WO2012171487A1 - Aryloxy quinolines derivatives and the treating use thereof - Google Patents

Aryloxy quinolines derivatives and the treating use thereof Download PDF

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WO2012171487A1
WO2012171487A1 PCT/CN2012/077016 CN2012077016W WO2012171487A1 WO 2012171487 A1 WO2012171487 A1 WO 2012171487A1 CN 2012077016 W CN2012077016 W CN 2012077016W WO 2012171487 A1 WO2012171487 A1 WO 2012171487A1
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decyloxy
yloxy
phenyl
piperidin
cyclopropane
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PCT/CN2012/077016
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French (fr)
Chinese (zh)
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陈从喜
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天津隆博基因药物科技有限公司
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Priority to CN201280028921.8A priority Critical patent/CN103748074B8/en
Publication of WO2012171487A1 publication Critical patent/WO2012171487A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4

Definitions

  • the invention belongs to the field of medicinal chemistry, and more particularly to a class of aryloxyquinoline derivatives, salts of the compounds, and medicaments using the compounds or salts thereof as active ingredients, mainly for treating tyrosine with protein Acid kinase receptors are especially diseases associated with c-Met, VEGFR and the like. Background technique
  • Protein kinases represent a large family of proteins that play a key role in the regulation of cellular function processes. Protein kinases can cause a variety of tumors due to mutations or rearrangements that can cause signals to go to process disorders or abnormalities, leading to abnormal cell growth, differentiation, metabolism, and biological behavior. Protein kinases mainly include serine/threonine kinases and tyrosine kinases, in which protein tyrosine kinases play an important role in the signaling pathways of tumor cells, transmitting extracellular signals into cells and amplifying and regulating them. A series of physiological processes such as tumor cell proliferation, differentiation and apoptosis are the centers of cell signal transduction mechanisms.
  • c-Met kinase is a hepatocyte growth factor receptor and is a member of the tyrosine kinase receptor family. c-Met kinase is widely present in epithelial tissues and plays an important role in embryo development and wound healing. Recent studies have shown that c-Met kinase exhibits abnormally high expression in tumor tissues such as lung cancer, colon cancer, liver cancer, rectal cancer, gastric cancer, kidney cancer, ovarian cancer, glioma, melanoma, breast cancer, and prostate cancer. Mutation or activity changes. c-Met kinase can promote the proliferation of tumor cells, regulate the migration of tumor cells, enhance the invasive ability of tumor cells and induce the formation of tumor blood vessels. At present, c-Met kinase has become an important target for anti-tumor drug research.
  • c-Met is the intersection of many pathways leading to tumor formation and metastasis. It plays an important role in the formation and metastasis of primary tumors. Simultaneous interference with many pathways can be achieved with c-Met as a target. Therefore, c-Met is a promising target for anti-tumor metastasis treatment and has become one of the hotspots of anti-tumor drug research.
  • Hepatocyte growth factor also known as the dispersing factor, is a ligand for the tyrosine kinase receptor c-Met and As a fibroblast-derived factor that induces the dispersion of epithelial cells, it has a mitogenic and induced morphogenesis effect on many epithelial cells.
  • HGF stimulates vascular endothelial growth factor and up-regulates the expression of molecules and their receptors involved in extracellular matrix proteolysis. In order to produce a biological effect, HGF must bind to its receptor c-Met, the receptor tyrosine kinase.
  • the specific membrane receptor of HGF is the expression product of the protooncogene c-Met, and its gene is located on chromosome 7q31, and the size of 110Kb contains 21 exons. Its promoter domain contains a number of regulatory sequences, including AP1, AP2, NF2JB, and SP1.
  • the HGF/c-Met signaling pathway plays an important role in the development of tumors. Specific binding of HGF to the c-Met receptor protein induces a conformational change in the c-Met receptor protein, activating the tyrosine protein kinase (PTK) in the receptor's intracellular protein kinase domain, which is HGF/c- The primary link of the Met signal transduction pathway.
  • PTK tyrosine protein kinase
  • the present invention provides a class of aryloxyquinoline derivatives having selective tyrosine protein kinase inhibitors whose main function is to exert anticancer effects by inhibiting tyrosine protein kinase activity.
  • the major tyrosine protein kinases inhibited by such compounds are c-Met, Abl, P38 ⁇ , PDGF-R and the like. Of course, such compounds may also inhibit other disease-associated protein kinases.
  • An object of the present invention is to provide an aryloxyquinoline derivative and a salt thereof or a solvate thereof.
  • a second object of the present invention is to provide a process for producing the above aryloxyquinoline derivatives and salts thereof or solvates thereof.
  • a third object of the present invention is to provide a pharmaceutical composition comprising the above aryloxyquinoline derivative and a salt thereof or a solvate thereof.
  • a fourth object of the present invention is to provide the use of the above aryloxyquinoline derivatives and salts thereof or solvates thereof.
  • the present invention provides an aryloxyquinoline derivative having the structure of formula (I), Oen
  • R 2 , R 3 , R4 are each independently selected from hydrogen, C r C 3 alkyl; optionally, R 2 , R 3 may form a 3-6 membered carbocyclic ring with the carbon atom to which it is attached, or R 2 , R 3, wherein one of R4 may be connected to form a 4-8 membered azacyclic ring.
  • X is hydrogen or a halogen atom
  • Ar is an aryl or heteroaryl group, and may be substituted by halogen, C r C 4 alkyl, halogenated C r C 4 alkyl, C r C 4 alkoxy, - alkoxy;
  • R 5 and R 6 are each independently selected from hydrogen, dC 4 alkyl, and may be optionally substituted by dC 4 alkoxy, 5-10 membered heterocyclic ring or 3-10 membered carbocyclic group;
  • R 7 is dC 4 alkyl, which may be optionally substituted by a 5-10 membered heterocyclic ring or a 3-10 membered carbocyclic group;
  • n 0, 1, 2 or 3;
  • n 1, 2 or 3;
  • G is 3-10 yuan containing N heterocyclic ring, and can be optionally substituted
  • Ri , R 5 , Ar, m and X are as defined by the structure of formula (I);
  • the invention provides a preferred compound of the formula (II): N-(3-Fluoro-4-(6-decyloxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)morpholine_4 -yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-diamide;
  • R 7 , Ar, X, m are as defined by the structure of formula (I);
  • the invention provides preferred compounds of the structure of formula (III):
  • the compounds provided herein have the structure of formula (IV):
  • R 7 , Ar, X, m are as defined by the structure of formula (I);
  • the invention provides a preferred compound of the formula (IV): ⁇ (3-fluoro-4-(6-decyloxy-7-((1-(2-( ⁇ )) Sulfo)ethyl)piperidin-4-yl)nonyloxy)quinoline-4-yloxy) Phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-diphthalamide;
  • a pharmaceutically acceptable salt thereof can form a salt with an acid, and a salt of a quinoline derivative can be produced by a method well known to those skilled in the art.
  • the common salts include organic acid salts, inorganic acid salts, and the like.
  • organic acid salts are citrate, fumarate, oxalate, malate, lactate, camphor sulfonate, p-toluene, barium salt, etc.; Salts include hydrohalides, sulfates, phosphates, nitrates, and the like.
  • a lower alkyl acid such as sulfonic acid, trifluorosulfonium sulfonic acid, etc.
  • it can form an oxime sulfonate, a trifluorosulfonium sulfonate; and an aryl sulfonic acid, such as benzenesulfonic acid or p-toluenesulfonic acid.
  • an organic carboxylic acid such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid, etc.
  • the -C 4 alkyl group includes a decyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, or a tert-butyl group.
  • the halogen includes fluorine, chlorine, bromine and iodine.
  • the halogenated C r C 4 alkyl group means having one or more surface groups on the dC 4 carbon chain, such as a trifluoromethyl group.
  • the invention provides a process for the preparation of the above compounds:
  • each of the above compounds in the above-mentioned production method is as defined in the compound of the formula (I).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above aryloxyquinoline derivative or a salt or solvate of the compound as an active ingredient.
  • the pharmaceutical composition may also contain one or more pharmaceutically acceptable carriers including conventional diluents in the pharmaceutical field, excipients, fillers, binders, wetting agents, disintegrants, absorption promotion Agent, surfactant, adsorption carrier, lubricant, etc., if necessary To add flavoring agents, sweeteners, and the like.
  • the pharmaceutical composition of the present invention can be prepared into various forms such as tablets, powders, granules, capsules, oral liquids and injectable preparations, and the medicaments of the above respective dosage forms can be prepared according to a conventional method in the pharmaceutical field.
  • the present invention provides the use of an aryloxyquinoline derivative of the present invention or a salt or solvate of the compound for treating a human or animal disease associated with a tyrosine kinase, particularly c-Met, VEGFR, including treatment of hyperplasia Sexual diseases such as cancer, or inflammatory diseases.
  • the inventors of the present invention confirmed by experiments that the compound of the present invention has an anti-value-inhibiting action against a human gastric cancer cell line (MGC-803), and can be applied to a drug for treating solid tumors or blood cancer associated with human or animal cell proliferation.
  • MMC-803 human gastric cancer cell line
  • Step 8 Synthesis of 4-(4-(2-fluoro-4-nitrophenoxy)-6-methoxyoxyquinolin-7-yloxy)piperidine-1-indolyl tert-butyl ester
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 1 The synthesis procedure is referred to in Example 1.
  • Example 53 Compound of the present invention is swollen; i cell proliferation inhibition test
  • the tumor cells were trypsinized, they were seeded in a 96-well microplate at a density of 3,000 per well. Incubate for 24 hours in 10% FBS in complete medium. Add the test compound and solvent control, the final compound concentration is 10nmol / L to 5 ( ⁇ mol / L. Then cultured in complete medium for 72 hours. Add MTS reagent (Promega) according to the instructions, at 37 °C C0 2 The culture was incubated for 2 hours in an incubator, and then the absorbance at 490 nm was read on an ELISA plate reader, and the inhibition rate and IC 5 value were calculated.
  • MTS reagent Promega
  • XL-184 is N-(4-((6,7-dimethoxyoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl) Cyclopropane-1, 1-diamide.
  • the target compound has a high inhibitory effect on proliferation of MGC-803 (stomach cancer cells). Most of the compounds are superior to the positive drug Cabozantinib, which is equivalent to the activity of doxorubicin. In addition, the target compound has a higher affinity for BGC-823 (stomach cancer cells). High in vitro proliferation inhibition is superior to the positive drug Cabozantinib.
  • Example 54 Enzyme inhibition assay of the compounds of the invention c-Met and VEGFR2
  • the tyrosine kinase c-Met was expressed in the laboratory using the insect baculovirus expression system, and was affinity-purified by Ni-NTA column, and tested to meet the experimental requirements;
  • the kinase reaction substrate Poly(Glu, Tyr)B 4:1 was purchased from Sigma;
  • Monoclonal antibody against phosphotyrosine PY99 was purchased from Santa Cruz;
  • Horseradish peroxidase-labeled goat anti-mouse IgG was purchased from Calbiochem;
  • ATP, DTT, OPD were purchased from Amresco;
  • the ELISA plate was purchased from Corning; PF2341066 was purchased from LC LabORATORIES;
  • the enzyme reaction substrate Poly(Glu, Tyr)B 4:1 was diluted to 20 g/ml with PBS without potassium ions, coated with the enzyme plate, and reacted at 37 °C for 12-16 h, and discarded in the well. liquid.
  • test sample was first prepared in DMSO with 10 - 2 M stock solution, and stored at -20 ° C after being dispensed. Dilute to the desired concentration with reaction buffer before use, and add it to the test well to make it The corresponding final concentration is reached in the 100 ⁇ reaction system. A positive control well was also established and the positive control compound PF2341066 was added.
  • ATP solution diluted with the reaction buffer (ATP final concentration of 5 ⁇ ) was added, and finally, the test tyrosine kinase diluted with the reaction buffer was added.
  • the total volume of the reaction system is 100 ⁇ l. Negative control wells and enzyme-free control wells were also established.
  • Horseradish peroxidase-labeled goat anti-mouse IgG 100 ⁇ /well was added and shaken at 37 ° C for 30 min. The plate was washed three times with T-PBS.
  • the tyrosine kinase VEGFR2 was expressed in the laboratory using the insect baculovirus expression system, and was affinity-purified by Ni-NTA column, and tested to meet the experimental requirements; the kinase reaction substrate Poly(Glu, Tyr) 4:1 was purchased from Sigma Corporation;
  • Monoclonal antibody against phosphotyrosine PY99 was purchased from Santa Cruz;
  • Horseradish peroxidase-labeled goat anti-mouse IgG was purchased from Calbiochem;
  • ATP, DTT, OPD were purchased from Amresco;
  • the ELISA plate was purchased from Corning;
  • Sul l248 was purchased from LC LabORATORIES
  • the enzyme reaction substrate Poly(Glu, Tyr) 4:1 was diluted to 20 g/ml with PBS without potassium ion, coated with the enzyme plate, and reacted at 37 ° C for 12-16 h, discarding the liquid in the well. .
  • test sample was first prepared into 10 - 2 M stock solution in DMSO, and stored at - 20 ° C after being dispensed. Dilute to the desired concentration with the reaction buffer before use, and add it to the test well to make it The corresponding final concentration is reached in the 100 ⁇ reaction system. A positive control well was also established and the positive control compound SU11248 was added.
  • Horseradish peroxidase-labeled goat anti-mouse IgG 100 ⁇ /well was added and shaken at 37 °C for 30 min. The plate was washed three times with T-PBS.
  • the aryloxyquinoline derivative compound of the present invention has an anti-inhibitory inhibitory effect on a human gastric cancer cell line (MGC-803), and can be applied to a drug for treating solid tumors or blood cancer associated with cell proliferation of human or animal cells.

Abstract

Disclosed herein are aryloxy quinolines derivatives，and the said compounds are compounds of formula (I) or pharmaceutically acceptable salts thereof or solvates, wherein R1, R2, R3, R4, m, n, X, Z, Ar are defined detailedly in the description. Furthermore, medicaments comprising said compounds or salts as active components and the use for treating conditions and disorders relating to protein-tyrosine kinase receptors, especially c-Met, VEGFR are also described.

Description

芳氧基喹啉类衍生物及其治疗用途  Aryloxyquinoline derivatives and therapeutic uses thereof
技术领域 Technical field
本发明属于药物化学领域， 更具体地说， 涉及一类芳氧基喹啉类衍生物， 该 化合物的盐， 和以该化合物或其盐为活性成分的药物， 主要用于治疗与蛋白酪氨 酸激酶受体尤其是与 c-Met, VEGFR等有关的疾病。 背景技术  The invention belongs to the field of medicinal chemistry, and more particularly to a class of aryloxyquinoline derivatives, salts of the compounds, and medicaments using the compounds or salts thereof as active ingredients, mainly for treating tyrosine with protein Acid kinase receptors are especially diseases associated with c-Met, VEGFR and the like. Background technique
蛋白激酶代表了一大家族在对细胞功能过程的调控中起关键作用的蛋白质。 蛋白激酶由于突变或重排，可引起信号转到过程障碍或出现异常，导致细胞生长、 分化、 代谢和生物学行为异常， 因而可诱发多种肿瘤。 蛋白激酶主要包括丝氨酸 /苏氨酸激酶和酪氨酸激酶，其中蛋白酪氨酸激酶在肿瘤细胞的信号传导通路中占 有十分重要的地位， 将细胞外的信号传递到细胞内并加以放大， 调节着肿瘤细胞 增殖、 分化、 凋亡等一系列生理过程， 是细胞信号转导机制的中心。 研究表明， 近 80%的致癌基因都含有酪氨酸激酶编码。抑制酪氨酸激酶受体可以有效控制下 游信号的磷酸化， 从而抑制肿瘤细胞的生长。  Protein kinases represent a large family of proteins that play a key role in the regulation of cellular function processes. Protein kinases can cause a variety of tumors due to mutations or rearrangements that can cause signals to go to process disorders or abnormalities, leading to abnormal cell growth, differentiation, metabolism, and biological behavior. Protein kinases mainly include serine/threonine kinases and tyrosine kinases, in which protein tyrosine kinases play an important role in the signaling pathways of tumor cells, transmitting extracellular signals into cells and amplifying and regulating them. A series of physiological processes such as tumor cell proliferation, differentiation and apoptosis are the centers of cell signal transduction mechanisms. Studies have shown that nearly 80% of oncogenes contain tyrosine kinase codes. Inhibition of tyrosine kinase receptors can effectively control the phosphorylation of downstream signals, thereby inhibiting the growth of tumor cells.
c-Met激酶是肝细胞生长因子受体，是酪氨酸激酶受体家族成员之一。 c-Met 激酶广泛存在于上皮组织中， 在胚胎发育和创伤愈合中发挥着重要的作用。 最近 研究表明， c-Met激酶在肺癌、 结肠癌、 肝癌、 直肠癌、 胃癌、 肾癌、 卵巢癌、 神经胶质瘤、 黑色素瘤、 乳腺癌、 ***癌等肿瘤组织中呈现异常的高表达、 突 变或活性改变。 c-Met激酶能够促进肿瘤细胞的增殖， 调节肿瘤细胞的迁移， 增 强肿瘤细胞的侵袭能力并引发肿瘤新生血管的生成。 目前 c-Met激酶已经成为抗 肿瘤药物研究的一个重要靶点。  c-Met kinase is a hepatocyte growth factor receptor and is a member of the tyrosine kinase receptor family. c-Met kinase is widely present in epithelial tissues and plays an important role in embryo development and wound healing. Recent studies have shown that c-Met kinase exhibits abnormally high expression in tumor tissues such as lung cancer, colon cancer, liver cancer, rectal cancer, gastric cancer, kidney cancer, ovarian cancer, glioma, melanoma, breast cancer, and prostate cancer. Mutation or activity changes. c-Met kinase can promote the proliferation of tumor cells, regulate the migration of tumor cells, enhance the invasive ability of tumor cells and induce the formation of tumor blood vessels. At present, c-Met kinase has become an important target for anti-tumor drug research.
绝大多数恶性肿瘤的致死性是原发性肿瘤局部侵袭并转移至其它组织的结 果。 c-Met是导致肿瘤形成及转移的许多通路的交叉点， 在原发性肿瘤的形成和 转移中起着重要的作用，以 c-Met 为靶标可相对容易的实现对许多通路的同时干 扰， 因而 c-Met是抗肿瘤转移治疗的一个极有希望的靶点， 已成为抗肿瘤药物研 究的热点之一。  The lethality of most malignant tumors is the result of local invasion of the primary tumor and metastasis to other tissues. c-Met is the intersection of many pathways leading to tumor formation and metastasis. It plays an important role in the formation and metastasis of primary tumors. Simultaneous interference with many pathways can be achieved with c-Met as a target. Therefore, c-Met is a promising target for anti-tumor metastasis treatment and has become one of the hotspots of anti-tumor drug research.
肝细胞生长因子（HGF )又称分散因子是酪氨酸激酶受体 c-Met 的配体并且 作为一种可以诱导上皮细胞分散的成纤维细胞衍生因子，对许多上皮细胞均具有 促有丝***、 诱导形态发生的作用。 此外， HGF能刺激血管内皮生长因子， 还可 上调与细胞外基质蛋白水解相关的分子及其受体的表达。 为了产生生物效应， HGF 必须与其受体 c-Met 即受体酪氨酸激酶相结合。 HGF 的特异性膜受体是原 癌基因 c-Met 的表达产物， 其基因定位于染色体 7q31,大小级 110Kb含 21个外 显子。 其启动域包含许多的调控序列， 包括 AP1、 AP2、 NF2JB和 SP1 等。 Hepatocyte growth factor (HGF), also known as the dispersing factor, is a ligand for the tyrosine kinase receptor c-Met and As a fibroblast-derived factor that induces the dispersion of epithelial cells, it has a mitogenic and induced morphogenesis effect on many epithelial cells. In addition, HGF stimulates vascular endothelial growth factor and up-regulates the expression of molecules and their receptors involved in extracellular matrix proteolysis. In order to produce a biological effect, HGF must bind to its receptor c-Met, the receptor tyrosine kinase. The specific membrane receptor of HGF is the expression product of the protooncogene c-Met, and its gene is located on chromosome 7q31, and the size of 110Kb contains 21 exons. Its promoter domain contains a number of regulatory sequences, including AP1, AP2, NF2JB, and SP1.
