Heterocyclic derivatives as mrgprx2 antagonists and uses thereof

Abstract

The present invention relates to: a compound having a novel structure represented by chemical formula I, as an MAS-related G-protein coupled receptor member X2 (MRGPRX2) antagonist, or a stereoisomer or pharmaceutically acceptable salt thereof; a pharmaceutical composition comprising same; and a method using same and uses thereof, for preventing or treating one or more diseases selected from allergic diseases, inflammatory bowel disease, arthritis, and migraine.

Description

[0001] Description of the Invention

[0002]

Title of invention

[0003]

Technical Field

[0004]

Background Technology

[0005] MRGPRX2 (Mas-related G-protein coupled receptor member X2) protein is a mast cell receptor that degranulates in an immunoglobulin E (Ig E)-independent manner. It is functionally expressed in the skin and is known to exhibit activity against multiple agonists, including receptors for basophils and eosinophils, endogenous peptides, allergens, infectious agents, toxins, and FDA-approved drugs.

[0006] Indications associated with MRGPRX2 include neuroinflammatory, painful, itchy, and pruritic skin diseases, including chronic spontaneous urticaria (CSU) and atopic dermatitis (AD). The molecular mechanism and pathophysiological role are that the number of positive cells for this protein MRGPRX2 is increased in the skin of patients with chronic spontaneous urticaria, and further studies have confirmed that patients with CSU develop a wheal reaction to intradermal application of this protein as an agoni st (Allergy Asthma Immunol Res. 2021 May; 13(3): 498-506). In addition, when the murine homolog of MRGPRX2 was knocked out, house dust mite-induced allergic reactions were reduced, and it was confirmed to reduce immune cell recruitment and inflammation-induced hypersensitivity in a mouse model of post-surgical inflammatory pain (Neuron. 2019 Feb 6; 101(3): 412-420). Therefore, there is a need for the development of compounds that can mediate allergic reaction disorders and allergic diseases, including anaphylaxis, chronic pruritus, inflammatory disorders, and pain disorders, as antagonists that can block various pruritic mediators that activate MRGPRX2. Prior art literature Non-patent literature

[0007] (0001) Allergy Asthma Immunol Res. 2021 May; 13(3): 498-506

[0008] (0002) Neuron. 2019 Feb 6; 101(3): 412-420

[0009]

Contents of the invention

[0010]

Technical Problem

[0011]

Technical Solution

[0012] <Chemical Formula 1> In chemical formula I,

[0013] Yi and Y2 are each independently N or , Y3 is N, CH or , a is 0 or 1, - represents a single bond or a double bond;

[0014] Li is -0- or C1-C6 alkylene;

[0015] Ri and R2 are each independently H or halogen;

[0016] L2 is a single bond, - CH(Ra)- (wherein, Ra is H or C1-C6 alkyl), C3-C6 cycloalkylene, or - N(Rb)- (Rb is H or C1-C6 alkyl);

[0017] R4 is H or halogen,

[0018] R5 is halogen, C1-C6 haloalkyl, -CF3, -0-CC1-C6 haloalkyl), -0-CH2-CF3, or In the present invention, "a bond" means a case where adjacent atoms or atomic groups are directly bonded. For example, in the case of a pentavalent single bond in X- Y- Z, it means X- Z. In the present invention, "Cm- Cn" (wherein m and n are each independently an integer greater than or equal to 1, and m < n) means the number of carbons, for example, 'C1-C6 alkyl' means alkyl having 1 to 6 carbons. In the present invention, "may be substituted" means substituted or unsubstituted. In the present invention, "-" means a single bond or a double bond.

[0019] (double bond) and is determined according to the chemical bond that satisfies the valence of atoms. Specifically, - X===^Y- means -XY- or - X=Y-. For example, - X - Y- can represent - CH=CH-, - CH=N-, - N=CH-, - Ofe- NH-, - NH- Ofe-, -S-CH2-, -CH2-S-, etc. In the present invention, unless otherwise stated, "alkyl" means - C nH2n+l refers to a straight-chain or branched saturated hydrocarbon group (wherein n is an integer greater than or equal to 1). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc. In the present invention, unless otherwise specified, "alkylene" refers to a divalent functional group derived from alkyl defined as above. In the present invention, unless otherwise specified, "cycloalkyl" refers to a saturated hydrocarbon ring having 3 or more carbon atoms, and the saturated hydrocarbon ring includes both monocyclic and polycyclic structures. In addition, it means including both bicyclic structures such as a bridged ring or a spiro structure. Examples of cycloalkyl include, but are not limited to, one or more selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalenyl, spiro[4.4]nonanyl, spiro[3.3]heptanyl, bicyclo[3.1.dihexanyl, bicyclo[3.1.1]heptanyl, and bicyclo[2.2.1]heptanyl. In the present invention, unless otherwise stated, "cycloalkylene" means a divalent functional group derived from cycloalkyl defined as above. In the present invention, unless otherwise stated, "haloalkyl" means a functional group in which at least one of the H of the alkyl defined as above is independently substituted with a halogen. Examples of haloalkyl include, but are not limited to, -CF3, -CH2-CF3, -CF2H, -CCI3, -CH2-CCI3, -CCI2H, -CF2CI, -CFH-CHs, -CF2-CH3, -CFCI2, etc.In the present invention, “-0-haloalkyl” means a structure in which the haloalkyl defined above is connected with -0-, for example, -O-CFs, -O-CH2-CF3, -O-CF2H, -O-CCI3, -O-CH2-CCI3, -O-CCI2H, -O-CF2CI, -O-CFH-CHs, -O-CF2-CH3, -O-CFCI2, etc., but is not limited thereto. In the present invention, “halogen” may be F, Cl, Br, or I. In addition, terms and abbreviations used in this specification have their original meanings unless otherwise defined. Chemical formula. there is. The compound represented by chemical formula I may include a compound represented by chemical formula la or lb below.

[0020] <Chemical Formula Ia> In the chemical formula la, Ri, R2, Li, Yi to Y4, a, L2, RS, b and R' are each a chemical formula

[0021] Same as described in I. In the chemical formula lb, Ri, R2, Li, Yi to Y4, a, L2 and Rs are each the same as described in the chemical formula I. In one embodiment, in the chemical formula I At this time, Ri and R2 can each independently be halogen.

[0022] Li is -0- or C1-C6 alkylene;

[0023] Ri and R2 are each independently H or halogen, and at least one of Ri and R2 is halogen,

[0024] L2 is a single bond, - CH(Ra)- (where, Ra is H or C1-C6 alkyl),

[0025] (wherein, an integer from 0 to 3), or - N (Rb) - (wherein, Rb is C1-C6 alkyl); It can be substituted with halogen, and is 0 or 1,

[0026] R3 is C1-C6 alkyl, C1-C6 haloalkyl, - CH2- CF3, or - NRcRd, and Rc and Rd are each independently H or C1-C6 alkyl,

[0027] R4 is H or halogen,

[0028] R5 is halogen, C1-C6 haloalkyl, - 0- (Cl- C6 haloalkyl), -CFs, - 0- CH『 CF3, or The novel compound according to the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof shown in Table 1 below.

