CN111788207B - Dioxane quinoline compound and preparation method and application thereof - Google Patents

Dioxane quinoline compound and preparation method and application thereof Download PDF

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CN111788207B
CN111788207B CN201980012397.7A CN201980012397A CN111788207B CN 111788207 B CN111788207 B CN 111788207B CN 201980012397 A CN201980012397 A CN 201980012397A CN 111788207 B CN111788207 B CN 111788207B
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CN111788207A (en
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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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Beijing Scitech MQ Pharmaceuticals Ltd
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • 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
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    • 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
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    • A—HUMAN NECESSITIES
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    • 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
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
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    • 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

Abstract

Disclosed are dioxanoquinolines having formula (I) or a pharmaceutically acceptable salt thereof. The invention also provides a compound of formula (I) and its pharmaceutically acceptable salts for the preparation and use as a medicament for the treatment of tyrosine kinase related diseases as inhibitors of tyrosine kinases such as VEGFR-2 and c-MET.

Description

Dioxane quinoline compound and preparation method and application thereof
Technical Field
The invention relates to a dioxane quinoline compound, a pharmaceutically acceptable salt, an isomer, a hydrate, a solvate or a prodrug thereof, and a preparation method and application thereof.
Background
Receptor Tyrosine Kinases (RTKs) span the cell membrane and affect the transmission of biochemical signals across the cell membrane, and consist of an extracellular domain containing a ligand binding site, a single transmembrane domain, and an intracellular domain containing tyrosine protein kinase activity. Binding of the ligand to the receptor stimulates receptor-associated tyrosine kinase activity, which leads to phosphorylation of tyrosine residues on the receptor and other intracellular molecules, which in turn initiates a cascade of signals leading to a variety of cellular responses. The overexpression of the tyrosine receptor activates a downstream signal transduction pathway, finally leads to the abnormal transformation and proliferation of cells, and promotes the generation and development of tumors.
VEGFR (vascular endothelial growth factor) is one of receptor tyrosine kinase families, and a series of biochemical and physiological processes are generated by combining with VEGF (vascular endothelial growth factor) serving as a ligand of VEGFR, so that new blood vessels are finally formed. The generation of tumor vessels and their permeability is mainly regulated by Vascular Endothelial Growth Factor (VEGF), which acts via at least two different receptors (VEGFR-1, VEGFR-2). Studies according to Jakeman, Kolch, Connolly et al show that: 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 cell growth factor induces the angiogenic phenotype by inducing endothelial cell proliferation, protease expression and migration and subsequent formation of capillary cellular tissue. Thus, antagonism of VEGF by chelation of VEGF by antibodies can lead to inhibition of tumor growth (Kim et al, 1993, Nature 362: 841-844).
Since VEGFR-2 is mainly distributed in vascular endothelial cells, it can bind to VEGF-A, VEGF-C, VEGF-D, VEGF-E. The effects of VEGF in stimulating endothelial cell proliferation, increasing vascular permeability and neovascularization are primarily achieved by binding to and activating VEGFR-2. If the activity of VEGFR-2 is blocked, the growth and metastasis of tumor can be inhibited through direct and indirect ways, and further the ideal anti-tumor effect is achieved. Therefore, the search for small molecule inhibitors with high activity and selectivity for VEGFR-2 is a promising strategy for tumor therapy.
The hepatocyte growth factor receptor (c-MET) is one of the tyrosine kinase receptors, and its abnormal activation plays an important role in the development and progression of various malignancies, including lung cancer. Hepatocyte Growth Factor (HGF) is a specific ligand of c-MET, and after being combined with HGF, the c-MET plays a biological role through an HGF/c-MET signal channel. The HGF/c-MET signal channel can induce a series of biological effects of cell proliferation, dispersion, migration, organ morphogenesis, angiogenesis and the like. Aberrant activation of c-MET may manifest as receptor overexpression, gene mutation, amplification, ectopy, rearrangement, and the like. These changes can lead to down-stream signaling pathway disorders such as serine/threonine protein kinase (AKT), extracellular signal kinase (ERK), phosphatidylinositol-3-hydroxykinase, retinoblastoma inhibitory protein (Rb) pathway, and the like, mediating processes such as tumorigenesis, invasion and metastasis, angiogenesis, epithelial-mesenchymal transition, 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. The targeted therapy targeting c-MET has shown its important implications in the treatment of a variety of malignancies, including lung cancer.
During the treatment process of using the antitumor drug, the interaction of multiple signal pathways can influence the action effect of the antitumor drug, for example, the interaction of the HFG/c-MET signal pathway and other pathways influences the treatment effect of the antitumor drug, and drug resistance is generated. Therefore, the multi-kinase target combined drug becomes a new anti-tumor treatment means, and the successful marketing of Crizotinib and Cabozantinib indicates that the development of the multi-kinase target inhibitor has good potential and application value.
Cabozantinib is a small molecule inhibitor of protein kinase, and has inhibitory effect on various kinases such as c-MET, VEGFR-2, Ret, Kit, AXL, etc. Cabozantinib can inhibit phosphorylation of c-MET and VEGFR-2 in tumor model, and shows effective anti-tumor metastasis and anti-angiogenesis activity in preclinical drug effect model. No increase in tumor burden was observed in the pulmonary tumor metastasis model treated with Cabozantinib compared to inhibitors acting on VEGFR targets alone, suggesting that Cabozantinib is a potent inhibitor of tumor angiogenesis and metastasis in tumor patients with dysregulated c-MET and VEGFR-2 signaling pathways. The FDA approved Cabozantinib for marketing on day 29/11 of 2012 for the treatment of patients with progressive, metastatic Medullary Thyroid Carcinoma (MTC).
Inhibitors that act on multiple targets like Cabozantinib have many advantages, and studies on this type of inhibitor are also very hot. The medicines on the market at present are few, the available channels are limited, and the medicines on the market have the problems of drug resistance, side effects and the like in use. Therefore, compared with the single-target inhibitors which are already on the market, the multi-target small molecule inhibitor has better treatment effect and application prospect.
Disclosure of Invention
The present invention provides compounds represented by formula (I), pharmaceutically acceptable salts, isomers, hydrates, solvates, or prodrugs thereof, which are useful for treating or preventing diseases caused by tyrosine kinases (e.g., VEGFR-2 and/or c-MET), including certain variants of the tyrosine kinase receptor.
Figure GDA0002622842180000031
In the formula (I), the compound is shown in the specification,
q is CH;
g is O;
z is CH;
l is selected from the group consisting of
Figure GDA0002622842180000032
Wherein X is H or C1-C3Alkyl groups of (a); y is H or C1-C3Alkyl groups of (a); n is 0-3, and when n is 0, L represents
Figure GDA0002622842180000033
R1Is H, C1-C9Alkyl radical, C3-C7Cycloalkyl of (2), 4-to 7-membered heterocyclyl, C3-C7Cycloalkyl-substituted C of1-C6Alkyl, 4-7 membered heterocyclyl substituted C1-C6Alkyl, substituted C1-C9Alkyl, said substituted C1-C9The substituent of the alkyl is hydroxyl, C1-C6Alkoxy group of (C)1-C6Alkylthio or-NR of6R7One or more than one of the components (A),
R6and R7Are each independently H, C1-C6Alkyl, hydroxy substituted C1-C6Alkyl radical, C1-C3Alkoxy-substituted C1-C6An alkyl group;
the above-mentioned 4-7-membered heterocyclic group is a 4-7-membered heterocyclic group containing 1 to 2 atoms selected from N, O, S, and the 4-7-membered heterocyclic group is unsubstituted or substituted by C1-C3Alkyl radical, C1-C3Acyl substituted or oxidized by one to two oxygen atoms;
R2is H, C1-C3Alkyl or halogen of (a);
R3is H, C1-C3Alkyl or halogen of (a);
R4is H, C1-C3Alkyl or halogen of (a);
R5is H, C1-C9Alkyl radical, C3-C7Cycloalkyl of, C3-C7Cycloalkyl-substituted C1-C6Alkyl, aryl-substituted C1-C6Alkyl, heteroaryl or heteroaryl substituted C1-C6An alkyl group;
said aryl, heteroaryl being unsubstituted or substituted by C1-C3Alkyl of (C)1-C3Alkoxy group of (C)1-C3Alkylthio, mono-or di-C of1-C3One or more than one of alkyl substituted amino, halogen, trifluoromethyl, aryloxy and methylsulfonyl;
the heteroaryl group is a monocyclic or bicyclic group containing 1-3 heteroatoms selected from N, O, S and containing 5 to 10 ring atoms.
According to a preferred embodiment, R1Is H, C1-C6Alkyl radical, C3-C6Cycloalkyl of (2), 5-to 6-membered heterocyclyl, C3-C6Cycloalkyl-substituted C of1-C3Alkyl, 5-6 membered heterocyclyl substituted C1-C3Alkyl, substituted C1-C6Alkyl, said substituted C1-C6The substituent of the alkyl is hydroxyl, C1-C3Alkoxy group of (C)1-C3Alkylthio or-NR of6R7，
R6And R7Are each independently-H, C1-C3Alkyl, hydroxy substituted C1-C3Alkyl radical, C1-C3Alkoxy-substituted C1-C3An alkyl group, a carboxyl group,
the above-mentioned 5-6-membered heterocyclic group is a 5-6-membered heterocyclic group containing 1 to 2 atoms selected from N, O, S, said 5-6-membered heterocyclic group being unsubstituted or substituted by C1-C3Alkyl radical, C1-C3Acyl groups are substituted or oxidized by one to two oxygen atoms.
