Novel 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivatives and methods for producing the same

Abstract

The present invention aims to provide novel 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivatives that exhibit anti-cancer activity through eIF2α phosphorylation. The synthesized novel derivatives exhibit eIF2α phosphorylation effects and cancer cell proliferation inhibitory activity in vitro, and can be used as metabolic anti-cancer agents in pharmaceuticals and health functional food compositions for the prevention and treatment of leukemia, as well as rare cancers such as breast cancer, brain tumors, and sarcomas.

Description

[Technical Field]

[0001] The present invention relates to a novel 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative and a method for producing the same. [Background technology]

[0002] Research into regulating the synthesis of proteins related to the metabolism of cancer cells to induce cancer cell death has recently gained attention. Tumor-associated proteins are coded by so-called "weak" mRNA, which is expressed at a minimal level in normal cells but increases dramatically in cancer cells.

[0003] One representative target for regulating such tumor factors is the phosphorylation of eIF2α (alpha subunit of eukaryotic initiation factor 2), a representative eukaryotic translation initiation factor. eIF2α is phosphorylated by four kinases: HRI, PERK, GCN2, and PKR, and each of these kinases is activated in response to cellular stress. As a result, phosphorylated eIF2α can suppress protein biosynthesis.

[0004] During the carcinogenesis process of cells, eIF2 is overexpressed, leading to a surge in the translation of weak mRNA. Phosphorylating eIF2α can suppress the translation of weak mRNA, potentially resulting in the suppression of tumor factor expression. However, to date, no small molecule candidate substances with eIF2α phosphorylation activity have been reported to enter clinical trials. Therefore, research into novel substances with superior eIF2α phosphorylation activity is necessary, and the development of metabolic anticancer agents utilizing this mechanism is urgently needed. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] An object of the present invention is to provide a compound selected from a 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof or a stereoisomer thereof.

[0006] Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer containing the compound as an active ingredient.

[0007] Still another object of the present invention is to provide a pharmaceutical composition for an antimetabolic cancer agent containing the compound as an active ingredient.

[0008] Still another object of the present invention is to provide a method for suppressing cancer cell metabolism including the step of administering the compound.

[0009] Still another object of the present invention is to provide a health functional food composition for preventing or improving cancer containing the compound as an active ingredient.

Means for Solving the Problems

[0010] In order to achieve the above object, the present invention provides a compound selected from a 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof or a stereoisomer thereof.

[0011] [Chemical Formula 1]

Chemical Formula

[0012] In the above chemical formula 1,

[0013] R 1 and R 2These are each the same or different and are 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).

[0014] Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer, which contains the aforementioned compound as an active ingredient.

[0015] Furthermore, the present invention provides a pharmaceutical composition for metabolic anticancer agents containing the aforementioned compound as an active ingredient.

[0016] Furthermore, the present invention provides a method for suppressing cancer cell metabolism, which includes the step of administering the aforementioned compound.

[0017] Furthermore, the present invention provides a health functional food composition for the prevention or improvement of cancer, which contains the aforementioned compound as an active ingredient. [Effects of the Invention]

[0018] The present invention relates to a compound selected from 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative compounds that exhibit anticancer activity through eIF2α phosphorylation, a pharmaceutically acceptable salt thereof, a solvide thereof, or a stereoisomer thereof. The newly synthesized derivative exhibits eIF2α phosphorylation effect and in vitro cancer cell proliferation inhibitory activity, and can be used as a metabolic anticancer agent in pharmaceutical and health functional food compositions for the prevention and improvement of leukemia and other rare cancers such as breast cancer, brain tumors, and sarcomas. [Brief explanation of the drawing]

[0019] [Figure 1] This is a diagram illustrating a design strategy for novel 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivatives. [Figure 2]This figure shows the confirmed effect of a novel 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative on eIF2α phosphorylation. [Figure 3] This figure shows the results of confirming the antiproliferative activity of a novel 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative. [Modes for carrying out the invention]

[0020] The present invention will be described in more detail below.

[0021] A crucial step in the initiation of protein synthesis is the formation of a complex composed of eIF2, GTP, and Met-tRNAi. This complex plays a vital role in normal cellular function, and abnormalities in its regulation are known to induce various diseases, making it a target for the development of new therapeutic agents. The inventors of this invention have synthesized 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative compounds with diverse substituents, and have confirmed that these novel derivatives exhibit eIF2α phosphorylation effects and in vitro cancer cell proliferation inhibitory activity, thus completing the present invention.

[0022]

[0023] To achieve the above objective, the present invention provides compounds 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.

[0024] [C1] [ka]

[0025] In the above chemical formula 1, R 1 and R 2These can be the same or different and may be selected from the group consisting of hydrogen (H), halogens, trifluoromethyl (CF3), nitro (NO2), (C1-C4) alkoxy, trifluoromethoxy (OCF3), cyano (CN), nitro (NO2), (C1-C4) alkylsulfonyl, and aminosulfonyl (SO2NH2).

[0026] Preferably, the 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative compound is R in Chemical Formula 1. 1 R is selected from the group consisting of hydrogen (H), halogens, trifluoromethyl (CF3), nitro (NO2), and (C1-C2) alkoxys. 2 This can be selected from the group consisting of chlorine (Cl), trifluoromethyl (CF3), trifluoromethoxy (OCF3), cyano (CN), nitro (NO2), (C1-C2) alkylsulfonyl, and aminosulfonyl (SO2NH2).

[0027] Preferably, the 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative compound is R in Chemical Formula 1. 1 R is selected from the group consisting of hydrogen (H), fluorine (F), chlorine (Cl), trifluoromethyl (CF3), and nitro (NO2), 2 The compound can be selected from the group consisting of chlorine (Cl), trifluoromethyl (CF3), trifluoromethoxy (OCF3), cyano (CN), nitro (NO2), methylsulfonyl (SO2Me), and aminosulfonyl (SO2NH2).

