mL)中分别加入1-((4-氟苯基)胺基甲酰基)环丙基-1-甲酰氯(24mg,0.1mmol)的二氯甲烷(0.5mL)溶液和三乙胺(0.1mL)，室温搅拌反应5小时，加水淬灭，过滤得到浅黄色固体，由制备液相纯化得白色固体产物24mg，收率43％； 1H NMR(600MHz,DMSO-d 6)δ10.33(s,1H),10.00(s,1H),8.41(d,J＝5.2Hz,1H),7.86(d,J＝13.1Hz,1H),7.63(dd,J＝8.7,5.0Hz,2H),7.45(d,J＝8.9Hz,1H),7.25-7.13(m,3H),7.05(s,1H),6.39(d,J＝5.2Hz,1H),4.34(s,4H),4.25–4.10(m,2H),1.47(d,J＝3.9Hz,4H),1.41(t,J＝6.9Hz,3H).MS:562[M+H] +。
实施例8.N-(4-((5-(3-(二甲氨基)丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000029
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量二甲氨基丙基氯代替溴乙烷进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),9.99(s,1H),8.41(d,J＝5.2Hz,1H),7.85(dd,J＝13.2,2.4Hz,1H),7.68–7.56(m,2H),7.45(d,J＝8.7Hz,1H),7.23(t,J＝9.0Hz,1H),7.15(t,J＝8.9Hz,2H),7.05(s,1H),6.40(d,J＝5.2Hz,1H),4.35(s,4H),4.16(t,J＝6.5Hz,2H),2.42-2.32(m,2H),2.20(s,6H),1.94(t,J＝6.9Hz,2H),1.47(d,J＝2.3Hz,4H).MS:619[M+H] +。
实施例9.N-(4-((5-(3-(哌啶-1-基)丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000030
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量(哌啶-1-基)丙基氯代替溴乙烷进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),9.99(s,1H),8.41(d,J＝5.2Hz,1H),7.85(d,J＝13.1Hz,1H),7.69–7.59(m,2H),7.45(d,J＝9.0Hz,1H),7.23(t,J＝9.0Hz,1H),7.20–7.10(m,2H),7.05(s,1H),6.40(d,J＝5.2Hz,1H),4.35(s,4H),4.16(t,J＝6.5Hz,2H),2.41(d,J＝29.1Hz,6H),1.95(t,J＝7.4Hz,2H),1.62–1.44(m,8H),1.39(Br,2H).MS:659[M+H] +。
实施例10.N-(3-氟-4-((5-(2-甲氧基乙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000031
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量甲氧基乙基溴代替溴乙烷进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.32(s,1H),9.99(s,1H),8.41(d,J＝5.2Hz,1H),7.86(dd,J＝13.3,2.5Hz,1H),7.72–7.56(m,2H),7.50–7.36(m,1H),7.24(t,J＝9.0Hz,1H),7.18–7.11(m,2H),7.08(s,1H),6.40(dd,J＝5.2,1.0Hz,1H),4.35(s,4H),4.29–4.17(m,2H),3.79–3.67(m,2H),3.34(s,3H),1.47(d,J＝2.0Hz,4H).MS:592[M+H] +。
实施例11.N-(4-((5-(环丙基甲氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000032
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量环丙基甲基溴代替溴乙烷进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.31(s,1H),9.99(s,1H),8.40(d,J＝5.2Hz,1H),7.85(dd,J＝13.3,2.4Hz,1H),7.63(dd,J＝9.1,5.1Hz,2H),7.45(d,J＝8.8Hz,1H),7.26–7.20(m,1H),7.15(t,J＝8.9Hz,2H),7.02(s,1H),6.39(d,J＝5.2Hz,1H),4.35(s,4H),3.97(d,J＝7.1Hz,2H),1.47(d,J＝2.1Hz,4H),1.36–1.25(m,1H),0.73–0.55(m,2H),0.43–0.31(m,2H).MS:588[M+H] +。
实施例12.N-(4-((5-(异丁基氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000033
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量异丁基溴代替溴乙烷进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.31(s,1H),9.99(s,1H),8.41(d,J＝5.2Hz,1H),7.85(dd,J＝13.3,2.4Hz,1H),7.69–7.57(m,2H),7.50–7.39(m,1H),7.23(t,J＝9.0Hz,1H),7.18–7.11(m,2H),7.05(s,1H),6.40(dd,J＝5.2,1.0Hz,1H),4.35(s,4H),3.90(d,J＝6.5Hz,2H),2.11(dt,J＝13.3,6.7Hz,1H),1.47(d,J＝2.0Hz,4H),1.03(d,J＝6.7Hz,6H).MS:590[M+H] +。
实施例13.N-(3-氟-4-((5-(3-羟基丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000034