[0029] [Table 1] In the present invention, the term "stereoisomer" includes diastereomers and optical isomers, and includes a single enantiomer, a mixture of enantiomers including a racemate, a single diastereomer, and a mixture of diastereomers. These isomers can be separated by resolution using conventional techniques, such as column chromatography or HPLC. Alternatively, they can be stereospecifically synthesized using optically pure starting materials and / or reagents of a known arrangement. Specifically, the isomer may be an optical isomer. In the present invention, "pharmaceutically acceptable" may mean physiologically acceptable and not typically causing an allergic reaction such as gastrointestinal disorder or dizziness or a similar reaction when administered to a subject. In the present invention, “pharmaceutically acceptable salt” means a salt commonly used in the pharmaceutical industry, and the pharmaceutically acceptable salt of the present invention can be prepared by a conventional method known to those skilled in the art.For example, pharmaceutically acceptable salts include inorganic ion salts made of calcium, potassium, sodium or magnesium, etc.; inorganic acid salts made of hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid or sulfuric acid, etc.; organic acid salts made of acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid or vanillic acid, etc.; sulfonic acid salts made of methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid, etc.; amino acid salts made of glycine, arginine or lysine, etc. And amine salts prepared with trimethylamine, triethylamine, ammonia, pyridine or picoline, etc., but the types of salts meant in the present invention are not limited by these listed salts. For example, the pharmaceutically acceptable salt may be hydrochloride. The pharmaceutically acceptable salt of the present invention can be prepared by a conventional method known to those skilled in the art. The compound having the novel structure of the present invention (the compound represented by the chemical formula I and the compound shown in Table 1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof can effectively inhibit MRGPRX2 and effectively block the expression of MRGPRX2 at a low concentration. The compound having the novel structure of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof can effectively inhibit calcium mobilization (calcium mobi 1 izat ion) in cells and can significantly inhibit calcium mobilization in cells even at a low concentration. The compound having the novel structure of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof can effectively inhibit degranulation of mast cells and can significantly inhibit degranulation of mast cells even at a low concentration.The compound having a novel structure of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof can significantly prevent or treat allergic diseases, inflammatory bowel diseases, arthritis, or migraines. The compound having a novel structure of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof can significantly prevent or treat allergic diseases including chronic urticaria, anaphylaxis, non-histaminergic pruritus, psoriasis, asthma, atopic dermatitis, or rosacea; inflammatory bowel diseases; arthritis; or migraines. The compound having a novel structure of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof has little or no side effects, can exhibit excellent pharmacokinetic properties (excellent absorption rate, bioavailability), can be appropriately distributed to each tissue upon administration, can exhibit a desired pharmacological effect (prevention or treatment of allergic diseases, inflammatory bowel diseases, arthritis, or migraines, etc.) in each tissue, and can be effectively metabolized in the body. Pharmaceutical composition, treatment method, and use The present invention provides a pharmaceutical composition comprising a compound having a novel structure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Hereinafter, the “compound having a novel structure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof” according to the present invention is the same as the compound represented by the chemical formula I described above, the stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the compound represented by Table 1, the stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and therefore, redundant detailed descriptions are omitted. The present invention provides a pharmaceutical composition for preventing or treating a disease including at least one selected from allergic diseases, inflammatory bowel diseases, arthritis, and migraines, comprising a compound having a novel structure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.In the present invention, allergic diseases may include chronic urticaria, anaphylaxis, non-histamine pruritus, psoriasis, asthma, atopic dermatitis, or rosacea. The pharmaceutical composition of the present invention may further include one or more pharmaceutically acceptable carriers in addition to the compound according to the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for administration. Pharmaceutically acceptable carriers are those commonly used in the art, and specifically, may be, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidine, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzonate, propyl hydroxybenzonate, talc, magnesium stearate, or mineral oil. The pharmaceutical composition of the present invention may further include, in addition to the above components, a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, a preservative, a dispersing agent, a stabilizer, etc. In addition, the pharmaceutical composition of the present invention may be formulated in the form of oral dosage forms such as tablets, powders, granules, pills, capsules, suspensions, emulsions, oral solutions, emulsions, syrups, etc., external preparations, suppositories, or sterile injectable solutions using pharmaceutically acceptable carriers and excipients, and may be manufactured in the form of unit doses or may be manufactured by inserting into multi-dose containers. The preparations may be manufactured by a conventional method used in formulation in the art or by a method disclosed in Remington's Pharmaceutical Science (19th ed., 1995), and may be formulated into various preparations depending on each disease or ingredient.The pharmaceutical composition of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) depending on the intended method, and the dosage varies depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease. The compound of the present invention, its stereoisomer or its pharmaceutically acceptable salt may be administered once or several times a day, but is not necessarily limited thereto. The daily dosage of the compound having a novel structure according to the present invention, its stereoisomer or its pharmaceutically acceptable salt may be specifically about 0.1 to about 10,000 mg / kg, about 1 to about 8,000 mg / kg, about 5 to about 6,000 mg / kg, or about 10 to about 4,000 mg / kg, and more specifically about 50 to about 2,000 mg / kg, but is not limited thereto. The pharmaceutical composition of the present invention may further include one or more components that exhibit the same or similar medicinal effect or can bring about synergy in medicinal effect when used in combination, in addition to the compound having a novel structure according to the present invention, its stereoisomer or its pharmaceutically acceptable salt. The pharmaceutical composition of the present invention may be administered in combination with other therapeutic agents and may be administered sequentially or simultaneously with conventional therapeutic agents. In the present invention, "prevention" means any action of suppressing or delaying the onset of a disease including at least one selected from allergic diseases, inflammatory bowel diseases, arthritis, and migraines by a compound having a novel structure of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.In the present invention, "treatment" means all acts in which the symptoms of a disease including at least one selected from among allergic diseases, inflammatory bowel diseases, arthritis, and migraines are improved or beneficially changed by administering a pharmaceutical composition containing (as an active ingredient) a compound having a novel structure according to the present invention, a compound of Table 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The present invention provides a method for preventing or treating a disease including at least one selected from among allergic diseases, inflammatory bowel diseases, arthritis, and migraines, comprising the step of administering to a subject a compound having a novel structure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same. In the present invention, "administration" means introducing a predetermined substance to a subject by an appropriate method. In the present invention, "subject" means all animals including rats, mice, and livestock, including humans who have developed or may develop a disease, and may specifically be mammals including humans, but is not limited thereto. Selected from allergic diseases, inflammatory bowel diseases, arthritis and migraines of the present invention.

[0030] A method for preventing or treating a disease comprising one or more of the compounds of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be administered in a therapeutically effective amount. In the present invention, the term "therapeutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, which may be determined by a person skilled in the art based on factors including the patient's sex, age, weight, health condition, type and severity of the disease, activity of the drug, sensitivity to the drug, administration method, administration time, administration route, excretion rate, treatment period, drugs used in combination or simultaneously, and other factors well known in the medical field. It is preferable that a specific therapeutically effective amount for a specific patient be applied differently depending on various factors including the type and degree of response to be achieved, the specific composition including whether other agents are used in some cases, the patient's age, body weight, general health, sex and diet, the time of administration, the route of administration and the secretion rate of the composition, the treatment period, drugs used together or simultaneously with the specific composition, and similar factors well known in the medical field. The present invention provides the use of a compound having a novel structure, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the prevention or treatment of a disease including at least one selected from allergic diseases, inflammatory bowel diseases, arthritis and migraines. The present invention provides the use of a compound having a novel structure, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the prevention or treatment of a disease including at least one selected from allergic diseases, inflammatory bowel diseases, arthritis and migraines. Matters mentioned in the compound according to the present invention, the pharmaceutical composition containing the same, the method using the same and the use thereof apply equally unless they are inconsistent with each other.

