Quinazoline derivative compound and use thereof

Abstract

The present invention relates to a quinazoline derivative compound, a pharmaceutically acceptable salt thereof, a compound selected from a solvate thereof or a stereoisomer thereof, and a composition thereof for preventing or treating protease activated receptor 2 (PAR2) overexpression-mediated diseases. The present invention designs and synthesizes a novel compound having a quinazoline frame as a PAR2 antagonist and confirms the effects of anti-inflammation, inhibition of vascular aging, improvement of lipid metabolism, and inhibition of cancer cell growth, and accordingly, the novel compound according to the present invention can be used as an effective therapeutic agent for inflammatory diseases, vascular aging, metabolic diseases, and cancer diseases, which are PAR2 overexpression-mediated diseases.

Description

Quinazoline derivative compounds and uses thereof

[0001] The present invention provides quinazoline derivative compounds and uses thereof.

[0002] Protease-activated receptor 2 (PAR2) is a member of the G-protein-coupled receptor (GPCR) family that is irreversibly activated by cleavage of its N-terminus. The transmembrane receptor domain initiates cellular signaling cascades in response to inflammatory signals and other stimuli. After the intact N-terminal domain is removed, tethered ligands activate intracellular G protein- or β-arrestin-mediated signaling pathways, inducing a wide range of intracellular physiological responses. PAR2 is a central mediator of diseases such as cancer, inflammation, asthma, pancreatitis, and irritable bowel syndrome. PAR2 antagonists are expected to act as anticancer or anti-inflammatory agents by blocking pathways associated with cancer cell proliferation or inflammatory responses.

[0003] An object of the present invention is to provide a compound selected from quinazoline derivative compounds, pharmaceutically acceptable salts thereof, solvates thereof, or stereoisomers thereof.

[0004] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease mediated by PAR2 (Protease-activated receptor 2) overexpression, comprising as an active ingredient a compound selected from a quinazoline derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0005] Another object of the present invention is to provide a health functional food composition for preventing or improving a disease mediated by PAR2 (Protease-activated receptor 2) overexpression, comprising as an active ingredient a compound selected from a quinazoline derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0006] Another object of the present invention is to provide a reagent composition for inhibiting PAR2 (Protease-activated receptor 2) expression, which comprises as an active ingredient a compound selected from a quinazoline derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0007] To achieve the above object, the present invention provides a compound selected from a quinazoline derivative compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof:

[0008] [Chemical Formula 1]

[0009]

[0010] In the above chemical formula 1,

[0011] R 1 , R 2 and R 3 are each the same or different, and are one of unsubstituted or substituted (C3-C15)cycloalkyl, unsubstituted or substituted (C5-C15)aryl and unsubstituted or substituted heteroaryl having 5 to 15 atoms containing one or more heteroatoms selected from the group consisting of N, O and S,

[0012] The above substituted (C3-C15)cycloalkyl, substituted (C5-C15)aryl and substituted heteroaryl having 5 to 15 atoms may be substituted identically or differently, and may be substituted with at least one selected from the group consisting of hydroxy, halogen, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, trifluoromethyl and trifluoromethoxy.

[0013] In addition, the present invention provides a pharmaceutical composition for preventing or treating a disease mediated by PAR2 (Protease-activated receptor 2) overexpression, comprising a compound selected from the quinazoline derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof as an active ingredient.

[0014] In addition, the present invention provides a health functional food composition for preventing or improving a disease mediated by PAR2 (Protease-activated receptor 2) overexpression, which comprises as an active ingredient a compound selected from the quinazoline derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0015] In addition, the present invention provides a reagent composition for inhibiting PAR2 (Protease-activated receptor 2) expression, which comprises as an active ingredient a compound selected from the quinazoline derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0016] The present invention relates to a compound selected from a quinazoline derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof or a stereoisomer thereof, and a composition thereof for preventing or treating a disease mediated by PAR2 (Protease-activated receptor 2) overexpression. A novel compound having a quinazoline skeleton as a PAR2 antagonist was designed and synthesized, and its anti-inflammatory, vascular aging inhibition, lipid metabolism improvement and cancer cell growth inhibition effects were confirmed. Therefore, the novel compound according to the present invention can be utilized as an effective treatment for inflammatory diseases, vascular aging, metabolic diseases and cancer diseases, which are diseases mediated by PAR2 overexpression.

[0017] Figure 1a shows a schematic diagram of the synthesis of quinazoline derivatives.

[0018] Figure 1b shows the chemical structures of quinazoline derivatives.

[0019] Figure 2 shows the cytotoxicity of 40 quinazoline derivatives in vascular endothelial cells.

[0020] Figure 3 shows the reactive oxygen species (ROS) scavenging activity of 40 kinds of quinazoline derivatives.

[0021] Figure 4 shows the NF-κB transcriptional activity inhibitory activity of 40 quinazoline derivatives.

[0022] Figure 5 shows the expression levels of IL-1β and CCL5 induced by PAR2 activator treatment with quinazoline derivatives.

[0023] Figure 6 shows the anti-inflammatory effect of N-(4-(benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide (hereinafter referred to as compound 5013) in vascular endothelial cells.

[0024] Figure 7 shows the lipid metabolism-related improving effect of compound 5013 in human hepatocytes (HepG2).

[0025] Figure 8 shows the anti-inflammatory effect of compound 5013 in kidney tissue of db / db metabolic disease mice.

[0026] Figure 9 shows the anti-inflammatory effect and lipid metabolism-related improvement effect (C) of N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-methylbenzamide (hereinafter referred to as compound 5015) and N-(4-((2,3-dihydro-1H-inden-5-yl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide (hereinafter referred to as compound 5032) in the liver (A) and kidney (B) tissues of ApoE knockout mice.

[0027] Figure 10 shows the inhibitory effect of compound 5013 on vascular aging in the kidney of db / db metabolic disease mice.

[0028] Figure 11 shows the inhibitory effect of compounds 5015 and 5032 on vascular aging in liver tissue of ApoE-deficient mice.

[0029] Figure 12a shows the weight loss effect of compound 5013 in a high-fat diet-administered mouse model, and Figure 12b shows the insulin resistance effect of compound 5013 in a high-fat diet-administered mouse model.

[0030] Figure 13 shows the weight loss and serum changes of compound 5013 in diabetic / metabolic disease db / db mice.

[0031] Figure 14 shows the effect of compound 5013 on improving insulin resistance and reducing fat synthesis.

[0032] Figure 15 shows the cell killing effects of compounds 5009 and 5017 in cancer cell lines.

[0033] Figure 16 shows the pharmacophore and molecular dynamics (MD) analysis results of the PAR2-compound 5013 complex.

[0034] Figure 17 shows the pharmacophore and molecular dynamics (MD) analysis results of the PAR2-compound 5015 complex.

[0035] Hereinafter, the present invention will be described in more detail.

[0036]

[0037] The present invention provides a compound selected from a quinazoline derivative compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof:

[0038] [Chemical Formula 1]

[0039]

[0040] In the above chemical formula 1,

[0041] R 1 , R 2 and R 3 are each the same or different, and are one of unsubstituted or substituted (C3-C15)cycloalkyl, unsubstituted or substituted (C5-C15)aryl and unsubstituted or substituted heteroaryl having 5 to 15 atoms containing one or more heteroatoms selected from the group consisting of N, O and S,

[0042] The above substituted (C3-C15)cycloalkyl, substituted (C5-C15)aryl and substituted heteroaryl having 5 to 15 atoms may be substituted identically or differently, and may be substituted with at least one selected from the group consisting of hydroxy, halogen, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, trifluoromethyl and trifluoromethoxy.

[0043] In the above chemical formula 1, R 1 is an unsubstituted or substituted naphthyl, wherein the substituted naphthyl is substituted with at least one selected from the group consisting of halogen, (C1-C5)alkyl, (C1-C5)alkoxy and trifluoromethyl, and R 2is an unsubstituted or substituted (C5-C15)aryl or an unsubstituted or substituted heteroaryl of 5 to 15 atoms containing one or more heteroatoms selected from the group consisting of N, O and S, wherein the substituted (C5-C15)aryl or substituted heteroaryl of 5 to 15 atoms is substituted with one or more selected from the group consisting of halogen, (C1-C5)alkyl, (C1-C5)alkoxy and trifluoromethyl, and R 3 is an unsubstituted or substituted phenyl, and the substituted phenyl may be substituted with one or more selected from the group consisting of halogen, (C1-C5)alkyl, (C1-C5)alkoxy, and trifluoromethyl, but is not limited thereto.

[0044] In the above chemical formula 1, R 1 is unsubstituted naphthyl, and R 2 Is , , and one or two phenyl substituted with chlorine or fluorine, R 3 may be substituted with one to three selected from the group consisting of chlorine, methyl, tert-butyl, methoxy and trifluoromethyl.

[0045] In the above chemical formula 1, R 2 Is , , and one of substituted phenyl, wherein the substituted phenyl may be substituted with either chlorine or fluorine.

[0046]

[0047] The compound represented by the above chemical formula 1 may be selected from the following group of compounds:

[0048] (1)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide;

[0049] (2)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-1-yl)quinazolin-6-yl)-3,4-dichlorobenzamide;

[0050] (3)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-methylbenzamide;

[0051] (4)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(tert-butyl)benzamide;

[0052] (5)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-1-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide) ;

[0053] (6)N-(4-((3-Chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide;

[0054] (7) 3,4-Dichloro-N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)benzamide;

[0055] (8)N-(4-((3-Chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-methylbenzamide;

[0056] (9) 4-(tert-Butyl)-N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)benzamide;

[0057] (10)N-(4-((3-Chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide;

[0058] (11)N-(4-((2,3-Dihydro-1H-inden-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide;

[0059] (12) 3,4-Dichloro-N-(4-((2,3-dihydro-1H-inden-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)benzamide;

[0060] (13)N-(4-((2,3-Dihydro-1H-inden-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-methylbenzamide;

[0061] (14) 4-(tert-Butyl)-N-(4-((2,3-dihydro-1H-inden-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)benzamide;

[0062] (15)N-(4-((2,3-Dihydro-1H-inden-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide;

[0063] (16)N-(4-((9H-Fluoren-2-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide;

[0064] (17)N-(4-((9H-Fluoren-2-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-3,4-dichlorobenzamide;

[0065] (18)N-(4-((9H-Fluoren-2-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-methylbenzamide;

[0066] (19)N-(4-((9H-Fluoren-2-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(tert-butyl)benzamide;

[0067] (20)N-(4-((9H-Fluoren-2-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide;

[0068] (21)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide;

[0069] (22)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4-dichlorobenzamide;

[0070] (23)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-methylbenzamide;

[0071] (24)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(tert-butyl)benzamide;

[0072] (25)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide;

[0073] (26)N-(4-((3-Chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide;

[0074] (27) 3,4-Dichloro-N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)benzamide;

[0075] (28)N-(4-((3-Chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-methylbenzamide;

[0076] (29) 4-(tert-Butyl)-N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)benzamide;

[0077] (30)N-(4-((3-Chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide;

[0078] (31)N-(4-((2,3-Dihydro-1H-inden-5-yl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide;

[0079] (32) 3,4-Dichloro-N-(4-((2,3-dihydro-1H-inden-5-yl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)benzamide;

[0080] (33)N-(4-((2,3-Dihydro-1H-inden-5-yl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-methylbenzamide;

[0081] (34) 4-(tert-Butyl)-N-(4-((2,3-dihydro-1H-inden-5-yl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)benzamide;

[0082] (35)N-(4-((2,3-Dihydro-1H-inden-5-yl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide;

[0083] (36)N-(4-((9H-Fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide;

[0084] (37)N-(4-((9H-Fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4-dichlorobenzamide;

[0085] (38)N-(4-((9H-Fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-4-methylbenzamide;

[0086] (39)N-(4-((9H-fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(tert-butyl)benzamide; and

[0087] (40)N-(4-((9H-Fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide).

[0088]

[0089] In addition, the present invention provides a pharmaceutical composition for preventing or treating a disease mediated by PAR2 (Protease-activated receptor 2) overexpression, comprising a compound selected from the quinazoline derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof as an active ingredient.

[0090] The above quinazoline derivative compounds are N-(4-(benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide, N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-methylbenzamide, N-(4-((2,3-dihydro-1H-inden-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-methylbenzamide, 4-(tert-butyl)-N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)benzamide, 4-(tert-butyl)-N-(4-((2,3-dihydro-1H-inden-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)benzamide, 3,4-dichloro-N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)benzamide, N-(4-((2,3-dihydro-1H-inden-5-yl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide, N-(4-(benzo[d][1,3]dioxol-5-yl N-(4-((9H-fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-4-methylbenzamide, N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide, It may be any one selected from the group consisting of 4-(tert-butyl)-N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)benzamide and N-(4-((9H-fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(tert-butyl)benzamide, but is not limited thereto.

[0091] The above PAR2 (Protease-activated receptor 2) overexpression-mediated disease may be one of inflammatory diseases, vascular aging, metabolic diseases, and cancer diseases, but is not limited thereto.

[0092] The above inflammatory disease may be one of, but is not limited to, allergic disease, inflammatory bowel disease, systemic lupus erythematosus, inflammatory collagen vascular disease, glomerulonephritis, inflammatory skin disease, sarcoidosis, retinitis, gastritis, hepatitis, enteritis, pancreatitis, and nephritis.

[0093] The above metabolic disease may be one of, but is not limited to, obesity, diabetes, hyperlipidemia, hypertriglyceridemia, liver disease, arteriosclerosis, stroke, myocardial infarction, hyperglycemia, insulin resistance disease, and hyperinsulinemia.

[0094] The above cancer disease may be one of, but is not limited to, prostate cancer, colon cancer, lung cancer, breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, liver cancer, skin cancer, head or neck cancer, brain cancer, laryngeal cancer, bladder cancer, esophagus cancer, thyroid cancer, kidney cancer, and rectal cancer.

[0095] In another embodiment of the present invention, the pharmaceutical composition may further comprise one or more additives selected from the group consisting of suitable carriers, excipients, disintegrants, sweeteners, coating agents, bulking agents, lubricants, glidants, flavoring agents, antioxidants, buffers, bacteriostatic agents, diluents, dispersants, surfactants, binders and lubricants commonly used in the manufacture of pharmaceutical compositions.

[0096] Specifically, carriers, excipients, and diluents may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like. These solid preparations may be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like, into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, they may contain various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspending agents can be propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases can include witepsol, macrogol, tween 61, cacao butter, laurin butter, and glycerogelatin.

[0097] According to one embodiment of the present invention, the pharmaceutical composition can be administered to a subject in a conventional manner via intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, intranasal, inhalational, topical, rectal, oral, intraocular or intradermal routes.

[0098] The dosage of the active ingredient according to the present invention may vary depending on the condition and weight of the subject, the type and degree of the disease, the drug form, the route and period of administration, and may be appropriately selected by a person skilled in the art, and the daily dosage may be 0.01 mg / kg to 200 mg / kg, preferably 0.1 mg / kg to 200 mg / kg, and more preferably 0.1 mg / kg to 100 mg / kg. Administration may be once a day or divided into several times, and the scope of the present invention is not limited thereby.

[0099]

[0100] In addition, the present invention provides a health functional food composition for preventing or improving a disease mediated by PAR2 (Protease-activated receptor 2) overexpression, which comprises as an active ingredient a compound selected from the quinazoline derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0101] The above health functional food may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.

[0102] In addition, it may contain fruit pulp for the production of natural fruit juice, synthetic fruit juice, and vegetable drinks. These ingredients may be used independently or in combination. Furthermore, the health functional food composition may be in the form of any one of meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, gum, ice cream, soup, beverage, tea, functional water, drink, alcohol, and vitamin complex.

[0103] In addition, the above health functional food may additionally contain food additives, and its suitability as a “food additive” is determined by the specifications and standards for the relevant item in accordance with the general provisions and general testing methods of the Food Additives Codex approved by the Ministry of Food and Drug Safety, unless otherwise provided.

[0104] Examples of items listed in the above "Food Additives Codex" include chemically synthesized products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, kohlrabi pigment, and guar gum; and mixed preparations such as sodium L-glutamate preparations, alkaline agents added to noodles, preservative preparations, and tar color preparations.

[0105] At this time, the content of the effective ingredient added to the food during the process of manufacturing the health functional food can be appropriately increased or decreased as needed, and preferably, it can be added so that it is included in an amount of 1 to 90 parts by weight per 100 parts by weight of the food.

[0106]

[0107] A reagent composition for inhibiting PAR2 (Protease-activated receptor 2) expression is provided, which comprises as an active ingredient a compound selected from the above quinazoline derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0108] Hereinafter, to aid understanding of the present invention, examples and other embodiments will be described in detail. However, the following examples and other embodiments merely illustrate the content of the present invention and are not intended to limit the scope of the present invention. The examples and other embodiments of the present invention are provided to more fully explain the present invention to those of average skill in the art.

[0109]

[0110] <Experimental Example>

[0111] 1. Computational modeling and docking simulation

[0112] Computational modeling and docking simulation were used to search for new active compounds for the discovered key target molecules. The protein sequence of PAR2 was converted into a 3D structure based on the 3D structure of PAR1 using the SWISS-MODEL website (https: / swissmodel.expasy.org / ). Compounds to be used for docking simulation were converted to mol files using Chemsketch software (https: / www.acdlabs.com / resources / free-chemistry-software-apps / chemsketch-freeware / ), and then converted to file formats (pdb, mol2) suitable for docking simulation using UCSF Chimera software (https: / www.cgl.ucsf.edu / chimera / ). To perform docking simulation experiments, three programs were used: Autodock Vina (https: / vina.scripps.edu / ), Autodock 4 (https: / autodock.scripps.edu / ), and Dock6 (https: / dock.compbio.ucsf.edu / DOCK_6 / index.htm).

[0113]

[0114] 2. ADMET Analysis

[0115] To predict the pharmacokinetics of new active compounds, we performed an ADMET analysis. ADMET is an analytical method that predicts the extent of a drug's absorption, distribution, metabolism, excretion, and toxicity in the body, based on its structure. For this analysis, we utilized two websites: PreADMET (https: / preadmet.webservice.bmdrc.org / ) and ADMETlab 2.0 (https: / admetmesh.scbdd.com / ).

