Novel 2-((trans-4-(4-aryloxy) cyclohexyl) amino) quinazolinone derivative and preparation method thereof

Abstract

The purpose of the present invention is to provide a novel 2-((trans-4-(4-aryloxy) cyclohexyl) amino) quinazolinone derivative which exhibits anti-cancer activity through eIF2 [alpha] phosphorylation. The novel synthesized derivatives exhibit eIF2alpha phosphorylation and in vitro cancer cell proliferation inhibitory activity, and thus can be used as metabolic anticancer agents in pharmaceutical and health functional food compositions for the prevention and amelioration of leukemia and other rare cancers (e.g., breast cancer, brain tumor and sarcoma).

Description

Technical Field

[0001] The present invention provides novel 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivatives and methods for their preparation. Background Art

[0002] Recently, attention has focused on studying the cause of cancer cell death by regulating the synthesis of proteins related to the metabolism of cancer cells. Tumor-related proteins are encoded by so-called "weak" mRNAs, and although their expression in normal cells is negligible, their expression increases sharply in cancer cells.

[0003] As a target for regulating these carcinogenic factors, phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α, a representative factor for eukaryotic translation initiation) can be proposed. eIF2α is phosphorylated by four kinases, HRI, PERK, GCN2, and PKR, and each kinase is activated by cellular stress. Therefore, phosphorylated eIF2α can inhibit protein biosynthesis.

[0004] During the process of cell carcinogenesis, eIF2 is overexpressed and rapidly accelerates the translation of weak mRNAs. Since phosphorylation of eIF2α can inhibit the translation of weak mRNAs, it can also cause inhibition of the expression of carcinogenic factors. However, to date, no small molecule candidates showing the effect of eIF2α phosphorylation have entered clinical trials. Therefore, it is necessary to study new substances with excellent eIF2α phosphorylation and to develop metabolic anticancer agents using this mechanism. Summary of the Invention Technical Objectives

[0005] The object of the present disclosure is to provide a compound selected from the group consisting of 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivatives, pharmaceutically acceptable salts thereof, solvates thereof, or stereoisomers thereof.

[0006] Another object of the present disclosure is to provide a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition comprising the compound as an active ingredient.

[0007] Another object of the present disclosure is to provide a pharmaceutical composition for a metabolic anticancer agent, the pharmaceutical composition comprising the compound as an active ingredient.

[0008] Another object of the present disclosure is to provide a method for inhibiting cancer cell metabolism, the method comprising administering the compound.

[0009] Another object of the present disclosure is to provide a health functional food composition for preventing or improving cancer, the health functional food composition comprising the compound as an active ingredient. Technical Solutions

[0010] To achieve the above object, the present disclosure provides a compound selected from 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivatives represented by the following Chemical Formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof.

[0011] [Chemical Formula 1]

[0012]

[0013] In Chemical Formula 1,

[0014] R 1 and R 2 may be the same or different and each is independently selected from the group consisting of hydrogen (H), halogen, trifluoromethyl (CF3), nitro (NO2), (C1-C4) alkoxy, trifluoromethoxy (OCF3), cyano (CN), nitro (NO2), (C1-C4) alkylsulfonyl, and aminosulfonyl (SO2NH2).

[0015] In addition, the present disclosure provides a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition comprising the compound as an active ingredient.

[0016] In addition, the present invention provides a pharmaceutical composition for metabolizing an anticancer agent, the pharmaceutical composition comprising the compound as an active ingredient.

[0017] In addition, the present disclosure provides a method for inhibiting cancer cell metabolism, the method comprising administering the compound.

[0018] In addition, the present disclosure provides a health functional food composition for preventing or improving cancer, the health functional food composition comprising the compound as an active ingredient. Advantageous Effects

[0019] The present disclosure relates to a compound selected from 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivatives, a pharmaceutically acceptable salt thereof, a solvate thereof, or a stereoisomer thereof, which exhibits anticancer activity through eIF2α phosphorylation. Among them, the newly synthesized derivatives exhibit eIF2α phosphorylation and in vitro cancer cell proliferation inhibitory activity, and thus can be used as metabolic anticancer agents for drugs and health functional food compositions for preventing and improving leukemia and rare cancers (e.g., breast cancer, brain tumor, and sarcoma). BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 Shows a design strategy for a new 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative.

[0021] Figure 2 Identification of the effect of the new 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivatives on eIF2α phosphorylation

[0022] Figure 3 The identification results of the anti-proliferative activity of the new 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivatives are shown. Detailed Description of the Invention

[0023] Hereinafter, the present disclosure will be described in more detail.

[0024] A key step in the initiation of protein synthesis is the formation of a complex composed of eIF2, GTP, and Met-tRNAi. Since this complex plays an important role in performing normal cell functions and is known to cause various diseases when abnormal regulation occurs, it has attracted attention as a target for the development of new therapeutic agents. Therefore, the inventors of the present disclosure synthesized 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative compounds having various substituents to identify the eIF2α phosphorylation effect and in vitro cancer cell proliferation inhibitory activity exhibited by the newly synthesized derivatives, and completed the present disclosure.

[0026] To achieve the above object, the present disclosure provides a compound selected from 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative compounds represented by the following Chemical Formula 1, pharmaceutically acceptable salts thereof, solvates thereof, or stereoisomers thereof.

[0027] [Chemical Formula 1]

[0028]

[0029] In Chemical Formula 1, R 1 and R 2 may be the same or different and each is independently selected from the group consisting of hydrogen (H), halogen, trifluoromethyl (CF3), nitro (NO2), (C1-C4) alkoxy, trifluoromethoxy (OCF3), cyano (CN), nitro (NO2), (C1-C4) alkylsulfonyl, and aminosulfonyl (SO2NH2).

[0030] Preferably, the 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative compound in Chemical Formula 1 may have R selected from the group consisting of hydrogen (H), halogen, trifluoromethyl (CF3), nitro (NO2), and (C1-C2) alkoxy. 1, and R selected from the group consisting of chlorine (Cl), trifluoromethyl (CF3), trifluoromethoxy (OCF3), cyano (CN), nitro (NO2), (C1-C2) alkylsulfonyl, and sulfamoyl (SO2NH2) 2 .

[0031] Preferably, the 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative compound in Chemical Formula 1 may have R selected from the group consisting of hydrogen (H), fluorine (F), chlorine (Cl), trifluoromethyl (CF3), and nitro (NO2) 1 , and R selected from the group consisting of chlorine (Cl), trifluoromethyl (CF3), trifluoromethoxy (OCF3), cyano (CN), nitro (NO2), methylsulfonyl (SO2Me), and sulfamoyl (SO2NH2) 2 .

[0032] Preferably, the 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative compound may be represented by the following Chemical Formula 1-1.

[0033] [Chemical Formula 1-1]

[0034]

[0035] In Chemical Formula 1-1, R 1 may be chlorine (Cl) or trifluoromethyl (CF3), and R 2 may be selected from the group consisting of trifluoromethyl (CF3), nitro (NO2), cyano (CN), and methylsulfonyl (SO2Me).