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量3-溴丙醇代替溴乙烷进行反应得到白色固体产物； 1H NMR(600MHz,DMSO-d 6)δ10.32(s,1H),10.00(s,1H),8.41(dd,J＝5.2,0.9Hz,1H),7.86(d,J＝12.6Hz,1H),7.63(dd,J＝9.0,4.9Hz,2H),7.45(d,J＝9.0Hz,1H),7.24(t,J＝9.0Hz,1H),7.15(t,J＝8.9Hz,2H),7.06(s,1H),6.39(d,J＝5.2Hz,1H),4.60(t,J＝5.1Hz,1H),4.35(s,4H),4.19(t,J＝6.4Hz,2H),3.60(q,J＝5.9Hz,2H),1.95(t,J＝6.3Hz,2H),1.46(q,J＝3.3Hz,4H).MS:592[M+H] +。
实施例14.N-(3-氟-4-((5-(3-甲氧基丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000035
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量甲氧基丙基溴代替溴乙烷进行反应得到白色固体产物； 1H NMR(600MHz,DMSO-d 6)δ10.32(s,1H),10.00(s,1H),8.41(d,J＝5.2Hz,1H),7.99–7.81(m,1H),7.63(dd,J＝9.0,5.1Hz,2H),7.45(d,J＝9.0Hz,1H),7.24(t,J＝9.0Hz,1H),7.15(t,J＝8.9Hz,2H),7.06(s,1H),6.40(d,J＝5.2Hz,1H),4.35(s,4H),4.17(t,J＝6.4Hz,2H),3.51(t,J＝6.3Hz,2H),3.27(s,3H),2.03(t,J＝6.4Hz,2H),1.46(q,J＝3.4Hz,4H).MS:606[M+H] +。
实施例15.N-(3-氟-4-((5-(3-((2-甲氧基乙基)(甲基)氨基)丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000036
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量3-溴-N-(2-甲氧基乙基)-N-甲基丙基-1-胺代替溴乙烷进行反应得到白色固体产物； 1H NMR(600MHz,DMSO-d 6)δ10.33(s,1H),10.01(s,1H),8.41(d,J＝5.2Hz,1H),7.86(dd,J＝13.2,2.4Hz,1H),7.68–7.59(m,2H),7.45(dt,J＝8.8,1.6Hz,1H),7.24(t,J＝9.0Hz,1H),7.20–7.09(m,2H),7.05(s,1H),6.39(d,J＝5.2Hz,1H),4.35(s,4H),4.15(t,J＝6.4Hz,2H),3.41(t,J＝5.9Hz,2H),3.21(s,3H),2.52(td,J＝6.6,6.1,4.4Hz,4H),2.22(s,3H),1.93(q,J＝6.7Hz,2H),1.47(q,J＝3.3,2.9Hz,4H).MS:663[M+H] +。
实施例16.N-(3-氟-4-((5-异丙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000037
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量异丙基溴代替溴乙烷进行反应得到白色固体产物； 1H NMR(600MHz,DMSO-d 6)δ10.32(s,1H),10.00(s,1H),8.40(d,J＝5.2Hz,1H),7.86(dd,J＝13.2,2.5Hz,1H),7.65–7.62(m,2H),7.45(dd,J＝8.9,1.9Hz,1H),7.22(d,J＝9.1Hz,1H),7.17–7.13(m,2H),7.06(s,1H),6.38(d,J＝5.2Hz,1H),4.82–4.80(m,1H),4.34(s,4H),1.47(t,J＝3.5Hz,4H),1.36(d,J＝6.0Hz,6H).MS:576[M+H] +。
实施例17.N-(3-氟-4-((5-((四氢呋喃-3-基)氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000038
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量对甲苯磺酸四氢呋喃-3-酯代替溴乙烷进行反应得到白色固体产物； 1H NMR(600MHz,DMSO-d 6)δ10.33(s,1H),10.00(s,1H),8.42(d,J＝5.2Hz,1H),7.86(dd,J＝13.2,2.4Hz,1H),7.67–7.57(m,2H),7.45(dd,J＝8.4,2.1Hz,1H),7.24(t,J＝9.0Hz,1H),7.15(t,J＝8.9Hz,2H),7.03(s,1H), 6.40(d,J＝5.2Hz,1H),5.24–5.16(m,1H),4.35(s,4H),3.96(dd,J＝10.3,4.5Hz,1H),3.92–3.84(m,2H),3.78(td,J＝8.3,4.7Hz,1H),2.36–2.29(m,1H),2.09–2.03(m,1H),1.47(q,J＝3.3Hz,4H).MS:604[M+H] +。
实施例18.N-(3-氟-4-((5-((四氢吡喃-4-基)氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000039
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量对甲苯磺酸四氢吡喃-4-酯代替溴乙烷进行反应得到白色固体产物； 1H NMR(600MHz,DMSO-d 6)δ10.33(s,1H),10.00(s,1H),8.41(d,J＝5.2Hz,1H),7.90–7.81(m,1H),7.63(dd,J＝9.0,5.1Hz,2H),7.46(d,J＝8.8Hz,1H),7.24(t,J＝9.1Hz,1H),7.18–7.14(m,3H),6.39(d,J＝5.2Hz,1H),4.80(dt,J＝9.0,4.7Hz,1H),4.35(s,4H),3.89(dt,J＝11.6,4.3Hz,2H),3.55(ddd,J＝12.0,9.8,2.7Hz,2H),2.07(d,J＝10.7Hz,2H),1.67(dtd,J＝13.2,9.3,4.1Hz,2H),1.50–1.39(m,4H).MS:618[M+H] +。
实施例19.N-(4-((5-(3-(4-乙酰基哌嗪-1-基)丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000040