[0116]

[0117] 3. Cell culture

[0118] YPEN-1 vascular endothelial cells, a rat endothelial cell line, and HepG2 human hepatocytes were purchased from ATCC for experiments. DMEM nutrient medium containing antibiotics (100 units / mL penicillin, 100 μg / mL streptomycin) and 10% fetal bovine serum (FBS) in a 5% CO2 incubator at 37°C was purchased from Welgene (Welgene, Daegu) and used in the experiments.

[0119]

[0120] 4. Cytotoxicity measurement

[0121] In this experiment, cytotoxicity and cell viability were measured by dispensing each cell into a 96-well culture vessel and treating the cells with the derivatives at each concentration for 24 hours. Afterwards, 10 μL of EZ-cytox solution (Daeillab, Seoul) was added and reacted for 2–3 hours. The inhibitory concentrations of the derivative compounds for cytotoxicity and cell viability were measured by absorbance at a wavelength of 450 nm using a microplate reader.

[0122]

[0123] 5. Laboratory animals

[0124] To ensure ethical conduct, the animals were trained in the experimental plan, procedures, and precautions prior to use, and were approved by the Pusan ​​National University Ethics Committee. The animal housing room temperature was maintained at 20±1℃, relative humidity at 55±5%, and the light / dark cycle was controlled at 12-hour intervals.

[0125]

[0126] (1) Metabolic diabetes disease model mouse model

[0127] To confirm the improvement of metabolic diseases by quinazoline derivatives in vivo, compound 5013 (MHY5013) was orally administered once daily at 2 or 6 mg / kg for 16 days to C57BL / 6J mice fed a high-fat diet (HFD) ad libitum.

[0128] To determine the long-term effects of compound 5013, C57BL / 6J mice were fed a high-fat diet ad libitum for 12 weeks, and compound 5013 was administered orally once daily at 2 or 6 mg / kg for 4 weeks, starting at week 9. After the end of the diet, the mice were euthanized, and organs and blood were collected for analysis.

[0129]

[0130] (2) ApoE-deficient mice

[0131] To confirm the improvement of vascular inflammation and vascular aging by quinazoline derivatives in vivo, ApoE KO mice (6-week-old, male, weighing approximately 30 g) were purchased from the Central Laboratory Animal Center (Seoul, Korea) and acclimated to the laboratory environment for 1 week. Then, they were fed a high-fat diet for 6 weeks in an animal breeding room automatically set to 22±2℃ temperature, 50±5% humidity, and 12-h light / dark cycle. The drug was administered at 4 mg / kg for 5 days.

[0132]

[0133] (3) Obese / diabetic db / db mouse model

[0134] To confirm the in vivo improvement of diabetic metabolic disease by quinazoline derivatives, 8-week-old db / db mice, a genetically obese animal model due to leptin receptor deficiency, were purchased from the Central Laboratory Animal Center (Seoul, Korea) and acclimated to the laboratory environment for 1 week. Food and water were provided ad libitum. The PAR2 antagonist was administered orally once daily at 2 or 6 mg / kg for 18 days. After the end of the feeding period, the mice were euthanized, and organs and blood samples were collected for analysis.

[0135]

[0136] 6. RNA isolation, cDNA synthesis, and qRT-PCR (quantitative real-time polymerase chain reaction) analysis

[0137] Total RNA was isolated from mouse tissues and cells treated with PAR2 antagonists using Ribo-Ex (GeneAll Biotechnology, Seoul, Korea), and cDNA was synthesized using Suprime Script RT Premix with random hexamer cDNA Synthesis Kit (GeNet Bio, Daejeon, Korea). To quantify the relative expression of inflammatory cytokine genes by PAR2 antagonists, real-time PCR (CFX-96, Bio-rad, Hercules, CA, USA) was performed using SensiFAST™ SYBR No-ROX dye (Bioline, London, UK) and each gene-specific primer. The expression level of each gene was calculated by correcting it with the relative expression level of GAPDH (glyceraldehyde-3-phosphate dehydrogenase).

[0138]

[0139] 7. Western blot

[0140] After lysis of mouse tissues or cells treated with PAR2 antagonist for 20 minutes with 30 μL NP40 buffer (50 mM Tris-HCl pH 8.0, 1% NP40, Triton X-100, 150 mM NaCl, Protease inhibitor cocktail), the concentration of the extracted protein was measured (BCA protein assay, Pierce, Rockford, IL, USA). Each tissue or cell protein was subjected to 8-10% SDS PAGE (polyacrylamide gel electrophoresis), and the proteins present in the gel were transferred to a PVDF membrane using semi-dry transfer (Bio-Rad Laboratories, Hercules, CA, USA) at 25 V for 10 minutes. The membrane with the transferred protein was blocked with 5% skim milk (in 10% TBST) solution for 1 hour at room temperature to prevent nonspecific reactions. Afterwards, the primary antibody was reacted overnight at 4°C, and the HRP-conjugated secondary antibody was reacted for 1 hour. After color development using the ECL reagent SuperSignal West Pico Chemiluminescent Substrate kit (Advansta, San Jose, CA, USA), each labeled protein was identified using a Davinch-Chemi imager (Davinch-K, Seoul, Korea).

[0141]

[0142] <Example 1> Method for synthesizing quinazoline derivatives (Figure 1a)

[0143] Synthesis Example 1: 6-Nitro-1H-benzo[d][1,3]oxazine-2,4-dione (hereinafter referred to as Compound 1)

[0144] A sulfuric acid solution (80 mL) containing isatoic anhydride (16 g, 98 mmol) was slowly added to a sulfuric acid solution (16 mL) containing KNO3 (9.92 g, 98 mmol) at 0°C. After stirring at room temperature for 1 hour, the reaction mixture was slowly poured into 400 mL of ice water. After stirring at room temperature for 30 minutes, the resulting solid was filtered to obtain pure compound 1 (yield: 77%) as a yellow solid.

[0145] 1 H NMR (500 MHz, DMSO-d6)d12.31 (s, 1H), 8.55 (d, 1H,J= 2.5 Hz), 8.50 (dd, 1H,J= 9.0, 2.0 Hz), 7.28 (d, 1H,J= 9.0 Hz); 13 C NMR (100 MHz, DMSO-d6)d159.2, 147.1, 146.7, 143.2, 131.9, 125.2, 117.3, 111.8.

[0146]

[0147] Synthesis Example 2: 2-Amino-5-nitrobenzamide (hereinafter referred to as Compound 2)

[0148] Ammonia water (40 mL) was added to a 1,4-dioxane solution (60 mL) containing compound 1 [6-nitro-1H-benzo[d][1,3]oxazine-2,4-dione (15.78 g, 76 mmol)] and stirred at 80°C for 3 h. After cooling the reaction mixture to room temperature, the pH was adjusted to 7 with 2 M HCl aqueous solution. The resulting solid was filtered to obtain pure compound 2 (yield: 44%) as a yellow solid.

[0149] 1 H NMR (500 MHz, DMSO-d6)d8.51 (s, 1H), 7.97 (d, 1H,J= 9.0 Hz), 7.86 (brs, 2H), 6.75 (d, 1H,J= 9.0 Hz), 3.52 (s, 2H); 13C NMR (100 MHz, DMSO-d6)d170.3, 156.3, 135.6, 128.1, 127.0, 116.6, 112.8.

[0150]

[0151] Synthetic Example 3: 2-(naphthalen-1-yl)-6-nitroquinazoline-4(3H)-one (hereinafter referred to as compound 3) and 2-(naphthalen-2-yl)-6-nitroquinazoline-4(3H)-one (hereinafter referred to as compound 4)

[0152] A DMSO solution (20 mL) containing compound 2 [2-amino-5-nitrobenzamide (2 g, 11 mmol)], NaHSO3 (2.3 g, 22 mmol), and 1-naphthaldehyde (1.72 g, 11 mmol) or 2-naphthaldehyde (1.72 g, 11 mmol) was stirred under reflux for 24 h. After cooling to room temperature, ice water (50 mL) was added and stirred at room temperature for 1 h. The resulting solid was filtered and recrystallized from chloroform and methanol to obtain compound 3 as a yellow solid (yield: 75%) and compound 4 as a brown solid (yield: 75%).

[0153] Compound 3: 1 H NMR (500 MHz, DMSO-d6)d13.12 (brs, 1H), 8.88 (s, 1H), 8.57 (dd, 1H,J= 8.0, 2.0 Hz), 8.20 (d, 1H,J= 7.5 Hz), 8.13 (d, 1H,J= 7.5 Hz), 8.04 (d, 1H,J= 8.0 Hz), 7.90 (d, 1H,J= 8.0 Hz), 7.82 (d, 1H,J= 8.0 Hz), 7.64 (t, 1H,J= 8.0 Hz), 7.59 (t, 1H,J= 8.0 Hz), 7.57 (t, 1H,J=8.0 Hz); 13C NMR (100 MHz, DMSO-d6)d162.7, 148.6, 147.8, 140.3, 134.4, 133.1, 131.1, 129.4, 129.2, 128.6, 128.2, 128.0, 127.5, 127.4, 125.0, 123.2, 122.8, 107.0.

[0154] Compound 4: 1 H NMR (500 MHz, DMSO-d6)d12.23 (s, 1H), 8.70 (s, 1H), 8.24 (d, 1H,J= 9.0 Hz), 8.00 (d, 1H,J= 8.5 Hz), 7.99 (d, 1H,J= 8.5 Hz), 7.96 (d, 1H,J= 9.0 Hz), 7.58 (t, 2H,J= 8.5 Hz), 7.50 (d, 1H,J= 8.5 Hz), 7.23 (d, 1H,J= 2.5 Hz), 7.11 (dd, 1H,J= 8.5, 2.5 Hz); 13 C NMR (100 MHz, DMSO-d6)d162.7, 148.6, 147.8, 140.3, 134.4, 133.1, 131.1, 129.4, 129.2, 128.6, 128.2, 128.0, 127.5, 127.4, 125.0, 123.2, 122.8, 107.0.

[0155]

[0156] Synthesis Example 4: 4-chloro-2-(naphthalen-1-yl)-6-nitroquinazoline (hereinafter referred to as compound 5) and 4-chloro-2-(naphthalen-2-yl)-6-nitroquinazoline (hereinafter referred to as compound 6)

[0157] A 1,4-dioxane solution (20 mL) containing phosphoryl chloride (9.4 mL, 0.1 mol) and compound 3 [2-(naphthalen-1-yl)-6-nitroquinazoline-4(3H)-one (2 g, 6.3 mmol)] or compound 4 [2-(naphthalen-2-yl)-6-nitroquinazoline-4(3H)-one (2 g, 6.3 mmol)] was stirred under reflux for 24 h, then cooled to room temperature, and the reaction mixture was very slowly added into ice water (900 mL). Ammonia water was very slowly added to adjust the pH to 6, and the resulting solid was filtered to obtain compound 5 (yield: 72%) as a brown solid and compound 6 (yield: 70%) as a brown solid, respectively. Since compounds 5 and 6 were unstable, they were used in the next reaction without further purification.

[0158]

[0159] Synthetic Example 5: General Synthetic Method for 2-(naphthalen-1-yl)-6-nitroquinazolin-4-amine Compounds (hereinafter referred to as Compounds 7, 8, 9 and 10) and 2-(naphthalen-2-yl)-6-nitroquinazolin-4-amine Compounds (hereinafter referred to as Compounds 11, 12, 13 and 14)

[0160] Diisopropylethylamine (4.8 mmol) was slowly added to a DMSO solution (4 mL) containing compound 5 [4-chloro-2-(naphthalen-1-yl)-6-nitroquinazoline (1.2 mmol)] or compound 6 [4-chloro-2-(naphthalen-2-yl)-6-nitroquinazoline (1.2 mmol)] and an amine compound [3,4-(methylenedioxy)aniline, 3-chloro-4-fluoroaniline, 5-aminoindane, or 2-aminofluorene] (1.2 mmol) at 0°C. After stirring at 100°C for 6 h and cooling, the reaction mixture was added to ice water (20 mL) and stirred for 30 min. The produced solid was filtered, ether and methanol were added to the filtered solid, and the mixture was stirred at room temperature for 1 hour. The remaining solid was filtered and washed with methanol to obtain the pure compound 7-14 below.

[0161]

[0162] Synthesis Example 6: N-(Benzo[d][1,3]dioxol-5-yl)-2-(naphthalen-1-yl)-6-nitroquinazolin-4-amine (hereinafter referred to as compound 7)

[0163] Dark brown solid; yield, 85%; 1 H NMR (500 MHz, DMSO-d6)d10.42 (s, 1H), 9.63 (s, 1H), 8.72 (d, 1H,J= 8.0 Hz), 8.52 (d, 1H,J= 7.0 Hz), 8.04 (d, 1H,J= 7.0 Hz), 8.00 (d, 1H,J= 8.0 Hz), 7.94 (d, 1H,J= 8.0 Hz), 7.93 (d, 1H,J= 8.0 Hz), 7.57 (t, 1H,J= 8.0 Hz), 7.51 (d, 1H,J= 2.0 Hz), 7.50 (t, 1H,J= 8.0 Hz), 7.47 (t, 1H,J= 8.0 Hz), 7.17 (dd, 1H,J= 8.5, 2.0 Hz), 6.87 (d, 1H,J= 8.5 Hz), 5.94 (s, 2H); 13 C NMR (100 MHz, DMSO-d6)d165.8, 159.6, 154.5, 147.7, 145.0, 144.8, 136.8, 134.2, 133.3, 131.3, 131.0, 130.2, 129.6, 128.9, 127.4, 127.1, 127.0, 126.6, 125.8, 121.5, 117.0, 113.5, 108.5, 105.9, 101.8.

[0164]

[0165] Synthesis Example 7: N-(3-chloro-4-fluorophenyl)-2-(naphthalen-1-yl)-6-nitroquinazolin-4-amine (hereinafter referred to as compound 8)

[0166] Brown solid; yield, 78%; 1H NMR (500 MHz, DMSO-d6)d10.62 (brs, 1H), 9.69 (s, 1H), 8.81 (d, 1H,J= 8.0 Hz), 8.60 (dd, 1H,J= 7.0, 2.5 Hz), 8.28 (dd, 1H,J= 7.0, 2.5 Hz), 8.12 (d, 1H,J= 8.0 Hz,), 8.08 (d, 1H,J= 8.0 Hz), 8.05 (d, 1H,J= 8.0 Hz), 8.01 (d, 1H,J= 9.0 Hz), 7.85 - 7.82 (m, 1H), 7.63 (t, 1H,J= 8.0 Hz), 7.57 (t, 1H,J= 8.0 Hz), 7.55 (t, 1H,J= 8.0 Hz), 7.43 (t, 1H,J= 9.0 Hz).

[0167]

[0168] Synthesis Example 8: N-(2,3-dihydro-1H-indene-5-yl)-2-(naphthalen-1-yl)-6-nitroquinazolin-4-amine (hereinafter referred to as compound 9)

[0169] Brown solid; yield, 60%; 1 H NMR (500 MHz, DMSO-d6)d10.45 (s, 1H), 9.69 (s, 1H), 8.82 (d, 1H,J= 8.0 Hz), 8.54 (dd, 1H,J= 7.5, 1.5 Hz), 8.10 (d, 1H,J= 7.5 Hz), 8.03 (d, 1H,J= 8.0 Hz), 7.97 (d, 1H,J= 8.0 Hz), 7.96 (s, 1H), 7.77 (d, 1H,J= 8.0 Hz), 7.59 (t, 1H,J= 8.0 Hz), 7.54 (d, 1H,J= 8.0 Hz), 7.53 (t, 1H,J= 8.0 Hz), 7.51 (t, 1H,J= 8.0 Hz), 7.18 (d, 1H,J= 8.0 Hz), 2.80 (d, 4H,J= 3.0 Hz), 1.99 (p, 2H,J= 7.5 Hz); 13C NMR (100 MHz, DMSO-d6)d165.8, 154.5, 145.0, 144.6, 140.7, 137.1, 136.7, 134.2, 131.3, 131.0, 130.1, 129.8, 128.9, 127.3, 127.0, 126.5, 125.7, 124.6, 121.7, 121.5, 120.0, 119.9, 113.5, 113.4, 33.1, 32.5, 25.8.

[0170]

[0171] Synthesis Example 9: N-(9H-fluoren-2-yl)-2-(naphthalen-1-yl)-6-nitroquinazolin-4-amine (hereinafter referred to as compound 10)

[0172] Brown solid; yield, 53%; 1 H NMR (500 MHz, DMSO-d6)d10.58 (s, 1H), 9.73 (s, 1H), 8.91 (d, 1H,J= 8.0 Hz), 8.54 (d, 1H,J= 7.5 Hz), 8.20 (s, 1H), 8.16 (d, 1H,J= 7.5 Hz), 8.05 (d, 1H,J= 8.0 Hz), 7.99 (d, 1H,J= 8.0 Hz), 7.98 (d, 1H,J= 8.0 Hz), 7.89 (d, 1H,J= 7.5 Hz), 7.85 (d, 1H,J= 7.5 Hz), 7.82 (d, 1H,J= 7.5 Hz), 7.62 (t, 1H,J= 8.0 Hz), 7.54 (t, 1H,J= 8.0 Hz), 7.53 (t, 1H,J= 8.0 Hz), 7.53 (d, 1H,J= 7.5 Hz), 7.34 (t, 1H,J= 7.5 Hz), 7.26 (t, 1H,J= 7.5 Hz), 3.84 (s, 2H).

[0173]

[0174] Synthesis Example 10: N-(Benzo[d][1,3]dioxol-5-yl)-2-(naphthalen-2-yl)-6-nitroquinazolin-4-amine (hereinafter referred to as compound 11)

[0175] Brown solid; yield, 63%;1 H NMR (500 MHz, DMSO-d6)d10.45 (s, 1H), 9.63 (d, 1H,J= 2.0 Hz), 8.97 (s, 1H), 8.54 (dd, 1H,J= 9.0, 2.5 Hz), 8.50 (d, 1H,J= 7.5 Hz), 8.03 (d, 2H,J= 7.5 Hz), 8.00 (d, 1H,J= 9.0 Hz), 7.97 (d, 1H,J= 7.5 Hz), 7.65 (d, 1H,J= 2.0 Hz), 7.60 (t, 1H,J= 7.5 Hz), 7.58 (t, 1H,J=7.5 Hz), 7.36 (dd, 1H,J=8.5, 2.0 Hz), 7.07 (d, 1H,J= 8.5 Hz), 6.11 (s, 2H); 13 C NMR (100 MHz, DMSO-d6)d164.3, 162.8, 159.5, 154.8, 147.8, 144.7, 135.7, 135.1, 133.3, 133.2, 130.2, 129.7, 129.4, 128.7, 128.3, 128.2, 127.5, 127.3, 125.7, 121.5, 116.7, 113.9, 108.6, 105.5, 102.0.

