Quinoline compound, preparation method therefor, pharmaceutical composition and medical use thereof

Abstract

The present invention relates to the field of medicines, and in particular to a compound represented by formula (I), and a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof. The present invention further relates to a preparation method for the compound, a pharmaceutical composition comprising the compound, and medical use and method for the compound and the pharmaceutical composition. The compound of the present invention can block VEGF / VEGFR pathway, can prevent or treat diseases related to the VEGF / VEGFR pathway, for example, significantly inhibits the activity of a protein kinase such as VEGF, and has anti-tumor activity.

Description

Quinoline compound, preparation method thereof, pharmaceutical composition and medical use thereof

[0001] This application is based on and claims priority to the Chinese patent application with application number 202310774707.7 and application date June 28, 2023. All application contents of the Chinese patent application are hereby introduced as a whole into this application. Technical Field

[0002] The present invention belongs to the field of medicine, and specifically relates to quinoline compounds, their pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, solvates or polymorphs, and also relates to preparation methods, pharmaceutical compositions and their medical uses. Background Art

[0003] Protein tyrosine kinases (TPKs) are crucial factors in cell signaling, participating in a range of cellular functions and closely related to cell growth, differentiation, and proliferation. They catalyze the transfer of the gamma-phosphate group of ATP to tyrosine residues on many important proteins, phosphorylating the phenolic hydroxyl group and thereby transmitting signals. Tyrosine kinases belong to the protein kinase family and can be divided into two major groups based on their structure: receptor tyrosine kinases (PTKs) and non-receptor PTKs. These two groups can be further divided into multiple genera based on structural homology. There are 518 kinase genes in the human body, of which 90 PTKs have been discovered, including 58 receptor tyrosine kinases and 32 non-receptor tyrosine kinases. Receptor-type tyrosine kinases, including platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), and fibroblast growth factor receptor (FGFR), typically possess an extracellular domain, a transmembrane region, and an intracellular kinase domain. Clinical cancer studies have shown that these receptors and their ligands are crucially involved in many tumors. Many cancers involve overexpression of related growth factors, leading to excessive tyrosine phosphorylation signals entering cells. Non-receptor-type tyrosine kinases (nrPTKs) generally lack extracellular structures and are typically membrane-bound or located in the cytoplasm. These kinases include Abl kinase, Src kinase, and C-terminal Src kinase. In tumor tissues, nrPTKs are frequently activated, which in turn activates downstream signaling pathways, promoting cell proliferation, resisting apoptosis, and contributing to tumor initiation and progression. TPKs are categorized into receptor-dependent tyrosine protein kinases (RTKs) and non-receptor-dependent tyrosine protein kinases. Receptor-dependent, or catalytic, receptors connect the cell's interior and exterior through transmembrane enzyme-protein receptors. Binding to growth factor ligands activates signal transduction. Receptor-type tyrosine protein kinases include EGFR, PDGFR, and M-CSF, as well as FGFR, VEGFR, and HGFR. RTKs all contain active intracellular domains. Tumorigenesis is closely linked to the binding of receptors and their corresponding ligands. Most malignant tumors are associated with overexpression of growth factors, leading to abnormal tyrosine phosphorylation signals being transmitted to cells. Activated receptors in tumor cells bind to and activate downstream molecules, conferring tyrosine kinase activity and promoting cell proliferation.

[0004] Angiogenesis is the process by which new blood vessels sprout or break off from pre-existing vessels. Under normal physiological conditions, angiogenesis is a complex process involving the coordinated action of pro-angiogenic and anti-angiogenic factors. Abnormal angiogenesis can lead to a range of diseases, including retinopathy, arthritis, endometriosis, atherosclerosis, and cancer. Folkman demonstrated in the early 1970s that the growth and metastasis of primary tumors depend on the formation of new blood vessels. Indeed, tumor growth requires new capillaries to supply nutrients and remove metabolic waste. New blood vessels also aid in the later metastasis of tumor cells.

[0005] Angiogenesis depends on multiple growth factors, among which VEGF has become a research hotspot due to its specificity and importance for endothelial cells in tumor angiogenesis. VEGF, also known as vascular permeability factor, is the most potent growth factor among the many factors that stimulate angiogenesis. It acts directly on endothelial cells, promoting mitosis and the growth of new blood vessels. Members of the VEGF family include A, B, C, D, E, and placental growth factor. Most malignant tumor cells secrete VEGF, and metastatic tumor cells release VEGF to stimulate local angiogenesis.

[0006] VEGFR, a specific receptor for VEGF, is highly expressed in tumor angiogenesis. Vascular endothelial cells are genetically stable, making VEGFR inhibitors less likely to develop resistance and more readily reach their target sites, accumulating at high concentrations within tumor tissues. There are three main types of VEGFR: VEGFR-1 (FLT-1), VEGFR-2 (KDR), and VEGFR-3 (FLT-4). VEGFR is a highly specific transmembrane receptor, with a protein structure consisting of an extracellular domain, a transmembrane domain, and an intracellular domain. The extracellular domain is the binding site for VEGF and contains seven immunoglobulin-like functional domains; the intracellular domain contains an insert protein tyrosine kinase (PTK). The biological function of VEGFR is to transmit and amplify signals step by step through a cascade of phosphorylation reactions following binding to its ligand, triggering corresponding biological effects in cells. This induction leads to the division, proliferation, and migration of endothelial cells, enhanced capillary permeability, plasma extravasation, and the formation of numerous peripheral blood vessels.

[0007] Research has shown that the VEGF / VEGFR pathway is closely linked to tumor angiogenesis and lymphangiogenesis. This signaling pathway creates a favorable microenvironment for tumor survival and development, promoting the formation of microvessels and accessing a rich nutrient supply. Lymphangiogenesis plays a more crucial role in tumor spread. Therefore, blocking the VEGF / VEGFR signaling pathway can effectively inhibit tumor angiogenesis and lymphangiogenesis, thereby suppressing tumor growth and metastasis.

[0008] Summary of the Invention

[0009] The present invention aims to provide a small molecule compound that acts on VEGFR, blocking the VEGF / VEGFR pathway and preventing or treating diseases associated with the VEGF / VEGFR pathway. For example, it exhibits potent angiogenesis inhibition and anti-tumor activity, and has potential to improve, prevent, and treat various other diseases associated with abnormal angiogenesis and proliferation.

[0010] The present inventors have discovered through research that the compound having the following general formula (I) can act on the VEGF / VEGFR pathway, significantly inhibit the activity of protein kinases such as VEGF, and has a significant anti-tumor effect.

[0011] The first aspect of the present invention relates to a compound represented by formula (I), a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof;

[0012] in,

[0013] R1 and R2 are each independently selected from hydrogen, alkyl, alkoxy, alkoxycarbonyl, aminoalkanoyl, alkylaminocarbonyl;

[0014] R3 is selected from wherein R4 is selected from -(NR6) n1 -C(O)-(NR7) n2 -, R6 and R7 are each independently selected from H, alkyl; n1 and n2 are each independently selected from 0, 1; R5 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, cycloalkyl, cycloalkenyl, H, alkenyl, alkynyl, alkylaminocarbonyl, aminocarbonyl, cyano; the substitution is substituted by one or more of the following substituents: halogen, alkyl, alkoxy, haloalkyl, nitro, cycloalkyl, aryl.

[0015] In any embodiment of the first aspect of the present invention, R1 and R2 are each independently selected from hydrogen, C1-C6 straight or branched alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, amino C1-C6 alkanoyl, C1-C6 alkylaminocarbonyl.

[0016] In any embodiment of the first aspect of the present invention, R1 and R2 are each independently selected from amino C1-C6 alkanoyl, C1-C6 alkoxy, and C1-C6 alkylaminocarbonyl.

[0017] In any embodiment of the first aspect of the present invention, R1 and R2 are each independently selected from carbamoyl and methoxy.

[0018] In any embodiment of the first aspect of the present invention, R3 is selected from wherein R4 is selected from -(NR6) n1 -C(O)-(NR7) n2 -, R6 and R7 are each independently selected from H, C1-C6 alkyl; n1 and n2 are each independently selected from 0, 1; R5 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heterocyclyl; the substitution is substituted by one or more of the following substituents: halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, nitro, 3-6 membered cycloalkyl, 5-10 membered aryl.

[0019] In any embodiment of the first aspect of the present invention, R3 is selected from wherein R4 is selected from -C(O)NH-, -C(O)-, -C(O)N(CH3)-, -NH(CO)NH-, R5 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, ethyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted methyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted naphthyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl; the substitution is substituted by one or more of the following substituents: fluorine, methyl, chlorine, methoxy, trifluoromethyl, ethoxy, nitro, bromine, cyclopropyl, phenyl.

[0020] In any embodiment of the first aspect of the present invention, R3 is selected from wherein R4 is selected from -C(O)NH-, -C(O)-, -C(O)N(CH3)-, -NH(CO)NH-, R5 is selected from Phenyl, Ethyl, methyl, Benzyl,

[0021] In any embodiment of the first aspect of the present invention, R3 is selected from

[0022] In any embodiment of the first aspect of the present invention, the compound is selected from:

[0023] In any embodiment of the first aspect of the present invention, R3 is selected from wherein R4 is selected from -C(O)NH-, -C(O)-, -C(O)N(CH3)-, -NH(CO)NH-, R5 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, ethyl, substituted thiazolyl, substituted or unsubstituted methyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted naphthyl, substituted or unsubstituted oxazolyl, substituted isoxazolyl; the substitution is substituted by one or more of the following substituents: fluorine, methyl, chlorine, methoxy, trifluoromethyl, ethoxy, nitro, bromine, cyclopropyl, phenyl.

[0024] In any embodiment of the first aspect of the present invention, R3 is selected from wherein R4 is selected from -C(O)NH-, -C(O)-, -C(O)N(CH3)-, -NH(CO)NH-, R5 is selected from Phenyl, Ethyl, methyl, Benzyl,

[0025] In any embodiment of the first aspect of the present invention, R3 is selected from

[0026] The second aspect of the present invention provides a method for preparing the compound of the first aspect of the present invention, which is any one of the following methods A to E;

[0027] The method A comprises:

[0028] 1-Naphthoic acid was subjected to mesylation and alkali fusion reaction to obtain intermediate 4;

[0029] Intermediate 4 is reacted with intermediate 5 to obtain intermediate 6, which is then reacted with amine using Hobt and EDCI as condensing agents to obtain target compound 8; alternatively, intermediate 4 is reacted with amine using Hobt and EDCI as condensing agents to obtain intermediate 7, which is then reacted with intermediate 5 to obtain target compound 8;

[0030] The method B comprises:

[0031] Intermediate 5 is reacted with 2-hydroxy-6-naphthoic acid to obtain intermediate 10;

[0032] The intermediate 10 is subjected to amide condensation with an amino compound to obtain the target compound 11;

[0033] The method C comprises:

[0034] Intermediate 5 was reacted with 5-hydroxyindole to give intermediate 13;

[0035] Intermediate 13 is reacted with intermediate 14 to obtain target compound 15;

[0036] The method D comprises:

[0037] The raw intermediate 16 was reacted with Hobt and EDCI to obtain intermediate 17;

[0038] Intermediate 17 is reacted with NH2R5 to give intermediate 18;

[0039] Intermediate 18 is reacted with 4-hydroxyaniline to give intermediate 20;

[0040] Intermediate 20 reacts with intermediate 5 to obtain target compound 21;

[0041] The method E comprises:

[0042] The starting compound 22 is condensed and acylated to obtain the intermediate 23;

[0043] Intermediate 23 reacts with intermediate 5 to undergo nucleophilic substitution reaction to obtain target compound 24;

[0044] The above R1, R2 and R5 are defined as described in the first aspect of the present invention.

[0045] The preparation method of the compound of the present invention may include (but is not limited to) the above method. In the specific operation process, the steps in the method can be expanded or combined as needed.

[0046] The third aspect of the present invention relates to a pharmaceutical composition comprising the compound of the first aspect of the present invention, its pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph; optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0047] In any embodiment of the third aspect of the present invention, the pharmaceutical composition further comprises other drugs and / or immunomodulators for treating tumors (for example, one or more selected from immune checkpoint inhibitors, antibiotics, alkylating agents, antimetabolites, hormones, immunoactive agents, and interferon-type active agents).

[0048] In any embodiment of the third aspect of the present invention, the other drugs for treating tumors are drugs for treating tumors other than the compound of the first aspect of the present invention, its pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, solvates and polymorphs.

[0049] The fourth aspect of the present invention relates to the use of the compound of the first aspect of the present invention, its pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph, or the pharmaceutical composition of the third aspect of the present invention in the preparation of a medicament for preventing and / or treating diseases related to the VEGF / VEGFR pathway.

[0050] The fifth aspect of the present invention relates to a method for preventing and / or treating diseases related to the VEGF / VEGFR pathway, comprising administering an effective amount of a compound of the first aspect of the present invention, a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, or an effective amount of a pharmaceutical composition of the third aspect of the present invention to a subject in need.

[0051] The compound of the first aspect of the present invention, its pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph, or an effective amount of the pharmaceutical composition of the third aspect of the present invention is used to prevent and / or treat diseases related to the VEGF / VEGFR pathway.

[0052] In any embodiment, the disease associated with the VEGF / VEGFR pathway is selected from one or more of atherosclerosis, pulmonary fibrosis, retinopathy, endometriosis, arthritis and cancer.

[0053] In any embodiment, the cancer is selected from one or more of skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, prostate cancer, colon cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), bone cancer, brain cancer, rectal cancer, esophageal cancer, kidney cancer (e.g., renal parenchymal cancer), tongue cancer, cervical cancer, uterine corpus cancer, endometrial cancer, testicular cancer, melanoma, lymphoma, thyroid tumor, glioma, astrocytoma, and hepatocellular carcinoma.

[0054] The aforementioned compounds are listed below:

[0055] The products, methods and applications of the present invention have been described through preferred embodiments. It is obvious that relevant personnel can modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention, and the resulting technical solutions are all included in the scope of protection required by the present invention.

[0056] The term "pharmaceutically acceptable salt" as used herein includes salts of the compounds of the present invention formed with pharmaceutically acceptable inorganic or organic acids or base salts formed with pharmaceutically acceptable bases. Acid salts include, but are not limited to, hydrochlorides, hydrobromides, hydroiodides, nitrates, sulfates, bisulfates, phosphates, hydrogenphosphates, acetates, propionates, butyrates, oxalates, pivalates, adipates, alginate, lactates, citrates, tartrates, succinates, maleates, fumarates, picrates, aspartates, gluconates, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and pamoates; base salts include, but are not limited to, ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, organic base salts such as dicyclohexylamine and N-methyl-D-glucamine salts, and amino acid salts such as arginine and lysine salts.

[0057] The term "base" in the present invention is generally any substance known as a base in organic synthesis without particular limitation, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydride, potassium hydride, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, triethylamine, trimethylamine, N-methylmorpholine, N,N-dimethylaniline, pyridine, isoquinoline, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium methoxide, etc.

[0058] The term "pharmaceutically acceptable carrier" in the present invention includes, but is not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, beeswax, polyethylene-polyoxypropylene block polymers and lanolin.