[0036] In an exemplary embodiment, the 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative compound may be selected from, but not limited to, the group consisting of: 2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one; 2-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)quinazolin-4(1H)-one; 4-(((1,4-trans)-4-((4-oxo-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzonitrile; 2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one; 7-fluoro-2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one; 7-fluoro-2-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)quinazolin-4(1H)-one; 4-(((1,4-trans)-4-((7-fluoro-4-oxo-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzonitrile; 7-fluoro-2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one; 7-chloro-2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one; 7-chloro-2-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)quinazolin-4(1H)-one; 4-(((1,4-trans)-4-((7-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzonitrile; 7-chloro-2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one; 4-(((1,4-trans)-4-((7-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide; 7-(trifluoromethyl)-2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one; 2-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)-7-(trifluoromethyl)quinazolin-4(1H)-one; 4-(((1,4-trans)-4-((4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzonitrile; 2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)-7-(trifluoromethyl)quinazolin-4(1H)-one; 4-(((1,4-trans)-4-((4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide;2-(((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl)amino)-7-(trifluoromethyl)quinazolin-4(1H)-one; 2-(((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl)amino)-7-(trifluoromethyl)quinazolin-4(1H)-one; 7-nitro-2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one; 7-nitro-2-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)quinazolin-4(1H)-one; 4-(((1,4-trans)-4-((7-nitro-4-oxo-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzonitrile; 2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)-7-nitroquinazolin-4(1H)-one; 6-chloro-2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one; 6-chloro-2-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)quinazolin-4(1H)-one; 4-(((1,4-trans)-4-((6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzonitrile; and 6-chloro-2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one.;

[0038] In addition, the present disclosure provides a pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition comprising the compound as an active ingredient.

[0039] Preferably, the compound according to the present disclosure can promote the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α).

[0040] Preferably, the cancer can be but is not limited to blood cancer, breast cancer, sarcoma or brain cancer.

[0041] In addition, the present invention provides a pharmaceutical composition for metabolizing an anticancer agent, the pharmaceutical composition comprising the compound as an active ingredient.

[0042] In addition, the present disclosure provides a method for inhibiting cancer cell metabolism, the method comprising administering the compound.

[0043] The compound can block the metabolism of cancer cells by promoting the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), thereby killing cancer cells.

[0044] Metabolic anticancer agents are referred to as the fourth generation of anticancer agents after chemotherapy, targeted anticancer agents, and immunotherapy, and are anticancer agents that selectively kill only cancer cells by blocking the metabolic processes of cancer cells. Different from existing anticancer treatments, metabolic anticancer agents cause more active cell division in cancer cells than in normal cells in a way that blocks the metabolic activity of cancer cells. In particular, during the process of inhibiting cancer cell growth, metabolic anticancer agents reduce cancer cell metabolism by more than 50% with little damage to normal cells.

[0045] As used herein, pharmaceutically acceptable salts can be one or more basic salts selected from the group consisting of sodium salts, potassium salts, calcium salts, lithium salts, magnesium salts, cesium salts, aminium salts, ammonium salts, triethylammonium salts, and pyridinium salts, but are not limited thereto.

[0046] In addition, pharmaceutically acceptable salts can be one or more acidic salts selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, phosphoric acid, citric acid, acetic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid, glutaric acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, and aspartic acid, but are not limited thereto.

[0047] In addition to the above components, the pharmaceutical compositions of the present disclosure may further comprise pharmaceutically acceptable carriers, excipients, or diluents for administration. Carriers, excipients, and diluents may include lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginates / esters, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl paraben, propyl paraben, talc, magnesium stearate, and mineral oil.

[0048] The pharmaceutical composition of the present disclosure can be formulated into oral preparations (such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols), topical preparations, suppositories or sterile injection solutions respectively according to conventional methods for use. Specifically, in formulation, common diluents or excipients (such as fillers, extenders, binders, wetting agents, disintegrants and surfactants) can be used for preparation. Solid preparations for oral administration include but are not limited to tablets, pills, powders, granules and capsules. In addition to the active ingredient, these solid preparations can be prepared by mixing at least one or more excipients (such as starch, calcium carbonate, sucrose, lactose and gelatin). In addition, in addition to simple excipients, lubricants (such as magnesium stearate and talc) can also be used. In addition to liquids and liquid paraffin for oral administration, various excipients (such as wetting agents, sweeteners, flavoring agents and preservatives) can be added for preparation. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations and suppositories. Non-aqueous solvents and suspensions that can be used include propylene glycol, polyethylene glycol, vegetable oils (such as olive oil) and injectable esters (such as ethyl oleate). Matrix materials that can be used for suppositories include witepsol, macrogol, Tween 61, cocoa butter, laurin fat and glycerogelatin.

[0049] It is alleged that the pharmaceutical composition of the present disclosure can be prepared into oral or parenteral preparations, and can be administered by oral, intravenous, intracerebroventricular, intradermal, intramuscular, intraperitoneal, nasal or epidural routes, but not limited thereto.

[0050] The appropriate dose of the pharmaceutical composition of the present disclosure varies according to the condition and body weight of the patient, the degree of the disease, the drug form and time, and can be appropriately selected by those skilled in the art, such that the daily dose of the composition is preferably 0.01 mg / kg to 100 mg / kg, and can be administered once or several times a day as needed.

[0052] In addition, the present disclosure provides a health functional food composition for preventing or improving cancer, and the health functional food composition contains the compound as an active ingredient.

[0053] The above-mentioned health-functional food composition may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents (e.g., synthetic flavoring agents and natural flavoring agents), coloring agents, and thickening agents (such as cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickening agents, pH regulators, stabilizers, preservatives, glycerin, alcohols, and carbonating agents used in carbonated beverages. In addition, it may contain the pulp used in the production of natural fruit juices, synthetic fruit juices, and vegetable beverages. These ingredients may be used alone or in combination. Furthermore, the health-functional food composition may be in any form such as meat, sausage, bread, chocolate, confectionery, snacks, desserts, pizza, ramen, chewing gum, ice cream, soup, beverage, tea, functional water, drink, alcohol, and vitamin complexes.

[0054] In addition, the health-functional food composition may further contain food additives, and unless otherwise specified, the applicability as a food additive is determined by referring to the standards and guidelines related to the corresponding items of the general rules and general test methods of the Korean Food Additives Codex approved by the Ministry of Food and Drug Safety.

[0055] Items listed in the Korean Food Additives Codex may include, for example, chemically synthesized compounds (e.g., ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid), natural additives (e.g., persimmon pigment, licorice extract, crystalline cellulose, sorghum pigment, and guar gum), and mixed preparations (e.g., sodium L-glutamate preparation, alkaline agent added to noodles, preservatives, and tar coloring agents).

[0056] Here, in the process of manufacturing the health-functional food composition, the content of the composition according to the present disclosure added to the food may be appropriately adjusted as needed. Examples

[0057] Hereinafter, the present disclosure will be described in more detail through examples and test examples. These examples and test examples are only intended to more specifically explain the present disclosure, and those skilled in the art will understand that the scope of the present disclosure is not limited by these examples and test examples according to the gist of the present disclosure.