According to a preferred embodiment, R1Selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydropyren-1-yl-ethyl, tetrahydropyren-1-yl-propyl, piperidin-1-yl-ethyl, piperidin-1-yl-propyl, piperazin-1-yl-ethyl, piperazin-1-yl-propyl, morpholin-4-yl-ethyl, morpholin-4-yl-propyl, methylpiperazin-4-yl-ethyl, methylpiperazin-4-yl-propyl, N-formylpiperazin-4-yl-ethyl, N-formylpiperazin-4-yl-propyl, N-formylbenzyl-4-yl-propyl, N-methyl-propyl, N-, N-acetylpiperazin-4-ylethyl, N-acetylpiperazin-4-ylpropyl, (1, 1-dioxothiomorpholinyl) -4-ylethyl, (1, 1-dioxothiomorpholinyl) -4-ylpropyl, methylthioethyl, methylthiopropyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, dimethylaminopentyl, dimethylaminohexyl, diaminohexyl, diaminobutylEthylaminoethyl, diethylaminopropyl, hydroxyethyl, hydroxypropyl, hydroxyethylaminoethyl, hydroxypropylaminoethyl, hydroxyethylaminopropyl, methoxyethylaminoethyl, methoxypropylaminoethyl, methoxyethylaminopropyl, aminoethyl, aminopropyl, aminobutyl, N-methyl-N-hydroxyethylaminoethyl, N-methyl-N-hydroxypropylaminoethyl, N-methyl-N-hydroxyethylaminopropyl, N-methyl-N-methoxyethylaminoethyl, N-methyl-N-methoxypropylaminoethyl, N-methyl-N-methoxyethylaminopropyl, 2-methyl-2-hydroxypropyl, 3-methyl-3-hydroxybutyl, one or more of (3S) -3-aminobutyl, (3R) -3-aminobutyl, (3S) -3-hydroxybutyl and (3R) -3-hydroxybutyl.
According to a preferred embodiment, R1Selected from: butyl, isobutyl, pentyl, isopentyl, hexyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, 4-dimethylpiperidin-1-ylethyl, 4-dimethylpiperidin-1-ylpropyl, oxetan-3-yl.
According to a preferred embodiment, R2、R3、R4The halogen in (1) is Cl or F.
According to a preferred embodiment, R5is-H, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C3-C6Cycloalkyl-substituted C1-C3Alkyl, aryl-substituted C1-C3Alkyl, heteroaryl or heteroaryl substituted C1-C3Alkyl, aryl and heteroaryl have C as substituent1-C3Alkyl of (C)1-C3Alkoxy group of (C)1-C3Alkylthio, mono-or di-C of1-C3One or more of alkyl-substituted amino, halogen, trifluoromethyl, aryloxy and methylsulfonyl;
the heteroaryl group is a monocyclic or bicyclic group containing 1-2 heteroatoms selected from N, O, S and containing 5 to 10 ring atoms.
More preferably, R5Selected 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, 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) phenyl, 3- (trifluoromethyl) -4-fluorophenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-fluorophenyl, 3-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 3-fluoro-4- (trifluoromethyl) phenyl, 2-fluoro-5- (trifluoromethyl) phenyl, 3- (trifluoromethyl) -4-fluorophenyl, and, 2-fluoro-4-chlorophenyl, 2-fluoro-5-chlorophenyl, 3-fluoro-4-chlorophenyl, 3-fluoro-5-chlorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-4- (trifluoromethyl) phenyl, 2-chloro-5- (trifluoromethyl) phenyl, 3-chloro-4- (trifluoromethyl) phenyl, 3-chloro-5- (trifluoromethyl) phenyl, 3- (trifluoromethyl) -4-chlorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl, 3-chloro-4-fluorophenyl, benzyl, phenethyl, 4-fluorobenzyl, naphthalen-1-yl, trifluoromethyl, 3-methyl-isoxazol-5-yl, 4-phenoxyphenyl, 3- (methylsulfonyl) phenyl, 4- (methylsulfonyl) phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 3-methoxybenzyl or 4-methoxybenzyl.
The present application also provides a compound represented by formula (I), a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof,
Figure GDA0002622842180000061
in the formula (I), the compound is shown in the specification,
q is CH;
g is O;
z is CH;
l is selected from the group consisting of
Figure GDA0002622842180000062
Wherein X is H or C1-C3Alkyl groups of (a); y is H or C1-C3Alkyl groups of (a); n is 0-3, and when n is 0, L represents
Figure GDA0002622842180000063
R1Is selected from 1 to 3 of C1-C3Acyl, halogen, trifluoromethyl, cyano, -CONH2、-NRaRbOr C substituted by a substituent in a 4-7 membered heteroalicyclic group1-C6Alkyl, the 4-7 membered heteroalicyclic group is a 4-7 membered heteroalicyclic group containing 1-2 atoms selected from N, O, S as ring atoms, and the 4-7 membered heteroalicyclic group is substituted with 1 to 3 atoms selected from halogen, C1-C3Alkyl, hydroxy, -NH of2、C1-C3Substituted by a substituent in the acyl group,
Raand RbEach independently is-H, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy-substituted C1-C6Alkyl radical, C1-C3Alkylthio substituted C1-C6Alkyl, mono-or di-C1-C3Alkyl substituted amino substituted C1-C6Alkyl or unsubstituted amino substituted C1-C6An alkyl group;
R2、R3、R4each independently is H, C1-C3Alkyl or halogen of (a);
R5is-H, C1-C9Alkyl radical, C3-C7Cycloalkyl of, C3-C7Cycloalkyl-substituted C1-C6Alkyl, aryl-substituted C1-C6Alkyl, heteroaryl or heteroaryl substituted C1-C6An alkyl group;
the aryl and heteroaryl are unsubstituted or substituted by 1-3 substituents selected from hydroxy, amino, cyano, C1-C3Alkyl of (C)1-C3Alkoxy group of (C)1-C3Alkylthio, mono-or di-C of1-C3One or more substituents selected from alkyl substituted amino, halogen, trifluoromethyl and methylsulfonyl;
the above heteroaryl group is a monocyclic or bicyclic group containing 1 to 3 heteroatoms selected from N, O, S and containing 5 to 10 ring atoms.
According to a preferred embodiment, wherein R1Is selected from 1 to 3 of C1-C3Acyl, -F, trifluoromethyl, cyano, -CONH2、-NRaRbOr C substituted by a substituent in a 4-7 membered heteroalicyclic group1-C6An alkyl group, the 4-7-membered heteroalicyclic group is a 4-7-membered heteroalicyclic group containing 1-2 atoms selected from N, O, S as ring atoms, and the 4-7-membered heteroalicyclic group is substituted with 1 to 3 atoms selected from-F, C1-C3Alkyl, hydroxy, -NH of2、C1-C3Substituted by a substituent in the acyl group,
Raand RbEach independently is-H, C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy-substituted C1-C3Alkyl radical, C1-C3Alkylthio substituted C1-C3Alkyl, mono-or di-C1-C3Alkyl substituted amino substituted C1-C3Alkyl or unsubstituted amino substituted C1-C3An alkyl group;
R2、R3、R4each independently is-H, -F, or-Cl;
R5is-H, aryl-substituted C1-C3Alkyl, heteroaryl or heteroaryl substituted C1-C3The aryl and the heteroaryl are unsubstituted or substituted by 1 to 3 groups selected from hydroxyl, amino, cyano and C1-C3Alkyl of (C)1-C3Alkoxy group of (C)1-C3Alkylthio, mono-or di-C of1-C3One or more substituents selected from alkyl substituted amino, halogen, trifluoromethyl and methylsulfonyl;
the heteroaryl group is a monocyclic or bicyclic group containing 5 to 10 ring atoms; heteroaryl contains 1-2 heteroatoms selected from N, O, S.
More preferably, R1Selected from cyanomethyl, cyanoethyl, cyanopropyl, -CH2CONH2、-CH2CF3、
Figure GDA0002622842180000071
4-methyl-4-hydroxypiperidin-1-ylpropyl, 4-methyl-4-hydroxypiperidin-1-ylethyl, 4-methyl-4-aminopiperidin-1-ylpropyl, 4-methyl-4-aminopiperidin-1-ylethyl, 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.
The present invention provides pharmaceutically acceptable salts of compounds of formula (I), wherein said salts are acidic/anionic or basic/cationic salts; pharmaceutically acceptable acid/anion salts typically take the form in which the basic nitrogen is protonated by an inorganic or organic acid, representative organic or inorganic acids include hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, formic, acetic, propionic, glycolic, lactic, succinic, maleic, tartaric, malic, citric, fumaric, gluconic, benzoic, mandelic, methanesulfonic, isethionic, benzenesulfonic, oxalic, palmitic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclamic, salicylic, hexonic, trifluoroacetic acids. Pharmaceutically acceptable basic/cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.
The invention provides a method for preparing the compound or a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof, which is characterized by comprising the following steps of preparing a compound shown as a formula (I) by reacting a compound shown as a formula (II ') with a compound shown as a formula (III'), wherein Q, G, Z, L, R represents1、R2、R3、R4And R5As is defined above in the foregoing description,
Figure GDA0002622842180000081
the invention provides a method for preparing the compound or a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof, which is characterized by comprising the following steps of preparing a compound shown as a formula (I) by reacting a compound shown as a formula (II') with a compound shown as a formula (III), wherein Q, G, Z, L, R is contained1、R2、R3、R4And R5As is defined above in the foregoing description,
Figure GDA0002622842180000082
the present invention provides intermediates for the preparation of the above compounds, a compound of formula (II') wherein, Q, G, Z, R1、R2、R3And R4As is defined above in the foregoing description,
Figure GDA0002622842180000083
Detailed Description
Unless otherwise indicated, the following terms used in the present application (including the specification and claims) have the definitions given below. In this application, the use of "or" and "means" and/or "unless stated otherwise. Furthermore, the use of the terms "including" and other forms, such as "including", "comprising", and "having", are not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
The term "substituted" as used herein includes complex substituents (e.g., phenyl, aryl, heteroalkyl, heteroaryl), suitably 1 to 5 substituents, preferably 1 to 3 substituents, and most preferably 1 to 2 substituents, which are freely selectable from the list of substituents.
Unless otherwise specified, alkyl includes saturated straight-chain, branched-chain hydrocarbon radicals, C1-C9C representing a carbon atom number of 1 to 9 of the alkyl group1-C3Such asThe carbon atom number of the alkyl group being 1 to 3, e.g. C1-C6The alkyl group includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-methylpentyl and the like. Alkoxy is an alkyl-O-group formed from the previously described linear or branched alkyl groups with-O-. Similarly, alkenyl and alkynyl groups include straight chain, branched chain alkenyl or alkynyl groups.