[0059] The term "alkyl" in the present invention refers to a hydrocarbon group formed by removing a hydrogen atom from an alkane molecule. 1-6 Alkyl, C 1-4 Alkyl, C 1-2 Alkyl; specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.

[0060] The term "alkoxy" in the present invention refers to a group provided in the form of alkyl-O-, wherein "alkyl" is as defined above. For example, C 1-6 Alkoxy, C 1-4 Alkoxy, C 1-2 Alkoxy; specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.

[0061] The term "alkoxycarbonyl" in the present invention refers to a group provided in the form of alkoxy-C(O)-, wherein "alkoxy" is as defined above. For example, C 1-6 Alkoxycarbonyl, C 1-4 Alkoxycarbonyl, C 1-2 Alkoxycarbonyl; specific examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl and the like.

[0062] The term "alkanoyl" in the present invention refers to a group formed by removing the hydroxyl group from a saturated fatty acid containing a single carboxyl group. 1-6 Alkanoyl, C 1-4 Alkanoyl, C 1-2 Alkanoyl; specific examples include, but are not limited to, formyl, acetyl, n-propionyl, isopropionyl, and the like.

[0063] The term "aminoalkanoyl" in the present invention is a group provided in the form of NH2-alkanoyl-, wherein "alkanoyl" is as defined above. For example, amino C 1-6 Alkanoyl, amino C 1-4 Alkanoyl, amino C 1-2 Alkanoyl; specific examples include, but are not limited to, carbamoyl, aminoacetyl, amino-n-propionyl, aminoisopropionyl, amino-n-butyryl, and the like.

[0064] The term "alkylaminoacyl" in the present invention is a group provided in the form of alkyl-NH-C(O)-, wherein "alkyl" is as defined above. For example, C 1-6 Alkyl, C 1-4 Alkyl, C 2-6 Alkyl, C 1-2 Alkylaminoacyl; specific examples include, but are not limited to, methylaminoacyl, ethylaminoacyl, n-propylaminoacyl, isopropylaminoacyl, n-butylaminoacyl and the like.

[0065] The term "aryl" in the present invention refers to a monocyclic or condensed ring group having aromatic properties, such as a 5-10-membered aryl, a 5-8-membered aryl, or a 5-6-membered aryl; specific examples include, but are not limited to, phenyl, naphthyl, anthracenyl, and phenanthrenyl.

[0066] The term "heteroaryl" as used herein refers to a monocyclic or condensed ring group with aromatic properties containing at least one heteroatom, such as a 5-10-membered heteroaryl, a 5-8-membered heteroaryl, a 5-7-membered heteroaryl, or a 5-6-membered heteroaryl. Specific examples include, but are not limited to, porphyrinyl, pyrazolyl, pyrrolyl, thiazolyl, pyridyl, imidazolyl, and quinolinyl.

[0067] The term "heterocyclyl" as used herein refers to a monocyclic or polycyclic saturated hydrocarbon group containing at least one heteroatom, such as a 5-10-membered heterocyclyl, a 5-8-membered heterocyclyl, a 5-7-membered heterocyclyl, or a 5-6-membered heterocyclyl. Specific examples include, but are not limited to, piperazinyl and morpholinyl.

[0068] The term "cycloalkyl" as used herein refers to a group formed by removing a hydrogen atom from a monocyclic saturated alkane ring, such as a 3- to 6-membered cycloalkyl group or a 5- to 6-membered cycloalkyl group. Specific examples include, but are not limited to, cyclobutane, cyclopentane, and cyclohexane.

[0069] The compounds of the present invention, their pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, solvates or polymorphs, or pharmaceutical compositions of the present invention have systemic and / or local effects and can therefore be administered via suitable routes, such as oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, topical administration, or in the form of implants. Administration can be performed in dosage forms suitable for these routes of administration.

[0070] Suitable for oral administration are known administration forms which deliver the active ingredient rapidly and / or in a modified manner, such as tablets (uncoated or coated, e.g. with an enteric coating or a film coating), capsules, sugar-coated tablets, granules, pellets, powders, emulsions, suspensions and aerosols.

[0071] With parenteral administration it is possible to avoid the absorption step (intravenous, intraarterial, intracardial, intraspinal or intramedullary administration) or to include the absorption (intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal administration). Suitable administration forms for parenteral administration are, in particular, preparations in the form of solutions, suspensions, emulsions, lyophilizates and sterile powders for injection and infusion.

[0072] Suitable other routes of administration include, for example, drugs for inhalation (particularly powder inhalation, spray), nasal drops / solutions, sprays; tablets or capsules for lingual, sublingual or buccal administration, suppositories, preparations for the ears and eyes, vaginal capsules, aqueous suspensions (lotions, shaken mixtures), lipophilic suspensions, ointments, creams, emulsions, pastes, dusting powders or implants, such as stents.

[0073] The active ingredient can be converted into the described administration form by methods known per se. It can be achieved with inert, non-toxic suitable pharmaceutical excipients. It particularly includes carriers (e.g., microcrystalline cellulose), solvents (e.g., liquid polyethylene glycol), emulsifiers (e.g., sodium lauryl sulfate), dispersants (e.g., polyvinyl pyrrolidone), synthetic and natural biopolymers (e.g., proteins), stabilizers (e.g., antioxidants and ascorbic acid), colorants (e.g., inorganic pigments such as iron oxide), or flavorings and / or taste-masking agents. In suitable cases, the active ingredient can be present in one or more of the above-mentioned carriers in the form of microencapsulation.

[0074] In addition to the compound of the present invention, its pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph, the above-mentioned pharmaceutical preparation may also contain other pharmaceutically active ingredients. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] FIG1 is a graph showing the inhibitory effects of compounds 12 and 28 on HUVECs cell angiogenesis in vitro.

[0076] FIG2 is a graph showing the inhibitory effects of compounds 12 and 28 on HepG2 liver cancer xenograft tumors in nude mice.

[0077] FIG3 shows the inhibitory effects of compounds 12 and 28 on human thyroid cancer 8305C xenograft tumors in nude mice.

[0078] Figure 4 shows the immunohistochemical effects of compounds 12 and 28 on angiogenesis and proliferation inhibition of human thyroid cancer 8305C xenograft tumors in nude mice. DETAILED DESCRIPTION

[0079] The following examples are provided to provide those skilled in the art with a complete disclosure of how to prepare and evaluate the methods and compounds claimed herein. These examples are merely illustrative of the present invention and are not intended to limit the scope of the present invention.

[0080] The preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be more conveniently prepared by combining various synthetic methods optionally described in this specification or known in the art, and such combinations can be more easily carried out by those skilled in the art.

[0081] The following examples are illustrative of preferred embodiments of the present invention and do not constitute any limitation to the present invention.

[0082] For all of the following examples, standard procedures and purification methods known to those skilled in the art were used. Unless otherwise indicated, all temperatures are expressed in degrees Celsius. The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) or mass spectrometry (MS). Melting points were determined using an RY-1 melting point apparatus; the thermometer is uncalibrated and is given in degrees Celsius. 1 HNMR was measured using a JEOL JNM-ECA-400 nuclear magnetic resonance instrument. Mass spectra were measured using an API 3000 (ESI) mass spectrometer. All reaction solvents were not subjected to standardization pretreatment unless otherwise noted. In the following examples, unless otherwise specified, % refers to mass percentage. Silica gel for column chromatography was produced by Qingdao Ocean Chemical Plant (200-300 mesh); silica gel plates for thin-layer chromatography were prefabricated thin-layer chromatography silica gel plates produced by Yantai Institute of Chemical Industry. The compounds of the present invention can be prepared according to conventional methods in the art using appropriate reagents, raw materials, and purification methods known to those skilled in the art.

[0083] Example 1: Synthesis of 4-[5-[(4-fluorophenyl)carbamoyl)]naphthalene-2-yl]-7-methoxy-6-quinolinecarboxamide (Compound 1)

[0084] 1.1 Methyl 4-[(2,2-dimethyl-4,6-dioxo-1,3-dioxane-5-methylene)amino]-2-methoxybenzoate (2)

[0085] 50.0 g (347.0 mmol) of cycloisopropyl malonate, 100.0 g (942.0 mmol) of trimethyl orthoformate, and 125 mL of isopropyl alcohol were added to a 250 mL three-necked flask and heated under reflux with stirring for 40 min. 25.0 g (138.0 mmol) of methyl 2-methoxy-4-aminobenzoate was added and refluxed with stirring for another 10 min. The mixture was cooled to room temperature and filtered. The filter cake was washed with diethyl ether (50 mL x 2) and dried under vacuum to give 42.75 g of a yellow crystalline solid (yield 92.4%), mp 200-202°C. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 11.22 (s, 1H), 8.67 (s, 1H), 7.69 (d, J = 8.5Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.16 (dd, J=8.5, 2.1Hz, 1H), 3.84 (s, 3H), 3.76 (d, J=16.9Hz, 3H), 1.67 (d, J=17.1Hz, 6H). ESI-MS m / z:336.1[M+H] + .

[0086] 1.2 Methyl 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylate (3)

[0087] 20 g (59.6 mmol) of product (2) (1.1) and 100 mL of diphenyl ether were added to a 250 mL round-bottom flask, heated to 200°C and stirred for 30 min. After the reaction, the temperature was lowered to 40°C, ether was added, and stirred for 30 min. The mixture was filtered, and the filter cake was washed with ether and dried in vacuo to obtain 12.6 g of a light yellow solid (3) with a yield of 90.5% and an mp of 243-246°C. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 11.64 (s, 1H), 8.39 (s, 1H), 7.83 (dd, J=7.5, 5 .8Hz, 1H), 6.98 (s, 1H), 5.95 (dd, J=7.5, 1.1Hz, 1H), 3.85 (s, 3H), 3.77 (s, 3H). ESI-MS m / z:234.2[M+H] + .

[0088] 1.3 Methyl 4-chloro-7-methoxyquinoline-6-carboxylate (4)

[0089] 5.0 g (21 mmol) of product (3) (1.2) and 15 mL of thionyl chloride were added to a 100 mL round-bottom flask and stirred at reflux under nitrogen for 1 h. The thionyl chloride was evaporated under reduced pressure, and the remaining light yellow solid was added to 200 mL of saturated sodium bicarbonate solution (containing 3 mL of ethyl acetate), stirred until no bubbles appeared, filtered, and the filter cake was washed with water and used directly in the next reaction.

[0090] 1.4 4-Chloro-7-methoxyquinoline-6-carboxamide (5)

[0091] 1.3g of filter cake (intermediate 4), 150mL of 28% aqueous ammonia, and 5mL of ethyl acetate were added to a round-bottom flask and stirred at room temperature for 6h. Filtered, the filter cake was washed with water, and vacuum dried to obtain 3.86g of a light yellow solid (5) with a yield of 76.1% and mp of 214-218°C. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 8.78 (d, J=4.8Hz, 1H), 8.46 (s, 1H), 7.80 (s, 1H), 7.89 (s, 1H), 7.59 (s, 1H), 7.64 (d, J=4.8Hz, 1H), 4.00 (s, 3H). ESIMS m / z:237.0[M+H] + .

[0092] 1.5 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea

[0093] 4 g (27.9 mmol) of 4-amino-3-chlorophenol and 14 mL of DMF were added to a 50 mL round-bottom flask. 3.8 g (48.4 mmol) of pyridine was added dropwise under ice-cooling. 4.9 g (31.6 mmol) of phenyl chloroformate was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1.5 h to obtain the intermediate. 2.39 g (41.5 mmol) of cyclopropylamine was slowly added dropwise under ice-cooling and stirred at room temperature for 5 h. 81.2 mL of water and 7.2 mL of hydrochloric acid (6 mol·L -1 ), stirred overnight, filtered, washed, and dried in vacuo to obtain 4.84 g of a gray solid with a yield of 77.3% and mp 155-159°C. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 9.47 (s, 1H), 7.66 (d, J = 8.9Hz, 1H), 7.54 (s, 1H), 6.80 (d, J = 2.7Hz, 1 H), 6.75 (d, J=2.7Hz, 1H), 6.63 (dd, J=8.9, 2.8Hz, 1H), 0.58 (td, J=6.8, 4.8Hz, 2H), 0.43~0.26 (m, 2H). ESI-MSm / z:227.5[M+H] + ,249.1[M+Na] + .

[0094] 1.6 Sodium 6-sulfonate-1-naphthoic acid

[0095] 5.00 g (29.04 mmol) of 1-naphthoic acid was added to a 50 mL eggplant-shaped bottle, and 6.0 mL of concentrated sulfuric acid was added to the eggplant-shaped bottle at room temperature. The temperature was slowly raised to 115°C and kept constant for 3 h. TLC monitoring showed that the reaction was complete. The reaction mother liquor was slowly added dropwise to 30 ml of water. After cooling to room temperature, the pH was adjusted to about 4 with saturated NaOH (the solution color changed from wine red to milky white with a large amount of solid precipitation). Filter by suction, wash the filter cake with a small amount of distilled water to obtain a light yellow solid, and vacuum dry to obtain 5.01 g of the product with a yield of 62.7%. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 13.16 (s, 1H), 8.81 (d, J = 9.0Hz, 1H), 8.27 ~ 8.20 ( m, 2H), 8.15 (dd, J=7.2, 1.2Hz, 1H), 7.82 (dd, J=9.0, 1.8Hz, 1H), 7.64~7.53 (m, 1H). ESI-MSm / z:257[MH] - .

[0096] 1.7 6-Hydroxy-1-naphthoic acid

[0097] 5.00g (18.25mmol) of 6-sodium sulfonate-1-naphthoic acid was ground into a fine powder in a mortar and divided into three batches. 15.00g (165.00mmol) of KOH was added to a 100mL crucible and heated to about 300°C with an electric heating mantle (KOH melted). The ground 6-sodium sulfonate-1-naphthoic acid was added to the crucible in batches (stirring while adding during the heating process). After the addition is complete, stir at a constant temperature for 10 minutes and stop heating. Cool to about 50°C and slowly add 25.0mL of water. The liquid in the crucible will become turbid. Then transfer the liquid in the crucible to a beaker and adjust the pH to about 2 with concentrated hydrochloric acid (a large amount of off-white solid precipitates in the solution during the adjustment process). Filter with suction, wash the filter cake with a small amount of water, and vacuum dry to obtain 1.55g of off-white solid with a yield of 44.9%. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 13.03 (s, 1H), 9.93 (s, 1H), 8.72 (d, J=10.1Hz, 1H), 8.02~7.76 (m, 2H), 7.45 (dd, J=8.1, 7.3Hz, 1H), 7.30-6.98 (m, 2H). ESI-MSm / z:257[MH] - .