[0059] [Synthesis Example] Synthesis of 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone

[0060] (1) Urea cyclization

[0061] Phenol containing a mixture of aminobenzoic acid (1.0 eq) and urea (5.0 eq) was heated to 200 °C. After stirring for 17 h, the reaction mixture was cooled to 100 °C, and then water was added dropwise. The reaction mixture was cooled to room temperature, and the resulting solid was filtered and washed / dried with ethanol to obtain quinazoline dione.

[0063] (2-1) Dichlorination using N,N-diethylaniline

[0064] N,N-Diethylaniline (30 mol%) was added to a stirred solution of POCl3 (10.0 eq) containing the above quinazoline dione (1.0 eq), and the mixture was heated to 180 °C. After 5 h to 17 h, the reaction mixture was cooled to 0 °C. The reaction mixture was poured into ice water and quenched with 6N sodium hydroxide (NaOH). The organic layer was extracted three times with dichloromethane (CH2Cl2), dried over magnesium sulfate (MgSO4), concentrated, and purified by flash column chromatography on silica gel to obtain dichloroquinazoline.

[0066] (2-2) Dichlorination using PCl5

[0067] A mixture of quinazoline dione (1.0 eq) and PCl5 (3.7 eq) in POCl3 (10.0 eq) was heated to 180 °C. After stirring for 5 h to 17 h, the reaction mixture was cooled to 0 °C. The reaction mixture was poured into ice water and quenched with 6N sodium hydroxide (NaOH). The organic layer was extracted three times with dichloromethane (CH2Cl2), dried over magnesium sulfate (MgSO4), concentrated, and purified by flash column chromatography on silica gel to obtain dichloroquinazoline.

[0069] (3) Monohydroxylation

[0070] A mixture of the above dichloroquinazoline (1.0 eq) in 1N NaOH / THF (1:1) was stirred at room temperature. After 6 h, the reaction mixture was adjusted to pH 5 with acetic acid, and the precipitated solid was filtered and dried to obtain monohydroxyquinazolinone.

[0072] (4) Nucleophilic aromatic substitution

[0073] Diisopropylethylamine (3.0 eq) was added to a stirred DMF solution containing monohydroxyquinazoline (1.0 eq) and 4-(aryloxy)cyclohexylamine (1.5 eq) in DMF, and the mixture was heated to 80 °C. After 17 h, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (EtOAc). The organic layer was washed with water (3 times) and dried over magnesium sulfate (MgSO4). The resulting residue was concentrated in vacuo and purified by flash column chromatography on silica gel to afford 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone.

[0075] [Synthesis Example 2] Specific Synthesis Example of 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone Derivative

[0076] (1) 2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one (hereinafter referred to as Compound 1)

[0077]

[0078] At ambient temperature, (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (152 mg, 0.56 mmol) and N,N-diisopropylethylamine (203 μL, 1.17 mmol) were added to a DMF solution (3 mL) containing 2-chloroquinazolin-4(1H)-one (69.6 mg, 0.39 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to afford 21.0 mg (13%) of Compound 1 as a white solid. 1 H NMR (DMSO-d6, 400 MHz) δ 10.62 (s, 1H), 7.88 (d, 1H, J = 8.0 Hz), 7.62 (d, 2H, J = 8.3 Hz), 7.55 (m, 1H), 7.26 (d, 1H, J = 8.4 Hz), 7.14 (d, 2H, J = 8.2 Hz), 7.09 (t, 1H, J = 7.4 Hz), 6.25 (d, 1H, J = 7.0 Hz), 4.50 (m, 1H), 3.87 (m, 1H), 2.08 (m, 2H), 2.06 (m, 2H), 1.55 (m, 2H), 1.44 (m, 2H); 1313C NMR (DMSO-d6, 100 MHz) δ 161.9, 160.3, 151.1, 149.8, 134.2, 131.6, 128.6, 127.0, 127.0, 126.0, 125.9, 124.6, 123.3, 121.6, 121.3, 121.0, 120.7, 120.4, 117.4, 115.8, 74.4, 47.7, 29.5, 29.4.

[0081] (2) 2-(((1,4-trans)-4-(4-Nitrophenoxy)cyclohexyl)amino)quinazolin-4(1H)-one (hereinafter referred to as Compound 2)

[0082]

[0083] At ambient temperature, (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (195 mg, 0.83 mmol) and N,N-diisopropylethylamine (287 μL, 1.65 mmol) were added to a DMF solution (3 mL) containing 2-chloroquinazolin-4(1H)-one (100 mg, 0.55 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to give 43.8 mg (21%) of Compound 2 as a brown solid.

[0084] 1 1H NMR (DMSO-d6, 400 MHz) δ 10.61 (s, 1H), 8.18 (d, 2H, J = 9.3 Hz), 7.88 (d, 1H, J = 7.8 Hz), 7.55 (t, 1H, J = 7.7 Hz), 7.26 (d, 1H, J = 8.2 Hz), 7.17 (d, 2H, J = 9.2 Hz), 7.09 (t, 1H, J = 7.3 Hz), 6.26 (d, 1H, J = 6.3 Hz), 4.59 (m, 1H), 3.88 (m, 1H), 2.08 (m, 4H), 1.58 (m, 2H), 1.46 (m, 2H); 13 13C NMR (DMSO-d6, 125 MHz) δ 163.0, 161.9, 151.2, 149.9, 140.5, 134.3, 126.0, 126.0, 124.7, 121.7, 117.4, 115.8, 75.2, 47.7, 40.02, 29.5, 29.4.

[0086] (3) 4-(((1,4-trans)-4-((4-oxo-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzonitrile (hereinafter referred to as Compound 3)

[0087]

[0088] At ambient temperature, 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (324 mg, 1.50 mmol) and N,N-diisopropylethylamine (523 μL, 3.00 mmol) were added to a DMF solution (5 mL) containing 2-chloroquinazolin-4(1H)-one (180 mg, 1.00 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to give 100 mg (28%) of Compound 3 as an off-white solid.

[0089] 1 1H NMR (DMSO-d6, 500 MHz) δ 10.60 (s, 1H), 7.88 (d, 1H, J = 7.8 Hz), 7.74 (d, 2H, J = 8.7 Hz), 7.55 (t, 1H, J = 7.6 Hz), 7.26 (d, 1H, J = 8.2 Hz), 7.13 (d, 2H, J = 8.7 Hz), 7.09 (t, 1H, J = 7.4 Hz), 6.25 (d, 1H, J = 6.7 Hz), 4.52 (m, 1H), 3.87 (m, 1H), 2.07 (m, 2H), 2.06 (m, 2H), 1.55 (m, 2H), 1.44 (m, 2H); 13 13C NMR (DMSO-d6, 125 MHz) δ 161.9, 161.1, 151.2, 149.9, 134.3, 126.0, 124.7, 121.7, 119.3, 117.4, 116.4, 102.5, 74.6, 47.7, 29.5, 29.4.

[0091] (4) 2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one (hereinafter referred to as Compound 4)

[0092]

[0093] At ambient temperature, (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (222 mg, 0.83 mmol) and N,N-diisopropylethylamine (287 μL, 1.65 mmol) were added to a DMF solution (5 mL) containing 2-chloroquinazolin-4(1H)-one (100 mg, 0.55 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to afford 74.0 mg (32%) of the white solid compound 4.