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量4-乙酰基哌嗪-1-基丙基氯代替溴乙烷进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),9.93(s,1H),8.35(d,J＝5.2Hz,1H),7.79(dd,J＝13.3,2.4Hz,1H),7.64–7.49(m,2H),7.42–7.33(m,1H),7.17(t,J＝9.1Hz,1H),7.12–7.05(m,2H),7.01(s,1H),6.36–6.25(m,1H),4.29(s,4H),4.12(t,J＝6.4Hz,2H),3.38(s,4H),2.48(br,2H),2.41–2.11(m,4H),1.93(s,5H),1.40(q,J＝3.2Hz,4H).MS:702[M+H] +。
实施例20.N-(4-((5-(氰基甲氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000041
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量溴乙腈代替溴乙烷进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.34(s,1H),10.00(s,1H),8.47(d,J＝5.2Hz,1H),7.87(dd,J＝13.3,2.4Hz,1H),7.68–7.59(m,2H),7.50–7.43(m,1H),7.33–7.23(m,2H),7.20–7.10(m,2H),6.49–6.43(m,1H),5.38(s,2H),4.38(s,4H),1.47(q,J＝3.4Hz,4H).MS:573[M+H] +。
实施例21.N-(4-((5-(3-(4-甲基哌嗪-1-基)丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基) 氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000042
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量4-甲基哌嗪-1-基丙基溴代替溴乙烷进行反应得到白色固体产物； 1H NMR(600MHz,DMSO-d 6)δ10.32(s,1H),10.00(s,1H),8.41(dd,J＝5.2,1.4Hz,1H),7.86(d,J＝13.2Hz,1H),7.63(dd,J＝8.7,5.1Hz,2H),7.45(d,J＝8.9Hz,1H),7.24(t,J＝9.2Hz,1H),7.15(td,J＝8.8,1.5Hz,2H),7.05(d,J＝1.4Hz,1H),6.39(d,J＝5.3Hz,1H),4.35(s,4H),4.18–4.13(m,2H),2.45(t,J＝7.2Hz,2H),2.40–2.29(m,8H),2.14(s,3H),1.94(t,J＝6.9Hz,2H),1.47(d,J＝3.8Hz,4H).MS:674[M+H] +。
实施例22.N-(3-氟-4-((5-(3-(4-羟基-4-甲基哌啶-1-基)丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000043
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量(4-羟基-4-甲基哌啶-1-基)丙基溴代替溴乙烷进行反应得到白色固体产物； 1H NMR(600MHz,DMSO-d 6)δ10.33(s,1H),10.00(s,1H),8.41(d,J＝5.2Hz,1H),7.86(dd,J＝13.1,2.4Hz,1H),7.66–7.60(m,2H),7.45(dt,J＝8.5,1.7Hz,1H),7.24(t,J＝9.0Hz,1H),7.17–7.11(m,2H),7.05(s,1H),6.39(d,J＝5.2Hz,1H),4.35(s,4H),4.16(t,J＝6.4Hz,2H),2.50(br,4H),2.42(br,2H),2.01–1.90(m,2H),1.55–1.42(m,8H),1.10(s,3H).MS:689[M+H] +。
实施例23.N-(4-((5-(3-(环丁基(甲基)氨基)丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000044
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量3-(环丁基(甲基)氨基)丙基溴代替溴乙烷进行反应得到白色固体产物； 1H NMR(600MHz,DMSO-d 6)δ10.33(s,1H),10.01(s,1H),8.42(d,J＝5.2Hz,1H),7.87(dd,J＝13.2,2.5Hz,1H),7.67–7.59(m,2H),7.46(dt,J＝8.9,1.7Hz,1H),7.25(t,J＝9.0Hz,1H),7.19–7.11(m,2H),7.06(s,1H),6.40(d,J＝5.2Hz,1H),4.35(s,4H),4.16(t,J＝6.4Hz,2H),2.79(t,J＝7.6Hz,1H),2.38(t,J＝7.0Hz,2H),2.06(s,3H),2.02–1.94(m,2H),1.91(p,J＝6.7Hz,2H),1.76(ddd,J＝11.2,6.4,2.2Hz,2H),1.65–1.55(m,2H),1.47(dd,J＝4.4,3.0Hz,4H).MS:659[M+H] +。
实施例24.N-(4-((5-(3-(1,1-硫代吗啉二氧化物-4-基)丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000045
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量3-(1,1-硫代吗啉二氧化物-4-基)丙基溴代替溴乙烷进行反应得到白色固体产物； 1H NMR(600MHz,DMSO-d 6)δ10.33(s,1H),10.00(s,1H),8.41(d,J＝5.2Hz,1H),7.86(dd,J＝13.2,2.4Hz,1H),7.63(dd,J＝8.9,5.2Hz,2H),7.45(dd,J＝8.9,2.3Hz,1H),7.24(t,J＝9.0Hz,1H),7.15(t,J＝8.9Hz,2H),7.09(s,1H),6.39(d,J＝5.2Hz,1H),4.35(s,4H),4.18(t,J＝6.4Hz,2H),3.11(t,J＝5.2Hz,4H),2.92(dd,J＝7.2,3.5Hz,4H),2.65(t,J＝7.0Hz,2H),1.96(p,J＝6.7Hz,2H),1.47(q,J＝3.3Hz,4H).MS:709[M+H] +。