[0176]

[0177] Synthesis Example 11: N-(3-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-nitroquinazolin-4-amine (hereinafter referred to as compound 12)

[0178] Brown solid; yield, 62%; 1H NMR (500 MHz, DMSO-d6)d10.61 (brs, 1H), 9.61 (d, 1H,J= 2.0 Hz), 8.97 (s, 1H), 8.55 (dd, 1H,J= 9.0, 2.5 Hz), 8.52 (dd, 1H,J= 9.5, 2.0 Hz), 8.46 (dd, 1H,J= 9.0, 2.5 Hz), 8.04 (d, 2H,J= 8.5 Hz), 8.02 (d, 1H,J= 8.5 Hz), 7.98 (d, 1H,J= 7.0 Hz), 7.91 - 7.88 (m, 1H), 7.61 (t, 1H,J= 8.5 Hz), 7.60 (d, 1H,J= 7.0 Hz), 7.58 (t, 1H,J= 8.5 Hz).

[0179]

[0180] Synthesis Example 12: N-(2,3-dihydro-1H-indene-5-yl)-2-(naphthalen-2-yl)-6-nitroquinazolin-4-amine (hereinafter referred to as compound 13)

[0181] Orange solid; yield, 62%; 1 H NMR (500 MHz, DMSO-d6)d10.42 (s, 1H), 9.62 (d, 1H,J= 2.0 Hz), 8.94 (s, 1H), 8.50 (dd, 2H,J= 8.5, 2.0 Hz), 8.00 (d, 1H,J= 8.5 Hz), 7.98 (d, 1H,J= 8.5 Hz), 7.97 (d, 1H,J= 8.5 Hz), 7.95 (d, 1H,J= 8.5 Hz), 7.94 (s, 1H), 7.66 (d, 1H,J= 8.0 Hz), 7.58 (t, 1H,J= 8.5 Hz), 7.57 (t, 1H,J= 8.5 Hz), 7.34 (d, 1H,J= 8.0 Hz), 3.00 (t, 1H,J= 7.5 Hz), 2.92 (t, 1H,J= 7.5 Hz), 2.11 (p, 1H,J= 7.5 Hz).

[0182]

[0183] Synthesis Example 13: N-(9H-fluoren-2-yl)-2-(naphthalen-2-yl)-6-nitroquinazolin-4-amine (hereinafter referred to as compound 14)

[0184] Brown solid; yield, 69%; 1 H NMR (500 MHz, DMSO-d6)d10.61 (s, 1H), 9.71 (s, 1H), 9.23 (s, 1H), 8.57 (d, 1H,J= 8.0 Hz), 8.55 (d, 1H,J= 8.0 Hz), 8.35 (s, 1H), 8.06 (d, 1H,J= 8.0 Hz), 8.04 (d, 1H,J= 8.0 Hz), 8.03 (d, 1H,J= 8.0 Hz), 8.01 (d, 1H,J= 8.0 Hz), 8.00 (d, 1H,J= 7.5 Hz), 7.96 (d, 1H,J= 7.5 Hz), 7.92 (d, 1H,J= 7.5 Hz), 7.62 (d, 1H,J= 7.5 Hz), 7.60 (t, 1H,J= 8.0 Hz), 7.57 (t, 1H,J= 8.0 Hz), 7.41 (t, 1H,J= 7.5 Hz), 7.32 (t, 1H,J= 7.5 Hz), 4.06 (s, 2H).

[0185]

[0186] Synthesis Example 14: General Synthesis Method of 2-(naphthalen-1-yl)quinazoline-4,6-diamine Derivative

[0187] To a DMF solution (3 mL) containing the above compounds 7-14 (0.7 mmol), a (NH4)2S solution (yellow solution with a sulfur content of 5.0-6.0%, 7 mmol) was added, and the mixture was stirred at 80°C for 24 hours. After cooling, the reaction mixture was added to ice water (50 mL), stirred for 1 hour, and the resulting solid was filtered. The filtered solid was purified by silica gel column chromatography using a developing solvent of methylene chloride:methanol = 40:1 to obtain the following compounds 15-22.

[0188]

[0189] Synthesis Example 15:N4 -(Benzo[d][1,3]dioxol-5-yl)-2-(naphthalen-1-yl)quinazoline-4,6-diamine (hereinafter referred to as compound 15)

[0190] Brown solid; yield, 62%; 1 H NMR (500 MHz, DMSO-d6)d9.36 (s, 1H), 8.76 (d, 1H,J= 8.5 Hz), 7.97 (d, 1H,J= 8.5 Hz), 7.95 (d, 2H,J= 8.5 Hz), 7.62 (s, 1H), 7.61 (d, 1H,J= 8.5 Hz), 7.57 (t, 1H,J= 8.5 Hz), 7.51 (t, 1H,J= 8.5 Hz), 7.48 (t, 1H,J= 8.5 Hz), 7.40 (s, 1H), 7.26 (d, 1H,J= 8 Hz), 7.24 (d, 1H,J= 8.5 Hz), 6.85 (d, 1H,J= 8 Hz), 5.94 (s, 2H), 5.61 (brs, 2H); 13 C NMR (100 MHz, DMSO-d6)d162.5, 161.6, 152.7, 152.2, 148.3, 142.8, 139.7, 139.0, 136.2, 134.3, 134.2, 133.5, 133.3, 132.0, 131.3, 131.0, 130.6, 129.1, 120.3, 120.2, 113.1, 109.6, 106.7, 106.3.

[0191]

[0192] Synthesis Example 16:N 4 -(3-chloro-4-fluorophenyl)-2-(naphthalen-1-yl)quinazoline-4,6-diamine (hereinafter referred to as compound 16)

[0193] Brown solid; yield, 58%; 1H NMR (500 MHz, DMSO-d6)d9.53 (s, 1H), 8.73 (d, 1H,J= 9.5 Hz), 8.27 (dd, 1H,J= 7.5, 2.5 Hz), 7.94 (d, 1H,J= 7.5 Hz), 7.91 (d, 1H,J= 9.5 Hz), 7.90 (d, 1H,J= 9.5 Hz), 7.78 - 7.75 (m, 1H), 7.59 (d, 1H,J= 9.5 Hz), 7.52 (t, 1H,J= 9.5 Hz), 7.46 (t, 1H,J= 9.5 Hz), 7.44 (t, 1H,J= 9.5 Hz), 7.34 (d, 1H,J= 1.5 Hz), 7.28 (t, 1H,J= 8.5 Hz), 7.24 (dd, 1H,J= 8.5, 1.5 Hz), 5.63 (s, 2H); 13 C NMR (100 MHz, DMSO-d6)d157.4, 156.4, 154.7, 152.3, 148.3, 143.9, 137.9 (d,J= 28.3 Hz), 134.3, 131.4, 129.7 (d,J= 13.9 Hz), 128.8 (d,J= 7.2 Hz), 127.1, 126.8, 126.3, 125.8, 124.7, 123.7, 122.3 (d,J= 6.7 Hz), 119.4 (d,J= 18.1 Hz), 117.0 (d,J= 21.4 Hz), 115.6, 101.6.

[0194]

[0195] Synthesis Example 17:N 4 -(2,3-dihydro-1H-indene-5-yl)-2-(naphthalen-1-yl)quinazoline-4,6-diamine (hereinafter referred to as compound 17)

[0196] Brown solid; yield, 62%; 1H NMR (500 MHz, DMSO-d6)d9.35 (s, 1H), 8.85 (d, 1H,J= 8.0 Hz), 8.01 (d, 1H,J= 7.0 Hz), 7.95 (d, 1H,J= 7.0 Hz), 7.95 (d, 1H,J= 8.0 Hz), 7.83 (s, 1H), 7.62 (d, 1H,J= 8.0 Hz), 7.57 (t, 1H,J= 8.0 Hz), 7.56 (d, 1H,J= 8.0 Hz), 7.52 (t, 1H,J= 8.0 Hz), 7.50 (t, 1H,J= 8.0 Hz), 7.44 (d, 1H,J= 2.0 Hz), 7.27 (dd, 1H,J= 8.5, 2.0 Hz), 7.13 (d, 1H,J= 8.5 Hz), 5.60 (s, 2H), 2.78 (t, 4H,J= 6.5 Hz), 1.98 (p, 2H,J= 6.5 Hz).

[0197]

[0198] Synthesis Example 18:N 4 -(9H-fluoren-2-yl)-2-(naphthalen-1-yl)quinazoline-4,6-diamine (hereinafter referred to as compound 18)

[0199] Brown solid; yield, 60%; 1 H NMR (500 MHz, DMSO-d6)d9.58 (s, 1H), 8.90 (d, 1H,J= 8.0 Hz), 8.27 (s, 1H), 8.06 (d, 1H,J= 7.5 Hz), 7.97 (d, 1H,J= 7.5 Hz), 7.97 (d, 1H,J= 8.0 Hz), 7.90 (d, 1H,J= 8.0 Hz), 7.80 (d, 1H,J= 8.0 Hz), 7.79 (d, 1H,J= 7.5 Hz), 7.66 (d, 1H,J= 7.5 Hz), 7.60 (t, 1H,J= 8.0 Hz), 7.54 - 7.50 (m, 4H), 7.32 (t, 1H,J= 7.5 Hz), 7.30 (d, 1H,J= 7.5 Hz), 7.22 (t, 1H,J= 7.5 Hz), 5.66 (brs, 2H), 3.83 (s, 2H); 13C NMR (100 MHz, DMSO-d6)d157.7, 156.7, 148.1, 143.9, 143.4, 141.8, 139.7, 137.8, 136.8, 134.3, 131.5, 129.6, 129.5, 128.9, 128.8, 127.4, 126.6, 126.6, 126.3, 125.9, 125.6, 124.5, 121.2, 120.4, 120.0, 119.2, 115.8, 102.0, 37.1.

[0200]

[0201] Synthesis Example 19:N 4 -(Benzo[d][1,3]dioxol-5-yl)-2-(naphthalen-2-yl)quinazoline-4,6-diamine (hereinafter referred to as compound 19)

[0202] Brown solid; yield, 85%; 1 H NMR (500 MHz, DMSO-d6)d9.36 (s, 1H), 8.85 (s, 1H), 8.49 (d, 1H,J= 8.5 Hz), 7.96 (d, 2H,J= 8.5 Hz), 7.92 (d, 1H,J= 8.5 Hz), 7.73 (s, 1H), 7.64 (d, 1H,J= 9.0 Hz), 7.53 (t, 1H,J= 8.5 Hz), 7.52 (t, 1H,J= 8.5 Hz), 7.41 (d, 1H,J= 9.0 Hz), 7.37 (s, 1H), 7.25 (d, 1H,J=8.5 Hz), 7.01 (d, 1H,J= 8.5 Hz), 6.06 (s, 2H), 5.60 (s, 2H).

[0203]

[0204] Synthesis Example 20:N 4 -(3-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)quinazoline-4,6-diamine (hereinafter referred to as compound 20)

[0205] Brown solid; yield, 92%; 1H NMR (500 MHz, DMSO-d6)d9.64 (s, 1H), 8.86 (s, 1H), 8.56 (d, 1H,J= 8.0 Hz), 8.51 (d, 1H,J= 8.0 Hz), 8.00 (d, 1H,J= 8.0 Hz), 7.98 (d, 1H,J= 8.0 Hz), 7.93 (d, 1H,J= 9.0 Hz), 7.92 (s, 1H), 7.90 - 7.86 (m, 1H), 7.68 (d, 1H,J= 8.5 Hz), 7.54 (t, 1H,J= 8.0 Hz), 7.50 (t, 1H,J= 8.0 Hz), 7.37 (s, 1H), 7.29 (d, 1H,J= 8.5 Hz), 5.69 (s, 2H).

[0206]

[0207] Synthesis Example 21:N 4 -(2,3-dihydro-1H-indene-5-yl)-2-(naphthalen-2-yl)quinazoline-4,6-diamine (hereinafter referred to as compound 21)

[0208] Reddish brown solid; yield, 60%; 1 H NMR (500 MHz, DMSO-d6)d9.38 (s, 1H), 8.87 (s, 1H), 8.52 (d, 1H,J= 9.0 Hz), 8.04 (s, 1H), 7.97 (d, 2H,J= 9.0 Hz), 7.93 (d, 1H,J= 9.0 Hz), 7.68 (d, 1H,J= 9.0 Hz), 7.65 (d, 1H,J= 9.0 Hz), 7.55 (t, 1H,J= 9.0 Hz), 7.53 (t, 1H,J= 8.0 Hz), 7.42 (d, 1H,J= 2.0 Hz), 7.29 (d, 1H,J= 8.5 Hz), 7.26 (dd, 1H,J= 8.5, 2.0 Hz), 5.59 (s, 2H), 2.99 (t, 1H,J= 7.0 Hz), 2.90 (t, 1H,J= 7.0 Hz), 2.10 (p, 1H,J= 7.0 Hz).

[0209]

[0210] Synthesis Example 22:N 4-(9H-fluoren-2-yl)-2-(naphthalen-2-yl)quinazoline-4,6-diamine (hereinafter referred to as compound 22)

[0211] Brown solid; yield, 58%; 1 H NMR (500 MHz, DMSO-d6)d9.58 (s, 1H), 8.94 (s, 1H), 8.52 (d, 1H,J= 8.5 Hz), 8.44 (s, 1H), 8.03 (d, 1H,J= 8.5 Hz), 8.00 (d, 2H,J= 8.5 Hz), 7.97 (d, 1H,J= 9.0 Hz), 7.94 (d, 1H,J= 7.5 Hz), 7.88 (d, 1H,J= 7.5 Hz), 7.69 (d, 1H,J= 9.0 Hz), 7.61 (d, 1H,J= 7.5 Hz), 7.55 (t, 1H,J= 8.5 Hz), 7.53 (t, 1H,J= 8.5 Hz), 7.48 (d, 1H,J= 2.0 Hz), 7.38 (t, 1H,J= 7.5 Hz), 7.30 (dd, 1H,J= 7.5, 2.0 Hz), 7.27 (t, 1H,J= 7.5 Hz), 5.64 (s, 2H), 4.05 (s, 1H).

[0212]

[0213] Synthesis Example 23: General Synthesis Method of N-(4-arylamino-2-(naphthalen-1-yl)quinazolin-6-yl)benzamide Derivatives

[0214] Anhydrous pyridine (0.35 mmol) was added to an anhydrous CH2Cl2 solution (2 mL) containing the above compounds 15-18 (0.07 mmol) or 19-22 (0.07 mmol) and a benzoyl chloride derivative [4-(trifluoromethyl)benzoyl chloride, 3,4-dichlorobenzoyl chloride, p-toluoyl chloride, 4-tert-butylbenzoyl chloride, or 3,4,5-trimethoxybenzoyl chloride] (0.08 mmol), and the mixture was stirred at room temperature for 12 hours. The volatile components including the solvent were evaporated under reduced pressure, and ether, methanol, and a saturated NaHCO3 solution were added to the remaining residue, and the mixture was stirred at room temperature for 10 minutes. The resulting solid was filtered to obtain the following compounds 23-42 and 43-62 as solids.

[0215]

[0216] Synthesis Example 24: N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide (23 = hereinafter referred to as compound 5013)

[0217] Dark brown solid; yield, 40%; 1 H NMR (500 MHz, DMSO-d6)d10.87 (s, 1H), 9.89 (s, 1H), 8.94 (s, 1H), 8.78 (d, 1H,J= 8.0 Hz), 8.26 (d, 2H,J= 8.0 Hz), 8.04 (d, 2H,J= 8.5 Hz), 8.01 (d, 1H,J= 8.0 Hz), 8.00 (d, 1H,J= 8.0 Hz), 7.98 (d, 2H,J= 8.5 Hz), 7.89 (d, 1H,J= 8.0 Hz), 7.61 (t, 1H,J= 8.0 Hz), 7.58 (d, 1H,J= 2.0 Hz), 7.54(t, 1H,J= 8.0 Hz), 7.51 (t, 1H,J= 8.0 Hz), 7.24 (dd, 1H,J= 8.0, 2.0 Hz), 6.88 (d, 1H,J= 8.0 Hz), 5.97 (s, 2H); 13C NMR (100 MHz, DMSO-d6)d165.1, 161.7, 158.4, 148.3, 147.6, 144.1, 139.0, 137.6, 136.8, 134.3, 134.2, 132.3 (q, 2 J C-F = 32.0 Hz), 131.4, 130.1, 129.3, 129.3, 129.2, 129.2, 129.0, 128.8, 127.2, 126.8, 126.4, 126.2 (q, 3 J C-F = 4.0 Hz), 125.8 (q, 1 J C-F = 272.0 Hz), 116.3, 114.9, 114.3, 108.4, 105.5, 101.6; LRMS (ESI+)m / z578.16 (M+H) + .

[0218]

[0219] Synthesis Example 25: N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-1-yl)quinazolin-6-yl)-3,4-dichlorobenzamide (24 = hereinafter referred to as compound 5009)

[0220] Yellow solid; yield, 31%; 1 H NMR (500 MHz, DMSO-d6)d10.76 (s, 1H), 9.86 (s, 1H), 8.88 (s, 1H), 8.77 (d, 1H,J= 8.0 Hz), 8.32 (d, 1H,J= 1.5 Hz), 8.04 - 8.00 (m, 4H), 7.97 (d, 1H,J= 8.0 Hz), 7.89 (d, 1H,J= 8.5 Hz), 7.87 (d, 1H,J= 8.5 Hz), 7.60 (t, 1H,J= 8.0 Hz), 7.57 (d, 1H,J= 2.0 Hz), 7.53 (t, 1H,J= 8.0 Hz), 7.50 (t, 1H,J= 8.0 Hz), 7.22 (dd, 1H,J= 8.0, 2.0 Hz), 6.88 (d, 1H,J= 8.0 Hz), 5.96 (s, 2H); 13C NMR (100 MHz, DMSO-d6)d163.9, 161.7, 158.4, 147.6, 144.1, 137.6, 136.8, 135.4, 135.3, 134.2, 134.2, 132.1, 131.6, 131.4, 130.3, 130.1, 129.1, 129.0, 129.0, 128.8, 128.7, 127.1, 126.8, 126.4, 125.8, 116.3, 114.8, 114.2, 108.4, 105.5, 101.6; LRMS (ESI+) m / z 579.12 (M+H) + .