[0094] 1 H NMR (DMSO-d6, 500 MHz) δ 10.60 (s, 1H), 7.88 (dd, 1H, J = 7.9, 1.6 Hz), 7.82 (d, 2H, J = 8.9 Hz), 7.55 (ddd, 1H, J = 8.2, 7.1, 1.7 Hz), 7.26 (d, 1H, J = 8.2 Hz), 7.19 (d, 2H, J = 9.0 Hz), 7.09 (t, 1H, J = 7.4 Hz), 6.25 (d, 1H, J = 6.9 Hz), 4.55 (m, 1H), 3.88 (m, 1H), 3.15 (s, 3H), 2.08 (m, 4H), 1.57 (m, 2H), 1.46 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 161.9, 161.4, 151.2, 149.9, 134.3, 132.3, 129.3, 126.0, 124.7, 121.7, 117.4, 115.8, 74.6, 47.7, 44.0, 29.5, 29.4.

[0096] (5) 7-Fluoro-2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one (hereinafter referred to as compound 5)

[0097]

[0098] At ambient temperature, (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (194 mg, 0.75 mmol) and N,N-diisopropylethylamine (261 μL, 1.50 mmol) were added to a DMF solution (5 mL) containing 2-chloro-7-fluoroquinazolin-4(1H)-one (100 mg, 0.50 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to give 35.4 mg (17%) of the white solid compound 5.

[0099] 1 1H NMR (DMSO-d6, 500 MHz) δ 10.61 (s, 1H), 7.91 (dd, 1H, J = 8.6, 6.8 Hz), 7.60 (d, 2H, J = 8.7 Hz), 7.13 (d, 2H, J = 8.6 Hz), 6.95 (dd, 1H, J = 11.0, 2.2 Hz), 6.89 (td, 1H, J = 8.6, 2.4 Hz), 6.35 (s, 1H), 4.49 (m, 1H), 3.88 (m, 1H), 2.07 (m, 4H), 1.55 (m, 2H), 1.45 (m, 2H); 13 13C NMR (DMSO-d, 125 MHz) δ 167.2, 165.2, 161.2, 160.4, 153.6, 153.4, 150.8, 129.0, 128.9, 127.9, 127.1, 127.0, 127.0, 127.0, 125.7, 123.6, 121.4, 121.3, 121.0, 120.8, 120.5, 115.9, 114.4, 110.1, 109.9, 109.5, 109.3, 74.4, 47.8, 29.4.

[0101] (6) 7-Fluoro-2-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)quinazolin-4(1H)-one (hereinafter referred to as compound 6)

[0102]

[0103] At ambient temperature, (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (269 mg, 1.14 mmol) and N,N-diisopropylethylamine (397 μL, 2.28 mmol) were added to a DMF solution (5 mL) containing 2-chloro-7-fluoroquinazolin-4(1H)-one (150 mg, 0.76 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to afford 89.5 mg (30%) of the brown solid compound 6.

[0104] 1 H NMR (DMSO-d6, 500 MHz) δ 10.63 (s, 1H), 8.18 (d, 2H, J = 9.3 Hz), 7.92 (dd, 1H, J = 8.7, 6.8 Hz), 7.17 (d, 2H, J = 9.3 Hz), 6.97 (dd, 1H, J = 10.7, 1.5 Hz), 6.92 (td, 1H, J = 8.7, 2.2 Hz), 6.40 (s, 1H), 4.59 (m, 1H), 3.88 (m, 1H), 2.08 (m, 4H), 1.57 (m, 2H), 1.47 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 167.2, 165.2, 162.9, 161.1, 153.5, 153.4, 150.7, 140.5, 128.9, 128.8, 126.0, 115.7, 114.4, 110.1, 109.9, 109.5, 109.3, 75.1, 47.7, 29.4, 29.3.

[0107] *(7) 4-(((1,4-trans)-4-((7-fluoro-4-oxo-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzonitrile (hereinafter referred to as compound 7)

[0108]

[0109] At ambient temperature, 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (162 mg, 0.75 mmol) and N,N-diisopropylethylamine (261 μL, 1.50 mmol) were added to a DMF solution (5 mL) containing 2-chloro-7-fluoroquinazolin-4(1H)-one (100 mg, 0.50 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to afford 42.6 mg (22%) of the white solid compound 7.

[0110] 1 H NMR (DMSO-d6, 500 MHz) δ 7.92 (dd, 1H, J = 8.7, 6.7 Hz), 7.74 (d, 2H, J = 8.9 Hz), 7.13 (d, 2H, J = 8.9 Hz), 6.97 (dd, 1H, J = 11.0, 2.4 Hz), 6.92 (td, 1H, J = 8.7, 2.5 Hz), 6.49 (s, 1H), 4.52 (m, 1H), 3.87 (m, 1H), 2.06 (m, 4H), 1.54 (m, 2H), 1.45 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 167.2, 165.3, 161.2, 161.1, 153.6, 153.5, 150.8, 134.3, 129.0, 128.9, 119.3, 116.4, 114.4, 110.2, 110.0, 109.5, 109.3, 102.6, 74.6, 47.8, 29.4.

[0112] (8) 7-Fluoro-2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one (hereinafter referred to as compound 8)

[0113]

[0114] At ambient temperature, (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (202 mg, 0.75 mmol) and N,N-diisopropylethylamine (261 μL, 1.50 mmol) were added to a DMF solution (5 mL) containing 2-chloro-7-fluoroquinazolin-4(1H)-one (100 mg, 0.50 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to give 37.6 mg (17%) of the white solid compound 8.

[0115] 1 H NMR (DMSO-d6, 500 MHz) δ 10.65 (s, 1H), 7.92 (d, 1H, J = 8.7, 6.8 Hz), 7.82 (d, 2H, J = 8.9 Hz), 7.18 (d, 2H, J = 8.9 Hz), 6.97 (dd, 1H, J = 10.9, 2.0 Hz), 6.92 (td, 1H, J = 8.6, 2.3 Hz), 6.45 (s, 1H), 4.54 (m, 1H), 3.88 (m, 1H), 3.15 (s, 3H), 2.07 (m, 4H), 1.56 (m, 2H), 1.46 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 167.2, 165.2, 161.3, 161.2, 153.5, 153.4, 150.8, 132.3, 129.3, 128.9, 128.8, 115.8, 114.4, 110.1, 109.9, 109.4, 109.3, 74.6, 47.7, 44.0, 29.4.

[0117] (9) 7-Chloro-2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one (hereinafter referred to as compound 9)

[0118]

[0119] At ambient temperature, (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (362 mg, 1.40 mmol) and N,N-diisopropylethylamine (486 μL, 2.79 mmol) were added to a DMF solution (7 mL) containing 2,7-dichloroquinazolin-4(1H)-one (200 mg, 0.93 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to afford 68.0 mg (17%) of the white solid compound 9.