实施例25.N-(3-氟-4-((5-(3-(吡咯-1-基)丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000046
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量3-(吡咯-1-基)丙基溴代替溴乙烷进行反应得到白色固体产物； 1H NMR(600MHz,DMSO-d 6)δ10.34(s,1H),10.01(s,1H),8.41(d,J＝5.2Hz,1H),7.86(dd,J＝13.1,2.4Hz,1H),7.63(dd,J＝8.9,5.0Hz,2H),7.45(dd,J＝8.9,2.3Hz,1H),7.24(t,J＝9.0Hz,1H),7.15(t,J＝8.8Hz,2H),7.06(s,1H),6.40(d,J＝5.2Hz,1H),4.35(s,4H),4.18(t,J＝6.4Hz,2H),2.73(t,J＝7.3Hz,2H),2.66(d,J＝5.9Hz,4H),2.03(q,J＝6.9Hz,2H),1.80–1.68(m,4H),1.47(t,J＝3.9Hz,4H).MS:645[M+H] +。
实施例26.N-(3-氟-4-((5-(3-氰基丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000047
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量溴丁腈代替溴乙烷进行反应得到白色固体产物； 1H NMR(600MHz,DMSO-d 6)δ10.33(s,1H),10.00(s,1H),8.42(d,J＝5.2Hz,1H),7.86(dd,J＝13.2,2.4Hz,1H),7.63(dd,J＝9.0,5.1Hz,2H),7.45(dd,J＝9.0,2.3Hz,1H),7.24(t,J＝9.0Hz,1H),7.15(t,J＝8.9Hz,2H),7.10(s,1H),6.41(d,J＝5.2Hz,1H),4.36(s,4H),4.20(t,J＝6.1Hz,2H),2.69(t,J＝7.2Hz,2H),2.12(p,J＝6.7Hz,2H),1.47(t,J＝3.6Hz,4H).MS:601[M+H] +。
实施例27.N-(4-((5-((6-(二甲氨基)己基)氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000048
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量6-二甲氨基己基溴代替溴乙烷进行反应得到白色固体产物； 1H NMR(600MHz,DMSO-d 6)δ10.34(s,1H),10.01(s,1H),8.41(d,J＝5.2Hz,1H),7.86(d,J＝13.0Hz,1H),7.63(dd,J＝8.8,5.1Hz,2H),7.45(d,J＝8.9Hz,1H),7.24(t,J＝9.0Hz,1H),7.15(t,J＝8.7Hz,2H),7.05(s,1H),6.39(d,J＝5.2Hz,1H),4.35(s,4H),4.12(t,J＝6.5Hz,2H),2.31(t,J＝7.4Hz,2H),2.20(s,6H),1.80(q,J＝7.1Hz,2H),1.49-1.43(m,8H),1.36(q,J＝7.8Hz,2H).MS:661[M+H] +。
实施例28.N-(3-氟-4-((5-(氧杂环丁烷-3-氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000049
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量对甲基苯磺酸氧杂环丁烷-3-酯代替溴乙烷进行反应得到白色固体产物； 1H NMR(600MHz,DMSO-d 6)δ10.33(s,1H),10.00(s,1H),8.41(d,J＝5.2Hz,1H),7.87(d,J＝13.2Hz,1H),7.73–7.57(m,2H),7.45(s,1H),7.24(s,1H),7.15(t,J＝8.8Hz,2H),6.70(s,1H),6.41(d,J＝5.2Hz,1H),5.45(h,J＝5.1Hz,1H),5.07–4.87(m,2H),4.62(dd,J＝7.4,4.9Hz,2H),4.38(s,4H),1.45(s,4H).MS:590[M+H] +。
实施例29.N-(3-氟-4-((5-(3-(4,4-二甲基哌啶-1-基)丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000050
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量(4,4-二甲基哌啶-1-基)丙基溴代替溴乙烷进行反应得到白色固体产物； 1H NMR(600MHz,DMSO-d 6)δ10.32(s,1H),10.00(s,1H),8.41(d,J＝5.2Hz,1H),7.89–7.81(m,1H),7.63(dd,J＝9.0,5.1Hz,2H),7.45(d,J＝8.7Hz,1H),7.24(t,J＝9.1Hz,1H),7.15(t,J＝8.9Hz,2H),7.05(s,1H),6.39(d,J＝5.2Hz,1H),4.35(s,4H),4.15(t,J＝6.4Hz,2H),2.46-2.36(m,6H),1.98–1.92(m,2H),1.47(q,J＝3.3Hz,4H),1.35–1.30(m,4H),0.90(s,6H).MS:687[M+H] +。
实施例30.N-(3-氟-4-((5-(3-(4-氨基-4-甲基哌啶-1-基)丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000051
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量(4-氨基-4-甲基哌啶-1-基)丙基溴代替溴乙烷进行反应得到白色固体产物； 1H NMR(600MHz,DMSO-d 6)δ10.31(s,1H),9.97(s,1H),8.34(d,J＝5.2Hz,1H),8.30(s,2H),7.79(dd,J＝13.2,2.4Hz,1H),7.61–7.50(m,2H),7.39(dt,J＝8.7,1.7Hz,1H),7.17(t,J＝9.1Hz,1H),7.12–7.04(m,2H),6.98(s,1H),6.33(d,J＝5.2Hz,1H),4.28(s,4H),4.09(t,J＝6.4Hz,2H),2.59–2.52(m,4H),2.19(s,2H),1.92–1.84(m,2H),1.66–1.48(m,4H),1.40(dd,J＝5.4,3.6Hz,4H),1.14(s,3H).MS:688[M+H] +。