[0221]

[0222] Synthesis Example 26: N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-methylbenzamide (25 = hereinafter referred to as compound 5017)

[0223] Yellow solid; yield, 30%; 1 H NMR (500 MHz, DMSO-d6)d10.61 (s, 1H), 9.89 (s, 1H), 8.92 (s, 1H), 8.76 (d, 1H,J= 8.0 Hz), 8.09 (d, 1H,J= 7.0 Hz), 8.03 (d, 1H,J= 7.0 Hz), 8.02 (d, 1H,J= 8.0 Hz), 8.02 (d, 2H,J= 9.0 Hz), 7.98 (d, 1H,J= 8.0 Hz), 7.86 (d, 1H,J= 8.0 Hz), 7.60 (t, 1H,J= 8.0 Hz), 7.59 (s, 1H), 7.53 (t, 1H,J= 8.0 Hz), 7.50 (t, 1H,J= 8.0 Hz), 7.37 (d, 2H,J= 9.0 Hz), 7.26 (d, 1H,J= 8.0 Hz), 6.87 (d, 1H,J= 8.0 Hz), 5.96 (s, 2H), 2.40 (s, 3H); 13C NMR (100 MHz, DMSO-d6)d166.0, 161.1, 158.5, 147.6, 144.3, 142.6, 137.6, 134.2, 134.0, 132.2, 131.3, 130.3, 130.0, 129.7, 129.3, 129.1, 128.9, 128.4, 127.0, 126.9, 126.5, 125.8, 116.5, 114.6, 114.2, 108.4, 105.6, 101.7, 31.3; LRMS (ESI+)m / z525.13 (M+H) + .

[0224]

[0225] Synthesis Example 27: N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(tert-butyl)benzamide (26 = hereinafter referred to as compound 5025)

[0226] Dark brown solid; yield, 47%; 1 H NMR (500 MHz, DMSO-d6)d10.55 (s, 1H), 9.90 (s, 1H), 8.94 (s, 1H), 8.76 (d, 1H,J= 7.5 Hz), 8.04 (d, 1H,J= 7.0 Hz), 8.02 (d, 1H,J= 7.0 Hz), 8.01 (d, 1H,J= 7.5 Hz), 7.99 (d, 2H,J= 8.5 Hz), 7.98 (d, 2H,J=7.5 Hz), 7.87 (d, 1H,J= 7.5 Hz), 7.60 (t, 1H,J= 7.5 Hz), 7.59 (d, 2H,J= 8.5 Hz), 7.57 (d, 1H,J= 2.0 Hz), 7.53 (t, 1H,J= 7.5 Hz), 7.51 (t, 1H,J= 7.5 Hz), 7.23 (dd, 1H,J= 8.5, 2.0 Hz), 6.88 (d, 1H,J= 8.5 Hz), 5.97 (s, 2H), 1.33 (s, 9H); 13C NMR (100 MHz, DMSO-d6)d166.1, 161.4, 158.4, 155.4, 147.6, 144.1, 137.5, 134.2, 132.4, 131.4, 130.1, 129.1, 129.0, 128.8, 128.2, 127.5, 127.1, 126.9, 126.4, 126.0, 125.8, 125.6, 116.4, 114.4, 114.3, 108.4, 105.5, 101.6, 35.4, 31.6; LRMS (ESI-)m / z565.28 (MH) - .

[0227]

[0228] Synthesis Example 28: N-(4-(Benzo[d][1,3]dioxol-5-ylmino)-2-(naphthalen-1-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide (27 = hereinafter referred to as compound 5021)

[0229] Brown solid; yield, 30%; 1 H NMR (500 MHz, DMSO-d6)d10.66 (s, 1H), 9.94 (s, 1H), 8.87 (s, 1H), 8.76 (d, 1H,J= 7.5 Hz), 8.15 (d, 1H,J= 7.5 Hz), 8.03 (d, 1H,J= 7.5 Hz), 8.01 (d, 1H,J= 8.5 Hz), 7.98 (d, 1H,J= 8.5 Hz), 7.88 (d, 1H,J= 8.5 Hz), 7.61 (s, 1H), 7.60 (t, 1H,J= 8.5 Hz), 7.53 (t, 1H,J=8.5 Hz), 7.51 (t, 1H,J= 8.5 Hz), 7.43 (s, 2H), 7.28 (d, 1H,J= 8.0 Hz), 6.86 (d, 1H,J= 8.0 Hz), 5.95 (s, 2H), 3.89 (s, 6H), 3.74 (s, 3H); 13C NMR (100 MHz, DMSO-d6)d165.5, 161.4, 158.4, 153.4, 147.6, 144.2, 141.3, 141.3, 137.3, 134.2, 131.4, 130.2, 130.0, 129.5, 129.1, 128.9, 127.1, 126.9, 126.4, 125.8, 121.6, 121.5, 116.3, 115.0, 114.2, 108.4, 106.1, 105.5, 101.7, 60.8, 56.9; LRMS (ESI+) m / z 601.26 (M+H) + .

[0230]

[0231] Synthesis Example 29: N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide (28 = hereinafter referred to as compound 5011)

[0232] Brown solid; yield, 72%; 1 H NMR (500 MHz, DMSO-d6)d10.98 (s, 1H, CONH), 10.51 (brs, 1H), 9.07 (s, 1H), 8.69 (d, 1H,J= 8.0 Hz), 8.27 (d, 2H,J= 8.0 Hz), 8.23 ​​(d, 1H,J= 4.5 Hz), 8.13 (d, 1H,J= 8.0 Hz), 8.07 (d, 1H,J= 8.0 Hz), 8.05 (d, 1H,J= 8.0 Hz), 8.01 (d, 1H,J= 8.0 Hz), 8.00 (d, 1H,J= 8.0 Hz), 7.97 (d, 2H,J= 8.0 Hz), 7.78 (d, 1H,J= 8.0 Hz), 7.64 (t, 1H,J= 8.0 Hz), 7.57 (t, 2H,J= 8.0 Hz), 7.40 (t, 1H,J= 8.0 Hz); 13C NMR (100 MHz, DMSO-d6)d165.2, 160.7, 158.6, 154.6 (d,J= 240.2 Hz), 138.8, 137.8, 136.8, 134.2, 132.4 (q,J= 32.0 Hz), 132.2, 131.1, 129.8, 129.6, 129.4, 129.4, 129.3, 129.0, 127.4, 126.7, 126.3 (q,J= 4.0 Hz), 125.8 (q,J= 272.0 Hz), 125.6, 124.0 (d,J=6.7 Hz), 119.6 (d,J= 18.2 Hz), 117.2 (d,J= 21.4 Hz), 114.7, 114.1; LRMS (ESI-)m / z585.19 (MH) - .

[0233]

[0234] Synthesis Example 30: 3,4-dichloro-N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)benzamide (29 = hereinafter referred to as compound 5007)

[0235] Yellow solid; yield, 32%; 1 H NMR (500 MHz, DMSO-d6)d10.83 (s, 1H), 10.23 (brs, 1H), 8.98 (s, 1H), 8.76 (d, 1H,J= 7.0 Hz), 8.32 (d, 1H,J= 1.5 Hz), 8.26 (d, 1H,J= 4.5 Hz), 8.08 (d, 1H,J= 9.0 Hz), 8.06 (d, 1H,J= 9.0 Hz), 8.04 (d, 1H,J= 7.0 Hz), 8.04 (d, 1H,J= 7.0 Hz), 8.00 (d, 1H,J= 7.0 Hz), 7.95 (d, 1H,J= 8.5 Hz), 7.88 (d, 1H,J= 8.5 Hz,), 7.81 (t, 1H,J= 4.5 Hz), 7.63 (t, 1H,J= 7.0 Hz), 7.56 (t, 1H,J= 7.0 Hz), 7.55 (t, 1H,J= 7.0 Hz), 7.39 (t, 1H,J= 9.5 Hz); 13C NMR (100 MHz, DMSO-d6)d164.0, 159.7, 158.6, 153.9 (d,J=241.2 Hz), 137.6, 135.5, 135.3, 134.2, 132.1, 131.6, 131.1, 131.0, 130.3, 129.8, 129.5, 129.0, 128.8, 127.4, 126.7, 126.7, 126.6, 125.8, 125.7, 123.9 (d,J= 6.7 Hz), 119.4 (d,J= 18.2 Hz), 117.2 (d,J= 21.5 Hz), 114.6, 114.1; LRMS (ESI-)m / z585.13 (MH) - .

[0236]

[0237] Synthesis Example 31: N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-methylbenzamide (30 = hereinafter referred to as compound 5015)

[0238] Orange solid; yield, 98%; 1 H NMR (500 MHz, DMSO-d6)d10.68 (s, 1H), 10.16 (s, 1H), 9.00 (s, 1H), 8.79 (d, 1H,J= 8.0 Hz), 8.31 (d, 1H,J= 4.5 Hz), 8.16 (d, 1H,J= 9.0 Hz), 8.06 (d, 1H,J= 9.0 Hz), 8.02 (d, 2H,J= 8.0 Hz), 8.00 (d, 2H,J= 7.5 Hz), 7.91 (d, 1H,J= 8.0 Hz), 7.86 (t, 1H,J= 4.5 Hz), 7.61 (t, 1H,J= 8.0 Hz), 7.55 (t, 1H,J= 8.0 Hz), 7.54 (t, 1H,J= 8.0 Hz), 7.36 (d, 2H,J= 7.5 Hz), 7.35 (t, 1H,J= 7.0 Hz), 2.39 (s, 3H); 13C NMR (100 MHz, DMSO-d6)d166.1, 161.1, 158.1, 153.9 (d,J=241.2 Hz), 148.0, 142.6, 137.8, 137.5, 137.4, 134.3, 132.2, 131.4, 130.2, 129.7, 129.2, 129.1, 128.9, 128.4, 127.0, 127.0, 126.4, 125.8, 124.5, 123.1 (d,J= 6.7 Hz), 119.4 (d,J= 18.2 Hz), 117.0 (d,J=21.5 Hz), 114.3, 114.2, 21.7; LRMS (ESI+)m / z533.13 (M+H) + .

[0239]

[0240] Synthesis Example 32: 4-(tert-butyl)-N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)benzamide (31 = hereinafter referred to as compound 5023)

[0241] Yellow solid; yield, 25%; 1 H NMR (500 MHz, DMSO-d6)d10.57 (s, 1H), 10.08 (s, 1H), 9.00 (s, 1H), 8.81 (dd, 1H,J= 8.0, 2.0 Hz), 8.28 (dd, 1H,J= 6.5, 2.0 Hz), 8.07 (d, 2H,J= 7.0 Hz), 8.05 (d, 1H,J= 7.0 Hz), 8.02 (d, 1H,J= 8.0 Hz), 7.99 (d, 1H,J= 8.0 Hz), 7.99 (d, 2H,J= 7.0 Hz), 7.92 (d, 1H,J=8.0 Hz), 7.84 - 7.82 (m, 1H), 7.61 (t, 1H,J= 8.0 Hz), 7.59 (d, 2H,J= 7.0 Hz), 7.55 (t, 1H,J= 8.0 Hz), 7.54 (t, 1H,J= 8.0 Hz), 7.38 (t, 1H,J= 6.5 Hz), 1.33 (s, 9H); 13C NMR (100 MHz, DMSO-d6)d166.2, 161.1, 158.1, 155.4, 153.2 (d,J= 242.2 Hz), 148.1, 137.7, 137.5 (d,J= 2.8 Hz), 137.3, 134.3, 132.4, 131.4, 130.2, 129.2, 129.1, 128.9, 128.2, 127.0, 127.0, 126.4, 126.0, 125.8, 124.6, 123.2 (d,J= 6.7 Hz), 119.4 (d,J=18.0 Hz), 117.1 (d,J= 21.5 Hz), 114.3, 114.0, 35.4, 31.6; LRMS (ESI-)m / z573.27 (MH) - .

[0242]

[0243] Synthesis Example 33: N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide (32 = hereinafter referred to as compound 5019)

[0244] Brown solid; yield, 35%; 1 H NMR (500 MHz, DMSO-d6)d10.58 (s, 1H), 10.19 (s, 1H), 8.93 (s, 1H), 8.77 (d, 1H,J= 7.0 Hz), 8.28 (d, 1H,J= 4.5 Hz), 8.10 (d, 1H,J= 8.0 Hz), 8.07 (d, 1H,J= 7.0 Hz), 8.05 (d, 1H,J= 8.0 Hz), 8.00 (dd, 1H,J= 7.0, 3.0 Hz), 7.82 (t, 1H,J= 4.5 Hz), 7.63 (t, 1H,J= 7.0 Hz), 7.56 (t, 1H,J= 7.0 Hz), 7.55 (t, 1H,J= 7.0 Hz), 7.41 (s, 2H), 7.39 (t, 1H,J= 9.0 Hz), 3.89 (s, 6H), 3.75 (s, 3H); 13C NMR (100 MHz, DMSO-d6)d165.5, 161.1, 158.1, 153.9 (d,J=241.2 Hz), 153.4, 141.4, 137.7, 136.5, 134.2, 131.3, 130.0, 129.8, 129.4, 129.3, 128.9, 127.2, 126.9, 126.6, 125.8, 125.8, 124.9, 123.5 (d,J= 6.7 Hz), 119.4 (d,J= 16.8 Hz), 117.2 (d,J= 21.6 Hz), 114.8, 114.2, 106.1, 60.8, 56.9; LRMS (ESI+)m / z504.19 (M+H) + .

[0245]

[0246] Synthesis Example 34: N-(4-((2,3-dihydro-1H-indene-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide (33 = hereinafter referred to as compound 5012)

[0247] Brown solid; yield, 27%; 1 H NMR (500 MHz, DMSO-d6)d11.30 (s, 1H), 9.28 (s, 1H), 8.42 (s, 1H), 8.32 (d, 2H,J= 7.5 Hz), 8.16 (d, 2H,J= 7.5 Hz), 8.11 (d, 1H,J= 8.0 Hz), 8.04 (d, 1H,J= 7.0 Hz), 8.01 (d, 1H,J= 7.0 Hz), 7.96 (d, 2H,J= 8.0 Hz), 7.90 (d, 1H,J= 8.0 Hz), 7.69 (t, 1H,J= 8.0 Hz), 7.64 (t, 1H,J= 8.0 Hz), 7.60 (s, 1H), 7.58 (t, 1H,J= 8.0 Hz), 7.41 (d, 1H,J= 8.0 Hz), 7.21 (d, 1H,J= 8.0 Hz), 2.78 (t, 4H,J= 7.5 Hz), 1.96 (p, 2H,J= 7.5 Hz); 13C NMR (125 MHz, DMSO-d6)d165.1, 159.3, 158.5, 144.6, 142.7, 138.9, 138.2, 135.4, 135.2, 133.7, 133.6, 132.7, 132.1 (q, 2 J C-F = 32.0 Hz), 131.0, 130.6, 130.4, 130.2, 129.4, 128.9, 127.7, 127.2, 126.9, 126.0 (q, 3 J C-F = 4.0 Hz), 125.5 (q, 1 J C-F = 272.0 Hz), 124.6, 123.3, 121.5, 121.1, 115.6, 113.4, 32.9, 32.4, 25.6; LRMS (ESI-)m / z573.27 (MH) - .

[0248]

[0249] Synthesis Example 35: 3,4-dichloro-N-(4-((2,3-dihydro-1H-indene-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)benzamide (34 = hereinafter referred to as compound 5008)

[0250] Brown solid; yield, 54%; 1H NMR (500 MHz, DMSO-d6)d10.93 (s, 1H), 9.06 (s, 1H), 8.34 (s, 1H), 8.21 (d, 1H,J= 7.5 Hz), 8.14 (d, 1H,J= 9.0 Hz), 8.10 (d, 1H,J= 9.0 Hz), 8.06 (s, 1H), 8.02 (d, 2H,J= 7.5 Hz), 7.96 (d, 1H,J= 7.5 Hz), 7.89 (d, 1H,J= 9.0 Hz), 7.85 (d, 1H,J= 9.0 Hz), 7.70 (s, 1H), 7.65 (t, 1H,J= 7.5 Hz), 7.59 (t, 1H,J= 7.5 Hz), 7.57 (t, 1H,J= 7.5 Hz), 7.47 (d, 1H,J= 8.0 Hz), 7.19 (d, 1H,J= 8.0 Hz), 2.79 (t, 4H,J= 8.0 Hz), 1.97 (p, 2H,J= 8.0 Hz); 13 C NMR (125 MHz, DMSO-d6)d163.8, 158.6, 157.7, 145.4, 144.4, 135.3, 135.0, 133.9, 133.6, 131.9, 131.4, 130.9, 130.5, 130.2, 129.4, 128.9, 128.8, 128.6, 128.5, 127.7, 127.0, 126.6, 125.7, 125.6, 125.5, 124.4, 122.4, 121.9, 120.2, 115.0, 113.9, 32.9, 32.3, 25.7; LRMS (ESI-)m / z573.18 (MH) - .

[0251]

[0252] Synthesis Example 36: N-(4-((2,3-dihydro-1H-indene-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-methylbenzamide (35 = hereinafter referred to as compound 5016)

[0253] Brown solid; yield, 28%; 1H NMR (500 MHz, DMSO-d6)d10.82 (s, 1H), 9.25 (s, 1H), 8.57 (dd, 1H,J= 8.5, 2.5 Hz), 8.42 (s, 1H), 8.24 (d, 1H,J= 8.5 Hz), 8.21 (d, 1H,J= 8.5 Hz), 8.06 (d, 1H,J= 8.5 Hz), 8.05 (d, 1H,J= 8.5 Hz), 7.99 (d, 2H,J= 8.0 Hz), 7.99 (d, 1H,J= 8.5 Hz), 7.70 (t, 1H,J= 8.5 Hz), 7.64 (s, 1H), 7.64 (t, 1H,J= 8.5 Hz), 7.62 (t, 1H,J= 8.5 Hz), 7.58 (d, 1H,J= 8.0 Hz), 7.40 (d, 2H,J= 8.0 Hz), 7.22 (d, 1H,J= 8.0 Hz), 2.79 (t, 4H,J= 8.0 Hz), 2.41 (s, 3H), 1.97 (p, 2H,J= 8.0 Hz); 13 C NMR (125 MHz, DMSO-d6)d166.0, 159.3, 157.8, 145.4, 144.6, 142.8, 133.7, 133.6, 131.5, 130.5, 130.4, 130.0, 129.8, 129.6, 128.9, 128.5, 128.4, 127.7, 127.2, 127.0, 125.7, 125.5, 124.6, 123.2, 122.5, 121.9, 121.4, 115.1, 113.5, 32.9, 32.4, 25.6, 21.6; LRMS (ESI-)m / z519.27 (MH) - .