[0028] Preferably, the 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative compound is characterized by being represented by the following chemical formula 1-1.

[0029] [Case 1-1] [ka]

[0030] In the chemical formula 1-1, R 1 is 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).

[0031] As an example, the 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative compound is 2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one [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 [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 [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[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-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one]; 7-Fluoro-2-(((1,4-trans)-4-(4-nitrophenoxy)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[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- 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-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazolin- 4(1H)-one];7-Chloro-2-(((1,4-trans)-4-(4-nitrophenoxy)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[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[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[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 (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[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[4-(((1,4-trans)-4-((4-Oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzonitrile[4-(((1,4-trans)-4-((4-Oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin [lin-2-yl)amino)cyclohexyl)oxy)benzonitrile]; 2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)-7-(trifluoromethyl)quinazolin-4(1H)-one [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[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]; 2-(((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl)amino)-7-(trifluoromethyl (Lu)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-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one]; 7-Nitro-2-(((1,4-trans)-4-(4-nitrophenoxy)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[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[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(1 H)-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[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[6-Chloro-2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)quinazolin-4(1H)-one];The group can be selected from, but is not limited to, those consisting of the following:

[0032]

[0033] Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of cancer, which contains the aforementioned compound as an active ingredient.

[0034] Preferably, the compounds according to the present invention can promote the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α).

[0035] Preferably, the cancers are, but not limited to, blood cancers, breast cancers, sarcomas, or brain cancers.

[0036] Furthermore, the present invention provides a pharmaceutical composition for metabolic anticancer agents containing the aforementioned compound as an active ingredient.

[0037] Furthermore, the present invention provides a method for suppressing cancer cell metabolism, which includes the step of administering the aforementioned compound.

[0038] The aforementioned compound can promote the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), thereby blocking the metabolism of cancer cells and causing them to die.

[0039] The aforementioned metabolic anticancer agents are called the fourth generation of anticancer agents, succeeding chemoanticancer agents, targeted anticancer agents, and immunoanticancer agents. They work by blocking the metabolic activity of cancer cells, which undergo cell division more actively than normal cells. Unlike existing anticancer treatments, they selectively kill only cancer cells by blocking the metabolic processes of cancer cells. In particular, they are characterized by reducing the metabolic rate of cancer cells by more than 50% and suppressing cancer cell growth with almost no damage to normal cells.

[0040] In the present invention, the pharmaceutically acceptable salt is 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, triethylaminium salts, and pyridinium salts, but is not limited thereto.

[0041] Furthermore, it should be explicitly stated that the pharmaceutically acceptable salts are one or more acidic salts selected from the group consisting of hydrochloric acid, bromate, sulfuric acid, sulfurous acid, phosphoric acid, citric acid, acetic acid, maleic acid, fumaric acid, glucosane, 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.

[0042] The pharmaceutical compositions of the present invention may, for administration, contain pharmaceutically acceptable carriers, excipients, or diluents in addition to the components described above. Examples of such carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginic acid, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, amorphous cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0043] The pharmaceutical compositions of the present invention can be used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, as well as topical preparations, suppositories, or sterile injection solutions, by conventional methods. In particular, when preparing dosage forms, they are compounded using commonly used fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, and other diluents or excipients. Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, and capsules. Such solid preparations are compounded by mixing at least one or more excipients, such as starch, calcium carbonate, sucrose, lactose, and gelatin, in addition to the active ingredient. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquids for oral administration, other than liquid paraffin, are compounded by adding various excipients, such as wetting agents, sweeteners, fragrances, and preservatives. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include vitepsol, macrogol, tween 61, cocoa butter, lauric butter, and glycerogenous gelatin.

[0044] The pharmaceutical compositions of the present invention can be manufactured in oral or parenteral formulations and can be administered orally, intravenously, intraventricularly, intradermally, intramuscularly, intraperitoneally, nasally, or epidurally.

[0045] The appropriate dosage of the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, the severity of the disease, the drug form, and the time elapsed, but can be appropriately selected by those skilled in the art. Therefore, the daily dosage of the composition is preferably 0.01 to 100 mg / kg, and can be administered once or several times a day as needed.

[0046]

[0047] Furthermore, the present invention provides a health functional food composition for the prevention or improvement of cancer, which contains the aforementioned compound as an active ingredient.

[0048] The aforementioned functional health food composition may contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and fillers (for cheese, chocolate, etc.), pectinic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, and carbonating agents used in carbonated beverages. In addition, it may contain fruit pulp for the production of natural fruit juices, composite fruit juices, and vegetable beverages. Such components can be used independently or in combination. Furthermore, the functional health food composition may also be in any one of the following forms: meat, sausage, bread, chocolate, candy, snacks, sweets, pizza, ramen, gum, ice cream, soup, drinking water, tea, functional water, beverages, alcohol, and vitamin complexes.

[0049] Furthermore, the aforementioned health functional food composition may further contain food additives, and unless otherwise specified, the suitability of a food additive shall be determined according to the standards and criteria for that item, such as the general provisions and general test methods of the Food Additives Code approved by the Ministry of Food and Drug Safety.

[0050] Examples of items listed in the aforementioned Food Additives Code include chemically synthesized products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as indigo dye, licorice extract, crystalline cellulose, sorghum dye, and guar gum; and mixed preparations such as L-sodium glutamate preparations, alkaline agents added to noodles, preservative preparations, and tar dye preparations.

[0051] In this case, the composition according to the present invention, which is added to food during the process of manufacturing the health functional food composition, can be appropriately adjusted in amount as needed.