[0098] 1.8 6-(6-Carbamoyl-7-methoxyquinolin-4-yloxy)-1-naphthoic acid

[0099] 6-Hydroxy-1-naphthoic acid (9, 1.08 g, 5.74 mmol), cesium carbonate (5.2 g, 16.0 mmol), and DMF (11.0 mL) were added sequentially to an eggplant-shaped flask (under nitrogen protection) and stirred at room temperature for 10 min. 4-Chloro-7-methoxyquinoline-6-carboxamide (5, 0.8 g, 3.39 mmol) was then added to the flask. The mixture was stirred at room temperature for 10 min, then the temperature was slowly raised to 75°C and the reaction was continued for 5 h. After completion of the reaction as monitored by TLC, the reaction solution was cooled to room temperature, 20.0 mL of distilled water was added, and the pH was adjusted to 4-5 with saturated NaHCO₃. A large amount of solid precipitated. The filter cake was filtered, washed with a small amount of water, and vacuum dried to obtain a white solid. Yield: 1.7 g, yield: 68.9%. 1H-NMR (400MHz, DMSO-d6) δ (ppm): 9.05 (d, J=9.5Hz, 1H), 8.73 (s, 1H), 8.69 (d, J=5.2Hz, 1H), 8.20 (s, 1H), 8.18 (s, 1H), 7.96 (d, J= 2.5Hz, 1H), 7.90 (s, 1H), 7.78 (s, 1H), 7.67 (t, J=5.3Hz, 1H), 7.65~7.62 (m, 1H), 7.56 (s, 1H), 6.64 (d, J=5.2Hz, 1H), 4.05 (s, 3H). ESI-MSm / z:387[MH] - .

[0100] 1.9 Synthesis of 4-(5-[(4-fluorophenyl)carbamoyl)]naphthalene-2-yl)-7-methoxy-6-quinolinecarboxamide

[0101] 0.30 g (0.77 mmol) of 6-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-1-naphthoic acid (10), 0.30 g of EDCI (1.54 mmol), 0.21 g of Hobt (1.54 mmol), and DMF (5.0 mL) were placed in an eggplant-shaped flask, protected by nitrogen, and stirred under ice bath conditions. After 1 h, the reaction was complete as monitored by TLC. Then, p-fluoroaniline was added to the eggplant-shaped flask, the ice bath was removed, and the reaction was allowed to proceed at room temperature for 5 h. The reaction was complete as monitored by TLC. 50.0 mL of distilled water was added to the reaction solution and stirred for 30 min. The mixture was then filtered, and the filter cake was washed with distilled water (10 mL x 3). The mixture was then dried under vacuum to obtain a pale yellow solid. Column chromatography (dichloromethane-methanol, volume ratio 20:1) yielded 0.10 g of a white solid, with a yield of 27.0%. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.71 (s, 1H), 8.74 (s, 1H), 8.71 (d, J = 5.2Hz, 1H), 8.3 6(d, J=9.2Hz, 1H), 8.12 (d, J=8.2Hz, 1H), 7.97 (d, J=2.6Hz, 1H), 7.89 (s, 1H), 7.88~7.83 (m, 2H), 7.81 (dd, J=7.1, 1.0Hz, 1H), 7.78 (s, 1H), 7.69 (dd, J=8.2, 7.1Hz, 1H), 7.60 (dd , J=9.2, 2.6Hz, 1H), 7.57 (s, 1H), 7.30~7.18 (m, 2H), 6.63 (d, J=5.2Hz, 1H), 4.06 (s, 3H). ESI-MSm / z:482.4[M+H] + ,504.0[M+Na] + .

[0102] Example 2: 4-(5-[(3,4-dimethylphenyl)carbamoyl)]naphthalene-2-yl)-7-methoxy-6-quinolinecarboxamide (Compound 2)

[0103] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain 0.08 g. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.46 (s, 1H), 8.73 (s, 1H), 8.70 (d, J=5.2Hz, 1H), 8.34 (d, J= 9.2Hz,1H),8.09(d,J=8.3Hz,1H),7.94(d,J=2.5Hz,1H),7.87(s,1H),7.76(dd,J=5.4,4.6Hz,2H),7.67(d,J=8.1Hz,1H),7.62(d,J=1.3Hz,1H), 7.58(dd,J=9.2,2.6Hz,1H),7.56(s,1H),7.52(dd,J=8.2,1.9Hz,1H),7. 13(d,J=8.2Hz,1H),6.63(s,1H),4.05(s,3H),2.24(s,3H),2.21(s,3H). ESI-MS m / z:492.2[M+H] + ,514.4[M+Na] + .

[0104] Example 3: 4-(5-[(phenyl)carbamoyl)]naphthalene-2-yl)-7-methoxy-6-quinolinecarboxamide (Compound 3)

[0105] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain 0.11 g. 1H-NMR (400MHz, DMSO-d6) δ (ppm): 10.66 (s, 1H), 8.73 (s, 1H), 8.70 (d, J = 5.2Hz, 1H), 8.36 (d ,J=9.3Hz,1H),8.11(d,J=8.5Hz,1H),7.96(d,J=2.5Hz,1H),7.91(s,1H),7.84(s,1H),7.82 (d,J=4.2Hz,1H),7.79(d,J=2.9Hz,1H),7.72~7.66(m,1H),7.60(dd,J=9.2,2.6Hz,1H),7. 56(s,1H),7.39(t,J=7.9Hz,2H),7.14(t,J=8.4Hz,1H),6.62(d,J=5.2Hz,1H),4.05(s,3H). ESI-MS m / z:464.1[M+H] + , 486.1[M+Na]+.

[0106] Example 4: 4-(5-[(4-pyridyl)carbamoyl)]naphthalene-2-yl)-7-methoxy-6-quinolinecarboxamide (Compound 4)

[0107] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain 0.11 g. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 11.05 (s, 1H), 8.73 (s, 1H), 8.71 (d, J = 5.2Hz, 1H), 8.53 (d ,J=5.0Hz,2H),8.35(d,J=9.2Hz,1H),8.15(d,J=8.3Hz,1H),7.98(d,J=2.6Hz,1H),7.89(s ,1H),7.85(dd,J=7.1,1.2Hz,1H),7.81(dd,J=4.9,1.5Hz,2H),7.77(s,1H),7.70(dd,J=8. 3,7.1Hz,1H),7.61(dd,J=9.2,2.6Hz,1H),7.56(s,1H),6.63(d,J=5.2Hz,1H),4.05(s,3H). ESI-MS m / z:465.1[M+H]+, 487.1[M+Na] + ,929.3[2M+Na] + .

[0108] Example 5: 4-(5-[(3-chlorophenyl)carbamoyl)]naphthalene-2-yl)-7-methoxy-6-quinolinecarboxamide (Compound 5)

[0109] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain 0.07 g. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.84 (s, 1H), 8.73 (s, 1H), 8.71 (d, J = 5.2Hz, 1H), 8.36 (d, J=9.2Hz,1H),8.13(d,J=7.7Hz,1H),8.05(d,J=2.0Hz,1H),7.97(d,J=2.3Hz,1H),7.90(s,1H ),7.82(d,J=7.1Hz,1H),7.78(s,1H),7.76~7.66(m,2H),7.60(dd,J=9.2,2.5Hz,1H),7.56(s ,1H),7.42(t,J=8.1Hz,1H),7.21(dd,J=6.4,2.9Hz,1H),6.63(d,J=5.2Hz,1H),4.05(s,3H). ESI-MS m / z:498.1[M+H] + .

[0110] Example 6: 4-(5-[(4-methoxyphenyl)carbamoyl)]naphthalene-2-yl)-7-methoxy-6-quinolinecarboxamide (Compound 6)

[0111] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain 0.16 g. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.52 (s, 1H), 8.73 (s, 1H), 8.70 (d, J=4.4Hz, 1H), 8.36 (d, J= 9.6Hz, 1H), 8.10 (d, J = 8.8Hz, 1H), 7.96 (d, J = 2.8Hz, 1H), 7.90 (s, 1H), 7.78 (d, J = 7.7Hz, 2H), 7.74 (d, J = 8.9Hz, 2H), 7.71~7. 64(m,1H),7.59(dd,J=9.2,2.5Hz,1H),7.56(s,1H),6.96(d,J=9.1Hz,2H),6.62(d,J=5.3Hz,1H),4.05(s,3H),3.76(s,3H). ESI-MS m / z:494.1[M+H] + ,516.1[M+Na] + .

[0112] Example 7: 4-(5-[(ethyl)carbamoyl)]naphthalene-2-yl)-7-methoxy-6-quinolinecarboxamide (Compound 7)

[0113] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain 0.13 g. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 8.74 (s, 1H), 8.71 (d, J = 5.4Hz, 1H), 8.64 (t ,J=5.7Hz,1H),8.37(d,J=9.3Hz,1H),8.04(dd,J=6.6,3.0Hz,1H),7.93(d,J= 2.5Hz,2H),7.81(s,1H),7.62(dd,J=6.7,3.8Hz,1H),7.57(dd,J=9.0,2.7Hz ,1H),6.62(d,J=5.3Hz,1H),4.05(s,3H),3.34(m,2H),1.19(t,J=7.2Hz,3H). ESI-MS m / z:416.1[M+H] + ,438.1[M+Na] + , 831.1[2M+H] + , 853.2[2M+Na] + .

[0114] Example 8: 4-(5-[(2,3-dimethylphenyl)carbamoyl)]naphthalene-2-yl)-7-methoxy-6-quinolinecarboxamide (Compound 8)

[0115] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain 0.09 g. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.47 (s, 1H), 8.73 (s, 1H), 8.70 (d, J = 5.2Hz, 1H), 8.34 (d, J = 9 .2Hz,1H),8.09(d,J=7.7Hz,1H),7.95(d,J=2.5Hz,1H),7.88(s,1H),7.77(d,J=7.9Hz,2H),7.70 ~7.64(m,1H),7.62(d,J=1.9Hz,1H),7.59(dd,J=9.3,2.6Hz,1H),7.56(s,1H),7.52(dd,J=8.2, 2.0Hz, 1H), 7.13 (d, J = 8.4Hz, 1H), 6.62 (d, J = 5.2Hz, 1H), 4.05 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H). ESI-MS m / z:492.1[M+H] + ,514.1[M+Na] + , 530.1[M+K] + .

[0116] Example 9: 4-(5-[(4-methylphenyl)carbamoyl)]naphthalene-2-yl)-7-methoxy-6-quinolinecarboxamide (Compound 9)

[0117] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain 0.11 g. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.55 (s, 1H), 8.73 (s, 1H), 8.70 (d, J = 5.0Hz, 1H), 8.3 5(d,J=9.2Hz,1H),8.10(d,J=8.8Hz,1H),7.95(d,J=2.6Hz,1H),7.89(s,1H),7.78(d,J =7.4Hz,2H),7.72(s,1H),7.70(s,1H),7.66(d,J=7.5Hz,1H),7.59(dd,J=9.1,2.7Hz,1 H), 7.56 (s, 1H), 7.19 (d, J = 8.4Hz, 2H), 6.62 (d, J = 5.2Hz, 1H), 4.05 (s, 3H), 2.30 (s, 3H). ESI-MS m / z:478.1[M+H] + ,500.1[M+Na] + .

[0118] Example 10: 4-(5-[(3-methylphenyl)carbamoyl)]naphthalene-2-yl)-7-methoxy-6-quinolinecarboxamide (Compound 10)

[0119] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain 0.10 g. 1H-NMR (400MHz, DMSO-d6) δ (ppm): 10.57 (s, 1H), 8.73 (s, 1H), 8.70 (d, J = 5.2Hz, 1H), 8.35 (d, J =9.1Hz,1H),8.10(d,J=8.2Hz,1H),7.95(d,J=2.5Hz,1H),7.89(s,1H),7.78(d,J=6.8Hz,2H), 7.70(s,1H),7.67(d,J=7.8Hz,1H),7.60(d,J=2.2Hz,1H),7.58(d,J=2.2Hz,1H),7.56(s,1H), 7.26(t,J=7.8Hz,1H), 6.96(d,J=6.9Hz,1H), 6.62(d,J=5.2Hz,1H), 4.05(s,3H), 2.33(s,3H). ESI-MS m / z:478.1[M+H] + ,500.1[M+Na] + .

[0120] Example 11: 4-(5-[(3-trifluoromethylphenyl)carbamoyl)]naphthalene-2-yl)-7-methoxy-6-quinolinecarboxamide (Compound 11)

[0121] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain 0.09 g. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 11.01 (s, 1H), 8.73 (s, 1H), 8.72 (d, J = 5.3Hz, 1H), 8.36 (d ,J=8.9Hz,1H),8.14(d,J=8.2Hz,1H),8.05(d,J=8.3Hz,2H),7.98(d,J=2.5Hz,1H),7.89(s, 1H),7.85(dd,J=7.2,1.1Hz,1H),7.78(s,1H),7.76(s,1H),7.70(dd,J=8.3,7.2Hz,1H),7. 62(d,J=2.5Hz,1H),7.60(d,J=2.5Hz,1H),7.57(s,1H),6.65(d,J=5.1Hz,1H),4.05(s,3H). ESI-MS m / z:532.1[M+H] + ,554.1[M+Na] + .

[0122] Example 12: 4-(5-[(3,5-dimethylphenyl)carbamoyl)]naphthalene-2-yl)-7-methoxy-6-quinolinecarboxamide (Compound 12)

[0123] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain 0.09 g. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.49 (s, 1H), 8.73 (s, 1H), 8.70 (d, J = 5.2Hz, 1 H),8.33(d,J=9.2Hz,1H),8.09(d,J=8.2Hz,1H),7.95(d,J=2.3Hz,1H),7.89(s,1 H),7.76(d,J=7.1Hz,2H),7.70~7.64(m,1H),7.59(dd,J=9.1,2.3Hz,1H),7.56(s ,1H),7.45(s,2H),6.78(s,1H),6.62(d,J=5.2Hz,1H),4.05(s,3H),2.28(s,6H). ESI-MS m / z:492.1[M+H] + ,514.1[M+Na] + .

[0124] Example 13: 4-(5-[(3-fluorophenyl)carbamoyl)]naphthalene-2-yl)-7-methoxy-6-quinolinecarboxamide (Compound 13)

[0125] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain 0.09 g. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.86 (s, 1H), 8.73 (s, 1H), 8.71 (d, J = 5.2Hz, 1H), 8.35 (d ,J=9.2Hz,1H),8.12(d,J=8.3Hz,1H),7.96(d,J=2.6Hz,1H),7.89(s,1H),7.82(dd,J=7.1,1 .1Hz,2H),7.77(s,1H),7.69(dd,J=8.2,7.2Hz,1H),7.62~7.57(m,2H),7.56(s,1H),7.42(t d, J=8.3, 6.9Hz, 1H), 6.98 (tdd, J=9.1, 2.6, 0.8Hz, 1H), 6.63 (d, J=5.2Hz, 1H), 4.05 (s, 3H). ESI-MS m / z:482.1[M+H] + ,504.1[M+Na] + .

[0126] Example 14: 4-(5-[(3,5-dichlorophenyl)carbamoyl)]naphthalene-2-yl)-7-methoxy-6-quinolinecarboxamide (Compound 14)

[0127] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain 0.09 g. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.98 (s, 1H), 8.73 (s, 1H), 8.71 (d, J = 5.2Hz, 1H) ,8.37(d,J=9.3Hz,1H),8.14(d,J=8.3Hz,1H),7.97(d,J=2.5Hz,1H),7.92(d,J=1.8 Hz,2H),7.89(s,1H),7.84(d,J=6.4Hz,2H),7.77(s,1H),7.74~7.67(m,1H),7.60(d d,J=9.3,2.6Hz,1H),7.56(s,1H),7.39(s,1H),6.63(d,J=5.2Hz,1H),4.05(s,3H). ESI-MS m / z:533.1[M+H] + ,555.1[M+Na] + .