[0254]

[0255] Synthesis Example 37: 4-(tert-butyl)-N-(4-((2,3-dihydro-1H-indene-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)benzamide (36 = hereinafter referred to as compound 5024)

[0256] Brown solid; yield, 31%; 1H NMR (500 MHz, DMSO-d6)d10.54 (s, 1H), 9.86 (s, 1H), 8.96 (s, 1H), 8.85 (d, 1H,J= 8.0 Hz), 8.07 (d, 1H,J=9.0 Hz), 8.03 (d, 1H,J= 9.0 Hz), 8.00 (d, 2H,J= 8.5 Hz), 7.96 (d, 1H,J= 8.0 Hz), 7.89 (d, 1H,J= 8.0 Hz), 7.79 (d, 1H,J= 8.0 Hz), 7.61 (t, 1H,J= 8.0 Hz), 7.60 (s, 1H), 7.59 (d, 2H,J= 8.5 Hz), 7.56 (t, 1H,J= 8.0 Hz), 7.55 (d, 1H,J= 8.0 Hz), 7.54 (t, 1H,J= 8.0 Hz), 7.16 (d, 1H,J= 8.0 Hz), 2.80 (t, 4H,J= 8.0 Hz), 1.99 (p, 2H,J= 8.0 Hz), 1.33 (s, 9H); 13 C NMR (125 MHz, DMSO-d6)d162.9, 159.3, 158.9, 145.6, 144.6, 143.0, 137.0, 135.4, 133.7, 132.7, 131.7, 130.8, 130.2, 129.7, 128.9, 128.8, 128.5, 128.3, 127.8, 127.4, 126.7, 125.8, 125.5, 124.6, 123.4, 121.6, 120.8, 115.1, 113.4, 35.6, 35.2, 31.4, 31.3, 25.6; LRMS (ESI-)m / z561.29 (MH) - .

[0257]

[0258] Synthesis Example 38: N-(4-((2,3-dihydro-1H-indene-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide (37 = hereinafter referred to as compound 5020)

[0259] Brown solid; yield, 45%; 1H NMR (500 MHz, DMSO-d6)d10.56 (s, 1H), 9.87 (s, 1H), 8.88 (s, 1H), 8.84 (d, 1H,J= 8.0 Hz), 8.06 (d, 2H,J= 6.5 Hz), 8.00 (d, 1H,J= 8.0 Hz), 7.98 (d, 1H,J= 8.0 Hz,), 7.89 (d, 1H,J= 8.0 Hz), 7.81 (s, 1H), 7.60 (t, 1H,J= 8.0 Hz), 7.54 (t, 1H,J= 8.0 Hz), 7.53 (d, 1H,J=8.0 Hz), 7.52 (t, 1H,J= 8.0 Hz), 7.42 (s, 2H), 7.15 (d, 1H,J= 8.0 Hz), 3.89 (s, 6H), 3.75 (s, 3H), 2.79 (t, 4H,J= 8.0 Hz), 1.98 (p, 2H,J= 8.0 Hz); 13 C NMR (125 MHz, DMSO-d6)d165.3, 161.4, 158.1, 153.2, 148.0, 144.2, 140.9, 139.4, 138.0, 137.4, 137.0, 134.1, 131.2, 129.9, 129.9, 129.1, 129.0, 128.8, 128.7, 127.1, 126.6, 126.2, 125.7, 124.4, 121.1, 119.3, 114.9, 114.2, 105.8, 60.6, 56.6, 33.0, 32.3, 25.7; LRMS (ESI-)m / z595.33 (MH) - .

[0260]

[0261] Synthesis Example 39: N-(4-((9H-fluoren-2-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide (38 = hereinafter referred to as compound 5014)

[0262] Brown solid; yield, 40%; 1H NMR (500 MHz, DMSO-d6)d11.57 (brs, 1H), 11.19 (s, 1H), 9.29 (s, 1H), 8.53 (d, 1H,J= 8.0 Hz), 8.30 (d, 2H,J= 8.0 Hz), 8.27 (d, 1H,J= 8.0 Hz), 8.18 (d, 1H,J= 8.5 Hz), 8.09 (d, 1H,J= 8.5 Hz), 8.05 (d, 1H,J= 8.0 Hz), 8.04 (s, 1H), 8.04 (d, 1H,J= 8.0 Hz), 7.98 (d, 2H,J= 8.0 Hz), 7.90 (d, 1H,J= 7.5 Hz), 7.84 (d, 1H,J= 7.5 Hz), 7.76 (d, 1H,J= 7.5 Hz), 7.69 (t, 1H,J= 8.0 Hz), 7.66 (t, 1H,J= 8.0 Hz), 7.63 (t, 1H,J= 8.0 Hz), 7.55 (d, 1H,J= 7.5 Hz), 7.34 (t, 1H,J= 7.5 Hz), 7.28 (t, 1H,J= 7.5 Hz), 3.86 (s, 2H); 13 C NMR (125 MHz, DMSO-d6)d165.1, 159.3, 158.6, 143.7, 143.6, 140.9, 139.8, 138.9, 138.2, 136.3, 133.7, 132.6, 132.3 (q,J= 32.0 Hz), 131.0, 130.6, 130.5, 130.4, 130.2, 129.4, 128.9, 127.8, 127.3, 127.3, 127.2, 126.2, 126.0 (q,J= 4.0 Hz), 125.6, 125.5, 125.5 (q, 1 J C-F = 272.0 Hz), 124.0, 122.1, 120.6, 120.4, 115.6, 113.6, 36.9; LRMS (ESI+)m / z623.25 (M+H) + .

[0263]

[0264] Synthesis Example 40: N-(4-((9H-fluoren-2-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-3,4-dichlorobenzamide (39 = hereinafter referred to as compound 5010)

[0265] Reddish brown solid; yield, 45%; 1 H NMR (500 MHz, DMSO-d6)d11.01 (s, 1H), 9.17 (s, 1H), 8.62 (d, 1H,J= 8.5 Hz), 8.36 (d, 1H,J= 1.0 Hz), 8.19 (d, 1H,J= 9.0 Hz), 8.15 (d, 1H,J= 9.0 Hz), 8.08 (d, 1H,J= 8.5 Hz), 8.06 (s, 1H), 8.05 (d, 1H,J= 8.5 Hz), 8.03 (d, 1H,J= 8.5 Hz), 8.01 (s, 1H), 7.88 (d, 2H,J= 7.5 Hz), 7.83 (d, 1H,J= 7.5 Hz), 7.79 (d, 1H,J= 7.5 Hz), 7.67 (t, 1H,J= 8.5 Hz), 7.63 (t, 1H,J= 8.5 Hz), 7.61 (t, 1H,J= 8.5 Hz), 7.54 (d, 2H,J= 7.5 Hz), 7.34 (t, 1H,J= 7.5 Hz), 7.26 (t, 1H,J= 7.5 Hz), 3.85 (s, 2H); 13 C NMR (100 MHz, DMSO-d6)d164.1, 159.1, 144.0, 143.7, 141.3, 139.2, 139.1, 138.4, 138.3, 138.3, 138.2, 137.4, 137.3, 135.5, 135.1, 134.1, 132.2, 131.9, 131.6, 130.9, 130.4, 129.8, 129.1, 128.8, 127.6, 127.5, 127.2, 127.1, 126.6, 125.8, 125.7, 123.3, 121.4, 120.5, 115.3, 114.0, 94.6, 37.1; LRMS (ESI-)m / z621.17 (MH) - .

[0266]

[0267] Synthesis Example 41: N-(4-((9H-fluoren-2-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-methylbenzamide (40 = hereinafter referred to as compound 5018)

[0268] Brown solid; yield, 71%; 1 H NMR (500 MHz, DMSO-d6)d10.36 (s, 1H), 9.29 (s, 1H), 8.92 (d, 1H,J= 8.5 Hz), 8.38 (s, 1H), 8.31 (d, 1H,J= 8.0 Hz), 8.13 (d, 1H,J= 8.0 Hz), 8.10 (d, 2H,J= 7.5 Hz), 8.02 (d, 1H,J= 8.5 Hz), 8.00 (s, 1H), 7.90 (d, 1H,J= 8.5 Hz), 7.86 (d, 1H,J= 8.5 Hz), 7.84 (d, 1H,J= 7.5 Hz), 7.81 (d, 1H,J= 7.5 Hz), 7.63 (t, 1H,J= 8.5 Hz), 7.56 (t, 1H,J= 8.5 Hz), 7.54 (t, 1H,J= 8.5 Hz), 7.42 (d, 1H,J= 7.5 Hz), 7.38 (d, 2H,J= 7.5 Hz), 7.33 (t, 1H,J= 7.5 Hz), 7.24 (t, 1H,J= 7.5 Hz), 7.15 (d, 1H,J= 7.5 Hz), 3.85 (s, 2H), 2.41 (s, 3H); 13 C NMR (125 MHz, DMSO-d6)d165.8, 158.0, 143.7, 143.3, 141.6, 139.5, 138.4, 138.1, 138.0, 137.5, 136.8, 134.1, 132.1, 131.3, 129.9, 129.6, 129.5, 129.1, 128.7, 128.7, 128.4, 128.1, 127.2, 127.1, 126.7, 126.5, 126.2, 125.8, 125.5, 121.2, 120.3, 120.0, 119.3, 114.5, 114.3, 37.0, 21.4; LRMS (ESI-)m / z567.26 (MH)- .

[0269]

[0270] Synthesis Example 42: N-(4-((9H-fluoren-2-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(tert-butyl)benzamide (41 = hereinafter referred to as compound 5026)

[0271] Brown solid; yield, 54%; 1 H NMR (500 MHz, DMSO-d6)d10.75 (s, 1H), 10.18 (s, 1H), 9.13 (s, 1H), 8.91 (d, 1H,J= 7.5 Hz), 8.29 (s, 1H), 8.16 (d, 1H,J= 9.0 Hz), 8.12 (d, 1H,J= 9.0 Hz), 8.04 (d, 2H,J= 8.0 Hz), 8.02 (d, 1H,J= 7.5 Hz), 7.99 (d, 1H,J= 7.5 Hz), 7.95 (d, 1H,J= 7.5 Hz), 7.90 (d, 1H,J= 7.0 Hz), 7.83 (d, 1H,J= 7.0 Hz), 7.81 (d, 1H,J= 7.0 Hz), 7.63 (t, 1H,J= 7.5 Hz), 7.60 (t, 1H,J= 7.5 Hz), 7.56 (t, 1H,J= 7.5 Hz), 7.53 (d, 2H,J= 8.0 Hz), 7.33 (t, 1H,J= 7.0 Hz), 7.28 (d, 1H,J= 7.0 Hz), 7.24 (t, 1H,J= 7.0 Hz), 3.85 (s, 2H), 1.33 (s, 9H); LRMS (ESI-)m / z609.36 (MH) - .

[0272]

[0273] Synthesis Example 43: N-(4-((9H-fluoren-2-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide (42 = hereinafter referred to as compound 5022)

[0274] Brown solid; yield, 72%; 1H NMR (500 MHz, DMSO-d6)d10.89 (s, 1H), 9.22 (s, 1H), 8.54 (s, 1H), 8.31 (d, 1H,J= 8.0 Hz), 8.19 (d, 1H,J= 8.0 Hz), 8.07 (d, 1H,J= 7.5 Hz), 8.06 (s, 1H), 8.05 (d, 1H,J= 7.5 Hz), 8.04 (d, 1H,J= 8.0 Hz), 7.90 (d, 1H,J= 8.0 Hz), 7.85 (d, 1H,J= 7.5 Hz), 7.78 (d, 1H,J= 7.5 Hz), 7.70 (t, 1H,J= 8.0 Hz), 7.67 (t, 1H,J= 8.0 Hz), 7.64 (t, 1H,J= 8.0 Hz), 7.55 (d, 1H,J= 7.5 Hz), 7.47 (s, 2H), 7.35 (t, 1H,J= 7.5 Hz), 7.28 (t, 1H,J= 7.5 Hz), 7.22 (d, 1H,J= 7.5 Hz), 3.91 (s, 6H), 3.86 (s, 2H), 3.76 (s, 3H); 13 C NMR (125 MHz, DMSO-d6)d165.3, 161.3, 158.0, 153.2, 148.0, 143.8, 143.3, 141.5, 140.9, 139.1, 137.4, 137.2, 137.1, 134.1, 131.2, 130.0, 129.9, 129.1, 128.9, 128.7, 127.2, 127.1, 126.7, 126.6, 126.3, 125.8, 125.5, 121.4, 120.3, 120.0, 119.5, 114.9, 114.3, 105.8, 60.6, 56.6, 37.0; LRMS (ESI-)m / z643.30 (MH) - .

[0275]

[0276] Synthesis Example 44: N-(4-(Benzo[d][1,3]dioxol-5-ylmino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide (43 = hereinafter referred to as compound 5033)

[0277] Yellow solid; yield, 77%; 1 H NMR (500 MHz, DMSO-d6)d11.09 (s, 2H), 9.11 (s, 1H), 9.01 (s, 1H), 8.35 (d, 1H,J= 9.0 Hz), 8.26 (d, 3H,J= 8.0 Hz), 8.17 (d, 1H,J= 8.0 Hz), 8.07 (d, 1H,J= 9.0 Hz), 8.01 (d, 1H,J= 9.0 Hz), 7.99 (d, 1H,J= 9.0 Hz), 7.94 (d, 2H,J= 8.0 Hz), 7.65 (t, 1H,J= 9.0 Hz), 7.62 (t, 1H,J= 9.0 Hz), 7.52 (s, 1H), 7.30 (dd, 1H,J= 8.5, 1.5 Hz), 7.08 (d, 1H,J= 8.5 Hz), 6.12 (s, 2H); 13 C NMR (125 MHz, DMSO-d6)d165.0, 158.7, 156.8, 147.6, 145.5, 138.3, 138.1, 135.1, 132.6, 132.3 (q, 2 J C-F = 32.0 Hz), 132.1, 130.2, 129.6, 129.2, 129.2, 128.9, 128.2, 127.6, 126.0 (q, 3 J C-F = 4.0 Hz), 125.9 (q, 1 J C-F = 272.0 Hz), 125.1, 124.4 (q,J= 271.1 Hz), 117.8, 114.9, 113.6, 108.3, 106.1, 102.0; LRMS (ESI-)m / z577.20 (MH) - .

[0278]

[0279] Synthesis Example 45: N-(4-(Benzo[d][1,3]dioxol-5-ylmino)-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4-dichlorobenzamide (44 = hereinafter referred to as compound 5029)

[0280] Brown solid; yield, 93%; 1 H NMR (500 MHz, DMSO-d6)d10.87 (s, 2H), 8.97 (s, 1H), 8.93 (s, 1H), 8.41 (d, 1H,J= 8.5 Hz), 8.31 (s, 1H), 8.07 (d, 2H,J= 9.0 Hz), 8.03 (d, 3H,J= 8.5 Hz), 7.99 (d, 1H,J= 8.5 Hz), 7.87 (d, 1H,J= 8.5 Hz), 7.62 - 7.59 (m, 3H), 7.33 (d, 1H,J= 8.0 Hz), 7.06 (d, 1H,J=8.0 Hz), 6.11(s, 2H); LRMS (ESI-)m / z577.15 (MH) - .

[0281]

[0282] Synthesis Example 46: N-(4-(Benzo[d][1,3]dioxol-5-ylmino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-methylbenzamide (45 = hereinafter referred to as compound 5037)

[0283] Brown solid; yield, 97%; 1 H NMR (500 MHz, DMSO-d6)d10.54 (s, 1H), 9.97 (s, 1H), 8.94 (s, 1H), 8.91 (s, 1H), 8.51 (d, 1H,J= 9.0 Hz), 8.04 (d, 1H,J= 8.0 Hz), 8.02 (d, 2H,J= 8.5 Hz), 7.97 (d, 2H,J= 8.0 Hz), 7.94 (d, 1H,J= 8.0 Hz), 7.93 (d, 1H,J= 9.0 Hz), 7.67 (d, 1H,J= 1.5 Hz), 7.57 (t, 2H,J=8.5 Hz), 7.39 (dd, 1H,J= 9.0, 1.5 Hz), 7.37 (d, 2H,J= 8.0 Hz), 7.04 (d, 1H,J= 9.0 Hz), 6.09 (s, 2H), 2.40 (s, 3H); 13C NMR (125 MHz, DMSO-d6)d165.8, 158.4, 158.1, 147.5, 143.8, 142.4, 137.1, 136.2, 134.4, 134.1, 133.2, 132.0, 129.6, 129.3, 129.0, 128.6, 128.3, 128.2, 128.1, 128.1, 127.5, 127.0, 125.5, 115.9, 114.6, 114.5, 108.3, 104.9, 101.6, 21.5; LRMS (ESI+) m / z 525.17 (M+H) + .

[0284]

[0285] Synthesis Example 47: N-(4-(Benzo[d][1,3]dioxol-5-ylmino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(tert-butyl)benzamide (46 = hereinafter referred to as compound 5045)

[0286] Brown solid; yield, 43%; 1 H NMR (500 MHz, DMSO-d6)d10.68 (s, 2H), 9.06 (s, 1H), 8.96 (s, 1H), 8.40 (d, 1H,J= 8.0 Hz), 8.11 (d, 2H,J= 8.5 Hz), 8.08 (d, 1H,J= 8.0 Hz), 8.03 (d, 1H,J= 8.0 Hz), 8.02 (d, 1H,J= 8.0 Hz), 8.00 (d, 2H,J= 8.0 Hz), 7.64 (t, 1H,J= 8.0 Hz), 7.62 (t, 1H,J= 8.0 Hz), 7.59 (d, 2H,J= 8.0 Hz), 7.57 (s, 1H), 7.32 (dd, 1H,J= 8.5, 1.5 Hz), 7.07 (d, 1H,J= 8.5 Hz), 6.12 (s, 2H), 1.33 (s, 9H); 13C NMR (125 MHz, DMSO-d6)d166.1, 158.7, 156.8, 155.4, 147.6, 145.4, 138.6, 135.7, 135.0, 132.7, 132.3, 131.9, 130.1, 129.6, 128.9, 128.3, 128.2, 127.6, 125.8, 125.2, 117.7, 114.5, 113.8, 108.4, 106.1, 102.0, 35.2, 31.4; LRMS (ESI-)m / z565.28 (MH) - .