[0052] The present invention will be described in more detail below through examples and experimental examples. These examples and experimental examples are merely for the purpose of illustrating the present invention in more detail, and it will be obvious to those skilled in the art that the scope of the present invention is not limited by these examples and experimental examples, as is the gist of the invention.

[0053]

[0054] [Synthesis Example] Synthesis of 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone

[0055] (1) Urea cyclization

[0056] A phenol mixture containing aminobenzoic acid (1.0 eq) and urea (5.0 eq) was heated to 200°C. After stirring for 17 hours, the reaction mixture was cooled to 100°C, and water was added dropwise. The reaction mixture was cooled to room temperature, the resulting solid was filtered, and washed / dried with ethanol to obtain quinazolinedione.

[0057]

[0058] (2-1) Dichlorination using N,N-diethylaniline

[0059] N,N-diethylaniline (30 mol%) was added to a stirred POCl3 (10.0 eq) solution containing the aforementioned quinazolinedione (1.0 eq), and the mixture was heated to 180°C. After 5 to 17 hours, 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.

[0060]

[0061] (2) Dichlorination using PCl5

[0062] A mixture of 1.0 eq of POCl3, consisting of 1.0 eq of quinazoline dione and 3.7 eq of PCl5, was heated to 180°C. After stirring for 5 to 17 hours, 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.

[0063]

[0064] (3) Monohydroxylation

[0065] The mixture of 1N NaOH / THF (1:1) and the aforementioned dichloroquinazoline (1.0 eq) was stirred at room temperature. After 6 hours, the reaction mixture was adjusted to pH 5 with acetic acid, the precipitated solid was filtered, dried, and obtained mono-hydroxyquinazolinone.

[0066]

[0067] (4) Aromatic nucleophilic substitution

[0068] Diisopropylethylamine (3.0 eq) was added to a stirred DMF solution containing monohydroxyquinazoline (1.0 eq) and 4-(aryloxy)cyclohexylamine (1.5 eq) from DMF, and the mixture was heated to 80°C. After 17 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (HCl). The organic layer was washed with water (3 times) and dried over magnesium sulfate (MgSO4). The resulting residue was concentrated under vacuum and purified by flash column chromatography on silica gel to obtain 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone.

[0069]

[0070] [Synthesis Example 2] Specific synthesis example of a 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivative

[0071] (1) 2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazoline-4(1H)-one (hereinafter referred to as Compound 1)

[0072] [ka]

[0073] To a 3 mL solution of DMF containing 2-chloroquinazolin-4(1H)-one (69.6 mg, 0.39 mmol), (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 at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (ELISA). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from SiO / MeOH (10:1) and purified to obtain 21.0 mg (13%) of compound 1 as a white solid.

[0074] 1 H NMR (DMSO-d6, 400MHz) δ10.62(s, 1H), 7.88(d, 1H, J=8.0Hz), 7.62(d, 2H, J=8.3Hz), 7.55(m, 1H), 7.26(d, 1H, J=8.4Hz), 7.14(d, 2H, J =8.2Hz), 7.09(t, 1H, J=7.4Hz), 6.25(d, 1H, J=7.0Hz), 4.50(m, 1H), 3.87(m, 1H), 2.08(m, 2H), 2.06(m, 2H), 1.55(m, 2H), 1.44(m, 2H); 13 C NMR (DMSO-d6, 100MHz) δ161.9, 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.

[0075]

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

[0077] [ka]

[0078] To a 3 mL DMF solution containing 2-chloroquinazoline-4(1H)-one (100 mg, 0.55 mmol), (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 at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (ELISA). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from ELISA / MeOH (10:1) and purified to obtain 43.8 mg (21%) of compound 2 as a brown solid.

[0079] 1 H NMR (DMSO-d6, 400MHz) δ10.61(s, 1H), 8.18(d, 2H, J=9.3Hz), 7.88(d, 1H, J=7.8Hz), 7.55(t, 1H, J=7.7Hz), 7.26(d, 1H, J=8.2Hz), 7. 17(d, 2H, J=9.2Hz), 7.09(t, 1H, J=7.3Hz), 6.26(d, 1H, J=6.3Hz), 4.59(m, 1H), 3.88(m, 1H), 2.08(m, 4H), 1.58(m, 2H), 1.46(m, 2H); 13 C NMR (DMSO-d6, 125MHz) δ163.0, 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.

[0080]

[0081] (3) 4-(((1,4-trans)-4-((4-oxo-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzonitrile (hereinafter referred to as Compound 3)

[0082] [ka]

[0083] To a 5 mL DMF solution containing 2-chloroquinazoline-4(1H)-one (180 mg, 1.00 mmol), 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (324 mg, 1.50 mmol) and N,N-diisopropylethylamine (523 μL, 3.00 mmol) were added at ambient temperature. After stirring at 80°C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (RINKAN). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from RINKAN / MeOH (10:1) and purified to obtain 100 mg (28%) of compound 3 as an ivory solid.

[0084] 1 H NMR (DMSO-d6, 500MHz) δ10.60(s, 1H), 7.88(d, 1H, J=7.8Hz), 7.74(d, 2H, J=8.7Hz), 7.55(t, 1H, J=7.6Hz), 7.26(d, 1H, J=8.2Hz), 7.13(d, 2H, J=8.7Hz), 7.09(t, 1H, J=7.4Hz), 6.25(d, 1H, J=6.7Hz), 4.52(m, 1H), 3.87(m, 1H), 2.07(m, 2H), 2.06(m, 2H), 1.55(m, 2H), 1.44(m, 2H); 13C NMR (DMSO-d6, 125MHz) δ161.9, 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.