[0128] Example 15: 4-((5-((cyclopropylmethyl)carbamoyl)naphthalen-2-yl)oxy)-7-methoxyquinoline-6-carboxamide (Compound 15)

[0129] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain a yellow solid, 0.06 g. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.73 (d, J = 2.5 Hz, 2H), 8.69 (d, J = 5.3 Hz, 1H), 8.38 (d,J=9.3Hz,1H),8.04(dd,J=6.4,3.2Hz,1H),7.93–7.87(m,2H),7.78(s,1H),7 .62(q,J=3.6Hz,2H),7.60–7.54(m,2H),6.60(d,J=5.2Hz,1H),4.05(s,3H),3.2 4(t,J=6.3Hz,2H),1.12(d,J=17.0Hz,1H),0.51–0.45(m,2H),0.31–0.27(m,2H). 13C NMR(151MHz,DMSO-d6)δ(ppm)168.16,165.74,161.23,158.05,153.25,151.59,151.44,135.04,134.22,129.28,128. 38,127.62,126.04,125.17,124.89,124.61,121.13,117.64,114.60,107.85,103.76,56.12,43.22,10.91,3.17(2C). MS[M+H] + 442.18.

[0130] Example 16: 7-methoxy-4-((5-((3-methoxyphenyl)carbamoyl)naphthalen-2-yl)oxy)quinoline-6-carboxamide (Compound 16)

[0131] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain a yellow solid, 0.06 g. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.61 (s, 1H), 8.71–8.65 (m, 2H), 8.31 (d, J = 9.3Hz, 1H), 8.07 (d, J = 8.3Hz, 1H), 7.92 (d, J = 2.6Hz, 1H) ,7.86(s,1H),7.75(d,J=7.8Hz,2H),7.51(d,J=8.1Hz,2H),7.35(d,J=8.2Hz,1H),6.59(d,J=5.2Hz,1H),4.02(s,3H),3.73(s,3H). 13 C NMR (151MHz, DMSO-d6) δ (ppm): 165.48, 164.21, 159.58, 157.89, 156.50, 151.76, 150.12, 150.08, 138.82, 133.17, 132.71, 128.23, 127 .90,126.56,125.92,124.54,123.81,123.67,123.05,119.92,116.17,113.08,110.55,107.61,106.36,104.07,102.30,54.59,53.41. MS[M+H] + 494.18.

[0132] Example 17: 4-((5-((4-ethoxyphenyl)carbamoyl)naphthalen-2-yl)oxy)-7-methoxyquinoline-6-carboxamide (Compound 17)

[0133] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain a yellow solid, 0.06 g. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.50 (s, 1H), 8.80–8.68 (m, 2H), 8.36 (d, J = 9.1Hz, 1H),8.10(d,J=8.3Hz,1H),7.96(d,J=2.5Hz,1H),7.90(s,1H),7.80–7.65(m,5H),7.62–7.50( m, 2H), 6.95 (d, J = 9.1Hz, 2H), 6.63 (d, J = 5.2Hz, 1H), 4.08–3.98 (m, 5H), 1.33 (t, J = 7.0Hz, 3H). 13 C NMR (151MHz, DMSO-d6) δ (ppm) 166.52, 165.69, 161.47, 158.22, 154.80, 153.01, 151.53, 151.06, 134.99, 134.26, 132.22, 129.62, 128. 79,128.23,127.58,126.12,125.33,124.69,121.35(2C),120.65,117.75,114.62,114.31(2C),107.52,103.83,63.04,56.16,14.60. MS[M+H] + 508.19.

[0134] Example 18: 7-methoxy-4-((5-((5-methylthiazol-2-yl)carbamoyl)naphthalen-2-yl)oxy)quinoline-6-carboxamide (Compound 18)

[0135] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain a yellow solid, 0.06 g. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.68 (s, 1H), 8.76 (dt, J = 6.9, 2.7Hz, 2H), 8 .55(dd,J=8.4,1.4Hz,1H),8.42(d,J=9.1Hz,1H),8.17(s,1H),8.03–7.99(m ,1H),7.95–7.88(m,2H),7.82(s,1H),7.57(s,1H),7.53(dd,J=8.4,4.4Hz, 1H), 7.25 (d, J = 1.2Hz, 1H), 6.71 (d, J = 5.5Hz, 1H), 4.07 (s, 3H), 2.42 (s, 3H). 13C NMR(151MHz,DMSO-d6)δ(ppm)168.09,165.70,161.30,158.15,153.13,151.63,151.40,151.05,139.54,134.56,131.61, 130.80,127.99,127.62,125.95,125.31,124.62,121.75,120.64,119.76,117.87,114.61,107.69,103.86,56.15,11.06. MS[M+H] + 485.13.

[0136] Example 19: 7-methoxy-4-((5-((4-methylthiazol-2-yl)carbamoyl)naphthalen-2-yl)oxy)quinoline-6-carboxamide (Compound 19)

[0137] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain a yellow solid, 0.06 g. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.77 (s, 1H), 8.77 (dd, J = 4.4, 1.4Hz, 1H), 8.74 (s, 1H) ),8.70(d,J=5.3Hz,1H),8.55(dd,J=8.4,1.4Hz,1H),8.43(d,J=9.2Hz,1H),8.15(d, J=8.4Hz,1H),7.98(d,J=2.6Hz,1H),7.93–7.87(m,2H),7.79(s,1H),6.89(d,J=1.1H z, 1H), 6.64 (d, J = 5.3Hz, 1H), 6.25–6.22 (m, 1H), 4.06 (s, 3H), 2.09 (d, J = 1.1Hz, 3H). 13 C NMR (151MHz, DMSO-d6) δ (ppm) 166.55, 165.72, 161.15, 158.07, 153.25, 151.64 (d, J = 7.2Hz), 146.70, 134.31, 131.51, 13 0.89,128.00,127.62,126.68,125.94,125.23,124.61,121.78,117.85,114.62,108.10,107.86,103.84,56.13,16.78. MS[M+H] + 485.13.

[0138] Example 20: 7-methoxy-4-((5-(methylcarbamoyl)naphthalen-2-yl)oxy)quinoline-6-carboxamide (Compound 20)

[0139] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain a yellow solid, 0.06 g. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.75 (s, 1H), 8.72 (d, J = 5.4Hz, 1H), 8.56 (d, J = 4.5Hz ,1H),8.40(d,J=9.2Hz,1H),8.08–8.01(m,1H),7.93(d,J=2.6Hz,1H),7.92–7.90(m, 1H), 7.80 (s, 1H), 7.64–7.60 (m, 2H), 7.58–7.55 (m, 2H), 6.64 (d, J = 5.4Hz, 1H), 4.06 (s, 3H), 2.89–2.86 (m, 4H). 13 C NMR (151MHz, DMSO-d6) δ (ppm): 169.26 (2C), 166.28, 161.89, 158.68, 153.71, 152.00, 135.44, 134.80, 129.9 5,129.05,128.20,126.61,125.80,125.50,125.20,121.68,118.20,115.17,108.29,104.32,56.70,26.66. MS[M+H] + 402.14.

[0140] Example 21: 7-methoxy-4-((5-(4-methylpiperazine-1-carbonyl)naphthalen-2-yl)oxy)quinoline-6-carboxamide (Compound 21)

[0141] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain a yellow solid, 0.06 g. 1H NMR (400MHz, Chloroform-d) δ (ppm): 9.30 (s, 1H), 8.63 (s, 1H), 7.95 (d, J = 9.0Hz, 1H), 7 .82(d,J=8.3Hz,2H),7.63(d,J=2.2Hz,1H),7.53(s,1H),7.52–7.48(m,1H),7.41(dd,J =7.1,1.3Hz,1H),7.36(dd,J=9.1,2.2Hz,1H),6.47(d,J=5.0Hz,1H),6.29(d,J=3.9Hz, 1H), 4.10 (s, 3H), 4.04 (brs, 2H), 3.31 (q, J = 5.5Hz, 2H), 2.61 (brs, 2H), 2.34 (brs, 5H). 13 C NMR (151MHz, Chloroform-d) δ (ppm): 168.99, 166.21, 162.73, 158.40, 153.72, 152.60, 152.06, 134.63, 134.20, 128.89, 128. 60,127.66,126.34,123.79,121.99,121.84,118.43,116.02,108.32(2C),103.72,56.40,55.43,54.81,47.04,45.89,41.58. MS[M+H] + 471.20.

[0142] Example 22: 7-methoxy-4-((5-(morpholine-4-carbonyl)naphthalen-2-yl)oxy)quinoline-6-carboxamide (Compound 22)

[0143] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain a yellow solid, 0.06 g. 1H NMR (400MHz, Chloroform-d) δ (ppm): 9.33 (s, 1H), 8.67 (d, J = 5.3Hz, 1H), 8.00 (d, J = 9.1Hz, 1H), 7. 87(d,J=8.4Hz,2H),7.68(d,J=2.5Hz,1H),7.59(d,J=5.0Hz,1H),7.55(d,J=8.3Hz,1H),7.47(s,1H ),7.41(dd,J=9.0,2.4Hz,1H),6.52(d,J=5.1Hz,1H),6.47(s,1H),4.14(s,3H),4.09–3.92(m,1H) ,3.87(t,J=5.4Hz,2H),3.59(dddd,J=17.5,11.2,8.4,3.1Hz,2H),3.48(s,1H),3.38–3.24(m,2H). 13 C NMR (151MHz, Chloroform-d) δ (ppm): 169.12, 166.21, 162.77, 158.47, 153.59, 152.48, 152.09, 134.65, 133.87, 129.02, 128 .59,127.64,127.54,126.36,123.88,122.10,121.91,118.48,115.99,108.24,103.70,67.15,67.02,56.42,47.75,42.31. MS[M+H] + 458.17.

[0144] Example 23: 4-((6-((3,5-dimethoxyphenyl)carbamoyl)naphthalen-2-yl)oxy)-7-methoxyquinoline-6-carboxamide (Compound 23)

[0145] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain a yellow solid, 0.06 g. 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.60 (s, 1H), 8.74 (s, 1H), 8.71 (d, J = 5.2Hz, 1H), 8.35 (d, J = 9.2Hz, 1H), 8.11 (d, J = 8.2Hz, 1H), 7.9 6(d,J=2.6Hz,1H),7.91(s,1H),7.82–7.75(m,2H),7.68(dd,J=8.3,7.1Hz,1H),7.61(dd,J=9.2,2.6Hz,1H),7.57(s,1H),7.12(d,J =2.3Hz, 2H), 6.63 (d, J = 5.2Hz, 1H), 6.31 (t, J = 2.3Hz, 1H), 4.06 (s, 3H), 3.75 (s, 3H). 13 CNMR (151MHz, DMSO-d6) δ (ppm): 167.05, 165.74, 161.18, 160.40 (2C), 158.07, 153.23, 151.60, 151.55, 140.85, 134.64, 134.24, 129. 81,128.09,127.46,126.06,125.38,125.23,124.60,121.46,117.73,114.61,107.81,103.83,98.14(2C),95.70,56.14,55.05(2C). MS[M+H] + 524.17.

[0146] Example 24: 7-methoxy-4-((5-(naphthalen-2-ylcarbamoyl)naphthalen-2-yl)oxy)quinoline-6-carboxamide (Compound 24)

[0147] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain a yellow solid, 0.06 g. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 10.89 (s, 1H), 8.73 (d, J = 14.0Hz, 1H), 8.60 (s, 1H), 8.43 (d, J = 9.2Hz, 1H), 8.14 (d, J = 8.0Hz, 1H), 7.99 (s, 1H), 7 .91(dd,J=16.8,9.9Hz,5H),7.81(s,2H),7.72(s,1H),7.62(d,J=8.6Hz ,1H),7.57(s,1H),7.52(s,1H),7.46(s,1H),6.65(s,1H),4.06(s,3H). 13C NMR(151MHz,DMSO-d6)δ(ppm): 167.81,166.29,161.73,158.64,153.83,1 52.24,152.19,137.33,135.30,134.87,133.89,130.55,130.42,128.85, 128.71,128.09,127.99,127.96,126.98,126.69,125.98,125.79,125.33 ,125.20,122.09,121.00,118.31,116.61,115.21,108.43,104.44,56.70. MS[M+H] + 514.18.

[0148] Example 25: 7-methoxy-4-((5-((3-methoxyphenyl)(methyl)carbamoyl)naphthalen-2-yl)oxy)quinoline-6-carboxamide (Compound 25)

[0149] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain a yellow solid, 0.06 g. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.74 (s, 1H), 8.70 (d, J = 5.2Hz, 1H), 8.17 (d, J = 9.0Hz, 1H), 7.90 (s, 1H), 7.79 (d, J = 8.9Hz, 3H),7.55(d,J=10.7Hz,2H),7.38(s,2H),7.03(s,1H),6.77(s,2H),6.63(s,1H),6.52(s,1H),4.05(s,3H),3.51(s,6H). 13 C NMR (101MHz, DMSO-d6) δ (ppm): 169.40, 166.33, 161.75, 159.77, 158.65, 153.83, 152.27, 151.99, 145.33, 135.55, 134.31, 130.04, 128.92 ,128.81,127.93,126.38,126.18,125.80,125.56,125.22,121.79,1 19.35,118.17,115.23,113.08,108.51,104.29,56.74,55.54,37.48. MS[M+H] + 508.18.

[0150] Example 26: 7-methoxy-4-((5-(oxazol-2-ylcarbamoyl)naphthalen-2-yl)oxy)quinoline-6-carboxamide (Compound 26)

[0151] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain a yellow solid, 0.06 g. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 11.85 (s, 1H), 8.73 (s, 1H), 8.70 (d, J = 5.2Hz, 1H), 8.40 (d, J = 8.9Hz, 1H), 8.14 (d, J = 8.4Hz, 1H), 8.02– 7.95(m,2H),7.90(s,1H),7.87(s,1H),7.78(s,1H),7.70–7.60(m,2H),7.56(s,1H),7.21(s,1H),6.63(d,J=5.2Hz,1H),4.05(s,3H). 13 CNMR(151MHz,DMSO-d6)δ(ppm):167.00,166.31,161.65,158.61,153.87,153.52,152.27, 152.23,137.21,134.88,132.80,131.34,128.43,128.01,127.42,126.84 ,126.50,125.77,125.16,122.33,118.38,115.19,108.47,104.47,56.69. MS[M+H] + 455.14.