HGF/c-Met信号通路在肿瘤的发生发展中具有重要的作用。 HGF 与 c-Met 受体蛋白特异性结合后，诱导 c-Met 受体蛋白发生构象改变， 激活受体胞内蛋白 激酶结构域中的酪氨酸蛋白激酶（PTK ) , 这是 HGF/c-Met信号转导通路的首要 环节。在大部分肿瘤细胞中 c-Met 靠近胞内区的 4磷酸化位点的酪氨酸残基发生 自身碑酸化， 接着通过一系列的磷酸化反应活化磷脂酶（PLC y ) , 磷酸肌醇 3 激酶（PI3K ) , Ras蛋白， Src 蛋白， 接头蛋白 Gabl 和生长因子受体结合蛋白 2 ( Grb2 )等蛋白的酪氨酸碑酸化。 经瀑布式的磷酸化反应， 将信号逐级放大， 最终转入细胞核内的转录机制， 从而调节肿瘤细胞的增值、 迁移和侵袭能力。 发明内容  The HGF/c-Met signaling pathway plays an important role in the development of tumors. Specific binding of HGF to the c-Met receptor protein induces a conformational change in the c-Met receptor protein, activating the tyrosine protein kinase (PTK) in the receptor's intracellular protein kinase domain, which is HGF/c- The primary link of the Met signal transduction pathway. In most tumor cells, the tyrosine residue of the 4-phosphorylation site near c-Met near the intracellular region undergoes its own acidification, followed by a series of phosphorylation reactions to activate phospholipase (PLC y), phosphoinositide 3 Tyrosine acidification of proteins such as kinase (PI3K), Ras protein, Src protein, adaptor protein Gabl and growth factor receptor binding protein 2 (Grb2). Through waterfall-type phosphorylation, the signal is amplified step by step, and finally transferred to the transcriptional mechanism in the nucleus, thereby regulating the proliferation, migration and invasion of tumor cells. Summary of the invention
本发明提供了一类芳氧基喹啉类衍生物， 其具有选择性的酪氨酸蛋白激酶抑 制剂， 它们的主要作用是通过抑制酪氨酸蛋白激酶活性而发挥其抗癌作用。 这类 化合物所抑制的主要酪氨酸蛋白激酶有 c-Met、 Abl、 P38 β 、 PDGF-R等。 当然， 这类化合物也可能抑制其它与疾病相关的蛋白激酶。  The present invention provides a class of aryloxyquinoline derivatives having selective tyrosine protein kinase inhibitors whose main function is to exert anticancer effects by inhibiting tyrosine protein kinase activity. The major tyrosine protein kinases inhibited by such compounds are c-Met, Abl, P38 β, PDGF-R and the like. Of course, such compounds may also inhibit other disease-associated protein kinases.
本发明的目的是提供一种芳氧基喹啉类衍生物及其盐或它们的溶剂化物。 本发明的第二个目的是提供上述芳氧基喹啉类衍生物及其盐或它们的溶剂 化物的制备方法。  An object of the present invention is to provide an aryloxyquinoline derivative and a salt thereof or a solvate thereof. A second object of the present invention is to provide a process for producing the above aryloxyquinoline derivatives and salts thereof or solvates thereof.
本发明的第三个目的是提供包含上述芳氧基喹啉类衍生物及其盐或它们的 溶剂化物的药物组合物。  A third object of the present invention is to provide a pharmaceutical composition comprising the above aryloxyquinoline derivative and a salt thereof or a solvate thereof.
本发明的第四个目的是提供上述芳氧基喹啉类衍生物及其盐或它们的溶剂 化物的用途。  A fourth object of the present invention is to provide the use of the above aryloxyquinoline derivatives and salts thereof or solvates thereof.
具体地说， 本发明提供了一种芳氧基喹啉类衍生物， 具有式 ( I )结构， oen
Figure imgf000004_0001
Specifically, the present invention provides an aryloxyquinoline derivative having the structure of formula (I), Oen
Figure imgf000004_0001
或其药学上可接受的盐或溶剂化物  Or a pharmaceutically acceptable salt or solvate thereof
其中： 为 d-C4烷基; Wherein: is dC 4 alkyl;
R2, R3, R4分别独立地选自氢、 CrC3烷基； 任选地， R2, R3可与其相连的 碳原子形成 3-6元碳环， 或者， R2, R3其中之一可与 R4相连形成 4-8元氮杂环。 R 2 , R 3 , R4 are each independently selected from hydrogen, C r C 3 alkyl; optionally, R 2 , R 3 may form a 3-6 membered carbocyclic ring with the carbon atom to which it is attached, or R 2 , R 3, wherein one of R4 may be connected to form a 4-8 membered azacyclic ring.
X为氢或面素原子；  X is hydrogen or a halogen atom;
Ar为芳基或杂芳基， 并可被卤素， CrC4烷基， 卤代 CrC4烷基， CrC4烷氧 基， -^烷氧基取代；
Figure imgf000004_0002
Ar is an aryl or heteroaryl group, and may be substituted by halogen, C r C 4 alkyl, halogenated C r C 4 alkyl, C r C 4 alkoxy, - alkoxy;
Figure imgf000004_0002
R5、 R6分别独立地选自氢、 d-C4烷基， 并可被 d-C4烷氧基， 5-10元杂环 或 3-10元碳环基任意取代； R 5 and R 6 are each independently selected from hydrogen, dC 4 alkyl, and may be optionally substituted by dC 4 alkoxy, 5-10 membered heterocyclic ring or 3-10 membered carbocyclic group;
R7 为 d-C4烷基， 可被 5-10元杂环或 3-10元碳环基任意取代； R 7 is dC 4 alkyl, which may be optionally substituted by a 5-10 membered heterocyclic ring or a 3-10 membered carbocyclic group;
m为 0, 1 , 2或 3;  m is 0, 1, 2 or 3;
n为 1 , 2或 3;  n is 1, 2 or 3;
G为 3-10元含 N杂环， 并可被任意取代  G is 3-10 yuan containing N heterocyclic ring, and can be optionally substituted
在一种优选的实施方案中， （Π )结构：  In a preferred embodiment, the (Π) structure:
Figure imgf000004_0003
Figure imgf000004_0003
Ri , R5, Ar、 m和 X如式（I )结构所定义； Ri , R 5 , Ar, m and X are as defined by the structure of formula (I);
或其药学上可接受的盐或溶剂化物。  Or a pharmaceutically acceptable salt or solvate thereof.
在一种特别优选的实施方案中， 本发明提供了式（ II )结构的优选化合物： N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基） 会啉 _4-基氧基）苯基） -N- (4-氟苯基）环丙烷 -1, 1-二曱酰胺； In a particularly preferred embodiment, the invention provides a preferred compound of the formula (II): N-(3-Fluoro-4-(6-decyloxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)morpholine_4 -yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基） 会啉 _4-基氧基）苯基） -N-苯基环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)morpholine_4 -yloxy)phenyl)-N-phenylcyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基） 会啉 _4-基氧基）苯基） -N- (2-氟苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)morpholine_4 -yloxy)phenyl)-N-(2-fluorophenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基） 会啉 _4-基氧基）苯基） -N- (3-氟苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)morpholine_4 -yloxy)phenyl)-N-(3-fluorophenyl)cyclopropane-1,1-diamide;
N- (4-氟 -3- (三氟曱基)苯基） -N- (3-氟 -4- (6-曱氧基 -7- ( 1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱酰胺； N-(4-Fluoro-3-(trifluoromethyl)phenyl)-N-(3-fluoro-4-(6-decyloxy-7-(1-(2-(decylamino))-2 -oxoethyl)piperidin-4-yloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N- (3-氯 -4-氟苯基） -N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙 基）哌啶 -4-基氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱酰胺； N-(3-chloro-4-fluorophenyl)-N-(3-fluoro-4-(6-decyloxy-7-(1-(2-(decyl))-2-oxoethyl) Piperidin-4-yloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基） 会啉 _4-基氧基）苯基） -N- (3-氟 -4-曱基苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)morpholine_4 -yloxy)phenyl)-N-(3-fluoro-4-mercaptophenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基） 喹啉 _4-基氧基）苯基） -N- (4- (三氟曱基）苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)quinoline_4 -yloxy)phenyl)-N-(4-(trifluoromethyl)phenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基） 喹啉 _4-基氧基）苯基） -N- (3- (三氟曱基）苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)quinoline_4 -yloxy)phenyl)-N-(3-(trifluoromethyl)phenyl)cyclopropane-1,1-diamide;
N- (3-氯 -2-氟苯基） -N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙 基）哌啶 -4-基氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-chloro-2-fluorophenyl)-N-(3-fluoro-4-(6-decyloxy-7-(1-(2-(decylamino)-2-oxoethyl) Piperidin-4-yloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N- ( 4-氯 -3- (三氟曱基）苯基） -N- ( 3-氟 -4- ( 6-曱氧基 -7- (1- (2- (曱胺基 ) -2-氧代乙基）哌啶 -4-基氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱酰胺； N-(4-chloro-3-(trifluoromethyl)phenyl)-N-( 3-fluoro-4-(6-decyloxy-7-(1-(2-(indenyl))-2 -oxoethyl)piperidin-4-yloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N- (2-氯 -6-曱基苯基） -N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代 乙基）哌啶 -4-基氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱酰胺； N-(2-chloro-6-mercaptophenyl)-N-(3-fluoro-4-(6-decyloxy-7-(1-(2-(indenyl))-2-oxoyl) Piperidin-4-yloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基） 曱 氧基）喹啉 -4-基氧基）苯基） -N- (4-氟苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(indenyl)-2-oxoethyl)piperidin-4-yl) decyloxy) quin Borano-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基） 曱 氧基）喹啉 -4-基氧基）苯基） -N-苯基环丙烷 -1, 1-二曱酰胺； N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(indolyl)-2-oxoethyl)piperidin-4-yl)) Oxy)quinolin-4-yloxy)phenyl)-N-phenylcyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基） 曱 氧基）喹啉 -4-基氧基）苯基） -N- (2-氟苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(indenyl)-2-oxoethyl)piperidin-4-yl) decyloxy) quin Physo-4-yloxy)phenyl)-N-(2-fluorophenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基） 曱 氧基）喹啉 -4-基氧基）苯基） -N- (3-氟苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(indenyl)-2-oxoethyl)piperidin-4-yl) decyloxy) quin Physo-4-yloxy)phenyl)-N-(3-fluorophenyl)cyclopropane-1,1-diamide;
N- (4-氟 -3- (三氟曱基)苯基） -N- (3-氟 -4- (6-曱氧基 -7- ( (1-(2-(曱胺基） -2-氧代乙基）哌啶 -4-基 )曱氧基 )喹啉 -4-基氧基 )苯基 )环丙烷 -1, 1-二曱酰胺； N-(4-Fluoro-3-(trifluoromethyl)phenyl)-N-(3-fluoro-4-(6-decyloxy-7-((1-(2-(ylamino))- 2-oxoethyl)piperidin-4-yl)decyloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N- ( 3-氯 -4-氟苯基 ) -N- ( 3-氟 -4- ( 6-曱氧基 -7- ( (1- (2- (曱胺基 ) -2-氧代 乙基）哌啶 -4-基） 曱氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱酰胺； N-(3-chloro-4-fluorophenyl)-N-(3-fluoro-4-(6-decyloxy-7-((1-(2-(nonyl))-2-oxo) ()piperidin-4-yl)nonyloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基） 曱 氧基）喹啉 -4-基氧基）苯基） -N- (3-氟 -4-曱基苯基）环丙烷 -1, 1-二曱酰胺； N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(indenyl)-2-oxoethyl)piperidin-4-yl) decyloxy) quin Physo-4-yloxy)phenyl)-N-(3-fluoro-4-indolylphenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基） 曱 氧基）喹啉 -4-基氧基）苯基） -N- (4- (三氟曱基）苯基）环丙烷 -1, 1-二曱酰胺；N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(indenyl)-2-oxoethyl)piperidin-4-yl) decyloxy) quin Physo-4-yloxy)phenyl)-N-(4-(trifluoromethyl)phenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基） 曱 氧基 )喹啉 -4-基氧基 )苯基 ) -N- ( 3- (三氟曱基）苯基 )环丙烷 -1, 1-二曱酰胺；N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(indenyl)-2-oxoethyl)piperidin-4-yl) decyloxy) quin Borano-4-yloxy)phenyl)-N-(3-(trifluoromethyl)phenyl)cyclopropane-1,1-diamide;
N- ( 3-氯 -2-氟苯基 ) -N- ( 3-氟 -4- ( 6-曱氧基 -7- ( (1- (2- (曱胺基 ) -2-氧代 乙基）哌啶 -4-基） 曱氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱酰胺； N-(3-chloro-2-fluorophenyl)-N-(3-fluoro-4-(6-decyloxy-7-((1-(2-(nonyl))-2-oxo) ()piperidin-4-yl)nonyloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N- (4-氯 -3- (三氟曱基）苯基） -N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺 基） -2-氧代乙基）哌啶 -4-基） 曱氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱 酰胺；  N-(4-chloro-3-(trifluoromethyl)phenyl)-N-(3-fluoro-4-(6-decyloxy-7-((1-(2-(ylamino))) 2-oxoethyl)piperidin-4-yl)nonyloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N- (2-氯 -6-曱基苯基） -N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺基） -2- 氧代乙基）哌啶 -4-基） 曱氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱酰胺； N-(2-chloro-6-mercaptophenyl)-N-(3-fluoro-4-(6-decyloxy-7-((1-(2-(nonyl))-2-oxo) Ethyl)piperidin-4-yl)nonyloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N-(4-氟苯基) -N-(4-(6-曱氧基 -7-((1 -(2-(曱胺基) -2-氧代乙基)哌啶 -4-基)曱氧基) 喹啉 -4-基氧基)苯基)环丙烷 -1,1-二曱酰胺； N-(4-fluorophenyl)-N-(4-(6-decyloxy-7-((1-(2-(indolyl)-2-oxoethyl)piperidin-4-yl) Alkoxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N-(4-(6-曱氧基 -7-((1 -(2-(曱胺基) -2-氧代乙基)哌啶 -4-基)曱氧基)喹啉 -4-基氧 基)苯基) -N-苯基环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(6-decyloxy-7-((1 -(2-(indolyl)-2-oxoethyl)piperidin-4-yl)decyloxy)quinoline-4- Benzyl)phenyl)-N-phenylcyclopropane-1,1-dicarbamide;
N-(2-氟苯基) -N-(4-(6-曱氧基 -7-((1 -(2-(曱胺基) -2-氧代乙基)哌啶 -4-基)曱氧基) 喹啉 -4-基氧基)苯基)环丙烷 -1,1-二曱酰胺； N-(2-Fluorophenyl)-N-(4-(6-decyloxy-7-((1-(2-(indolyl)-2-oxoethyl)piperidin-4-yl)曱oxy) Quinoline-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N-(3-氟苯基) -N-(4-(6-曱氧基 -7-((1-(2-(曱胺基) -2-氧代乙基)哌啶 -4-基)曱氧基) 喹啉 -4-基氧基)苯基)环丙烷 -1,1-二曱酰胺；  N-(3-Fluorophenyl)-N-(4-(6-decyloxy-7-((1-(2-(indolyl)-2-oxoethyl)piperidin-4-yl) Alkoxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N-(4-(7-((l-(2-胺基 -2-氧代乙基)哌啶 -4-基）曱氧基) -6-曱氧基喹啉 -4-基氧基） 苯基) -N-苯基环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(7-((1-(2-amino-2-oxoethyl)piperidin-4-yl) decyloxy)-6-methoxyoxyquinolin-4-yloxy Phenyl)-N-phenylcyclopropane-1,1-diphthalamide;
N-(4-(7-((l-(2-胺基 -2-氧代乙基)哌啶 -4-基）曱氧基) -6-曱氧基喹啉 -4-基氧基） 苯基) -N-(4-氟苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(7-((1-(2-amino-2-oxoethyl)piperidin-4-yl) decyloxy)-6-methoxyoxyquinolin-4-yloxy Phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarbamide;
N-(4-(7-((l-(2-胺基 -2-氧代乙基)哌啶 -4-基）曱氧基) -6-曱氧基喹啉 -4-基氧基） 苯基) -N-(2-氟苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(7-((1-(2-amino-2-oxoethyl)piperidin-4-yl) decyloxy)-6-methoxyoxyquinolin-4-yloxy Phenyl)-N-(2-fluorophenyl)cyclopropane-1,1-diphthalamide;
N-(4-(7-((l-(2-胺基 -2-氧代乙基)哌啶 -4-基）曱氧基) -6-曱氧基喹啉 -4-基氧基） 苯基) -N-(3-氟苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(7-((1-(2-amino-2-oxoethyl)piperidin-4-yl) decyloxy)-6-methoxyoxyquinolin-4-yloxy Phenyl)-N-(3-fluorophenyl)cyclopropane-1,1-dicarbamide;
N-(4-(7-((l-(2-胺基 -2-氧代乙基）哌啶 -4-基）曱氧基) -6-曱氧基喹啉 -4-基氧 基) -3 -氟苯基) -N-苯基环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(7-((1-(2-amino-2-oxoethyl)piperidin-4-yl) decyloxy)-6-methoxyoxyquinolin-4-yloxy -3 -fluorophenyl)-N-phenylcyclopropane-1,1-dicarbamide;
N-(4-(7-((l-(2-胺基 -2-氧代乙基）哌啶 -4-基）曱氧基) -6-曱氧基喹啉 -4-基氧 基) -3 -氟苯基) -N-(4-氟苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(7-((1-(2-amino-2-oxoethyl)piperidin-4-yl) decyloxy)-6-methoxyoxyquinolin-4-yloxy -3 -fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarbamide;
N-(4-(7-((l-(2-胺基 -2-氧代乙基）哌啶 -4-基）曱氧基) -6-曱氧基喹啉 -4-基氧 基) -3 -氟苯基) -N-(3 -氟苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(7-((1-(2-amino-2-oxoethyl)piperidin-4-yl) decyloxy)-6-methoxyoxyquinolin-4-yloxy -3 -fluorophenyl)-N-(3-fluorophenyl)cyclopropane-1,1-dicarbamide;
N-(4-(7-((l-(2-胺基 -2-氧代乙基）哌啶 -4-基）曱氧基) -6-曱氧基喹啉 -4-基氧 基) -3 -氟苯基) -N-(2-氟苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(7-((1-(2-amino-2-oxoethyl)piperidin-4-yl) decyloxy)-6-methoxyoxyquinolin-4-yloxy -3 -fluorophenyl)-N-(2-fluorophenyl)cyclopropane-1,1-dicarbamide;
或其药学上可接受的盐。  Or a pharmaceutically acceptable salt thereof.
在一种优 构：  In an advantage:
Figure imgf000007_0001
Figure imgf000007_0001
其中， 、 R7、 Ar、 X、 m如式（I )结构所定义; Wherein, R 7 , Ar, X, m are as defined by the structure of formula (I);
或其药学上可接受的盐或溶剂化物。 在一种特别优选的实施方案中， 本发明提供了式 (III)结构的优选化合物：Or a pharmaceutically acceptable salt or solvate thereof. In a particularly preferred embodiment, the invention provides preferred compounds of the structure of formula (III):
N-(3-氟 -4-(6-曱氧基 -7-((1 -(2- (曱磺胺基）乙基)哌啶 -4-基）曱氧基)喹啉 -4-基氧 基)苯基) -N-(4-氟苯基)环丙烷 - 1 , 1 -二曱酰胺； N-(3-Fluoro-4-(6-decyloxy-7-((1 -(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy)quinolin-4-yl Oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarbamide;
N-(3-氟 -4-(6-曱氧基 -7-((1 -(2- (曱磺胺基）乙基)哌啶 -4-基）曱氧基)喹啉 -4-基氧 基)苯基) -N-苯基环丙烷 - 1 , 1 -二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-((1 -(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy)quinolin-4-yl Oxy)phenyl)-N-phenylcyclopropane-1,1-diphthalamide;
N-(3-氟 -4-(6-曱氧基 -7-((1 -(2- (曱磺胺基）乙基)哌啶 -4-基）曱氧基)喹啉 -4-基氧 基)苯基) -N-(2-氟苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-((1 -(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy)quinolin-4-yl Oxy)phenyl)-N-(2-fluorophenyl)cyclopropane-1,1-dicarbamide;
N-(3-氟 -4-(6-曱氧基 -7-((1 -(2- (曱磺胺基）乙基)哌啶 -4-基）曱氧基)喹啉 -4-基氧 基)苯基) -N-(3 -氟苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-((1 -(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy)quinolin-4-yl Oxy)phenyl)-N-(3-fluorophenyl)cyclopropane-1,1-dicarbamide;
N-(4-氟苯基) -N-(4-(6-曱氧基 -7-((1-(2- (曱磺胺基）乙基)哌啶 -4-基）曱氧基)喹 啉 -4-基氧基)苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(4-fluorophenyl)-N-(4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy) Quinoline-4-yloxy)phenyl)cyclopropane-1,1-dicarbamide;
N-(4-(6-曱氧基 -7-((1-(2- (曱磺胺基）乙基)哌啶 -4-基)曱氧基)喹啉 -4-基氧基)苯 基) -N-苯基环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy)quinolin-4-yloxy)benzene -N-phenylcyclopropane-1,1-dicarbamide;
N-(2-氟苯基) -N-(4-(6-曱氧基 -7-((1-(2- (曱磺胺基）乙基)哌啶 -4-基）曱氧基)喹 啉 -4-基氧基)苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(2-fluorophenyl)-N-(4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy) Quinoline-4-yloxy)phenyl)cyclopropane-1,1-dicarbamide;
N-(3-氟苯基) -N-(4-(6-曱氧基 -7-((1-(2- (曱磺胺基）乙基)哌啶 -4-基）曱氧基)喹 啉 -4-基氧基)苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(3-Fluorophenyl)-N-(4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy) Quinoline-4-yloxy)phenyl)cyclopropane-1,1-dicarbamide;
或其药学上可接受的盐。  Or a pharmaceutically acceptable salt thereof.