[0120] 1 H NMR (DMSO-d6, 400 MHz) δ 10.71 (s, 1H), 7.86 (m, 1H), 7.62 (d, 2H, J = 8.2 Hz), 7.26 (s, 1H), 7.14 (d, 2H, J = 8.2 Hz), 7.09 (d, 1H, J = 8.4 Hz), 6.42 (s, 1H), 4.50 (m, 1H), 3.87 (m, 1H), 2.06 (m, 4H), 1.49 (m, 4H); 13 C NMR (DMSO-d6, 125 MHz) δ 161.5, 160.5, 152.5, 150.9, 139.2, 128.2, 128.0, 127.2, 127.2, 127.2, 127.1, 125.9, 123.7, 122.0, 121.6, 121.4, 121.2, 120.9, 120.7, 116.2, 116.0, 74.5, 48.1, 29.6, 29.5.

[0122] (10) 7-Chloro-2-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)quinazolin-4(1H)-one (hereinafter referred to as compound 10)

[0123]

[0124] At ambient temperature, (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (331 mg, 1.40 mmol) and N,N-diisopropylethylamine (486 μL, 2.79 mmol) were added to a DMF solution (7 mL) containing 2,7-dichloroquinazolin-4(1H)-one (200 mg, 0.93 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to give 60.6 mg (16%) of the title compound 10 as a light brown solid.

[0125] 1 H NMR (DMSO-d6, 500 MHz) δ 10.71 (s, 1H), 8.19 (d, 2H, J = 9.3 Hz), 7.86 (d, 1H, J = 8.5 Hz), 7.26 (d, 1H, J = 1.5 Hz), 7.18 (d, 2H, J = 9.3 Hz), 7.10 (dd, 1H, J = 8.4, 1.8 Hz), 6.44 (s, 1H), 4.60 (m, 1H), 3.87 (m, 1H), 2.08 (m, 4H), 1.57 (m, 2H), 1.47 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 162.9, 161.3, 152.4, 150.8, 140.5, 138.9, 128.0, 126.0, 123.6, 121.8, 116.2, 115.7, 75.1, 47.8, 37.4, 29.4.

[0127] *

[0128] (11) 4-(((1,4-trans)-4-((7-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzonitrile (hereinafter referred to as Compound 11)

[0129]

[0130] At ambient temperature, 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (273 mg, 1.26 mmol) and N,N-diisopropylethylamine (439 μL, 2.52 mmol) were added to a DMF solution (6 mL) containing 2,7-dichloroquinazolin-4(1H)-one (180 mg, 0.84 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to give 161 mg (49%) of the white solid compound 11.

[0131] 1 H NMR (DMSO-d6, 500 MHz) δ 10.36 (s, 1H), 7.85 (d, 1H, J = 8.5 Hz), 7.74 (d, 2H, J = 8.7 Hz), 7.26 (d, 1H, J = 1.2 Hz), 7.13 (d, 2H, J = 8.7 Hz), 7.09 (dd, 1H, J = 8.4, 1.4 Hz), 6.55 (m, 1H), 4.52 (m, 1H), 3.86 (m, 1H), 2.06 (m, 4H), 1.54 (m, 2H), 1.45 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 161.5, 161.1, 152.4, 151.0, 138.9, 134.3, 128.1, 123.5, 121.8, 119.3, 116.4, 116.2, 102.5, 74.6, 47.9, 29.4.

[0133] (12) 7-Chloro-2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one (hereinafter referred to as compound 12)

[0134]

[0135] At ambient temperature, (1R,4R)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (190 mg, 0.71 mmol) and N,N-diisopropylethylamine (246 μL, 1.41 mmol) were added to a DMF solution (3 mL) containing 2,7-dichloroquinazolin-4(1H)-one (100 mg, 0.47 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to afford 114 mg (55%) of the ivory solid compound 12.

[0136] 1 H NMR (DMSO-d6, 500 MHz) δ 10.69 (s, 1H), 7.86 (d, 1H, J = 8.5 Hz), 7.82 (d, 2H, J = 8.7 Hz), 7.26 (s, 1H), 7.18 (d, 2H, J = 8.7 Hz), 7.09 (d, 1H, J = 8.5 Hz), 6.54 (s, 1H), 4.54 (m, 1H), 3.87 (m, 1H), 3.15 (s, 3H), 2.07 (m, 4H), 1.55 (m, 2H), 1.46 (m, 2H); 13 C NMR (DMSO-d6, 100 MHz) δ 161.6, 161.3, 152.4, 151.0, 138.8, 132.3, 129.3, 128.0, 123.5, 121.7, 116.2, 115.8, 74.6, 47.9, 44.0, 29.4.

[0138] (13) 4-(((1R,4R)-4-((7-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide (hereinafter referred to as compound 13)

[0139]

[0140] At ambient temperature, 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzenesulfonamide (150 mg, 0.56 mmol) and N,N-diisopropylethylamine (193 μL, 1.11 mmol) were added to a DMF solution (2.5 mL) containing 2,7-dichloroquinazolin-4(1H)-one (79.5 mg, 0.37 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to afford 43.9 mg (26%) of the white solid compound 13.

[0141] 1 H NMR (DMSO-d6, 500 MHz) δ 10.70 (s, 1H), 7.86 (d, 1H, J = 8.4 Hz), 7.73 (d, 2H, J = 8.5 Hz), 7.26 (s, 1H), 7.19 (s, 2H), 7.11 (d, 2H, J = 8.4 Hz), 7.09 (m, 1H), 6.43 (s, 1H), 4.49 (m, 1H), 3.86 (m, 1H), 2.06 (m, 4H), 1.54 (m, 2H), 1.45 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 161.3, 159.9, 152.4, 150.8, 139.0, 136.0, 128.0, 127.8, 123.6, 121.7, 116.2, 115.4, 74.3, 47.9, 29.4.

[0143] (14) 7-(Trifluoromethyl)-2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one (hereinafter referred to as compound 14)

[0144]

[0145] At ambient temperature, (1R,4R)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (190 mg, 0.71 mmol) and N,N-diisopropylethylamine (209 μL, 1.20 mmol) were added to a DMF solution (3 mL) containing 2-chloro-7-(trifluoromethyl)quinazolin-4(1H)-one (100 mg, 0.40 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to afford 112 mg (30%) of the white solid compound 14.

[0146] 1 H NMR (DMSO-d6, 500 MHz) δ 10.86 (s, 1H), 8.05 (d, 1H, J = 8.0 Hz), 7.62 (d, 2H, J = 8.2 Hz), 7.51 (s, 1H), 7.34 (d, 1H, J = 7.3 Hz), 7.14 (d, 2H, J = 8.2 Hz), 6.49 (s, 1H), 4.50 (m, 1H), 3.90 (m, 1H), 2.08 (m, 4H), 1.55 (m, 2H), 1.47 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 161.2, 160.3, 151.4, 150.9, 134.5, 134.2, 134.0, 133.7, 127.9, 127.7, 127.1, 127.1, 127.0, 127.0, 127.0, 125.7, 124.9, 123.6, 122.8, 121.5, 121.4, 121.3, 121.0, 120.8, 120.6, 120.5, 120.1, 117.1, 115.9, 74.4, 48.0, 29.5, 29.4.

[0148] (15) 2-(((1R,4R)-4-(4-nitrophenoxy)cyclohexyl)amino)-7-(trifluoromethyl)quinazolin-4(1H)-one (hereinafter referred to as compound 15)

[0149]

[0150] At ambient temperature, (1R,4R)-4-((4-nitrophenoxy)amino)cyclohexan-1-amine (113 mg, 0.48 mmol) and N,N-diisopropylethylamine (167 μL, 0.96 mmol) were added to a DMF solution (3 mL) containing 2-chloro-7-(trifluoromethyl)quinazolin-4(1H)-one (80.0 mg, 0.32 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to afford 43.9 mg (30%) of the title compound 15 as a pale yellow solid.