[0085]

[0086] (4) 2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)quinazoline-4(1H)-one (hereinafter referred to as compound 4)

[0087] [ka]

[0088] To a 5 mL DMF solution containing 2-chloroquinazoline-4(1H)-one (100 mg, 0.55 mmol), (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 at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (siRNA). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from siRNA / MeOH (10:1) and purified to obtain 74.0 mg (32%) of compound 4 as a white solid.

[0089] 1H NMR (DMSO-d6, 500MHz) δ10.60(s, 1H), 7.88(dd, 1H, J=7.9, 1.6Hz), 7.82(d, 2H, J=8.9Hz), 7.55(ddd, 1H, J=8.2, 7.1, 1.7Hz), 7.26(d, 1H, J=8.2Hz), 7.19(d, 2H, J=9.0Hz), 7.09(t, 1H, J=7.4Hz), 6.25(d, 1H, J=6.9Hz), 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, 125MHz) δ161.9, 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.

[0090]

[0091] (5) 7-Fluoro-2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazoline-4(1H)-one (hereinafter referred to as compound 5)

[0092] [ka]

[0093] To a 5 mL solution of DMF containing 2-chloro-7-fluoroquinazolin-4(1H)-one (100 mg, 0.50 mmol), (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexane-1-amine (194 mg, 0.75 mmol) and N,N-diisopropylethylamine (261 μL, 1.50 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (siRNA). The combined organic layer was dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from siRNA / MeOH (10:1) and purified to obtain 35.4 mg (17%) of compound 5 as a white solid.

[0094] 1 H NMR (DMSO-d6, 500MHz) δ10.61(s, 1H), 7.91(dd, 1H, J=8.6, 6.8Hz), 7.60(d, 2H, J=8.7Hz), 7.13(d, 2H, J=8.6Hz), 6.95(dd, 1H) , J=11.0, 2.2Hz), 6.89(td, 1H, J=8.6, 2.4Hz), 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 C NMR (DMSO-d6, 125MHz) δ167.2, 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.

[0095]

[0096] (6) 7-Fluoro-2-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)quinazoline-4(1H)-one (hereinafter referred to as compound 6)

[0097] [ka]

[0098] To a 5 mL solution of DMF containing 2-chloro-7-fluoroquinazoline-4(1H)-one (150 mg, 0.76 mmol), (1,4-trans)-4-(4-nitrophenoxy)cyclohexane-1-amine (269 mg, 1.14 mmol) and N,N-diisopropylethylamine (397 μL, 2.28 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (siRNA). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from siRNA / MeOH (10:1) and purified to obtain 89.5 mg (30%) of compound 6 as a brown solid.

[0099] 1 H NMR (DMSO-d6, 500MHz) δ10.63(s, 1H), 8.18(d, 2H, J=9.3Hz), 7.92(dd, 1H, J=8.7, 6.8Hz), 7.17(d, 2H, J=9.3Hz), 6.97(dd, 1H) , J=10.7, 1.5Hz), 6.92(td, 1H, J=8.7, 2.2Hz), 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, 125MHz) δ167.2, 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.

[0100]

[0101]

[0102] (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)

[0103] [ka]

[0104] To a 5 mL solution of DMF containing 2-chloro-7-fluoroquinazoline-4(1H)-one (100 mg, 0.50 mmol), 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (162 mg, 0.75 mmol) and N,N-diisopropylethylamine (261 μL, 1.50 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (siRNA). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from siRNA / MeOH (10:1) and purified to obtain 42.6 mg (22%) of compound 7 as a white solid.

[0105] 1 H NMR (DMSO-d6, 500MHz) δ7.92(dd, 1H, J=8.7, 6.7Hz), 7.74(d, 2H, J=8.9Hz), 7.13(d, 2H, J=8.9Hz), 6.97(dd, 1H, J=11. 0, 2.4Hz), 6.92(td, 1H, J=8.7, 2.5Hz), 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, 125MHz) δ167.2, 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.

[0106]

[0107] (8) 7-Fluoro-2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)quinazoline-4(1H)-one (hereinafter referred to as compound 8)

[0108] [ka]

[0109] To a 5 mL solution of DMF containing 2-chloro-7-fluoroquinazoline-4(1H)-one (100 mg, 0.50 mmol), (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexane-1-amine (202 mg, 0.75 mmol) and N,N-diisopropylethylamine (261 μL, 1.50 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (siRNA). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from siRNA / MeOH (10:1) and purified to obtain 37.6 mg (17%) of compound 8 as a white solid.

[0110] 1 H NMR (DMSO-d6, 500MHz) δ10.65(s, 1H), 7.92(d, 1H, J=8.7, 6.8Hz), 7.82(d, 2H, J=8.9Hz), 7.18(d, 2H, J=8.9Hz), 6.97(dd, 1H, J=10. 9, 2.0Hz), 6.92(td, 1H, J=8.6, 2.3Hz), 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, 125MHz) δ167.2, 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.

[0111]

[0112] (9) 7-Chloro-2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazoline-4(1H)-one (hereinafter referred to as compound 9)

[0113] [ka]

[0114] To a 7 mL DMF solution containing 2,7-dichloroquinazoline-4(1H)-one (200 mg, 0.93 mmol), (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexane-1-amine (362 mg, 1.40 mmol) and N,N-diisopropylethylamine (486 μL, 2.79 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (SiO). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from SiO / MeOH (10:1) and purified to obtain 68.0 mg (17%) of compound 9 as a white solid.

[0115] 1 H NMR (DMSO-d6, 400MHz) δ10.71(s, 1H), 7.86(m, 1H), 7.62(d, 2H, J=8.2Hz), 7.26(s, 1H), 7.14(d, 2H, J=8.2Hz), 7.09(d, 1H, J=8.4Hz), 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, 125MHz) δ161.5, 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.