在一种优 施方案中， 本发明提供的化合物具有式（IV ) 结构：  In one embodiment, the compounds provided herein have the structure of formula (IV):
Figure imgf000008_0001
Figure imgf000008_0001
其中， 、 R7、 Ar、 X、 m如式（I )结构所定义； Wherein, R 7 , Ar, X, m are as defined by the structure of formula (I);
或其药学上可接受的盐或溶剂化物。  Or a pharmaceutically acceptable salt or solvate thereof.
在一种特别优选的实施方案中， 本发明提供了式 (IV)结构的优选化合物： Ν·(3-氟 -4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基)曱氧基)喹啉 -4-基氧基) 苯基) -N-(4-氟苯基)环丙烷 - 1 , 1 -二曱酰胺； In a particularly preferred embodiment, the invention provides a preferred compound of the formula (IV): Ν·(3-fluoro-4-(6-decyloxy-7-((1-(2-(曱)) Sulfo)ethyl)piperidin-4-yl)nonyloxy)quinoline-4-yloxy) Phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-diphthalamide;
Ν·(3-氟 -4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基)曱氧基)喹啉 -4-基氧基) 苯基) -Ν-苯基环丙烷 - 1 , 1 -二曱酰胺； Ν ·(3-Fluoro-4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy)quinolin-4-yl Oxy)phenyl)-indole-phenylcyclopropane-1,1-dicarbamide;
Ν·(3-氟 -4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基)曱氧基)喹啉 -4-基氧基) 苯基) -Ν-(2-氟苯基)环丙烷 - 1 , 1 -二曱酰胺； Ν ·(3-Fluoro-4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy)quinolin-4-yl Oxy)phenyl)-indole-(2-fluorophenyl)cyclopropane-1,1-dicarbamide;
Ν·(3-氟 -4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基)曱氧基)喹啉 -4-基氧基) 苯基) -Ν-(3-氟苯基)环丙烷 - 1 , 1 -二曱酰胺； Ν ·(3-Fluoro-4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy)quinolin-4-yl Oxy)phenyl)-indole-(3-fluorophenyl)cyclopropane-1,1-dicarbamide;
Ν-(4-氟苯基) -Ν-(4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基）曱氧基)喹啉 -4-基氧基)苯基)环丙烷 - 1 , 1 -二曱酰胺；  Ν-(4-fluorophenyl)-indole-(4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy) Quinoline-4-yloxy)phenyl)cyclopropane-1,1-dicarbamide;
Ν-(4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基）曱氧基)喹啉 -4-基氧基)苯 基) -Ν-苯基环丙烷 - 1 , 1 -二曱酰胺；  Ν-(4-(6-decyloxy-7-((1-(2-(sulfo)ethyl)piperidin-4-yl) decyloxy) quinolin-4-yloxy)benzene - Ν-phenylcyclopropane-1,1-dicarbamide;
Ν-(2-氟苯基) -Ν-(4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基）曱氧基)喹啉 -4-基氧基)苯基)环丙烷 - 1 , 1 -二曱酰胺；  Ν-(2-fluorophenyl)-indole-(4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl) decyloxy) Quinoline-4-yloxy)phenyl)cyclopropane-1,1-dicarbamide;
Ν-(3-氟苯基) -Ν-(4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基）曱氧基)喹啉 -4-基氧基)苯基)环丙烷 - 1 , 1 -二曱酰胺；  Ν-(3-fluorophenyl)-indole-(4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl) decyloxy) Quinoline-4-yloxy)phenyl)cyclopropane-1,1-dicarbamide;
或其药学上可接受的盐。 本发明化合物如含有碱性基团， 则可与酸成盐， 釆用本领域技术人员所熟知 的方法可以制备喹啉类衍生物的盐。  Or a pharmaceutically acceptable salt thereof. The compound of the present invention, if it contains a basic group, can form a salt with an acid, and a salt of a quinoline derivative can be produced by a method well known to those skilled in the art.
在本发明的实施方案中， 所述常见盐包括有机酸盐、 无机酸盐等。 通常比较 常用的有机酸盐有枸橼酸盐、 富马酸盐、 草酸盐、 苹果酸盐、 乳酸盐、 樟脑磺酸 盐、 对曱苯横酸盐、 曱横酸盐等； 无机酸盐有氢卤酸盐、 硫酸盐、 磷酸盐、 硝酸 盐等。  In an embodiment of the invention, the common salts include organic acid salts, inorganic acid salts, and the like. Commonly used organic acid salts are citrate, fumarate, oxalate, malate, lactate, camphor sulfonate, p-toluene, barium salt, etc.; Salts include hydrohalides, sulfates, phosphates, nitrates, and the like.
例如， 与低级烷基横酸， 如曱磺酸， 三氟曱磺酸等可形成曱磺酸盐、 三氟曱 磺酸盐；与芳基磺酸，如苯磺酸或对曱苯磺酸等可形成对曱苯磺酸盐、苯磺酸盐； 与有机羧酸， 如乙酸， 富马酸， 酒石酸， 草酸， 马来酸， 苹果酸， 琥珀酸或柠檬 酸等可形成相应的盐； 与氨基酸， 如谷氨酸或天冬氨酸可形成谷氨酸盐或天冬氨 酸盐。 与无机酸， 如氢！ ¾酸（如氢氟酸、 氢溴酸、 氢碘酸、 氢氯酸） ， 硝酸， 碳 酸， 酸或碑酸等也可形成相应的盐。 在本发明的实施方案中， 所述的 -C4烷基包括了曱基、 乙基、 丙基、 异丙 基、 丁基、 异丁基、 或叔丁基。 所述的卤素包括了氟、 氯、 溴和碘。 卤代的 CrC4 烷基是指在 d-C4碳链上具有一个或多个面代， 例如三氟曱基等。 For example, with a lower alkyl acid, such as sulfonic acid, trifluorosulfonium sulfonic acid, etc., it can form an oxime sulfonate, a trifluorosulfonium sulfonate; and an aryl sulfonic acid, such as benzenesulfonic acid or p-toluenesulfonic acid. And the like may form p-toluenesulfonate, besylate; and an organic carboxylic acid, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid, etc. may form a corresponding salt; A glutamate or aspartate can be formed with an amino acid such as glutamic acid or aspartic acid. With inorganic acids like hydrogen! 3⁄4 acids (such as hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid), nitric acid, carbonic acid, acid or streptoic acid can also form the corresponding salts. In an embodiment of the invention, the -C 4 alkyl group includes a decyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, or a tert-butyl group. The halogen includes fluorine, chlorine, bromine and iodine. The halogenated C r C 4 alkyl group means having one or more surface groups on the dC 4 carbon chain, such as a trifluoromethyl group.
另一方面， 本发明提供了上述化合物的制备方法： In another aspect, the invention provides a process for the preparation of the above compounds:
-A)化合物合成：  -A) Compound Synthesis:
Figure imgf000010_0001
Figure imgf000010_0001
更具体地说， 对式（Π)化合物釆用下列路线合成:  More specifically, the compound of the formula (Π) is synthesized by the following route:
Figure imgf000010_0002
Figure imgf000010_0002
(νπ) (IX)
Figure imgf000010_0003
(νπ) (IX)
Figure imgf000010_0003
(X) ( II ) 对式 (III)化合物采用下列路线合成： (X) ( II ) The compound of formula (III) is synthesized by the following route:
Figure imgf000011_0001
Figure imgf000011_0001
( III )  (III)
Figure imgf000011_0002
Figure imgf000011_0002
并且， 在所述制备方法中的上述化合物中各个取代基如式（I )化合物中所 定义的。  Further, each of the above compounds in the above-mentioned production method is as defined in the compound of the formula (I).
第三个方面， 本发明提供包含上述芳氧基喹啉类衍生物或该化合物的盐或溶 剂化物为活性成分的药物组合物。该药物组合物还可以含有一种或多种药学上可 接受的载体， 所述载体包括药学领域的常规稀释剂， 赋形剂， 填充剂， 粘合剂， 湿润剂， 崩解剂， 吸收促进剂， 表面活性剂， 吸附载体， 润滑剂等， 必要时还可 以加入香味剂，甜味剂等。本发明药物组合物可以制成片剂，粉剂，粒剂，胶嚢， 口服液及注射用药等多种形式， 上述各剂型的药物均可以按照药学领域的常规方 法制备。 In a third aspect, the present invention provides a pharmaceutical composition comprising the above aryloxyquinoline derivative or a salt or solvate of the compound as an active ingredient. The pharmaceutical composition may also contain one or more pharmaceutically acceptable carriers including conventional diluents in the pharmaceutical field, excipients, fillers, binders, wetting agents, disintegrants, absorption promotion Agent, surfactant, adsorption carrier, lubricant, etc., if necessary To add flavoring agents, sweeteners, and the like. The pharmaceutical composition of the present invention can be prepared into various forms such as tablets, powders, granules, capsules, oral liquids and injectable preparations, and the medicaments of the above respective dosage forms can be prepared according to a conventional method in the pharmaceutical field.
第四方面， 本发明提供本发明芳氧基喹啉类衍生物或该化合物的盐或溶剂化 物治疗人或动物与酪氨酸激酶特别是 c-Met,VEGFR有关的疾病的用途， 包括治 疗增生性疾病如癌症、 或炎症类疾病等。 本发明发明人通过实验证实， 本发明化 合物对人胃癌细胞株 (MGC-803)具有抗增值抑制作用， 可应用治疗人或动物细胞 增殖性相关的实体瘤或血癌的药物中。 本发明的较佳实施方式  In a fourth aspect, the present invention provides the use of an aryloxyquinoline derivative of the present invention or a salt or solvate of the compound for treating a human or animal disease associated with a tyrosine kinase, particularly c-Met, VEGFR, including treatment of hyperplasia Sexual diseases such as cancer, or inflammatory diseases. The inventors of the present invention confirmed by experiments that the compound of the present invention has an anti-value-inhibiting action against a human gastric cancer cell line (MGC-803), and can be applied to a drug for treating solid tumors or blood cancer associated with human or animal cell proliferation. Preferred embodiment of the invention
下面通过实施例来说明本发明的可实施性， 本领域的技术人员应当理解， 根 据现有技术的教导， 对相应的技术特征进行修改或替换， 仍然属于本发明要求保 护的范围。  The exemplification of the present invention will be described below by way of examples, and those skilled in the art will understand that modifications or substitutions of the corresponding technical features in accordance with the teachings of the prior art still fall within the scope of the claimed invention.
实施例 1. N- ( 3-氟 -4- ( 6-曱氧基 -7- ( 1- ( 2- (曱胺基） -2-氧代乙基）哌啶 -4- 基氧基）喹啉 -4-基氧基）苯基） -N- ( 4-氟苯基）环丙烷 -1,1-二曱酰胺的合成（化 合物 1 ) Example 1. N- (3- fluoro-4- (6-oxy Yue - 7 - (1- (2- (Yue amino) -2-oxoethyl) piperidin-4-yloxy) Synthesis of quinoline-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-diamide (Compound 1)
Figure imgf000012_0001
Figure imgf000012_0001
步骤 1. 2-苄氧基 -1-曱氧基 - -硝基苯的合成
Figure imgf000012_0002
Step 1. Synthesis of 2-benzyloxy-1-decyloxy-nitrobenzene
Figure imgf000012_0002
将 lO.Og 2-曱氧基 -5-硝基苯酚和 12.2g无水碳酸钾加入 250ml三颈瓶中， 再 加入 150ml Ν,Ν-二曱基曱酰胺， 磁力搅拌下緩慢滴加 11. lg溴化苄， 约十分钟滴 完， 将体系升温至 40 °C反应过夜， 减压旋掉一部分溶剂后， 倒入水水中， 析出大 量固体， 抽滤， 滤饼用碱水洗至滤液不发黄为止， 晾干， 得 2-苄氧基 -1-曱氧基 -4- 硝基苯 15.1 g, 产率 98%。 步骤 2. 3-苄氧基 -4-曱氧
Figure imgf000013_0001
Add lO.Og 2-decyloxy-5-nitrophenol and 12.2g anhydrous potassium carbonate to a 250ml three-necked flask, then add 150ml of hydrazine, hydrazine-dihydrazinamide, and slowly add 11. Lg benzyl bromide, after about 10 minutes, the system is heated to 40 ° C for overnight reaction, and a part of the solvent is depressurized under reduced pressure, poured into water, a large amount of solid is precipitated, suction filtration, and the filter cake is washed with alkali water until the filtrate is not sent. The yellow color was dried to give 15.1 g of 2-benzyloxy-1-decyloxy-4-nitrobenzene in a yield of 98%. Step 2. 3-Benzyloxy-4-oxo
Figure imgf000013_0001
将 15.0 g 2-苄氧基 -1-曱氧基 -4-硝基苯， 25.9 g铁粉， 9.3 g 氯化铵， 150 ml 乙 醇， 50ml水加入 500 ml干净三颈瓶中， 氮气保护下，机械搅拌下回流反应 lh , 趁热过滤， 滤液减压浓缩， 加水， 乙酸乙酯萃取， 酯层用饱和的碳酸钾水溶液洗 两遍， 水洗两次， 无水硫酸钠干燥， 浓缩得 12.6 g砖红色粉末， 产率 95%  Add 15.0 g of 2-benzyloxy-1-decyloxy-4-nitrobenzene, 25.9 g of iron powder, 9.3 g of ammonium chloride, 150 ml of ethanol, 50 ml of water to a 500 ml clean three-necked flask under nitrogen protection. The mixture was refluxed under mechanical stirring for 1 h, filtered while hot, and the filtrate was concentrated under reduced pressure. Water was evaporated, ethyl acetate was evaporated. The ester layer was washed twice with a saturated aqueous solution of potassium carbonate, washed twice, dried over anhydrous sodium sulfate and evaporated. Brick red powder, yield 95%
步骤 3. 5- ( ( 3-苄氧基 -4-曱氧基苯胺基） 亚曱基） -2 , 2-二曱基 -1 , 3-二噁 烷 -4, 6-二酮的合成
Figure imgf000013_0002
Step 3. Synthesis of 5-((3-benzyloxy-4-decyloxyanilinyl) fluorenyl)-2,2-dimercapto-1,3-dioxane-4,6-dione
Figure imgf000013_0002
将 12 .0 g 3-苄氧基 -4-曱氧基苯胺, 10.7g 5- (曱氧基亚氧基） -2 , 2-二曱基 -1 , 3-二噁烷 -4, 6-二酮， 200 ml异丙醇置于 500 ml单颈瓶中， 加热回流反应 lh, 冷却， 过滤， 滤饼用异丙醇洗两次， 得 19.1g 淡黄色粉末， 产率 94.9% 12.0 g of 3-benzyloxy-4-decyloxyaniline, 10.7 g of 5-(decyloxyoxy)-2,2-dimercapto-1,3-dioxane-4,6 - Diketone, 200 ml of isopropanol was placed in a 500 ml single-necked flask, heated to reflux for 1 h, cooled, filtered, and the filter cake was washed twice with isopropyl alcohol to give 19.1 g of pale yellow powder, yield 94.9%.
步骤 4. 7-苄氧基 -6-曱氧基 -4-醇的合成  Step 4. Synthesis of 7-benzyloxy-6-decyloxy-4-ol
Figure imgf000013_0003
Figure imgf000013_0003
将 13.1 g 5- ( ( 3-苄氧基 -4-曱氧基苯胺基）亚曱基） -2, 2-二曱基 -1 , 3-二噁 烷 -4, 6-二酮, 14.5g联苯， 60ml二苯醚加入 100ml三颈瓶中， 氮气保护下加热至 220°C反应， 约 lh 敦掉油浴， 待体系降温到 50°C左右， 加入***， 有大量固体析 出， 抽滤， 用***洗得棕红色粉末， 粗品 8.2g, 无需处理直接用于下一步。  13.1 g of 5-((3-benzyloxy-4-nonyloxyanilino)indenyl)-2,2-dimercapto-1,3-dioxane-4,6-dione, 14.5 g biphenyl, 60ml diphenyl ether was added to a 100ml three-necked flask, heated to 220 ° C under nitrogen protection, about 1h to remove the oil bath, to cool the system to about 50 ° C, add ether, a large amount of solid precipitation, pumping Filtration, washing with diethyl ether to give a brown-brown powder, 8.2 g of crude material.
步骤 5. 7-苄氧基 -4-氯 -6-曱  Step 5. 7-Benzyloxy-4-chloro-6-anthracene
Figure imgf000013_0004
Figure imgf000013_0004
将 8.0g 7-苄氧基 -6-曱氧基喹啉 -4-醇, 30ml三氯氧碑加入到 100ml三颈瓶中， 氮气保护下加热回流 5h,减压旋干， 向瓶内加入水水， 加碳酸钠调 PH至 8-9, 加 二氯曱烷有机层用无水硫酸钠干燥， 拌样过柱得 7.1g 白色粉末， mp:135°C-1368.0 g of 7-benzyloxy-6-decyloxyquinolin-4-ol, 30 ml of triclosan is added to a 100 ml three-necked flask. Under the protection of nitrogen, the mixture was heated under reflux for 5 h, and then dried under reduced pressure. Water was added to the bottle, and the mixture was adjusted to pH 8-9 with sodium carbonate. The organic layer of dichloromethane was dried over anhydrous sodium sulfate. White powder, mp: 135°C-136
°C °C
步骤 6. 7-苄氧基 -4- ( 2- -4-硝基酚氧基） -6-曱基喹啉的合成  Step 6. Synthesis of 7-benzyloxy-4-(2--4-nitrophenoxy)-6-mercaptoquinoline
Figure imgf000014_0001
Figure imgf000014_0001
将 3.0g 7-苄氧基 -4-氯 -6-曱基喹啉， 3.2g 2-氟 -4-硝基苯酚， 50ml二苯酸加入 到 100ml 三颈瓶中， 氮气保护下加热到 160°C反应， 约 5h后， 冷却至室温， 过 滤， 滤饼用饱和的氢氧化钠洗得淡黄色粉末， 2.65g, 无需纯化直接用于下一步。  3.0 g of 7-benzyloxy-4-chloro-6-mercaptoquinoline, 3.2 g of 2-fluoro-4-nitrophenol, 50 ml of diphenyl acid were added to a 100 ml three-necked flask and heated to 160 under nitrogen. After reacting for about 5 h, it was cooled to room temperature, filtered, and filtered, washed with saturated sodium hydroxide to give a pale yellow powder, 2.65 g, which was used in the next step without purification.
步骤 7. 4- ( 2-氟 -4-硝基 -6-曱氧基喹啉 -7-醇的合成  Step 7. Synthesis of 4-(2-fluoro-4-nitro-6-decyloxyquinolin-7-ol
Figure imgf000014_0002
Figure imgf000014_0002
将 2.5g 7-苄氧基 -4- ( 2-氟 -4-硝基酚氧基） -6-曱基喹啉加入到 30ml 33%HBr 的醋酸溶液中， 常温搅拌反应 3h, 加入 100ml***， 过滤得白色固体 2.1g。  2.5 g of 7-benzyloxy-4-(2-fluoro-4-nitrophenoxy)-6-mercaptoquinoline was added to 30 ml of 33% HBr in acetic acid, stirred at room temperature for 3 h, and added with 100 ml of diethyl ether. , filtered to give a white solid (2.1 g).
步骤 8. 4- ( 4- ( 2-氟 -4-硝基酚氧基） -6-曱氧基喹啉 -7-基氧基）哌啶 -1-曱酰 叔丁酯的合成  Step 8. Synthesis of 4-(4-(2-fluoro-4-nitrophenoxy)-6-methoxyoxyquinolin-7-yloxy)piperidine-1-indolyl tert-butyl ester
Figure imgf000014_0003
Figure imgf000014_0003
将 l.Og 4- ( 2-氟 -4-硝基酚氧基） -6-曱氧基喹啉 -7-醇， 1.3g 4-羟基哌啶 -1-曱 酰叔丁酯， 1.3g无水碳酸钾， 异丙醇 50ml加热回流反应过夜， 旋干， 加水， 乙 酸乙酯萃取。 酯层碱洗， 饱和氯化钠水溶液洗两次， 无水^ 酸钠干燥， 浓缩， 过 硅胶柱得淡黄色固体 0.4g。  1. Og 4-(2-Fluoro-4-nitrophenoxy)-6-decyloxyquinolin-7-ol, 1.3 g 4-hydroxypiperidine-1-decanoyl tert-butyl ester, 1.3 g Anhydrous potassium carbonate and 50 ml of isopropanol were heated and refluxed overnight, dried, and water was added, and ethyl acetate was evaporated. The ester layer was washed with alkali, washed twice with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated.
步骤 9. 4- ( 2-氟 -4-硝基酚氧基） -6-曱氧基 -7- (哌啶 -4-基氧基）喹啉的合成
Figure imgf000015_0001
Step 9. Synthesis of 4-(2-fluoro-4-nitrophenoxy)-6-methoxy-7-(piperidin-4-yloxy)quinoline
Figure imgf000015_0001
将 0.35g4- (4- (2-氟 -4-硝基酚氧基） -6-曱氧基喹啉 -7-基氧基）哌啶 -1-曱酰 叔丁酯加入到三氟乙酸和二氯曱烷（ 1: 1) 20ml溶液中， 室温搅拌 2h, 旋干， 得 0.3g淡黄色油状物， 无需处理直接用于下一步。  0.35 g of 4-(4-(2-fluoro-4-nitrophenoxy)-6-methoxyoxyquinolin-7-yloxy)piperidine-1-indolyl tert-butyl ester was added to trifluoroacetic acid And 20 ml of dichloromethane (1:1), stirred at room temperature for 2 h, and then evaporated to dryness.