[0031]

Effect of the invention

[0032]

Form for carrying out the invention

[0033] [Example 1]

[0034] Scheme 1

[0035] Synthesis of 1—Fluoro—3—(4—nitrophenoxy)benzene

[0036] 1.0 equivalent (1.0 eq) of 3-fluorophenol and 1.5 equivalent (1.5 eq) of 1-bromo-4-nitrobenzene, Cesium carbonate,

[0037] 2.0 equivalents (2.0 eq) of CS2CO3, 3.0 equivalents (3.0 eq) of cuprous iodide (Cui), and 3.0 equivalents (3.0 eq) of N,N-dimethylglycine (N,N-dimethylglycine) were dissolved in 45 mL / g of 1,4-dioxane, and the reaction mixture was stirred at 130°C. After completion of the reaction, the residue was filtered through celite with ethyl acetate (EA), concentrated, and extracted with ethyl acetate (EA) and water (H2O). The ethyl acetate (EA) layer was dried over magnesium sulfate (MgS04), concentrated under reduced pressure, and purified by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound.

[0038] Synthesis of 4—(3—fluorophenoxy)aniline (4~(3~f luorophenoxy)aniline)

[0039] 1.0 equivalent (1.0 eq) of 1-fluoro-3-(4-nitrophenoxy)benzene and 3.0 equivalent (3.0 eq) of tetrahydroxydiboron (B2(0H)4) were added to 1 mL / g of dimethylformamide (DMF) and stirred at room temperature (rt). 4, 4-dipyridine (0.5 mol%) was slowly added dropwise to the reaction mixture. After confirming the completion of the reaction, the mixture was extracted with ethyl acetate (EA) and water (OW). The ethyl acetate (EA) layer was dried over magnesium sulfate (MgS04), concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound.

[0040] 3-(3-(4-(3-Fluorophenoxy)phenyl)-1-methylureido)-N,N-dimethylbenzenesulfonamide (3—(3—(4—(3—fluorophenoxy)phenyl)—1—methylureido)— Synthesis of dimethyl benzenesulfonamide) (Example 1)

[0041] 1.0 equivalent (1.0 eq) of 4-(3-Fluorophenoxy)aniline (4-(3-fluorophenoxy)aniline) was dissolved in 5 mL / g of tetrahydrofuran (THF), then 1.5 equivalents (1.5 eq) of pyridine was added, and the temperature was lowered to 0 °C. 1.2 equivalents (1.2 eq) of phenyl chloroformate was slowly added, then the temperature was slowly raised to room temperature and stirred for 4 hours. 1.5 equivalents (1.5 eq) of N,N-dimethyl-3-(methylamino)benzenesulfonamide and 2.0 equivalents (2.0 eq) of N,N-Diisopropylethylamine (DIPEA) were added as in situ and stirred at 80 °C for 2 hours. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using ethyl acetate (EA) and brine. The ethyl acetate (EA) layer was dried over magnesium sulfate (MgSO4) and then concentrated under reduced pressure and purified by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound, Example 1 compound.

[0042] [Table 2] [Example 2]

[0043] Scheme 2

[0044] Synthesis of 5—(3—fluorophenoxy)~2~nitropyridine (5~(3~f !uorophenoxy)~2~nitropyridine)

[0045] 1.0 equivalent (1.0 eq) of 5-bromo-2-nitropyridine was dissolved in 5 mL / g of dimethyl sulfoxide (DMSO). 1.2 equivalents (1.2 eq) of 3-fluorophenol and 1.5 equivalents (1.5 eq) of cesium carbonate (CS2CO3) were added, and the mixture was stirred at 60°C for about 20 hours. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using ethyl acetate (EA) and washed thoroughly with brine. The remaining moisture in the organic layer was completely removed with magnesium sulfate (MgS04) and then filtered. The filtrate was concentrated under reduced pressure and purified and separated by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound.

[0046] Synthesis of 5—(3—fluorophenoxy)pyridin—2—amine

[0047] 1.0 equivalent (1.0 eq) of 5-(3-f luorophenoxy)-2-nitropyridine was dissolved in 2 mL / g of ethanol (EtOH). 10 wt% of palladium / carbon (Pd / C) was added and stirred at room temperature (rt) under hydrogen. After confirming the completion of the reaction, the mixture was filtered through a Celite filter. The filtrate was concentrated under reduced pressure and purified by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound.

[0048] Scheme 3 Synthesis of phenyl (5-(3-fluorophenoxy)pyridin-2-yl)carbamate

[0049] 1.0 equivalent (1.0 eq) of 5-(3-fluorophenoxy)pyridin-2-amine (5-(3- f 1 uo r ophenoxy ) pyr idi n-2-am i ne ) was dissolved in 5 mL / g of tetrahydrofuran (THF). 1.2 equivalents (1.2 eq) of phenyl chloroformate and 1.5 equivalents (1.5 eq) of triethylamine (TEA) were added to the reaction mixture at 0°C. The mixture was stirred at room temperature for about 1 hour. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using ethyl acetate (EA) and brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate (MgS04) and then filtered. The filtrate was concentrated under reduced pressure and purified and separated by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound.

[0050] Synthesis of 3-(5-(3-f luorophenoxy)pyridin-2-yl)-1-(3-f luorophenyl)-1-methylurea (Example 2) 1.0 equivalent (1.0 eq) of phenyl (5-(3-f luor ophenoxy)pyridin-2-yl)carbamate was dissolved in 3 mL / g of 1,4-dioxane. As reactant Al, 1.5 equivalents (1.5 eq) of 3-fluoro-N-methylaniline and 2.0 equivalents (2.0 eq) of N,N-diisopropylethylamine (DIPEA) were added and stirred at 90°C for about 1 hour. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using ethyl acetate (EA) and brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate (MgS04) and then filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound, Example 2 Compound.

[0051] [Table 3]

[0052] [Example 3]

[0053] 3-(3-(5-(3-fluorophenoxy)pyridin-2-yl)-1-methylureido)-N,N-dimethylbenzenesulfone 0Synthesis of {White}ide (3— (3— (5— (3— f luor ophenoxy ) pyr idin— 2— y 1 ) — l—methylureido)—N,N— dimethyl benzenesulfonamide) (Example 3) The compound of Example 3 was prepared as the title compound in substantially the same manner as described in the method for preparing the compound of Example 2, except that 1.5 equivalents (1.5 eq) of reactant A2 in Table 4 was used instead of 1.5 equivalents (1.5 eq) of reactant A1 in scheme 3 of the method for preparing the compound of Example 2.