Cycloalkyl, meaning a cyclic group formed by carbon atoms, e.g. C3-C7Cycloalkyl groups of (a) may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and similarly, cyclic alkenyl groups are also included.
The term "aryl" as used herein, unless otherwise specified, refers to an unsubstituted or substituted aromatic radical, such as phenyl, naphthyl, anthracenyl.
"oxidized by one to two oxygen atoms" means that a sulfur atom is oxidized by one oxygen atom to form a double bond linkage between sulfur and oxygen, or by two oxygen atoms to form a double bond linkage between sulfur and two oxygens.
The term "heterocyclyl", as used herein, unless otherwise specified, represents an unsubstituted or substituted stable 3 to 8 membered monocyclic saturated ring system consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, O, S, wherein the N, S heteroatoms may be optionally oxidized and the N heteroatoms may be optionally quaternized. Examples of such heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl oxide, piperidinyl oxide, dioxolanyl, dioxanyl tetrahydroimidazolyl, tetrahydrooxazolyl, thiomorpholino sulfoxide, thiomorpholino sulfone, and oxadiazolyl.
The term "heteroaryl" as used herein, unless otherwise specified, represents an unsubstituted or substituted stable 5 or 6 membered monocyclic aromatic ring system, and may also represent an unsubstituted or substituted 9 or 10 ring atom fused benzene or bicyclic heteroaromatic ring system consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, O, S, wherein the N, S heteroatom may be oxidized and the N heteroatom may also be quaternized. The heteroaryl group may be attached to any heteroatom 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, indolyl, azaindolyl, indazolyl, azaindazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenylyl, quinolinyl, or isoquinolinyl.
The term "carbonyl" refers to the group-C (O) -.
Whenever the term "alkyl" or "aryl" or any of their prefix roots appear in the name of a substituent (e.g., aralkyl, dialkylamino), it is to be considered as encompassing those limitations given above for "alkyl" and "aryl". Specified number of carbon atoms (e.g., C)1-C6) Will independently represent the number of carbon atoms in an alkyl moiety or an alkyl moiety in a larger substituent (where alkyl is taken as its prefix root).
The present invention also provides methods for preparing the corresponding compounds, and the compounds described herein can be prepared using a variety of synthetic methods, including the methods described below, and the compounds of the present invention, or pharmaceutically acceptable salts, isomers, or hydrates thereof, can be synthesized using the methods described below, and synthetic methods known in the art of organic chemical synthesis, or by variations on these methods as understood by those skilled in the art, with preferred methods including, but not limited to, the methods described below.
In one embodiment, the compounds of formula (I) of the present invention are prepared by reacting a compound of formula (II ') with a compound of formula (III') or formula (III), wherein Q, G, Z, L, R1、R2、R3、R4And R5As described previously.
Figure GDA0002622842180000101
The invention further provides an intermediate for preparing the compound shown as the formula (I), namely, the compound shown as the formula (II'), wherein, Q, G, Z, R1、R2、R3And R4As is defined above in the foregoing description,
Figure GDA0002622842180000102
the compounds of the present invention may be prepared by the following methods or by technical schemes known to those skilled in the art,
Figure GDA0002622842180000111
step 1) carrying out nitration reaction, preferably, the nitration reaction conditions are nitric acid and acetic acid.
Step 2) carrying out a nitro reduction reaction, wherein the nitro reduction is carried out by adopting the conventional operation of the technicians in the field;
preferably, the nitro-reduction reaction conditions 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;
in the step 3), the 1- (8-methoxy-6-amino-2, 3-d dihydrobenzo [ b ] [1,4] dioxan-5-) ethan-1-one and methyl formate or ethyl formate in an organic solvent under the catalysis of a base to obtain 10-hydroxy-5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] -quinoline, wherein the organic solvent comprises but is not limited to dioxane, tetrahydrofuran, tertiary butanol, ethanol and methanol or a combination of more than two of the dioxane, the tetrahydrofuran, the tertiary butanol, the ethanol and the methanol; the base includes but is not limited to sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide; the reaction may also be carried out under heating at a temperature ranging from room temperature to reflux.
Reacting 10-hydroxy-5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] -quinoline with a chlorinating agent in an organic solvent to prepare 10-chloro-5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] -quinoline, wherein the chlorinating agent is phosphorus oxychloride; the organic solvent comprises but is not limited to one or the combination of more than two of benzene, toluene, chlorobenzene and xylene; the reaction can also be carried out in the presence of an organic base, such as triethylamine or diisopropylethylamine.
In the step 4a), the 5-hydroxy-10-chloro-2, 3-dihydro- [1,4] dioxano [2,3-f ] -quinoline is obtained by the action of Lewis acid in an organic solvent, wherein the Lewis acid is boron tribromide or boron trichloride; the organic solvent is dichloromethane.
5-hydroxy-10-chloro-2, 3-dihydro- [1,4] in step 4b)]Dioxane [2,3-f ]]-quinoline and R1X in an organic solvent to prepare a compound shown as a formula III-A, wherein R1As defined hereinbefore; organic solvents include, but are not limited to, one or a combination of two of tetrahydrofuran, dioxane, DMF, DMA, DMSO, acetonitrile; r1X in X is chlorine, bromine, iodine, mesylate, tosylate or triflate.
Step 5) mixing the compound shown in the formula III-A with the formula V 'in an organic solvent, and heating to 100-140 ℃ to obtain a compound shown in IV'; the organic solvent is selected from one or the combination of more than two of toluene, chlorobenzene, xylene, DMF, DMA and DMSO.
Step 6) carrying out a nitro reduction reaction, wherein the nitro reduction can be carried out by a person skilled in the art in a conventional way;
preferably, 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) in a preferred embodiment, when reacting a compound of formula (III ') with a compound of formula (II' -A), formula (III ') can be reacted with an acylating agent and then with formula (II' -A).
Preferably, 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.
In another embodiment, the compound of formula (III ') is reacted with a compound of formula (II' -A) in the presence of a condensing agent to give a compound of formula (I-C),
preferably, the condensing agent includes, but is not limited to, carbodiimide type condensing agents, onium salt type condensing agents, organic phosphorus type condensing agents and one or more of other types of condensing agents, preferably N, N-Dicyclohexylcarbodiimide (DCC), N-Diisopropylcarbodiimide (DIC), hydroxybenzotriazole (HOBt), N-Diisopropylethylamine (DIEA), 1-hydroxy-7-azobenzotriazol (HOAt), O-benzotriazol-N, N '-tetramethyluronium tetrafluoroborate (TBTU), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), 2- (7-oxybenzotriazole) -N, N' -tetramethyluronium Hexafluorophosphate (HBTU), 6-chlorobenzotriazole-1, 1,3, 3-tetramethyluronium Hexafluorophosphate (HCTU), 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), propylphosphoric anhydride (T3P), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), 1-ethyl (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), benzotriazol-1-yl-oxytriazolidinphosphonium hexafluorophosphate (PyBOP), (3H-1,2, 3-triazolo [4,5-b ] pyridin-3-oxy) tri-1-pyrrolidinophosphonium hexafluorophosphate (PyAOP);
preferably, this step is carried out in an organic base including, but not limited to, one or a combination of two or more of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2, 6-dimethylpyridine, 1, 8-diazabicycloundecen-7-ene or N-methylmorpholine.
When R is1is-CH3In the case of this, the step 4a and the step 4b may be omitted, and the operation of the step 5) may be performed after the completion of the step 4).
Meanwhile, for example, the order of step 4a, step 4b and step 5 is not fixed, and step 5 may be performed first, and then step 4a and step 4b may be performed.
It is clear that the compounds of formula I, isomers, crystalline forms or prodrugs, and pharmaceutically acceptable salts thereof, may exist in solvated as well as unsolvated forms. For example, the solvated form may be water soluble. The present invention includes all such solvated and unsolvated forms.
The compounds of the invention may have asymmetric carbon atoms and, depending on their physicochemical differences, such diastereomeric mixtures may be separated into the individual diastereomers by methods well known in the art, for example, chromatography or fractional crystallization. Enantiomers can be separated by first converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitably optically active compound, separating the diastereomers, and then converting (hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention.
The compounds of the present invention as active ingredients, as well as methods for preparing the compounds, are the subject of the present invention. Furthermore, some crystalline forms of the compounds may exist as polymorphs and as such may be included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of this invention.
The compounds of the invention may be used in therapy in free form or, where appropriate, in the form of pharmaceutically acceptable salts or other derivatives. As used herein, the term "pharmaceutically acceptable salts" 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 and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art. The salts may be formed by reacting a compound of the invention with a suitable free base or acid. Including, but not limited to, salts formed 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, or by using methods well known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, caproates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, laurylsulfates, malates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoate, pectinates, persulfates, per3-phenylpropionates, phosphates, picrates, propionates, stearates, sulfates, thiocyanates, P-toluenesulfonate, undecanoate, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include the appropriate non-toxic ammonium, quaternary ammonium, and amine-based cations formed using such salts as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.
In addition, the term "prodrug" as used herein means a compound which can be converted in vivo to a compound of the formula (I) of the present invention. This conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent compound in the blood or tissue.
The pharmaceutical compositions of the invention comprise a compound of structural formula (I) as described herein or a pharmaceutically acceptable salt thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressive agent, an anticancer agent, an antiviral agent, an anti-inflammatory agent, an antifungal agent, an antibiotic, or an additional active agent that is an anti-vascular hyperproliferative compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle.
The compounds of the present invention may be used alone or in combination with one or more other compounds of the present invention or with one or more other agents. When administered in combination, the therapeutic agents may be formulated for simultaneous administration or for sequential administration at different times, or the therapeutic agents may be administered as a single composition. By "combination therapy" is meant the use of a compound of the invention in combination with another agent, either by co-administration of each agent simultaneously or by sequential administration of each agent, in either case, for the purpose of achieving optimal effect of the drug. Co-administration includes simultaneous delivery dosage forms, as well as separate dosage forms for each compound. Thus, administration of the compounds of the invention may be used concurrently with other therapies known in the art, for example, radiation therapy or adjunctive therapies such as cytostatic agents, cytotoxic agents, other anti-cancer agents, etc. in the treatment of cancer to ameliorate the symptoms of the cancer. The present invention is not limited to the order of administration; the compounds of the invention may be administered previously, concurrently, or after other anti-cancer or cytotoxic agents.