[0116]

[0117] (10)7-Chloro-2-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)quinazoline-4(1H)-one (hereinafter referred to as compound 10)

[0118] [ka]

[0119] To a 7 mL solution of DMF containing 2,7-dichloroquinazoline-4(1H)-one (200 mg, 0.93 mmol), (1,4-trans)-4-(4-nitrophenoxy)cyclohexane-1-amine (331 mg, 1.40 mmol) and N,N-diisopropylethylamine (486 μL, 2.79 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (siRNA). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from siRNA / MeOH (10:1) and purified to obtain 60.6 mg (16%) of compound 10 as a light brown solid.

[0120] 1 H NMR (DMSO-d6, 500MHz) δ10.71(s, 1H), 8.19(d, 2H, J=9.3Hz), 7.86(d, 1H, J=8.5Hz), 7.26(d, 1H, J=1.5Hz), 7.18(d, 2H, J=9.3Hz), 7.10(dd, 1H, J=8.4, 1.8Hz), 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, 125MHz) δ162.9, 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.

[0121]

[0122]

[0123] (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)

[0124] [ka]

[0125] To a 6 mL DMF solution containing 2,7-dichloroquinazoline-4(1H)-one (180 mg, 0.84 mmol), 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (273 mg, 1.26 mmol) and N,N-diisopropylethylamine (439 μL, 2.52 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (SiO). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from SiO / MeOH (10:1) and purified to obtain 161 mg (49%) of compound 11 as a white solid.

[0126] 1 H NMR (DMSO-d6, 500MHz) δ10.36(s, 1H), 7.85(d, 1H, J=8.5Hz), 7.74(d, 2H, J=8.7Hz), 7.26(d, 1H, J=1.2Hz), 7.13(d, 2H, J=8.7Hz), 7.09(dd, 1H, J=8.4, 1.4Hz), 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, 125MHz) δ161.5, 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.

[0127]

[0128] (12)7-Chloro-2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)quinazoline-4(1H)-one (hereinafter referred to as compound 12)

[0129] [ka]

[0130] To a 3 mL DMF solution containing 2,7-dichloroquinazoline-4(1H)-one (100 mg, 0.47 mmol), (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexane-1-amine (190 mg, 0.71 mmol) and N,N-diisopropylethylamine (246 μL, 1.41 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (SiO). The combined organic layer was dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from SiO / MeOH (10:1) and purified to obtain 114 mg (55%) of compound 12 as an ivory solid.

[0131] 1 H NMR (DMSO-d6, 500MHz) δ10.69(s, 1H), 7.86(d, 1H, J=8.5Hz), 7.82(d, 2H, J=8.7Hz), 7.26(s, 1H), 7.18(d, 2H, J=8.7Hz) ), 7.09(d, 1H, J=8.5Hz), 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, 100MHz) δ161.6, 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.

[0132]

[0133] (13) 4-(((1,4-trans)-4-((7-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide (hereinafter referred to as compound 13)

[0134] [ka]

[0135] To a 2.5 mL solution of DMF containing 2,7-dichloroquinazoline-4(1H)-one (79.5 mg, 0.37 mmol), 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzenesulfonamide (150 mg, 0.56 mmol) and N,N-diisopropylethylamine (193 μL, 1.11 mmol) were added at ambient temperature. After stirring at 80°C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (HCl). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from HCl / MeOH (10:1) and purified to obtain 43.9 mg (26%) of compound 13 as a white solid.

[0136] 1 H NMR (DMSO-d6, 500MHz) δ10.70(s, 1H), 7.86(d, 1H, J=8.4Hz), 7.73(d, 2H, J=8.5Hz), 7.26(s, 1H), 7.19(s, 2H), 7. 11(d, 2H, J=8.4Hz), 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, 125MHz) δ161.3, 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.

[0137]

[0138] (14)7-(trifluoromethyl)-2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazoline-4(1H)-one (hereinafter referred to as compound 14)

[0139] [ka]

[0140] To a 3 mL DMF solution containing 2-chloro-7-(trifluoromethyl)quinazolin-4(1H)-one (100 mg, 0.40 mmol), (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexane-1-amine (190 mg, 0.71 mmol) and N,N-diisopropylethylamine (209 μL, 1.20 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (SiO). The combined organic layer was dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from SiO / MeOH (10:1) and purified to obtain 112 mg (30%) of compound 14 as a white solid.

[0141] 1 H NMR (DMSO-d6, 500MHz) δ10.86(s, 1H), 8.05(d, 1H, J=8.0Hz), 7.62(d, 2H, J=8.2Hz), 7.51(s, 1H), 7.34(d, 1H, J =7.3Hz), 7.14(d, 2H, J=8.2Hz), 6.49(s, 1H), 4.50(m, 1H), 3.90(m, 1H), 2.08(m, 4H), 1.55(m, 2H), 1.47(m, 2H); 13C NMR (DMSO-d6, 125MHz) δ161.2, 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.

[0142]

[0143] (15) 2-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)-7-(trifluoromethyl)quinazoline-4(1H)-one (hereinafter referred to as compound 15)

[0144] [ka]

[0145] To a 3 mL solution of DMF containing 2-chloro-7-(trifluoromethyl)quinazoline-4(1H)-one (80.0 mg, 0.32 mmol), (1,4-trans)-4-(4-nitrophenoxy)cyclohexane-1-amine (113 mg, 0.48 mmol) and N,N-diisopropylethylamine (167 μL, 0.96 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (HCl). The combined organic layer was dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from HCl / MeOH (10:1) and purified to obtain 43.9 mg (30%) of compound 15 as a bright yellow solid.