[0152] Example 27: 7-methoxy-4-((5-((2-methoxyphenyl)carbamoyl)naphthalen-2-yl)oxy)quinoline-6-carboxamide (Compound 27)

[0153] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain a yellow solid, 0.06 g. 1H NMR (400MHz, DMSO-d6) δ (ppm): 9.73 (s, 1H), 8.75 (s, 1H), 8.70 (d, J = 5.2Hz, 1H), 8.47 (d, J = 9 .2Hz,1H),8.10(d,J=8.3Hz,1H),7.95(d,J=2.6Hz,1H),7.90(d,J=6.8Hz,2H),7.84–7.77(m ,2H),7.67(t,J=7.6Hz,1H),7.61(dd,J=9.2,2.5Hz,1H),7.56(s,1H),7.27–7.18(m,1H),7. 12(d,J=8.2Hz,1H),7.02(t,J=7.5Hz,1H),6.62(d,J=5.2Hz,1H),4.05(s,3H),3.85(s,3H). 13 C NMR(151MHz,DMSO-d6)δ(ppm):167.53,166.28,161.79,158.64,153.83,152.19,152.14,152.10,135.24,134.85,130.32,128.88,128 .23,127.29,126.65,126.46,125.85,125.74,125.22,124.89,121.94,120.73,118.27,115.20,112.05,108.43,104.38,56.69,56.23. MS[M+H] + 494.18.

[0154] Example 28: 7-methoxy-4-((5-((5-methylisoxazol-3-yl)carbamoyl)naphthalen-2-yl)oxy)quinoline-6-carboxamide (Compound 28)

[0155] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain a yellow solid, 0.06 g. 1H NMR (400MHz, DMSO-d6) δ (ppm): 11.60 (s, 1H), 8.74 (s, 1H), 8.70 (d, J = 5.2Hz, 1H), 8 .37(d,J=9.2Hz,1H),8.16–8.09(m,1H),7.97(d,J=2.5Hz,1H),7.90(s,1H),7.83(d d,J=7.2,1.2Hz,1H),7.79(s,1H),7.66(dd,J=8.3,7.1Hz,1H),7.61(dd,J=9.3,2.5 Hz, 1H), 7.56 (s, 1H), 6.86 (s, 1H), 6.62 (d, J = 5.2Hz, 1H), 4.05 (s, 3H), 2.45 (s, 3H). 13 C NMR(151MHz,DMSO-d6)δ(ppm):170.12,167.45,166.29,161.68,158.83,158.61,153.85,152.24,152.21,134.83,133.38 ,131.07,128.51,128.05,126.70,126.51,125.76,125.18,122.22,118.37,115.19,108.48,104.43,97.29,56.69,12.63. MS[M+H] + 469.15.

[0156] Example 29: 7-methoxy-4-((5-((3-methylisoxazol-5-yl)carbamoyl)naphthalen-2-yl)oxy)quinoline-6-carboxamide (Compound 29)

[0157] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain a yellow solid, 0.06 g. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.25 (s, 1H), 8.75 (s, 1H), 8.72 (d, J = 5.2Hz, 1 H),8.40(d,J=9.2Hz,1H),8.17(d,J=8.3Hz,1H),7.98(d,J=2.5Hz,1H),7.90( d,J=6.0Hz,1H),7.77(s,1H),7.70(t,J=7.7Hz,1H),7.64(dd,J=9.3,2.6Hz,1 H), 7.58 (s, 1H), 6.65 (d, J = 5.3Hz, 1H), 6.45 (s, 1H), 4.07 (s, 3H), 2.28 (s, 3H). 13C NMR(151MHz,DMSO-d6)δ(ppm):165.72, 165.07,161.16,161.06,160.66,158.05,153.29,151.76,151.67,134.31,131.95,130.91,127.84,12 7.46,126.44,125.92,125.22,124.59,121.83,117.82,114.63,107.91,103.93,89.61,56.13,11.32. MS[M+H] + 469.15.

[0158] Example 30: 7-methoxy-4-((5-(3-(3-methoxyphenyl)ureido)naphthalen-2-yl)oxy)quinoline-6-carboxamide (Compound 30)

[0159] The method was similar to that of Example 1. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 20:1) to obtain a yellow solid, 0.06 g. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.10 (s, 1H), 8.87 (s, 1H), 8.78 (s, 1H), 8.71 (d, J = 5.2Hz, 1H), 8.31 (d ,J=9.2Hz,1H),8.05(dd,J=7.6,1.1Hz,1H),7.92–7.86(m,2H),7.78(s,1H),7.69(d,J=8.2Hz,1H),7. 62(dd,J=9.2,2.5Hz,1H),7.59–7.53(m,2H),7.27(t,J=2.2Hz,1H),7.23(t,J=8.1Hz,1H),7.01(dt,J =8.1, 1.0Hz, 1H), 6.64 (d, J = 5.3Hz, 1H), 6.60 (ddd, J = 8.3, 2.5, 0.9Hz, 1H), 4.08 (s, 3H), 3.77 (s, 3H). 13 C NMR(151MHz,DMSO-d6)δ(ppm):165.75,161.32,159.69,158.05,153.29,152.78,151.63,151.39,140.88,134.81,134.61,129.57,127 .06,125.10,124.72,124.49,123.89,122.67,120.12,117.92,117.37,114.64,110.41,107.86,107.29,103.84,103.68,56.13,54.86. MS[M+H]+ 509.16.

[0160] Example 31: 4-((6-((cyclopropylmethyl)carbamoyl)naphthalen-2-yl)oxy)-7-methoxyquinoline-6-carboxamide (Compound 31)

[0161] 31.1 6-((6-Carbamoyl-7-methoxyquinolin-4-yl)oxy)-2-naphthoic acid (10)

[0162] 6-Hydroxy-2-naphthoic acid (1.91 g, 10.17 mmol) was dissolved in dimethyl sulfoxide (35 mL). Cesium carbonate (8.26 g, 25.42 mmol) was added and stirred at room temperature for 10 minutes. Compound 5 (2.00 g, 8.5 mmol) was then added and heated to 95°C for 10 hours. TLC confirmed the complete reaction of compound 5. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The aqueous layer was collected and the pH was adjusted to 6.5 with 1N HCl. A large amount of solid was produced. The filter cake was filtered and washed three times with water. The crude product was air-dried to obtain the desired product, which was recrystallized from MeOH to obtain the desired product as an orange-yellow solid (2.91 g, 88.5% yield). MS 1 H NMR (400MHz, DMSO-d6) δ (ppm): 13.13 (s, 1H), 8.69–8.62 (m, 3H), 8.27 (d, J = 8.9Hz, 1H), 7.98 (s, 2H), 7.86 ( t,J=3.1Hz,2H),7.74(s,1H),7.55(dd,J=8.8,2.3Hz,1H),7.51(s,1H),6.61(d,J=5.2Hz,1H),4.00(s,3H). [M+H] + 388.20.

[0163] 31.2 4-((6-((cyclopropylmethyl)carbamoyl)naphthalen-2-yl)oxy)-7-methoxyquinoline-6-carboxamide

[0164] Compound 10 (0.30 g, 0.77 mmol) was dissolved in dichloromethane (10 mL), and HATU (0.59 g, 1.55 mmol) and DIPEA (0.25 g, 1.93 mmol) were added. After reacting at room temperature for 30 minutes, cyclopropylmethylamine (0.07 g, 0.93 mmol) was added and the reaction continued at room temperature for 4 hours. TLC confirmed the complete reaction of compound 10. Solids were produced during the reaction. The filter cake was filtered, air-dried, and purified by column chromatography (MeOH / CH2Cl2, 1 / 80 to 1 / 40) to obtain the desired product as a white solid, 0.11 g, in a 32.1% yield. 1H NMR(400MHz,DMSO-d6)δ(ppm):8.75(t,J=5.7Hz,1H),8.68(s,1H),8.66(d,J=5.2Hz,1H),8 .51(d,J=1.2Hz,1H),8.17(d,J=9.0Hz,1H),7.96(d,J=1.2Hz,2H),7.85(dd,J=5.3,2.3Hz,2 H),7.74(d,J=2.4Hz,1H),7.54(d,J=2.4Hz,1H),7.52(d,J=2.2Hz,1H),6.61(d,J=5.2Hz,1H ),4.01(s,3H),3.22–3.12(m,2H),1.10–0.99(m,1H),0.47–0.38(m,2H),0.27–0.19(m,2H). 13 C NMR (151MHz, DMSO-d6) δ (ppm): 166.43, 166.27, 161.72, 158.67, 153.77, 153.25, 152.06, 135.61, 132.39, 132.26, 130. 57,128.01,127.94,125.82,125.66,125.21,121.71,117.51,115.23,108.32,104.61,56.70,44.20,11.52,3.87(2C). MS[M+H] + 442.1760.

[0165] Example 32: 7-methoxy-4-((6-((5-methylthiazol-2-yl)carbamoyl)naphthalen-2-yl)oxy)quinoline-6-carboxamide (Compound 32)

[0166] The method was similar to that of Example 31. The product was separated by column chromatography (MeOH / CH2Cl2, 1 / 80 to 1 / 40) to obtain a yellow solid, 0.11 g. 1H NMR (400MHz, DMSO-d6) δ (ppm): 12.60 (s, 1H), 8.80 (d, J = 1.8Hz, 1H), 8.68 (s, 1H), 8.66 (d ,J=5.2Hz,1H),8.21(d,J=9.0Hz,1H),8.12(dd,J=8.6,1.8Hz,1H),8.01(d,J=8.7Hz,1H), 7.88(d,J=2.4Hz,1H),7.86–7.84(m,1H),7.74(s,1H),7.57(dd,J=8.9,2.4Hz,1H),7.52 (s, 1H), 7.22 (q, J = 1.2Hz, 1H), 6.63 (d, J = 5.3Hz, 1H), 4.01 (s, 3H), 2.36 (d, J = 1.2Hz, 3H). 13 C NMR(151MHz,DMSO-d6)δ(ppm):165.71,164.79,160.91,158.06,153.36,153.31,151.69(2C),135.69,132.08,129.8 2,129.42,129.02,127.75,126.39,125.24,124.62,121.42,116.95(2C),114.69,107.92(2C),104.21,56.13,11.06. MS[M+H] + 485.12.

[0167] Example 33: 7-methoxy-4-((6-((3-methoxyphenyl)carbamoyl)naphthalen-2-yl)oxy)quinoline-6-carboxamide (Compound 33)

[0168] The method was similar to that of Example 31. The product was separated by column chromatography (MeOH / CH2Cl2, 1 / 80 to 1 / 40) to obtain a yellow solid, 0.11 g. 1H NMR (400MHz, DMSO-d6) δ (ppm): 10.39 (s, 1H), 8.71–8.67 (m, 2H), 8.64 (d, J = 1.4Hz, 1H), 8.24 ( d,J=8.9Hz,1H),8.04(d,J=1.7Hz,2H),7.88(d,J=2.5Hz,1H),7.85(s,1H),7.72(s,1H),7.57( dd,J=8.9,2.5Hz,1H),7.53(s,1H),7.50(t,J=2.2Hz,1H),7.41(dd,J=8.1,1.8Hz,1H),7.25( t, J=8.1Hz, 1H), 6.68 (dd, J=9.0, 2.5Hz, 1H), 6.65 (d, J=5.2Hz, 1H), 4.02 (s, 3H), 3.75 (s, 3H). 13 C NMR(151MHz,DMSO-d6)δ(ppm):165.73,165.36,160.96,159.41,158.07,153.32,153.05,151.71,140.34,135.31,132.05,131.84,129 .89,129.37,127.98,127.64,125.33,125.23,124.65,121.31,116.91,114.73,112.50,109.15,107.93,105.98,104.20,56.13,54.95. MS[M+H] + 494.16.

[0169] Example 34: 4-((6-((4-ethoxyphenyl)carbamoyl)naphthalen-2-yl)oxy)-7-methoxyquinoline-6-carboxamide (Compound 34)

[0170] The method was similar to that of Example 31. The product was separated by column chromatography (MeOH / CH2Cl2, 1 / 80 to 1 / 40) to obtain a yellow solid, 0.11 g. 1H NMR(400MHz,DMSO-d6)δ(ppm):10.34(s,1H),8.75–8.69(m,2H),8.66(s,1H), 8.27(d,J=9.0Hz,1H),8.12–8.02(m,2H),7.92(d,J=2.5Hz,1H),7.89(s,1H),7 .78(s,1H),7.75–7.70(m,2H),7.60(dd,J=8.9,2.5Hz,1H),7.57(s,1H),6.98 –6.91(m,2H),6.68(d,J=5.2Hz,1H),4.08–3.98(m,3H),1.34(t,J=7.0Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ(ppm):165.70,164.85,161.12,158.13,154.78,153.19,152.89,151.48,135.19,132.20,132.09,131.80,12 9.94,127.80,127.58,125.31,124.65,121.89(2C),121.25,116.95,114.69,114.21(2C),107.74(2C),104.14,63.00,56.14,14.63. MS[M+H] + 508.18.

[0171] Example 35: 7-methoxy-4-((6-(thiazol-2-ylcarbamoyl)naphthalen-2-yl)oxy)quinoline-6-carboxamide (Compound 35)

[0172] The method was similar to that of Example 31. The product was separated by column chromatography (MeOH / CH2Cl2, 1 / 80 to 1 / 40) to obtain a yellow solid, 0.11 g. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.79 (s, 1H), 8.88 (d, J = 1.8Hz, 1H), 8.72 (d, J = 6.7Hz, 2H), 8.27 (d, J = 8.9Hz, 1H), 8.19 (dd, J = 8.6, 1.8Hz, 1H), 8.08 (d, J =8.7Hz,1H),7.93(d,J=2.5Hz,1H),7.90(s,1H),7.78(s,1H),7.65–7.59(m, 2H), 7.57 (s, 1H), 7.32 (d, J = 3.6Hz, 1H), 6.69 (d, J = 5.2Hz, 1H), 4.06 (s, 3H). 13C NMR(151MHz,DMSO-d6)δ(ppm):165.72,164.94,160.90,158.76,158.06,153.42,153.32,151.70,135.74,132.11,129.81 ,129.26,129.09,127.80,125.24,125.21,124.62,121.45,116.95,114.70,113.81,107.93(2C),104.23,56.14.MS[M+H] + 471.11.

[0173] Example 36: 4-((6-(Isoxazolyl-3-ylcarbamoyl)naphthalen-2-yl)oxy)-7-methoxyquinoline-6-carboxamide (Compound 36)

[0174] The method was similar to that of Example 31. The product was separated by column chromatography (MeOH / CH2Cl2, 1 / 80 to 1 / 40) to obtain a yellow solid, 0.11 g. 1 H NMR(400MHz,DMSO-d6)δ(ppm):11.67(s,1H),8.90(s,1H),8.80(s,1H),8.7 4(d,J=4.9Hz,2H),8.27(d,J=8.9Hz,1H),8.12(d,J=8.8Hz,1H),8.07(d,J= 8.6Hz,1H),7.94(d,J=2.4Hz,1H),7.91(s,1H),7.80(s,1H),7.63(dd,J=8. 8, 2.4Hz, 1H), 7.58 (s, 1H), 7.13 (s, 1H), 6.71 (d, J = 5.1Hz, 1H), 4.06 (s, 3H). 13 C NMR(151MHz,DMSO-d6)δ(ppm):171.96,165.72,165.25,160.94,160.08,158.07,153.34,153.30,151.65,135.66,13 2.05,130.16,129.78,128.90,127.74,125.27,124.62,121.42,116.93,114.70,107.88(2C),104.23,99.74,56.14. MS[M+H] + 455.13.