To prepare the pharmaceutical compositions of this invention, one or more compounds or salts of formula (I) as the active ingredient may be intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation designed for administration by any convenient route, e.g. oral or parenteral. 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, which is published by the United states society of pharmacy and British pharmaceutical society.
The pharmaceutical compositions of the invention may be in a form, for example, suitable for oral administration, for example, as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injection such as clear solutions, suspensions, emulsions; or for topical application such as creams; or as suppositories for rectal administration. The pharmaceutical compositions may also be in unit dosage form suitable for single use administration of the precise dosage. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and the compound as an active ingredient prepared in accordance with the present invention, and may also include other medicinal or pharmaceutical agents, carriers, adjuvants, and the like.
Therapeutic compounds may also be administered to mammals other than humans. The dosage of the drug administered to a mammal will depend on the species of the animal and its disease state or disorder in which it is suffering. The therapeutic compound may be administered to the animal in the form of a capsule, bolus, tablet or solution. Therapeutic compounds may also be administered into the animal by injection or infusion. We prepared these pharmaceutical forms according to conventional means which meet the criteria of veterinary practice. Alternatively, the pharmaceutical composition may be mixed with animal feed for feeding to the animal, and thus, the concentrated feed supplement or premix may be prepared for mixing with conventional animal feed.
It is a further object of the present invention to provide a method for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising a compound of the present invention.
The invention also includes the use of a compound of the invention, or a pharmaceutically acceptable derivative thereof, for the manufacture of a medicament for the treatment of cancer (including non-solid tumors, primary or metastatic cancer, as noted elsewhere herein and including one or more other treatments for which the cancer is resistant or refractory) as well as other diseases (including but not limited to ocular fundus disease, psoriasis, atheroma, pulmonary fibrosis, liver fibrosis, bone marrow fibrosis, etc.). Such cancers include, but are not limited to: non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumors, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-hodgkin lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumors, B-cell and T-cell lymphomas, lymphoma, multiple myeloma, biliary sarcoma, bile duct cancer.
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items. The examples provided below are intended to better illustrate the invention, all temperatures being in degrees Celsius unless otherwise indicated.
Intermediate: preparation of 10-chloro-5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinoline
Figure GDA0002622842180000161
Step 1) preparation of 1- (8-methoxy-6-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-5-yl) ethyl-1-one
1- (8-methoxy-2, 3-dihydrobenzo [ b ]][1,4]Dioxane-5-yl) ethyl-1-one (20.8g,100mmol), nitric acid (22mL) and acetic acid (44mL) were placed in a round bottom flask and stirred until the reaction was completed, poured into crushed ice and filtered with suction to obtain 16.5g of a yellow solid product with a yield of 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]+。
Step 2) preparation of 1- (8-methoxy-6-amino-2, 3-dihydrobenzo [ b ] [1,4] dioxan-5-yl) ethyl-1-one
1- (8-methoxy-6-nitro-2, 3-dihydrobenzo [ b)][1,4]Putting dioxane-5-yl) ethyl-1-ketone (16.5g,65mmol) into a reaction bottle, adding palladium carbon (2g) under a hydrogen environment, stirring till the reaction is finished, and carrying out suction filtration and concentration to obtain a white solid product 13.7g, wherein the yield is 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]+。
Step 3) preparation of 10-hydroxy-5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinoline
1- (6-amino-8-methoxy-2, 3-dihydrobenzo [ b ]][1,4]Dioxane-5-yl) ethyl-1-ketone (13.7g,62mmol) and ethyl formate (27.5g,372mmol) are dissolved in dioxane, sodium tert-butoxide (17.8g,186mmol) is added and stirred until the raw materials disappear, 10ml of methanol is added and stirred continuously until the reaction is finished, hydrochloric acid is used for neutralizing the reaction liquid to be neutral, and then the reaction liquid is filtered, concentrated to obtain 14.4g of a white solid product with the yield of 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]+。
Step 4) preparation of 10-chloro-5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinoline
Reacting 10-hydroxy-5-methoxy-2, 3-dihydro- [1, 4%]Dioxane [2,3-f ]]Quinoline (14.4g,61mmol) is placed in a reaction bottle, toluene is added to dissolve the quinoline, triethylamine (42mL,305mmol) and phosphorus oxychloride (17mL,183mmol) are added to the solution, the solution is heated and stirred until the reaction is finished, the solvent is evaporated, the obtained solid is washed by sodium bicarbonate aqueous solution and filtered by suction, 14.1 g of off-white solid is obtained, and the yield is 92%.1HNMR(400MHz,DMSO-d6)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]+。
Preparation of intermediate 1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylic acid
Figure GDA0002622842180000171
Adding 1, 1-cyclopropyl dicarboxylic acid (1.04 g) into anhydrous tetrahydrofuran (20mL), slowly dropwise adding triethylamine (0.84g) into the stirred suspension under the ice-water bath condition, stirring for half an hour, then dropwise adding thionyl chloride (1.1g) at the temperature of 0 ℃, continuing stirring for 1 hour after the addition is finished, then respectively adding triethylamine (0.8g) and a tetrahydrofuran (10mL) solution of 4-fluoroaniline (0.9g), and completing the reaction and stirring for 2 hours; concentrating, dissolving in 1N sodium hydroxide, extracting with ethyl acetate, adjusting pH of water phase to 2.0 with 1N dilute hydrochloric acid solution, stirring for half an hour, filtering to obtain white solid product 1.1g, and collectingThe ratio was 62%, MS: 224[ M + H]+。
Preparation of intermediate 1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-formyl chloride
Figure GDA0002622842180000172
Heating, refluxing and stirring 1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylic acid (111mg, 0.5mmol) in thionyl chloride (2mL) for reaction, clarifying the reaction solution, continuing refluxing for 1 hour, cooling, and concentrating to obtain a light yellow solid product of 120mg with the yield of 100%;
example 1 preparation of N- (4-fluorophenyl) -N- (4- ((5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] -quinolin-10-yl) oxy) phenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000181
Step 1): mixing 10-chloro-5-methoxy-2, 3-dihydro- [1, 4%]Dioxane [2,3-f ]]Quinoline (251mg,1mmol) and p-nitrophenol (139mg,1mmol) were placed in a reaction flask, chlorobenzene was added, heated to reflux and stirred until the reaction was complete. Cooling, filtering, washing the obtained solid with potassium carbonate water solution to obtain light yellow solid (5-methoxy-10- (4-nitrophenoxy) -2, 3-dihydro- [1,4]]Dioxane [2,3-f ]]Quinoline) 250mg, yield 71%. MS 355[ M + H]+。
Step 2): putting the product (250mg,0.7mmol) obtained in the step 1) into a reaction bottle, adding methanol and Raney nickel (250mg), stirring under a hydrogen environment until the reaction is finished, performing suction filtration and concentration to obtain a white solid product (4- ((5-methoxy-2, 3-dihydro- [1, 4)]Dioxane [2,3-f ]]Quinolin-10-yl) oxy) aniline) 226mg, yield 99%. MS 325[ M + H ]]+。
Step 3): placing the product obtained in the step 2) (226mg,0.7mmol) and 1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylic acid into a reaction bottle, adding N, N-dimethylformamide for dissolution, and then adding 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (380mg,1mmol) anddiethyl isopropylamine (0.25mL,1.5mmol), stirred until the reaction is finished, added with sodium carbonate aqueous solution for washing, filtered and chromatographed to obtain 296 mg of white solid with the yield of 80%.1HNMR(300MHz,DMSO-d6)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]+。
Example 2 preparation of N- (3-fluoro-4- ((5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000182
Step 1) preparation of 10- (2-fluoro-4-nitrophenoxy) -5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] -quinoline
Reference example 1, step 1), was conducted by replacing p-nitrophenol with the same molar equivalent of 2-fluoro-4-nitrophenol.1HNMR(400MHz,DMSO-d6)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]+。
Step 2) preparation of 3-fluoro-4- ((5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) aniline
Reference example 1, step 2) was conducted in the same molar equivalent of 10- (2-fluoro-4-nitrophenoxy) -5-methoxy-2, 3-dihydro- [1, 4%]Dioxane [2,3-f ]]Quinoline substituted 5-methoxy-10- (4-nitrophenoxy) -2, 3-dihydro- [1, 4-]Dioxane [2,3-f ]]-quinoline.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]+。
Step 3) preparation of N- (3-fluoro-4- ((5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Reference example 1, step 3) was conducted to obtain 3-fluoro-4- ((5-methoxy-2, 3-dihydro- [1, 4) in the same molar equivalent]Dioxane [2,3-f ]]Quinolin-10-yl) oxy) aniline as a substitute for 4- ((5-methoxy-2, 3-dihydro- [1, 4-dihydro-)]Dioxane [2,3-f ]]Quinolin-10-yl) oxy) aniline.1HNMR(400MHz,DMSO-d6)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]+。
Example 3 preparation of N- (2-fluoro-4- ((5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Step 1) preparation of 10- (3-fluoro-4-nitrophenoxy) -5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinoline
Reference example 1, step 1), was conducted by replacing p-nitrophenol with 3-fluoro-4-nitrophenol in the same molar equivalent. MS 373[ M + H ]]+。
Step 2) preparation of 2-fluoro-4- ((5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) aniline
Reference example 1, step 2) was conducted in the same molar equivalent of 10- (3-fluoro-4-nitrophenoxy) -5-methoxy-2, 3-dihydro- [1, 4%]Dioxane [2,3-f ]]Quinoline substituted 5-methoxy-10- (4-nitrophenoxy) -2, 3-dihydro- [1, 4-]Dioxane [2,3-f ]]And (3) quinoline.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]+。
Step 3) preparation of N- (2-fluoro-4- ((5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000201