[0054] [Table 4]

[0055] [Example 4]

[0056] CS2CO3

[0057] Cni 130 C

[0058] Scheme 4 Synthesis of 6—(3—fluorophenoxy)pyridin—3—amine

[0059] 1.0 equivalent (1.0 eq) of 6-bromopyridin-3-amine was dissolved in 6 mL / g of dimethyl sulfoxide (DMSO). 1.5 equivalents (1.5 eq) of 3-fluorophenol, 3.0 equivalents (3.0 eq) of cesium carbonate (CS2CO3), and 0.1 equivalent (0.1 eq) of cuprous iodide (Cui) were added, and the mixture was stirred at 130°C for about 20 hours. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using ethyl acetate (EA) and washed thoroughly with brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate (MgS04) and then filtered. The filtrate was concentrated under reduced pressure and purified and separated by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound.

[0060] Scheme 5 Synthesis of phenyl (6—(3—fluorophenoxy)pyridin—3—yl)carbamate

[0061] 1.0 equivalent (1.0 eq) of 6-(3-fluorophenoxy)pyridin-3-amine (6-(3-f 1 uor ophenoxy)pyridin-3-amine) was dissolved in 5 mL / g of tetrahydrofuran (THF). 1.2 equivalents (1.2 eq) of phenyl chloroformate and 1.5 equivalents (1.5 eq) of triethylamine (TEA) were added to the reaction mixture at 0°C. The mixture was stirred at room temperature for about 1 hour. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using ethyl acetate (EA) and brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate (MgSO) and then filtered. The filtrate was concentrated under reduced pressure and purified and separated by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound.

[0062] Synthesis of 1-(3-chlorophenyl)-3-(6-(3-fluorophenoxy)pyridin-3-yl)-1-methylurea (Example 4) 1.0 equivalent (1.0 eq) of phenyl (6-(3-f luorophenoxy)pyridin-3-yl)carbamate was dissolved in 3 mL / g of 1,4-dioxane. 1.5 equivalents (1.5 eq) of 3-chloro-N-methylaniline and 2.0 equivalents (2.0 eq) of N,N-diisopropylethylamine (DIPEA) were added and stirred at 90°C for about 1 hour. After confirming the completion of the reaction, distilled water was added and the organic layer was extracted using ethyl acetate (EA) and brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate (MgS04) and then filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (hexane:ethyl acetate)

[0063] (EA) ) was purified and separated to obtain the title compound, Example 4 compound. [Table 5]

[0064] [Example 5] phenyl c Scheme 6

[0065] Synthesis of 5—(3—fluorophenoxy)pyrazine—2—amine

[0066] 1.3 equivalents (1.3 eq) of 5-bromopyrazin-2-amine and 1.0 equivalents (1.0 eq) of 3-f luorophenol were dissolved in 9 mL / g of 1,4-dioxane. 1.5 equivalents (1.5 eq) of cesium carbonate (CS2CO3), 0.2 equivalents (0.2 eq) of cuprous iodide (Cui), and 0.2 equivalents (0.2 eq) of N,N-dimethylglycine were stirred at 90°C for approximately 15 hours. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using ethyl acetate (EA) and brine. The remaining moisture in the organic layer was completely removed with magnesium sulfate (MgS04) and then filtered. The filtrate was concentrated under reduced pressure, and the crude product obtained was purified by column chromatography and concentrated in vacuo to obtain the title compound. Synthesis of Phenyl (5—(3—fluorophenoxy)pyrazine—2—yl)carbamate

[0067] 1 equivalent (1 eq) of 5-(3-fluorophenoxy)pyrazin-2-amine (5-(3-f 1 fluorophenoxy)pyrazin-2-amine) was dissolved in 5 mL / g of tetrahydrofuran (THF). 1.2 equivalents (1.2 eq) of phenyl chloroformate and 1.5 equivalents (1.5 eq) of triethylamine (TEA) were added to the reaction mixture at 0°C. The mixture was stirred at room temperature for about 1 hour. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using ethyl acetate (EA) and brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate (MgS04) and then filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified by column chromatography and concentrated in vacuo to obtain the title compound.

[0068] Synthesis of 3-(3-(5-(3-f luor ophenoxy)pyrazin-2-yl)-l-methylureido)-N,N-dimethylbenzenesulfonamide (Example 5) 1.0 equivalent (1.0 eq) of phenyl (5-(3-f 1 uor ophenoxy)pyrazin-2-yl)carbamate was dissolved in 3 mL / g of 1,4-dioxane. 1.5 equivalents (1.5 eq) of N,N-dimethyl-3-(methylamino)benzenesulfonamide and 2.0 equivalents (2.0 eq) of N,N-diisopropylethylamine (DIPEA) were added and stirred at 90°C for about 1 hour. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using ethyl acetate (EA) and brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate (MgS04) and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography and concentrated in vacuo to obtain the title compound, Example 5 compound. [Table 6]

[0069] [Example 6]

[0070] Scheme 7

[0071] Synthesis of 3—(3—fluorophenoxy)~5"nitropyridine (3~(3~f luorophenoxy)~5~ nitropyridine)

[0072] 1.0 eq of 3-bromo-5-nitropyridine was dissolved in 5 mL / g of dimethyl sulfoxide (DMSO). 1.5 eq of 3-fluorophenol, 3.0 eq of potassium carbonate (K2CO3), and 0.1 eq of cuprous iodide (Cui) were added, and the mixture was stirred at 130°C for about 12 hours. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using ethyl acetate (EA), and washed thoroughly with brine. The remaining moisture in the organic layer was completely removed with magnesium sulfate (MgSO) and then filtered. Column chromatography (hexane

[0073] (hexane): The title compound was obtained by purification and separation with ethyl acetate (EA).

[0074] Synthesis of 5-(3-fluorophenoxy)pyridin-3-amine

[0075] 3-(3-fluorophenoxy)-5-nitropyridine was dissolved in 4 mL / g of ethanol (EtOH). 10 wt% of palladium / carbon (Pd / C) was added and stirred for 2 hours under hydrogen. After confirming the completion of the reaction, the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound. Synthesis of phenyl (5—(3—fluorophenoxy)pyridin— 3—yl)carbamate

[0076] 1.0 equivalent (1.0 eq) of 5-(3-fluorophenoxy)pyridin-3-amine (5-(3-f 1 uor ophenoxy)pyridin-3-amine) was dissolved in 5 mL / g of tetrahydrofuran (THF). 1.2 equivalents (1.2 eq) of phenyl chloroformate and 1.5 equivalents (1.5 eq) of triethylamine (TEA) were added to the reaction mixture at 0°C. The mixture was stirred at room temperature for about 1 hour. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using ethyl acetate (EA) and brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate (MgSO) and then filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified and separated by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound.

[0077] Synthesis of 1-(3-chlorophenyl)-3-(5-(3-fluorophenoxy)pyridin-3-yl)-1-methylurea (Example 6) 1.0 equivalent (1.0 eq) of phenyl (5-(3-f luorophenoxy)pyridin-3-yl)carbamate was dissolved in 3 mL / g of 1,4-dioxane. 3-chloro-N-methylaniline (1.5 eq) and N,N-diisopropylethylamine (DIPEA) 2.0 eq were added and stirred at 90°C for about 1 hour. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using ethyl acetate (EA) and brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate (MgS04) and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (hexane: ethyl acetate (EA)) to obtain the title compound, Example 6.