实施例31.N-(3-氯-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000052
以与实施例7相似的方法进行制备，不同之处在于，步骤1中以2-氯-4-硝基苯酚代替2-氟-4-硝基苯酚，步骤3中以吗啉-1-基丙基氯代替溴乙烷进行反应得到白色固体产物； 1H NMR(600MHz,DMSO-d 6)δ10.28(s,1H),10.02(s,1H),8.43(d,J＝5.2Hz,1H),8.05(d,J＝2.5Hz,1H),7.69–7.62(m,2H),7.60(dd,J＝8.9,2.5Hz,1H),7.22–7.13(m,3H),7.09(s,1H),6.34(d,J＝5.2Hz,1H),4.38–4.30(m,4H),4.20(t,J＝6.3Hz,2H),3.63(s,4H),2.42(br,6H),2.01(d,J＝16.4Hz,2H),1.47(t,J＝3.1Hz,4H).MS:677[M+H] +。
实施例32.N-(3-氟-4-((5-(2-羟基乙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000053
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量2-溴乙醇代替溴乙烷进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.34(s,1H),10.01(s,1H),8.44(d,J＝5.3Hz,1H),7.87(dd,J＝13.2,2.4Hz,1H),7.64(dd,J＝8.9,5.1Hz,2H),7.47(dd,J＝8.9,2.3Hz,1H),7.26(t,J＝9.0Hz,1H),7.15(t,J＝8.9Hz,2H),7.09(s,1H),6.43(d,J＝5.3Hz,1H),4.96(s,1H),4.36(s,4H),4.15(t,J＝4.9Hz,2H),3.81(t,J＝4.9Hz,2H),1.48(t,J＝2.9Hz,4H).MS:578[M+H] +。
实施例33.N-(4-((5-((1-氨基环丙基)甲氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000054
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量4-甲基苯磺酸(1-((四丁基氧羰基)氨基)环丙基)甲基酯代替溴乙烷进行反应得到白色固体产物；
1H NMR(400MHz,DMSO-d 6)δ10.32(s,1H),10.00(s,1H),8.40(d,J＝5.2Hz,1H),7.85(dd,J＝13.3,2.4Hz,1H),7.73–7.57(m,2H),7.45(dd,J＝8.9,2.3Hz,1H),7.19(dt,J＝35.1,9.0Hz,3H),7.03(s,1H),6.39(d,J＝5.1Hz,1H),4.36(q,J＝4.5Hz,4H),4.02(s,2H),1.47(t,J＝2.9Hz,4H),0.62(dt,J＝9.6,2.1Hz,4H).MS:603[M+H] +。
实施例34.N-(3-氟-4-((5-(2-羟基-2-甲基丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000055
以与实施例7相似的方法进行制备，不同之处在于，步骤3中以等当量1-溴-2-甲基丙基-2-醇代替溴乙烷进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ10.32(s,1H),10.00(s,1H),8.41(d,J＝5.2Hz,1H),7.86(dd,J＝13.2,2.4Hz,1H),7.69–7.59(m,2H),7.49–7.40(m,1H),7.24(t,J＝9.0Hz,1H),7.19–7.11(m,2H),7.04(s,1H),6.40(dd,J＝5.2,1.0Hz,1H),4.69(s,1H),4.36(d,J＝1.8Hz,4H),3.87(s,2H),1.47(t,J＝2.7Hz,4H),1.25(s,6H).MS:606[M+H] +。
实施例35.N-(2-氯-5-氟-4-((5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000056
以与实施例7相似的方法进行制备，不同之处在于，步骤1中以等当量5-氯-2-氟-4-硝基苯酚代替2-氟-4-硝基苯酚进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ11.37(s,1H),9.72(s,1H),8.46(d,J＝5.1Hz,1H),8.26(d,J＝12.8Hz,1H),7.63–7.48(m,3H),7.18(t,J＝8.9Hz,2H),7.09(s,1H),6.57(d,J＝5.2Hz,1H),4.32(s,4H),3.92(s,3H),1.71(s,2H),1.63(s,2H).MS:582[M+H] +。
实施例36.N-(2-氯-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-N-(4-氟苯基)环丙基-1,1-二甲酰胺
Figure PCTCN2019073260-appb-000057
以与实施例7相似的方法进行制备，不同之处在于，步骤1中以等当量3-氯-4-硝基苯酚代 替2-氟-4-硝基苯酚，步骤3中以等当量吗啉-1-基丙基氯代替溴乙烷进行反应得到白色固体产物； 1H NMR(600MHz,DMSO-d 6)δ10.83(s,1H),9.89(s,1H),8.51(d,J＝5.1Hz,1H),8.03(d,J＝9.0Hz,1H),7.59(dd,J＝8.9,5.1Hz,2H),7.28(d,J＝2.7Hz,1H),7.18(t,J＝8.9Hz,2H),7.13(d,J＝9.2Hz,1H),7.05(dd,J＝9.0,2.8Hz,1H),6.64(d,J＝5.1Hz,1H),4.36–4.14(m,6H),3.84–3.63(m,2H),3.26(s,4H),2.51(br,4H),2.26–2.11(m,2H),1.66(q,J＝4.3,3.7Hz,2H),1.60(q,J＝4.9,4.2Hz,2H).MS:677[M+H] +。
实验例1.小分子化合物抑制c-MET激酶活性的测试
基于Perkin Elmer公司的LANCE TR-FRET技术，测试方法如下：
1.化合物稀释：从最高浓度2500nM开始进行3倍梯度稀释后共11个浓度(本实验使用的药物的最大终浓度为2500nM，最低终浓度为0.042nM)。
2.用排枪取2.5μL经梯度稀释的化合物，加入384孔板中。