Reference example 1, step 3) was conducted to obtain 2-fluoro-4- ((5-methoxy-2, 3-dihydro- [1, 4) in the same molar equivalent]Dioxane [2,3-f ]]Quinolin-10-yl) oxy) aniline as a substitute for 4- ((5-methoxy-2, 3-dihydro- [1, 4-dihydro-)]Dioxane [2,3-f ]]Quinolin-10-yl) oxy) aniline.1HNMR(400MHz,DMSO-d6)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]+。
Example 4 preparation of N- (4-fluorophenyl) -N- (4- ((5- (3-morpholinopropoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000202
Step 1) adding 10-chloro-5-methoxy-2, 3-dihydro- [1, 4%]Dioxane [2,3-f ]]Quinoline (251mg,1mmol) was dissolved in dichloromethane, 1 mol per liter of a dichloromethane solution of boron tribromide (3mL,3mmol) was added dropwise, and the reaction was stirred until completion. Concentrating to obtain light yellow solid product (5-hydroxy-10-chloro-2, 3-dihydro- [1,4]]Dioxane [2,3-f ]]Quinoline) 236mg, yield 99%. MS:238[ M + H]+。
Step 2) dissolving the product (236mg,1mmol) obtained in step 1) in N, N-dimethylformamide, adding 4- (3-chloropropyl) morpholine (163mg,1mmol) and potassium carbonate (414mg,3mmol), heating and stirring until the reaction is completed. Adding water and ethyl acetate, extracting, concentrating the organic phase, and performing column chromatography to obtain white solid (10-chloro-5- (3-morpholine propoxy) -2, 3-dihydro- [1,4]]Dioxane [2,3-f ]]-quinoline) 291mg, yield 80%.1H NMR(400MHz,DMSO-d6)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]+。
Step 3) preparation of 5- (3-Morpholinopropoxy) -10- (4-Nitrophenoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinoline
Reference example 1, step 1) was conducted in the same molar equivalent of 10-chloro-5- (3-morpholinopropoxy) -2, 3-dihydro- [1, 4%]Dioxane [2,3-f ]]Quinoline substituted 10-chloro-5-methoxy-2, 3-dihydro- [1, 4%]Dioxane [2,3-f ]]Quinoline. MS 468[ M + H]+。
Step 4) preparation of 4- ((5- (3-Morpholinopropoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] -quinolin-10-yl) oxy) aniline
Reference example 1, step 2) was conducted in the same molar equivalent of 5- (3-morpholinopropoxy) -10- (4-nitrophenoxy) -2, 3-dihydro- [1, 4%]Dioxane [2,3-f ]]Quinoline substituted 5-methoxy-10- (4-nitrophenoxy) -2, 3-dihydro- [1, 4-]Dioxane [2,3-f ]]And (3) quinoline.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]+。
Step 5) preparation of N- (4-fluorophenyl) -N- (4- ((5- (3-morpholinopropoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) cyclopropane-1, 1-dicarboxamide
Reference example 1, step 3) was conducted in the same molar equivalents of 4- ((5- (3-morpholinopropoxy) -2, 3-dihydro- [1, 4)]Dioxane [2,3-f ]]Quinolin-10-yl) oxy) aniline as a substitute for 4- ((5-methoxy-2, 3-dihydro- [1, 4-dihydro-)]Dioxane [2,3-f ]]Quinolin-10-yl) oxy) aniline.1HNMR(400MHz,DMSO-d6)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]+。
Example 5 preparation of N- (3-fluoro-4- ((5- (3-morpholinopropoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Step 1 to step 2 are the same as step 1 to step 2 of the preparation of example 4.
Step 3) preparation of 10- (2-fluoro-4-nitrophenoxy) -5- (3-morpholinopropoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinoline
Figure GDA0002622842180000221
Reference example 4, step 3), the same molar equivalent of 2-fluoro-4 nitrophenol was used instead of p-nitrophenol. MS 486[ M + H]+。
Step 4) preparation of 3-fluoro-4- ((5- (3-morpholinopropoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) aniline
Figure GDA0002622842180000222
Reference example 1, step 2) was conducted in the same molar equivalent of 10- (2-fluoro-4-nitrophenoxy) -5- (3-morpholinopropoxy) -2, 3-dihydro- [1, 4%]Dioxane [2,3-f ]]Quinoline substituted 5-methoxy-10- (4-nitrophenoxy) -2, 3-dihydro- [1, 4-]Dioxane [2,3-f ]]And (3) quinoline.1H NMR(400MHz,DMSO-d6)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]+。
Step 5) preparation of N- (3-fluoro-4- ((5- (3-morpholinopropoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000231
Reference example 1, step 3), operating at the same molar equivalents3-fluoro-4- ((5- (3-morpholinepropoxy) -2, 3-dihydro- [1, 4)]Dioxane [2,3-f ]]-quinolin-10-yl) oxy) aniline for 4- ((5-methoxy-2, 3-dihydro- [1, 4)]Dioxane [2,3-f ]]Quinolin-10-yl) oxy) aniline.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]+。
Example 6 preparation of N- (2-fluoro-4- ((5- (3-morpholinopropoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Step 1 to step 2 are the same as step 1 to step 2 of the preparation of example 4.
Step 3) preparation of 10- (3-fluoro-4-nitrophenoxy) -5- (3-morpholinopropoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinoline
Figure GDA0002622842180000232
Reference example 4, step 3), the same molar equivalent of 3-fluoro-4 nitrophenol was used instead of p-nitrophenol.1H NMR(400MHz,DMSO-d6)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]+。
Step 4) preparation of 2-fluoro-4- ((5- (3-morpholinopropoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) aniline
Figure GDA0002622842180000241
Reference example 1, step 2) was conducted in the same molar equivalent of 10- (3-fluoro-4-nitrophenoxy) -5- (3-morpholinopropoxy) -2, 3-dihydro- [1, 4%]Dioxane [2,3-f ]]-quinoline substituted 5-methoxy-10- (4-nitrophenoxy) -2, 3-dihydro- [1,4]Dioxane [2,3-f ]]And (3) quinoline.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]+。
Step 5) preparation of N- (2-fluoro-4- ((5- (3-morpholinopropoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000242
Reference example 1, step 3) was conducted in the same molar equivalent of 2-fluoro-4- ((5- (3-morpholinopropoxy) -2, 3-dihydro- [1, 4)]Dioxane [2,3-f ]]Quinolin-10-yl) oxy) aniline as a substitute for 4- ((5-methoxy-2, 3-dihydro- [1, 4-dihydro-)]Dioxane [2,3-f ]]Quinolin-10-yl) oxy) aniline.1H NMR(400MHz,DMSO-d6)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]+。
Example 7N- (4- ((5-ethoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) -3-fluorophenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000251
Step 1.10-chloro-5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinoline (2.5g,10mmol), 2-fluoro-4-nitrophenol (1.6g,10mmol) and potassium carbonate (2.1g,15mmol) in DMF (20mL) was heated to 80 ℃ for reaction for 3 hours, cooled, slurried with water, filtered and dried to give a white-like solid product (10- (2-fluoro-4-nitrophenoxy) -5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinoline) 3.5g, yield 94%;
step 2, adding the product (350mg, 1mmol) obtained in the step 1 into an acetic acid solution (33 percent, 5mL) of hydrogen bromide, heating to 90 ℃, reacting for 15 hours, cooling, adding ethyl acetate (15mL), pulping, filtering and drying to obtain a light green solid (10- (2-fluoro-4-nitrophenoxy) -2, 3-dihydro- [1, 4-nitro-phenoxy) -2, 3-dihydro- [1]Dioxane [2,3-f ]]Bishydrobromide salt of quinolin-5-ol) 3.8g, yield 87%, MS 359[ M + H]+；
Step 3, adding bromoethane (165mg,1.5mmol) and potassium carbonate (280mg,2mmol) into a DMF (5mL) solution of the product (440mg,1mmol) obtained in the step 2 respectively, heating to 80 ℃, reacting for 10 hours, cooling, adding water, extracting with ethyl acetate, washing with a saturated sodium chloride solution, drying, concentrating, and purifying by column chromatography to obtain a light yellow solid product (320mg of 10- (2-fluoro-4-nitrophenoxy) -5-ethoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinoline), wherein the yield is 83%;
step 4, adding raney nickel into the methanol (30mL) solution of the product (320mg) obtained in the step 3, stirring and reacting for 3 hours at room temperature under the hydrogen atmosphere, filtering, washing, and concentrating the filtrate to obtain a purple solid product (3-fluoro-4- ((5-ethoxy-2, 3-dihydro- [1, 4)]Dioxane [2,3-f ]]Quinolin-10-yl) oxy) aniline) 290mg, yield 81%, MS:357[ M + H ], (M + H)]+；
Step 5, adding a dichloromethane (0.5mL) solution of 1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-formyl chloride (24mg,0.1mmol) and triethylamine (0.1mL) into an NMP solution (1mL) of the product (36mg, 0.1mmol) obtained in the step 4 respectively, stirring at room temperature for reaction for 5 hours, adding water for quenching, filtering to obtain a light yellow solid, and purifying a preparation liquid phase to obtain a white solid product 24mg with the yield of 43%;1H NMR(600MHz,DMSO-d6)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]+。
example 8N- (4- ((5- (3- (dimethylamino) propoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) -3-fluorophenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000261
Preparation was carried out in a similar manner to example 7, except that in step 3, an equivalent amount of dimethylaminopropyl chloride was reacted instead of ethyl bromide to give a white solid product;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]+。
example 9N- (4- ((5- (3- (piperidin-1-yl) propoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) -3-fluorophenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000262
Preparation was carried out in a similar manner to example 7, except that in step 3, an equivalent amount of (piperidin-1-yl) propyl chloride was reacted instead of ethyl bromide to give a white solid product;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]+。
example 10N- (3-fluoro-4- ((5- (2-methoxyethoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000263
The preparation was carried out in a similar manner to example 7, except that in step 3, an equivalent amount of methoxyethyl bromide was reacted instead of ethyl bromide to give a white solid product;1H NMR(400MHz,DMSO-d6)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]+。
example 11N- (4- ((5- (cyclopropylmethoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) -3-fluorophenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000271
Preparation was carried out in a similar manner to example 7, except that in step 3, an equivalent amount of cyclopropylmethyl bromide was reacted instead of ethyl bromide to give a white solid product;1H NMR(400MHz,DMSO-d6)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]+。
example 12N- (4- ((5- (isobutyloxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) -3-fluorophenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000272
Preparation was carried out in a similar manner to example 7, except that in step 3, ethyl bromide was replaced with an equivalent of isobutyl bromide to give a white solid product;1H NMR(400MHz,DMSO-d6)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]+。
example 13N- (3-fluoro-4- ((5- (3-hydroxypropoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000281
Preparation was carried out in a similar manner to example 7, except that in step 3, 3-bromopropanol of equivalent weight was reacted instead of ethyl bromide to give a white solid product;1H NMR(600MHz,DMSO-d6)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]+。