[0078] [Table 7] [Example 7]

[0079] Scheme 8

[0080] Synthesis of 4—(3—fluorophenoxy)pyridin— 2—amine 1.0 equivalent (1.0 eq) of 4-bromopyridin- 2-amine was dissolved in 6 mL / g of pyr idine. 2.0 equivalents (2.0 eq) of 3-fluorophenol, 2.0 equivalents (2.0 eq) of potassium carbonate (K2CO3), and 0.2 equivalents (0.2 eq) of copper oxide (Ct^O) were added, and the mixture was stirred under reflux for about 18 hours. After confirming the completion of the reaction, the mixture was concentrated under reduced pressure to remove pyridine. After adding distilled water, the organic layer was extracted using ethyl acetate (EA). The remaining moisture in the organic layer was completely removed with magnesium sulfate (MgS04) and then filtered. The filtrate was concentrated under reduced pressure, and the crude product obtained was purified and separated by column chromatography (hexane: ethyl acetate (EA)) to obtain the title compound. Synthesis of phenyl (4—(3—fluorophenoxy)pyridin— 2—yl)carbamate

[0081] 1.0 equivalent (1.0 eq) of 4-(3-fluorophenoxy)pyridin-2-amine (4-(3-f 1 uor ophenoxy)pyridin-2-amine) was dissolved in 5 mL / g of tetrahydrofuran (THF). 1.2 equivalents (1.2 eq) of phenyl chloroformate and 1.5 equivalents (1.5 eq) of triethylamine (TEA) were added to the reaction mixture at 0°C. The mixture was stirred at room temperature for about 1 hour. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using ethyl acetate (EA) and brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate (MgS04) and then filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified and separated by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound.

[0082] Synthesis of 3-(3-(4-(3-fluorophenoxy)pyridin-2-yl)-1-methylureido)-N,N-dimethylbenzenesulfonamide (Example 7) 1.0 equivalent (1.0 eq) of phenyl (4-(3-fluorophenoxy)pyridin-2-yl)carbamate was dissolved in 3 mL / g of 1,4-dioxane. 1.5 equivalents (1.5 eq) of N,N-dimethyl-3-(methylamino)benzenesulfonamide and 2 equivalents (2.0 eq) of N,N-diisopropylethylamine (DIPEA) were added and stirred at 90°C for about 1 hour. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using ethyl acetate (EA) and brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate (MgS04) and then filtered. The filtrate was concentrated under reduced pressure, and the crude product obtained was purified by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound, Example 7.

[0083] [Table 8]

[0084] [Example 8]

[0085] Scheme 9

[0086] Synthesis of 4-(N,N-dimethylsulfamoyl)-N-(5-(3-fluorophenoxy)pyridin-2-yl)benzamide (Example 8)

[0087] 5-(3-Fluorophenoxy)pyridin-2-amine

[0088] 1.0 equivalent (1.0 eq) was dissolved in 5 mL / g of tetrahydrofuran (THF). 1.0 equivalent (1.0 eq) of 4-(N,N-dimethylsulfamoyl)benzoyl chloride and 1.0 equivalent (1.0 eq) of triethylamine (TEA) were added, and the mixture was stirred at room temperature for about 30 minutes. After confirming the completion of the reaction, distilled water was added, and then the organic layer was extracted using ethyl acetate (EA) and brine. The remaining water in the organic layer was completely removed with magnesium sulfate (MgSO4) and then filtered. The crude product obtained by concentrating the filtrate under reduced pressure was purified and separated by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound, Compound of Example 8.

[0089] [Table 9]

[0090] [Example 9]

[0091] CS2CO3 + [Cul,N,N-dimethylglycine N NH2 F 人 人 OH 1,4-Dioxane JL X Jl J

[0092] 90°C F O N

[0093] Scheme 10

[0094] Synthesis of 5—(3—fluorophenoxy)pyrazin—2—amine

[0095] 1.3 equivalents (1.3 eq) of 5-bromopyrazin-2-amine and 1.0 equivalents (1.0 eq) of 3-fluorophenol were dissolved in 3 mL / g of 1,4-dioxane. 1.5 equivalents (1.5 eq) of cesium carbonate (CS2CO3), 0.2 equivalents (0.2 eq) of cuprous iodide (Cui), and 0.2 equivalents (0.2 eq) of N,N-dimethylglycine were added and stirred at 90°C for about 15 hours. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using ethyl acetate (EA) and brine. The remaining moisture in the organic layer was completely removed with magnesium sulfate (MgS04) and then filtered. The filtrate was concentrated under reduced pressure and purified and separated by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound.

[0096] Scheme 11

[0097] Synthesis of N-(5-(3-fluorophenoxy)pyrazin-2-yl)-3-(methylsulfonamido)benzamide (N—(5—(3—f 1 uor ophenoxy)pyrazin—2—y 1 ) —3—( me t hy 1 su 1 f onam i do ) benz am i de ) (Example 9)

[0098] 1.0 equivalent (1.0 eq) of 5-(3-fluorophenoxy)pyrazin-2-amine (5-(3-f 1 uor ophenoxy)pyrazin-2-amine) was dissolved in 5 mL / g of tetrahydrofuran (THF). 1.0 equivalent (10 eq) of 3-(methylsulfonamido)benzoyl chloride and 1.0 equivalent (1.0 eq) of triethylamine (TEA) were added, and the mixture was stirred at room temperature for about 30 minutes. After confirming the completion of the reaction, distilled water was added, and the organic layer was extracted using ethyl acetate (EA) and brine. The moisture remaining in the organic layer was completely removed with magnesium sulfate (MgS04) and then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified and separated by column chromatography (hexane: ethyl acetate (EA)) to obtain the title compound, Example 9. [Table 1]

[0099] [Example 10]

[0100] Scheme 12

[0101] Synthesis of 5—(2,4—difluorophenoxy)—2—nitropyridine

[0102] 5-Fluoro-2-nitropyridine 1.0 equivalent (1.0 eq),

[0103] 1.12 eq of 2, 4-difluorophenol, cesium carbonate (CS2CO3)

[0104] 1.3 equivalents (1.3 eq) was added to 15 mL / g of acetonitrile (ACN), and the reaction mixture was stirred at room temperature for 16 hours. After confirming the completion of the reaction, the mixture was distilled under reduced pressure to remove the solvent. Methylene chloride (MC) and distilled water were added to the reaction mixture for washing three times, the organic layer was separated, dried over magnesium sulfate (MgSO₄), and then concentrated. The obtained concentrate was used in the next step without further purification.

[0105] 5-(2,4-Difluorophenoxy)pyridin-2-amine (5-(2,4-

[0106] Difluorophenoxy)pyridin-2-amine) synthesis

[0107] 1.0 equivalent (1.0 eq) of 5-(2,4-Difluorophenoxy)-2-nitropyridine, 10.0 equivalents (10.0 eq) of ammonium chloride (NH₄Cl), and 10.0 equivalents (10.0 eq) of zinc (Zn) were added to 1,4-dioxane / distilled water (7:1 v / v, total 4 mL / g), and the mixture was stirred at room temperature for 4 hours. After confirming the completion of the reaction, distilled water and ethyl acetate (EA) were added to the reaction mixture, and the mixture was filtered through a celite filter. The organic layer of the filtrate was extracted, the remaining moisture in the organic layer was dried over magnesium sulfate (MgSO₄), and then concentrated. The concentrate was purified and separated by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound as the target compound.