[0146] 1H NMR (DMSO-d6, 500MHz) δ10.87(s, 1H), 8.18(d, 2H, J=9.3Hz), 8.05(d, 1H, J=8.3Hz), 7.50(s, 1H), 7.34(d, 1H, J =8.1Hz), 7.17(d, 2H, J=9.4Hz), 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, 100MHz) δ162.9, 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.

[0147]

[0148] (16) 4-(((1,4-trans)-4-((4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzonitrile (hereinafter referred to as compound 16)

[0149] [ka]

[0150] To a 3 mL solution of DMF containing 2-chloro-7-(trifluoromethyl)quinazoline-4(1H)-one (100 mg, 0.40 mmol), 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (130 mg, 0.60 mmol) and N,N-diisopropylethylamine (209 μL, 1.20 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (HCl). The combined organic layer was dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from HCl / MeOH (10:1) and purified to obtain 48.6 mg (28%) of compound 16 as a white solid.

[0151] 1 H NMR (DMSO-d6, 500MHz) δ11.11(s, 1H), 8.05(d, 1H, J=8.2Hz), 7.74(d, 2H, J=8.8Hz), 7.49(s, 1H), 7.33(d, 1H, J=8.2 Hz), 7.14(d, 2H, J=8.8Hz), 6.92(d, 1H, J=4.9Hz), 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, 125MHz) δ161.0, 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.

[0152]

[0153] (17)2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)-7-(trifluoromethyl)quinazoline-4(1H)-one (hereinafter referred to as compound 17)

[0154] [ka]

[0155] To a 3 mL solution of DMF containing 2-chloro-7-(trifluoromethyl)quinazoline-4(1H)-one (80.0 mg, 0.32 mmol), (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexane-1-amine (129 mg, 0.48 mmol) and N,N-diisopropylethylamine (167 μL, 0.96 mmol) were added at ambient temperature. After stirring at 80°C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (SiO). The combined organic layer was dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from SiO / MeOH (10:1) and purified to obtain 37.4 mg (24%) of compound 17 as an ivory solid.

[0156] 1 H NMR (DMSO-d6, 500MHz) δ8.05 (d, 1H, J=8.2Hz), 7.82 (d, 2H, J=8.8Hz), 7.50 (s, 1H), 7.33 (d, 1H, J=8.0Hz), 7.20 (d, 2H, J=8.8Hz), 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, 125MHz) δ161.3, 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.

[0157]

[0158] (18) 4-(((1,4-trans)-4-((4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide (hereinafter referred to as compound 18)

[0159] [ka]

[0160] To a 3 mL solution of DMF containing 2-chloro-7-(trifluoromethyl)quinazoline-4(1H)-one (80.0 mg, 0.32 mmol), 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzenesulfonamide (104 mg, 0.39 mmol) and N,N-diisopropylethylamine (167 μL, 0.96 mmol) were added at ambient temperature. After stirring at 80°C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (siRNA). The combined organic layer was dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from siRNA / n-hexane (3:2) and purified to obtain 22.2 mg (14%) of compound 18 as a white solid.

[0161] 1 H NMR (DMSO-d6, 500MHz) δ10.89(s, 1H), 8.06(d, 1H, J=8.2Hz), 7.73(d, 2H, J=8.9Hz), 7.51(s, 1H), 7.35(d, 1H, J=7.8Hz) ), 7.19(s, 2H), 7.11(d, 2H, J=8.9Hz), 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, 125MHz) δ161.3, 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.

[0162]

[0163]

[0164] (19)2-(((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl)amino)-7-(trifluoromethyl)quinazoline-4(1H)-one (hereinafter referred to as compound 19)

[0165] [ka]

[0166] To a 3 mL DMF solution containing 2-chloro-7-(trifluoromethyl)quinazoline-4(1H)-one (80.0 mg, 0.32 mmol), (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 at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (siRNA). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from siRNA / CH2Cl2 (1:4) and purified to obtain 16.7 mg (12%) of compound 19 as a white solid.

[0167] 1 H NMR (DMSO-d6, 500MHz) δ10.92(s, 1H), 8.05(d, 1H, J=8.2Hz), 7.51(s, 1H), 7.35(d, 1H, J=8.1Hz), 7.30(d, 2H, J=7.8Hz) ), 6.99(d, 2H, J=8.0Hz), 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, 125MHz) δ161.4, 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.

[0168]

[0169]

[0170] (20)2-(((1,4-trans)-4-(4-chlorophenoxy)cyclohexyl)amino)-7-(trifluoromethyl)quinazoline-4(1H)-one (hereinafter referred to as compound 20)

[0171] [ka]

[0172] To a 3 mL DMF solution containing 2-chloro-7-(trifluoromethyl)quinazoline-4(1H)-one (100 mg, 0.40 mmol), (1,4-trans)-4-(4-(trifluoromethoxy)phenoxy)cyclohexan-1-amine (166 mg, 0.60 mmol) and N,N-diisopropylethylamine (210 μL, 1.21 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (ELISA). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from ELISA / CH2Cl2 (1:3) and purified to obtain 6 mg (14%) of compound 20 as a white solid.

[0173] 1 H NMR (DMSO-d6, 500MHz) δ10.84(s, 1H), 8.05(d, 1H, J=8.2Hz), 7.51(s, 1H), 7.35(d, 1H, J=8.1Hz), 7.27(d, 2H, J=8.7Hz) ), 7.06(d, 2H, J=9.1Hz), 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); 13C NMR (DMSO-d6, 125MHz) δ161.1, 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.