步骤 10.2- (4- (4- (2-氟 -4-硝基酚氧基） -6-曱氧基喹啉 -7-基氧基）哌啶 -1- 基） -N-曱基乙酰胺  Step 10.2-(4-(4-(2-Fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yloxy)piperidin-1-yl)-N-decyl Amide
Figure imgf000015_0002
Figure imgf000015_0002
将 0.2g4- (2-氟 -4-硝基酚氧基） -6-曱氧基 -7- (哌啶 -4-基氧基）喹啉， 0.06g 2-氯 -N-曱基乙酰胺， 0.15g无水碳酸钾， 30ml乙腈置于 50ml单颈瓶中， 加热回 流反应 3h, 旋干， 加水， 乙酸乙酯萃取， 酯层再用饱和氯化钠水溶液洗两次， 无 水硫酸钠干燥， 浓缩得 0.2g淡黄色粉末。  0.2 g of 4-(2-fluoro-4-nitrophenoxy)-6-methoxy-7-(piperidin-4-yloxy)quinoline, 0.06 g of 2-chloro-N-decyl Amide, 0.15g anhydrous potassium carbonate, 30ml acetonitrile in 50ml single-necked flask, heated under reflux for 3h, spin dry, add water, extract with ethyl acetate, then wash the ester layer twice with saturated aqueous sodium chloride, anhydrous sulfuric acid The sodium was dried and concentrated to give a pale yellow powder.
步骤 11.2- (4- (4- (4-胺基 -2-氟酚氧基） -6-曱氧基喹啉 -7-基氧基）哌啶 -1- 基） -N-曱基乙酰胺  Step 11.2-(4-(4-(4-Amino-2-fluorophenoxy)-6-methoxyquinolin-7-yloxy)piperidin-1-yl)-N-decyl Amide
Figure imgf000015_0003
Figure imgf000015_0003
将 0.15g 2- ( 4- ( 4- ( 2-氟 -4-硝基酚氧基 ) -6-曱氧基喹啉 -7-基氧基 )哌啶 -1- 基） -N-曱基乙酰胺，还原铁粉 0.2g,无水氯化铵 O.lg加入到 30ml乙醇和水（4: 1)溶液中， 氮气保护下， 回流反应 lh, 趁热过滤， 滤液浓缩， 加水， 乙酸乙酯 萃取， 酯层再用饱和氯化钠水溶液洗两次， 无水硫酸钠干燥， 浓缩得 0.12g淡黄 色油^ 物。  0.15 g of 2-(4-(4-(2-fluoro-4-nitrophenoxy)-6-methoxyoxyquinolin-7-yloxy)piperidin-1-yl)-N-oxime Acetylamine, reduced iron powder 0.2g, anhydrous ammonium chloride O.lg added to 30ml ethanol and water (4: 1) solution, under nitrogen protection, reflux reaction for 1h, hot filtered, filtrate concentrated, water, acetic acid The ethyl ester was extracted, and the ester layer was washed twice with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated.
步骤 12.N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4- 基氧基）喹啉 -4-基氧基）苯基） -N- (4-氟苯基）环丙烷 -1,1-二曱酰胺的合成
Figure imgf000016_0001
Step 12. N-(3-Fluoro-4-(6-decyloxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)quinoline Synthesis of phenyl-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-diamide
Figure imgf000016_0001
在氮气和水浴条件下， 将 O.lg 2- ( 4- ( 4- ( 4-胺基 -2-氟酚氧基） -6-曱氧基 喹啉 -7-基氧基 )哌啶 -1-基 ) -N-曱基乙酰胺加入到 50ml三颈瓶中， 加 10ml无水 四氢呋喃溶解， 緩慢滴加 2ml含 0.03g 1- ( 4-氟苯基曱酰胺基）环丙烷曱酰氯的 四氢呋喃溶液， 滴毕， 常温反应 3h, 旋干， 加水， 乙酸乙酯萃取， 酯层再用饱和 氯化钠水溶液洗两次，无水硫酸钠干燥，浓缩，通过柱层析得 60mg灰白色粉末。  O.lg 2-(4-(4-(4-Amino-2-fluorophenoloxy)-6-decyloxyquinolin-7-yloxy)piperidine- under nitrogen and water bath conditions 1-Base)-N-mercaptoacetamide was added to a 50 ml three-necked flask, dissolved in 10 ml of anhydrous tetrahydrofuran, and 2 ml of 1-(4-fluorophenylphosphonamido)cyclopropanoyl chloride was slowly added dropwise. The tetrahydrofuran solution was added dropwise, and the mixture was stirred at room temperature for 3 h. EtOAc was evaporated. EtOAc.
JHNMR (DMSO-d6) (ppm):5 1.47 (s, 4H), 1.81 (m, 2H), 2.07 (m, 2H), 2.42 (m, 2H), 2.64 (d, 3H), 2.76 (m, 2H), 2.97(s, 2H), 3.95 (s, 3H), 4.66 (m,lH), 6.41 (d, IH), 7.16(m, 2H), 7.47 (m, 2H), 7.53 (m, 2H), 7.65 (m, 2H), 7.78 (d, IH), 7.91 (d, IH), 8.46 (d, IH), 10.03 (s, IH), 10.41 (s, IH). J HNMR (DMSO-d 6 ) (ppm): 5 1.47 (s, 4H), 1.81 (m, 2H), 2.07 (m, 2H), 2.42 (m, 2H), 2.64 (d, 3H), 2.76 ( m, 2H), 2.97 (s, 2H), 3.95 (s, 3H), 4.66 (m, lH), 6.41 (d, IH), 7.16 (m, 2H), 7.47 (m, 2H), 7.53 (m , 2H), 7.65 (m, 2H), 7.78 (d, IH), 7.91 (d, IH), 8.46 (d, IH), 10.03 (s, IH), 10.41 (s, IH).
实施例 2. N- ( 3-氟 -4- ( 6-曱氧基 -7- ( 1- ( 2- (曱胺基 ) -2-氧代乙基）哌啶 -4- 基氧基）喹啉 -4- -1, 1-二曱酰胺（化合物 2 )  Example 2. N-(3-Fluoro-4-(6-methoxy-7-(1-(2-(nonyl)-2-oxoethyl)piperidin-4-yloxy)) Quinoline-4--1,1-diamide (Compound 2)
Figure imgf000016_0002
Figure imgf000016_0002
XHNMR (DMSO-d6) (ppm):5 1.48 (s, 4H), 1.82 (m, 2H), 2.06 (m, 2H), 2.50 (m, 2H), 2.63 (d, 3H), 2.74 (m, 2H), 2.96 (s, 2H), 3.96 (s, 3H), 4.65(m, IH), 6.41 (d, IH), 7.07 (m, IH), 7.30(m, 2H), 7 .47 (m, 2H), 7.53 (m, 2H), 7.63 (d, 2H), 7.78 (d, IH), 7.90 (dd, IH), 8.46 (d, IH), 10.01 (s, IH), 10.38 (s, IH). X HNMR (DMSO-d 6 ) (ppm): 5 1.48 (s, 4H), 1.82 (m, 2H), 2.06 (m, 2H), 2.50 (m, 2H), 2.63 (d, 3H), 2.74 ( m, 2H), 2.96 (s, 2H), 3.96 (s, 3H), 4.65 (m, IH), 6.41 (d, IH), 7.07 (m, IH), 7.30 (m, 2H), 7.47 (m, 2H), 7.53 (m, 2H), 7.63 (d, 2H), 7.78 (d, IH), 7.90 (dd, IH), 8.46 (d, IH), 10.01 (s, IH), 10.38 ( s, IH).
实施例 3. N- ( 3-氟 -4- ( 6-曱氧基 -7- ( 1- ( 2- (曱胺基 ) -2-氧代乙基）哌啶 -4- 基氧基）喹啉 -4-基氧基）苯基） -N- ( 2-氟苯基）环丙烷 -1, 1-二曱酰胺（化合物 3 ) Example 3. N-(3-Fluoro-4-(6-methoxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)) Quinoline-4-yloxy)phenyl)-N-(2-fluorophenyl)cyclopropane-1,1-diamide (Compound 3)
Figure imgf000017_0001
Figure imgf000017_0001
XHNMR (DMSO-d6) (ppm):5 1.58 (s, 4H), 1.82 (m, 2H), 2.06 (m, 2H), 2.38 (m, 2H), 2.63 (d, 3H), 2.73 (m, 2H), 2.94(s, 2H), 3.95 (s, 3H), 4.65(m, IH), 6.42 (d, IH), 7.20 (m, 2H), 7.27(m, IH), 7 .47 (m, 2H), 7.53 (m, 2H), 7.85 (m, IH), 7.86 (m, 2H), 8.46 (d, IH), 10.28 (s, IH), 10.38 (s, IH). X HNMR (DMSO-d 6 ) (ppm): 5 1.58 (s, 4H), 1.82 (m, 2H), 2.06 (m, 2H), 2.38 (m, 2H), 2.63 (d, 3H), 2.73 ( m, 2H), 2.94 (s, 2H), 3.95 (s, 3H), 4.65 (m, IH), 6.42 (d, IH), 7.20 (m, 2H), 7.27 (m, IH), 7.47 (m, 2H), 7.53 (m, 2H), 7.85 (m, IH), 7.86 (m, 2H), 8.46 (d, IH), 10.28 (s, IH), 10.38 (s, IH).
实施例 4. N- ( 3-氟 -4- ( 6-曱氧基 -7- ( 1- ( 2- (曱胺基） -2-氧代乙基）哌啶 -4- 基氧基）喹啉 -4-基氧基）苯基） -N- ( 3-氟苯基）环丙烷 -1 , 1-二曱酰胺（化合物 4 ) Example 4. N- (3- fluoro-4- (6-oxy Yue - 7 - (1- (2- (Yue amino) -2-oxoethyl) piperidin-4-yloxy) Quinoline-4-yloxy)phenyl)-N-(3-fluorophenyl)cyclopropane-1, 1-diamide (Compound 4)
Figure imgf000017_0002
Figure imgf000017_0002
XHNMR (DMSO-d6) (ppm): δ 1.48 (s, 4Η), 1.80 (m, 2H), 2.06 (m, 2H), 2.38 (m, 2H), 2.63 (d, 3H), 2.73 (m, 2H), 2.94(s, 2H), 3.95 (s, 3H), 4.65(m, IH), 6.41 (d, IH), 6.90 (t, IH), 7.35-7.75(m, 9H), 8.46 (d, IH), 10.23 (s, IH), 10.33 (s, IH). X H NMR (DMSO-d 6 ) (ppm): δ 1.48 (s, 4Η), 1.80 (m, 2H), 2.06 (m, 2H), 2.38 (m, 2H), 2.63 (d, 3H), 2.73 ( m, 2H), 2.94 (s, 2H), 3.95 (s, 3H), 4.65 (m, IH), 6.41 (d, IH), 6.90 (t, IH), 7.35-7.75 (m, 9H), 8.46 (d, IH), 10.23 (s, IH), 10.33 (s, IH).
实施例 5. N- ( 4-氟 -3- (三氟曱基)苯基) -N- ( 3-氟 -4- ( 6-曱氧基 -7- ( 1- ( 2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基）喹啉 -4-基氧基）苯基）环丙烷 -1 , 1- 二曱酰胺（化合 5 )  Example 5. N-(4-Fluoro-3-(trifluoromethyl)phenyl)-N-(3-fluoro-4-(6-decyloxy-7-(1-(2-(nonyl)amine) (2-oxoethyl)piperidin-4-yloxy)quinolin-4-yloxy)phenyl)cyclopropane-1, 1-diamide (5)
Figure imgf000017_0003
Figure imgf000017_0003
合成步骤参照实施例 1。 XHNMR (DMSO-d6) (ppm): δ 1.48 (s, 4H), 1.80 (m, 2H), 2.04 (m, 2H), 2.40 (m, 2H), 2.63 (d, 3H), 2.73 (m, 2H), 2.93(s, 2H), 3.94(s, 3H), 4.65 (m,lH), 6.41 (d, 1H), 7.42-7.53(m, 5H), 7.75 (d, 1H), 7.90 (m, 2H), 8.16 (dd, 1H), 8.46 (d, 1H), 10.34 (s, 1H), 10.39 (s, 1H). The synthesis procedure is referred to in Example 1. X H NMR (DMSO-d 6 ) (ppm): δ 1.48 (s, 4H), 1.80 (m, 2H), 2.04 (m, 2H), 2.40 (m, 2H), 2.63 (d, 3H), 2.73 ( m, 2H), 2.93(s, 2H), 3.94(s, 3H), 4.65 (m,lH), 6.41 (d, 1H), 7.42-7.53 (m, 5H), 7.75 (d, 1H), 7.90 (m, 2H), 8.16 (dd, 1H), 8.46 (d, 1H), 10.34 (s, 1H), 10.39 (s, 1H).
实施例 6. N- ( 3-氯 -4-氟苯基 ) -N- ( 3-氟 -4- ( 6-曱氧基 -7- ( 1- ( 2- (曱胺基 ) -2-氧代乙基）哌啶 -4-基氧基）喹啉 -4-基氧基）苯基）环丙烷 -1 , 1-二曱酰胺（化 合物 6 )  Example 6. N-(3-Chloro-4-fluorophenyl)-N-(3-fluoro-4-(6-decyloxy-7-(1-(2-(decylamino))-2- Oxoethyl)piperidin-4-yloxy)quinolin-4-yloxy)phenyl)cyclopropane-1, 1-diamide (Compound 6)
Figure imgf000018_0001
Figure imgf000018_0001
XHNMR (DMSO-d6) (ppm): δ 1.47 (s, 4Η), 1.81 (m, 2H), 2.06 (m, 2H), 2.38 (m, 2H), 2.63 (d, 3H), 2.73 (m, 2H), 2.93(s, 2H), 3.94(s, 3H), 4.64 (m,lH), 6.41 (d, 1H), 7.36-7.58(m, 6H), 7.76 (d, 1H), 7.88-7.97 (m, 2H), 8.46 (d, 1H), 10.19 (s, 1H), 10.37 (s, 1H). X H NMR (DMSO-d 6 ) (ppm): δ 1.47 (s, 4Η), 1.81 (m, 2H), 2.06 (m, 2H), 2.38 (m, 2H), 2.63 (d, 3H), 2.73 ( m, 2H), 2.93 (s, 2H), 3.94 (s, 3H), 4.64 (m, lH), 6.41 (d, 1H), 7.36-7.58 (m, 6H), 7.76 (d, 1H), 7.88 -7.97 (m, 2H), 8.46 (d, 1H), 10.19 (s, 1H), 10.37 (s, 1H).
实施例 7. N- ( 3-氟 -4- ( 6-曱氧基 -7- ( 1- ( 2- (曱胺基） -2-氧代乙基）哌啶 -4- 基氧基）喹啉 -4-基氧基）苯基） -N- ( 3-氟 -4-曱基苯基）环丙烷 -1 , 1-二曱酰胺 (化合物 7 ) Example 7. N-(3-Fluoro-4-(6-decyloxy- 7- (1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)) Quinoline-4-yloxy)phenyl)-N-(3-fluoro-4-indolylphenyl)cyclopropane-1, 1-diamide (Compound 7)
Figure imgf000018_0002
Figure imgf000018_0002
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
JHNMR (DMSO-d6) (ppm): δ 1.47 (s, 4Η), 1.81 (m, 2H), 2.05 (m, 2H), 2.18(s,3H) ,2.38 (m, 2H), 2.63 (d, 3H), 2.73 (m, 2H), 2.94(s, 2H), 3.95 (s, 3H), 4.65(m 1H), 6.41 (d, 1H), 7.20 (m, 1H), 7.28(m, 1H), 7 .41-7.57 (m, 5H), 7.77 (m, 1H), 7.89 (d, 1H), 8.46 (d, 1H), 10.10 (s, 1H), 10.35 (s, 1H). J HNMR (DMSO-d 6 ) (ppm): δ 1.47 (s, 4Η), 1.81 (m, 2H), 2.05 (m, 2H), 2.18 (s, 3H), 2.38 (m, 2H), 2.63 ( d, 3H), 2.73 (m, 2H), 2.94 (s, 2H), 3.95 (s, 3H), 4.65 (m 1H), 6.41 (d, 1H), 7.20 (m, 1H), 7.28 (m, 1H), 7.41-7.57 (m, 5H), 7.77 (m, 1H), 7.89 (d, 1H), 8.46 (d, 1H), 10.10 (s, 1H), 10.35 (s, 1H).
实施例 8. N- ( 3-氟 -4- ( 6-曱氧基 -7- ( 1- ( 2- (曱胺基） -2-氧代乙基）哌啶 -4- 基氧基）喹啉 -4-基 MO苯基） -N- ( 4- (三氟曱基）苯基）环丙烷 -1, 1-二曱酰 胺（化合物 8 ) Example 8. N- (3- fluoro-4- (6-oxy Yue - 7 - (1- (2- (Yue amino) -2-oxoethyl) piperidin-4 Benzyloxy)quinolin-4-yl MOphenyl)-N-(4-(trifluoromethyl)phenyl)cyclopropane-1,1-dicarbamide (Compound 8)
Figure imgf000019_0001
Figure imgf000019_0001
XHNMR (DMSO-d6) (ppm): δ 1.49 (s, 4Η), 1.80 (m, 2H), 2.05(m, 2H), 2.39 (m, 2H), 2.63 (d, 3H), 2.73 (m, 2H), 2.95(s, 2H), 3.95 (s, 3H), 4.65 (m,lH), 6.41 (d, 1H), 7.41-7.53(m, 4H), 7.68-7.89 (m, 6H), 7.91 (d, 1H), 8.46 (d, 1H), 10.34 (s, 1H), 10.40 (s, 1H). X H NMR (DMSO-d 6 ) (ppm): δ 1.49 (s, 4 Η), 1.80 (m, 2H), 2.05 (m, 2H), 2.39 (m, 2H), 2.63 (d, 3H), 2.73 ( m, 2H), 2.95 (s, 2H), 3.95 (s, 3H), 4.65 (m, lH), 6.41 (d, 1H), 7.41-7.53 (m, 4H), 7.68-7.89 (m, 6H) , 7.91 (d, 1H), 8.46 (d, 1H), 10.34 (s, 1H), 10.40 (s, 1H).
实施例 9. N- ( 3-氟 -4- ( 6-曱氧基 -7- ( 1- ( 2- (曱胺基） -2-氧代乙基）哌啶 -4- 基氧基）喹啉 -4-基 苯基） -N- ( 3- (三氟曱基）苯基）环丙烷 -1, 1-二曱酰 胺（化合物 9 )  Example 9. N-(3-Fluoro-4-(6-decyloxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)) Quinoline-4-ylphenyl)-N-(3-(trifluoromethyl)phenyl)cyclopropane-1,1-diamide (Compound 9)
Figure imgf000019_0002
Figure imgf000019_0002
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 710 (M+l)。  MS (FAB): 710 (M+l).
实施例 10. N- ( 3-氯 -2-氟苯基 ) -N- ( 3-氟 -4- ( 6-曱氧基 -7- ( 1- ( 2- (曱胺基 ) -2-氧代乙基）哌啶 -4-基氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱酰胺（化 合物 10 )  Example 10. N-(3-Chloro-2-fluorophenyl)-N-(3-fluoro-4-(6-decyloxy-7-(1-(2-(decylamino))-2- Oxoethyl)piperidin-4-yloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide (Compound 10)
Figure imgf000019_0003
Figure imgf000019_0003
合成步骤参照实施例 1。 XHNMR (DMSO-d6) (ppm): δ 1.58 (s, 4H), 1.81 (m, 2H), 2.06 (m, 2H), 2.37 (m, 2H), 2.63 (d, 3H), 2.73 (m, 2H), 2.94(s, 2H), 3.95(s, 3H), 4.64 (m,lH), 6.41 (d, IH), 7.23 (m,lH),7.37-7.54(m, 5H), 7.75-7.90 (m, 3H), 8.46 (d, IH), 10.29 (s, IH), 10.47 (s IH). The synthesis procedure is referred to in Example 1. X H NMR (DMSO-d 6 ) (ppm): δ 1.58 (s, 4H), 1.81 (m, 2H), 2.06 (m, 2H), 2.37 (m, 2H), 2.63 (d, 3H), 2.73 ( m, 2H), 2.94 (s, 2H), 3.95 (s, 3H), 4.64 (m, lH), 6.41 (d, IH), 7.23 (m, lH), 7.37-7.54 (m, 5H), 7.75 -7.90 (m, 3H), 8.46 (d, IH), 10.29 (s, IH), 10.47 (s IH).