[0108] Scheme 13 ~(5~(2,4~Difluorophenoxy)pyridin-2-yl)~4-(methylsulfonyl 0}mido)benz 0Synthesis of {N - (5 - (2,4 - difluorophenoxy)pyridin - 2 - yl) - 4 - (methylsulfonamido)benzamide} (Example 10) As reactant B1, 1.0 equivalent (1.0 eq) of 4 - (methylsulfonamido)benzoic acid was dissolved in 9 mL / g of methylene chloride (MC), then 2.0 equivalents (2.0 eq) of N,N - diisopropylethylamine (DIPEA) and 1.5 equivalents (1.5 eq) of hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU) were added, and the mixture was stirred for 10 minutes. 1.2 equivalents (1.2 eq) of 5 - (2,4 - difluorophenoxy)pyridin - 2 - amine was slowly added, and then the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted with methylene chloride (MC) and water (H2O), the organic layer was dried over magnesium sulfate (MgSO4), and then concentrated under reduced pressure. The title compound, the compound of Example 10, was obtained by purification and separation by column chromatography (hexane:ethyl acetate (EA)).

[0109] [Table  11]

[0110] [Examples 11 to 14] The compounds of Examples 11 to 14 below in Table 12 were prepared in substantially the same manner as described in the preparation method of the compound of Example 10, except that 1.0 equivalent (1.0 eq) of reactant B2 in Table 12 was used instead of 1.0 equivalent (1.0 eq) of reactant B1 in Scheme 13 of the preparation method of the compound of Example 10.

[0111] [Table 12]

[0112] [Example 15]

[0113] Scheme 14

[0114] 2-Fluoro-5-(methylsulfonamido)benzoic acid (2-f luoro-5-

[0115] Synthesis of (methylsulfonamido)benzoic acid

[0116] 5-Amino-2-f luorobenzoic acid (5-Amino-2-f luorobenzoic acid) was added to 1.0 equivalent (1.0 eq) of methylene chloride (MC) and cooled to 0°C, then 2.5 equivalents (2.5 eq) of pyridine were added. After stirring for 10 minutes, 1.2 equivalents (1.2 eq) of methanesulfonyl chloride was slowly added, and the mixture was stirred at room temperature for 12 hours. After concentration under reduced pressure, the title compound was obtained by purification and separation by column chromatography (methylene chloride (MC) : methanol (MeOH)).

[0117] N~(5~(2,4-difluorophenoxy)pyridin-2-yl)-2-fluoro-5-(methylsulfonamido)benz O}P}ide ( N— ( 5— ( 2,4— dif 1 uor ophenoxy ) pyr idin— 2— y 1 ) — 2— f 1 uor o— 5 —

[0118] Synthesis of (methylsulfonamido)benzamide (Example 15)

[0119] 2-Fluoro-5-(methylsulfonamido)benzoic acid (2-f luoro-5-

[0120] 1.0 equivalent (1.0 eq) of (methylsulfonamido)benzoic acid was dissolved in 10 mL / g of methylene chloride (MC), and then 2.0 equivalents (2.0 eq) of N,N-diisopropylethylamine (DIPEA) and 1.5 equivalents (1.5 eq) of hexafluorophosphate azabenzotriazole tetramethyluronium (HATU) were added and stirred for 10 minutes. 5-(2,4-difluorophenoxy)pyridin-2-amine (5-(2,4-

[0121] 1.2 equivalents (1.2 eq) of Difluorophenoxy)pyridin-2-amine were slowly added and stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted with methylene chloride (MC) and water (C0), and the organic layer was extracted, the remaining moisture was dried over magnesium sulfate (MgS04), and concentrated under reduced pressure. The title compound, Example 15, was obtained through purification and separation by column chromatography (hexane:ethyl acetate (EA)).

[0122] [Table 13]

[0123] [Example 16]

[0124] Scheme 15 Synthesis of tert-butyl (3-((5-(2,4-difluorophenoxy)pyridin-2-yl)carbamoyl)phenyl)carbamate

[0125] 1.0 equivalent (1.0 eq) of 3-((tert-butoxycarbonyl)amino)benzoic acid in methylene chloride (MC)

[0126] After dissolving in 10 mL / g, 2.0 equivalents (2.0 eq) of N,N-diisopropylethylamine (DIPEA) and 1.5 equivalents (1.5 eq) of azabenzotriazole tetramethyluronium hexafluorophosphate (HATU) were added and stirred for 10 minutes. 1.2 equivalents (1.2 eq) of 5-(2,4-difluorophenoxy)pyridin-2-amine was slowly added and stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted with methylene chloride (MC) and water (C0), and the remaining moisture was dried over magnesium sulfate (MgS04) and concentrated under reduced pressure. The title compound was obtained by purification and separation using column chromatography (hexane:ethyl acetate (EA)).

[0127] Synthesis of 3-amino- N- (5- (2, 4-difluorophenoxy)pyridin-2-yl)benzamide (3-am i no- N- ( 5- ( 2, 4-difluorophenoxy )pyr i din-2-yl )benz am i de ) tert-butyl (3- ((5- (2, 4-difluorophenoxy )pyridin-2-yl )carbamoyl )phenyl )carbamate) 1.0 eq. of methylene chloride (MC) was added and the temperature was lowered to 0°C. After adding 10.0 equivalents (10.0 eq) of trifluoroacetic acid (TFA), the mixture was slowly raised to room temperature and stirred for 5 hours. After confirming the completion of the reaction, the reaction mixture was distilled under reduced pressure to remove the solvent, obtaining the title compound. Synthesis of (N— (5— (2,4— dif luoroDhenoxy)pyridin— 2— yl )— 3— (ethylsulfonamido)benzamide) (Example 16)

[0128] 1.0 equivalent (1.0 eq) of 3-amino-N-(5-(2,4-difluorophenoxy)pyridin-2-yl)benzamide and 10 mL / g of methylene chloride (MC) were added, and the temperature was lowered to 0°C. 5.0 equivalents (5.0 eq) of triethylamine (TEA) and 1.2 equivalents (1.2 eq) of ethanesulfonyl chloride as the reactant C1 were added, and the temperature was slowly raised to room temperature and stirred for 12 hours. After completion of the reaction, the mixture was extracted with methylene chloride (MC) and water (H2O), and the organic layer was dried over magnesium sulfate (MgS04) and concentrated under reduced pressure. The title compound, Example 16, was obtained by purification and separation using column chromatography (hexane:ethyl acetate (EA)).

[0129] [Table 14]

[0130] [Examples 17 to 20] Compounds of Examples 17 to 20 in Table 15 were prepared in substantially the same manner as described in the method for preparing the compound of Example 16, except that 1.0 equivalent (1.0 eq) of reactant C2 in Table 15 was used instead of 1.0 equivalent (1.0 eq) of reactant C1 in Scheme 16 in the method for preparing the compound of Example 16.