[0151] 1 H NMR (DMSO-d6, 500 MHz) δ 10.87 (s, 1H), 8.18 (d, 2H, J = 9.3 Hz), 8.05 (d, 1H, J = 8.3 Hz), 7.50 (s, 1H), 7.34 (d, 1H, J = 8.1 Hz), 7.17 (d, 2H, J = 9.4 Hz), 6.52 (s, 1H), 4.59 (m, 1H), 3.90 (m, 1H), 2.09 (m, 4H), 1.58 (m, 2H), 1.49 (m, 2H); 13 C NMR (DMSO-d6, 100 MHz) δ 162.9, 161.2, 151.3, 150.9, 140.5, 134.5, 134.2, 133.9, 133.6, 127.9, 127.6, 126.0, 125.2, 122.5, 121.4, 120.1, 119.7, 117.0, 115.7, 75.1, 47.9, 29.4, 29.3.

[0153] (16)4-(((1R,4R)-4-((4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzonitrile (hereinafter referred to as compound 16)

[0154]

[0155] At ambient temperature, 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (130 mg, 0.60 mmol) and N,N-diisopropylethylamine (209 μL, 1.20 mmol) were added to a DMF solution (3 mL) containing 2-chloro-7-(trifluoromethyl)quinazolin-4(1H)-one (100 mg, 0.40 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to give 48.6 mg (28%) of the white solid compound 16.

[0156] 1 H NMR (DMSO-d6, 500 MHz) δ 11.11 (s, 1H), 8.05 (d, 1H, J = 8.2 Hz), 7.74 (d, 2H, J = 8.8 Hz), 7.49 (s, 1H), 7.33 (d, 1H, J = 8.2 Hz), 7.14 (d, 2H, J = 8.8 Hz), 6.92 (d, 1H, J = 4.9 Hz), 4.54 (m, 1H), 3.90 (m, 1H), 2.07 (m, 4H), 1.55 (m, 2H), 1.47 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 161.0, 151.3, 151.0, 134.4, 134.2, 134.1, 133.9, 133.6, 127.6, 127.1, 124.9, 122.7, 121.4, 121.4, 120.6, 120.1, 119.2, 116.9, 116.3, 102.5, 74.4, 47.8, 29.2.

[0158] (17) 2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)-7-(trifluoromethyl)quinazolin-4(1H)-one (hereinafter referred to as compound 17)

[0159]

[0160] At ambient temperature, (1R,4R)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (129 mg, 0.48 mmol) and N,N-diisopropylethylamine (167 μL, 0.96 mmol) were added to a DMF solution (3 mL) containing 2-chloro-7-(trifluoromethyl)quinazolin-4(1H)-one (80.0 mg, 0.32 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to afford 37.4 mg (24%) of the compound 17 as an off-white solid.

[0161] 1 H NMR (DMSO-d6, 500 MHz) δ 8.05 (d, 1H, J = 8.2 Hz), 7.82 (d, 2H, J = 8.8 Hz), 7.50 (s, 1H), 7.33 (d, 1H, J = 8.0 Hz), 7.20 (d, 2H, J = 8.8 Hz), 7.12 (s, 1H), 4.57 (m, 1H), 3.92 (m, 1H), 3.15 (s, 3H), 2.08 (m, 4H), 1.57 (m, 2H), 1.49 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 161.3, 160.3, 151.4, 151.2, 134.3, 134.1, 133.8, 133.6, 132.3, 129.3, 127.7, 127.1, 124.9, 122.7, 121.4, 120.6, 120.1, 116.9, 115.8, 74.4, 47.7, 44.0, 29.2.

[0163] (18)4-(((1R,4R)-4-((4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide (hereinafter referred to as compound 18)

[0164]

[0165] At ambient temperature, 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzenesulfonamide (104 mg, 0.39 mmol) and N,N-diisopropylethylamine (167 μL, 0.96 mmol) were added to a DMF solution (3 mL) containing 2-chloro-7-(trifluoromethyl)quinazolin-4(1H)-one (80.0 mg, 0.32 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / n-hexane (3:2) to afford 22.2 mg (14%) of the white solid compound 18.

[0166] 1 H NMR (DMSO-d6, 500 MHz) δ 10.89 (s, 1H), 8.06 (d, 1H, J = 8.2 Hz), 7.73 (d, 2H, J = 8.9 Hz), 7.51 (s, 1H), 7.35 (d, 1H, J = 7.8 Hz), 7.19 (s, 2H), 7.11 (d, 2H, J = 8.9 Hz), 6.53 (s, 1H), 4.50 (m, 1H), 3.89 (m, 1H), 2.08 (m, 4H), 1.54 (m, 2H), 1.47 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 161.3, 159.9, 151.4, 151.0, 136.0, 134.2, 134.0, 127.8, 127.7, 127.1, 124.9, 122.8, 121.4, 120.6, 120.1, 117.1, 115.4, 74.4, 48.0, 29.5, 29.4.

[0169] (19) 2-(((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl)amino)-7-(trifluoromethyl)quinazolin-4(1H)-one (hereinafter referred to as compound 19)

[0170]

[0171] At ambient temperature, (1,4-trans)-4-(4-chlorophenoxy)cyclohexan-1-amine (87.0 mg, 0.48 mmol) and N,N-diisopropylethylamine (167 μL, 0.96 mmol) were added to a DMF solution (3 mL) containing 2-chloro-7-(trifluoromethyl)quinazolin-4(1H)-one (80.0 mg, 0.32 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / CH2Cl2 (1:4) to give 16.7 mg (12%) of the white solid compound 19.

[0172] 1 H NMR (DMSO-d6, 500 MHz) δ 10.92 (s, 1H), 8.05 (d, 1H, J = 8.2 Hz), 7.51 (s, 1H), 7.35 (d, 1H, J = 8.1 Hz), 7.30 (d, 2H, J = 7.8 Hz), 6.99 (d, 2H, J = 8.0 Hz), 6.57 (s, 1H), 4.36 (m, 1H), 3.88 (m, 1H), 2.06 (m, 2H), 2.05 (m, 2H), 1.51 (m, 2H), 1.44 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 161.4, 156.2, 151.3, 151.1, 134.4, 134.1, 133.8, 133.6, 129.3, 127.6, 127.1, 124.9, 124.1, 122.7, 121.4, 120.6, 120.1, 117.4, 117.0, 74.4, 48.00, 29.52, 29.38.

[0175] (20) 2-(((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl)amino)-7-(trifluoromethyl)quinazolin-4(1H)-one (hereinafter referred to as compound 20)

[0176]

[0177] At ambient temperature, (1R,4R)-4-(4-(trifluoromethoxy)phenoxy)cyclohexan-1-amine (166 mg, 0.60 mmol) and N,N-diisopropylethylamine (210 μL, 1.21 mmol) were added to a DMF solution (3 mL) containing 2-chloro-7-(trifluoromethyl)quinazolin-4(1H)-one (100 mg, 0.40 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / CH2Cl2 (1:3) to afford 6 mg (14%) of the white solid compound 20.