example 14N- (3-fluoro-4- ((5- (3-methoxypropoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000282
Preparation was carried out in a similar manner to example 7, except that in step 3, an equivalent amount of methoxypropyl bromide was reacted instead of ethyl bromide to give a white solid product;1H NMR(600MHz,DMSO-d6)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]+。
example 15N- (3-fluoro-4- ((5- (3- ((2-methoxyethyl) (methyl) amino) propoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000291
Preparation was carried out in a similar manner to example 7, except that in step 3, 3-bromo-N- (2-methoxyethyl) -N-methylpropyl-1-amine was reacted in an equivalent amount instead of ethyl bromide to give a white solid product;1H NMR(600MHz,DMSO-d6)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]+。
example 16N- (3-fluoro-4- ((5-isopropoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000292
Preparation was carried out in a similar manner to example 7, except thatIn the step 3, equivalent isopropyl bromide is used for replacing bromoethane to react to obtain a white solid product;1H NMR(600MHz,DMSO-d6)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]+。
example 17N- (3-fluoro-4- ((5- ((tetrahydrofuran-3-yl) oxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000293
Preparation was carried out in a similar manner to example 7, except that in step 3, tetrahydrofuran-3-yl p-toluenesulfonate was reacted in an equivalent amount in place of ethyl bromide to give a white solid product;1H NMR(600MHz,DMSO-d6)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]+。
example 18N- (3-fluoro-4- ((5- ((tetrahydropyran-4-yl) oxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000301
Preparation was carried out in a similar manner to example 7 except that tetrahydropyran-4-yl p-toluenesulfonate was reacted in step 3 in an equivalent amount instead of bromoethane to give a white solid product;1H NMR(600MHz,DMSO-d6)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]+。
example 19N- (4- ((5- (3- (4-acetylpiperazin-1-yl) propoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) -3-fluorophenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000302
Preparation was carried out in a similar manner to example 7, except that in step 3, 4-acetylpiperazin-1-ylpropyl chloride in equivalent amount was reacted instead of ethyl bromide to give a white solid product;1H NMR(400MHz,DMSO-d6)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]+。
example 20N- (4- ((5- (cyanomethoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) -3-fluorophenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000311
The preparation was carried out in a similar manner to example 7, except that in step 3, bromoethane was replaced by equivalent bromoacetonitrile to give a white solid product;1H NMR(400MHz,DMSO-d6)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]+。
example 21N- (4- ((5- (3- (4-methylpiperazin-1-yl) propoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) -3-fluorophenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000312
Preparation was carried out in a similar manner to example 7, except that in step 3, 4-methylpiperazin-1-ylpropyl bromide in equivalent amount was reacted instead of ethyl bromide to give a white solid product;1H NMR(600MHz,DMSO-d6)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]+。
example 22N- (3-fluoro-4- ((5- (3- (4-hydroxy-4-methylpiperidin-1-yl) propoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000321
Preparation was carried out in a similar manner to example 7, except that in step 3, an equivalent amount of (4-hydroxy-4-methylpiperidin-1-yl) propyl bromide was reacted instead of ethyl bromide to give a white solid product;1H NMR(600MHz,DMSO-d6)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]+。
example 23N- (4- ((5- (3- (cyclobutyl (methyl) amino) propoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) -3-fluorophenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000322
Preparation was carried out in a similar manner to example 7 except that 3- (cyclobutyl (methyl) amino) propyl bromide in equivalent amount was reacted in step 3 instead of ethyl bromide to give a white solid product;1H NMR(600MHz,DMSO-d6)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]+。
example 24N- (4- ((5- (3- (1, 1-thiomorpholinedioxide-4-yl) propoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) -3-fluorophenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000331
Preparation was carried out in a similar manner to example 7, except that in step 3, an equivalent amount of 3- (1, 1-thiomorpholinedioxide-4-yl) propyl bromide was reacted instead of ethyl bromide to give a white solid product;1H NMR(600MHz,DMSO-d6)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]+。
example 25N- (3-fluoro-4- ((5- (3- (pyrrolidin-1-yl) propoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000332
Preparation was carried out in a similar manner to example 7, except that in step 3,3- (pyrrolidin-1-yl) propyl bromide was reacted in an equivalent amount instead of bromoethane to give a white solid product;1H NMR(600MHz,DMSO-d6)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]+。
example 26N- (3-fluoro-4- ((5- (3-cyanopropoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000333
Preparation was carried out in a similar manner to example 7, except that in step 3, bromoethane was replaced by equivalent amounts of bromobutyronitrile to give a white solid product;1H NMR(600MHz,DMSO-d6)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]+。
example 27N- (4- ((5- ((6- (dimethylamino) hexyl) oxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) -3-fluorophenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000341
Preparation was carried out in a similar manner to example 7, except that 6-dimethylaminohexylbromide having an equivalent weight was reacted in step 3 instead of ethyl bromide to give a white solid product;1H NMR(600MHz,DMSO-d6)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]+。
example 28N- (3-fluoro-4- ((5- (oxetan-3-oxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000342
Preparation was carried out in a similar manner to example 7, except that in step 3, oxetan-3-yl p-toluenesulfonate was reacted in an equivalent amount in place of ethyl bromide to give a white solid product;1H NMR(600MHz,DMSO-d6)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]+。
example 29N- (3-fluoro-4- ((5- (3- (4, 4-dimethylpiperidin-1-yl) propoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000351
Preparation was carried out in a similar manner to example 7, except that in step 3, an equivalent amount of (4, 4-dimethylpiperidin-1-yl) propyl bromide was reacted instead of ethyl bromide to give a white solid product;1H NMR(600MHz,DMSO-d6)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]+。
example 30N- (3-fluoro-4- ((5- (3- (4-amino-4-methylpiperidin-1-yl) propoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000352
Preparation was carried out in a similar manner to example 7, except that in step 3, an equivalent amount of (4-amino-4-methylpiperidin-1-yl) propyl bromide was reacted instead of ethyl bromide to give a white solid product;1H NMR(600MHz,DMSO-d6)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]+。
example 31N- (3-chloro-4- ((5- (3-morpholinopropoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000361
Preparation was carried out in a similar manner to example 7 except that 2-chloro-4-nitrophenol was used in place of 2-fluoro-4-nitrophenol in step 1 and 4- (3-chloropropyl) morpholine was used in place of bromoethane in step 3 to give a white solid product;1H NMR(600MHz,DMSO-d6)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]+。
example 32N- (3-fluoro-4- ((5- (2-hydroxyethoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000362
Preparation was carried out in a similar manner to example 7, except that in step 3, 2-bromoethanol having an equivalent weight was reacted instead of ethyl bromide to give a white solid product;1H NMR(400MHz,DMSO-d6)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]+。
example 33N- (4- ((5- ((1-aminocyclopropyl) methoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) -3-fluorophenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000363
Preparation was carried out in a similar manner to example 7 except that in step 3, an equivalent amount of 4-methylbenzenesulfonic acid (1- ((tert-butyloxycarbonyl) amino) cyclopropyl) methyl ester was reacted instead of bromoethane to give a white solid product;
1H NMR(400MHz,DMSO-d6)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]+。
example 34N- (3-fluoro-4- ((5- (2-hydroxy-2-methylpropoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000371
Preparation was carried out in a similar manner to example 7, except that in step 3, 1-bromo-2-methylpropyl-2-ol in equivalent amount was reacted instead of bromoethane to give a white solid product;1H NMR(400MHz,DMSO-d6)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]+。
example 35N- (2-chloro-5-fluoro-4- ((5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000372
To and withExample 7 was prepared in a similar manner except that 5-chloro-2-fluoro-4-nitrophenol was reacted in step 1 in an equivalent amount instead of 2-fluoro-4-nitrophenol to give a white solid product;1H NMR(400MHz,DMSO-d6)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]+。
example 36N- (2-chloro-4- ((5- (3-morpholinopropoxy) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide
Figure GDA0002622842180000381
Preparation was carried out in a similar manner to example 7, except that in step 1, 2-fluoro-4-nitrophenol was replaced by an equivalent of 3-chloro-4-nitrophenol and in step 3, bromoethane was replaced by an equivalent of 4- (3-chloropropyl) morpholine to give a white solid product;1H NMR(600MHz,DMSO-d6)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]+。
EXPERIMENTAL EXAMPLE 1 test for the inhibition of c-MET kinase Activity by Small molecule Compounds
Based on the LANCE TR-FRET technique of Perkin Elmer, the test method is as follows:
1. compound dilution: a total of 11 concentrations were obtained starting from the highest 2500nM concentration at a 3-fold gradient (2500 nM maximum final concentration and 0.042nM minimum final concentration of drug used in this experiment).
2. mu.L of the compound diluted in a gradient was taken with a discharge gun and added to a 384-well plate.
3. Adding an enzyme: mu.L of 2X c-MET kinase solution (concentration: 2nM) was added to the corresponding reaction well of 384-well plate by a line gun, mixed well and pre-reacted at room temperature for 5 minutes.
4. Discharging 2.5 μ L4X Ultra heightTMThe JAK-1(Tyr1023) Peptide (400 nM concentration)/ATP (40. mu.M) mixture was added to the corresponding reaction wells of a 384-well plate.