[0131] [Table 15]

[0132] [Example 21]

[0133] Scheme 17 5~(2,4-difluorophenoxy)pyrazine-2-amine (5~(2,4~

[0134] D if 1 uor ophenoxy ) pyr az in— 2— am i ne ) synthesis

[0135] 1.0 eq of 2-amino-5-bromopyrazine, 1.2 eq of 2,4-difluorophenol, 1.5 eq of cesium carbonate (CS2CO3), 0.2 eq of cuprous iodide (Cui), and 0.2 eq of N,N-dimethylglycine were added to 20 mL / g of 1,4-dioxane. The mixture was stirred under reflux for 2 hours. After confirming the completion of the reaction, the reaction mixture was distilled under reduced pressure to remove the solvent. The concentrate was washed with ethyl acetate (EA), saturated sodium carbonate (Na2C03) solution, and brine, and the organic layer was separated. The organic layer was dried over magnesium sulfate (MgS04), concentrated under reduced pressure, and acetonitrile (ACN) and water (ObO) were added to the concentrate. The mixture was stirred at room temperature for 1 hour, and the precipitated insoluble solid was removed by filtration. The organic layer was extracted using ethyl acetate (EA) and brine, and the remaining moisture was dried over magnesium sulfate (MgS04) and concentrated. The obtained crude product was purified and separated by column chromatography (hexane: ethyl acetate (EA)) to obtain the title compound as the target compound.

[0136] Synthesis of N-(5-(2,4-difluorophenoxy)pyrazin-2-yl)-3-(methylsulfonamido)benzamide (N—(5—(2,4— dif 1 fluorophenoxy)pyr az i n-2-y 1 )-3-( me t hy 1 su 1 f onam i do ) benz am i de ) (Example 21)

[0137] 1.0 equivalent (1.0 eq) of 3-(methylsulfonamido)benzoic acid was dissolved in 5 mL / g of methylene chloride (MC), 2.0 equivalents (2.0 eq) of N,N-diisopropylethylamine (DIPEA) and 1.5 equivalents (1.5 eq) of azabenzotriazole tetramethyluronium hexafluorophosphate (HATU) were added, and the mixture was stirred for 10 minutes. 1.2 equivalents (1.2 eq) of 5-(2,4-Di f luorophenoxy)pyrazin-2-amine was slowly added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the organic layer was extracted using methylene chloride (MC) and water (ObO), the remaining moisture was dried with magnesium sulfate (MgS04), and then concentrated under reduced pressure. The residue was purified and separated by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound, Example 21.

[0138] [Table 16]

[0139] [Example 22]

[0140] Scheme 18 N-(5-(3-fluorobenzyl)thiazol-2-yl)-4-(trifluoromethyl)benzamide

[0141] (N— (5— (3— f luorobenzyl )thiazol— 2— yl )— 4— (tri f luoromethyl )benzamide) (Example

[0142] 22) Synthetic reactant 1.0 equivalent (1.0 eq) of 4-(trifluoromethyl)benzoic acid was dissolved in 10 mL / g of methylene chloride (MC), then 2.0 equivalents (2.0 eq) of N,N-diisopropylethylamine (DIPEA) and 1.5 equivalents (1.5 eq) of azabenzotriazole tetramethyluronium hexafluorophosphate (HATU) were added and stirred for 10 minutes. 1.2 equivalents (1.2 eq) of 5-(3-fluorobenzyl)thiazol-2-amine was slowly added and stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted with methylene chloride (MC) and water (C0), and the methylene chloride (MC) layer was dried with magnesium sulfate (MgS04) and concentrated under reduced pressure. The residue was purified and separated by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound, Example 22.

[0143] [Table 17]

[0144] [Examples 23 to 33] Compounds of Examples 23 to 33 in Table 18 were prepared in substantially the same manner as described in the method for preparing the compound of Example 22, except that 1.0 equivalent (1.0 eq) of reactant D2 in Table 18 was used instead of 1.0 equivalent (1.0 eq) of reactant D1 in Scheme 18 of the method for preparing the compound of Example 22.

[0145] [Table 18]

[0146] [Example 34]

[0147] Synthesis of Scheme 19 5—(3—fluorophenoxy)thiazol—2—amine (5—(3—fluorophenoxy)thiazol—2—amine)

[0148] 1.3 equivalents (1.3 eq) of 3-fluorophenol was dissolved in 30 mL / g of acetone, and then 2.0 equivalents (2.0 eq) of cesium carbonate (Cs2CO3) was added. After stirring for 10 minutes, 1.0 equivalent (1.0 eq) of 5-bromothiazol-2-amine was added, and the mixture was refluxed and stirred for about 12 hours. After completion of the reaction, the mixture was filtered through a celite filter with acetone and then concentrated, and extracted with ethyl acetate (EA) and water. The organic layer was dried with magnesium sulfate (MgSO4) and then concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound.

[0149] Scheme 二十

[0150] Synthesis of N-(5-(3-fluorophenoxy)thiazol-2-yl)-3-(methylsulfonamido)benzamide (Example 34)

[0151] It should be noted that there is an error in the Chinese text you provided. "成0" should be "水", and the corrected translation of "二十" should be "20". The corrected translation is as follows: Synthesis of Scheme 19 5—(3—fluorophenoxy)thiazol—2—amine (5—(3—fluorophenoxy)thiazol—2—amine)

[0148] 1.3 equivalents (1.3 eq) of 3-fluorophenol was dissolved in 30 mL / g of acetone, and then 2.0 equivalents (2.0 eq) of cesium carbonate (Cs2CO3) was added. After stirring for 10 minutes, 1.0 equivalent (1.0 eq) of 5-bromothiazol-2-amine was added, and the mixture was refluxed and stirred for about 12 hours. After completion of the reaction, the mixture was filtered through a celite filter with acetone and then concentrated, and extracted with ethyl acetate (EA) and water. The organic layer was dried with magnesium sulfate (MgSO4) and then concentrated under reduced pressure, and purified and separated by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound.

[0149] Scheme 20

[0150] Synthesis of N-(5-(3-fluorophenoxy)thiazol-2-yl)-3-(methylsulfonamido)benzamide (Example 34)

[0151] 1.0 equivalent (1.0 eq) of 3-(methylsulfonamido)benzoic acid was dissolved in 10 mL / g of methylene chloride (MC), 2.0 equivalents (2.0 eq) of N,N-diisopropylethylamine (DIPEA) and 1.5 equivalents (1.5 eq) of azabenzotriazole tetramethyluronium hexafluorophosphate (HATU) were added, and the mixture was stirred for 10 minutes. 1.2 equivalents (1.2 eq) of 5-(3-fluorophenoxy)thiazol-2-amine was slowly added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted with methylene chloride (MC) and water (C0), and the methylene chloride (MC) layer was dried over magnesium sulfate (MgS04) and concentrated under reduced pressure. The residue was purified and separated by column chromatography (hexane:ethyl acetate (EA)) to obtain the title compound, Example 34. [Table 19]