实施例 11. N- ( 4-氯 -3- (三氟曱基）苯基） -N- ( 3-氟 -4- ( 6-曱氧基 -7- ( 1- ( 2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱酰胺（化 11 )  Example 11. N-(4-Chloro-3-(trifluoromethyl)phenyl)-N-(3-fluoro-4-(6-decyloxy-7-(1-(2-(decylamine)) (2-oxoethyl)piperidin-4-yloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide (Chemical 11)
Figure imgf000020_0001
Figure imgf000020_0001
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 744 (M+l)。  MS (FAB): 744 (M+l).
实施例 12. N- ( 2-氯 -6-曱基苯基） -N- ( 3-氟 -4- ( 6-曱氧基 -7- ( 1- ( 2- (曱胺 基） -2-氧代乙基）哌啶 -4-基 喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱酰胺 (化合物 12 )  Example 12. N-(2-Chloro-6-fluorenylphenyl)-N-(3-fluoro-4-(6-decyloxy-7-(1-(2-(nonylamino))-2 -oxoethyl)piperidin-4-ylquinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide (Compound 12)
Figure imgf000020_0002
Figure imgf000020_0002
XHNMR (DMSO-d6) (ppm): δ 1.59 (s, 4Η), 1.81 (m, 2H), 2.05 (m, 2H), 2.23(s,3H) ,2.38 (m, 2H), 2.63 (d, 3H), 2.73 (m, 2H), 2.93(s, 2H), 3.95 (s, 3H), 4.65(m: IH), 6.41 (d, IH), 7.24 (m,2H), 7 .36-7.54 (m, 5H), 7.76 (d, IH), 7.92 (dd, IH), 8.46 (d, IH), 9.59 (s, IH), 10.86 (s, IH). X H NMR (DMSO-d 6 ) (ppm): δ 1.59 (s, 4 Η), 1.81 (m, 2H), 2.05 (m, 2H), 2.23 (s, 3H), 2.38 (m, 2H), 2.63 ( d, 3H), 2.73 (m, 2H), 2.93 (s, 2H), 3.95 (s, 3H), 4.65 (m : IH), 6.41 (d, IH), 7.24 (m, 2H), 7.36 -7.54 (m, 5H), 7.76 (d, IH), 7.92 (dd, IH), 8.46 (d, IH), 9.59 (s, IH), 10.86 (s, IH).
实施例 13. N- ( 3-氟 -4- ( 6-曱氧基 -7- ( ( 1- ( 2- (曱胺基） -2-氧代乙基）哌 啶 -4-基） 曱氧基）喹啉 -4-基氧基）苯基） -N- ( 4-氟苯基）环丙烷 -1 , 1-二曱酰 胺（化合物 13 ) Example 13. N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(indolyl)-2-oxoethyl)piperidin-4-yl)) Oxy)quinolin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1, 1-diamide (Compound 13)
Figure imgf000021_0001
Figure imgf000021_0001
XHNMR (DMSO-d6) (ppm): δ 1.47 (m, 6H), 1.81 (m, 3H), 2.10 (m, 2H),2.62 (d, 3H), 2.91 (m, 4H), 3.95(s, 3H), 4.02 (d, 2H), 6.41 (d, 1H), 7.14-7.18 (m,2H), 7 .40-7.45 (m, 2H), 7.52 (m, 2H),7.62-7.66 (m, 3H), 7.92 (dd, 1H), 8.46 (d, 1H), 10.03 (s, 1H), 10.41 (s, 1H). X H NMR (DMSO-d 6 ) (ppm): δ 1.47 (m, 6H), 1.81 (m, 3H), 2.10 (m, 2H), 2.62 (d, 3H), 2.91 (m, 4H), 3.95 ( s, 3H), 4.02 (d, 2H), 6.41 (d, 1H), 7.14-7.18 (m, 2H), 7.40-7.45 (m, 2H), 7.52 (m, 2H), 7.62-7.66 ( m, 3H), 7.92 (dd, 1H), 8.46 (d, 1H), 10.03 (s, 1H), 10.41 (s, 1H).
实施例 14. N- ( 3-氟 -4- ( 6-曱氧基 -7- ( ( 1- ( 2- (曱胺基） -2-氧代乙基）哌 啶 -4-基） 曱氧基）喹啉 -4-基氧基）苯基） 苯基环丙烷 -1, 1-二曱酰胺（化合 物 14 )  Example 14. N-(3-Fluoro-4-(6-methoxy-7-((1-(2-(indolyl)-2-oxoethyl)piperidin-4-yl)) Oxy)quinolin-4-yloxy)phenyl)phenylcyclopropane-1,1-diamide (Compound 14)
Figure imgf000021_0002
Figure imgf000021_0002
XHNMR (DMSO-d6) (ppm): δ 1.44-1.48 (m, 6Η), 1.80 (m, 3H), 2.08 (m, 2H),2.63 (d, 3H), 2.83-2.90 (m, 4H), 3.96(s, 3H), 4.02 (d, 2H), 6.41 (d, 1H), 7.08 (m,lH), 7 .30-7.33 (m, 2H), 7.41-7.45 (m, 2H), 7.53 (m, 2H),7.62-7.67 (m, 3H), 7.91 (dd, 1H), 8.46 (d, 1H), 10.01 (s, 1H), 10.38 (s, 1H). X H NMR (DMSO-d 6 ) (ppm): δ 1.44-1.48 (m, 6Η), 1.80 (m, 3H), 2.08 (m, 2H), 2.63 (d, 3H), 2.83-2.90 (m, 4H) ), 3.96(s, 3H), 4.02 (d, 2H), 6.41 (d, 1H), 7.08 (m, lH), 7.30-7.33 (m, 2H), 7.41-7.45 (m, 2H), 7.53 (m, 2H), 7.62-7.67 (m, 3H), 7.91 (dd, 1H), 8.46 (d, 1H), 10.01 (s, 1H), 10.38 (s, 1H).
实施例 15. N- ( 3-氟 -4- ( 6-曱氧基 -7- ( ( 1- ( 2- (曱胺基） -2-氧代乙基）哌 啶 -4-基） 曱氧基）喹啉 -4-基氧基）苯基） -N- ( 3-氟苯基）环丙烷 -1 , 1-二曱酰 胺 (化合物 15 ) Example 15. N-(3-Fluoro-4-(6-methoxy-7-((1-(2-(nonyl))-2-oxoethyl)piperidin-4-yl)indole Oxy)quinolin-4-yloxy)phenyl)-N-(3-fluorophenyl)cyclopropane-1, 1-diamide (Compound 15)
Figure imgf000022_0001
Figure imgf000022_0001
XHNMR (DMSO-d6) (ppm): δ 1.43-1.48 (m, 6H), 1.82 (m, 3H), 2.09 (m, 2H), 2.62 (d, 3H), 2.90 (m, 4H), 3.95(s, 3H), 4.01 (d, 2H), 6.42 (d, IH), 6.98-7.12 (m, 2H), 7 .40-7.44 (m, 3H), 7.52 (m, 2H),7.66-7.67 (m, 2H), 7.89 (dd, IH), 8.46 (d, IH), 10.23 (s, IH), 10.34 (s, IH). X H NMR (DMSO-d 6 ) (ppm): δ 1.43-1.48 (m, 6H), 1.82 (m, 3H), 2.09 (m, 2H), 2.62 (d, 3H), 2.90 (m, 4H), 3.95(s, 3H), 4.01 (d, 2H), 6.42 (d, IH), 6.98-7.12 (m, 2H), 7.40-7.44 (m, 3H), 7.52 (m, 2H), 7.66- 7.67 (m, 2H), 7.89 (dd, IH), 8.46 (d, IH), 10.23 (s, IH), 10.34 (s, IH).
实施例 16. N- ( 3-氟 -4- ( 6-曱氧基 -7- ( ( 1- ( 2- (曱胺基） -2-氧代乙基）哌 啶 -4-基） 曱氧基）喹啉 -4-基氧基）苯基） -N- ( 2-氟苯基）环丙烷 -1 , 1-二曱酰 胺 (化合物 16 )  Example 16. N-(3-Fluoro-4-(6-methoxy-7-((1-(2-(nonyl))-2-oxoethyl)piperidin-4-yl)indole Oxy)quinolin-4-yloxy)phenyl)-N-(2-fluorophenyl)cyclopropane-1, 1-diamide (Compound 16)
Figure imgf000022_0002
Figure imgf000022_0002
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 674 (M+l)。  MS (FAB): 674 (M+l).
实施例 17. N- ( 4-氟 -3- (三氟曱基)苯基 ) -N- ( 3-氟 -4- ( 6-曱氧基 -7- ( ( 1- ( 2- (曱胺基） -2-氧代乙基）哌啶 -4-基）曱氧基）喹啉 -4-基 苯基）环丙烷 -1, 1-二曱酰胺（ 17 )  Example 17. N-(4-Fluoro-3-(trifluoromethyl)phenyl)-N-(3-fluoro-4-(6-decyloxy-7-((1-(2-(2-) Amino)-2-oxoethyl)piperidin-4-yl)decyloxy)quinolin-4-ylphenyl)cyclopropane-1,1-diamide (17)
Figure imgf000022_0003
合成步骤参照实施例 1。
Figure imgf000022_0003
The synthesis procedure is referred to in Example 1.
MS(FAB):742(M+1)  MS (FAB): 742 (M+1)
实施例 18. N- (3-氯 -4-氟苯基） -N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺 基） -2-氧代乙基）哌啶 -4-基） 曱氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱 酰胺（化合物 18  Example 18. N-(3-Chloro-4-fluorophenyl)-N-(3-fluoro-4-(6-decyloxy-7-((1-(2-(nonylamino))-2 -oxoethyl)piperidin-4-yl)nonyloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide (Compound 18
Figure imgf000023_0001
Figure imgf000023_0001
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 708(M+1)。  MS (FAB): 708 (M + 1).
实施例 19. N- (3-氟 -4- (6-曱氧基 -7- ( ( 1- ( 2- (曱胺基） -2-氧代乙基）哌 啶 -4-基） 曱氧基）喹啉 -4-基氧基）苯基） -N- (3-氟 -4-曱基苯基）环丙烷 -1, 1- 二曱酰胺（化合物 19)  Example 19. N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(indolyl)-2-oxoethyl)piperidin-4-yl)) Oxy)quinolin-4-yloxy)phenyl)-N-(3-fluoro-4-mercaptophenyl)cyclopropane-1, 1-diamide (Compound 19)
Figure imgf000023_0002
Figure imgf000023_0002
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 688 (M+l)。  MS (FAB): 688 (M+l).
实施例 20. N- (3-氟 -4- (6-曱氧基 -7- ( ( 1- (2- (曱胺基） -2-氧代乙基）哌 啶 -4-基）曱«0喹啉 -4-基氧基）苯基） -N- ( 4- (三氟曱基）苯基）环丙烷 -1, 1-二甲酰胺（化合物 20)
Figure imgf000024_0001
Example 20. N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(indolyl)-2-oxoethyl)piperidin-4-yl)indole «0 quinolin-4-yloxy)phenyl)-N-(4-(trifluoromethyl)phenyl)cyclopropane-1, 1-dimethylamide (Compound 20)
Figure imgf000024_0001
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 724 (M+l)。  MS (FAB): 724 (M+l).
实施例 21. N- ( 3-氟 -4- ( 6-曱氧基 -7- ( ( 1- ( 2- (曱胺基） -2-氧代乙基）哌 啶 -4-基）曱«0喹啉 -4-基氧基）苯基） -N- ( 3- (三氟曱基）苯基）环丙烷 -1 , 1-二曱酰胺（化 21 )  Example 21. N-(3-Fluoro-4-(6-methoxy-7-((1-(2-(indolyl)-2-oxoethyl)piperidin-4-yl)indole) «0 quinolin-4-yloxy)phenyl)-N-(3-(trifluoromethyl)phenyl)cyclopropane-1, 1-diamide (21)
Figure imgf000024_0002
Figure imgf000024_0002
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 724 (M+l)。  MS (FAB): 724 (M+l).
实施例 22. N- ( 3-氯 -2-氟苯基 ) -N- ( 3-氟 -4- ( 6-曱氧基 -7- ( ( 1- ( 2- (曱胺 基） -2-氧代乙基）哌啶 -4-基） 曱氧基）喹啉 -4-基氧基）苯基）环丙烷 -1 , 1-二曱 酰胺（化合物 22 )  Example 22. N-(3-Chloro-2-fluorophenyl)-N-(3-fluoro-4-(6-decyloxy-7-((1-(2-(nonylamino))-2) -oxoethyl)piperidin-4-yl)nonyloxy)quinolin-4-yloxy)phenyl)cyclopropane-1, 1-diamide (Compound 22)
Figure imgf000024_0003
Figure imgf000024_0003
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 708(M+1)。  MS (FAB): 708 (M + 1).
实施例 23. N- ( 4-氯 -3- (三氟曱基）苯基 ) -N- ( 3-氟 -4- ( 6-曱氧基 -7- ( ( 1- ( 2- (曱胺基） -2-氧代乙基）哌啶 -4-基） 曱氧基）喹啉 -4-基氧基）苯基）环丙 烷 -1, 1-二曱酰 Example 23. N-(4-Chloro-3-(trifluoromethyl)phenyl)-N-(3-fluoro-4-(6-decyloxy-7- (1- (2-(Amidino)-2-oxoethyl)piperidin-4-yl)nonyloxy)quinoline-4-yloxy)phenyl)cyclopropane-1,1-dioxanoyl
Figure imgf000025_0001
Figure imgf000025_0001
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 758(M+1)  MS (FAB): 758 (M+1)
实施例 24. N- ( 2-氯 -6-曱基苯基 ) -N- ( 3-氟 -4- ( 6-曱氧基 -7- ( ( 1- ( 2- (曱 胺基） -2-氧代乙基）哌啶 -4-基） 曱氧基）喹啉 -4-基氧基）苯基）环丙烷 -1 , 1- 二曱酰胺（化合物  Example 24. N-(2-Chloro-6-mercaptophenyl)-N-(3-fluoro-4-(6-decyloxy-7-((1-(2-(nonylamino))- 2-oxoethyl)piperidin-4-yl)nonyloxy)quinolin-4-yloxy)phenyl)cyclopropane-1, 1-diamide (compound)
Figure imgf000025_0002
Figure imgf000025_0002
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 704 (M+l)。  MS (FAB): 704 (M+l).
实施例 25. N-(4-氟苯基) -N-(4-(6-曱氧基 -7-((1-(2- (曱胺基) -2-氧代乙基)哌啶 -4-基)曱氧基)喹 -4-基氧基)苯基)环丙烷 -1,1-二曱酰胺（化合物 25 )  Example 25. N-(4-Fluorophenyl)-N-(4-(6-decyloxy-7-((1-(2-(indolyl)-2-oxoethyl)piperidine). 4-yl)nonyloxy)quin-4-yloxy)phenyl)cyclopropane-1,1-diamide (Compound 25)
Figure imgf000025_0003
Figure imgf000025_0003
XHNMR (DMSO-d6) (ppm): δ 1.40-1.47 (m, 6Η), 1.78-1.81 (m, 3H), 2.05-2.10 (m, 2H), 2.63 (d, 3H), 2.79-2.90 (m, 4H), 3.94(s, 3H), 4.01 (d, 2H), 6.42 (d, 1H), 7.14-7.18 (m, 2H), 7.22-7.24 (m, 2H), 7.39 (s, 1H),7.50 (s, IH), 7.63-7.67 (m, 3H), 7.76-7.80 (d, 2H), 8.45 (d, IH), 10.07 (s, IH), 10.20 (s, IH). X H NMR (DMSO-d 6 ) (ppm): δ 1.40-1.47 (m, 6Η), 1.78-1.81 (m, 3H), 2.05-2.10 (m, 2H), 2.63 (d, 3H), 2.79-2.90 (m, 4H), 3.94(s, 3H), 4.01 (d, 2H), 6.42 (d, 1H), 7.14-7.18 (m, 2H), 7.22-7.24 (m, 2H), 7.39 (s, 1H), 7.50 (s, IH), 7.63-7.67 (m, 3H), 7.76-7.80 (d, 2H), 8.45 (d, IH), 10.07 (s, IH), 10.20 (s, IH).
实施例 26. N-(4-(6-曱氧基 -7-((l-(2- (曱胺基) -2-氧代乙基)哌啶 -4-基)曱氧基) 喹啉 -4-基氧基)苯基) -N- -1,1-二曱酰胺 (化合物 26 )  Example 26. N-(4-(6-Methoxy-7-((l-(2-(indenyl)-2-oxoethyl)piperidin-4-yl) methoxy) quinine Phenyl-4-yloxy)phenyl)-N-1,1-dicarbamide (Compound 26)
Figure imgf000026_0001
Figure imgf000026_0001
!HNMR (DMSO-d6) ( pm): δ 1.06-1.20( m,3H ),1.43-1.49 (m, 6Η), 1.78-1.81 (m, 3H), 2.05-2.11 (m, 2H), 2.62-2.63 (d, 3H), 2.82-2.90 (m, 4H), 3.94(s, 3H), 4.01-4.02 (d, 2H), 6.41-6.43 (d, IH), 7.06-7.09 (m, 2H), 7.22-7.42 (m, 5H), 7.51 (s, IH), 7.63-7.67 (m, 3H), 7.73-7.78 (d, 2H), 8.43-8.47 (d, IH), 10.07 (s, IH), 10.18 (s, IH). 实施例 27. N-(2-氟苯基) -N-(4-(6-曱氧基 -7-((l-(2- (曱胺基) -2-氧代乙基)哌啶 -4-基)曱氧 -4-基氧基)苯基)环丙烷 -1,1-二曱酰胺（化合物 27 ) ! HNMR (DMSO-d 6) (pm): δ 1.06-1.20 (m, 3H), 1.43-1.49 (m, 6Η), 1.78-1.81 (m, 3H), 2.05-2.11 (m, 2H), 2.62 -2.63 (d, 3H), 2.82-2.90 (m, 4H), 3.94(s, 3H), 4.01-4.02 (d, 2H), 6.41-6.43 (d, IH), 7.06-7.09 (m, 2H) , 7.22-7.42 (m, 5H), 7.51 (s, IH), 7.63-7.67 (m, 3H), 7.73-7.78 (d, 2H), 8.43-8.47 (d, IH), 10.07 (s, IH) , 10.18 (s, IH). Example 27. N-(2-Fluorophenyl)-N-(4-(6-decyloxy-7-((l-(2-(nonylamino))-2 -oxoethyl)piperidin-4-yl)phosphono-4-yloxy)phenyl)cyclopropane-1,1-diamide (Compound 27)
Figure imgf000026_0002
Figure imgf000026_0002
XHNMR (DMSO-d6) (ppm): δ 1.43-1.45(m, 2Η), 1.57-1.66 (m, 4H), 1.79-1.82(m, 3H), 2.05-2.11 (m, 2H), 2.62-2.63 (d, 3H), 2.82-2.90 (m, 4H), 3.94 (s, 3H), 4.01-4.02 (d, 2H), 6.43-6.44 (d, IH), 7.17-7.20 (m, 2H), 7.25-7.30 (m, 3H), 7.40 (s, 1H),7.51 (s, IH), 7.66-7.67 (m, IH), 7.73-7.75 (d, 2H), 7.91-7.94 (m, IH), 8.46-8.47 (d, IH), 10.04 (s, IH), 10.62 (s, IH). X H NMR (DMSO-d 6 ) (ppm): δ 1.43-1.45 (m, 2 Η), 1.57-1.66 (m, 4H), 1.79-1.82 (m, 3H), 2.05-2.11 (m, 2H), 2.62 -2.63 (d, 3H), 2.82-2.90 (m, 4H), 3.94 (s, 3H), 4.01-4.02 (d, 2H), 6.43-6.44 (d, IH), 7.17-7.20 (m, 2H) , 7.25-7.30 (m, 3H), 7.40 (s, 1H), 7.51 (s, IH), 7.66-7.67 (m, IH), 7.73-7.75 (d, 2H), 7.91-7.94 (m, IH) , 8.46-8.47 (d, IH), 10.04 (s, IH), 10.62 (s, IH).
实施例 28. N-(3-氟苯基) -N-(4-(6-曱氧基 -7-((l-(2- (曱胺基) -2-氧代乙基)哌啶 -4-基)曱氧基)喹啉 -4- -1,1-二曱酰胺（化合物 28 ) Example 28. N-(3-Fluorophenyl)-N-(4-(6-decyloxy-7-((l-(2-(indolyl)-2-oxoethyl)piperidine). 4-yl)nonyloxy)quinoline-4-1,3- 1,1-diamide (Compound 28)
Figure imgf000027_0001
Figure imgf000027_0001
XHNMR (DMSO-d6) (ppm): δ 1.40-1.48 (m, 6Η), 1.79-1.81 (m, 3H), 2.05-2.11 (m, 2H), 2.62-2.63 (d, 3H), 2.82-2.90 (m, 4H), 3.94(s, 3H), 4.01-4.02 (d, 2H), 6.41-6.43 (d, IH), 6.88-6.93 (m, IH), 7.22-7.41 (m, 5H) 7.51 (s, IH), 7.64-7.78 (m, 4H), 8.46-8.48 (d, IH), 10.12 (s, IH), 10.28 (s, IH). X H NMR (DMSO-d 6 ) (ppm): δ 1.40-1.48 (m, 6Η), 1.79-1.81 (m, 3H), 2.05-2.11 (m, 2H), 2.62-2.63 (d, 3H), 2.82 -2.90 (m, 4H), 3.94(s, 3H), 4.01-4.02 (d, 2H), 6.41-6.43 (d, IH), 6.88-6.93 (m, IH), 7.22-7.41 (m, 5H) 7.51 (s, IH), 7.64-7.78 (m, 4H), 8.46-8.48 (d, IH), 10.12 (s, IH), 10.28 (s, IH).