[0175] Example 37: 7-methoxy-4-((1-((5-methylisoxazol-3-yl)carbamoyl)-1H-indol-5-yl)oxy)quinoline-6-carboxamide (Compound 37)

[0176] 37.1 4-((1H-Indol-5-yl)oxy)-7-methoxyquinoline-6-carboxamide (13)

[0177] 5-Hydroxyindole (0.29 g, 2.11 mmol) was dissolved in dimethyl sulfoxide (7 mL), and cesium carbonate (2.07 g, 6.36 mmol) was added. After reacting at room temperature for 30 min, 4-chloro-7-methoxyquinoline-6-carboxamide (0.5 g, 2.11 mmol) was added. The temperature was raised to 90°C and the reaction was continued for 3 h. TLC confirmed the complete reaction of the starting material. The mixture was cooled to room temperature and 100 mL of water was added to precipitate a large amount of solid. A brown solid was filtered and dried. The brown solid was purified by silica gel column chromatography (MeOH / CH2Cl2 / Et3N = 80 / 1 / 0.01) to obtain the desired product as a yellow solid, 0.35 g, in a 49.0% yield. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 11.32 (s, 1H), 8.76 (s, 1H), 8.60 (d, J = 5.3Hz, 1H), 7.82 (d, J = 50.0Hz, 1H), 7.53 (dt, J = 8.7, 0.7Hz, 1H) ,7.51(s,1H),7.49–7.43(m,2H),7.00(dd,J=8.7,2.4Hz,1H),6.48(ddd,J=2.9,1.9,0.9Hz,1H),6.39(d,J=5.3Hz,1H),4.04(s,3H). MS[M+H] + 334.10.

[0178] 37.2 7-Methoxy-4-((1-((5-methylisoxazol-3-yl)carbamoyl)-1H-indol-5-yl)oxy)quinoline-6-carboxamide

[0179] Compound 13 (0.20 g, 0.60 mmol) was dissolved in N,N-dimethylformamide (5 mL). KOH (0.05 g, 0.90 mmol) was added under ice-cooling. After 30 min of reaction, compound 14 (0.20 g, 0.90 mmol) was added and the reaction was continued at room temperature for 4 h. TLC confirmed the completion of the reaction of compound 13. The reaction solution was diluted with ethyl acetate and extracted with water. The mixture was washed once with saturated aqueous NH4Cl and once with saturated aqueous NaCl. The organic layer was collected, dried over anhydrous Na2SO4, and concentrated to obtain the crude product. The crude product was slurried with MeOH / CH2Cl2 to obtain the title compound as a white solid, 0.12 g, in a 42.0% yield. 1H NMR (400MHz, DMSO-d6) δ (ppm): 11.31 (s, 1H), 8.75 (s, 1H), 8.66 (d, J = 5.4Hz, 1H), 8.39 (d, J = 8.9Hz, 1H), 8.22 (d, J = 3.8Hz, 1H), 7.94–7.73 (m, 2H), 7 .59(d,J=2.5Hz,1H),7.54(s,1H),7.28(dd,J=9.0,2.5Hz,1H),6.81(d,J= 3.7Hz, 1H), 6.73 (s, 1H), 6.49 (d, J = 5.3Hz, 1H), 4.05 (s, 3H), 2.45 (s, 3H). 13 C NMR(151MHz,DMSO-d6)δ(ppm):169.69,165.69,162.55,158.43,158.19,152.84,150.86,148.94(2C),133.20 ,131.05,126.88,125.14,124.77,117.42,116.80,114.45,112.76,107.27(2C),102.97,96.76,56.13,12.06. MS[M+H] + 458.13.

[0180] Example 38: N-Benzyl-N'-[4-[(6-formamido-7-methoxy-4-quinolyl)oxy]phenyl]-1,1-cyclopropanedicarboxamide (Compound 38)

[0181] 38.1 N-Benzyl-N'-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide (20)

[0182] Place 1.0 g (7.69 mmol) of 1,1-cyclopropyldicarboxylic acid, 4.40 g of EDCI (23.07 mmol), 3.11 g of Hobt (23.07 mmol), and DMF (15.0 mL) in an eggplant-shaped flask under nitrogen atmosphere and stir in an ice bath. After 1 hour, the reaction is complete as monitored by TLC. Benzylamine is then slowly added to the flask, followed by a 3-hour ice bath. The reaction is complete as monitored by TLC. Then, p-hydroxyaniline is slowly added to the flask, the ice bath removed, and the reaction is allowed to react at room temperature for 5 hours. The reaction is complete as monitored by TLC. Add 50.0 mL of distilled water to the reaction mixture, stir for 30 minutes, and filter. Wash the filter cake with distilled water (10.0 mL x 3). Vacuum dry to obtain a white solid, which is then separated by column chromatography (dichloromethane-methanol, 60:1 volume ratio) to yield 0.59 g of a white solid. 1H-NMR (400MHz, DMSO-d6) δ (ppm): 9.52 (s, 1H), 9.34 (s, 1H), 9.21 (s, 1H), 7.65 (dd, J = 8.6, 1.0Hz, 2H), 7.44~7.3 7(m,2H),7.33~7.24(m,2H),7.05(t,J=7.3Hz,1H),6.72~6.64(m,2H),2.63(t,J=7.9Hz,4H),1.91~1.71(m,2H). ESI-MS m / z:311.1[M+H] + ,333.1[M+Na] + ,643.2[2M+Na] + .

[0183] 38.2 N-Benzyl-N'-[4-[(6-formamido-7-methoxy-4-quinolyl)oxy]phenyl]-1,1-cyclopropanedicarboxamide

[0184] N-Benzyl-N'-(4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide (20) (0.55 g, 1.78 mmol), DMF (5.0 mL), and cesium carbonate (0.62 g, 1.90 mmol) were added to an eggplant-shaped flask (under nitrogen protection) and stirred at room temperature for 10 min. 4-Chloro-7-methoxyquinoline-6-carboxamide (5) (0.3 g, 1.27 mmol) was then added to the flask and the temperature was slowly raised to 75°C. After 24 h of constant temperature reaction, TLC monitoring indicated that the reaction was complete. The reaction solution was cooled to room temperature and 20.0 ml of distilled water was added. A large amount of solid precipitated. The filter cake was filtered, washed with a small amount of water, and vacuum dried to obtain a brown solid. Column chromatography (dichloromethane-methanol, volume ratio 40:1) yielded 0.09 g of a white solid. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 9.84 (s, 1H), 9.65 (s, 1H), 8.69 (s, 1H), 8.66 (d, J = 5.3 Hz,1H),7.88(s,1H),7.87~7.83(m,2H),7.77(s,1H),7.70(d,J=1.0Hz,1H),7.68(d,J=0 .7Hz,1H),7.52(s,1H),7.33(s,1H),7.32(s,1H),7.30~7.25(m,2H),7.11~7.04(m,1H), 6.51 (d, J = 5.4Hz, 1H), 4.04 (s, 3H), 2.69 (t, J = 7.8Hz, 4H), 1.86 (dt, J = 15.5, 7.8Hz, 2H). ESI-MS m / z:511.2[M+H] + ,533.1[M+Na]+ .

[0185] Example 39: N-[4-[(6-formamido-7-methoxy-4-quinolyl)oxy]phenyl]-N'-(4-methylphenyl)-1,1-cyclopropanedicarboxamide (Compound 39)

[0186] The method was similar to that of Example 38. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 40:1) to obtain 0.09 g of a white solid. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.21 (s, 1H), 9.95 (s, 1H), 8.69 (s, 1H), 8.66 (d, J = 5.2Hz, 1H), 7.87 (s, 1H), 7.77 (t, J = 7.3Hz, 3H), 7.5 2(s,2H),7.49(s,1H),7.29~7.24(m,2H),7.12(d,J=8.2Hz,2H),6.47(d,J=5.3Hz,1H),4.03(s,3H),3.26(s,3H),2.48(t,J=7.9Hz,4H). ESI-MS m / z:511.2[M+H] + ,533.1[M+Na] + .

[0187] Example 40: N-[4-[(6-formamido-7-methoxy-4-quinolyl)oxy]phenyl]-N'-(3,5-dimethylphenyl)-1,1-cyclopropanedicarboxamide (Compound 40)

[0188] The method was similar to that of Example 38. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 40:1) to obtain 0.09 g of a white solid. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 9.52 (s, 1H), 9.34 (s, 1H), 9.21 (s, 1H), 7.65 (dd, J=8.6, 1.0Hz, 2 H),7.44~7.37(m,2H),7.33~7.24(m,2H),7.05(t,J=7.3Hz,1H),3.35(s,6H)2.63(t,J=7.9Hz,4H). ESI-MS m / z:325.1[M+H] + ,347.1[M+Na] + .

[0189] Example 41: N-phenyl-N'-[4-[(6-formamido-7-methoxy-4-quinolyl)oxy]phenyl]-1,1-cyclopropanedicarboxamide (Compound 41)

[0190] The method was similar to that of Example 38. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 40:1) to obtain 0.09 g of a white solid. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.19 (s, 1H), 10.07 (s, 1H), 8.69 (s, 1H), 8.67 (d, J = 5.1Hz, 1H), 7.88 (s, 1H), 7.80 (s, 1H), 7.78 (s ,2H),7.63(d,J=8.3Hz,2H),7.52(s,1H),7.37~7.21(m,4H),7.07(t,J=7.4Hz,1H),6.48(d,J=5.2Hz,1H),4.04(s,3H),1.48(s,4H). ESI-MS m / z:497.1[M+H] + ,519.1[M+Na] + .

[0191] Example 42: N-[4-[(6-formamido-7-methoxy-4-quinolyl)oxy]phenyl]-N'-(3,4-dimethylphenyl)-1,1-cyclopropanedicarboxamide (Compound 42)

[0192] The method was similar to that of Example 38. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 40:1) to obtain 0.09 g of a white solid. 1 H-NMR(400MHz,DMSO-d6)δ(ppm):10.20(s,1H),9.91(s,1H),8.68(s,1H),8.66(d ,J=5.3Hz,1H),7.87(s,1H),7.79(s,1H),7.77(s,2H),7.52(s,1H),7.39(s,1H), 7.35(d,J=8.0Hz,1H),7.29~7.27(m,1H),7.25(t,J=2.7Hz,1H),7.06(d,J=8.3Hz ,1H),6.47(d,J=5.2Hz,1H),4.03(s,3H),2.19(s,3H),2.17(s,3H),1.48(s,4H). ESI-MS m / z:524.1[M+H] + ,537.1[M+Na] + .

[0193] Example 43: N-[4-[(6-formamido-7-methoxy-4-quinolyl)oxy]phenyl]-N'-(4-methoxyphenyl)-1,1-cyclopropanedicarboxamide (Compound 43)

[0194] The method was similar to that of Example 38. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 40:1) to obtain 0.09 g of a white solid. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.24 (s, 1H), 9.83 (s, 1H), 8.65 (s, 1H), 8.62 (d, J = 5.2Hz, 1H), 7.84 (s, 1H), 7.74 (d, J = 8.9Hz, 3H), 7.48 (t, J = 4.5Hz, 3H), 7.28 ~ 7.17 (m, 2H), 6.90 ~ 6.78 (m, 2H), 6.43 (d, J = 5.3Hz, 1H), 3.99 (s, 3H), 3.68 (s, 3H), 1.43 (s, 4H). ESI-MS m / z:527.1[M+H] + ,549.1[M+Na] + , 1053.3[2M+H] + .

[0195] Example 44: 7-Methoxy-4-(4-(3-methylbenzoyl)phenoxy)quinoline-6-carboxamide (Compound 44)

[0196] 44.1 Synthesis of N-(4-hydroxyphenyl)-3-methylbenzamide (23)

[0197] 1.0 g (7.30 mmol) of 4-aminobenzoic acid (22), 1.67 g of EDCI (8.76 mmol), 1.17 g of Hobt (8.76 mmol), and DMF (10.0 mL) were placed in an eggplant-shaped flask under nitrogen protection and stirred in an ice bath. After 1 h, the reaction was complete as monitored by TLC. p-Aminophenol was then added to the flask, the ice bath was removed, and the reaction was allowed to proceed at room temperature for 5 h. The reaction was complete as monitored by TLC. 50.0 mL of distilled water was added to the reaction solution and stirred for 30 min. The mixture was filtered, and the filter cake was washed with distilled water (10.0 ml x 3) and dried in vacuo to obtain 0.87 g of a white solid. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 9.92 (s, 1H), 9.22 (s, 1H), 7.84 (d, J = 8.2Hz, 2H), 7.55~7.49 (m, 2H), 7.31 (d, J=8.0Hz, 2H), 6.77~6.69 (m, 2H), 2.38 (s, 3H). ESI-MS m / z:228.1[M+H] + ,250.1[M+Na] + .

[0198] 44.2 7-Methoxy-4-(4-(3-methylbenzoyl)phenoxy)quinoline-6-carboxamide

[0199] 0.30 g (1.32 mmol) of N-(4-hydroxyphenyl)-3-methylbenzamide (23), DMF (5.0 mL), and 0.56 g (1.71 mmol) of cesium carbonate were added to an eggplant-shaped flask (under nitrogen protection) and stirred at room temperature for 10 min. 4-Chloro-7-methoxyquinoline-6-carboxamide (5) (0.3 g, 1.27 mmol) was then added to the flask and the temperature was slowly raised to 75°C. After 24 h of constant temperature reaction, TLC monitoring indicated that the reaction was complete. The reaction solution was cooled to room temperature and 20.0 mL of distilled water was added, resulting in the precipitation of a large amount of solid. The filter cake was washed with a small amount of water and vacuum dried to obtain a brown solid. Column chromatography (dichloromethane-methanol, volume ratio 40:1) yielded 0.09 g of a white solid. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.36 (s, 1H), 8.70 (s, 1H), 8.67 (d, J = 5.3Hz, 1H), 7.97 ~ 7.92 (m, 2H), 7.90 (d, J = 8.2Hz, 3H), 7.78 (s, 1H), 7.53 (s, 1H), 7.36 (d, J = 8.4Hz, 2H), 7.34 ~ 7.28 (m, 2H), 6.51 (d, J = 5.2Hz, 1H), 4.04 (s, 3H), 2.40 (s, 3H). ESI-MS m / z:428.1[M+H] + ,450.1[M+Na] + .

[0200] Example 45: 7-Methoxy-4-(4-(4-methylbenzoyl)phenoxy)quinoline-6-carboxamide (Compound 45)

[0201] The method was similar to that of Example 44. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 40:1) to obtain 0.09 g of a white solid. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.38 (s, 1H), 8.71 (s, 1H), 8.68 (d, J = 5.2Hz, 1H), 7.96 ~ 7.93 (m, 2H), 7.86 (s, 1H), 7.79 (s, 1H), 7.77 (dd, J =8.2,2.4Hz,1H),7.74(s,1H),7.53(s,1H),7.43(dd,J=4.6,2.3Hz,2H),7.33~7.30(m,2H),6.52(d,J=5.2Hz,1H),4.04(s,3H),2.42(s,3H). ESI-MS m / z:428.1[M+H] + ,450.1[M+Na]+ .