3.加酶：用排枪取5μL 2X c-MET激酶溶液(浓度为2nM)加入到384孔板相应的反应孔中，混匀后室温预反应5分钟。
4.排枪取2.5μL 4X Ultra ULight TM-JAK-1(Tyr1023)Peptide(浓度为400nM)/ATP(浓度为40μM)混合液加入到384孔板相应的反应孔中。
5.阴性对照：在384孔板孔加入2.5μL/孔4X底物/ATP混合液和7.5μL 1X Kinase Assay Buffe。
6.阳性对照：在384孔板中加入2.5μL/孔4X底物/ATP混合液，2.5μL/孔含16％DMSO的1X Kinase Assay Buffer，5μL/孔2X c-MET激酶溶液。反应体系中DMSO的终浓度为4％。
7.离心混匀，避光室温反应60分钟。
8.终止酶促反应：用排枪取5μL 4X终止液加入到384孔板中孔中，离心混匀，室温反应5分钟。
9.显色反应：用排枪取5μL 4X检测液加入到384孔板中孔中进行显色，离心混匀，室温反应60分钟。
10.将384孔板放入Envision读板仪读板，调取相应的程序检测信号。
11.原始数据的分析和处理：
12.将药物浓度和相应抑制率输入GraphPad Prism5计算处理，化合物的抑制率的计算方法如下：抑制率(％)＝(阳性孔读值-实验孔读值)/(阳性对照孔读值-阴性对照孔读值)x100％。用GraphPad Prism5软件处理得出相应的IC50值(酶最高抑制率50％时的化合物浓度)。
表1列出了本发明中部分化合物对酪氨酸激酶c-MET抑制活性的测定结果，其中A表示IC 50小于或等于50nM，B表示IC 50大于50nM但小于或等于500nM，C表示IC 50大于500nM但小于或等于5000nM，D表示IC 50大于5000nM。
表1、本发明部分化合物对c-MET酪氨酸激酶抑制活性测定结果
Figure PCTCN2019073260-appb-000058
实验例2.小分子化合物抑制VEGFR-2激酶活性的测试
基于Perkin Elmer公司的LANCE TR-FRET技术，测试方法如下：
1.化合物稀释：从最高浓度2500nM开始进行3倍梯度稀释后共11个浓度(本实验使用的药物的最大终浓度为2500nM，最低终浓度为0.042nM)。
2.用排枪取2.5μL经梯度稀释的化合物，加入384孔板中。
3.加酶：用排枪取5μL 2X VEGFR-2激酶溶液(浓度为0.5nM)加入到384孔板相应的反应孔中，混匀后室温预反应30分钟。
4.排枪取2.5μL 4X Ultra ULight TM-JAK-1(Tyr1023)Peptide(浓度为200nM)/ATP(浓度为40μM)混合液加入到384孔板相应的反应孔中。
5.阴性对照：在384孔板孔加入2.5μL/孔4X底物/ATP混合液和7.5μL 1X Kinase Assay Buffe。
6.阳性对照：在384孔板中加入2.5μL/孔4X底物/ATP混合液，2.5μL/孔含16％DMSO的1X Kinase Assay Buffer，5μL/孔2X VEGFR-2激酶溶液。反应体系中DMSO的终浓度为4％。
7.离心混匀，避光室温反应60分钟。
8.终止酶促反应：用排枪取5μL 4X终止液加入到384孔板中孔中，离心混匀，室温反应5分钟。
9.显色反应：用排枪取5μL 4X检测液加入到384孔板中孔中进行显色，离心混匀， 室温反应60分钟。
10.将384孔板放入Envision读板仪读板，调取相应的程序检测信号。
11.原始数据的分析和处理：
将药物浓度和相应抑制率输入GraphPad Prism5计算处理，化合物的抑制率的计算方法如下：抑制率(％)＝(阳性孔读值-实验孔读值)/(阳性对照孔读值-阴性对照孔读值)x100％。用GraphPad Prism5软件处理得出相应的IC 50值(酶最高抑制率50％
时的化合物浓度)。
表2列出了本发明中部分化合物对酪氨酸激酶VEGFR-2抑制活性的测定结果，其中A表示IC 50小于或等于50nM，B表示IC 50大于50nM但小于或等于500nM，C表示IC 50大于500nM但小于或等于5000nM，D表示IC 50大于5000nM。
表2、本发明部分化合物对VEGFR-2酪氨酸激酶抑制活性测定结果
Figure PCTCN2019073260-appb-000059
实验例3.小分子化合物对MHCC97H细胞增殖抑制活性的测试
具体实验步骤如下：
1.化合物稀释：从最高浓度5000nM开始进行3倍梯度稀释后共9个浓度(本实验使用的药物的最大终浓度为5000nM，最低终浓度为0.76nM)。
2.收集MHCC97H细胞后转移至15mL离心管中，以1000rpm的速度离心5分钟。
3.弃去上清液，加入完全培养液，吹打均匀，取10μL细胞悬浮液和10μL 0.4％台盼蓝混匀，用细胞计数仪进行计数，记录细胞数及存活率；
4.每孔接种5000细胞/80μL的细胞悬液到96孔板中；
5.在每孔中加入20μL对应的上述用培养液稀释过的5×化合物溶液，混合摇匀；
6.培养72小时后每孔加入10μL CCK-8试剂，培养2小时(可以根据颜色深浅来调节反应时间)；
7.在多功能读板机于450nm处读其OD值。
8.数据处理：细胞存活率(％)＝[(As-Ab)/(Ac-Ab)]*100％
As：实验孔(含有细胞的培养基、CCK-8、化合物)的OD值，
Ac：对照孔(含有细胞的培养基、CCK-8)的OD值，
Ab：空白孔(不含细胞和化合物的培养基、CCK-8)的OD值，
然后将数值导入Graphpad Prism5软件进行曲线拟合，计算IC50。
表3列出了本发明中部分化合物对MHCC97H细胞系增殖抑制活性的测试结果，。
表3、本发明部分化合物对MHCC97H细胞增殖抑制活性的测试结果
Figure PCTCN2019073260-appb-000060
本发明所提供的生物学数据表明，本发明的化合物有利于治疗或预防由于VEGFR-2或c-MET激酶异常而引起的疾病。因此，本发明的化合物有利于治疗癌症，包括原发性和转移性癌症，包括实体瘤。此类癌症包括但不限于:非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细 胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌等。本发明的化合物也包括治疗耐一种或多种其它治疗方法的癌症。本发明的化合物还可用于与VEGFR-2激酶和/或c-MET激酶有关的除了癌症以外的其他疾病，包括但不限于眼底疾病，银屑病、风湿性关节炎、动脉粥样化、肺纤维化、肝纤维化。本发明的化合物可以作为单一疗法或联合疗法，可以与多个本发明的化合物联合用药或与本发明以外的其他药物联合用药。
以上所述仅为本发明的较佳实施方式而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (16)