实施例 29. N-(4-(7-((l-(2-胺基 -2-氧代乙基)哌啶 -4-基)曱氧基 )-6-曱氧基喹啉 -4-基氧基)苯基) - -苯基环丙烷 -1,1-二曱酰胺（化合物 29 )  Example 29. N-(4-(7-((1-Amino-2-oxoethyl)piperidin-4-yl)decyloxy)-6-decyloxyquinoline-4 -yloxy)phenyl)-phenylcyclopropane-1,1-diamide (Compound 29)
Figure imgf000027_0002
Figure imgf000027_0002
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
JHNMR (DMSO-d6) (ppm): δ 1.26-1.35 (m, 7Η)1.42-1.49 (m, 6Η), 1.81-1.84 (m, 3H), 2.2 l(m, IH), 2.96 (m, 3H), 3.94(s, 3H), 4.01-4.03 (d, 2H), 6.41-6.43 (d, IH), 7.05-7.10 (m, IH), 7.22-7.36 (m, 6H), 7.40 (s, IH), 7.51 (s, IH), 7.63-7.69 (m, 3H), 7.76-7.78 (d, 2H), 8.45-8.47 (d, IH), 10.08 (s, IH), 10.19(s, IH). J HNMR (DMSO-d 6 ) (ppm): δ 1.26-1.35 (m, 7Η) 1.42-1.49 (m, 6Η), 1.81-1.84 (m, 3H), 2.2 l(m, IH), 2.96 (m) , 3H), 3.94(s, 3H), 4.01-4.03 (d, 2H), 6.41-6.43 (d, IH), 7.05-7.10 (m, IH), 7.22-7.36 (m, 6H), 7.40 (s , IH), 7.51 (s, IH), 7.63-7.69 (m, 3H), 7.76-7.78 (d, 2H), 8.45-8.47 (d, IH), 10.08 (s, IH), 10.19(s, IH ).
实施例 30. N-(4-(7-((l-(2-胺基 -2-氧代乙基)哌啶 -4-基)曱氧基 )-6-曱氧基喹啉 -4-基氧基)苯基) -N-(4-氟苯基)环丙烷 -1,1-二曱酰胺（化合物 30 )
Figure imgf000028_0001
Example 30. N-(4-(7-((1-Amino-2-oxoethyl)piperidin-4-yl)decyloxy)-6-decyloxyquinoline-4 -yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-diamide (Compound 30)
Figure imgf000028_0001
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
JHNMR (DMSO-d6) (ppm): δ 1.25-1.29 (m, 3H), 1.43-1.48 (m, 6H), 1.80-1.83 (m, 3H), 2.13 (m, 2H), 2.90 (m, 4H), 3.94(s, 3H), 4.01-4.02 (d, 2H), 6.41-6.42 (d, IH), 7.14-7.24 (m, 6H), 7.40 (s, IH), 7.51 (s, IH), 7.63-7.67 (m, 2H), 7.76-7.78 (d, 2H), 8.45-8.47 (d, IH), 10.08 (s, IH), 10.21 (s, IH). J HNMR (DMSO-d 6 ) (ppm): δ 1.25-1.29 (m, 3H), 1.43-1.48 (m, 6H), 1.80-1.83 (m, 3H), 2.13 (m, 2H), 2.90 (m) , 4H), 3.94(s, 3H), 4.01-4.02 (d, 2H), 6.41-6.42 (d, IH), 7.14-7.24 (m, 6H), 7.40 (s, IH), 7.51 (s, IH ), 7.63-7.67 (m, 2H), 7.76-7.78 (d, 2H), 8.45-8.47 (d, IH), 10.08 (s, IH), 10.21 (s, IH).
实施例 31. N-(4-(7-((l-(2-胺基 -2-氧代乙基)哌啶 -4-基)曱氧基 )-6-曱氧基喹啉 -4-基氧基)苯基) -N- -氟苯基)环丙烷 -1,1-二曱酰胺（化合物 31 )  Example 31. N-(4-(7-((1-Amino-2-oxoethyl)piperidin-4-yl)decyloxy)-6-methoxyoxyquinoline-4 -yloxy)phenyl)-N-fluorophenyl)cyclopropane-1,1-diamide (Compound 31)
Figure imgf000028_0002
Figure imgf000028_0002
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 642(M+1)。  MS (FAB): 642 (M + 1).
实施例 32. N-(4-(7-((l-(2-胺基 -2-氧代乙基)哌啶 -4-基)曱氧基 )-6-曱氧基喹啉 -4-基氧基)苯基) - -(3-氟苯基)环丙烷 -1,1-二曱酰胺（化合物 32 )  Example 32. N-(4-(7-((1-Amino-2-oxoethyl)piperidin-4-yl)decyloxy)-6-methoxyoxyquinoline-4 -yloxy)phenyl)-(3-fluorophenyl)cyclopropane-1,1-diamide (Compound 32)
Figure imgf000028_0003
Figure imgf000028_0003
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 642(M+1)。  MS (FAB): 642 (M + 1).
实施例 33. N-(4-(7-((l-(2-胺基 -2-氧代乙基)哌啶 -4-基)曱氧基 )-6-曱氧基喹啉 -4-基氧基 )-3-氟苯 -N-苯基环丙烷 -1,1-二曱酰胺（化合物 33 ) Example 33. N-(4-(7-((1-(2-Amino-2-oxoethyl)piperidin-4-yl)phosphonyloxy)-6-methoxyoxyquinoline -4-yloxy)-3-fluorobenzene-N-phenylcyclopropane-1,1-diamide (Compound 33)
Figure imgf000029_0001
Figure imgf000029_0001
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
JHNMR (DMSO-d6) (ppm): δ 1.23-1.28 (m, 3Η), 1.40-1.48 (m, 6H), 1.81-1.83 (m, 3H), 2.16 (m, IH), 2.63 (d, 3H), 2.93 (m, 4H), 3.94(s, 3H), 4.02-4.03 (d, 2H), 6.41-6.42 (d, IH), 7.06-7.10 (m, IH), 7.19-7.22 (m, 2H), 7.30-7.34 (m, 2H), 7.39-7.45 (m, 2H),7.53 (m, 2H), 7.63-7.67 (m, 2H), 7.89-7.93 (d, IH), 8.46-8.48 (d, IH), 10.01(s: IH), 10.39 (s, IH). J HNMR (DMSO-d 6 ) (ppm): δ 1.23-1.28 (m, 3Η), 1.40-1.48 (m, 6H), 1.81-1.83 (m, 3H), 2.16 (m, IH), 2.63 (d , 3H), 2.93 (m, 4H), 3.94(s, 3H), 4.02-4.03 (d, 2H), 6.41-6.42 (d, IH), 7.06-7.10 (m, IH), 7.19-7.22 (m , 2H), 7.30-7.34 (m, 2H), 7.39-7.45 (m, 2H), 7.53 (m, 2H), 7.63-7.67 (m, 2H), 7.89-7.93 (d, IH), 8.46-8.48 (d, IH), 10.01(s : IH), 10.39 (s, IH).
实施例 34. N-(4-(7-((l-(2-胺基 -2-氧代乙基)哌啶 -4-基)曱氧基 )-6-曱氧基喹啉 -4-基氧基 )-3-氟苯 -N-(4-氟苯基)环丙烷 -1,1-二曱酰胺（化合物 34 )  Example 34. N-(4-(7-((1-Amino-2-oxoethyl)piperidin-4-yl)decyloxy)-6-decyloxyquinoline-4 -yloxy)-3-fluorobenzene-N-(4-fluorophenyl)cyclopropane-1,1-diamide (Compound 34)
Figure imgf000029_0002
Figure imgf000029_0002
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
JHNMR (DMSO-d6) (ppm): δ 1.16-1.23 (m, 3Η), 1.41-1.48 (m, 6H), 1.81-1.83 (m, 3H), 2.13-2.18 (m, 2H), 2.63 (d, 3H), 2.90-2.93 (m, 4H), 3.96(s, 3H), 4.00-4.04 (d, 2H), 6.41-6.42 (d, IH), 7.11-7.23 (m, 4H), 7.41-7.45 (m, 2H), 7.53-7.56 (m, 2H), 7.63-7.67 (m, 2H), 7.90-7.93 (d, IH), 8.47-8.48 (d, IH), 10.04(s, IH), 10.42 (s, 1H)。 J HNMR (DMSO-d 6 ) (ppm): δ 1.16-1.23 (m, 3Η), 1.41-1.48 (m, 6H), 1.81-1.83 (m, 3H), 2.13-2.18 (m, 2H), 2.63 (d, 3H), 2.90-2.93 (m, 4H), 3.96(s, 3H), 4.00-4.04 (d, 2H), 6.41-6.42 (d, IH), 7.11-7.23 (m, 4H), 7.41 -7.45 (m, 2H), 7.53-7.56 (m, 2H), 7.63-7.67 (m, 2H), 7.90-7.93 (d, IH), 8.47-8.48 (d, IH), 10.04(s, IH) , 10.42 (s, 1H).
实施例 35. N-(4-(7-((l-(2-胺基 -2-氧代乙基)哌啶 -4-基)曱氧基 )-6-曱氧基喹啉 -4-基氧基 )-3-氟苯基) -N-(2-氟苯基)环丙烷 -1,1-二曱酰胺（化合物 35 )
Figure imgf000030_0001
Example 35. N-(4-(7-((1-Amino-2-oxoethyl)piperidin-4-yl)phosphonyl)-6-methoxyoxyquinoline-4 -yloxy)-3-fluorophenyl)-N-(2-fluorophenyl)cyclopropane-1,1-diamide (Compound 35)
Figure imgf000030_0001
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 660(M+1)。  MS (FAB): 660 (M + 1).
实施例 36. N-(4-(7-((l-(2-胺基 -2-氧代乙基)哌啶 -4-基)曱氧基 )-6-曱氧基喹啉 -4-基氧基 )-3-氟 -N-(3-氟苯基)环丙烷 -1,1-二曱酰胺（化合物 36 )  Example 36. N-(4-(7-((1-Amino-2-oxoethyl)piperidin-4-yl)decyloxy)-6-decyloxyquinoline-4 -yloxy)-3-fluoro-N-(3-fluorophenyl)cyclopropane-1,1-diamide (Compound 36)
Figure imgf000030_0002
Figure imgf000030_0002
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 660(M+1)  MS (FAB): 660 (M+1)
实施例 37. N-(3-氟 -4-(6-曱氧基 -7-((1-(2- (曱磺胺基）乙基)哌啶 -4-基)曱氧基) 4-基氧基) -N-(4-氟苯基)环丙烷 -1,1-二曱酰胺（化合物 37 )  Example 37. N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy) 4-. -oxy-)-N-(4-fluorophenyl)cyclopropane-1,1-diamide (Compound 37)
Figure imgf000030_0003
Figure imgf000030_0003
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 724 (M+l)。  MS (FAB): 724 (M+l).
实施例 38. N-(3-氟 -4-(6-曱氧基 -7-((1-(2- (曱磺胺基）乙基)哌啶 -4-基)曱氧基) 4-基氧基)苯基) -N-苯基环丙烷 -1,1-二曱酰胺 (化合物 38 )
Figure imgf000031_0001
Example 38. N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy) 4-. Benzyloxy)phenyl)-N-phenylcyclopropane-1,1-diamide (Compound 38)
Figure imgf000031_0001
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 706 (M+l)。  MS (FAB): 706 (M+l).
实施例 39. N-(3-氟 -4-(6-曱氧基 -7-((l-(2- (曱磺胺基）乙基)哌啶 -4-基)曱氧基) 喹啉 -4-基氧基) -N-(2-氟苯基)环丙烷 -1,1-二曱酰胺（化合物 39 )  Example 39. N-(3-Fluoro-4-(6-decyloxy-7-((l-(2-(sulfonyl)ethyl)piperidin-4-yl)methoxy)quinoline -4-yloxy)-N-(2-fluorophenyl)cyclopropane-1,1-diamide (Compound 39)
Figure imgf000031_0002
Figure imgf000031_0002
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 724 (M+l)。  MS (FAB): 724 (M+l).
实施例 40. N-(3-氟 -4-(6-曱氧基 -7-((1-(2- (曱磺胺基）乙基)哌啶 -4-基)曱氧基) 喹啉 -4-基氧基)苯 -N-(3-氟苯基)环丙烷 -1,1-二曱酰胺（化合物 40 )  Example 40. N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy)quinoline -4-yloxy)benzene-N-(3-fluorophenyl)cyclopropane-1,1-diamide (Compound 40)
Figure imgf000031_0003
Figure imgf000031_0003
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 724 (M+l)。  MS (FAB): 724 (M+l).
实施例 41. N-(4-氟苯基) -N-(4-(6-曱氧基 -7-((1-(2- (曱磺胺基）乙基)哌啶 -4-基) 曱氧基)喹啉 -4-基氧基)苯基)环丙烷 -1,1-二曱酰胺（化合物 41 )
Figure imgf000032_0001
Example 41. N-(4-Fluorophenyl)-N-(4-(6-decyloxy-7-((1-(2-(sulfonyl))))piperidin-4-yl)曱oxy)quinoline-4-yloxy)phenyl)cyclopropane-1,1-diamide (Compound 41)
Figure imgf000032_0001
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 706 (M+l)。  MS (FAB): 706 (M+l).
实施例 42. N-(4-(6-曱氧基 -7-((1-(2- (曱磺胺基）乙基)哌啶 -4-基）曱氧基)喹啉 -4-基氧基)苯基) -N- -1,1-二曱酰胺（化合物 42 )  Example 42. N-(4-(6-Methoxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl) decyloxy)quinolin-4-yl Oxy)phenyl)-N--1,1-diamide (Compound 42)
Figure imgf000032_0002
Figure imgf000032_0002
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 688 (M+l)。  MS (FAB): 688 (M+l).
实施例 43. N-(2-氟苯基) -N-(4-(6-曱氧基 -7-((1-(2- (曱磺胺基）乙基)哌啶 -4-基) 曱氧基)喹啉 -4-基氧 -1,1-二曱酰胺（化合物 43 )  Example 43. N-(2-Fluorophenyl)-N-(4-(6-decyloxy-7-((1-(2-(sulfonyl))))piperidin-4-yl)曱oxy)quinoline-4-yloxy-1,1-diamide (Compound 43)
Figure imgf000032_0003
Figure imgf000032_0003
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 706 (M+l)。  MS (FAB): 706 (M+l).
实施例 44. N-(3-氟苯基) -N-(4-(6-曱氧基 -7-((1-(2- (曱磺胺基）乙基)哌啶 -4-基) 曱氧基)喹啉 -4-基氧基)苯基)环丙烷 -1,1-二曱酰胺 (化合物 44 )
Figure imgf000033_0001
Example 44. N-(3-Fluorophenyl)-N-(4-(6-decyloxy-7-((1-(2-(sulfonyl))))piperidin-4-yl)曱oxy)quinoline-4-yloxy)phenyl)cyclopropane-1,1-diamide (Compound 44)
Figure imgf000033_0001
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 706 (M+l)。  MS (FAB): 706 (M+l).
实施例 45. N-(3-氟 -4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基)曱氧. 啉 -4-基氧基)苯 -N-(4-氟苯基)环丙烷 -1,1-二曱酰胺（化合物 45 )  Example 45. N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)oxime. porphyrin-4 -yloxy)benzene-N-(4-fluorophenyl)cyclopropane-1,1-diamide (Compound 45)
Figure imgf000033_0002
Figure imgf000033_0002
合成步骤参照实施例 1  Synthesis step reference embodiment 1
MS(FAB): 709 (M+l)。  MS (FAB): 709 (M+l).
实施例 46. N-(3-氟 -4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基)曱氧. 啉 -4-基氧基)苯基) - -苯基环丙烷 -1,1-二曱酰胺（化合物 46 )  Example 46. N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)oxime. porphyrin-4 -yloxy)phenyl)-phenylcyclopropane-1,1-diamide (Compound 46)
Figure imgf000033_0003
Figure imgf000033_0003
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 691 (M+l)。  MS (FAB): 691 (M+l).
实施例 47. N-(3-氟 -4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基)曱氧. 啉 -4-基氧基)苯基) -N-(2-氟苯基)环丙烷 -1,1-二曱酰胺（化合物 47 )
Figure imgf000034_0001
Example 47. N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)oxime. porphyrin-4 -yloxy)phenyl)-N-(2-fluorophenyl)cyclopropane-1,1-diamide (Compound 47)
Figure imgf000034_0001
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 709 (M+l)。  MS (FAB): 709 (M+l).
实施例 48. N-(3-氟 -4-(6-曱氧基 -7-((l-(2- (曱磺基）乙基)哌啶 -4-基)曱氧基)喹 啉 -4-基氧基)苯基 -N-(3-氟苯基)环丙烷 -1,1-二曱酰胺 （化合物 48 )  Example 48. N-(3-Fluoro-4-(6-decyloxy-7-((l-(2-(sulfo)ethyl)piperidin-4-yl)decyloxy)quinoline 4--4-yloxy)phenyl-N-(3-fluorophenyl)cyclopropane-1,1-diamide (Compound 48)
Figure imgf000034_0002
Figure imgf000034_0002
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 709 (M+l)。  MS (FAB): 709 (M+l).
实施例 49. N-(4-氟苯基) -N-(4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基)曱 氧基)喹啉 -4-基 -1,1-二曱酰胺（化合物 49 )  Example 49. N-(4-Fluorophenyl)-N-(4-(6-decyloxy-7-((1-(2-(sulfo)ethyl)piperidin-4-yl)).曱oxy)quinolin-4-yl-1,1-diamide (Compound 49)
Figure imgf000034_0003
Figure imgf000034_0003
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 691 (M+l)。  MS (FAB): 691 (M+l).
实施例 50. N-(4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基)曱氧基)喹啉 -4- 基氧基)苯基) -N-苯基环丙烷 -1,1-二曱酰胺（化合物 50 )
Figure imgf000035_0001
Example 50. N-(4-(6-Methoxy-7-((1-(2-(sulfo)ethyl)piperidin-4-yl) decyloxy)quinolin-4-yl Oxy)phenyl)-N-phenylcyclopropane-1,1-diamide (Compound 50)
Figure imgf000035_0001
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 673 (M+l)。  MS (FAB): 673 (M+l).
实施例 51. N-(2-氟苯基) -N-(4-(6-曱氧基 -7-((l-(2- (曱磺基）乙基)哌啶 -4-基)曱 氧基)喹啉 -4-基 -1,1-二曱酰胺（化合物 51 )  Example 51. N-(2-Fluorophenyl)-N-(4-(6-decyloxy-7-((l-(2-(sulfo)ethyl)piperidin-4-yl)).曱oxy)quinolin-4-yl-1,1-diamide (Compound 51)
Figure imgf000035_0002
Figure imgf000035_0002
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 691 (M+l)。  MS (FAB): 691 (M+l).
实施例 52. N-(3-氟苯基) -N-(4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基)曱 氧基)喹啉 -4-基 -1,1-二曱酰胺（化合物 52 )  Example 52. N-(3-Fluorophenyl)-N-(4-(6-decyloxy-7-((1-(2-(sulfo)ethyl)piperidin-4-yl)).曱oxy)quinolin-4-yl-1,1-diamide (Compound 52)
Figure imgf000035_0003
Figure imgf000035_0003
合成步骤参照实施例 1。  The synthesis procedure is referred to in Example 1.
MS(FAB): 691 (M+l)。  MS (FAB): 691 (M+l).
实施例 53. 本发明化合物对肿; i细胞增殖抑制试验 Example 53. Compound of the present invention is swollen; i cell proliferation inhibition test
将肿瘤细胞用胰酶消化后 , 以 3000个每孔的密度分种于 96孔微孔板， 在含 10% FBS的完全培养基里培养 24小时。 加入待测化合物和溶剂对照 , 最终化合 物浓度为 10nmol/L到 5(^mol/L。 然后在完全培养基里培养 72小时。根据说明书 的方法加入 MTS试剂 （ Promega ) , 在 37 °C C02培养箱中培养 2小时， 然后在 ELISA酶标仪上读取 490nm的吸收值， 计算其抑制率和 IC5。值。 After the tumor cells were trypsinized, they were seeded in a 96-well microplate at a density of 3,000 per well. Incubate for 24 hours in 10% FBS in complete medium. Add the test compound and solvent control, the final compound concentration is 10nmol / L to 5 (^mol / L. Then cultured in complete medium for 72 hours. Add MTS reagent (Promega) according to the instructions, at 37 °C C0 2 The culture was incubated for 2 hours in an incubator, and then the absorbance at 490 nm was read on an ELISA plate reader, and the inhibition rate and IC 5 value were calculated.