[0287]

[0288] Synthesis Example 48: N-(4-(Benzo[d][1,3]dioxol-5-ylmino)-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide (47 = hereinafter referred to as compound 5041)

[0289] Brown solid; yield, 54%; 1 H NMR (500 MHz, DMSO-d6)d11.10 (s, 1H), 10.82 (s, 1H), 9.05 (s, 1H), 8.99 (s, 1H), 8.34 (d, 1H,J= 9.0 Hz), 8.24 (d, 2H,J= 9.0 Hz), 8.07 (d, 1H,J= 9.0 Hz), 8.01 (d, 1H,J= 9.0 Hz), 7.99 (d, 1H,J= 9.0 Hz), 7.65 (t, 1H,J= 9.0 Hz), 7.61 (t, 1H,J= 9.0 Hz), 7.52 (s, 1H), 7.43 (s, 2H), 7.29 (d, 1H,J= 8.0 Hz), 7.06 (d, 1H,J= 8.0 Hz), 6.11 (s, 2H), 3.88 (s, 6H), 3.73 (s, 3H); 13C NMR (125 MHz, DMSO-d6)d165.3, 158.4, 153.2, 147.6, 144.5, 141.0, 137.8, 137.6, 137.5, 134.7, 133.0, 129.9, 129.7, 129.4, 129.0, 128.9, 128.6, 128.2, 128.1, 127.2, 125.3, 116.8, 116.6, 116.6, 115.0, 114.3, 108.4, 105.8, 105.4, 101.8, 60.6, 56.6; LRMS (ESI-)m / z599.26 (MH) - .

[0290]

[0291] Synthesis Example 49: N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide (48 = hereinafter referred to as compound 5031)

[0292] Brown solid; yield, 95%; 1 H NMR (500 MHz, DMSO-d6)d11.21 (brs, 1H), 11.09 (s, 1H), 9.13 (s, 1H), 8.97 (s, 1H), 8.39 (d, 1H,J= 9.0 Hz), 8.27 (d, 2H,J= 8.5 Hz), 8.26 (d, 2H,J= 8.0 Hz), 8.18 (d, 1H,J= 9.0 Hz), 8.05 (d, 1H,J= 9.0 Hz), 8.01 (d, 1H,J= 9.0 Hz), 7.97 (d, 1H,J= 7.5 Hz), 7.93 (d, 2H,J= 8.5 Hz), 7.86 - 7.83 (m, 1H), 7.64 (t, 1H,J= 9.0 Hz), 7.61 (t, 1H,J= 9.0 Hz), 7.58 (t, 1H,J= 7.5 Hz); 13C NMR (125 MHz, DMSO-d6)d165.0, 158.2, 158.0, 154.1 (d,J= 242.8 Hz), 138.6, 137.3, 136.8, 134.7, 133.1, 132.1 (q,J= 31.5 Hz), 130.6, 129.5, 129.4, 129.2, 128.8, 128.6, 128.2, 128.0, 127.3, 128.1 (q,J= 3.6 Hz), 125.3, 124.9, 124.4 (q,J= 270.6 Hz), 119.3 (d,J=18.3 Hz), 117.2 (d,J= 21.8 Hz), 114.5, 114.3; LRMS (ESI-)m / z565.28 (MH) - .

[0293]

[0294] Synthesis Example 50: 3,4-dichloro-N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)benzamide (49 = hereinafter referred to as compound 5027)

[0295] Brown solid; yield, 81%; 1 H NMR (500 MHz, DMSO-d6)d10.92 (s, 2H), 9.03 (s, 1H), 8.93 (s, 1H), 8.41 (d, 1H,J= 8.5 Hz), 8.33 (s, 1H), 8.30 (s, 1H), 8.12 (d, 2H,J= 8.0 Hz), 8.04 (d, 1H,J= 8.5 Hz), 8.03 (d, 2H,J= 8.5 Hz), 7.97 (d, 1H,J= 9.0 Hz), 7.86 (d, 1H,J= 8.5 Hz), 7.84 (dd, 1H,J= 8.5, 2.0 Hz), 7.62 (t, 1H,J= 8.0 Hz), 7.59 (t, 1H,J= 8.0 Hz), 7.57 (t, 1H,J= 9.0 Hz); 13C NMR (125 MHz, DMSO-d6)d163.7, 158.4, 157.1, 154.7 (d,J=243.4 Hz), 137.8, 135.9, 135.3, 134.9, 134.8, 132.8, 131.9, 131.3, 130.1, 130.0, 129.6, 129.5, 128.8, 128.6, 128.2, 127.4, 125.7, 125.1, 124.2, 119.4 (d,J= 18.4 Hz), 117.2 (d,J= 21.8 Hz), 114.5, 113.9; LRMS (ESI+) m / z 587.05 (M+H) + .

[0296]

[0297] Synthesis Example 51: N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-methylbenzamide (50 = hereinafter referred to as compound 5035)

[0298] Yellow solid; yield, 97%; 1 H NMR (500 MHz, DMSO-d6)d11.00 (brs, 1H), 10.71 (s, 1H), 9.10 (s, 1H), 8.97 (s, 1H), 8.41 (d, 1H,J= 8.5 Hz), 8.31 (d, 1H,J= 8.0 Hz), 8.19 (d, 1H,J= 8.0 Hz), 8.14 (d, 1H,J= 8.5 Hz), 8.06 (d, 1H,J= 8.5 Hz), 8.02 (d, 1H,J= 8.5 Hz), 7.98 (d, 3H,J= 8.0 Hz), 7.87 - 7.85 (m, 1H), 7.63 (t, 1H,J= 8.5 Hz), 7.61 (t, 1H,J= 8.5 Hz), 7.58 (t, 1H,J= 8.0 Hz), 7.36 (d, 2H,J= 8.0 Hz), 2.39 (s, 3H); 13C NMR (125 MHz, DMSO-d6)d165.9, 158.5, 156.8, 154.8 (d,J=242.8 Hz), 142.6, 138.5, 135.7, 135.0, 132.8, 131.7, 130.2, 129.9, 129.8, 129.5, 128.8, 128.7, 128.3, 128.2, 127.5, 126.0, 125.1, 124.4, 119.4 (d,J= 18.4 Hz), 117.2 (d,J= 21.8 Hz), 114.3, 113.8, 21.5; LRMS (ESI+) m / z 533.12 (M+H) + .

[0299]

[0300] Synthesis Example 52: 4-(tert-butyl)-N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)benzamide (51 = hereinafter referred to as compound 5043)

[0301] Brown solid; yield, 62%; 1 H NMR (500 MHz, DMSO-d6)d11.00 (brs, 1H), 10.71 (s, 1H), 9.11 (s, 1H), 8.96 (s, 1H), 8.43 (d, 1H,J= 8.5 Hz), 8.33 (d, 1H,J= 8.5 Hz), 8.14 (d, 2H,J= 8.0 Hz), 8.08 (d, 1H,J= 8.5 Hz), 8.04 (d, 1H,J= 8.5 Hz), 8.03 (d, 1H,J= 9.0 Hz), 8.00 (d, 2H,J= 8.0 Hz), 7.88 - 7.86 (m, 1H), 7.64 (t, 1H,J= 8.5 Hz), 7.62 (t, 1H,J= 8.5 Hz), 7.59 (d, 1H,J= 9.0 Hz), 7.58 (d, 2H,J= 8.0 Hz), 1.33 (s, 9H); 13C NMR (125 MHz, DMSO-d6)d166.1, 158.5, 156.9, 154.8 (d,J=247.1 Hz), 138.5, 135.8, 135.0, 132.8, 131.9, 130.8, 130.0, 129.8, 129.7, 129.5, 128.8, 128.6, 128.2, 128.2, 127.5, 126.7, 125.8, 125.8, 125.1, 124.4, 119.4 (d,J= 18.4 Hz), 117.2 (d,J= 21.6 Hz), 114.1, 113.9, 35.2, 31.4; LRMS (ESI+)m / z575.20 (M+H) + .

[0302]

[0303] Synthesis Example 53: N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide (52 = hereinafter referred to as compound 5039)

[0304] Brown solid; yield, 45%; 1 H NMR (500 MHz, DMSO-d6)d11.00 (brs, 1H), 10.63 (s, 1H), 8.93 (s, 2H), 8.49 (d, 1H,J= 8.5 Hz), 8.44 (d, 1H,J= 8.5 Hz), 8.12 (d, 1H,J= 9.0 Hz), 8.04 (d, 1H,J= 9.0 Hz), 8.01 (d, 1H,J= 8.5 Hz), 7.99 (d, 1H,J= 8.5 Hz), 7.97 (d, 1H,J= 9.0 Hz), 7.90 - 7.88 (m, 1H), 7.60 (t, 1H,J= 8.5 Hz), 7.58 (t, 1H,J= 8.5 Hz), 7.56 (d, 1H,J= 9.0 Hz), 7.41 (s, 2H), 3.89 (s, 6H), 3.74 (s, 3H); 13C NMR (125 MHz, DMSO-d6)d165.3, 158.1, 157.9, 154.8 (d,J=242.8 Hz), 153.2, 141.0, 138.1, 137.5, 134.6, 133.1, 129.8, 129.7, 129.4, 128.6, 128.6, 128.2, 127.9, 127.5, 127.4, 127.2, 125.3, 124.8, 123.3, 119.3 (d,J= 18.3 Hz), 117.2 (d,J= 21.6 Hz), 114.7, 114.3, 105.8, 60.6, 56.6; LRMS (ESI-)m / z607.20 (MH) - .

[0305]

[0306] Synthesis Example 54: N-(4-((2,3-dihydro-1H-indene-5-yl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide (53 = hereinafter referred to as compound 5032)

[0307] Yellow solid; yield, 40%; 1 H NMR (500 MHz, DMSO-d6)d10.82 (s, 1H), 9.90 (s, 1H), 8.96 (s, 1H), 8.92 (s, 1H), 8.56 (d, 1H,J= 8.5 Hz), 8.25 (d, 2H,J= 8.5 Hz), 8.02 (d, 1H,J= 9.0 Hz), 8.02 (d, 1H,J= 9.0 Hz), 8.01 (d, 1H,J= 8.5 Hz), 8.01 (s, 1H), 8.00 (d, 1H,J= 8.5 Hz), 7.96 (d, 2H,J= 8.5 Hz), 7.94 (d, 1H,J= 8.5 Hz), 7.80 (d, 1H,J= 8.0 Hz), 7.57 (t, 2H,J= 8.5 Hz), 7.32 (d, 1H,J= 8.0 Hz), 3.02 (t, 2H,J= 8.0 Hz), 2.93 (t, 2H,J= 8.0 Hz), 2.11 (p, 2H,J= 8.0 Hz); 13C NMR (125 MHz, DMSO-d6)d164.9, 158.7, 158.1, 148.3, 144.3, 139.4, 138.8, 138.1, 136.5, 136.4, 134.5, 133.2, 132.0 (q, 2 J C-F = 32.0 Hz), 129.3, 129.1, 129.0, 128.9, 128.3, 128.1, 127.5, 127.0, 126.1 (q, 3 J C-F = 4.0 Hz), 125.5, 124.4, 124.4 (q, 1 J C-F = 271.3 Hz), 120.8, 119.1, 114.9, 114.7, 33.1, 32.4, 25.8; LRMS (ESI-)m / z574.13 (MH) - .

[0308]

[0309] Synthesis Example 55: 3,4-dichloro-N-(4-((2,3-dihydro-1H-indene-5-yl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)benzamide (54 = hereinafter referred to as compound 5028)

[0310] Yellow solid; yield, 92%; 1H NMR (500 MHz, DMSO-d6)d10.95 (s, 1H), 9.06 (s, 1H), 8.96 (s, 1H), 8.32 (d, 1H,J= 1.5 Hz), 8.28 (d, 1H,J= 8.5 Hz), 8.15 (d, 1H,J= 8.5 Hz), 8.13 (d, 1H,J= 8.5 Hz), 8.08 (d, 1H,J= 8.5 Hz), 8.03 (d, 1H,J= 8.5 Hz), 8.02 (s, 1H), 8.01 (d, 1H,J= 8.5 Hz), 8.00 (d, 1H,J=8.5 Hz), 7.86 (d, 1H,J= 8.5 Hz), 7.82 (s, 1H), 7.65 (t, 1H,J= 8.5 Hz), 7.63 (t, 1H,J= 8.5 Hz), 7.60 (d, 1H,J= 8.5 Hz), 7.36 (d, 1H,J= 8.5 Hz), 2.99 (t, 2H,J= 8.5 Hz), 2.93 (t, 2H,J= 8.5 Hz), 2.11 (p, 2H,J= 8.5 Hz); 13 C NMR (125 MHz, DMSO-d6:CD3OD = 3:1)d168.5, 165.6, 163.1, 162.5, 149.2, 145.5, 143.9, 141.9, 140.1, 139.7, 139.6, 137.7, 136.7, 136.1, 135.9, 134.8, 134.1, 134.0, 133.4, 133.2, 133.1, 132.9, 132.8, 132.0, 129.9, 129.1, 126.3, 124.4, 119.5, 119.3, 118.8, 37.7, 37.1, 30.4; LRMS (ESI-)m / z573.02 (MH) - .

[0311]

[0312] Synthesis Example 56: N-(4-((2,3-dihydro-1H-indene-5-yl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-methylbenzamide (55 = hereinafter referred to as compound 5036)

[0313] Yellow solid; yield, 40%; 1H NMR (500 MHz, DMSO-d6)d10.51 (s, 1H), 9.91 (s, 1H), 8.95 (s, 1H), 8.91 (s, 1H), 8.55 (d, 1H,J= 8.5 Hz), 8.03 (d, 1H,J= 9.0 Hz), 8.02 (d, 1H,J= 9.0 Hz), 8.00 (d, 2H,J= 8.5 Hz), 7.99 (d, 2H,J= 8.5 Hz), 7.99 (d, 1H,J= 8.5 Hz), 7.67 (d, 1H,J= 8.0 Hz), 7.57 (s, 1H), 7.57 (t, 2H,J= 8.5 Hz), 7.38 (d, 2H,J= 8.5 Hz), 7.33 (d, 1H,J= 8.0 Hz), 3.00 (t, 2H,J= 8.0 Hz), 2.92 (t, 2H,J= 8.0 Hz), 2.40 (s, 3H), 2.11 (p, 2H,J=8.0 Hz); 13 C NMR (125 MHz, DMSO-d6)d165.8, 158.4, 158.1, 144.3, 142.4, 139.4, 138.0, 137.0, 134.5, 133.2, 132.1, 129.6, 129.3, 129.0, 128.4, 128.2, 128.1, 127.5, 127.5, 127.0, 125.5, 124.4, 120.9, 119.1, 114.7, 33.1, 32.4, 25.8, 21.5; LRMS (ESI-)m / z562.27 (MH) - .

[0314]

[0315] Synthesis Example 57: 4-(tert-butyl)-N-(4-((2,3-dihydro-1H-indene-5-yl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)benzamide (56 = hereinafter referred to as compound 5044)

[0316] Brown solid; yield, 45%; 1H NMR (500 MHz, DMSO-d6)d10.65 (s, 1H), 9.98 (s, 1H), 9.01 (s, 1H), 8.96 (s, 1H), 8.57 (d, 1H,J= 8.5 Hz), 8.09 (d, 1H,J= 8.5 Hz), 8.02 (d, 4H,J= 8.5 Hz), 7.96 (d, 1H,J= 8.5 Hz), 7.94 (d, 1H,J= 8.5 Hz), 7.90 (d, 2H,J= 8.5 Hz), 7.82 (s, 1H), 7.72 (d, 1H,J= 8.0 Hz), 7.59 (t, 1H,J= 8.5 Hz), 7.57 (t, 1H,J= 8.5 Hz), 7.32 (d, 1H,J= 8.0 Hz), 3.00 (t, 2H,J= 8.0 Hz), 2.91 (t, 2H,J= 8.0 Hz), 2.11 (p, 2H,J= 8.0 Hz), 1.33 (s, 9H); 13 C NMR (125 MHz, DMSO-d6)d165.9, 158.4, 158.1, 155.2, 148.0, 144.2, 139.2, 138.2, 137.1, 136.5, 134.4, 133.2, 132.3, 129.6, 129.3, 128.9, 128.6, 128.3, 128.1, 128.0, 127.5, 127.0, 125.8, 125.6, 124.4, 120.8, 119.0, 114.8, 114.4, 35.2, 33.1, 32.4, 31.4, 25.8; LRMS (ESI+)m / z563.32 (M+H) + .

[0317]

[0318] Synthesis Example 58: N-(4-((2,3-dihydro-1H-indene-5-yl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide (57 = hereinafter referred to as compound 5040)

[0319] Yellow solid; yield, 95%; 1H NMR (500 MHz, DMSO-d6)d10.70 (s, 2H), 9.02 (s, 1H), 8.97 (s, 1H), 8.41 (d, 1H,J= 8.0 Hz), 8.17 (d, 1H,J= 8.0 Hz), 8.13 (d, 1H,J= 9.0 Hz), 8.10 (d, 1H,J= 9.0 Hz), 8.04 (d, 1H,J= 8.0 Hz), 8.01 (d, 1H,J= 8.0 Hz), 7.86 (s, 1H), 7.66 (t, 1H,J= 8.0 Hz), 7.64 (t, 1H,J=8.0 Hz), 7.62 (d, 1H,J= 8.5 Hz), 7.43 (s, 2H), 7.37 (d, 1H,J= 8.5 Hz), 3.90 (s, 6H), 3.75 (s, 3H), 3.00 (t, 2H,J= 8.0 Hz), 2.93 (t, 2H,J= 8.0 Hz), 2.12 (p, 2H,J= 8.0 Hz); 13 C NMR (100 MHz, DMSO-d6)d165.6, 158.8, 153.6, 153.4, 144.7, 141.6, 141.4, 135.2, 133.0, 131.0, 130.7, 130.6, 130.0, 129.8, 129.7, 129.1, 129.0, 128.4, 125.4, 124.7, 122.2, 115.5, 106.4, 106.3, 106.2, 60.8, 56.9, 33.2, 32.7, 25.9; LRMS (ESI-)m / z595.29 (MH) - .