  1. 式(I)表示的化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药，
    Figure PCTCN2019073260-appb-100001
    式(I)中，
    Q为CH；
    G为O；
    Z为CH；
    L选自以下基团
    Figure PCTCN2019073260-appb-100002
    其中X为H或C 1-C 3的烷基；Y为H或C 1-C 3的烷基；n＝0-3，且当n＝0时，L表示
    Figure PCTCN2019073260-appb-100003
    R 1为H，C 1-C 9烷基，C 3-C 7的环烷基，4-7元杂环基，C 3-C 7的环烷基取代的C 1-C 6烷基，4-7元杂环基取代的C 1-C 6烷基，取代的C 1-C 9烷基，所述取代的C 1-C 9烷基的取代基为羟基、C 1-C 6的烷氧基、C 1-C 6的烷硫基或-NR 6R 7中的一种或一种以上，
    R 6和R 7分别独立地为H、C 1-C 6烷基、羟基取代的C 1-C 6烷基、C 1-C 3烷氧基取代的C 1-C 6烷基；
    上述4-7元杂环基为含有1-2个选自N、O、S中的原子的4-7元杂环基，4-7元杂环基不被取代或被C 1-C 3烷基、C 1-C 3酰基取代或被一至二个氧原子氧化；
    R 2为H、C 1-C 3的烷基或卤素；
    R 3为H、C 1-C 3的烷基或卤素；
    R 4为H、C 1-C 3的烷基或卤素；
    R 5为H，C 1-C 9烷基，C 3-C 7的环烷基，C 3-C 7环烷基取代的C 1-C 6烷基，芳基，芳基取代的C 1-C 6烷基，杂芳基或杂芳基取代的C 1-C 6烷基；
    所述芳基、杂芳基为不被取代或被C 1-C 3的烷基、C 1-C 3的烷氧基、C 1-C 3的烷硫基、 单或双C 1-C 3烷基取代的氨基、卤素、三氟甲基、芳氧基和甲砜基中的一种或一种以上取代；
    上述杂芳基为含有1-3个选自N、O、S中的杂原子且含有5至10个环原子的单环或双环基团。
  2. 根据权利要求1所述化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药，其中，R 1为H，C 1-C 6烷基，C 3-C 6的环烷基，5-6元杂环基，C 3-C 6的环烷基取代的C 1-C 3烷基，5-6元杂环基取代的C 1-C 3烷基，取代的C 1-C 6烷基，所述取代的C 1-C 6烷基的取代基为羟基、C 1-C 3的烷氧基、C 1-C 3的烷硫基或-NR 6R 7，
    R 6和R 7分别独立地为-H、C 1-C 3烷基、羟基取代的C 1-C 3烷基、C 1-C 3烷氧基取代的C 1-C 3烷基，
    上述5-6元杂环基为含有1-2个选自N、O、S中的原子的5-6元杂环基，所述5-6元杂环基不被取代或被C 1-C 3烷基、C 1-C 3酰基取代或被一至二个氧原子氧化。
  3. 根据权利要求1所述的化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药，其中，R 1选自甲基、乙基、丙基、异丙基、甲氧基乙基、甲氧基丙基、甲氧基丁基、甲氧基戊基、甲氧基己基、四氢呋喃-3-基、四氢-2H-吡喃-4-基、四氢吡咯-1-乙基、四氢吡咯-1-丙基、哌啶-1-乙基、哌啶-1-丙基、哌嗪-1-乙基、哌嗪-1-丙基、吗啉-4-乙基、吗啉-4-丙基、甲基哌嗪-4-乙基、甲基哌嗪-4-丙基、N-甲酰基哌嗪-4-乙基、N-甲酰基哌嗪-4-丙基、N-乙酰基哌嗪-4-乙基、N-乙酰基哌嗪-4-丙基、(1,1-二氧硫代吗啉基)-4-乙基、(1,1-二氧硫代吗啉基)-4-丙基、甲硫基乙基、甲硫基丙基、二甲氨基乙基、二甲氨基丙基、二甲氨基丁基、二甲氨基戊基、二甲氨基己基、二乙氨基乙基、二乙氨基丙基、羟基乙基、羟基丙基、羟乙基氨基乙基、羟丙基氨基乙基、羟乙基氨基丙基、甲氧基乙基氨基乙基、甲氧基丙基氨基乙基、甲氧基乙基氨基丙基、氨基乙基、氨基丙基、氨基丁基、N-甲基-N-羟乙基氨基乙基、N-甲基-N-羟丙基氨基乙基、N-甲基-N-羟乙基氨基丙基、N-甲基-N-甲氧基乙基氨基乙基、N-甲基-N-甲氧基丙基氨基乙基、N-甲基-N-甲氧基乙基氨基丙基、2-甲基-2-羟基丙基、3-甲基-3-羟基丁基、(3S)-3-氨基丁基、(3R)-3-氨基丁基、(3S)-3-羟基丁基或(3R)-3-羟基丁基中的一种或一种以上。
  4. 根据权利要求1所述的化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药，其中，R 1选自：丁基、异丁基、戊基、异戊基、己基、环丙基甲基、环丙基乙基、环丙基丙基、环丁基甲基、环丁基乙基、环丁基丙基、4,4-二甲基哌啶-1-乙基、4,4-二甲基哌啶-1-丙基、氧杂环丁烷-3-基。
  5. 根据权利要求1所述化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、 或前药，其中，R 2、R 3、R 4中，所述的卤素为Cl或F。
  6. 根据权利要求1所述的化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药，R 5为-H，C 1-C 6烷基，C 3-C 6环烷基，C 3-C 6环烷基取代的C 1-C 3烷基，芳基，芳基取代的C 1-C 3烷基，杂芳基或杂芳基取代的C 1-C 3烷基，所述的芳基、杂芳基的取代基为C 1-C 3的烷基、C 1-C 3的烷氧基、C 1-C 3的烷硫基、单或双C 1-C 3烷基取代的氨基、卤素、三氟甲基、芳氧基和甲砜基中的一种或一种以上；
    所述杂芳基为含有1-2个选自N、O、S中的杂原子且含有5至10个环原子的单环或双环基团。
  7. 根据权利要求6所述化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药，R 5选自H、甲基、乙基、丙基、异丙基、异戊基、环丙基、环丁基、环戊基、环己基、苯基、4-氟苯基、3-氟苯基、2-氟苯基、4-氯苯基、3-氯苯基、2-氯苯基、2,4-二氟苯基、2,5-二氟苯基、3,4-二氟苯基、2,4-二氯苯基、2,5-二氯苯基、3,4-二氯苯基、2-氟-4-(三氟甲基)苯基、2-氟-5-(三氟甲基)苯基、3-氟-4-(三氟甲基)苯基、3-氟-5-(三氟甲基)苯基、3-三氟甲基-4氟苯基、2-氟-4-氯苯基、2-氟-5-氯苯基、3-氟-4-氯苯基、3-氟-5-氯苯基、3-氯-4-氟苯基、2-氯-4-(三氟甲基)苯基、2-氯-5-(三氟甲基)苯基、3-氯-4-(三氟甲基)苯基、3-氯-5-(三氟甲基)苯基、3-三氟甲基-4-氯苯基、2-氯-4-氟苯基、2-氯-5-氟苯基、3-氯-4-氟苯基、苄基、苯乙基、4-氟苄基、萘-1-基、3-甲基-异噁唑-5-基、4-苯氧基苯基、3-(甲砜基)苯基、4-(甲砜基)苯基、吡啶-2-基、吡啶-3-基、吡啶-4-基、3-甲氧基苄基或4-甲氧基苄基。