[0152] <Experimental Example> Experimental Example 1. IP-one assay for confirming MrgprX2 activity The efficacy of the present compound was evaluated using a HEK293 stable cell line (hereinafter referred to as MrgprX2-HEK293) expressing human MrgprX2. The cells were cultured in a culture medium containing 10% FBS (Corning; 35-015-CV) and 1 ug / mL puromycin (Gibco; A1113802) in high glucose DMEM containing GlutaMAX (high glucose DMEM (Gibco; 10564029)) in a cell incubator at 37 °C and 5% CO2. The day before the experiment, MrgprX2-HEK293 cells were seeded at 10,000 cells per well in 100 μL of cell culture medium in a 96-well assay plate and cultured in a cell incubator (n=3). On the day of the experiment, the cell culture medium was carefully removed, and 100 μL of DPBS (Gibco; 14190-144) was dispensed into each well and then removed for washing. After that, the 10 mM compound dissolved in dimethyl sulfoxide (DMS0) was serially diluted in a 1:3 ratio and diluted in the assay buffer included in the IP-one Gq kit (Cisbio; 62IPAPEB) to prepare a total of 10 dilutions (from 1 nM to 30 μM). The final DMS0 concentration of each dilution was 0.3%, and an equal amount of DMS0 was added to the control group. 100 μL of the prepared compound dilutions were dispensed into washed MrgprX2-HEK293 cells and treated for 1 hour in a 5% CO2 cell culture incubator at 37 °C.Afterwards, to stimulate MrgprX2, 200 nM cortistatin-14 (Cort istat in-14 (hereinafter, Cortl4) (MedchemExpress: HY-P1932A)) was prepared in assay buffer and 100 uL was dispensed into each well. The final concentration of Cortl4 was 100 nM. For the action of Cortl4, MrgprX2-HEK293 cells were treated in a 5% CO2 cell incubator at 37 °C for 1 hour. Afterwards, all assay buffers in each well were removed, and 30 uL of lysis buffer included in the IP-One Gq kit was dispensed to lyse the cell membrane. After removing 15 uL of lysate, 6 uL of detection buffer included in the IP-ONE Gq kit was dispensed into the remaining half of the lysate and reacted at room temperature for 1 hour, protected from light. The plate was subjected to HTRF measurement using a Tecan Spark 10m instrument. The measured HTRF ratio was plotted and the IC50 value was calculated using GraphPad Prism 10. The results of Experimental Example 1 are shown in Table 20 below, and in Table 20, A, B, and C each represent the following.

[0153] A: IC5o < 500 nM, B: 500 nM < IC5o < 1 uM, C: 1 uM < IC5o < 3 uM, [Table 2] Experimental Example 2. Calcium mobilization assay Human MRGPRX2 stable cells (Creative-biogene) were cultured in DMEM (Gibco; 10564029) containing 1 ug / mL puromycin (Gibco) and 10% FBS (Corning) at 37 °C in a 5% CO2 incubator. The day before the experiment, 10,000 cells / well were transferred to a 96-well black plate with 100 μL cell culture medium and cultured in a cell incubator. On the day of the experiment, using the loading buffer of the Fura-2 QBT calcium kit (Molecular devices; R8197), the compound dissolved in DMS0 at a concentration of 10 was serially diluted 1:3 as an antagonist to prepare a 2x loading buffer that can treat from a final concentration of 1 nM to 30 iiM. 100 iiL of the 2x loading buffer was treated to each well, and the antagonist was reacted for 1 hour at 37°C. After that, the agonist of the compound, cortistatin-14 (MedchemExpress), was prepared as a 5x solution using HBSS buffer and dispensed into a 96-well v-bottom plate in the required amount. The cell plate prepared for calcium mobilization (Calcium mobi 1 izat ion) was placed in the Flexstation 3 (Molecular devices) together with the plate prepared with the agent, and 50 u L of the agent was administered to the cells using the auto injector included in the device.Flex mode was set to measure the fluorescence at wavelengths of Em 340, 380 nm, and EX 510 nM at 4-second intervals for a total of 90 seconds, starting 15 seconds before the administration of the agonist. Calcium mobilization was measured by calculating the measured values ​​as (Em 510 nm from Ex 340 nm) / (Em 510 nm from Ex 380 nm), and then the calcium mobilization according to the antagonist concentration was calculated using GraphPad Prism to display the IC50. The results of Experimental Example 2 are shown in Table 21 below, and in Table 21, A, B, and C each represent the following.

[0154] A: IC5o < 500 nM, B: 500 nM < IC5o < 1 uM, C: 1 uM < IC5o < 3 uM

[0155] [Table 21] Through the results of Experimental Examples 1 and 2 above, it was confirmed that the compound of the present invention has excellent efficacy as a MRGPRX2 antagonist.

Claims

【Scope of Claims】 【 Claim 11 A compound represented by the following chemical formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; <Chemical Formula 1> In chemical formula I, Yi and Y2 are each independently N or Y, Y3 is N, CH or E, a is 0 or 1, == indicates a single bond or double bond; Li is -0- or C1-C6 alkylene; Ri and R2 are each independently H or halogen; L2 is a single bond, -CH(Ra)- (wherein, Ra is H or C1-C6 alkyl), C3-C6 cycloalkylene, or - N(Rb)- (wherein, Rb is H or C1-C6 alkyl); One or more of H can be independently substituted with a halogen, and is 0 or 1, R3 is C1-C6 alkyl, C1-C6 haloalkyl, - CH2- CF3, or - NRcRd, and Rc and Rd are each independently H or C1-C6 alkyl, R4 is H or halogen, R5 is halogen, C1-C6 haloalkyl, -CF3, -0-CC1-C6 haloalkyl), -0-CH2-CF3, or am. 【A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising a compound represented by the following chemical formula la or chemical formula lb in claim 1; <화학식 Ia> <화학식 Ib> In the chemical formula la, Ri, R2, LI, Yi to Y4, a, L2, RS, b and R' are each a chemical formula Same as defined in I, and in chemical formula lb, Ri, R2, LI, Yi to Y4, a, L2 and R5 are each the same as defined in chemical formula I. 【

3. In claim 1, Li is -0- or C1-C6 alkylene; R1 and R2 are each independently H or halogen, provided that at least one of R1 and R2 is halogen; L2 is a single bond, - CH(Ra)- (where, Ra is H or C1-C6 alkyl), (wherein, an integer from 0 to 3), or - N (Rb) - (wherein, Rb is C1-C6 alkyl); 56 can be 0 or 1, R3 is C1-C6 alkyl, C1-C6 haloalkyl, - CH2- CF3, or - NRcRd, and Rc and Rd are independently H or C1-C6 alkyl, R4 is H or halogen, R5 is halogen, C1-C6 haloalkyl, -0-(Cl- C6 haloalkyl), -CFs, -O-CH2-CF3 or A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

4. A compound shown in the table below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 【

5. A pharmaceutical composition for the prevention or treatment of a disease including at least one selected from among chronic urticaria, anaphylaxis, non-histaminergic pruritus, psoriasis, asthma, atopic dermatitis, or rosacea; inflammatory bowel disease; arthritis; and migraine, comprising a compound according to any one of claims 1 to 4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. 61

6. A method for preventing or treating a disease including at least one selected from allergic diseases, inflammatory bowel diseases, arthritis, and migraines, comprising administering a compound according to any one of claims 1 to 4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

7. Use of a compound according to any one of claims 1 to 4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the prevention or treatment of a disease including at least one selected from allergic diseases, inflammatory bowel diseases, arthritis, and migraines.

8. Use of a compound according to any one of claims 1 to 4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a disease including at least one selected from allergic diseases, inflammatory bowel diseases, arthritis, and migraines. 62

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