[0320]

[0321] Synthesis Example 59: N-(4-((9H-fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide (58 = hereinafter referred to as compound 5034)

[0322] Orange solid; yield, 69%; 1H NMR (500 MHz, DMSO-d6)d11.32 (s, 1H), 11.10(s, 1H), 9.20 (s, 1H), 9.05 (s, 1H), 8.39 (d, 1H,J= 8.5 Hz), 8.29 (s, 1H), 8.28 (d, 2H,J= 8.0 Hz), 8.19 (d, 1H,J= 8.5 Hz), 8,19 (d, 1H,J= 9.0 Hz), 8.10 (d, 1H,J= 9.0 Hz), 8.04 (d, 2H,J= 8.5 Hz), 7.99 (d, 1H,J= 7.0 Hz), 7.98 (d, 1H,J= 7.0 Hz), 7.94 (d, 2H,J= 8.0 Hz), 7.89 (d, 1H,J= 7.0 Hz), 7.66 (t, 1H,J= 8.5 Hz), 7.64 (t, 1H,J= 8.5 Hz), 7.62 (d, 1H,J= 7.0 Hz), 7.41 (t, 1H,J= 7.0 Hz), 7.34 (t, 1H,J= 7.0 Hz), 4.05 (s, 2H); 13 C NMR (125 MHz, DMSO-d6)d166.7, 165.1, 158.7, 143.9, 143.7, 141.3, 138.5, 137.9, 135.1, 135.1, 134.0, 132.8, 132.8, 132.2 (q,J= 31.4 Hz), 130.6, 129.6, 129.2, 129.2, 129.0, 128.7, 128.3, 127.6, 127.4, 127.1, 126.1, 126.1 (q, 3 J C-F = 3.0 Hz), 125.7, 125.3, 124.4 (q, 1 J C-F = 271.0 Hz), 120.5, 115.1, 114.1, 37.1 ;LRMS (ESI-)m / z621.12 (M-H) - .

[0323]

[0324] Synthesis Example 60: N-(4-((9H-fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4-dichlorobenzamide (59 = hereinafter referred to as compound 5030)

[0325] Brown solid; yield, 97%; 1 H NMR (500 MHz, DMSO-d6)d11.00 (s, 1H), 10.93 (s, 1H), 9.09 (s, 1H), 9.01 (s, 1H), 8.46 (d, 1H,J= 7.5 Hz), 8.33 (d, 1H,J= 1.5 Hz), 8.26 (s, 1H), 8.15 (d, 1H,J= 7.5 Hz), 8.12 (d, 1H,J= 8.5 Hz), 8.09 (d, 1H,J= 8.5 Hz), 8.05 (d, 2H,J= 7.5 Hz), 8.04 (d, 1H,J= 8.0 Hz), 7.99 (d, 1H,J= 8.0 Hz), 7.93 (d, 2H,J= 7.5 Hz), 7.87 (d, 1H,J= 8.0 Hz), 7.65 (t, 1H,J= 7.5 Hz), 7.63 (t, 1H,J= 7.5 Hz), 7.63 (d, 1H,J= 8.0 Hz), 7.41 (t, 1H,J= 8.0 Hz), 7.33 (t, 1H,J= 8.0 Hz), 4.06 (s, 2H); 13 C NMR (100 MHz, DMSO-d6)d165.3, 158.7, 153.9, 144.1, 143.9, 143.8, 141.6, 135.5, 135.3, 135.1, 133.0, 132.9, 132.2, 131.7, 131.6, 130.7, 130.4, 130.3, 130.0, 129.8, 129.7, 129.3, 129.1, 129.0, 128.8, 128.5, 128.4, 127.6, 127.6, 127.1, 125.9, 125.8, 125.5, 120.6, 120.5, 115.3, 115.2, 37.3; LRMS (ESI-)m / z620.94 (MH) - .

[0326]

[0327] Synthesis Example 61: N-(4-((9H-fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-4-methylbenzamide (60 = hereinafter referred to as compound 5038)

[0328] Brown solid; yield, 42%; 1 H NMR (500 MHz, DMSO-d6)d10.57 (s, 1H), 10.07 (s, 1H), 9.00 (s, 1H), 8.98 (s, 1H), 8.60 (d, 1H,J= 8.5 Hz), 8.40 (s, 1H), 8.06 (d, 1H,J= 8.5 Hz), 8.05 (d, 1H,J= 9.0 Hz), 8.04 (d, 1H,J= 9.0 Hz), 7.99 (d, 2H,J= 8.5 Hz), 7.98 (d, 2H,J= 8.5 Hz), 7.97 (d, 1H,J= 7.5 Hz), 7.92 (d, 1H,J= 7.5 Hz), 7.90 (d, 1H,J= 7.5 Hz), 7.61 (d, 1H,J= 7.5 Hz), 7.58 (t, 1H,J= 8.5 Hz), 7.56 (t, 1H,J= 8.5 Hz), 7.40 (t, 1H,J= 7.5 Hz,), 7.37 (d, 2H,J= 8.5 Hz), 7.30 (t, 1H,J= 7.5 Hz), 4.06 (s, 2H), 2.40 (s, 3H); LRMS (ESI-)m / z567.29 (MH) - .

[0329]

[0330] Synthesis Example 62: N-(4-((9H-fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(tert-butyl)benzamide (61 = hereinafter referred to as compound 5046)

[0331] Brown solid; yield, 31%; 1H NMR (500 MHz, DMSO-d6)d10.58 (s, 1H), 10.08 (s, 1H), 9.00 (s, 1H), 8.98 (s, 1H), 8.59 (d, 1H,J=8.5 Hz), 8.40 (s, 1H, 8.05 (d, 1H,J= 8.5 Hz), 8.04 (d, 1H,J= 9.0 Hz), 8.02 (d, 1H,J= 9.0 Hz), 8.00 (d, 2H,J= 7.5 Hz), 7.96 (d, 1H,J= 8.5 Hz), 7.94 (d, 1H,J= 8.5 Hz), 7.92 (d, 1H,J= 8.0 Hz), 7.90 (d, 1H,J= 8.0 Hz), 7.61 (d, 1H,J= 8.0 Hz), 7.59 (t, 1H,J= 8.5 Hz), 7.56 (t, 1H,J= 8.5 Hz), 7.56 (d, 2H,J= 7.5 Hz), 7.52 (d, 1H,J= 8.0 Hz), 7.39 (t, 1H,J= 8.0 Hz), 7.29 (t, 1H,J= 8.0 Hz), 4.05 (s, 2H), 1.32 (s, 9H); LRMS (ESI-)m / z609.38 (MH) - .

[0332]

[0333] Synthesis Example 63: N-(4-((9H-fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide (62 = hereinafter referred to as compound 5042)

[0334] Brown solid; yield, 94%; 1H NMR (500 MHz, DMSO-d6)d10.63 (s, 1H), 10.48 (s, 1H), 9.00 (s, 1H), 8.99 (s, 1H), 8.52 (d, 1H,J= 8.5 Hz), 8.33 (s, 1H), 8.13 (d, 1H,J= 8.5 Hz), 8.07 (d, 2H,J= 8.5 Hz,), 8.06 (d, 1H,J= 8.5 Hz), 8.02 (d, 1H,J= 8.5 Hz), 7.98 (d, 1H,J= 8.0 Hz), 7.96 (d, 1H,J= 8.0 Hz), 7.62 (d, 1H,J= 8.0 Hz), 7.62 (d, 1H,J= 8.0 Hz), 7.61 (t, 1H,J= 8.5 Hz), 7.59 (t, 1H,J= 8.5 Hz), 7.43 (s, 2H), 7.40 (t, 1H,J= 8.0 Hz), 7.31 (t, 1H,J=8.0 Hz), 4.06 (s, 2H), 3.90 (s, 6H), 3.76 (s, 3H); LRMS (ESI-)m / z643.30 (MH) - .

[0335]

[0336] <Example 2> Cytotoxicity of 40 kinds of quinazoline derivatives

[0337] As a result of examining the cytotoxicity of 40 quinazoline derivatives on vascular endothelial cells, excluding two compounds, including 5009 and 5017, no cytotoxicity was observed at the experimental concentrations of 5 μM and 10 μM in the remaining 38 compounds (Fig. 2).

[0338]

[0339] <Example 3> Effect of 40 quinazoline derivatives on inhibiting radical oxygen species (ROS)

[0340] To measure the ROS scavenging activity of 40 quinazoline derivatives, a fluorescent probe, DCFH-DA, was used. Among the 40 derivatives, ROS production was significantly reduced by treatment with each of 19 synthetic compounds. By measuring the ROS scavenging activity per minute, it was confirmed that these compounds had the ability to scavenge ROS induced by SIN-1 (Fig. 3).

[0341]

[0342] <Example 4> Inhibitory effect of 40 quinazoline derivatives on NF-κB transcriptional activity

[0343] HEK293 cells were used to measure the degree of NF-κB transcriptional activation by 40 types of quinazoline derivatives. After transfecting human kidney cells with NF-κB, LPS (1 μg / mL), which induces NF-κB activation, and quinazoline derivatives were simultaneously treated at a concentration of 10 μM. After 6 hours, the cells were lysed and the substrate was added for luminescence measurement.

[0344] As a result, it was confirmed that quinazoline derivative compounds 5038, 5039, and 5046 significantly reduced the transcriptional activity of NF-κB induced by LPS (Fig. 4).

[0345]

[0346] <Example 5> Inhibitory effect of inflammatory cytokines / chemokines induced by PAR2 activator

[0347] These quinazoline derivative compounds were confirmed to suppress the expression of inflammatory cytokines (IL-1β) and chemokines (CCL5) in response to PAR2 activators. After pretreatment with antagonists at a concentration of 5 μM in vascular endothelial cells, YPEN-1 cells were activated by PAR2 activators (SLIGRL-NH2, 150 μM), and the changes in mRNA expression were confirmed using qRT-PCR.

[0348] As a result, among the 38 quinazoline derivatives, compound 5007, compound 5014, compound 5015, compound 5019, compound 5020, compound 5021, compound 5022, compound 5023, compound 5024, compound 5027, compound 5031, compound 5032, compound 5033, compound 5034, compound 5035, compound 5036, compound 5037, compound 5038, and compound 5046 significantly reduced IL-1β expression induced by PAR2 activators.

[0349] In addition, it was confirmed that the expression of CCL5 induced by PAR2 activators was significantly reduced by treatment with compound 5015, compound 5016, compound 5017, compound 5025, compound 5026, compound 5027, compound 5029, compound 5030, compound 5032, compound 5034, compound 5035, compound 5037, and compound 5043 (Figure 5).

[0350]

[0351] <Example 6> Anti-inflammatory effect of compound 5013 in vascular cells

[0352] Among the 40 quinazoline derivatives, to confirm the anti-inflammatory effect of compound 5013 on vascular endothelial cells (YPEN-1), cytotoxicity was first evaluated at high concentrations (0 to 20 μM) of compound 5013, and no cytotoxicity was observed even at the highest concentration of 20 μM.

[0353] After pretreatment with compound 5013 at different concentrations and treatment with LPS to induce intracellular inflammation, the suppression of the expression of LPS-induced inflammatory proteins was confirmed at the protein level through Western blot.

[0354] As a result, the phosphorylation of p65 increased in LPS-treated cells and the protein expression of inflammatory mediators COX-2 and p38 decreased in cells treated with compound 5013. In addition, cells treated with compound 5013 showed a concentration-dependent decrease in the mRNA expression of CCL5, CCL2, and TNF-α, which are target genes of the inflammatory transcription factor p65 (Fig. 6). From the above results, it was confirmed that compound 5013 has an anti-inflammatory effect in LPS-induced vascular endothelial cells.

[0355]

[0356] <Example 7> Lipid metabolism improvement effect of compound 5013

[0357] The expression levels of lipid metabolism-related genes and proteins of compound 5013 were confirmed using qRT-PCR and Western blot using human hepatocyte cell line (HepG2) in which lipid accumulation was induced by palmitate.

[0358] As a result, we confirmed that AMPK phosphorylation was activated by treatment with compound 5013, and that palmitate-induced metabolic diseases were significantly reduced by compound 5013 treatment in genes related to lipid synthesis (Fasn, Acc) and fatty acid oxidation (Scd-1) (Fig. 7). These results suggest that compound 5013 can be utilized as a material for the prevention and improvement of metabolic diseases by activating AMPK, inhibiting lipid synthesis, and increasing fatty acid oxidation.

[0359]

[0360] <Example 8> Anti-inflammatory effect of compound 5013 in db / db metabolic disease mice

[0361] To investigate the mechanisms of renal inflammation and vascular aging caused by chronic metabolic diseases, db / db mice were used. Because db / db mice have a mutation in the leptin receptor gene, they are used as a good mouse model for metabolic inflammatory diseases as a model of type 2 diabetes. Therefore, compound 5013 was administered to 8-week-old db / db metabolic disease mice at a dose of 2 mg / kg or 6 mg / kg (once / day) for 18 days, and the anti-inflammatory effect of compound 5013 was confirmed in renal tissue.

[0362] As a result, in the LPS-administered group, the phosphorylation of ERK, an inflammatory kinase, increased, the protein expression of p65, a transcription factor, increased, and the mRNA expression of TNF-α, a target gene of p65, increased. However, in the group administered compound 5013, the expression of these proteins and mRNA was confirmed to decrease. The above results showed that the administration of compound 5013 had the effect of reducing the inflammatory response in the kidney by suppressing the expression of inflammatory proteins and mRNA (Fig. 8).

[0363]

[0364] <Example 9> Anti-inflammatory effects of antagonist compounds 5015 and 5032 in ApoE-deficient mice

[0365] To confirm the anti-inflammatory effect of PAR2 antagonist compound 5015 (4 mg / kg) or compound 5032 (4 mg / kg) on ​​high-fat diet ApoE-deficient mice, the mRNA changes of TNF-α, IL-1α, and IL-1β in the liver and the mRNA changes of CCL5, CCL3, TNF-α, and iNOS in the kidney tissue were confirmed.

[0366] As a result, it was confirmed that the mRNA expression of these inflammatory cytokines was reduced in the livers of high-fat diet-fed ApoE-deficient mice administered the antagonist compound 5015 or compound 5032, compared to high-fat diet-fed ApoE-deficient mice not administered the antagonist (Figure 9A). In addition, the mRNA expression of inflammatory cytokines of compound 5032 was reduced in kidney tissue (Figure 9B). As a result of the above, it was confirmed that compound 5015 or compound 5032 reduced the expression of inflammatory cytokines in high-fat diet-fed ApoE-deficient mice, indicating that these antagonists have an anti-inflammatory effect.

[0367] Additionally, a decrease in triglyceride (TG) in the liver and serum was observed, and an improvement in fat metabolism was observed (Fig. 9C).

[0368]

[0369] <Example 10> Inhibitory effect of compound 5013 on vascular aging in the kidney of db / db metabolic disease mice

[0370] To confirm the inhibition of vascular aging by compound 5013 in vascular aging caused by metabolic disease, the mRNA expression of VCAM-1 (vascular cell adhesion molecule-1) and E-selectin, which are cell adhesion molecules, was confirmed in kidney tissues of db / db mice.

[0371] As a result, it was confirmed that the expression of these mRNAs decreased in a concentration-dependent manner in the group administered with compound 5013, and it was found that compound 5013 can regulate vascular aging caused by metabolic diseases (Fig. 10).

[0372]

[0373] <Example 11> Inhibitory effect of compound 5015 or compound 5032 on vascular aging and arteriosclerosis in the liver of high-fat diet ApoE-deficient mice

[0374] To confirm the effect of compound 5015 (4 mg / kg) and compound 5032 (4 mg / kg) on ​​improving vascular aging, the mRNA levels of VCAM, P-selectin, E-selectin, which are vascular adhesion molecules, and CCL2, a leukocyte attractant for vascular inflammation, were examined in the livers of high-fat diet ApoE-deficient mice.

[0375] As a result, it was confirmed that the mRNA expression of cell adhesion molecules, which are indicators of vascular aging, was reduced in high-fat diet-fed ApoE-deficient mice administered compound 5015 or compound 5032, compared to high-fat diet-fed ApoE-deficient mice that were not administered compound 5015 or compound 5032. The above results showed that compound 5015 or compound 5032 had an inhibitory effect on vascular aging and arteriosclerosis in high-fat diet-fed ApoE-deficient mice (Fig. 11).

[0376]

[0377] <Example 12> Effect of compound 5013 on reducing body weight and insulin resistance in mice fed a high-fat diet

[0378] The weight loss effect of 5013 was confirmed by inducing obesity and metabolic diseases with a high-fat diet. Compound 5013 was administered at 2 mg / kg or 6 mg / kg (once / day) while feeding a high-fat diet ad libitum for 16 days. As a result, the group administered compound 5013 showed a decrease in body weight during the experimental period compared to the group administered a high-fat diet, and in particular, the weight of white adipose tissue (WAT) was reduced. Therefore, it was assumed that the weight loss in high-fat diet-fed mice was due to a decrease in the weight of adipose tissue (Fig. 12a).

[0379] To confirm the long-term efficacy of compound 5013 in a metabolic disease model, mice were fed a high-fat diet ad libitum for 12 weeks, and compound 5013 was administered at 2 mg / kg or 6 mg / kg (once per day) starting from the 9th week. As a result, it was confirmed that the obese mouse group administered compound 5013 for 4 weeks showed a decrease in body weight compared to the high-fat diet-administered model. The results of an oral glucose tolerance test confirmed that diabetic symptoms were improved compared to the disease group and mice administered empagliflozin, a type 2 diabetes treatment. In addition, it was confirmed that blood triglyceride, fasting blood glucose, and insulin levels were significantly reduced. To confirm the improvement of diabetic symptoms in the liver, liver weight and the expression of proteins related to glucose metabolism were examined. As a result, it was confirmed that the group administered with compound 5013 had a significant decrease in liver weight, and the activity of pAMPK and pAKT increased and the activity of pIRS-1 (S307) decreased, indicating an effect of restoring insulin resistance (Figure 12b). The above results confirmed that compound 5013 is effective in an animal model of metabolic disease by improving body weight and insulin resistance.

[0380]

[0381] <Example 13> Weight loss and serum changes of compound 5013 in a diabetic / metabolic disease db / db mouse model

[0382] db / db mice administered Compound 5013 showed a decrease in body weight compared to mice that were not administered Compound 5013. In addition, changes in serum triglyceride levels were observed to decrease in a dose-dependent manner in the Compound 5013-administered group. Furthermore, blood insulin levels were measured to show a decrease in the db / db mouse group administered Compound 5013 compared to the unadministered group (Figure 13). These results indicate that Compound 5013 has an antidiabetic effect by lowering triglyceride and insulin levels.