[0174]

[0175] (21)7-Nitro-2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazoline-4(1H)-one (hereinafter referred to as compound 21)

[0176] [ka]

[0177] To a 5 mL solution of DMF containing 2-chloro-7-nitroquinazolin-4(1H)-one (150 mg, 0.67 mmol), (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexane-1-amine (259 mg, 1.00 mmol) and N,N-diisopropylethylamine (350 μL, 2.01 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (siRNA). The combined organic layer was dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from siRNA / MeOH (10:1) and purified to obtain 139 mg (47%) of compound 21 as a yellow solid.

[0178] 1H NMR (DMSO-d6, 500MHz) δ10.96(s, 1H), 8.09(d, 1H, J=8.7Hz), 7.93(s, 1H), 7.80(d, 1H, J=7.7Hz), 7.63(d, 2H, J =8.0Hz), 7.15(d, 2H, J=8.2Hz), 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, 125MHz) δ160.9, 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.

[0179]

[0180] (22)7-Nitro-2-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)quinazoline-4(1H)-one (hereinafter referred to as compound 22)

[0181] [ka]

[0182] To a 4 mL solution of DMF containing 2-chloro-7-nitroquinazoline-4(1H)-one (120 mg, 0.53 mmol), (1,4-trans)-4-(4-nitrophenoxy)cyclohexane-1-amine (188 mg, 0.80 mmol) and N,N-diisopropylethylamine (277 μL, 1.59 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (siRNA). The combined organic layer was dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from siRNA / MeOH (10:1) and purified to obtain 76.0 mg (34%) of compound 22 as a yellow solid.

[0183] 1 H NMR (DMSO-d6, 500MHz) δ10.94(s, 1H), 8.18(d, 2H, J=8.7Hz), 8.07(d, 1H, J=8.5Hz), 7.92(s, 1H), 7.79(d, 1H, J =8.0Hz), 7.18(d, 2H, J=8.7Hz), 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, 125MHz) δ163.0, 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.

[0184]

[0185] (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)

[0186] [ka]

[0187] To a 4 mL solution of DMF containing 2-chloro-7-nitroquinazoline-4(1H)-one (120 mg, 0.53 mmol), 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (173 mg, 0.80 mmol) and N,N-diisopropylethylamine (277 μL, 1.59 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (siRNA). The combined organic layer was dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from siRNA / MeOH (10:1) and purified to obtain 80.4 mg (37%) of compound 23 as a yellow solid.

[0188] 1H NMR (DMSO-d6, 500MHz) δ10.92(s, 1H), 8.07(d, 1H, J=8.7Hz), 7.91(s, 1H), 7.78(dd, 1H, J=8.6, 1.6Hz), 7.74(d, 2H) , J=8.7Hz), 7.14(d, 2H, J=8.8Hz), 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, 125MHz) δ161.0, 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.

[0189]

[0190] (24) 2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)-7-nitroquinazoline-4(1H)-one (hereinafter referred to as compound 24)

[0191] [ka]

[0192] To a 3 mL DMF solution containing 2-chloro-7-nitroquinazoline-4(1H)-one (100 mg, 0.44 mmol), (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexane-1-amine (173 mg, 0.80 mmol) and N,N-diisopropylethylamine (229 μL, 1.32 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (siRNA). The combined organic layer was dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from siRNA / MeOH (10:1) and purified to obtain 48.8 mg (24%) of compound 24 as a yellow solid.

[0193] 1H NMR (DMSO-d6, 500MHz) δ8.07(d, 1H, J=8.6Hz), 7.92(s, 1H), 7.82(d, 2H, J=8.4Hz), 7.79(d, 1H, J=8.8Hz), 7.19 (d, 2H, J=8.4Hz), 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, 125MHz) δ161.3, 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.

[0194]

[0195] (25)6-Chloro-2-(((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexyl)amino)quinazoline-4(1H)-one (hereinafter referred to as compound 25)

[0196] [ka]

[0197] To a 7 mL DMF solution containing 2,6-dichloroquinazoline-4(1H)-one (184 mg, 0.85 mmol), (1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexane-1-amine (331 mg, 1.28 mmol) and N,N-diisopropylethylamine (444 μL, 2.55 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (HCl). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from HCl / MeOH (10:1) and purified to obtain 45.0 mg (12%) of compound 25 as a pale yellow solid.

[0198] 1H NMR (DMSO-d6, 400MHz) δ11.00(s, 1H), 7.79(s, 1H), 7.61(d, 2H, J=7.0Hz), 7.54(d, 1H, J=6.7Hz), 7.26(d , 1H, J=8.1Hz), 7.14(d, 2H, J=7.2Hz), 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, 100MHz) δ160.8, 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.

[0199]

[0200] (26) 6-Chloro-2-(((1,4-trans)-4-(4-nitrophenoxy)cyclohexyl)amino)quinazoline-4(1H)-one (hereinafter referred to as compound 26)

[0201] [ka]

[0202] To a 3 mL DMF solution containing 2,6-dichloroquinazoline-4(1H)-one (100 mg, 0.44 mmol), (1,4-trans)-4-(4-nitrophenoxy)cyclohexane-1-amine ((1,4-trans)-4-(4-(trifluoromethyl)phenoxy)cyclohexan-1-amine; 156 mg, 0.66 mmol) and N,N-diisopropylethylamine (230 μL, 1.32 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (ELISA). The combined organic layers were dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from ELISA / MeOH (10:1) and purified to obtain 52.7 mg (29%) of compound 26 as a light brown solid.

[0203] 1 H NMR (DMSO-d6, 500MHz) δ8.18(d, 2H, J=9.2Hz), 7.80(d, 1H, J=2.2Hz), 7.56(dd, 1H, J=8.7, 2.2Hz), 7.27(d, 1H, J =8.7Hz), 7.17(d, 2H, J=9.1Hz), 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 C NMR (DMSO-d6, 125MHz) δ163.0, 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.