[0178] 1 H NMR (DMSO-d6, 500 MHz) δ 10.84 (s, 1H), 8.05 (d, 1H, J = 8.2 Hz), 7.51 (s, 1H), 7.35 (d, 1H, J = 8.1 Hz), 7.27 (d, 2H, J = 8.7 Hz), 7.06 (d, 2H, J = 9.1 Hz), 6.46 (s, 1H), 4.39 (m, 1H), 3.89 (m, 1H), 2.07 (m, 2H), 2.05 (m, 2H), 1.52 (m, 2H), 1.45 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 161.1, 156.2, 151.3, 150.8, 141.6, 141.6, 134.4, 134.2, 133.9, 133.7, 127.6, 127.1, 124.9, 123.2, 122.7, 122.5, 121.4, 121.2, 120.5, 120.1, 119.2, 117.2, 117.0, 116.8, 74.6, 48.0, 29.5, 29.4.

[0180] (21) 7-Nitro-2-(((1R,4R)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one (hereinafter referred to as compound 21)

[0181]

[0182] At ambient temperature, (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (259 mg, 1.00 mmol) and N,N-diisopropylethylamine (350 μL, 2.01 mmol) were added to a DMF solution (5 mL) containing 2-chloro-7-nitroquinazolin-4(1H)-one (150 mg, 0.67 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to afford 139 mg (47%) of the yellow solid compound 21.

[0183] 1 H NMR (DMSO-d6, 500 MHz) δ 10.96 (s, 1H), 8.09 (d, 1H, J = 8.7 Hz), 7.93 (s, 1H), 7.80 (d, 1H, J = 7.7 Hz), 7.63 (d, 2H, J = 8.0 Hz), 7.15 (d, 2H, J = 8.2 Hz), 6.60 (s, 1H), 4.52 (m, 1H), 3.91 (m, 1H), 2.09 (m, 1H), 1.57 (m, 2H), 1.49 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 160.9, 160.3, 151.8, 151.4, 151.2, 127.8, 127.0, 127.0, 126.9, 125.7, 123.5, 121.7, 121.4, 121.2, 121.0, 120.7, 120.5, 119.2, 115.8, 114.9, 74.3, 48.0, 29.4, 29.3.

[0185] (22) 7-Nitro-2-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)quinazolin-4(1H)-one (hereinafter referred to as compound 22)

[0186]

[0187] At ambient temperature, (1,4-trans)-4-(4-nitrophenoxy)cyclohexan-1-amine (188 mg, 0.80 mmol) and N,N-diisopropylethylamine (277 μL, 1.59 mmol) were added to a DMF solution (4 mL) containing 2-chloro-7-nitroquinazolin-4(1H)-one (120 mg, 0.53 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to afford 76.0 mg (34%) of the yellow solid compound 22.

[0188] 1 H NMR (DMSO-d6, 500 MHz) δ 10.94 (s, 1H), 8.18 (d, 2H, J = 8.7 Hz), 8.07 (d, 1H, J = 8.5 Hz), 7.92 (s, 1H), 7.79 (d, 1H, J = 8.0 Hz), 7.18 (d, 2H, J = 8.7 Hz), 6.63 (s, 1H), 4.60 (m, 1H), 3.91 (m, 1H), 2.10 (m, 4H), 1.59 (m, 2H), 1.50 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 163.0, 161.2, 151.9, 151.4, 140.6, 128.2, 126.1, 121.7, 119.2, 115.8, 115.5, 115.0, 75.2, 48.1, 29.4, 29.4.

[0190] (23) 4-(((1,4-trans)-4-((7-nitro-4-oxo-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzonitrile (hereinafter referred to as compound 23)

[0191]

[0192] At ambient temperature, 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (173 mg, 0.80 mmol) and N,N-diisopropylethylamine (277 μL, 1.59 mmol) were added to a DMF solution (4 mL) containing 2-chloro-7-nitroquinazolin-4(1H)-one (120 mg, 0.53 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to afford 80.4 mg (37%) of the yellow solid compound 23.

[0193] 1 H NMR (DMSO-d6, 500 MHz) δ 10.92 (s, 1H), 8.07 (d, 1H, J = 8.7 Hz), 7.91 (s, 1H), 7.78 (dd, 1H, J = 8.6, 1.6 Hz), 7.74 (d, 2H, J = 8.7 Hz), 7.14 (d, 2H, J = 8.8 Hz), 6.67 (s, 1H), 4.53 (m, 1H), 3.90 (m, 1H), 2.08 (m, 4H), 1.56 (m, 2H), 1.48 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 161.0, 151.7, 151.3, 134.2, 128.1, 121.7, 119.2, 116.3.114.8, 102.5, 74.5, 48.0, 29.4, 29.3.

[0195] (24) 2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)-7-nitroquinazolin-4(1H)-one (hereinafter referred to as compound 24)

[0196]

[0197] At ambient temperature, (1R,4R)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (173 mg, 0.80 mmol) and N,N-diisopropylethylamine (229 μL, 1.32 mmol) were added to a DMF solution (3 mL) containing 2-chloro-7-nitroquinazolin-4(1H)-one (100 mg, 0.44 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to afford 48.8 mg (24%) of the yellow solid compound 24.

[0198] 1 H NMR (DMSO-d6, 500 MHz) δ 8.07 (d, 1H, J = 8.6 Hz), 7.92 (s, 1H), 7.82 (d, 2H, J = 8.4 Hz), 7.79 (d, 1H, J = 8.8 Hz), 7.19 (d, 2H, J = 8.4 Hz), 6.78 (s, 1H), 4.54 (m, 1H), 3.92 (m, 1H), 3.15 (s, 3H), 2.09 (m, 4H), 1.57 (m, 2H), 1.50 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 161.3, 161.1, 151.7, 151.3, 132.3, 130.1, 129.3, 128.1, 121.7, 119.1, 115.8, 114.9, 74.6, 48.0, 44.0, 29.4, 29.3.

[0200] (25) 6-Chloro-2-(((1R,4R)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one (hereinafter referred to as compound 25)

[0201]

[0202] At ambient temperature, (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (331 mg, 1.28 mmol) and N,N-diisopropylethylamine (444 μL, 2.55 mmol) were added to a DMF solution (7 mL) containing 2,6-dichloroquinazolin-4(1H)-one (184 mg, 0.85 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to afford 45.0 mg (12%) of the title compound 25 as a pale yellow solid.

[0203] 1 H NMR (DMSO-d6, 400 MHz) δ 11.00 (s, 1H), 7.79 (s, 1H), 7.61 (d, 2H, J = 7.0 Hz), 7.54 (d, 1H, J = 6.7 Hz), 7.26 (d, 1H, J = 8.1 Hz), 7.14 (d, 2H, J = 7.2 Hz), 6.74 (s, 1H), 4.51 (m, 1H), 3.87 (m, 1H), 2.06 (m, 4H), 1.50 (m, 4H); 13 C NMR (DMSO-d6, 100 MHz) δ 160.8, 160.3, 150.3, 150.0, 134.2, 128.7, 127.0, 127.0, 126.8, 126.0, 125.3, 124.8, 123.3, 121.3, 121.0, 120.7, 120.6, 120.4, 118.5, 115.8, 74.3, 47.7, 30.7, 29.3.