[0383] In addition, to confirm the effect of compound 5013 on improving insulin resistance, the molecular mechanism was identified from proteins in liver tissue. PTP1B is an important enzyme that regulates insulin signaling in muscle, liver, and adipocytes. It is a negative regulator that dephosphorylates the insulin receptor substrate (IRS) and is involved in not only diabetes but also obesity. As a result of the experiment, the db / db mouse group administered compound 5013 increased IRS phosphorylation and Akt activity, and decreased PTP1B protein expression. In addition, the mRNA expression related to lipogenesis, such as ACC and FAS, was confirmed, and the mRNA expression was decreased in the db / db mouse group administered compound 5013 compared to the mouse group that was not administered (Figure 14). From the above results, it was found that compound 5013 has an effect on improving diabetes and fat accumulation by improving insulin resistance and reducing lipogenesis in the liver of db / db mice.

[0384]

[0385] <Example 14> Cancer cell growth inhibitory effect of novel quinazoline derivative compounds

[0386] To confirm the cancer cell growth inhibitory effect of quinazoline derivatives, cell viability was measured in five cancer cell lines. The cancer cells used in this experiment were MCF-7 (human breast epithelial cancer cells) (Figure 15A), MDA-MB-231 (human breast cancer cells) (Figure 15B), HCC-827 (human lung cancer cells) (Figure 15C), NCI-H358 (human non-small cell lung cancer cells) (Figure 15D), and HCT-116 (human colon cancer cells) (Figure 15E). Among the 40 quinazoline derivatives, compounds 5009 (MHY5009) and 5017 (MHY5017) were examined for their effects on cell proliferation in each of the five cancer cell lines. Compound 5009 or compound 5017 was added to each cell culture medium at various concentrations of 0, 1, 5, 10, and 20 μM, and cultured for 24 hours. The number of living cells was measured using EZ-cytox solution (Daeil, Korea).

[0387] As shown in Figure 15, when the two compounds were administered to each cancer cell, cell proliferation was decreased in a concentration-dependent manner in all cancer cells. Based on these results, compounds 5009 and 5017 are suggested to be potential anticancer agents.

[0388]

[0389] These experimental results confirm that the above compounds have anti-inflammatory, anti-vascular aging, metabolic disease improvement, and cancer cell growth inhibition effects, thereby supporting that the novel quinazoline derivative compounds according to the present invention can serve as promising leading substances in the development of therapeutic agents for vascular inflammation and metabolic diseases and anticancer.

[0390]

[0391] <Example 15> In silico analysis results of novel quinazoline derivative compounds

[0392] (1) Coupling strength with PAR2 using a docking simulation program

[0393] In silico analysis using bioinformatics software was performed to evaluate the efficacy of PAR2 inhibitors.

[0394] Table 1 below shows the binding affinity of PAR2 protein and quinazoline derivative compounds predicted using two docking simulation programs (Autodock Vina and LeDock). As a result, the analyzed derivative compound has a lower value than N-((S)-3-cyclohexyl-1-(((2S,3S)-1-(2,3-dihydrospiro[indene-1,4'-piperidin]-1'-yl)-3-methyl-1-oxopentan-2-yl)amino)-1-oxopropan-2-yl)isoxazole-5-carboxamide (hereinafter referred to as GB83) used as a PAR2 antagonist, which means that it binds more stably to PAR2 than GB83. I could tell.

[0395] Compound Autodock VinaLeDock Compound 5007-7.6-4.6 Compound 5008-8-4.38 Compound 5009-8-4.57 Compound 5010-7.3-4.19 Compound 5011-7.3-4.34 Compound 5012-7-4.29 Compound 5013-7.3-3.87 Compound 5014-6.2-4.21 Compound 5015-7.5-4.28 Compound 5016-7.9-4.31 Compound 5017-7.8-4.09 Compound 5018-7.2-4.05 Compound 5019-6.1-4.03 Compound 5020-6.2-3.92 Compound Compound 5021-6.1-4.02 Compound 5022-6.8-4.08 Compound 5023-6.7-4.04 Compound 5024-6.9-4.19 Compound 5025-6.7-4.13 Compound 5026-5.9-4.22 Compound 5027-7.3-4.41 Compound 5028-7.3-4.53 Compound 5029-6.9-4.13 Compound 5030-6.8-4.52 Compound 5031-5.9-4.23 Compound 5032-6.2-4.12 Compound 5033-6.4-3.81 Compound 5034-6.2-4.24 Compound Compound 5035-7.1-4.11 Compound 5036-6.6-4.32 Compound 5037-7-4.05 Compound 5038-6.8-4.23 Compound 5039-5.9-4.05 Compound 5040-6.1-3.93 Compound 5041-5.7-3.65 Compound 5042-6.2-4.12 Compound 5043-5.7-4.05 Compound 5044-6.1-4.02 Compound 5045-5.8-3.68 Compound 5046-6.1-4.17 GB83(Control)-5.6-3.76

[0396]

[0397] <Example 16> Pharmacophore and molecular dynamics (MD) analysis of PAR2 and quinazoline derivative compounds

[0398] Among 40 PAR2 antagonists, pharmacophore and molecular dynamics (MD) analyses were performed to predict the binding between PAR2 and compound 5013 or compound 5015.

[0399] First, it was confirmed that compound 5013 forms hydrogen bonds with two amino acids of PAR2, namely Val1 and Asp153, while the control GB83 forms one hydrogen bond with Ser245. In addition, molecular dynamics (MD) analysis was performed using the structure of the PAR2-compound 5013 complex to determine the root mean square deviation (RMSD), root mean square fluctuation (RMSF), and the number of hydrogen bonds. Comparing the RMSD values, compound 5013 is higher than GB83, but the value is maintained stably. In GB83, an irregular phenomenon of RMSD value fluctuation was found from the 70 ns to 100 ns interval. Since a phenomenon of value fluctuation was found in a relatively short interval in compound 5013, it was confirmed that compound 5013 maintains a relatively stable state when it forms a complex with PAR2. In the case of RMSF, the variability of compound 5013 and GB83 at each amino acid residue of PAR2 was generally similar. This result means that compound 5013 can have a similar effect to GB83 when bound to PAR2. In addition, the number of hydrogen bonds of GB83 and compound 5013 showed a similar pattern in the early time period, but in the later time period, compound 5013 showed more hydrogen bonds than GB83, and the section where the maximum number of hydrogen bonds, 4, was observed was also more in compound 5013, confirming that it had the same tendency as the pharmacophore analysis (Fig. 16).

[0400] Compound 5015 was predicted to form a hydrogen bond with the Asp153 residue, as was common with GB83. As a result of molecular dynamics analysis of the PAR2-5015 complex, although the RMSD value of compound 5015 was higher than that of GB83, the value was maintained stably, and in some sections, the value was confirmed to be more stable than GB83. In RMSF, the volatility of GB83 and compound 5015 at each amino acid residue was generally similar and showed a lower value than GB83. This means that compound 5015 can bind more stably than GB83 when bound to PAR2. In addition, the number of hydrogen bonds of GB83 and compound 5015 showed a similar tendency, and it was confirmed that compound 5015 showed more hydrogen bonds than GB83 after 40 ns (Fig. 17). The above analysis results show that compounds 5013 and 5015 bind more strongly to PAR2 than GB83.

[0401]

[0402] Additionally, among 40 quinazoline PAR2 antagonists, ADMET was analyzed using PreADMET (https: / preadmet.webservice.bmdrc.org / ), SwissADME (http: / www.swissadme.ch / ), and ADMETlab 2.0 (https: / admetmesh.scbdd.com / ) to determine the drug suitability of compound 5013, compound 5015, compound 5032, or compound 5038.

[0403] As a result, according to Table 2 below, the four antagonists had physicochemical properties similar to those of GB83, and all four did not pass the Lipinski Rule, but all compounds passed the Veber Rule, predicted the possibility of druglikeness, and showed values ​​equivalent to or better than GB83 in the absorption, distribution, metabolism, and excretion categories. In addition, in the toxicity category, compound 5013 was predicted to be non-toxic in all items including the Ames test. Compound 5015 did not show toxicity in items such as Rat Oral Acute Toxicity or Acute Toxicity Rule. In addition, compounds 5032 and 5038 did not show toxicity in carcinoma rat toxicity. When comprehensively analyzing the in silico analysis, it was found that all four PAR2 inhibitors had better efficacy and stability compared to existing drugs.

[0404] GB83 (Control) Compound 5013 Compound 5015 Compound 5032 Compound 50381. Physicochemical properties Molecular weight (g / mol) 548.72 578.54 532.99 574.20 568.23 H-bond acceptor 58465 H-bond donor 222222. Drug similarity Lipinski rule SuitableViolatedViolatedViolatedVeber ruleViolatedSuitableSuitableSuitableSuitablePfizer rule SuitableSuitableViolatedViolatedViolated3. AbsorptionHuman intestinal absorption (HIA %)95.15453697.17321896.34290496.36501496.283192Caco-2 cell permeability (nm s-1 )24.439625.400837.564425.094240.6032MDCK cell permeability (nm s-1 )0.1056050.04364920.04345810.04425590.0434483Skin permeability (logKp, cm h-1 )-3.11748-1.83079-1.98854-1.70601-1.817524. DistributionPlasma protein binding (%)90.35319492.52737897.97693294.92124391.712500Blood-brain barrier penetration0.7388451.472588.6399210.948410.59815. MetabolismCYP1A2 inhibitionNonNonNonNonNonCYP2C19 inhibitionNonNonNonNonNonCYP2C9 inhibitionNonInhibitorInhibitorInhibitorInhibitorCYP2D6 inhibitionNonNonNonNonNonCYP2D6 substrateNonNonNonNonNonCYP3A4 inhibitionInhibitorInhibitorInhibitorInhibitorCYP3A4 substrateSubstrateWeaklyWeaklyWeaklyWeakly6. ExcretionPgp inhibitionInhibitorInhibitorInhibitorInhibitorInhibitor7.ToxicityAmes testNon-mutagennon-mutagenMutagennon-mutagenMutagenCarcino_MouseNegativenegativePositivepositivePositiveCarcino_RatPositivenegativePositivenegativenegativeRat Oral Acute Toxicity0.9940.140.2570.8450.571Eye Corrosion0.0030.0030.0030.0030.003NR (Nuclear Receptor)-AR0.0190.220.3420.0730.488NR-AR-LBD0.0040.4150.2970.8090.796Acute Toxicity Rule00000SureChEMBL00000.

[0405]

[0406] The foregoing description of the present invention is for illustrative purposes only. Those skilled in the art will readily appreciate that modifications to other specific embodiments can be made without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

[0407] The scope of the present invention is indicated by the claims set forth below, and all changes or modifications derived from the meaning and scope of the claims and their equivalent concepts should be interpreted as being included in the scope of the present invention.

Claims

1. A compound selected from a quinazoline derivative compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof: [Chemical Formula 1] In the above chemical formula 1, R 1 , R 2 and R 3 are each the same or different, and are one of unsubstituted or substituted (C3-C15)cycloalkyl, unsubstituted or substituted (C5-C15)aryl and unsubstituted or substituted heteroaryl having 5 to 15 atoms containing one or more heteroatoms selected from the group consisting of N, O and S, The above substituted (C3-C15)cycloalkyl, substituted (C5-C15)aryl and substituted heteroaryl having 5 to 15 atoms may each be substituted identically or differently, and are substituted with at least one selected from the group consisting of hydroxy, halogen, cyano, (C1-C5)alkyl, (C1-C5)alkoxy, trifluoromethyl and trifluoromethoxy.

2. In claim 1, in the chemical formula 1, R 1 is an unsubstituted or substituted naphthyl, wherein the substituted naphthyl is substituted with at least one selected from the group consisting of halogen, (C1-C5)alkyl, (C1-C5)alkoxy and trifluoromethyl, R 2 is an unsubstituted or substituted (C5-C15)aryl or an unsubstituted or substituted heteroaryl of 5 to 15 atoms containing one or more heteroatoms selected from the group consisting of N, O and S, wherein the substituted (C5-C15)aryl or substituted heteroaryl of 5 to 15 atoms is substituted with one or more selected from the group consisting of halogen, (C1-C5)alkyl, (C1-C5)alkoxy and trifluoromethyl, R 3 A compound selected from a quinazoline derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof or a stereoisomer thereof, wherein the quinazoline is an unsubstituted or substituted phenyl, and the substituted phenyl is substituted with at least one selected from the group consisting of halogen, (C1-C5)alkyl, (C1-C5)alkoxy and trifluoromethyl.

3. In claim 1, in the chemical formula 1, R 1 is an unsubstituted naphthyl, R 2 Is , , and one of phenyl substituted with one or two chlorine or fluorine, R 3 A compound selected from the group consisting of a quinazoline derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof or a stereoisomer thereof, characterized in that one to three substituted phenyls are selected from the group consisting of chlorine, methyl, tert-butyl, methoxy and trifluoromethyl.

4. In claim 1, in the chemical formula 1, R 2 Is , , A compound selected from a quinazoline derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof, wherein the substituted phenyl is one of chlorine or fluorine substituted.

5. In claim 1, the compound represented by the chemical formula 1 is a quinazoline derivative compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof, characterized in that the compound is selected from the group of compounds below: (1)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide; (2)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-1-yl)quinazolin-6-yl)-3,4-dichlorobenzamide; (3)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-methylbenzamide; (4)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(tert-butyl)benzamide; (5)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-1-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide) ; (6)N-(4-((3-Chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide; (7) 3,4-Dichloro-N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)benzamide; (8)N-(4-((3-Chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-methylbenzamide; (9) 4-(tert-Butyl)-N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)benzamide; (10)N-(4-((3-Chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide; (11)N-(4-((2,3-Dihydro-1H-inden-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide; (12) 3,4-Dichloro-N-(4-((2,3-dihydro-1H-inden-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)benzamide; (13)N-(4-((2,3-Dihydro-1H-inden-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-methylbenzamide; (14) 4-(tert-Butyl)-N-(4-((2,3-dihydro-1H-inden-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)benzamide; (15)N-(4-((2,3-Dihydro-1H-inden-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide; (16)N-(4-((9H-Fluoren-2-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide; (17)N-(4-((9H-Fluoren-2-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-3,4-dichlorobenzamide; (18)N-(4-((9H-Fluoren-2-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-methylbenzamide; (19)N-(4-((9H-Fluoren-2-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(tert-butyl)benzamide; (20)N-(4-((9H-Fluoren-2-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide; (21)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide; (22)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4-dichlorobenzamide; (23)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-methylbenzamide; (24)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(tert-butyl)benzamide; (25)N-(4-(Benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide; (26)N-(4-((3-Chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide; (27) 3,4-Dichloro-N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)benzamide; (28)N-(4-((3-Chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-methylbenzamide; (29) 4-(tert-Butyl)-N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)benzamide; (30)N-(4-((3-Chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide; (31)N-(4-((2,3-Dihydro-1H-inden-5-yl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide; (32) 3,4-Dichloro-N-(4-((2,3-dihydro-1H-inden-5-yl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)benzamide; (33)N-(4-((2,3-Dihydro-1H-inden-5-yl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-methylbenzamide; (34) 4-(tert-Butyl)-N-(4-((2,3-dihydro-1H-inden-5-yl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)benzamide; (35)N-(4-((2,3-Dihydro-1H-inden-5-yl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide; (36)N-(4-((9H-Fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide; (37)N-(4-((9H-Fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4-dichlorobenzamide; (38)N-(4-((9H-Fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-4-methylbenzamide; (39)N-(4-((9H-fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(tert-butyl)benzamide; and (40)N-(4-((9H-Fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide).

6. A pharmaceutical composition for preventing or treating a disease mediated by PAR2 (Protease-activated receptor 2) overexpression, comprising as an active ingredient a compound selected from the quinazoline derivative compound of claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

7. In claim 6, the quinazoline derivative compound is N-(4-(benzo[d][1,3]dioxol-5-ylamino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide, N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-methylbenzamide, N-(4-((2,3-dihydro-1H-inden-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)-4-methylbenzamide, 4-(tert-butyl)-N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)benzamide, 4-(tert-butyl)-N-(4-((2,3-dihydro-1H-inden-5-yl)amino)-2-(naphthalen-1-yl)quinazolin-6-yl)benzamide, 3,4-Dichloro-N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)benzamide, N-(4-((2,3-dihydro-1H-inden-5-yl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(trifluoromethyl)benzamide, N-(4-(benzo[d][1,3]dioxol-5-yl N-(4-((9H-fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-4-methylbenzamide, N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)-3,4,5-trimethoxybenzamide, A pharmaceutical composition characterized by being any one selected from the group consisting of 4-(tert-butyl)-N-(4-((3-chloro-4-fluorophenyl)amino)-2-(naphthalen-2-yl)quinazolin-6-yl)benzamide and N-(4-((9H-fluoren-2-yl)amino-2-(naphthalen-2-yl)quinazolin-6-yl)-4-(tert-butyl)benzamide.

8. A pharmaceutical composition according to claim 6, wherein the disease mediated by PAR2 (Protease-activated receptor 2) overexpression is one of inflammatory diseases, vascular aging, metabolic diseases, and cancer diseases.

9. A pharmaceutical composition according to claim 8, characterized in that the inflammatory disease is one of allergic diseases, inflammatory bowel disease, systemic lupus erythematosus, inflammatory collagen vascular disease, glomerulonephritis, inflammatory skin disease, sarcoidosis, retinitis, gastritis, hepatitis, enteritis, pancreatitis, and nephritis.

10. A pharmaceutical composition according to claim 8, characterized in that the metabolic disease is one of obesity, diabetes, hyperlipidemia, hypertriglyceridemia, liver disease, arteriosclerosis, stroke, myocardial infarction, hyperglycemia, insulin resistance disease, and hyperinsulinemia.

11. A pharmaceutical composition according to claim 8, characterized in that the cancer disease is one of prostate cancer, colon cancer, lung cancer, breast cancer, ovarian cancer, uterine cancer, pancreatic cancer, lung cancer, stomach cancer, liver cancer, skin cancer, head or cervical cancer, brain cancer, laryngeal cancer, bladder cancer, esophageal cancer, thyroid cancer, kidney cancer, and rectal cancer.

12. A health functional food composition for preventing or improving a disease mediated by PAR2 (Protease-activated receptor 2) overexpression, comprising as an active ingredient a compound selected from the quinazoline derivative compound of claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

13. A reagent composition for inhibiting PAR2 (Protease-activated receptor 2) expression, comprising as an active ingredient a compound selected from the quinazoline derivative compound of claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

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