[0204]

[0205] (27) 4-(((1,4-trans)-4-((6-chloro-4-oxo-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzonitrile (hereinafter referred to as compound 27)

[0206] [ka]

[0207] To a 3 mL DMF solution containing 2,6-dichloroquinazoline-4(1H)-one (100 mg, 0.44 mmol), 4-(((1,4-trans)-4-aminocyclohexyl)oxy)benzonitrile (143 mg, 0.66 mmol) and N,N-diisopropylethylamine (230 μL, 1.32 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H₂O) and extracted with ethyl acetate (HCl). The combined organic layers were dried over MgSO₄ and concentrated under vacuum. The residue was recrystallized from HCl / MeOH (10:1) and purified to obtain 64.5 mg (37%) of compound 27 as a white solid.

[0208] 1 H NMR (DMSO-d6, 500MHz) δ10.78(s, 1H), 7.80(d, 1H, J=2.5Hz), 7.74(d, 2H, J=8.9Hz), 7.55(dd, 1H, J=8.8, 2.6Hz), 7.27( d, 1H, J=8.8Hz), 7.13(d, 2H, J=9.0Hz), 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, 125MHz) δ161.1, 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.

[0209]

[0210] (28) 6-Chloro-2-(((1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexyl)amino)quinazoline-4(1H)-one (hereinafter referred to as compound 28)

[0211] [ka]

[0212] To a 2 mL solution of DMF containing 2,6-dichloroquinazoline-4(1H)-one (70.0 mg, 0.33 mmol), (1,4-trans)-4-(4-(methylsulfonyl)phenoxy)cyclohexane-1-amine (133 mg, 0.50 mmol) and N,N-diisopropylethylamine (172 μL, 0.99 mmol) were added at ambient temperature. After stirring at 80 °C for 17 hours, the reaction mixture was quenched with water (H2O) and extracted with ethyl acetate (siRNA). The combined organic layer was dried over MgSO4 and concentrated under vacuum. The residue was recrystallized from siRNA / MeOH (10:1) and purified to obtain 70.8 mg (48%) of compound 28 as an ivory solid.

[0213] 1 H NMR (DMSO-d6, 500MHz) δ10.82(s, 1H), 7.82(d, 2H, J=8.8Hz), 7.80(m, 1H), 7.56(d, 1H, J=8.6Hz), 7.27(d, 1H, J=8.8Hz) ), 7.19(d, 2H, J=8.6Hz), 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, 125MHz) δ161.4, 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.

[0214]

[0215] [Example 1] Analysis of the multiplicity of eIF2α phosphorylation for 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivatives

[0216] The Pathscan phospho-eIF2α(Ser51) Sandwich ELISA Kit #7286 from Cell Signaling was used. K562 cell lines were cultured in serum-free RPMI medium at 37°C and 5% CO2. Cells were treated with compounds 1 to 28, prepared in the synthesis example described above, at a concentration of 10 μM. Six hours after compound treatment, the cells were lysed with the lysis buffer included in the kit, and 50 μg of protein was quantified. Subsequently, the ELISA assay was carried out according to the manufacturer's protocol to obtain absorbance. The absorbance for each obtained compound was standardized to a value with the control (DMSO-treated) set to 1. The results are the same as in Figure 1.

[0217]

[0218] [Example 2] Analysis of the antiproliferative activity of 2-((trans-4-(4-aryloxy)cyclohexyl)amino)quinazolinone derivatives against K562

[0219] The CCK-8 assay (cell counting kit-8 assay, Dojindo, Kumamoto, Japan) was performed. K562 cell lines were cultured at 37°C and 5% CO2 in RPMI medium supplemented with 10% FBS and 1% ABAM. Cells were treated with compounds 1, 9 through 12, 14 through 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, cells were treated with 10 μL of CCK-8 solution and cultured for 4 hours. The IC50 of each compound was then measured by measuring the absorbance at 450 nm. 50 The value was calculated. The result is the same as in Figure 2.

[0220]

[0221] Having described in detail certain aspects of the present invention, it will be clear to those skilled in the art that such specific descriptions are merely desirable examples and do not limit the scope of the invention. Therefore, the substantial scope of the present invention is defined by the claims and their equivalents.

Claims

1. 4-(((1,4-trans)-4-((4-oxo-7-(trifluoromethyl)-1,4-dihydroquinazolin-2-yl)amino)cyclohexyl)oxy)benzenesulfonamide compounds, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

2. A pharmaceutical composition for the prevention or treatment of cancer, comprising the compound described in claim 1, or a pharmaceutically acceptable salt, solvide, or stereoisomer thereof, as an active ingredient.

3. The pharmaceutical composition for the prevention or treatment of cancer according to claim 2, characterized in that the compound, or a pharmaceutically acceptable salt, solvide, or stereoisomer thereof, promotes the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α).

4. The pharmaceutical composition for the prevention or treatment of cancer according to claim 2, characterized in that the cancer is one or more selected from the group consisting of hematological cancers, breast cancers, sarcomas, and brain tumors.

5. A pharmaceutical composition for use as an anticancer agent, comprising the compound described in claim 1, or a pharmaceutically acceptable salt, solvide, or stereoisomer thereof, as an active ingredient.

6. The anticancer drug composition according to claim 5, characterized in that the compound, or a pharmaceutically acceptable salt, solvide, or stereoisomer thereof, promotes the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) and thereby blocks the metabolism of cancer cells.

7. A health functional food composition for the prevention or improvement of cancer, comprising the compound described in claim 1, or a pharmaceutically acceptable salt, solvide, or stereoisomer thereof, as an active ingredient.

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