[0205] (26) 6-Chloro-2-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)quinazolin-4(1H)-one (hereinafter referred to as Compound 26)

[0206]

[0207] At ambient temperature, (1R,4R)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine (156 mg, 0.66 mmol) and N,N-diisopropylethylamine (230 μL, 1.32 mmol) were added to a DMF solution (3 mL) containing 2,6-dichloroquinazolin-4(1H)-one (100 mg, 0.44 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to afford 52.7 mg (29%) of the title compound 26 as a light brown solid.

[0208] 1 1H NMR (DMSO-d6, 500 MHz) δ 8.18 (d, 2H, J = 9.2 Hz), 7.80 (d, 1H, J = 2.2 Hz), 7.56 (dd, 1H, J = 8.7, 2.2 Hz), 7.27 (d, 1H, J = 8.7 Hz), 7.17 (d, 2H, J = 9.1 Hz), 6.42 (s, 1H), 4.58 (m, 1H), 3.87 (m, 1H), 2.08 (m, 4H), 1.57 (m, 2H), 1.47 (m, 2H); 13 13C NMR (DMSO-d6, 125 MHz) δ 163.0, 161.1, 150.3, 150.0, 140.6, 134.3, 126.8, 126.0, 125.5, 124.9, 118.5, 115.8, 75.2, 47.8, 29.4.

[0210] (27) 4-(((1R,4R)-4-((6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzonitrile (hereinafter referred to as Compound 27)

[0211]

[0212] At ambient temperature, 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (143 mg, 0.66 mmol) and N,N-diisopropylethylamine (230 μL, 1.32 mmol) were added to a DMF solution (3 mL) containing 2,6-dichloroquinazolin-4(1H)-one (100 mg, 0.44 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to afford 64.5 mg (37%) of the white solid compound 27.

[0213] 1 H NMR (DMSO-d6, 500 MHz) δ 10.78 (s, 1H), 7.80 (d, 1H, J = 2.5 Hz), 7.74 (d, 2H, J = 8.9 Hz), 7.55 (dd, 1H, J = 8.8, 2.6 Hz), 7.27 (d, 1H, J = 8.8 Hz), 7.13 (d, 2H, J = 9.0 Hz), 6.39 (s, 1H), 4.52 (m, 1H), 3.86 (m, 1H), 2.06 (m, 4H), 1.54 (m, 2H), 1.45 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 161.1, 161.0, 150.4, 150.0, 134.3, 134.2, 126.8, 125.4, 124.8, 119.2, 118.4, 116.4, 102.5, 74.6, 47.8, 29.4.

[0215] (28) 6-Chloro-2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one (hereinafter referred to as compound 28)

[0216]

[0217] At ambient temperature, (1R,4R)-4-(4-(methylsulfonyl)phenoxy)cyclohexan-1-amine (133 mg, 0.50 mmol) and N,N-diisopropylethylamine (172 μL, 0.99 mmol) were added to a DMF solution (2 mL) containing 2,6-dichloroquinazolin-4(1H)-one (70.0 mg, 0.33 mmol). After stirring at 80 °C for 17 h, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (EtOAc). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was recrystallized and purified from EtOAc / MeOH (10:1) to afford 70.8 mg (48%) of the compound 28 as an off-white solid.

[0218] 1 H NMR (DMSO-d6, 500 MHz) δ 10.82 (s, 1H), 7.82 (d, 2H, J = 8.8 Hz), 7.80 (m, 1H), 7.56 (d, 1H, J = 8.6 Hz), 7.27 (d, 1H, J = 8.8 Hz), 7.19 (d, 2H, J = 8.6 Hz), 6.45 (s, 1H), 4.55 (m, 1H), 3.87 (m, 1H), 3.15 (s, 3H), 2.07 (m, 4H), 1.56 (m, 2H), 1.46 (m, 2H); 13 C NMR (DMSO-d6, 125 MHz) δ 161.4, 161.1, 150.3, 150.0, 134.3, 132.3, 129.3, 126.8, 125.5, 124.9, 118.5, 115.8, 74.6, 47.8, 44.0, 29.4.

[0220] [Example 1] Analysis of the fold change in eIF2α phosphorylation for 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivatives

[0221] Use the PathScan phospho-eIF2α(Ser51) Sandwich ELISA Kit #7286 from Cell Signaling. Culture the K562 cell line in serum-free RPMI medium at 37 °C in the presence of 5% CO2. Treat the cells with Compounds 1 to 28 prepared in the above Synthesis Examples at a concentration of 10 μM. After 6 hours of compound treatment, lyse the cells using the lysis buffer included in the kit, quantify and obtain 50 μg of protein. Thereafter, obtain the absorbance by performing an ELISA assay according to the manufacturer's protocol. Normalize the absorbance of each obtained compound to the value of the control (DMSO treatment) set to 1. The results are as Figure 1 shown.

[0223] [Example 2] Analysis of the anti-proliferative activity of 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivatives against K562

[0224] Perform a CCK-8 assay (Cell Counting Kit-8 assay, Dojindo, Kumamoto, Japan). Culture the K562 cell line in RPMI medium supplemented with 10% FBS and 1% ABAM at 37 °C in the presence of 5% CO2. Treat the cells with Compounds 1, 9 to 12, 14 to 17, and 25 at concentrations of 0 μM, 1.25 μM, 2.5 μM, 5 μM, 10 μM, and 20 μM, respectively. After 3 days of culture, treat with 10 μL of CCK-8 solution and then culture for 4 hours. Then, obtain the IC 50 value by measuring the absorbance at 450 nm. The results are as Figure 2 shown.

[0226] Although the specific parts of the present disclosure have been described in detail above, it is clear to those skilled in the art that the specific description is merely a preferred exemplary embodiment, and the scope of the present disclosure is not limited thereto. In other words, the substantial scope of the present disclosure is defined by the appended claims and their equivalents.

Claims

1. A compound selected from 4-(((1,4-trans)-4-((4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide, its pharmaceutically acceptable salts, its solvates or its stereoisomers.

2. A pharmaceutical composition for preventing or treating cancer, the pharmaceutical composition comprising the compound according to claim 1 as an active ingredient.

3. The pharmaceutical composition according to claim 2, wherein, The compound promotes the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α).

4. The pharmaceutical composition according to claim 2, wherein, The cancer is one or more selected from the group consisting of blood cancer, breast cancer, sarcoma or brain cancer.

5. A pharmaceutical composition for metabolizing an anticancer agent, the pharmaceutical composition comprising the compound according to claim 1 as an active ingredient.

6. The pharmaceutical composition according to claim 5, wherein, The compound blocks the metabolism of cancer cells by promoting the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α).

7. A method for inhibiting cancer cell metabolism, the method comprising administering the compound according to claim 1.

8. The method according to claim 7, wherein The compound blocks cancer cell metabolism by promoting the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α).

9. A health functional food composition for preventing or improving cancer, the health functional food composition comprising the compound according to claim 1 as an active ingredient.

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