5. Negative control: add 2.5. mu.L/well 4 Xsubstrate/ATP mix and 7.5. mu.L 1X Kinase Assay buffer to the 384 well plate.
6. Positive control: to a 384 well plate was added 2.5. mu.L/well of 4X substrate/ATP mix, 2.5. mu.L/well of 1X Kinase Assay Buffer containing 16% DMSO, 5. mu.L/well of 2X c-MET Kinase solution. The final concentration of DMSO in the reaction system was 4%.
7. And (4) centrifuging, mixing uniformly, and reacting for 60 minutes at room temperature in the dark.
8. Termination of the enzymatic reaction: and 5 mu L of 4X stop solution is taken by a discharging gun and added into a mesopore of a 384-pore plate, and the mixture is centrifuged and mixed evenly and reacted for 5 minutes at room temperature.
9. And (3) color development reaction: and (3) adding 5 mu L of 4X detection solution into a mesopore of a 384-pore plate by using a discharge gun for color development, centrifuging and uniformly mixing, and reacting for 60 minutes at room temperature.
10. And (3) putting the 384-well plate into an Envision plate reading instrument to read the plate, and calling a corresponding program detection signal.
11. Analysis and processing of raw data:
12. the drug concentration and the corresponding inhibition rate are input into GraphPad Prism5 for calculation, and the inhibition rate of the compound is calculated as follows: inhibition (%) - (positive well reading-experimental well reading)/(positive control well reading-negative control well reading) x 100%. Treatment with GraphPad Prism5 software gave the corresponding IC50 value (concentration of compound at which the highest inhibition of the enzyme was 50%).
Table 1 shows the results of the determination of the inhibitory activity of a part of the compounds of the present invention on the tyrosine kinase c-MET, wherein A represents IC50Less than or equal to 50nM, B represents IC50Greater than 50nM but less than or equal to 500nM, C represents IC50Greater than 500nM but less than or equal to 5000nM, D represents IC50Greater than 5000 nM.
TABLE 1 results of the determination of the inhibitory Activity of partial Compounds of the present invention on c-MET tyrosine kinase
Figure GDA0002622842180000391
EXAMPLE 2 test of the inhibition of VEGFR-2 kinase Activity by Small molecule Compounds
Based on the LANCE TR-FRET technique of Perkin Elmer, the test method is as follows:
1. compound dilution: a total of 11 concentrations were obtained starting from the highest 2500nM concentration at a 3-fold gradient (2500 nM maximum final concentration and 0.042nM minimum final concentration of drug used in this experiment).
2. mu.L of the compound diluted in a gradient was taken with a discharge gun and added to a 384-well plate.
3. Adding an enzyme: mu.L of 2X VEGFR-2 kinase solution (concentration: 0.5nM) was added to the corresponding reaction well of 384-well plate using a line gun, mixed well and pre-reacted at room temperature for 30 minutes.
4. Discharging 2.5 μ L4X Ultra heightTMThe JAK-1(Tyr1023) Peptide (200 nM)/ATP (40. mu.M) mixture was added to the corresponding reaction wells of a 384-well plate.
5. Negative control: add 2.5. mu.L/well 4 Xsubstrate/ATP mix and 7.5. mu.L 1X Kinase Assay buffer to the 384 well plate.
6. Positive control: to a 384 well plate was added 2.5. mu.L/well of 4X substrate/ATP mix, 2.5. mu.L/well of 1X Kinase Assay Buffer containing 16% DMSO, 5. mu.L/well of 2X VEGFR-2 Kinase solution. The final concentration of DMSO in the reaction system was 4%.
7. And (4) centrifuging, mixing uniformly, and reacting for 60 minutes at room temperature in the dark.
8. Termination of the enzymatic reaction: and 5 mu L of 4X stop solution is taken by a discharging gun and added into a mesopore of a 384-pore plate, and the mixture is centrifuged and mixed evenly and reacted for 5 minutes at room temperature.
9. And (3) color development reaction: and (3) adding 5 mu L of 4X detection solution into a mesopore of a 384-pore plate by using a discharge gun for color development, centrifuging and uniformly mixing, and reacting for 60 minutes at room temperature.
10. And (3) putting the 384-well plate into an Envision plate reading instrument to read the plate, and calling a corresponding program detection signal.
11. Analysis and processing of raw data:
the drug concentration and the corresponding inhibition rate are input into GraphPad Prism5 for calculation, and the inhibition rate of the compound is calculated as follows: inhibition (%) - (positive well reading-experimental well reading)/(positive control well reading-negative control well reading) x 100%. The corresponding IC was obtained by software processing of GraphPad Prism550Value (concentration of compound at which the highest inhibition of the enzyme was 50%).
Table 2 shows the results of the determination of the inhibitory activity of some of the compounds of the invention on the tyrosine kinase VEGFR-2, in which A denotes IC50Less than or equal to 50nM, B represents IC50Greater than 50nM but less than or equal to 500nM, C represents IC50Greater than 500nM but less than or equal to 5000nM, D represents IC50Greater than 5000 nM.
TABLE 2 results of the determination of VEGFR-2 tyrosine kinase inhibitory Activity of some of the Compounds of the invention
Figure GDA0002622842180000411
EXAMPLE 3 testing of the inhibitory Activity of Small molecule Compounds on MHCC97H cell proliferation
The specific experimental steps are as follows:
1. compound dilution: a total of 9 concentrations were obtained starting from the highest concentration of 5000nM after 3-fold gradient dilution (5000 nM for the maximum final concentration of drug and 0.76nM for the minimum final concentration in this experiment).
2. MHCC97H cells were collected and transferred to a 15mL centrifuge tube and centrifuged at 1000rpm for 5 minutes.
3. Discarding the supernatant, adding complete culture solution, blowing and beating uniformly, mixing 10 μ L of cell suspension and 10 μ L of 0.4% trypan blue uniformly, counting by using a cell counter, and recording the number of cells and the survival rate;
4. inoculating 5000 cells/80 μ L of cell suspension per well into a 96-well plate;
5. adding 20 μ L of the 5 × compound solution diluted with the culture medium into each well, mixing and shaking;
6. after 72 hours of culture, 10 mu L of CCK-8 reagent is added into each well, and the culture is carried out for 2 hours (the reaction time can be adjusted according to the color depth);
7. the OD value was read at 450nm on a multifunction plate reader.
8. Data processing: cell survival (%) - (As-Ab)/(Ac-Ab) ]. 100%
As: OD value of the experimental well (cell-containing medium, CCK-8, compound),
ac: OD value of control well (cell-containing medium, CCK-8),
ab: OD of blank wells (medium without cells and compounds, CCK-8),
the values were then introduced into Graphpad Prism5 software for curve fitting and IC50 was calculated.
Table 3 shows the results of the test of the proliferation inhibitory activity of a part of the compounds of the present invention on MHCC97H cell line.
TABLE 3 test results for the inhibitory Activity of some of the compounds of the invention on MHCC97H cell proliferation
Figure GDA0002622842180000421
The biological data provided herein demonstrate that the compounds of the invention are useful for treating or preventing diseases caused by abnormal VEGFR-2 or c-MET kinases. Accordingly, the compounds of the present 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, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumors, B-cell and T-cell lymphomas, lymphoma, multiple myeloma, biliary sarcoma, cholangiocarcinoma, and the like. The compounds of the invention also include the treatment of cancer resistant to one or more other therapeutic methods. The compounds of the present invention are also useful in diseases other than cancer associated with VEGFR-2 kinase and/or c-MET kinase, including but not limited to ocular fundus disease, psoriasis, rheumatoid arthritis, atheroma, pulmonary fibrosis, liver fibrosis. The compounds of the present invention may be administered as monotherapy or in combination therapy, in combination with a plurality of the compounds of the present invention or in combination with other drugs other than those of the present invention.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (22)

1. A compound represented by the formula (I), or a pharmaceutically acceptable salt thereof,
Figure FDA0002924536220000011
in the formula (I), the compound is shown in the specification,
q is CH;
g is O;
z is CH;
l is
Figure FDA0002924536220000012
Wherein n is 0-3, and when n is 0, L represents
Figure FDA0002924536220000013
R1Is H, C1-C6Alkyl radical, C3-C7Cycloalkyl of (2), 4-to 7-membered heterocyclyl, C3-C7Cycloalkyl-substituted C of1-C6Alkyl, 4-7 membered heterocyclyl substituted C1-C6Alkyl, substituted C1-C6Alkyl, said substituted C1-C6The substituent of the alkyl is hydroxyl, C1-C6Alkoxy group of (C)1-C6Alkylthio or-NR of6R7One or more than one of the components (A),
R6and R7Are each independently H, C1-C6Alkyl, hydroxy substituted C1-C6Alkyl radical, C1-C3Alkoxy-substituted C1-C6An alkyl group;
the above-mentioned 4-7-membered heterocyclic group is a 4-7-membered heterocyclic group containing 1 to 2 atoms selected from N, O, S, and the 4-7-membered heterocyclic group is unsubstituted or substituted by C1-C3Alkyl radical, C1-C3Acyl substituted or oxidized by one to two oxygen atoms;
R2is H, C1-C3Alkyl or halogen of (a);
R3is H, C1-C3Alkyl or halogen of (a);
R4is H, C1-C3Alkyl or halogen of (a);
R5is aryl or heteroaryl;
said aryl, heteroaryl being unsubstituted or substituted by C1-C3One or more than one of alkyl, halogen and trifluoromethyl;
the heteroaryl group is a monocyclic or bicyclic group containing 1 to 3 heteroatoms selected from N, O, S and containing 5 to 10 ring atoms;
the aryl group is selected from phenyl, naphthyl and anthryl.
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1Is H, C1-C6Alkyl radical, C3-C6Cycloalkyl of (2), 5-to 6-membered heterocyclyl, C3-C6Cycloalkyl-substituted C of1-C3Alkyl, 5-6 membered heterocyclyl substituted C1-C3Alkyl, substituted C1-C6Alkyl, said substituted C1-C6The substituent of the alkyl is hydroxyl, C1-C3Alkoxy group of (C)1-C3Alkylthio or-NR of6R7，
R6And R7Are each independently-H, C1-C3Alkyl, hydroxy substituted C1-C3Alkyl radical, C1-C3Alkoxy-substituted C1-C3An alkyl group, a carboxyl group,
the above-mentioned 5-6-membered heterocyclic group is a 5-6-membered heterocyclic group containing 1 to 2 atoms selected from N, O, S, said 5-6-membered heterocyclic group being unsubstituted or substituted by C1-C3Alkyl radical, C1-C3Acyl groups are substituted or oxidized by one to two oxygen atoms.