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000036_0001
Figure imgf000037_0001
化合物 46 2.403士 0.539 4.091 化合物 47 3.116±1.227 5.226 化合物 48 2.004士 0.338 1.906 化合物 49 1.493士 3.011 2.294 化合物 50 0.886士 0.106 1.492 化合物 51 0.607±0.205 1.591 化合物 52 1.931士 0.889 3.306 Compound 46 2.403 ± 0.539 4.091 Compound 47 3.116 ± 1.227 5.226 Compound 48 2.004 ± 0.338 1.906 Compound 49 1.493 ± 3.011 2.294 Compound 50 0.886 ± 0.106 1.492 Compound 51 0.607 ± 0.205 1.591 Compound 52 1.931 ± 0.889 3.306
Cabozantinib(XL- 184) 3.169±0.772 5.949  Cabozantinib (XL- 184) 3.169±0.772 5.949
阿霉素 0.191士 0.031 注： XL-184为 N- ( 4- ( ( 6,7-二曱氧基喹啉 -4-基） 氧基）苯基） -N- ( 4-氟 苯基）环丙烷 -1 , 1-二曱酰胺。  Doxorubicin 0.191 ± 0.031 Note: XL-184 is N-(4-((6,7-dimethoxyoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl) Cyclopropane-1, 1-diamide.
结论： 目标化合物对 MGC-803 (胃癌细胞）具有较高的体外增殖抑制作用， 大部分化合物优于阳性药 Cabozantinib,与阿霉素活性相当； 另外目标化合物对 BGC-823 (胃癌细胞）具有较高的体外增殖抑制作用，优于阳性药 Cabozantinib。 实施例 54. 本发明化合物 c-Met和 VEGFR2的酶抑制试验  Conclusion: The target compound has a high inhibitory effect on proliferation of MGC-803 (stomach cancer cells). Most of the compounds are superior to the positive drug Cabozantinib, which is equivalent to the activity of doxorubicin. In addition, the target compound has a higher affinity for BGC-823 (stomach cancer cells). High in vitro proliferation inhibition is superior to the positive drug Cabozantinib. Example 54. Enzyme inhibition assay of the compounds of the invention c-Met and VEGFR2
1化合物 XL-184、 化合物 13、 化合物 25分子水平 c-Met抑制活性筛选  1 compound XL-184, compound 13, compound 25 molecular level c-Met inhibitory activity screening
1.1实验方法 1.1 Experimental methods
酶联免疫吸附法 (Enzyme-Linked Immunosorbent Assay, ELISA)  Enzyme-Linked Immunosorbent Assay (ELISA)
1.2主要仪器 1.2 main instruments
可调波长式 ϋ孔板酶标仪 Molecular Devices SPECTRAMAX190o Adjustable wavelength microplate reader Molecular Devices SPECTRAMAX190 o
1.3主要试剂 1.3 main reagents
酪氨酸激酶 c-Met为本实验室利用昆虫杆状病毒表达***表达，用 Ni-NTA柱 亲和纯化得到， 并经检测符合实验要求；  The tyrosine kinase c-Met was expressed in the laboratory using the insect baculovirus expression system, and was affinity-purified by Ni-NTA column, and tested to meet the experimental requirements;
激酶反应底物 Poly(Glu,Tyr)B4:1购自 Sigma公司； The kinase reaction substrate Poly(Glu, Tyr)B 4:1 was purchased from Sigma;
抗磷酸化酪氨酸的单克隆抗体 PY99 购自 Santa Cruz公司；  Monoclonal antibody against phosphotyrosine PY99 was purchased from Santa Cruz;
辣根过氧化物酶标记羊抗鼠的 IgG 购自 Calbiochem公司；  Horseradish peroxidase-labeled goat anti-mouse IgG was purchased from Calbiochem;
ATP、 DTT、 OPD 购自 Amresco公司；  ATP, DTT, OPD were purchased from Amresco;
酶标板购自 Corning公司； PF2341066购自 LC LabORATORIES公司； The ELISA plate was purchased from Corning; PF2341066 was purchased from LC LabORATORIES;
其它试剂国产。  Other reagents are made in China.
1.4实验步骤 1.4 Experimental steps
(1) 酶反应底物 Poly(Glu,Tyr)B4:1用无钾离子的 PBS稀释成 20 g/ml, 包被酶 标板， 置 37 °C反应 12-16 h, 弃去孔中液体。 (1) The enzyme reaction substrate Poly(Glu, Tyr)B 4:1 was diluted to 20 g/ml with PBS without potassium ions, coated with the enzyme plate, and reacted at 37 °C for 12-16 h, and discarded in the well. liquid.
(2) T-PBS洗板三次， 每次 10 min。  (2) Wash the plate three times with T-PBS for 10 min each time.
(3) 于 37°C烘箱中干燥酶标板。 (3) drying microtiter plates at 3 7 ° C oven.
(4) 在包被好酶标板孔内加入受试样品：  (4) Add the test sample to the well of the coated ELISA plate:
受试样品先用 DMSO配制成 10-2 M的储存液， 分装后存放于 _ 20°C , 临用前 用反应緩冲液稀释到所需浓度， 加至实验孔内， 使其在 100 μΐ反应体系中达到相 应的终浓度。 同时设立阳性对照孔， 加入阳性对照化合物 PF2341066。 The test sample was first prepared in DMSO with 10 - 2 M stock solution, and stored at -20 ° C after being dispensed. Dilute to the desired concentration with reaction buffer before use, and add it to the test well to make it The corresponding final concentration is reached in the 100 μΐ reaction system. A positive control well was also established and the positive control compound PF2341066 was added.
(5)加入 ATP和受试酪氨酸激酶：  (5) Add ATP and tested tyrosine kinase:
加入用反应緩冲液稀释的 ATP溶液 （ ATP终浓度 5 μΜ ) , 最后， 加入用反 应緩冲液稀释的受试酪氨酸激酶。 反应体系总体积为 100 μ1。 同时设立阴性对照 孔和无酶对照孔。  ATP solution diluted with the reaction buffer (ATP final concentration of 5 μΜ) was added, and finally, the test tyrosine kinase diluted with the reaction buffer was added. The total volume of the reaction system is 100 μl. Negative control wells and enzyme-free control wells were also established.
(6) 将反应体系置于湿盒内， 37°C摇床避光反应 1 h, 反应结束后 T-PBS洗 板三次。  (6) The reaction system was placed in a wet box, and shaken at 37 ° C for 1 h in the shaker, and the plate was washed three times with T-PBS after the reaction.
(7)加入抗体 PY99 100 μΐ/孔， 37°C摇床反应 30 min。 T-PBS洗板三次。  (7) Add the antibody PY99 100 μΐ/well and shake for 37 min at 37 °C. The plate was washed three times with T-PBS.
(8)加入辣根过氧化物酶标记的羊抗鼠的 IgG 100 μΐ/孔， 37°C摇床反应 30 min。 T-PBS洗板三次。  (8) Horseradish peroxidase-labeled goat anti-mouse IgG 100 μΐ/well was added and shaken at 37 ° C for 30 min. The plate was washed three times with T-PBS.
(9)加入 OPD显色液 100 μΐ/孔， 室温避光反应 1 - 10 min。  (9) Add OPD coloring solution 100 μΐ/well, and avoid the light at room temperature for 1 - 10 min.
(10) 加入 2 M HB2SOB4 50 μΐ中止反应， 用可调波长式微孔板酶标仪 Molecular Devices SPECTRAMAX190测 B490值。 (10) The reaction was stopped by the addition of 2 M HB 2 SOB 4 50 μΐ, and the B 490 value was measured using a tunable wavelength microplate microplate reader Molecular Devices SPECTRAMAX190.
(11)样品的抑制率通过下列公式求得：  (11) The inhibition rate of the sample is obtained by the following formula:
化合物 OD值 -无酶对照孔 OD值  Compound OD value - no enzyme control well OD value
样品的抑制率％= ( 1 -
Figure imgf000039_0001
Sample inhibition rate %= ( 1 -
Figure imgf000039_0001
阴性对照 OD值 -无酶对照孔 OD值  Negative control OD value - no enzyme control well OD value
1.5实验结果 1.5 Experimental results
本发明化合物对受体酪氨酸激酶 c-Met酶活抑制率（％ )
Figure imgf000039_0002
XL- 184 89.7 71.7 43.4 13.9 9.5 2.9 17.7士 4.0 化合物 25 94.3 71.0 42.5 20.3 18.3 12.2 22.7±0.1 化合物 13 94.3 84.0 53.2 27.0 19.8 23.8 11.5±0.7 Inhibition rate of the receptor tyrosine kinase c-Met by the compound of the present invention (%)
Figure imgf000039_0002
XL- 184 89.7 71.7 43.4 13.9 9.5 2.9 17.7 士 4.0 Compound 25 94.3 71.0 42.5 20.3 18.3 12.2 22.7 ± 0.1 Compound 13 94.3 84.0 53.2 27.0 19.8 23.8 11.5 ± 0.7
2.化合物 XL-184、化合物 25、化合物 13分子水平 VEGFR2 (血管内皮生长因子 受体 2 )抑制活性筛选 2. Compound XL-184, compound 25, compound 13 molecular level VEGFR2 (vascular endothelial growth factor receptor 2) inhibitory activity screening
2.1实验方法 2.1 Experimental methods
酶联免疫吸附法 (Enzyme-Linked Immunosorbent Assay, ELISA)  Enzyme-Linked Immunosorbent Assay (ELISA)
2.2主要仪器 2.2 main instruments
可调波长式 ϋ孔板酶标仪 Molecular DevicesSPECTRAMAX190o Adjustable wavelength microplate reader Molecular Devices SPECTRAMAX190 o
2.3主要试剂 2.3 main reagents
酪氨酸激酶 VEGFR2 为本实验室利用昆虫杆状病毒表达***表达， 用 Ni-NTA柱亲和纯化得到，并经检测符合实验要求；激酶反应底物 Poly(Glu,Tyr)4:1 购自 Sigma公司； The tyrosine kinase VEGFR2 was expressed in the laboratory using the insect baculovirus expression system, and was affinity-purified by Ni-NTA column, and tested to meet the experimental requirements; the kinase reaction substrate Poly(Glu, Tyr) 4:1 was purchased from Sigma Corporation;
抗磷酸化酪氨酸的单克隆抗体 PY99 购自 Santa Cruz公司；  Monoclonal antibody against phosphotyrosine PY99 was purchased from Santa Cruz;
辣根过氧化物酶标记羊抗鼠的 IgG 购自 Calbiochem公司；  Horseradish peroxidase-labeled goat anti-mouse IgG was purchased from Calbiochem;
ATP、 DTT、 OPD 购自 Amresco公司；  ATP, DTT, OPD were purchased from Amresco;
酶标板购自 Corning公司；  The ELISA plate was purchased from Corning;
Sul l248购自 LC LabORATORIES公司；  Sul l248 was purchased from LC LabORATORIES;
其它试剂国产。  Other reagents are made in China.
2.4实验步骤 2.4 Experimental steps
(1) 酶反应底物 Poly(Glu,Tyr)4:1用无钾离子的 PBS稀释成 20 g/ml , 包被酶 标板， 置 37°C反应 12-16 h, 弃去孔中液体。 (1) The enzyme reaction substrate Poly(Glu, Tyr) 4:1 was diluted to 20 g/ml with PBS without potassium ion, coated with the enzyme plate, and reacted at 37 ° C for 12-16 h, discarding the liquid in the well. .
(2) T-PBS洗板三次， 每次 10 min。  (2) Wash the plate three times with T-PBS for 10 min each time.
(3) 于 37°C烘箱中干燥酶标板。 (3) drying microtiter plates at 3 7 ° C oven.
(4) 在包被好酶标板孔内加入受试样品：  (4) Add the test sample to the well of the coated ELISA plate:
受试样品先用 DMSO配制成 10-2 M的储存液， 分装后存放于 - 20°C , 临用 前用反应緩冲液稀释到所需浓度， 加至实验孔内， 使其在 100 μΐ反应体系中达到 相应的终浓度。 同时设立阳性对照孔， 加入阳性对照化合物 SU11248。 The test sample was first prepared into 10 - 2 M stock solution in DMSO, and stored at - 20 ° C after being dispensed. Dilute to the desired concentration with the reaction buffer before use, and add it to the test well to make it The corresponding final concentration is reached in the 100 μΐ reaction system. A positive control well was also established and the positive control compound SU11248 was added.
(5)加入 ΑΤΡ和受试酪氨酸激酶： 加入用反应緩冲液稀释的 ATP溶液 （ ATP终浓度 5 μ M ) , 最后， 加入用 反应緩冲液稀释的受试酪氨酸激酶。 反应体系总体积为 100 μ1。 同时设立阴性对 照孔和无酶对照孔。 (5) Add hydrazine and test tyrosine kinase: ATP solution diluted with reaction buffer (ATP final concentration of 5 μM) was added, and finally, the test tyrosine kinase diluted with the reaction buffer was added. The total volume of the reaction system was 100 μl. Negative control wells and enzyme-free control wells were also established at the same time.
(6) 将反应体系置于湿盒内， 37 °C摇床避光反应 1 h, 反应结束后 T-PBS洗 板三次。  (6) The reaction system was placed in a wet box, shaken at 37 °C for 1 h, and washed three times with T-PBS after the reaction.
(7)加入抗体 PY99 100 μΐ/孔， 37 °C摇床反应 30 min。 T-PBS洗板三次。  (7) Add the antibody PY99 100 μΐ/well, and shake at 37 °C for 30 min. The plate was washed three times with T-PBS.
(8)加入辣根过氧化物酶标记的羊抗鼠的 IgG 100 μΐ/孔， 37 °C摇床反应 30 min。 T-PBS洗板三次。  (8) Horseradish peroxidase-labeled goat anti-mouse IgG 100 μΐ/well was added and shaken at 37 °C for 30 min. The plate was washed three times with T-PBS.
(9)加入 OPD显色液 100 μΐ/孔， 室温避光反应 1 - 10 min。  (9) Add OPD coloring solution 100 μΐ/well, and avoid the light at room temperature for 1 - 10 min.
(10)加入 2 M ¾S04 50 μΐ中止反应， 用可调波长式微孔板酶标仪 Molecular Devices SPECTRAMAX190测 A490值。 (10) The reaction was stopped by the addition of 2 M 3⁄4S0 4 50 μΐ, and the A 490 value was measured using a tunable wavelength microplate reader Molecular Devices SPECTRAMAX190.
(1 1)样品的抑制率通过下列公式求得：  (1 1) The inhibition rate of the sample is obtained by the following formula:
化合物 OD值 -无酶对照孔 OD值  Compound OD value - no enzyme control well OD value
样品的抑制率％= ( 1 -
Figure imgf000041_0001
Sample inhibition rate %= ( 1 -
Figure imgf000041_0001
阴性对照 OD值 -无酶对照孔 OD值  Negative control OD value - no enzyme control well OD value
2.5实验结果 2.5 Experimental results
本发明化合物对受体酪氨酸激酶 VEGFR2酶活抑制率 （％ )  Inhibition rate of the receptor tyrosine kinase VEGFR2 by the compound of the present invention (%)
Figure imgf000041_0002
工业实用性
Figure imgf000041_0002
Industrial applicability
本发明芳氧基喹啉类衍生物化合物对人胃癌细胞株 (MGC-803)具有抗增值抑 制作用， 可应用治疗人或动物细胞增殖性相关的实体瘤或血癌的药物中。  The aryloxyquinoline derivative compound of the present invention has an anti-inhibitory inhibitory effect on a human gastric cancer cell line (MGC-803), and can be applied to a drug for treating solid tumors or blood cancer associated with cell proliferation of human or animal cells.

Claims

权 利 要 求 书 Claim
1、 一种芳氧基喹啉类衍生物， 具有式（ I )结构,  An aryloxyquinoline derivative having the structure of formula (I),
Z— fZ-f
Figure imgf000042_0001
Figure imgf000042_0001
或其药学上可接受的盐或溶剂化合物 其中： 为 d-C4烷基; Or a pharmaceutically acceptable salt or solvate thereof wherein: is dC 4 alkyl;
R2, R3, R4分别独立地选自氢、 CrC3烷基； 任选地， R2, R3与其相连的碳 原子形成 3-6元碳环， 此外 R2, R3其中之一可与 相连形成 4-8元氮杂环；R 2 , R 3 , R4 are each independently selected from hydrogen, C r C 3 alkyl; optionally, R 2 , R 3 forms a 3-6 membered carbocyclic ring with the carbon atom to which it is attached, in addition R 2 , R 3 One may be linked to form a 4-8 membered nitrogen heterocycle;
X为氢或面素原子； X is hydrogen or a halogen atom;
Ar为芳基或杂芳基， 并可被卤素， d-C4烷基， 卤代 CrC4烷基， CrC4烷氧 基， 或面代^-^烷氧基取代； Ar is an aryl or heteroaryl group and may be substituted by halogen, dC 4 alkyl, halo C r C 4 alkyl, C r C 4 alkoxy, or a halo- alkoxy group;
¾ 3⁄4
R7 R 7
Ζ=
Figure imgf000042_0002
7 ; Ζ=
Figure imgf000042_0002
7 ;
R5、 R6分别独立地选自氢、 d-C4烷基， 并可被 d-C4烷氧基， 5-10元杂环 或 3-10元碳环基任意取代； R 5 and R 6 are each independently selected from hydrogen, dC 4 alkyl, and may be optionally substituted by dC 4 alkoxy, 5-10 membered heterocyclic ring or 3-10 membered carbocyclic group;
R7 为 d-C4烷基， 可被 5-10元杂环或 3-10元碳环基任意取代； R 7 is dC 4 alkyl, which may be optionally substituted by a 5-10 membered heterocyclic ring or a 3-10 membered carbocyclic group;
m为 0, 1 , 2或 3;  m is 0, 1, 2 or 3;
n为 1 , 2或 3;  n is 1, 2 or 3;
G为 3-10元含 N杂环， 并可被任意取代。  G is a 3-10 membered N-containing heterocyclic ring and may be optionally substituted.
2、 根据权利要求 1所述的化合物， 其中， 所述的化合物具有式（II )结构， 或 其药学上可接受的盐或溶剂化合物：
Figure imgf000043_0001
The compound according to claim 1, wherein the compound has the structure of the formula (II), or a pharmaceutically acceptable salt or solvent compound thereof:
Figure imgf000043_0001
其中， 式（ II ) 中 、 R5, Ar、 m和 X如权利要求 1所定义。 Wherein, in the formula (II), R 5 , Ar, m and X are as defined in claim 1.