[0202] Example 46: 7-Methoxy-4-(4-(4-nitrobenzoyl)phenoxy)quinoline-6-carboxamide (Compound 46)

[0203] The method was similar to that of Example 44. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 40:1) to obtain 0.09 g of a white solid. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.77 (s, 1H), 8.72–8.67 (m, 2H), 8.41 (d, J = 9.5Hz, 2H), 8.22 (d, J = 7.9Hz, 2H), 7.9 5(d,J=9.0Hz,2H),7.90(s,1H),7.79(s,1H),7.53(s,1H),7.36(d,J=8.2Hz,2H),6.52(d,J=5.0Hz,1H),4.04(s,3H). ESI-MS m / z:459.1[M+H] + ,481.1[M+Na] + .

[0204] Example 47: 7-Methoxy-4-(4-(4-chlorobenzoyl)phenoxy)quinoline-6-carboxamide (Compound 47)

[0205] The method was similar to that of Example 44. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 40:1) to obtain 0.09 g of a white solid. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.51 (s, 1H), 8.70 (s, 1H), 8.68 (d, J = 5.3Hz, 1H), 8.04 ~ 7.99 (m, 2H), 7.96 ~ 7.92 (m, 2H), 7.89 (s, 1H), 7 .78(s,1H),7.67~7.65(m,1H),7.64~7.62(m,1H),7.53(s,1H),7.36~7.33(m,1H),7.33~7.30(m,1H),6.51(d,J=5.2Hz,1H),4.04(s,3H). ESI-MS m / z:448.1[M+H] + ,470.0[M+Na] + .

[0206] Example 48: 7-Methoxy-4-(4-(4-chloro-3-fluorobenzoyl)phenoxy)quinoline-6-carboxamide (Compound 48)

[0207] The method was similar to that of Example 44. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 40:1) to obtain 0.09 g of a white solid. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.54 (s, 1H), 8.70 (s, 1H), 8.68 (d, J = 5.3Hz, 1H) ,8.23(dd,J=7.1,2.3Hz,1H),8.02(ddd,J=8.7,4.8,2.3Hz,1H),7.93(d,J=2.2Hz,1 H),7.92(d,J=2.2Hz,1H),7.89(s,1H),7.78(s,1H),7.67~7.60(m,1H),7.53(s,1H ), 7.35 (d, J = 2.2Hz, 1H), 7.33 (d, J = 2.2Hz, 1H), 6.52 (d, J = 5.2Hz, 1H), 4.04 (s, 3H). ESI-MS m / z:465.1[M+H] + ,487.1[M+Na] + .

[0208] Example 49: 7-Methoxy-4-(4-(4-fluoro-3-bromobenzoyl)phenoxy)quinoline-6-carboxamide (Compound 49)

[0209] The method was similar to that of Example 44. The product was separated by column chromatography (dichloromethane-methanol, volume ratio 40:1) to obtain 0.09 g of a white solid. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 10.49 (s, 1H), 10.43 (d, J = 8.8Hz, 1H), 8.6 6(s,1H),8.64(d,J=5.2Hz,1H),8.30(dd,J=6.6,2.2Hz,1H),7.90(d,J=4.2H z,1H),7.88(d,J=4.2Hz,1H),7.84(s,1H),7.80(d,J=9.0Hz,1H),7.73(s,1H ), 7.49 (s, 1H), 7.31 ~ 7.27 (m, 2H), 6.48 (dt, J = 5.2, 1.1Hz, 1H), 4.00 (s, 3H). ESI-MS m / z:511.0[M+H] + ,433.0[M+Na] + .

[0210] Example 50: Inhibitory effect of compounds on VEGFR-2 kinase activity

[0211] Determination of the inhibitory activity of compounds against VEGFR tyrosine kinase

[0212] 1. Experimental materials and instruments

[0213] 2. Experimental steps

[0214] 1) Preparation of compound stock solution

[0215] All compounds were dissolved in DMSO and prepared into stock solutions of appropriate concentrations. Compounds used within three months were stored in a desiccator at room temperature, while others could be stored long-term at -20°C.

[0216] 2) Preparation of working solution

[0217] The compound stock solution was diluted with DMSO and serially diluted 3-fold, 12 times to obtain 12 concentration points. The starting concentration was determined based on the initial screening activity of the compound, starting at 0.05 mM or 1 mM.

[0218] 3) Prepare 1X kinase buffer

[0219] 1X kinase buffer was prepared by adding 4 volumes of distilled water to 1 volume of 5X enzymatic buffer (the reagent in the HTRF KinEASE-TK kit).

[0220] The prepared 1X kinase buffer contains: 5mM MgCl2; 1mM DTT; 1mM MnCl2;

[0221] 4) Titration of VEGFR-2 kinase (ATP, TK-substrate-biotin, both reagents in the HTRF KinEASE-TK kit)

[0222] Prepare 5X VEGFR-2 at 5 ng / μL using 1X kinase buffer.

[0223] 5X VEGFR-2 at 5 ng / μL was diluted 2-fold using 1X kinase buffer, and 8 concentration points were obtained by diluting 8 times.

[0224] Serial dilutions of VEGFR-2 were added to a 384-well plate (784075, Greiner) at 2 μL / well. 4 μL of 1X kinase buffer was then added to each well, and the plate was centrifuged at 1000 g for 30 seconds.

[0225] Prepare 5 μM 5X TK-substrate-biotin and 500 μM 5X ATP in 1X kinase buffer. Add 2 μL of 5X TK-substrate-biotin and 2 μL of 5X ATP to each well of the 384-well assay plate.

[0226] In the above 384 experimental plates, the starting concentration of kinase VEGFR-2 was 1 ng / μL, the concentrations of TK-substrate-biotin and ATP were 1 μM and 100 μM, respectively. The plates were centrifuged at 1000 g for 30 seconds, sealed, and placed at room temperature for 40 minutes.

[0227] Prepare 250 nM of 4X Sa-XL 665 (a reagent in the HTRF KinEASE-TK kit) using HTRF detection buffer (a reagent in the HTRF KinEASE-TK kit). Add 5 μL of Sa-XL 665 and 5 μL of TK-antibody-Cryptate (a reagent in the HTRF KinEASE-TK kit) to each well of the 384-well assay plate. Centrifuge at 1000 g for 30 seconds and incubate at room temperature for 60 minutes.

[0228] Fluorescence values ​​were read using an Envision 2104 plate reader. Excitation: 320 nm; Emission: 620 nm (Cryptate) and 665 nm (XL665).

[0229] 5) Determination of ATP Km value

[0230] Prepare 0.156 ng / μL of 5X VEGFR-2 with 1X kinase buffer. Add 2 μL of 5X VEGFR-2 to each well of the 384 assay plate. Add another 4 μL of 1X kinase buffer to each well of the 384 assay plate and centrifuge at 1000 g for 30 seconds.

[0231] Prepare 5 μM 5X TK-substrate-biotin in 1X kinase buffer. Perform a 3-fold serial dilution of ATP in 1X kinase buffer, starting at 300 μM. Dilute ATP 12 times to obtain 12 concentration points.

[0232] Add 2 μL of 5X TK-substrate-biotin and 2 μL of gradient diluted ATP to each well of the aforementioned 384 experimental plate, centrifuge at 1000 g for 30 seconds, seal the plate, and let it stand at room temperature for 40 minutes.

[0233] Prepare 250 nM of 4X Sa-XL 665 using HTRF detection buffer. Add 5 μL of 4X Sa-XL 665 and 5 μL of TK-antibody-Cryptate (from the HTRF KinEASE-TK kit) to each well of the 384-well assay plate. Centrifuge at 1000 g for 30 seconds and incubate at room temperature for 60 minutes.

[0234] Fluorescence values ​​were read using an Envision 2104 plate reader. Excitation: 320 nm; Emission: 620 nm (Cryptate) and 665 nm (XL665).

[0235] 6) Screening of compounds

[0236] Use an Echo550 to transfer 10 nL of the compound dilution prepared in step 2) to a 384-well plate (784075, Greiner). Centrifuge at 1000 g for 1 min, and seal the plate. Prepare 0.156 ng / μL of 5X VEGFR-2 in 1X kinase buffer. Add 5X VEGFR-2 to the 384-well plate above at 2 μL / well. Centrifuge at 1000 g for 30 s and incubate at room temperature for 10 min. Prepare 5 μM 5X TK-substrate-biotin and 500 μM 5X ATP in 1X kinase buffer. Add 2 μL of each to each well of the 384-well plate above at 2 μL / well. Centrifuge at 1000 g for 30 s, seal the plate, and incubate at room temperature for 40 min.

[0237] Prepare 250 nM of 4X Sa-XL 665 using HTRF detection buffer. Add 5 μL of 4X Sa-XL 665 and 5 μL of TK-antibody-Cryptate (from the HTRF KinEASE-TK kit) to each well of the 384-well assay plate. Centrifuge at 1000 g for 30 seconds and incubate at room temperature for 60 minutes.

[0238] Fluorescence values ​​were read using an Envision 2104 plate reader. Excitation: 320 nm; Emission: 620 nm (Cryptate) and 665 nm (XL665).

[0239] 7) Data Analysis

[0240] A. Calculate the 665 / 620 ratio for each well;

[0241] B. Calculate the inhibition percentage:

[0242] Inhibition percentage = 1-100% × (Signal cmpd -Signal Ave_PC ) / (Signal Ave_VC -Signal Ave_PC ).

[0243] Among them, Signal cmpd Indicates the 665 / 620 ratio of the experimental well; Signal Ave_PC Indicates the 665 / 620 ratio of the blank well (without cells and compounds); Signal Ave_VC represents the 665 / 620 ratio of the control well (without compound);

[0244] C. Plotting the curve and calculating the IC of the compound 50 ;

[0245] The relationship between the percent inhibition and the logarithm of the compound concentration was fitted using Graphpad 5.0 by the nonlinear regression (dose response - variable slope) method.

[0246] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*Hill Slope))

[0247] Y is the inhibition percentage, X is the logarithm of the compound concentration, Bottom is the maximum inhibition percentage, Top is the minimum inhibition percentage, and HillSlope is the slope coefficient.

[0248] 8) Test results

[0249] The results of HTRF experiments (Table 1) showed that 47 compounds had inhibitory activity against VEGFR2, of which 28 compounds had IC 50 The values ​​were less than 10 nM, and the enzyme inhibition activities of 19 compounds were better than the positive control Lenvatinib, among which the enzyme inhibition activities of compounds 6, 16, 26, and 28 were more than 4 times that of Lenvatinib.

[0250] Table 1 VEGFR2 enzyme inhibitory activity (IC 50 value)

[0251] Example 51: Inhibition of other tyrosine kinases by compounds

[0252] Referring to the method of Example 50, the inhibitory activity of the compound on other tyrosine kinases, including Kit, FGFR1, FGFR2, FGFR3, Flt1, PDGFβ, Met, EGFR, Flt4, PDGFα, and Ret, was determined.

[0253] 1. Experimental materials and instruments

[0254] 2. The test results are shown in Table 2.

[0255] Table 2. IC values ​​of the test compounds for inhibition of Kit, FGFR1 and other tyrosine kinases 50 (μM) Note: The numbers are example numbers. BIBF-1120, XL-184, AEE787, and lenvatinib are positive control drugs.

[0256] The compounds were tested for their inhibitory activity against multiple tyrosine kinases. The results showed that compounds 4, 9, 11, and 8 had good inhibitory activity against Kit, FGFR1, FGFR2, FGFR3, Flt1, PDGFβ, Flt4, PDGFα, Ret and other kinases, but had lower inhibitory activity against Met and EGFR.

[0257] Example 52: Evaluation of the Anti-Proliferation Activity of Compounds on HepG2, A549 and HUVECs Cells

[0258] The cell models used in this example were human lung cancer A549, human liver cancer HepG2 and human umbilical vein endothelial cells HUVECs. Based on the results of VEGFR2 enzyme inhibition activity evaluation, the proliferation inhibition activity of some compounds of the present invention on A549, HepG2 and HUVECs cells was determined.

[0259] 1. Experimental materials and instruments

[0260] 2. Experimental steps

[0261] (1) Solution preparation

[0262] ① Dissolve the selected compounds in DMSO to prepare a 10 mM stock solution. Store compounds used within three months in a desiccator at room temperature. Other compounds can be stored long-term at -20°C.

[0263] ② Dilute the above compound stock solutions and the positive reference compound, Lenvatinib, with DMSO, starting at 10 μM. Perform a 2-fold serial dilution across 8 concentrations, with a minimum of 0.078 μM, in experiments with A549, HepG2, and HUVECs cells. Oscillate on a shaker for 5 minutes.

[0264] (2) Cell dosing

[0265] ① A549, HepG2, and HUVECs cells in the logarithmic growth phase were seeded in 96-well plates with 3,000-4,000 cells per well. The plates were pre-cultured in an incubator for 24 hours (at 37° C., 5% CO 2 ).

[0266] ② Replace the culture medium in the well plate and add 100 μL of the corresponding concentration of compound and positive control to the culture plate.

[0267] ③ Incubate the culture plate in an incubator for 72 hours, add 10 μL of CCK-8 solution to each well, and incubate the culture plate in an incubator for 1-4 hours.

[0268] ④ Measure the absorbance at 450 nm using an enzyme-labeled instrument.

[0269] (3) Data processing

[0270] ①Calculate the inhibition percentage:

[0271] Inhibition percentage = 1-100% × (Signal cmpd -Signal Ave_PC ) / (Signal Ave_VC -Signal Ave_PC ).

[0272] Among them, Signal cmpd Indicates the absorbance of the experimental well; Signal Ave_PC Indicates the absorbance of blank wells (without cells and compounds); Signal Ave_VC represents the absorbance of the control well (without compound);

[0273] ②Calculate the IC of the compound 50 And Plot effect dose curve:

[0274] IC was calculated by fitting the logarithm of the percentage inhibition and compound concentration to a nonlinear regression (dose response - variable slope) using GraphPad 6.0. 50 value.

[0275] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0276] Y is the inhibition percentage, X is the logarithm of the compound concentration, Bottom is the maximum inhibition percentage, Top is the minimum inhibition percentage, and HillSlope is the slope coefficient.

[0277] 3. Experimental results

[0278] Table 3 shows the test results of the above compounds and the positive reference compound Lenvatinib on A549, HepG2, and HUVECs cells. In the A549 cell line, the compounds generally exhibited good anti-proliferative activity. Thirty compounds demonstrated superior anti-proliferative activity against A549 cells compared to the positive control drug Lenvatinib, with compounds 1, 10, 13, 27, and 44 exhibiting over five times the activity of Lenvatinib. In the HepG2 cell line, 27 compounds demonstrated superior anti-proliferative activity against A549 cells compared to the positive control drug Lenvatinib, with compounds 1, 2, 3, 5, 8, 10, 12, 14, 23, 39, 45, 46, and 49 exhibiting over ten times the activity of Lenvatinib. In HUVECs, seven compounds demonstrated superior anti-proliferative activity against HUVECs compared to Lenvatinib.

[0279] Table 3. Antiproliferative activity of compounds against A549, HepG2, and HUVECs cells (IC 50 value) ND: Not detected. The IC values ​​of compounds with inhibition rates less than 50% at 10 μM concentration were not fitted. 50 value.