  8. 式(I)表示的化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药，
    Figure PCTCN2019073260-appb-100004
    式(I)中，
    Q为CH；
    G为O；
    Z为CH；
    L选自以下基团
    Figure PCTCN2019073260-appb-100005
    其中X为H或C 1-C 3的烷基；Y为H或C 1-C 3的 烷基；n＝0-3，且当n＝0时，L表示
    Figure PCTCN2019073260-appb-100006
    R 1为由1至3个选自C 1-C 3酰基、卤素、三氟甲基、氰基、-CONH 2、-NR aR b或4-7元杂脂环基中的取代基所取代的C 1-C 6烷基，所述4-7元杂脂环基为含有1-2个选自N、O、S中的原子作为环原子的4-7元杂脂环基，且所述4-7元杂脂环基被1至3个选自卤素、C 1-C 3的烷基、羟基、-NH 2、C 1-C 3酰基中的取代基所取代，
    R a和R b各自独立地为-H、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基取代的C 1-C 6烷基、C 1-C 3烷硫基取代的C 1-C 6烷基、单或双C 1-C 3烷基取代的氨基取代的C 1-C 6烷基或者非取代的氨基取代的C 1-C 6烷基；
    R 2、R 3、R 4各自独立地为H、C 1-C 3的烷基或卤素；
    R 5为-H，C 1-C 9烷基，C 3-C 7的环烷基，C 3-C 7环烷基取代的C 1-C 6烷基，芳基，芳基取代的C 1-C 6烷基，杂芳基或杂芳基取代的C 1-C 6烷基；
    所述芳基、杂芳基不被取代或被1-3个选自羟基、氨基、氰基、C 1-C 3的烷基、C 1-C 3的烷氧基、C 1-C 3的烷硫基、单或双C 1-C 3烷基取代的氨基、卤素、三氟甲基和甲砜基中的一种或多种取代基取代；
    上述杂芳基为含有1-3个选自N、O、S中的杂原子且含有5至10个环原子的单环或双环基团。
  9. 根据权利要求8所述化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药，其中，R 1为由1至3个选自C 1-C 3酰基、-F、三氟甲基、氰基、-CONH 2、-NR aR b或4-7元杂脂环基中的取代基所取代的C 1-C 6烷基，所述4-7元杂脂环基为含有1-2个选自N、O、S中的原子作为环原子的4-7元杂脂环基，且所述4-7元杂脂环基被1至3个选自-F、C 1-C 3的烷基、羟基、-NH 2、C 1-C 3酰基中的取代基所取代，
    R a和R b各自独立地为-H、C 1-C 3烷基、C 3-C 6环烷基、C 1-C 3烷氧基取代的C 1-C 3烷基、C 1-C 3烷硫基取代的C 1-C 3烷基、单或双C 1-C 3烷基取代的氨基取代的C 1-C 3烷基或者非取代的氨基取代的C 1-C 3烷基；
    R 2、R 3、R 4各自独立地为-H、-F或-Cl；
    R 5为-H，芳基，芳基取代的C 1-C 3烷基，杂芳基或杂芳基取代的C 1-C 3烷基，所述的芳基、杂芳基为不被取代或被1-3个选自羟基、氨基、氰基、C 1-C 3的烷基、C 1-C 3的烷氧基、C 1-C 3的烷硫基、单或双C 1-C 3烷基取代的氨基、卤素、三氟甲基和甲砜基中的一种或多种取代基取代；
    所述杂芳基为含有1-2个选自N、O、S中的杂原子且含有5至10个环原子的单环或双环基团。
  10. 根据权利要求1至9所述的式(I)化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药，其中，所述化合物的药学上可接受的盐为选自所述化合物的盐酸盐、氢溴酸盐、氢碘酸盐、高氯酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、羟基乙酸盐、乳酸盐、琥珀酸盐、马来酸盐、酒石酸盐、苹果酸盐、柠檬酸盐、富马酸盐、葡萄糖酸盐、安息香酸盐、扁桃酸盐、甲磺酸盐、羟乙基磺酸盐、苯磺酸盐、草酸盐、棕榈酸盐、2-萘磺酸盐、对甲苯磺酸盐、环己氨基磺酸盐、水杨酸盐、己糖酸盐、三氟乙酸盐、铝盐、钙盐、氯普鲁卡因盐、胆碱盐、二乙醇胺盐、乙二胺盐、锂盐、镁盐、钾盐、钠盐和锌盐中的一种或多种。
  11. 一种制备权利要求1-9所述化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药的方法，其特征在于，包括以下步骤，由式(II＇)所示化合物与式(III＇)所示化合物反应制备得到式(I)化合物，其中Q、G、Z、L、R 1、R 2、R 3、R 4和R 5如权利要求1-9所定义，
    Figure PCTCN2019073260-appb-100007
  12. 一种制备权利要求1-9所述化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药的方法，其特征在于，包括以下步骤，由式(II＇)所示化合物与式(III)所示化合物反应制备得到式(I)化合物，其中Q、G、Z、L、R 1、R 2、R 3、R 4和R 5如权利要求1-9所定义，
    Figure PCTCN2019073260-appb-100008
  13. 一种式(II＇)所示的化合物，其中，Q、G、Z、R 1、R 2、R 3、和R 4如权利要求1-9所定义，
    Figure PCTCN2019073260-appb-100009
  14. 一种药用组合物，其由权利要求1-9所述的式(I)化合物或其药学上可接受的盐或其水合物或其前药与药学上可接受的载体或赋形剂组成。
  15. 一种药用组合物，其中包含权利要求1-9所述的式(I)的化合物、其药学上可接受的盐、水合物、溶剂化物、或前药作为活性成分，一个或多个其它的治疗剂，以及一种或多种药学上可接受的载体或赋形剂。
  16. 根据权利要求1-9中任一项所述的式(I)的化合物、其药学上可接受的盐、水合物、溶剂化物、或前药在制备治疗与酪氨酸激酶VEGFR-2和/或c-MET相关疾病的药物中的应用，所述疾病包括：眼底疾病、银屑病、风湿性关节炎、动脉粥样化、肺纤维化、肝纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌。
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