3、 根据权利要求 2所述的化合物， 为下列的化合物中的一种：  3. A compound according to claim 2 which is one of the following compounds:
N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基） 会啉 _4-基氧基）苯基） -N- (4-氟苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)morpholine_4 -yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基） 会啉 _4-基氧基）苯基） -N-苯基环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)morpholine_4 -yloxy)phenyl)-N-phenylcyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基） 会啉 _4-基氧基）苯基） -N- (2-氟苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)morpholine_4 -yloxy)phenyl)-N-(2-fluorophenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基） 会啉 _4-基氧基）苯基） -N- (3-氟苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)morpholine_4 -yloxy)phenyl)-N-(3-fluorophenyl)cyclopropane-1,1-diamide;
N- (4-氟 -3- (三氟曱基)苯基） -N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱酰胺； N-(4-Fluoro-3-(trifluoromethyl)phenyl)-N-(3-fluoro-4-(6-decyloxy-7-(1-(2-(nonylamino))-2 -oxoethyl)piperidin-4-yloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N- ( 3-氯 -4-氟苯基 ) -N- ( 3-氟 -4- ( 6-曱氧基 -7- ( 1- (2- (曱胺基 ) -2-氧代乙 基）哌啶 -4-基氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱酰胺； N-(3-chloro-4-fluorophenyl)-N-(3-fluoro-4-(6-decyloxy-7-(1-(2-(decylamino)-2-oxoethyl) Piperidin-4-yloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基） 会啉 _4-基氧基）苯基） -N- (3-氟 -4-曱基苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)morpholine_4 -yloxy)phenyl)-N-(3-fluoro-4-mercaptophenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基） 喹啉 _4-基氧基）苯基） -N- (4- (三氟曱基）苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)quinoline_4 -yloxy)phenyl)-N-(4-(trifluoromethyl)phenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基） 喹啉 _4-基氧基）苯基） -N- (3- (三氟曱基）苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-(1-(2-(indenyl)-2-oxoethyl)piperidin-4-yloxy)quinoline_4 -yloxy)phenyl)-N-(3-(trifluoromethyl)phenyl)cyclopropane-1,1-diamide;
N- ( 3-氯 -2-氟苯基 ) -N- ( 3-氟 -4- ( 6-曱氧基 -7- ( 1- (2- (曱胺基 ) -2-氧代乙 基）哌啶 -4-基氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-chloro-2-fluorophenyl)-N-(3-fluoro-4-(6-decyloxy-7-(1-(2-(decylamino)-2-oxoethyl) Piperidin-4-yloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N- (4-氯 -3- (三氟曱基）苯基） -N- (3-氟 -4- (6-曱氧基 -7- (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱酰胺；N-(4-chloro-3-(trifluoromethyl)phenyl)-N-(3-fluoro-4-(6-decyloxy-7-(1-(2-(ylamino))) -2-oxoethyl)piperidin-4-yloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N- ( 2-氯 -6-曱基苯基 ) -N- ( 3-氟 -4- ( 6-曱氧基 -7- (1- (2- (曱胺基 ) -2-氧代 乙基）哌啶 -4-基氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱酰胺； N-(2-chloro-6-mercaptophenyl)-N-(3-fluoro-4-(6-decyloxy-7-(1-(2-(indenyl))-2-oxoyl) Piperidin-4-yloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基） 曱 氧基）喹啉 -4-基氧基）苯基） -N- (4-氟苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(indenyl)-2-oxoethyl)piperidin-4-yl) decyloxy) quin Borano-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基） 曱 氧基）喹啉 -4-基氧基）苯基） -N-苯基环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(indenyl)-2-oxoethyl)piperidin-4-yl) decyloxy) quin Polin-4-yloxy)phenyl)-N-phenylcyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基） 曱 氧基）喹啉 -4-基氧基）苯基） -N- (2-氟苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(indenyl)-2-oxoethyl)piperidin-4-yl) decyloxy) quin Physo-4-yloxy)phenyl)-N-(2-fluorophenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基） 曱 氧基）喹啉 -4-基氧基）苯基） -N- (3-氟苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(indenyl)-2-oxoethyl)piperidin-4-yl) decyloxy) quin Physo-4-yloxy)phenyl)-N-(3-fluorophenyl)cyclopropane-1,1-diamide;
N- (4-氟 -3- (三氟曱基)苯基） -N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基 )曱氧基 )喹啉 -4-基氧基 )苯基 )环丙烷 -1, 1-二曱酰胺;  N-(4-Fluoro-3-(trifluoromethyl)phenyl)-N-(3-fluoro-4-(6-decyloxy-7-((1-(2-(nonylamino))- 2-oxoethyl)piperidin-4-yl)decyloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N- ( 3-氯 -4-氟苯基 ) -N- ( 3-氟 -4- ( 6-曱氧基 -7- ( (1- (2- (曱胺基 ) -2-氧代 乙基）哌啶 -4-基） 曱氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-chloro-4-fluorophenyl)-N-(3-fluoro-4-(6-decyloxy-7-((1-(2-(nonyl))-2-oxo) ()piperidin-4-yl)nonyloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基） 曱 氧基）喹啉 -4-基氧基）苯基） -N- (3-氟 -4-曱基苯基）环丙烷 -1, 1-二曱酰胺； N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(indenyl)-2-oxoethyl)piperidin-4-yl) decyloxy) quin Physo-4-yloxy)phenyl)-N-(3-fluoro-4-indolylphenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基） 曱 氧基）喹啉 -4-基氧基）苯基） -N- (4- (三氟曱基）苯基）环丙烷 -1, 1-二曱酰胺; N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(indenyl)-2-oxoethyl)piperidin-4-yl) decyloxy) quin Physo-4-yloxy)phenyl)-N-(4-(trifluoromethyl)phenyl)cyclopropane-1,1-diamide;
N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺基） -2-氧代乙基）哌啶 -4-基） 曱 氧基 )喹啉 -4-基氧基 )苯基 ) -N- ( 3- (三氟曱基）苯基 )环丙烷 -1, 1-二曱酰胺;  N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(indenyl)-2-oxoethyl)piperidin-4-yl) decyloxy) quin Borano-4-yloxy)phenyl)-N-(3-(trifluoromethyl)phenyl)cyclopropane-1,1-diamide;
N- ( 3-氯 -2-氟苯基 ) -N- ( 3-氟 -4- ( 6-曱氧基 -7- ( (1- (2- (曱胺基 ) -2-氧代 乙基）哌啶 -4-基） 曱氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱酰胺；  N-(3-chloro-2-fluorophenyl)-N-(3-fluoro-4-(6-decyloxy-7-((1-(2-(nonyl))-2-oxo) ()piperidin-4-yl)nonyloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N- (4-氯 -3- (三氟曱基）苯基） -N- (3-氟 -4- (6-曱氧基 -7- ( (1- (2- (曱胺 基） -2-氧代乙基）哌啶 -4-基） 曱氧基）喹啉 -4-基氧基）苯基）环丙烷 -1, 1-二曱 酰胺；  N-(4-chloro-3-(trifluoromethyl)phenyl)-N-(3-fluoro-4-(6-decyloxy-7-((1-(2-(ylamino))) 2-oxoethyl)piperidin-4-yl)nonyloxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N- (2-氯 -6-曱基苯基） -N- (3-氟 -4- (6-曱氧基 -7- ( ( 1- (2- (曱胺基） -2- 氧代乙基）哌啶 -4-基） 曱氧基）喹啉 -4-基氧基）苯基）环丙烷 -1 , 1-二曱酰胺；N-(2-chloro-6-mercaptophenyl)-N-(3-fluoro-4-(6-decyloxy-7-((1-(2-(decylamino))-2- Oxoethyl)piperidin-4-yl)nonyloxy)quinolin-4-yloxy)phenyl)cyclopropane-1, 1-diamide;
N-(4-氟苯基) -N-(4-(6-曱氧基 -7-((1 -(2-(曱胺基) -2-氧代乙基)哌啶 -4-基)曱氧基) 喹啉 -4-基氧基)苯基)环丙烷 -1,1-二曱酰胺； N-(4-fluorophenyl)-N-(4-(6-decyloxy-7-((1-(2-(indolyl)-2-oxoethyl)piperidin-4-yl) Alkoxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N-(4-(6-曱氧基 -7-((1-(2-(曱胺基) -2-氧代乙基)哌啶 -4-基）曱氧基)喹啉 -4-基氧 基)苯基) -N-苯基环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(6-decyloxy-7-((1-(2-(indolyl)-2-oxoethyl)piperidin-4-yl)decyloxy)quinoline-4- Benzyl)phenyl)-N-phenylcyclopropane-1,1-dicarbamide;
N-(2-氟苯基) -N-(4-(6-曱氧基 -7-((1 -(2-(曱胺基) -2-氧代乙基)哌啶 -4-基)曱氧基) 喹啉 -4-基氧基)苯基)环丙烷 -1,1-二曱酰胺；  N-(2-Fluorophenyl)-N-(4-(6-decyloxy-7-((1-(2-(indolyl)-2-oxoethyl)piperidin-4-yl) Alkoxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N-(3-氟苯基) -N-(4-(6-曱氧基 -7-((1 -(2-(曱胺基) -2-氧代乙基)哌啶 -4-基)曱氧基) 喹啉 -4-基氧基)苯基)环丙烷 -1,1-二曱酰胺；  N-(3-Fluorophenyl)-N-(4-(6-decyloxy-7-((1-(2-(indolyl)-2-oxoethyl)piperidin-4-yl) Alkoxy)quinolin-4-yloxy)phenyl)cyclopropane-1,1-diamide;
N-(4-(7-((l-(2-胺基 -2-氧代乙基)哌啶 -4-基）曱氧基) -6-曱氧基喹啉 -4-基氧基） 苯基) -N-苯基环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(7-((1-(2-amino-2-oxoethyl)piperidin-4-yl) decyloxy)-6-methoxyoxyquinolin-4-yloxy Phenyl)-N-phenylcyclopropane-1,1-diphthalamide;
N-(4-(7-((l-(2-胺基 -2-氧代乙基)哌啶 -4-基）曱氧基) -6-曱氧基喹啉 -4-基氧基） 苯基) -N-(4-氟苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(7-((1-(2-amino-2-oxoethyl)piperidin-4-yl) decyloxy)-6-methoxyoxyquinolin-4-yloxy Phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarbamide;
N-(4-(7-((l-(2-胺基 -2-氧代乙基)哌啶 -4-基）曱氧基) -6-曱氧基喹啉 -4-基氧基） 苯基) -N-(2-氟苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(7-((1-(2-amino-2-oxoethyl)piperidin-4-yl) decyloxy)-6-methoxyoxyquinolin-4-yloxy Phenyl)-N-(2-fluorophenyl)cyclopropane-1,1-diphthalamide;
N-(4-(7-((l-(2-胺基 -2-氧代乙基)哌啶 -4-基）曱氧基) -6-曱氧基喹啉 -4-基氧基） 苯基) -N-(3-氟苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(7-((1-(2-amino-2-oxoethyl)piperidin-4-yl) decyloxy)-6-methoxyoxyquinolin-4-yloxy Phenyl)-N-(3-fluorophenyl)cyclopropane-1,1-dicarbamide;
N-(4-(7-((l-(2-胺基 -2-氧代乙基）哌啶 -4-基）曱氧基) -6-曱氧基喹啉 -4-基氧 基) -3 -氟苯基) -N-苯基环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(7-((1-(2-amino-2-oxoethyl)piperidin-4-yl) decyloxy)-6-methoxyoxyquinolin-4-yloxy -3 -fluorophenyl)-N-phenylcyclopropane-1,1-dicarbamide;
N-(4-(7-((l-(2-胺基 -2-氧代乙基）哌啶 -4-基）曱氧基) -6-曱氧基喹啉 -4-基氧 基) -3 -氟苯基) -N-(4-氟苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(7-((1-(2-amino-2-oxoethyl)piperidin-4-yl) decyloxy)-6-methoxyoxyquinolin-4-yloxy -3 -fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarbamide;
N-(4-(7-((l-(2-胺基 -2-氧代乙基）哌啶 -4-基）曱氧基) -6-曱氧基喹啉 -4-基氧 基) -3 -氟苯基) -N-(3 -氟苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(7-((1-(2-amino-2-oxoethyl)piperidin-4-yl) decyloxy)-6-methoxyoxyquinolin-4-yloxy -3 -fluorophenyl)-N-(3-fluorophenyl)cyclopropane-1,1-dicarbamide;
N-(4-(7-((l-(2-胺基 -2-氧代乙基）哌啶 -4-基）曱氧基) -6-曱氧基喹啉 -4-基氧 基) -3 -氟苯基) -N-(2-氟苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(7-((1-(2-amino-2-oxoethyl)piperidin-4-yl) decyloxy)-6-methoxyoxyquinolin-4-yloxy -3 -fluorophenyl)-N-(2-fluorophenyl)cyclopropane-1,1-dicarbamide;
或其药学上可接受的盐。  Or a pharmaceutically acceptable salt thereof.
4、 根据权利要求 1所述的化合物， 其中， 所述的化合物具有式（III )结构， 或其药学上可接受 The compound according to claim 1, wherein the compound has a structure of the formula (III). Or pharmaceutically acceptable
Figure imgf000046_0001
Figure imgf000046_0001
其中， 式（III ) 、 R7、 Ar、 X、 m如权利要求 1所定义。 Wherein formula (III), R 7 , Ar, X, m are as defined in claim 1.
5、 根据权利要求 4所述的化合物， 为下列化合物中的一种：  5. A compound according to claim 4 which is one of the following compounds:
N-(3-氟 -4-(6-曱氧基 -7-((1-(2- (曱磺胺基）乙基)哌啶 -4-基）曱氧基)喹啉 -4-基氧 基)苯基) -N-(4-氟苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy)quinolin-4-yl Oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarbamide;
N-(3-氟 -4-(6-曱氧基 -7-((1-(2- (曱磺胺基）乙基)哌啶 -4-基）曱氧基)喹啉 -4-基氧 基)苯基) -N-苯基环丙烷 - 1 , 1 -二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy)quinolin-4-yl Oxy)phenyl)-N-phenylcyclopropane-1,1-diphthalamide;
N-(3-氟 -4-(6-曱氧基 -7-((1-(2- (曱磺胺基）乙基)哌啶 -4-基）曱氧基)喹啉 -4-基氧 基)苯基) -N-(2-氟苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy)quinolin-4-yl Oxy)phenyl)-N-(2-fluorophenyl)cyclopropane-1,1-dicarbamide;
N-(3-氟 -4-(6-曱氧基 -7-((1-(2- (曱磺胺基）乙基)哌啶 -4-基）曱氧基)喹啉 -4-基氧 基)苯基) -N-(3 -氟苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(3-Fluoro-4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy)quinolin-4-yl Oxy)phenyl)-N-(3-fluorophenyl)cyclopropane-1,1-dicarbamide;
N-(4-氟苯基) -N-(4-(6-曱氧基 -7-((1-(2- (曱磺胺基）乙基)哌啶 -4-基）曱氧基)喹 啉 -4-基氧基)苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(4-fluorophenyl)-N-(4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy) Quinoline-4-yloxy)phenyl)cyclopropane-1,1-dicarbamide;
N-(4-(6-曱氧基 -7-((1 -(2- (曱磺胺基）乙基)哌啶 -4-基)曱氧基)喹啉 -4-基氧基)苯 基) -N-苯基环丙烷 - 1 , 1 -二曱酰胺；  N-(4-(6-decyloxy-7-((1 -(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy)quinoline-4-yloxy)benzene -N-phenylcyclopropane-1,1-dicarbamide;
N-(2-氟苯基) -N-(4-(6-曱氧基 -7-((1-(2- (曱磺胺基）乙基)哌啶 -4-基）曱氧基)喹 啉 -4-基氧基)苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(2-fluorophenyl)-N-(4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy) Quinoline-4-yloxy)phenyl)cyclopropane-1,1-dicarbamide;
N-(3-氟苯基) -N-(4-(6-曱氧基 -7-((1-(2- (曱磺胺基）乙基)哌啶 -4-基）曱氧基)喹 啉 -4-基氧基)苯基)环丙烷 - 1 , 1 -二曱酰胺；  N-(3-Fluorophenyl)-N-(4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy) Quinoline-4-yloxy)phenyl)cyclopropane-1,1-dicarbamide;
或其药学上可接受的盐。  Or a pharmaceutically acceptable salt thereof.
6、 根据权利要求 1所述的化合物， 其中， 所述的化合物为式（IV )化合物， 或其药学上可接受的盐或溶剂化合物：
Figure imgf000047_0001
其中， 式（IV ) 中 、 R7、 Ar、 X、 m如权利要求 1所定义。 The compound according to claim 1, wherein the compound is a compound of the formula (IV), or a pharmaceutically acceptable salt or solvent compound thereof:
Figure imgf000047_0001
Wherein, in the formula (IV), R 7 , Ar, X, m are as defined in claim 1.
7、 根据权利要求 6所述的化合物， 为下列化合物中的一种：  7. A compound according to claim 6 which is one of the following compounds:
Ν·(3-氟 -4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基)曱氧基)喹啉 -4-基氧基) 苯基) -Ν-(4-氟苯基)环丙烷 - 1 , 1 -二曱酰胺； Ν ·(3-Fluoro-4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy)quinolin-4-yl Oxy)phenyl)-indole-(4-fluorophenyl)cyclopropane-1,1-dicarbamide;
Ν·(3-氟 -4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基)曱氧基)喹啉 -4-基氧基) 苯基) -Ν-苯基环丙烷 - 1 , 1 -二曱酰胺； Ν ·(3-Fluoro-4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy)quinolin-4-yl Oxy)phenyl)-indole-phenylcyclopropane-1,1-dicarbamide;
Ν·(3-氟 -4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基)曱氧基)喹啉 -4-基氧基) 苯基) -Ν-(2-氟苯基)环丙烷 - 1 , 1 -二曱酰胺； Ν ·(3-Fluoro-4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy)quinolin-4-yl Oxy)phenyl)-indole-(2-fluorophenyl)cyclopropane-1,1-dicarbamide;
Ν·(3-氟 -4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基)曱氧基)喹啉 -4-基氧基) 苯基) -Ν-(3-氟苯基)环丙烷 - 1 , 1 -二曱酰胺； Ν ·(3-Fluoro-4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy)quinolin-4-yl Oxy)phenyl)-indole-(3-fluorophenyl)cyclopropane-1,1-dicarbamide;
Ν-(4-氟苯基) -Ν-(4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基）曱氧基)喹啉 -4-基氧基)苯基)环丙烷 - 1 , 1 -二曱酰胺；  Ν-(4-fluorophenyl)-indole-(4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl)decyloxy) Quinoline-4-yloxy)phenyl)cyclopropane-1,1-dicarbamide;
Ν-(4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基）曱氧基)喹啉 -4-基氧基)苯 基) -Ν-苯基环丙烷 - 1 , 1 -二曱酰胺；  Ν-(4-(6-decyloxy-7-((1-(2-(sulfo)ethyl)piperidin-4-yl) decyloxy) quinolin-4-yloxy)benzene - Ν-phenylcyclopropane-1,1-dicarbamide;
Ν-(2-氟苯基) -Ν-(4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基）曱氧基)喹啉 -4-基氧基)苯基)环丙烷 - 1 , 1 -二曱酰胺；  Ν-(2-fluorophenyl)-indole-(4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl) decyloxy) Quinoline-4-yloxy)phenyl)cyclopropane-1,1-dicarbamide;
Ν-(3-氟苯基) -Ν-(4-(6-曱氧基 -7-((1-(2- (曱磺基）乙基)哌啶 -4-基）曱氧基)喹啉 -4-基氧基)苯基)环丙烷 - 1 , 1 -二曱酰胺；  Ν-(3-fluorophenyl)-indole-(4-(6-decyloxy-7-((1-(2-(sulfonyl)ethyl)piperidin-4-yl) decyloxy) Quinoline-4-yloxy)phenyl)cyclopropane-1,1-dicarbamide;
或其药学上可接受的盐。  Or a pharmaceutically acceptable salt thereof.
8、 一种含有 1个或多个权利要求 1-7 中任一权利要求所述的化合物或其药 学上可接受的盐的药物组合物。 A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.
9、 权利要求 1-7 中任一权利要求所述的化合物或其药学上可接受的盐在制 备治疗与酪氨酸激酶有关的疾病的药物中的应用。 9. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease associated with tyrosine kinase.
10. 根据权利要求 9所述的应用， 其中， 所述与酪氨酸激酶有关的疾病为与 人或动物细胞增殖性相关的实体瘤或血癌。 The use according to claim 9, wherein the tyrosine kinase-related disease is a solid tumor or blood cancer associated with human or animal cell proliferation.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018035950A1 (en) * 2016-08-26 2018-03-01 南昌弘益药业有限公司 Compound as tyrosine kinase inhibitor
WO2018035951A1 (en) * 2016-08-24 2018-03-01 南昌弘益药业有限公司 Novel quinoline compound
US9957233B1 (en) 2016-08-05 2018-05-01 Calitor Sciences, Llc Process for preparing substituted quinolin-4-ol compounds
WO2018133159A1 (en) * 2017-01-17 2018-07-26 南昌弘益药业有限公司 Method for preparing novel quinoline compound
WO2018170997A1 (en) * 2017-03-23 2018-09-27 南昌弘益药业有限公司 Method for preparing compound
CN109824587A (en) * 2017-11-23 2019-05-31 上海翔锦生物科技有限公司 The preparation method of tyrosine kinase inhibitor XJF007 and its intermediate

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102093421A (en) * 2011-01-28 2011-06-15 广州盈升生物科技有限公司 Phosphorus substituent group-containing quinoline compound and preparation method of quinoline compound as well as pharmaceutical composition containing quinoline compound and application of pharmaceutical composition
CN102408411A (en) * 2011-09-19 2012-04-11 广州盈升生物科技有限公司 Hydroximic acid compound containing quinolyl and preparation method thereof, and drug composition containing the compound and use thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2752421C (en) * 2009-03-21 2013-08-06 Ning Xi Amino ester derivatives, salts thereof and methods of use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102093421A (en) * 2011-01-28 2011-06-15 广州盈升生物科技有限公司 Phosphorus substituent group-containing quinoline compound and preparation method of quinoline compound as well as pharmaceutical composition containing quinoline compound and application of pharmaceutical composition
CN102408411A (en) * 2011-09-19 2012-04-11 广州盈升生物科技有限公司 Hydroximic acid compound containing quinolyl and preparation method thereof, and drug composition containing the compound and use thereof

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9957233B1 (en) 2016-08-05 2018-05-01 Calitor Sciences, Llc Process for preparing substituted quinolin-4-ol compounds
WO2018035951A1 (en) * 2016-08-24 2018-03-01 南昌弘益药业有限公司 Novel quinoline compound
CN107778285A (en) * 2016-08-24 2018-03-09 南昌弘益药业有限公司 A kind of quinolines noval chemical compound
WO2018035950A1 (en) * 2016-08-26 2018-03-01 南昌弘益药业有限公司 Compound as tyrosine kinase inhibitor
CN107778287A (en) * 2016-08-26 2018-03-09 南昌弘益药业有限公司 A kind of compound as tyrosine protein kinase inhibitor
WO2018133159A1 (en) * 2017-01-17 2018-07-26 南昌弘益药业有限公司 Method for preparing novel quinoline compound
CN108329298A (en) * 2017-01-17 2018-07-27 南昌弘益药业有限公司 A kind of quinolines noval chemical compound preparation method
WO2018170997A1 (en) * 2017-03-23 2018-09-27 南昌弘益药业有限公司 Method for preparing compound
CN108623565A (en) * 2017-03-23 2018-10-09 南昌弘益药业有限公司 A kind of preparation method of compound
CN109824587A (en) * 2017-11-23 2019-05-31 上海翔锦生物科技有限公司 The preparation method of tyrosine kinase inhibitor XJF007 and its intermediate

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