3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1Selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydropyren-1-yl-ethyl, tetrahydropyren-1-yl-propyl, piperidin-1-yl-ethyl, piperidin-1-yl-propyl, piperazin-1-yl-ethyl, piperazin-1-yl-propyl, morpholin-4-yl-ethyl, morpholin-4-yl-propyl, methylpiperazin-4-yl-ethyl, methylpiperazin-4-yl-propyl, N-formylpiperazin-4-yl-ethyl, N-formylpiperazin-4-yl-propyl, N-formylbenzyl-4-yl-propyl, N-methyl-propyl, N-, N-acetylpiperazin-4-ylethyl, N-acetylpiperazin-4-ylpropyl, (1, 1-dioxothiomorpholinyl) -4-ylethyl, (1, 1-dioxothiomorpholinyl) -4-ylpropyl, methylthioethyl, methylthiopropyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, dimethylaminopentyl, dimethylaminohexyl, diethylaminoethyl, diethylaminopropyl, hydroxyethyl, hydroxypropyl, hydroxyethylaminoethyl, hydroxypropylaminoethyl, hydroxyethylaminopropyl, methoxyethylaminoethyl, methoxypropylaminoethyl, aminoethyl, aminopropyl, aminobutyl, N-methyl-N-hydroxyethylaminoethyl, N-methyl-N-hydroxypropylaminoethyl, N-methyl-N-hydroxyethylaminopropyl, N-methyl-N-methoxyethylaminoethyl, N-methyl-N-methoxypropylaminoethyl, N-methyl-N-methoxyethylaminopropyl, 2-methyl-2-hydroxypropyl, 3-methyl-3-hydroxybutyl, (3S) -3-aminobutyl, (3R) -3-aminobutyl, (3S) -3-hydroxybutyl or (3One or more than one of R) -3-hydroxybutyl.
4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1Selected from: butyl, isobutyl, pentyl, isopentyl, hexyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, 4-dimethylpiperidin-1-ylethyl, 4-dimethylpiperidin-1-ylpropyl, oxetan-3-yl.
5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R2、R3、R4Wherein the halogen is Cl or F.
6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, R5Is phenyl, and the substituent of the phenyl is C1-C3One or more of alkyl, halogen and trifluoromethyl.
7. A compound according to claim 6, or a pharmaceutically acceptable salt thereof, R5Selected from the group consisting of phenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 3-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) phenyl, 3- (trifluoromethyl) -4-fluorophenyl, 2-fluoro-4-chlorophenyl, 2-fluoro-5-chlorophenyl, 3-fluoro-4-chlorophenyl, 2-fluoro-4-chlorophenyl, 3-chloro-4-chlorophenyl, and mixtures thereof, 3-fluoro-5-chlorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-4- (trifluoromethyl) phenyl, 2-chloro-5- (trifluoromethyl) phenyl, 3-chloro-4- (trifluoromethyl) phenyl, 3-chloro-5- (trifluoromethyl) phenyl, 3- (trifluoromethyl) -4-chlorophenyl, 2-chloro-4-fluorophenyl, or 2-chloro-5-fluorophenyl.
8. A compound represented by the formula (I), or a pharmaceutically acceptable salt thereof,
Figure FDA0002924536220000031
in the formula (I), the compound is shown in the specification,
q is CH;
g is O;
z is CH;
l is
Figure FDA0002924536220000032
Wherein n is 0-3, and when n is 0, L represents
Figure FDA0002924536220000033
R1Is selected from 1 to 3 halogen, cyano, -NRaRbOr C substituted by a substituent in a 4-7 membered heteroalicyclic group1-C6Alkyl, the 4-7 membered heteroalicyclic group is a 4-7 membered heteroalicyclic group containing 1-2 atoms selected from N, O, S as ring atoms, and the 4-7 membered heteroalicyclic group is substituted with 1 to 3 atoms selected from halogen, C1-C3Alkyl, hydroxy, -NH of2、C1-C3Substituted by a substituent in the acyl group,
Raand RbEach independently is-H, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy-substituted C1-C6Alkyl radical, C1-C3Alkylthio substituted C1-C6An alkyl group;
R2、R3、R4each independently is H, C1-C3Alkyl or halogen of (a);
R5is aryl or heteroaryl;
the aryl and heteroaryl are unsubstituted or substituted by 1-3 substituents selected from hydroxy, amino, cyano, C1-C3Substituted with one or more substituents selected from alkyl, halogen and trifluoromethyl;
the heteroaryl group is a monocyclic or bicyclic group containing 1 to 3 heteroatoms selected from N, O, S and containing 5 to 10 ring atoms;
the aryl group is selected from phenyl, naphthyl and anthryl.
9. A compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R1Is selected from 1 to 3 groups selected from-F, cyano, -NRaRbOr C substituted by a substituent in a 4-7 membered heteroalicyclic group1-C6An alkyl group, the 4-7-membered heteroalicyclic group is a 4-7-membered heteroalicyclic group containing 1-2 atoms selected from N, O, S as ring atoms, and the 4-7-membered heteroalicyclic group is substituted with 1 to 3 atoms selected from-F, C1-C3Alkyl, hydroxy, -NH of2、C1-C3Substituted by a substituent in the acyl group,
Raand RbEach independently is-H, C1-C3Alkyl radical, C3-C6Cycloalkyl radical, C1-C3Alkoxy-substituted C1-C3Alkyl radical, C1-C3Alkylthio substituted C1-C3An alkyl group;
R2、R3、R4each independently is-H, -F, or-Cl;
R5is phenyl, said phenyl is unsubstituted or substituted by 1-3 substituents selected from hydroxy, amino, cyano, C1-C3Is substituted with one or more substituents selected from the group consisting of alkyl, halogen and trifluoromethyl.
10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof,
q is CH;
g is O;
z is CH;
l represents
Figure FDA0002924536220000041
R1Is C1-C6Alkyl, or C substituted by 4-7 membered heterocyclic group1-C6Alkyl radical；
The above-mentioned 4-7-membered heterocyclic group is a 4-7-membered heterocyclic group containing 1 to 2 atoms selected from N, O, S, and the 4-7-membered heterocyclic group is unsubstituted or substituted by C1-C3Alkyl radical, C1-C3Acyl substituted or oxidized by one to two oxygen atoms;
R2is H or halogen;
R3is H or halogen;
R4is H or halogen;
R5is aryl; the aryl group is unsubstituted or substituted with one or more halogens.
11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof,
R1is C1-C6Alkyl, or C substituted by 5-6 membered heterocyclic group1-C3An alkyl group;
the above-mentioned 5-6-membered heterocyclic group is a 5-6-membered heterocyclic group containing 1 to 2 atoms selected from N, O, S.
12. A compound, or pharmaceutically acceptable salt thereof, according to claim 10, wherein R1Selected from the group consisting of methyl, ethyl, propyl, isopropyl, pyrrolidin-1-ylethyl, pyrrolidin-1-ylpropyl, piperidin-1-ylethyl, piperidin-1-ylpropyl, piperazin-1-ylethyl, piperazin-1-ylpropyl, morpholin-4-ylethyl, morpholin-4-ylpropyl, methylpiperazin-4-ylethyl, methylpiperazin-4-ylpropyl, N-formylpiperazin-4-ylethyl, N-formylpiperazin-4-ylpropyl, N-acetylpiperazin-4-ylethyl, N-acetylpiperazin-4-ylpropyl, (1, 1-dioxothiomorpholinyl) -4-ylethyl or (1, one or more than one of 1-dioxothiomorpholinyl) -4-yl propyl.
13. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
Figure FDA0002924536220000051
Figure FDA0002924536220000061
Figure FDA0002924536220000071
14. the compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt of the compound is selected from the hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, nitrate, phosphate, formate, acetate, propionate, glycolate, lactate, succinate, maleate, tartrate, malate, citrate, fumarate, gluconate, benzoate, mandelate, methanesulfonate, isethionate, benzenesulfonate, oxalate, palmitate, 2-naphthalenesulfonate, p-toluenesulfonate, cyclamate, salicylate, hexonate, trifluoroacetate, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, salts thereof, and pharmaceutically acceptable salts thereof, One or more of potassium, sodium and zinc salts.
15. A process for the preparation of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound of formula (II ') with a compound of formula (III') to produce a compound of formula (I), wherein Q, G, Z, L, R1、R2、R3、R4And R5As defined in any one of claims 1 to 13,
Figure FDA0002924536220000072
16. a process for the preparation of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, comprising the step of reacting a compound of formula (II') with a compound of formula (III) to produce a compound of formula (I), wherein Q, G, Z, L, R1、R2、R3、R4And R5As defined in any one of claims 1 to 13,
Figure FDA0002924536220000073
17. a compound of the formula (II') wherein Q, G, Z, R1、R2、R3And R4As defined in any one of claims 1 to 13,
Figure FDA0002924536220000081
18. a pharmaceutical composition consisting of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, as active ingredient, one or more additional therapeutic agents, and one or more pharmaceutically acceptable carriers or excipients.
20. Use of a compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease associated with the tyrosine kinases VEGFR-2 and/or c-MET, said disease comprising: fundus disease, psoriasis, rheumatoid arthritis, atheroma, pulmonary fibrosis, hepatic fibrosis, non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, nasopharyngeal cancer, esophageal cancer, brain tumor, lymphoma, multiple myeloma, sarcoma of biliary tract cancer, bile duct cancer.
21. The use according to claim 20, wherein the leukemia is chronic myelogenous leukemia, acute myelogenous leukemia.
22. The use of claim 20, wherein the lymphoma is non-hodgkin's lymphoma, B-cell and T-cell lymphoma.
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