[0280] Example 53: Evaluation of the Anti-Proliferation Activity of Compounds in Various Tumor Cells

[0281] Referring to the method of Example 52, the inhibitory activity of the compound on various tumor cells was determined, including human lung cancer (EBC-1, NCI-H1975), human liver cancer (SMMC-7721, PLCPRF5), human breast cancer (MCF7, ZR75-1, Hs578T, MDA-MB-231, HCC-38), human ovarian cancer (A2780, SKOV3), human renal cancer 786-O, human colorectal cancer (HT-29, NCI-H23, HCT-116), human gastric cancer Hs746T and human cervical cancer Hela cells.

[0282] 1. Experimental materials and instruments

[0283] 2. The test results are shown in Table 4: The five compounds all had good anti-proliferative activity against the eight types of tumor cells tested. Among them, compounds 12 and 45 had better anti-proliferative activity than Lenvatinib against 17 types of tumor cells.

[0284] Table 4. Antiproliferative activity of preferred compounds against various tumor cells (IC 50 value) ND: Not detected. The IC values ​​of compounds with inhibition rates less than 50% at the highest concentration of 27 μM were not fitted. 50 value.

[0285] Example 54: Anti-angiogenesis activity of compounds in vitro

[0286] In this example, HUVECs were selected as the cell model, and the inhibitory activity of some compounds of the present invention on HUVECs angiogenesis was determined.

[0287] 1. Experimental materials and instruments

[0288] 2. Experimental steps

[0289] (1) Prepare Matrigel

[0290] ① The day before the experiment, place the Matrigengel in an ice box and place it in a 4°C refrigerator to allow the gel to slowly melt overnight.

[0291] ② Before starting the experiment, always keep Matrigengel in an ice box.

[0292] ③Operate on ice. Mix the Matrigengel using a pre-cooled pipette tip.

[0293] (2) Laying Matrigel

[0294] Pre-chill a 96-well plate and pipette tips. Prepare two pre-chilled 1.5 mL centrifuge tubes for diluting the Matrigel. Dilute the Matrigel with basal DMEM medium at a 1:1 ratio and add 50 μL of Matrigel to each well, avoiding air bubbles. Incubate in a 37°C incubator for 45 minutes to 1 hour.

[0295] (3) Cell culture and solution preparation, drug addition

[0296] ① When HUVEC cells are 70-80% confluent, digest them and resuspend them in DMEM containing 10% FBS. Count them and add 50 μL of the resuspension solution to each well, with a concentration of 30,000 cells / well. Repeat three times.

[0297] ② Dissolve compounds 12 and 28 in DMSO to prepare 10 mM stock solutions. Store compounds used within three months in a desiccator at room temperature. Others can be stored long-term at -20°C.

[0298] ③ Dilute the aforementioned compound stock solutions and the positive reference compound, lenvatinib, with DMSO to three concentration points: 0.1, 1, and 10 μM. Oscillate on a shaker for 5 minutes. Incubate in a 37°C incubator. After four hours, angiogenesis is visible and images are acquired.

[0299] 3. Experimental results

[0300] The dose-effect curve was plotted with the logarithm of the test compound concentration as the horizontal axis and the number of angiogenesis as the vertical axis. As shown in Figure 1, the above-mentioned compounds and the positive reference compound Lenvatinib can significantly inhibit the in vitro angiogenesis of HUVECs cells. Among them, at the same dose, the inhibitory activity of compounds 12 and 28 is significantly better than that of Lenvatinib.

[0301] Example 55: In vivo activity of the compound against human liver cancer HepG2 transplanted tumors in nude mice

[0302] In this example, the cell model used was the liver cancer HepG2 cell line, and the inhibitory effect of the compound on the growth of tumor cell transplanted tumors in nude mice was determined. The evaluation method and results are described below.

[0303] 1. Experimental Materials and Instruments

[0304] 2. Establishment of Tumor Model

[0305] Human hepatoma cell lines HepG2 (from ATCC) were routinely cultured in high-glucose DMEM containing 10% fetal bovine serum at 37°C in a 5% CO2 incubator. After three passages in vitro, cells were harvested and digested when they grew to over 80% and the fusion rate reached the desired amount. The cells were washed with PBS and counted, and the cell concentration was adjusted to approximately 5×10 7 Place the 500 μg / mL in a 4 mL centrifuge tube and place on ice for later use.

[0306] Female Balb / C nude mice aged 4 to 5 weeks were selected and inoculated subcutaneously with HepG2 tumor cells, a human hepatocellular carcinoma cell line. The mice were placed on their side, and the axilla of the forelimbs was disinfected with 75% alcohol. 100 μL of cell suspension was drawn up with a 1 mL syringe and injected subcutaneously into the axilla, i.e., 5 x 10 6 cells / mouse / 100μL.

[0307] 3. Experimental Animal Grouping and Dosing

[0308] When the tumor grows to 90-150 mm 3 Afterwards, the animals were randomly divided into groups of 6 each and fed according to different dosing methods, namely:

[0309] Model control group: Oral administration of the same volume of blank solvent (DMSO: 0.5% sodium carboxymethylcellulose: distilled water = 1:1:8) every day;

[0310] Test group: 30 mg / kg (mouse body weight) of compound 12 and 28 solution were gavaged daily.

[0311] Positive control group: 30 mg / kg (mouse body weight) of Lenvatinib solution was administered orally every day.

[0312] The administration route was oral gavage, and the frequency of administration was once a day for 25 consecutive days. The day of the first administration was defined as the first day of the experiment. The changes in the tumor volume of the mice were measured and recorded every two days. Tumor volume was measured using a vernier caliper. The long diameter (a) and short diameter (b) of the tumor were measured and the tumor volume was calculated. The tumor volume V (mm 3 )=axb^ 2 After the experiment, mice were dissected and tumor weights were measured. Data were entered and statistically analyzed using GraphPad Prism 6 software. Data are expressed as mean ± SEM (standard error of mean) and analyzed using one-way ANOVA. P ≤ 0.05 was considered statistically significant.

[0313] 4. Experimental Results

[0314] As shown in Figure 2 and Table 5, the experimental results showed that compounds 12 and 28 significantly inhibited the growth of HepG2 transplanted tumors, and at the same dose, their effects were better than the positive drug Lenvatinib.

[0315] Table 5. Inhibitory effects of compounds 12 and 28 on HepG2 xenograft tumors in nude mice

[0316] Example 56: In vivo activity of the compound against human thyroid cancer 8305C transplanted tumors

[0317] In this example, the human thyroid cancer 8305C cell line was selected as the cell model to determine the inhibitory effect of the compound on the growth of tumor cell transplanted in nude mice. The evaluation method and results are described below.

[0318] 1. Experimental Materials and Instruments

[0319] 2. Establishment of Tumor Model

[0320] Human hepatoma cells HepG2 (from ATCC) were routinely cultured in high-glucose DMEM containing 10% fetal bovine serum at 37°C in a 5% CO2 incubator. After three passages in vitro, when the cells grew to more than 80% and the fusion rate reached the required amount, the cells were digested and collected. The cells were washed with PBS and counted, and the cell concentration was adjusted to approximately 5×10 7 Place the 500 μg / mL in a 4 mL centrifuge tube and place on ice for later use.

[0321] Female Balb / C nude mice aged 4 to 5 weeks were selected and inoculated subcutaneously with HepG2 tumor cells, a human hepatocellular carcinoma cell line. The mice were placed on their side, and the axilla of the forelimbs was disinfected with 75% alcohol. 100 μL of cell suspension was drawn up with a 1 mL syringe and injected subcutaneously into the axilla, i.e., 5 x 10 6 cells / mouse / 100μL.

[0322] 2. Experimental Animal Grouping and Dosing

[0323] When the tumor grows to 90-150 mm 3 Afterwards, the animals were randomly divided into groups of 6 each and fed according to different dosing methods, namely:

[0324] Model control group: Oral administration of the same volume of blank solvent (DMSO: 0.5% sodium carboxymethylcellulose: distilled water = 1:1:8) every day;

[0325] Test group: Oral administration of 60 mg / kg (mouse body weight) of compound 12, 28 solution, once every two days.

[0326] Positive control group: Oral administration of 60 mg / kg (mouse body weight) of Lenvatinib solution, once every two days.

[0327] The administration route was oral gavage, and the frequency of administration was once every two days for 20 consecutive days. The day of the first administration was defined as the first day of the experiment. The changes in the tumor volume of the mice were measured and recorded every two days. Tumor volume was measured using a vernier caliper. The long diameter (a) and short diameter (b) of the tumor were measured and the tumor volume was calculated. The tumor volume V (mm 3 )=axb^ 2 After the experiment, mice were dissected, tumors were weighed, and representative tumors were immunohistochemically stained for the endothelial differentiation marker CD31 and the proliferation marker Ki67. Data were entered and statistically analyzed using GraphPad Prism 6 software. Data are expressed as mean ± SEM (standard error of mean) and analyzed using one-way ANOVA. P ≤ 0.05 was considered statistically significant.

[0328] 3. Experimental Results

[0329] As shown in Figure 3 and Table 6, the experimental results show that compounds 12 and 28 significantly inhibited the growth of human thyroid cancer 8305C xenografts, and at the same dose, their efficacy was superior to that of the active agent Lenvatinib. With the extension of the dosing time, no significant tumor growth was observed in the compound 12 and 28 groups. As shown by the immunohistochemical results in Figures 4 (a) to (c), compounds 12 and 28 significantly inhibited the formation of new blood vessels in human thyroid cancer 8305C xenografts, and at the same dose, their efficacy was significantly superior to that of the active agent Lenvatinib.

[0330] Table 6. Inhibitory effects of compounds 12 and 28 on human thyroid cancer 8305C xenograft tumors in nude mice

[0331] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the technical principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A compound represented by formula (I), a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof; in, R1 and R2 are each independently selected from hydrogen, alkyl, alkoxy, alkoxycarbonyl, aminoalkanoyl, alkylaminocarbonyl; R3 is selected from Wherein, R4 is selected from -(NR6) n1 -C(O)-(NR7) n2 -, R6 and R7 are each independently selected from H, alkyl; n1 and n2 are each independently selected from 0, 1; R5 is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, cycloalkyl, cycloalkenyl, H, alkenyl, alkynyl, alkylaminocarbonyl, aminocarbonyl, cyano; the substitution is substituted by one or more of the following substituents: halogen, alkyl, alkoxy, haloalkyl, nitro, cycloalkyl, aryl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, wherein: R1 and R2 are each independently selected from hydrogen, C1-C6 straight or branched alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, aminoC1-C6 alkanoyl, C1-C6 alkylaminocarbonyl; Preferably, R1 and R2 are each independently selected from amino C1-C6 alkanoyl, C1-C6 alkoxy, C1-C6 alkylaminocarbonyl; More preferably, R1 and R2 are each independently selected from carbamoyl and methoxy.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, wherein: R3 is selected from Wherein, R4 is selected from -(NR6) n1 -C(O)-(NR7) n2 -, R6 and R7 are each independently selected from H, C1-C6 alkyl; n1 and n2 are each independently selected from 0, 1; R5 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered heterocyclyl; the substitution is substituted by one or more of the following substituents: halogen, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, nitro, 3-6 membered cycloalkyl, 5-10 membered aryl; Preferably, R3 is selected from Wherein, R4 is selected from -C(O)NH-, -C(O)-, -C(O)N(CH3)-, -NH(CO)NH-, R5 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, ethyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted methyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted naphthyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl; the substitution is substituted by one or more of the following substituents: fluorine, methyl, chlorine, methoxy, trifluoromethyl, ethoxy, nitro, bromine, cyclopropyl, phenyl; More preferably, R3 is selected from Wherein, R4 is selected from -C(O)NH-, -C(O)-, -C(O)N(CH3)-, -NH(CO)NH-, R5 is selected from Phenyl, Ethyl, methyl, Benzyl, More preferably, R3 is selected from 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, wherein: The compound is selected from:

5. A method for preparing the compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph, which is any one of the following methods A to E; The method A comprises: 1-Naphthoic acid was subjected to mesylation and alkali melting reaction to obtain intermediate 4; Intermediate 4 is reacted with intermediate 5 to obtain intermediate 6, and then intermediate 6 is reacted with amine using Hobt and EDCI as condensing agents to obtain target compound 8; or, intermediate 4 is reacted with amine using Hobt and EDCI as condensing agents to obtain intermediate 7, and then intermediate 7 is reacted with intermediate 5 to obtain target compound 8; The method B comprises: Intermediate 5 is reacted with 2-hydroxy-6-naphthoic acid to obtain intermediate 10; The intermediate 10 is subjected to amide condensation with an amino compound to obtain the target compound 11; The method C comprises: Intermediate 5 was reacted with 5-hydroxyindole to give intermediate 13; The intermediate 13 is reacted with the intermediate 14 to obtain the target compound 15; The method D comprises: The raw intermediate 16 was reacted with Hobt and EDCI to obtain intermediate 17; Intermediate 17 is reacted with NH2R5 to obtain intermediate 18; Intermediate 18 is reacted with 4-hydroxyaniline to give intermediate 20; The intermediate 20 is reacted with the intermediate 5 to obtain the target compound 21; The method E comprises: The starting compound 22 is condensed and acylated to obtain the intermediate 23; Intermediate 23 and intermediate 5 undergo nucleophilic substitution reaction to obtain target compound 24; The definitions of R1, R2 and R5 are as described in any one of claims 1 to 4.

6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof; Optionally, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

7. The pharmaceutical composition according to claim 6, further comprising other drugs and / or immunomodulators for treating tumors (such as one or more selected from immune checkpoint inhibitors, antibiotics, alkylating agents, antimetabolites, hormones, immunoactive agents, and interferon-type active agents).

8. Use of the compound according to any one of claims 1 to 4, its pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph, or the pharmaceutical composition according to claim 6 or 7 in the preparation of a medicament for preventing and / or treating diseases related to the VEGF / VEGFR pathway.

9. The use according to claim 8, wherein The disease related to the VEGF / VEGFR pathway is selected from one or more of atherosclerosis, pulmonary fibrosis, retinopathy, endometriosis, arthritis and cancer.

10. The use according to claim 9, wherein The cancer is selected from one or more of skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, prostate cancer, colon cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), bone cancer, brain cancer, rectal cancer, esophageal cancer, kidney cancer (e.g., renal parenchymal cancer), tongue cancer, cervical cancer, uterine body cancer, endometrial cancer, testicular cancer, melanoma, lymphoma, thyroid tumor, glioma, astrocytoma, and hepatocellular carcinoma.

11. A method for preventing and / or treating diseases related to the VEGF / VEGFR pathway, comprising administering an effective amount of a compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, or an effective amount of a pharmaceutical composition according to claim 6 or 7 to a subject in need thereof.

12. The method according to claim 11, wherein: The disease related to the VEGF / VEGFR pathway is selected from one or more of atherosclerosis, pulmonary fibrosis, retinopathy, endometriosis, arthritis and cancer.

13. A compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph thereof, or a pharmaceutical composition according to claim 6 or 7, for use in preventing and / or treating diseases related to the VEGF / VEGFR pathway.

14. The compound according to claim 13, its pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer, solvate or polymorph or pharmaceutical composition, wherein: The disease related to the VEGF / VEGFR pathway is selected from one or more of atherosclerosis, pulmonary fibrosis, retinopathy, endometriosis, arthritis and cancer.

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